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i Ph.D. Doctoral Dissertation Peter Kyriakoulis School of Psychology, Faculty of Arts, Health and Design, Swinburne University of Technology March 2019 The efficacy of cold facial immersion and the diving response in treating panic disorder Supervisors: Prof. David Liley, Dr. Mark Schier, Prof. Michael Kyrios & Prof. Greg Murray

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Page 1: R FROG IDFLD LPPHUVLR D WKH GLYLQJ UHVSRQVH LQ …€¦ · The diving response (DR) is an oxygen conserving adaptation that is activated by apnea (breath-holding) and cold facial

i

Ph.D. Doctoral Dissertation

Peter Kyriakoulis

School of Psychology, Faculty of Arts, Health and Design, Swinburne University of

Technology

March 2019

The efficacy of cold facial immersion and the diving response in treating panic

disorder

Supervisors: Prof. David Liley, Dr. Mark Schier, Prof. Michael Kyrios & Prof. Greg

Murray

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Table of Contents

ii

Table of Contents

Table of Contents ................................................................................................ ii

Abstract ....................................................................................................... xii

DECLARATION.............................................................................................. xiv

ACKNOWLEDGEMENTS .............................................................................. xv

List of Tables .........................................................................................................

...................................................................................................... xvi

List of Abbreviations........................................................................................ xxi

Overview of Thesis ......................................................................................... xxiii

Chapter 1 PANIC DISORDER ....................................................................... 1

Panic Disorder and Panic Attacks .................................................. 2

The Aetiology of Panic Disorder ..................................................... 5

Psychological Theories of PD Aetiology .................................................. 5

Conditioning Theories .......................................................... 5

Modern Learning Theory ..................................................... 7

Cognitive Theories ............................................................... 9

Anxiety Sensitivity Theory ................................................. 11

Biological Theories of PD Aetiology ..................................................... 13

Genetic Theories ................................................................ 13

Hormone Theory ................................................................ 14

Metabolic Theories............................................................. 15

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Neurochemical Theory ....................................................... 19

Respiratory and Hyperventilation Theories ......................... 21

Neuroanatomical Theories .................................................. 27

Summary ................................................................................................ 31

Physiology of Panic ........................................................................ 34

Treatments of Panic Disorder ....................................................... 36

Cognitive Behavioural Therapy (CBT)................................................... 40

Acceptance and Commitment Therapy (ACT) ..................... 43

In Vivo Exposure and Virtual Reality Exposure ................... 47

Psychodynamic Therapy ........................................................................ 50

Breathing Training ................................................................................. 50

Breathing Training Treatments ............................................ 52

Pharmacological Treatments ................................................................. 56

Summary of Chapter ..................................................................... 58

Chapter 2 The Diving Response and its Applications ................................... 60

Breath-holding (Apnea)................................................................. 60

The Diving Response (DR) ............................................................ 60

Breath-holding and Cold Facial Immersion ................................. 64

Free diving and Breath-Holding ................................................... 71

Individual Determinants in Breath-Hold Diving ..................................... 73

Adaptive Changes during Breath-hold and Apnea training ........ 77

Clinical Implications of the Diving Response ......................................... 89

Summary ............................................................................................... 91

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Chapter 3 Respiration and Panic Disorder ................................................... 92

Respiration..................................................................................... 92

Breathing and Chemosensitivity ............................................................. 95

Physiological Abnormalities and Disturbances in Panic Disorder

.................................................................................................................. 98

Panic Disorder and hypersensitivity to Carbon Dioxide ........................ 101

Carbon Dioxide and it role in Chemosensation ..................................... 105

Respiratory Provocation Tests .................................................... 110

Carbon Dioxide (CO2) ......................................................................... 110

Hyperventilation .................................................................................. 112

Breath-holding ..................................................................................... 112

Implications of the Diving Response in Treating Panic Disorder

................................................................................................................ 114

Research aims .............................................................................. 121

Chapter 4 OVERALL METHODOLOGY ................................................. 123

Overview of methodology ............................................................ 123

Ethics Approval ........................................................................... 123

Informed Consent ........................................................................ 124

Clinical Participants .................................................................... 125

Inclusion and Exclusion Criteria for participants with panic

disorder. ............................................................................................... 125

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Recruitment of Clinical Participants ..................................................... 126

Control Participants .................................................................... 127

Inclusion and Exclusion Criteria for participants with panic

disorder. ............................................................................................... 127

Recruitment of Control Participants ..................................................... 128

Overall Procedure ....................................................................... 130

Psychological Measures ....................................................................... 131

The Anxiety Sensitivity Index .......................................... 131

The Beck Anxiety Inventory ............................................ 131

The Discomfort Intolerance Scale ..................................... 132

The State-Trait Anxiety Inventory .................................... 132

The Panic Attack Cognitions Questionnaire...................... 133

The Acute Panic Inventory ............................................... 133

The Visual Analog Scale .................................................. 134

The Center for Epidemiological Studies Depression Scale 134

Physiological Measures ........................................................................ 135

Respiratory Challenges and Cold Facial Immersion Task ..................... 135

Breath-hold challenge....................................................... 135

Cold Facial Immersion Task ............................................. 136

CO2 Challenge .................................................................. 136

Physiological Materials ........................................................................ 137

Electrocardiogram (ECG) ................................................. 137

Pulse Oximeter ................................................................. 137

CO2 Inhalation Materials .................................................. 138

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Chapter 5 PRELIMINARY INVESTIGATION: RESPIRATORY

CHALLENGES AND COLD FACIAL IMMERSION ............. 139

Aim ............................................................................................... 139

Hypotheses ................................................................................... 140

Hypothesis 1 ........................................................................................ 140

Hypothesis 2 ........................................................................................ 140

Hypothesis 3 ........................................................................................ 140

Hypothesis 4 ........................................................................................ 140

Hypothesis 5 ........................................................................................ 140

Method ......................................................................................... 141

Participants .......................................................................................... 141

Health Screening .................................................................................. 142

Research Design .................................................................................. 142

Measures.............................................................................................. 142

Procedure ............................................................................................. 145

Data Cleaning ...................................................................................... 145

Statistical Analyses .............................................................................. 146

Results .......................................................................................... 147

Overview of Analysis........................................................................... 147

Participant demographics and correlations between pre-measures ........ 147

Data Analyses ...................................................................................... 151

Differences between groups in Breath-hold durations

(Condition A) ........................................................................ 151

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Physiological Differences in response to Cold Facial Immersion

Task (Condition B) ........................................................................... 152

Physiological Differences in response to the CO2 Challenge

(Condition C) ....................................................................................... 153

Physiological response pre and post CO2 administered prior to CFI

(Condition D) ....................................................................................... 154

Physiological response pre and post the CO2 + CFI task

(Condition D) ....................................................................................... 155

Psychological Measures and the effects of CO2 and CFI ...................... 156

Discussion .................................................................................... 165

Study Limitations ................................................................................. 174

Future Research .......................................................................... 177

Rationale for Study 2 ........................................................................... 177

Improvements of research protocol ............................................ 179

Chapter 6 STUDY 2. THE EFFECTS OF COLD FACIAL IMMERSION

ON CO2 SENSITIVITY ............................................................. 183

Aim ............................................................................................... 183

Hypotheses ................................................................................... 183

Hypothesis 1 ........................................................................................ 183

Hypothesis 2 ........................................................................................ 184

Method ....................................................................................... 184

Participants ........................................................................................ 184

Participant Sampling and Screening ................................................... 185

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Recruitment ....................................................................................... 186

Measures ............................................................................................ 186

Research Design ............................................................. 187

Procedure ........................................................................................... 189

Data Cleaning .................................................................................... 189

Statistical Analyses ............................................................................ 190

Results ........................................................................................ 191

Overview of Analysis ......................................................................... 191

Correlations between Pre-measures .................................................... 191

Physiological Differences at Time 2 (CO2 Challenge) and Time 3

(Cold Facial Immersion + CO2 Challenge) ........................................... 194

Psychological Measures and Effect of CFI on CO2 sensitivity ............ 197

Discussion .................................................................................. 206

Study Limitations ............................................................................... 208

Methodological Considerations for Future Research .......................... 209

Future Directions ............................................................................... 212

Chapter 7 QUALITATIVE EXPLORATION OF PANIC AND COLD

FACIAL IMMERSION .............................................................. 216

Rationale for Study 2: Qualitative Investigation ........................ 216

Aim ............................................................................................... 218

Method ......................................................................................... 218

Participants .......................................................................................... 218

Materials .............................................................................................. 219

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Procedure ............................................................................................. 219

Data Analysis ....................................................................................... 220

Results .......................................................................................... 222

Section 1. Challenges experienced in managing anxiety and panic

thoughts and symptoms ........................................................................ 223

Cognitive Disruption experienced during anxiety and panic

.............................................................................................. 225

Disability Burden of panic and anxiety ............................. 225

Anxiety and panic related fear .......................................... 226

Anxiety and panic cognitions ........................................... 228

Physiological Symptoms .................................................. 229

Section 2. Strategies used to manage anxiety and panic thoughts

and symptoms ...................................................................................... 230

Cognitive Strategies used to manage anxiety and panic .... 232

Physical Strategies ........................................................... 233

Mindfulness Strategies ..................................................... 234

Section 3. Experience with cold facial immersion task for clinical

participants .......................................................................................... 235

Initial experience with the cold facial immersion (CFI) task

.............................................................................................. 237

Experience after completing with the cold facial immersion

(CFI) task .............................................................................. 239

Practicing CFI .................................................................. 242

Perceived challenges with practicing CFI ......................... 242

Predicted regularity of practice ......................................... 244

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Utility of CFI in assisting panic/anxiety ............................ 245

Section 4. Experience with cold facial immersion task for control

participants .......................................................................................... 247

Initial experience of CFI ................................................... 249

Positive experience after practicing CFI ........................... 250

Perceived challenges with practicing CFI ......................... 252

Utility of CFI in assisting panic/anxiety ............................ 253

Discussion .................................................................................... 256

Challenges with management of anxiety and panic thoughts and

symptoms............................................................................................. 256

Strategies used to manage anxiety and panic thoughts and

symptoms............................................................................................. 262

Physical Strategies ............................................................................... 264

Mindfulness Strategies ......................................................................... 267

Experience of the Cold facial Immersion .............................................. 269

Study Limitations ................................................................................. 271

Implications and Conclusions............................................................... 273

Chapter 8 OVERALL CONCLUSIONS ....................................................... 274

References ..................................................................................................... 282

Appendix A: Ethics Approval ...................................................................... 362

Appendix B: Plain Language Statement and Consent Forms Group 1

(Clinical) and Group 2 (Control) for the Preliminary Study .... 369

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Appendix C: Plain Language Statement and Consent Forms Group 1

(Clinical) and Group 2 (Control) for Study 2 ............................ 378

Appendix D: Participant Information form and Health Screening ........... 387

Appendix E: Qualitative Questions ............................................................ 391

PUBLICATIONS AND AWARDS ARISING FROM THIS WORK ........... 394

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Abstract

The presence of respiratory abnormalities is quite common in panic disorder (PD)

patients. A common respiratory abnormality that has been detected amongst PD

patients is increased CO2 sensitivity. Klein (1993) postulated the existence of a false

suffocation alarm monitor, which is sensitive to detecting CO2 changes, such as those

that occur with panic attacks. Klein speculated that PD patients have enhanced CO2

sensitivity of their chemical chemoreceptors, which prompts the brain’s suffocation

monitor to erroneously signal a lack of oxygen and trigger a false suffocation alarm.

The diving response (DR) is an oxygen conserving adaptation that is activated by

apnea (breath-holding) and cold facial immersion (CFI). During the DR, individuals

experience a number of physiological changes including a significant decrease in

heart rate and redistribution of blood to vital organs. In many ways, the physiological

changes that are experienced during the DR, a feeling of calmness and relaxation are

the opposite of those experienced during a panic attack. Breath-hold divers have

notably lowered CO2 sensitivity and a more pronounced DR as a result of trained

effects. Three studies were conducted examining the application of CFI and the DR in

the treatment of panic disorder, and a common respiratory test used to study panic and

CO2 sensitivity, the 35% CO2 challenge, was employed. The investigation focused on

the immediate effects of breath-holding and cold facial immersion on panic symptoms

and its implications in changing CO2 sensitivity, in response to the CO2 challenge.

Significant reductions in both physiological and cognitive symptoms of panic were

noted in the clinical group following the CFI task, which demonstrates promise in the

utility of the CFI task. Qualitative research undertaken on the activation of the DR

yielded promising results in reducing panic symptoms and eliciting calming and

relaxing effects in participants. Hence, further investigation to determine the

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implications of the DR in treating PD is warranted, and more specifically how CFI

and alternative forms of activating the DR can be used as a potential intervention.

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DECLARATION

In accordance with Swinburne University’s Higher Degree Research Training

Statement of Practice (version 5.0), I hereby declare that this thesis:

• contains no material which has been accepted for the award of any other

degree or diploma, except where due reference is made in the text of the

examinable outcome;

• to the best of my knowledge, contains no material previously published or

written by another person except where due reference has been made in the

text of the examinable outcome, and

• where the work is based on joint research or publications, full disclosure of the

relative contributions of the respective workers or authors has been made.

I warrant that I have obtained, where necessary, permission from the copyright

owners to use any third-party copyright material reproduced in the thesis (such as

artwork, images, unpublished documents), or to use any of my own published work

(such as journal articles) in which the copyright is held by another party (such as

publisher, co-author).

__________________________ Peter Kyriakoulis

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ACKNOWLEDGEMENTS

I would like to extend a big thank you to everybody that participated in this research.

To the clinical participants with panic disorder and the control participants who

volunteered their time to try something novel. This research would not have been

possible and their contributions are appreciated and respected.

I also wish to thank my supervisors, Professor David Liley, Professor Michael Kyrios,

Dr. Mark Schier, and Professor Greg Murray for their guidance and support

throughout my candidature as a Ph.D. student.

My thanks and appreciation extends to all those who guided and mentored me along

the way including Professor Rafael Freire, Professor Denny Meyer and Associate

Professor Peter Malliaras for their amazing support.

I would especially like to thank my beautiful family, my wife and three boys, for their

patience, support and encouragement throughout the years.

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List of Tables

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List of Tables

Table 1. Experimental Conditions ................................................................. 142

Table 2. Battery of Psychological Assessments Administered Before,

During and After the Experimental Study .......................................... 143

Table 3. Demographic Information Categorical Data ..................................... 148

Table 4. Demographic Information Continuous Data ..................................... 149

Table 5. Correlations between Pre-measure Assessments .............................. 150

Table 6. Results of t-test and Descriptive Statistics for breath-hold (BH)

tasks for Clinical and Control groups................................................. 151

Table 7. Descriptive Statistics for Time 1 and Time 2 of the CO2 Challenge .. 153

Table 8. Descriptive Statistics for Heart Rate and Respiration rate before

and after CO2 Challenge .................................................................... 155

Table 9. Medians, Minimum, Maximum and Interquartile Ranges for

Psychological Measures at Time 1, Time 2 and Time 3. .................... 157

Table 10. Battery of Psychological Assessments Administered Before and

During the Study ............................................................................... 187

Table 11. Demographic Information Categorical Data ..................................... 192

Table 12. Demographic Information Continuous Data ..................................... 193

Table 13: Correlations between Pre-measure Assessments .............................. 194

Table 14. Descriptive Statistics for Respiration Rate (RR) before and after

Time 2 (CO2) and before and after Time 3 (CFI + CO2) .................... 195

Table 15. Descriptive Statistics for Heart Rate (HR) before and after

Time 2 (CO2) and after Time 3 (CFI + CO2) ...................................... 196

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Table 16. Medians, Minimum, Maximum and Interquartile Ranges for

Psychological Measures at Time 1, Time 2 and Time 3. .................... 198

Table 17. Themes and Categories in relation to Panic Cognitions and

Symptoms for Group 1 (Clinical Participants) ................................... 224

Table 18. Themes and Categories relating to panic management strategies

for Group 1 (Clinical participants) ..................................................... 231

Table 19. Themes and Categories regarding Participants Experiences of the

Cold Facial Immersion Task for Group 1 .......................................... 236

Table 20. Themes and Categories regarding Participants Experiences of the

Cold Facial Immersion Task for Group 2 .......................................... 248

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List of Figures

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List of Figures

Figure 1. Physical and cognitive symptoms of panic disorder. ............................. 4

Figure 2. Pathogenesis of panic attacks in panic disorder

(adapted from Vollmer et al. 2015). .................................................. 23

Figure 3. Long-term training effects of the Diving Reflex (Konstandinou

and Chairopoulou, 2017). .................................................................. 78

Figure 4. Long-term physiological adaptations in apnea-conditioned

individuals (Konstandinou and Chairopoulou, 2017). ........................ 79

Figure 5. Process for recruiting Clinical and Control participants and

Control participants. ........................................................................ 129

Figure 6. Experimental procedure for data collection for Group 1 (Clinical)

and Group 2 (Control) participants. ................................................. 144

Figure 7. Mean Heart rate for clinical group (n = 16) and control

group (n= 16) before and after cold facial immersion (CFI). ............ 152

Figure 8. Heart rate for clinical group (n = 16) and control group (n= 16)

at the start and completion of the cold facial immersion task

following CO2 Challenge. ............................................................... 156

Figure 9. Median and interquartile range of API scores for all participants

(clinical group and control group (N= 32) at Time 1, Time 2,

Time 3. ........................................................................................... 158

Figure 10. Median and interquartile range for ASI scores for all participants

(clinical and control groups) (N= 32) at Time 1, Time 2, Time 3. .... 159

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Figure 11. Median and interquartile range BAI scores for all participants

(clinical group and control group (N= 32) at Time 1, Time 2,

Time 3. ........................................................................................... 160

Figure 12. Median and interquartile range for PACQ scores for all participants

(clinical and control (N= 32) at Time 1, Time 2, Time 3. ................ 161

Figure 13. Median and interquartile range for STAI (State) scores for all

participants (clinical group and control group (N= 32) at Time 1,

Time 2, Time 3. .............................................................................. 162

Figure 14. Median and interquartile range for VAS-Participant scores for

all participants (clinical group and control group (N= 32) at Time 1,

Time 2, Time 3. .............................................................................. 163

Figure 15. Median and interquartile range for VAS-Researcher scores for all

participants (clinical group and control group (N= 32) at Time 1,

Time 2, Time 3. .............................................................................. 164

Figure 16. Experimental procedure for data collection for Group 1

(Clinical) and Group 2 (Control) participants. ............................. 188

Figure 17. Mean Heart Rate for all participants (clinical n = 15, and control

n = 15) pre and post the Cold Facial Immersion before CO2 at

Time 3. ........................................................................................... 197

Figure 18. Median and interquartile range for API scores for all participants

(clinical and control group (N=30) at Time 1, Time 2, and Time 3. . 199

Figure 19. Median and interquartile range for ASI scores for all participants

(clinical and control group) (N=30) at Time 1, Time 2, and Time 3. 200

Figure 20. Median and interquartile range BAI scores for all participants (clinical

and control group (N=30) at Time 1, Time 2, and Time 3. ............... 201

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xx

Figure 21. Median and interquartile range for PACQ scores for all participants

(clinical and control group (N=30) at Time 1, Time 2, and Time 3. . 202

Figure 2. Median and interquartile range for STAI scores for all

participants (clinical and control group (N=30) at Time 1,

Time 2, and Time 3. ........................................................................ 203

Figure 23. Median and interquartile range for VAS – Participant scores for all

participants (clinical and control group (N=30) at Time 1,

Time 2, and Time 3. ........................................................................ 204

Figure 24. Median and interquartile range for VAS-Researcher scores

for all participants (clinical and control group (N=30) at Time 1,

Time 2, and Time 3. ........................................................................ 205

Figure 25. Experimental procedure for the qualitative interviews for

Group 1 (clinical) and Group 2 (control) participants. ..................... 219

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List of Abbreviations

xxi

List of Abbreviations

ACT Acceptance and Commitment Therapy

ANS Autonomic Nervous System

AS Anxiety Sensitivity

BNST Bed nucleus of the stria terminalis

BH Breath-hold

BHT Breath-hold training

BT Breathing training

CO2 Carbon Dioxide

CeA Central Nucleus of Amygdala

CNS Central Nervous System

CBT Cognitive Behavioural Therapy

CFI Cold Facial Immersion

DR Diving Response

DPAG Dorsal Periaqueductal Gray

DMH/PeF- Dorsomedial perifornical hypothalamic

DRN Dorsal raphe nuclei

LC Locus Coeruleus

NPY Neuropeptide Y

O2 Oxygen

PA Panic Attack

Pas Panic Attacks

PD Panic Disorder

PFC Pre-frontal Cortex

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PNS Parasympathetic Nervous System

PaCO2 Partial pressure of carbon dioxide

PaO2 Partial pressure of oxygen

PAG Periaqueductal Grey

SNS Sympathetic Nervous System

VLPAG Ventro lateral periaqueductal gray

VRET Virtual Reality Exposure Therapy

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Overview of Thesis

Panic disorder (PD) is one of the most common anxiety disorders. It is

characterised by recurrent panic attacks, is often disabling, and usually follows a

chronic course if left untreated (Kessler et al., 2014). Frequently treatments are

ineffective and costly, hence greater knowledge of the underlying pathophysiology of

PD is required to assist with the development of effective treatments (Wemmie,

2011). Panic attacks (PAs) are experienced as highly distressing and are often

accompanied by a fear of impending doom, and a myriad of emotional, physiological,

behavioural, and cognitive symptoms. The pronounced bodily symptoms are often

misinterpreted as indications of somatic or mental illness, such as having a heart

attack or going crazy. Among the scariest of symptoms are the elevated heart rate and

the dysregulation of the autonomic nervous system.

Free diving is the sport of diving underwater on one single breath. It has been

characterised as calming and relaxing, inducing physiological effects that are opposite

to those experienced when having a panic attack. The key factors common to both

free diving and PAs are mental control and breathing control. Hence, it is plausible

that there is something to be learnt from the physiological adaptions and techniques

used in the sport of free diving, to assist individuals in better managing PAs. The

diving response (DR) is an innate human physiological adaptation that helps conserve

oxygen and increase breath-hold time under water. Free divers are known to be a

unique group of individuals as they do not only have exceptional breathing control but

also a pronounced DR as a result of trained effects (Schagatay, 2002).

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Chapter 1 provides a comprehensive overview of PD. The primary focus of

Chapter 1 is on the clinical phenomenology of PD, including current theoretical

understanding of the aetiology of PD. This chapter includes discussions of the

disorder’s diagnostic criteria, pathophysiology and the various theories that explain

the aetiology of PD, with a particular focus on the neuroanatomical theory of PD.

Various treatments of PD are also discussed including psychological and

physiological interventions.

Chapter 2 introduces the notion of apnea, cold facial immersion (CFI) and the

human adaptation known as the diving response (DR). The cardiorespiratory

mechanisms and physiological responses of the DR are discussed. This chapter also

focuses on discussing breath-holding and cold facial immersion as a way of eliciting

the DR. The sport of free diving is also introduced, with a particular focus on the

research regarding the physiological responses observed in free divers who are trained

in breath-hold diving, and whom demonstrate extraordinary trained effects with

regard to the DR. This research is used to explore the clinical implications of the DR

as valuable in the treatment of PD.

Chapter 3 discusses the relationship between respiration, anxiety, and PD.

This chapter provides an overview of the physiology, the mechanics of breathing and

discusses breathing and chemosensitivity in relation to PD. Cardiorespiratory

abnormalities and homeostatic disturbances and their link to PD are also explored.

Furthermore, respiratory provocation tests are discussed in terms of how they

complement the pathophysiology of PD.

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Chapter 4 presents the preliminary study, Respiratory Challenges, and Cold

Facial Immersion. The chapter provides a summary of the study aims, hypotheses,

the planned research design, outlining participant details, and research procedures. A

number of research questions arise from the literature review, including how

individuals that suffer from PD differ in their cardiorespiratory response to normal

individuals on a number of respiratory challenges such as breath-holding, the 35%

CO2 challenge, cold facial immersion (CFI) and the CO2 plus CFI task. Another

research question that the preliminary study sets out to investigate is whether the DR,

when activated via CFI, can reduce panic symptoms and cognitions. This chapter also

presents the results and discussion of this preliminary study. CFI is demonstrated to

have a powerful response in reducing panic symptoms, hence the research set out to

investigate whether CFI may be able to change CO2 sensitivity in response to the CO2

challenge. This chapter also discusses methodological considerations and

improvements for the subsequent study.

Chapter 6 provides an overview of study aims, hypotheses, the planned

research design, outlining participant details, and research procedures of the second

research study examining the effects of cold facial immersion on CO2 sensitivity. This

study explores the CO2 sensitivity in clinical and control participants and the reduction

of panic and anxiety symptoms following CFI and the activation of the DR. This

chapter also presents results and discussion of this study. The findings do not support

the short-term application of CFI (one single exposure). However, the findings

indicate decreased physiological and psychological symptoms anxiety/panic and

warrants further investigation of its applications.

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Chapter 7 presents a qualitative exploration of panic and cold facial immersion

(CFI). The chapter presents a thematic analysis of the common symptoms of panic

for the clinical participants and ways that they currently try to manage their

symptoms. Thematic analyses of all participants experience of cold facial immersion

are also presented, along with key challenges identified with its use as an intervention

and its utility from the perspective of their experience of the task. Given that CFI may

not always be easy nor practical to use, the key challenges, benefits and alternative

applications of how CFI can be used as an intervention are discussed including

alternative methods for activating the DR.

Finally, Chapter 8 presents the overall thesis conclusions including a

discussion and implications of all studies of the research and future directions.

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Chapter 1

PANIC DISORDER

Panic disorder (PD) is a severe and highly distressing prevalent anxiety

disorder characterised by spontaneous and recurrent panic attacks (PAs) (5th ed.;

DSM-5; American Psychiatric Association, 2013). It is characterised by a high

degree of subjective distress and is commonly occupationally and socially disabling

(Goodwin et al., 2005; Klerman et al., 1991; Wittchen, 1998). In terms of years of

life lived with disability rates, anxiety disorders ranked as the sixth leading cause of

all disability, with panic disorder (PD) being amongst the highest of the anxiety

disorders, accounting for more disability than severe mental disorders such as major

depressive disorder and schizophrenia (Baxter, Vos, Scott, Ferrai & Whiteford, 2010).

PD is among the anxiety disorders that can have a significant impact and

debilitating effect on peoples’ lives and has resulted in elevated levels of social,

marital, occupational and physical disability (Klerman, Weissman, Oulette, Johnson

& Greenwald, 1991). In both the primary health-care and community settings it is

regarded as one of the most costly mental health conditions (Kessler et al., 2005;

Meuret et al., 2017), carrying significant economic costs (Roehrig, 2016). While the

lifetime prevalence of PD (4.7%) (Meuret, Kroll & Ritz, 2017) is lower than that of

other anxiety disorders, it is still high. In particular, the prevalence of subthreshold

PD and PAs (22.7% lifetime) are very high (Roy-Byrne et al., 1999) and associated

with high individual and social costs (Batelaan et al., 2007; Kessler et al., 2006).

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PANIC DISORDER AND PANIC ATTACKS

Panic disorder was initially classified as a distinct nosological entity in the

third edition of the DSM (APA, 1980). The core syndrome and defining feature of

PD is a panic attack and in particular spontaneous panic. Spontaneous panic is

unexpected, as distinct from cued (expected) panic, and can occur at any time

(Schmidt, Lerew, & Jackson, 1997). PAs are characterised as intense and unexpected

fear responses to perceived threat that may include external stimuli (e.g., predators),

or internal stimuli arising in the body, also known as interoceptive signals (e.g., racing

heart), nociceptive triggers (e.g., painful stimuli), or threatening conspecifics (e.g.,

rivals) (Hamm et al., 2016). A panic attack has been defined as a discrete period of

intense dread or fear, accompanied by a number of physical and cognitive symptoms

(American Psychiatric Association, 2013), which are depicted in Figure 1.

PAs are a strong predictor in the subsequent development of a range of

psychological disorders such as mood disorders and anxiety disorders including but

not limited to PD ( Baillie & Rapee, 2005; Barlow 2002: Goodwin et al., 2005, Kinley

et al., 2011). As a result of its sudden or unexpected onset and brief length, it is

discrete as distinct from progressively building anxious arousal (Craske & Barlow,

2001). Sufferers of PD experience sudden and repeated PAs which are marked by a

fear of imminent danger or impending doom and an urge to flee, even in non-

dangerous situations. Like all basic emotions, strong action tendencies are associated

with PAs, including urges to escape, and to a lesser extent urge to fight. Hence, PAs

are believed to activate the fight or flight response, an autonomic reaction that is

activated in response to a perceived threat, or danger (Craske & Barlow, 2001).

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Figure 1. Physical and cognitive symptoms of panic disorder.

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Typically, intense fear experienced during PAs peaks in less than 10 minutes

and subsides in 30 minutes (American Psychiatric Association, 2013; Graeff, 2016).

PAs are characterised by acute physical symptoms which can include respiratory,

cardiovascular, vestibular and gastrointestinal symptoms (i.e., dyspnea, pounding or

racing heart, sweating, dizziness, chills, tingly or numb hands, chest/stomach pain,

abdominal discomfort) and psychological symptoms (i.e., fear of losing control, fear

of dying and fear of going crazy) (American Psychology Association, 2013; Goodwin

et al., 2005; Graeff, 2016)

In PD, panic attacks often have an unexpected quality, as they commonly

occur without an obvious trigger and resulting in individuals worrying and dreading

the possibility of having another attack (Craske & Barlow, 2001; Kircanski, Phil,

Craske, Epstein, & Wittchen, 2009). One such example is nocturnal panic, which

refers to waking abruptly from sleep in a state of panic, with no obvious trigger.

Nocturnal PAs are frequently experienced by individuals with PD (Craske & Tsao,

2005). More often, nocturnal PAs emerge from non-rapid eye movement (NREM)

sleep and thus are not commonly preceded by dreams (Barlow, 2014; Craske &

Barlow, 2007; Craske & Tsao, 2005). They are usually characterised by sudden

awakening, terror and intense physiological arousal. Most PD sufferers describe the

nocturnal attacks as less intense, with fewer symptoms, and less severe than the

diurnal PAs (Craske & Barlow, 1990). Panic attacks may even occur during states of

relaxation (Adler et al., 1987; Cohen et al., 1985).

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THE AETIOLOGY OF PANIC DISORDER

There are a range of theories which have sought to explain the development of

PAs and PD. Currently, there are five prominent theories that have been applied to

understanding the origins of PD. Broadly speaking theories of PD tend to fall into

two categories: psychological and biological theories and include conditioning

(Goldstein & Chambless, 1978) and related theories; cognitive theories (Beck &

Emery, 1985; Clark, 1986, 1988; Clark, 1996), anxiety sensitivity theory (McNally,

1994; Reiss, 1991), psychodynamic theories and biological theories, which

encompass neurobiological and neurochemical factors, metabolic and genetic

theories, respiratory and hyperventilation theories (Nardi & Freire, 2016).

Psychological Theories of PD Aetiology

Conditioning Theories

Conditioning theories have a long history in assisting the understanding of

anxiety disorders (Eysenck, 1979; Marks, 1969; Wolpe & Rowan, 1988) and were

among the first type of theories applied to examine the aetiology of PD (Eysenck,

1960; Eysenck & Rachman, 1965). According to conditioning theories, when stimuli,

events or situations, known as conditioned stimuli (CS), are paired with a panic attack

(PA) (including its somatic symptoms), learning may occur that results in the CS

triggering panic and anxiety when they are encountered again. During a PA, stimuli

from both the internal and external environments can become associated with panic

via the process of classical conditioning (Barlow, 2000; Battaglia and Ligari, 2005;

Bouton, Mineka and Barlow 2001; Goldstein & Chambless, 1978) and may

subsequently elicit a conditioned response (CR) of either anticipatory anxiety or

preceding panic (Bouton et al., 2011). This general theory has been applied to PD in

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various ways with the most noted work being that of Goldstein and Chambless (1978)

who coined the term “fear of fear”. Goldstein and Chambless (1978) posited that PD

patients learn to fear symptoms of anxiety through interoceptive classical conditioning

of internal physical sensations. Hence, fear of fear develops as a result of having PAs.

Following Goldstein and Chambless’ (1978) theory, the focus for conditioning theory

changed from exteroceptive conditioning (i.e., external triggers) used to understand

agoraphobia and situational panic to interoceptive conditioning (i.e., internal bodily

triggers) that more effectively assisted in understanding the cause of “spontaneous”

PAs or those that occur in the absence of an obvious trigger.

Various criticisms of early conditioning theories have been noted in the

literature. Interoceptive conditioning has been criticised as being conceptually

confusing due to panic and anxiety appearing to serve as CS, unconditioned stimuli

(US), conditioned response (CR) and unconditioned response (UR) indiscriminantly

(McNally, 1990, 1994; Reiss, 1987). Conditioning theory has also been criticised for

overpredicting panic; in theory, a fear or panic response should happen every time the

CS is encountered (e.g., a somatic symptom, such as sweating) (Clark, 1988).

Another criticism points to the observation that the fear or panic response does not

seem subject to extinction in trials that demonstrate that arousal and the somatic

sensations it generates are not followed by panic (Rachman, 1991; Seligman, 1988;

Van den Hout, 1998).

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Modern Learning Theory

A more modern perspective on classical conditioning and its many effects on

emotion and behaviour was proposed by Bouton et al. (2001), whose perspective

builds on growing evidence that anxiety and panic are at least partially unique

experiences. Research examining anxiety and panic related symptoms reveal these

two constructs are separate aspects of PD. That is, panic is accompanied by strong

autonomic arousal, extreme fear, and fight or flight response tendencies, whereas

anxiety is accompanied by apprehension, worry and tension (Barlow, 1988; Craske,

1999). Anxiety is seen as preparing the system for an anticipated trauma, whereas

panic deals with the one that is already in progress (Bouton et al., 2001). Panic and

anxiety are therefore different and this perspective is also consistent with

neurobiological research that supports the partially distinct emotional states of anxiety

and panic (e.g., Fanselow, 1994; Tovote, Fadok & Luthi, 2015). Hence panic or fear

allows the individual to combat or avoid/escape immediate threats or danger, whereas

anxiety increases vigilance and improves one’s ability to identify potential threats,

both serving important evolutionary functions in line with keeping the individual safe

(Duval, Javanbakht & Liberzon, 2015).

According to this perspective, a central factor in the development of PD is the

interaction of anxiety and panic. Anxiety may manifest as anticipatory anxiety and

thus contributes to PD maintenance via a positive feedback loop of anxiety and panic

(Barlow, 2000; Öhman et al., 2001). Bouton et al. (2001) propose that anxiety

potentiates panic, and the development and presence of conditioned anxiety, which in

turn exacerbates subsequent PAs. In keeping with earlier approaches to PD, Bouton

et al’s. (2001) perspective also highlights the fundamental role of early conditioning.

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They maintain that the conditioning that may occur during initial PAs in vulnerable

individuals sets the scene for the development of PD. Thus, these PAs become

associated with initially neutral interoceptive conditioned stimuli (CS) (i.e., heart

palpitations, dizziness) and exteroceptive CS (i.e., escalators and supermarkets)

through the associated learning process known as classical conditioning. For

instance, an individual who is sensitive to the sensation of their rapidly beating heart

may experience a panic attack at a time when they are happy and experiencing

excitement, as this is also a time when heart racing can occur and, hence in this

instance, it may serve as an interoceptive CS (Mineka & Zinbarg, 2006).

Furthermore, via the process of stimulus generalisation, autonomic constituents of

panic (e.g., irregular heart rate or the feeling of shortness of breath) may generalise to

similar non–arousal sensations (e.g., exercise–induced sensations) (Lissek et al., 2010;

White et al., 2006). Thus, through the proliferation of cues that trigger anticipatory

anxiety and panic, the initial spontaneous PAs may evolve into PD (Barlow, 2000;

Bouton et al., 2001; Lissek et al., 2010). The crucial feature here is the idea that the

conditioned anxiety that comes to be elicited by interoceptive and exteroceptive cues

associated with panic serves to amplify future panic reactions. Hence, anxiety

becomes an antecedent of panic (Bouton et al., 2001).

Some limitations have been noted with the learning theory of PD. Firstly the

onset symptoms in PD tend to develop usually at the same time, rather than one by

one, like in a vicious cycle pattern. This may explain why PAs do not always occur

following dangerous situations e.g., after a near miss car accident. Furthermore,

despite experiencing countless PAs which demonstrate that symptoms do not result in

dangerous outcomes, PD sufferers fail to learn and continue to fear their symptoms as

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being unsafe. This evidence lends further support to the argument that PAs are

merely due to false learning processes (Bandelow, Domschke & Baldwin, 2014).

Associative learning deficits in the learning of panic-cue relationships may render

PAs unsignalled and unpredictable in PD (Grillon, et al., 2007). Moreover, PAs

usually occur during a state of very low activity characterised by NREM sleep, where

cognitive processes are likely to be limited (McNally, 1994). Interoceptive conditional

responses are an example of this as they are not always dependent on conscious

awareness of triggering cues, but rather once acquired, these responses can be elicited

under sleep or anaesthesia (Craske & Barlow, 2007).

Cognitive Theories

Cognitive theories identify the “catastrophic misinterpretations” of an

individual’s own bodily symptoms and sensations as being pivotal to both the

development and maintenance of PD (Beck & Emery, 1985; Clark, 1986, 1988; Clark,

1996; Otto & Pollack, 2009; Salkovskis, 1988). According to this perspective, panic

develops when an individual focuses on his or her internal physical sensations

irrespective of whether they are produced by anxiety, which in turn leads to

catastrophic thoughts about their impending meaning, such as “I am having a heart

attack” or “I am dying”. The catastrophic thoughts, which in themselves are anxiety

provoking produce further somatic symptoms. This leads to more catastrophic

thinking, thus fuelling a vicious cycle that inevitably ends in a panic attack.

According to cognitive theories, it is the individual’s focus on internal bodily

symptoms and sensations that lead to persistent vigilance and hypersensitivity to

normal and common physical sensations (Bouton et al., 2001). Further support for the

cognitive theory is provided by a causal link between physiological sensations and

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fearful thoughts (Rachmann, Levitt & Lopatka, 1987). For instance, reading paired

word combinations related to somatic sensations and catastrophes (e.g., “palpitations

– die” and “breathless – suffocate”) has been found to increase the likelihood of PAs

(Clark, 1988). On the other hand, when catastrophic misinterpretations are reduced,

the likelihood of panic in response to panic provocation agents also decreases (Clark,

1996). Cognitive behavioural therapy has demonstrated efficacy in managing PD and

given it is proposed to target maladaptive cognitive processes this lends support for

the cognitive theory in the aetiology of PD (eg., Allen and Choate 2016; Clark et al.,

1994; Chen & Tsai, 2016; Barlow, 2000).

Whilst support has been found for cognitive explanations of PD, Bouton et al.

(2001) have highlighted limitations. Catastrophic cognitions are often found to occur

in patients suffering from PD. Although their causal role in creating PAs is

ambiguous, the persistence of such catastrophic cognitions facilitates the maintenance

of PD as sufferers engage in safety seeking behaviour and escape and/or avoid

situations where panic occurs (Salkovskis, Clark & Gelder, 1996). According to

Bouton et al. (2001), key concepts such as “catastrophic misinterpretations” are

considered vague as it is difficult to determine how they are acquired and measured

and who is likely to acquire these. Cognitive theories do not account for the

distinction between the emotional states of anxiety and panic, despite there being

emerging evidence to the contrary, (i.e., as supported by anxiety sensitivity theory).

A large body of research has demonstrated a relationship between anxiety

sensitivity and panic–related psychopathology (Bouton et al., 2001; Dixon, Sy, Kemp

& Deacon, 2013; McNally, 1994, 2000; Reiss, 1991; Poletti et al., 2015; Reiss &

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McNally, 1985, Schmidt, Lenew & Jackson, 1997; Taylor, 1995). Specifically,

findings from various sources including correlational studies, provocation tests,

intervention research, and prospective studies are suggestive that the fear of anxiety–

related somatic sensations play a crucial role in panic psychopathology (Dixon et al.,

2013). Nelson, Hodges, Hajcak, and Shankman (2015) reported in their study that the

different anxiety sensitivity dimensions have distinct relationships with the “acute”

and “potential” threat (i.e., fear and anxiety respectively). Various researchers have

indicated cognitive and personality factors (Craske & Waters, 2005; Mathews &

MacLeod, 2005; Watson & Clark, 1984) that may place individuals at risk for the

vigilance and misappraisals. In particular, “anxiety sensitivity” has been touted as

one such vulnerability factor (Olatunji & Wolitzky-Taylor, 2009).

Anxiety Sensitivity Theory

Anxiety sensitivity (AS) refers to the extent to which an individual believes

that their own bodily sensations and symptoms can have harmful consequences and,

as a construct, it is closely linked with fear of fear (Reiss & McNally, 1985).

Individuals with high AS may attribute shortness of breath to suffocation, or heart

palpitations to heart attack, as compared to individuals with low AS who may

experience discomfort but do not perceive sensations as threatening. Similarly to

cognitive theories of panic, AS posits that cognitive misappraisal is key to the

provocation of anxiety. Conversely, AS theory is distinguished from other

perspectives by virtue of its belief that AS is an enduring trait-like characteristic that

may precede the development of PAs. Furthermore theorists of AS (McNally, 1994;

Reiss, 1991) contend that individuals suffering PD often do not misinterpret the

causes of their sensations and are fully aware of them, but maintain their fear as a

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result of intrinsic beliefs about the possible harm of sensations to their body or mental

health (Bouton et al., 2001).

Whilst research has demonstrated support for the AS theory (Hayward, Killen,

Kraemer, & Taylor, 2000; Schmidt et al., 1997; Schmidt, Lerew, & Jackson, 1999),

what AS specifically predicts is questionable. Bouton et al. (2001) have indicated that

an empirically identified relationship between AS and PAs is small in many studies

(see also Schmidt et al., 1997, 1999; Weems, Hayward, Killen & Taylor, 2002).

Another point of criticism is that these studies have evaluated how AS may predict

PAs and worry about panic, rather than diagnosed PD. Furthermore, the work of

Hayward et al. (2000) challenges the notion of whether AS is the best predictor of

unexpected panic in comparison to negative affectivity. Hence, the causal

significance of AS of PD is not clearly defined in the literature. Although Dixon, et

al. (2013) in their study provided support that AS induced experimentally causes the

subsequent development of anxiety and panic. Panic sufferers are known to overreact

to bodily signs (Clark et al., 1997), which may be due to an anomaly in brain

structures such as the insula and the anterior cingulate gyrus which are responsible for

interoceptive integration (Uchida et al., 2008). In terms of anxiety sensitivity, the

sensation of suffocation is amongst the internal stimuli that seem to be related and

particularly important for panic patients (Klein, 1993).

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Biological Theories of PD Aetiology

Genetic Theories

Genetic and family studies are amongst the most prominent biological theories

suggesting that PD appears to run in families and that individuals who suffer from PD

may have an inherited genetic predisposition. Crowe, Noyes, Pauls and Slymen

(1983) studied the prevalence of PD among families of PD patients and found that

approximately 25% of patients with a diagnosis of PD had first degree relatives with

PD. Further evidence suggests that amongst first degree relatives of PD patients, up

to threefold increases in prevalence have been observed (Maier et al., 1993; Nocon et

al., 2008). Family and family history studies undertaken cross-culturally point to a

strong genetic influence being noted between first degrees relatives that have PD and

agoraphobia (Batagglia & Ogliari, 2005; Crowe et al., 1983).

Twin studies have also provided us with valuable information. Torgersen

(1983) examined concordance rates of anxiety disorders with PAs and reported in his

findings that 31% of the monozygotic twins had a similar diagnosis to each other

compared to 0% of the dizygotic (DZ) twins. One twin study that compared CO2

responsiveness among monozygotic and dizygotic twins found greater concordance

rates for monozygotic twins for panic induced by CO2 challenge (Bellodi et al., 1998).

Overall studies demonstrate 2-3 times higher concordance rates among dizygotic than

among monozygotic twins, lending support for there being a genetic contribution to

the development of PD (Shih et al., 2004). Other twin studies have proposed a link

between genetic factors and the pathogenesis of PD with heritability contributions,

ranging from 30-48% for PD and over 50% for agoraphobia (Hettema et al., 2001;

Kessler et al., 2005).

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A meta-analysis of three twin studies reported a genetic contribution to the

presence of PD of 43% (Hettema et al., 2001). Battaglia and Ogliari (2005), in

reviewing the literature confirmed that the moderate to high heritability estimates are

largely due to genetic influences, rather than environmentally shared influences.

Panic attacks were more than five times more frequent in monozygotic twins than in

dizygotic twins of patients with PD. However, the findings of this particular review

may not be conclusive as they only used a small number of twins and the results may

be explained by the fact that monozygotic twins share more similar environmental

experiences and are commonly treated more similarly than dizygotic twins (Maier,

Lichtermann, Minges, Oehrlein, & Franke, 1993).

Childhood separation anxiety disorder has also been known to correlate with

the increased early onset of PD and increased family loading (Battaglia et al., 1995;

Lipsitz et al., 1994). Robertson-Nay et al. (2012) in their twin studies demonstrated a

shared common genetic diathesis between adult onset PAs and childhood separation

anxiety disorder, suggesting a genetic etiologic link between the two phenotypes.

Criticisms of genetic theories have included failure to yet identify a mode of

inheritance in line with Mendelian patterns, thus pointing to an intricate genetic

inheritance model with interactions of multiple vulnerabilities and genes (Bandelow et

al., 2013). To date, only a very small number of risk genes have been identified with

not much known about gene-environment interactions specific to PD.

Hormone Theory

It has been well documented that hormones, particularly gonadal hormones,

play a significant role in influencing the frequency and intensity of PAs. Spontaneous

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PAs affect more women than men, and it is thought that in women the occurrence of

PAs may be linked to the production of reproductive hormones as they rarely start

before puberty or after menopause (Klein, Mannuzza, Chapman & Fyer, 1992).

Interestingly, a marked decrease of panic has been observed in PD patients during

pregnancy, delivery, and lactation, followed by post lactational exacerbation of panic

symptoms (Bandelow et al., 2006). These changes are related to increased levels of

estrogen, progesterone, and oxytocin during pregnancy and breastfeeding (Klein,

1993). Despite the pregnancy and childbirth period being thought of as one with

marked and heightened anxiety and common catastrophic interpretation of

physiological changes, PAs are less frequent and intense during this period,

suggesting that possibly some of the pregnancy hormones may serve to be protective

of PAs (Bandelow et al., 2006; Klein, 1993).

Metabolic Theories

Metabolic theories have also been popular with people who have a diagnosis

of PD being more sensitive to certain substances including injections of lactic acid,

elevated CO2 levels, caffeine, yohimbine, m-cholorophenylpiperazine,

cholecystokinin, nicotine, and alcohol than are their non–panic counterparts (Bourin

et al., 1997). Researchers have used various procedures in an attempt to reproduce

panic like symptoms in order to understand the aetiology of PD, including both

biological and cognitive models of panic. Cognitive factors such as sense of control

(Sanderson, Rapee & Barlow, 1989), persistence of catastrophic thinking (Clark,

1986) and anxiety sensitivity (McNally, 1989) are amongst some of the psychological

factors that are known to influence one’s response to the CO2 challenge (Carter,

Hollon, Carson & Shelton, 1995).

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Some of the earlier chemicals to trigger panic like symptoms in experimental

settings with humans included epinephrine and norepinephrine (Lindemann, 1935;

Lindemann & Finesinger, 1938; Wearn & Sturgis, 1919). Cholinergic agents have

also been used including parasympathomimetic methacholine and cholinesterase

inhibitor physostigmine in some studies (Lindemann & Finesinger, 1938; Paul &

Scolnick, 1981; Risch et al., 1981). Among the most common procedures used

include the pharmacological agent sodium lactate (Appleby et al., 1981; Haslam,

1974; Liebowitz, Gorman, Fyer, Dillon, & Klein, 1984; Pitts & McClure, 1967) and

hyperventilation and CO2 challenges (Gorman et al., 1984; Papp et al., 1989; van de

Hout & Griez 1974). Charney et al. (1984a) and Uhde (1990) were able to

demonstrate that caffeine challenge tests induce panic like symptoms suggesting a

potential implication of the adenosine system in explaining panic and anxiety.

Adenosine receptors are located and dispersed in all brain areas and regulate the

release of neurotransmitters and the action of neuromodulators (inhibitory and

excitatory functions) (Sebastiao & Ribeiro, 2009). Alternative procedures used have

included the administration of cholecystokinin tetrapeptide (CCK4) (Bradwejn et al.,

1991, 1992; Bradwejn & Kozycki 1994a ; Bradwejn & Koszycki, 1994b), yohibmine,

flumazenil, β-carboline, isoproterenol, piperoxan which act on the noradrenergic or

adrenergic systems (Charney, Woods, Goodman & Heninger, 1987; Charney et al.,

1990; Graeff, Garcia-Leal, Del-Ben & Guimaraes, 2005; Olpe et al., 1983; Pohl et

al., 1990).

Animal studies and brain imaging techniques such as fMRI (functional

magnetic resonance imaging), MRI, PET (positron emission tomography), SPECT

(near infrared spectroscopy) and electrical and chemical stimulation, as well as

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electrical recording, have also been used extensively in recent years to identify

specific brain regions which are implicated in the regulation of panic and anxiety

(Dresler et al., 2013; Duval, Javanbakht & Liberzon, 2015). Lueken et al. (2014), in

their study, found that the amygdala, hippocampus, and midbrain were amongst the

brain structures that were activated in specific phobia. A breakthrough in furthering

our understanding of panic occurred in the 1980s when it was observed that clinical

panic, as well as panic induced in the laboratory by lactate injections, did not activate

the hypothalamus-pituitary-adrenal (HPA) axis (Levin et al., 1987). Hence this

discovery differentiated stress like reactions and common fear from clinical panic.

For decades, the HPA axis (neuroendocrine stress system) activity has been

extensively investigated in patients with psychiatric illnesses, namely depression and

anxiety disorders (Abelson et al., 2007). More recently studies addressing the HPA-

system’s functioning in anxiety disorders have yielded mixed results (Bosch et al.,

2012; Plag et al., 2013), however it reported a general finding of increased basal

levels of cortisol in patients suffering from PD and HPA axis activation at both the

pituitary and the adrenal level (Van Duinen, et al, 2007).

Cognitive behavioural therapy and physical exercise have been shown to alter

the activity in the HPA system, specifically decreasing corticotrophin (ACTH) and

cortisol plasma-levels in response to a pharmacological panicogenic challenge

(Abelson et al., 2005). Several studies reported similar findings investigating the

short-term beneficial effects of physical exercise on the stress response (Deuster et al.,

1989; Lucia et al., 2001; Luger et al., 1987; Uusitalo et al., 1998). Plag et al. (2014)

provided evidence for a deferred and differential effect of endurance training on the

HPA stress response in both PD with and without agoraphobia. While results have

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been inconsistent, these studies have nevertheless revealed that patients with PD

suffer from HPA axis dysregulation (Abelson et al., 2007).

Despite inconclusive evidence whether the HPA axis is implicated in PD or

not, there is an emerging consensus that there are some key areas in the brain involved

in PD. Amongst the regions of the brain that are commonly identified to play a

crucial role in PD include the limbic area, particularly the amygdala, which is directly

associated with the fight or flight response (Schenberg, 2010), and the locus coeruleus

(LC), which appears to be involved in the sleep-wake cycle, arousal, anxiety and fear

(Redmond et al., 1976; Redmond & Huang, 1979). Other important areas that appear

to be implicated in the modulation of anxiety include the hypothalamus, pituitary

gland, especially anterior pituitary gland. These regions are responsible for both the

synthesis and release of stress related hormones (Tsigosa & Chrousos, 2002).

The observation that stress hormones including corticotrophin, cortisol and

glucocorticoids and prolactin remain unaltered during PAs provide us with a vital clue

in understanding the neurobiology of PD (Schenberg, 2010). Goosens et al. (2014),

investigated differences in three groups with descending sensitivity to CO2; panic

patients, healthy individuals, and experienced divers. They concluded that the

behavioural response that characterises PD patients is predominantly due to the neural

sensitivity to CO2 located in the brainstem area. To date, three brainstem areas

involved in both panic and chemosensitivity have been identified, these include the

periaqueductal gray (PAG), the raphe nuclei (RN), and the locus coeruleus (LC)

(Goosens et al., 2014). The LC which is located in the brain stem is a tiny nucleus

which contains 70% of all noradrenergic neurons in the brain. When stress activates

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the LC it results in increased noradrenaline release in LC projection sites including

the amygdala, pre-frontal cortex, and hippocampus (Charney, 2004). In animal

studies and in vitro studies, where molecules or cells may be studied outside their

natural environment, CO2 may directly activate neurons in the LC. Although direct in

vivo evidence in humans presently does not exist, Bailey et al. (2003) speculate that

CO2 effects may be mediated via the noradrenergic network. The noradrenergic

theory of PD which suggests an abnormal central noradrenergic function in PD

patients has been criticised by researchers, contending that the LC mediates arousal

rather than panic and sympathetic nervous system arousal (Samuels & Szabadi, 2008).

The PAG has also been implicated in the pathogenesis of panic, given that

patients that were awake whilst undergoing neurosurgery involving electrical

stimulation of the PAG, elicited symptoms remarkably similar to those reported by

PD patients when enduring a panic attack (Del-Ben & Graeff, 2009). These findings

support the notion of a continuous trait, based on one’s individual sensitivity response

to increasing concentrations detected of CO2 (Pine et al., 2000).

Neurochemical Theory

One prominent biological theory proposes that symptoms are caused by an

imbalance of one or more neurochemicals including serotonin, norepinephrine,

dopamine and gamma-amino butyric acid (GABA) that act as neurotransmitters in the

brain (Bourin, Baker & Bradwejn, 1998). Support for this theory is evidenced by a

reduction of symptoms that many patients who suffer from PD experience when

taking an antidepressant or anxiolytic medication (Nutt, 2005).

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In an attempt to explain the aetiology of PD, neurochemical theories propose a

deficiency in the serotonergic system or excess serotonin (Graeff, 2012). Other

neurochemical theories have implicated increases in the concentration of the

neuropeptide Y (NPY) in anxiety circuits which has been thought to be involved in

the consolidation of fear memories (Bandelow, Baldwin & Zwanzger, 2012;

Bandelow et al., 2013). NPY is a 36 amino acid peptide that is strongly expressed in

the cortical, limbic and hypothalamic regions of the mammalian brain (Allen, Adrian,

Allen, Tatemoto, & Crow, 1983). In particular, it is considered to be the most widely

expressed peptide in the brain and it can be found, in the basal ganglia, hypothalamus,

hippocampus, amygdala, nucleus accumbens, cortex, periaqueductal grey and the

lower brain stem (Adrian, Allen, Bloom, Ghatei & Rossor, 1983; Allen et al., 1983).

Evidence suggests that NPY possesses anxiolytic properties and functionally serves

the role as a protective neurochemical to facilitate stress resilience (Enman, Sabban,

McGonigle & Bockstaele, 2015). In the central nervous system (CNS), NPY plays a

vital role in energy homeostasis, pain, control of food intake and physiological

processes related to stress/stress resilience (Enman et al., 2015). Patients with anxiety

disorders have shown reduced concentrations of NPY, hence making them more

sensitive to stress and fear responses (Bandelow et al., 2013).

Among some of the neurochemical theories that have been proposed to

explain the aetiology of PD include a deficiency in the serotonergic system or excess

serotonin (Graeff, 2012), which may convey significant vulnerability as well as

adaptive factors. Johnson, Lowry, Truitt, and Shekhar (2012), attributed panic attack

vulnerability to faulty serotonergic inhibition of the dorsal periaqueductal grey

(DPAG) and autonomic medullary centers. Furthermore, a dysfunction in the

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endogenous opioid system was proposed by Preter and Klein (2008), which decreases

the threshold of the suffocation alarm. This hypothesis was supported by the findings

of Preter et al. (2011) who demonstrated that lactate infusions produced symptoms

that mimic those of PAs.

GABA is synthesized and released throughout the brain and is one of the

major inhibitory neurotransmitters in the CNS. GABA is strongly associated with

PAs and PD and it has been noted that panic patients have GABA activity deficits

(Johnson, Federici & Shekhar, 2014). Research by Nikolaus et al. (2010) has

demonstrated that patients with PD show reduced GABAA receptor binding in the

frontal cortex and a study by Goddard et al. (2001) discovered deficits in the central

GABA concentrations in panic patients.

Respiratory and Hyperventilation Theories

Respiratory and hyperventilation theories also fall under the neurobiological

theories, which attempt to explain the aetiology of panic. These theories propose that

PAs may be caused by a dysfunctional respiratory system (Freire & Nardi, 2012;

Gorman et al., 1984; Griez, Lousberg & Van den Hout, 1987; Woods et al., 1986). In

particular, it has been proposed that hyperventilation may be causally related to PAs,

given that during hyperventilation an imbalance occurs between O2 inhaled and CO2

exhaled, thus reducing CO2 levels in the body (Cowley & Roy-Byrne, 1987).

Individuals who hyperventilate in an attempt to compensate for the reduction in

respiratory rate experience secondary symptoms, which include shortness of breath,

dizziness, trembling, and palpitations (Freire & Nardi, 2012; Papp, Klein & Gorman,

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1993). It is important to note that these symptoms are also common to anxiety and

PAs.

Such findings led Klein (1993) to propose that the essential disturbance in PD

may be a dysfunctional suffocation monitor (a "suffocation false alarm") (SFA), in

which dyspnea is the dominant symptom. High CO2 levels usually serve as a marker

that the individual is in danger of imminent suffocation since increased levels of CO2

correspond with decreased levels of O2. According to Klein (1993), this suffocation

threshold is pathologically lowered in PD patients (i.e., SFA hypersensitive to CO2),

with increased levels of CO2 becoming a signal for low O2 supply. As a result, the

brain's suffocation monitor incorrectly misfires and signals a lack of O2, triggering an

SFA. Klein’s hypothesis is that since PD patients believe they are suffocating, they

experience shortness of breath and as a result begin hyperventilating in order to keep

CO2 levels well below the (abnormally low) suffocation threshold. Therefore, rather

than causing PAs, hyperventilation is a consequence and actually a defense against

the onset of panic (Klein, 1993). Breathing mechanisms are considered to be under

the management of a widespread cortical and subcortical network, involving

structures from the medulla, up to the hypothalamus, limbic area, and cortex.

The respiratory drive is largely controlled by the ventral respiratory nuclei

(VRN) located in the medulla. The VRN control phrenic nerve activity and sense pH

and CO2 levels of cerebrospinal fluid (Loeschcke, 1982; Ter Horst & Streefland,

1994). Schenberg (2010) postulated that the SFA hypothesis deduces that the

suffocation false alarm system may operate separately to the gas sensors which sense

pH levels and CO2 levels changing. The link between PAs and pH homeostatic

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imbalances caused by respiratory abnormalities such as hyperventilation in PD

patients forms the basis of the SFA theory of spontaneous panic, where CO2

hypersensitivity may exist due to the abnormal suffocation alarm monitor (Vollmer,

Strawn & Sah, 2015). Vollmer et al. (2015) propose a cycle of panic that explains

both cued (expected) and spontaneous (unexpected) PAs, whereby cued PAs are a

result of exteroceptive stimuli, and spontaneous PAs may be triggered by

interoceptive sensory stimuli (see Figure 2).

Figure 2. Pathogenesis of panic attacks in panic disorder (adapted from Vollmer et al.

2015).

When arterial CO2 is raised, brain arterioles dilate and blood flow increases.

On the contrary, when arterial CO2 is lowered, vasoconstriction occurs and cerebral

blood flow decreases. Vasolidatory alterations caused by arterial CO2 may be

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mediated by changes in extracellular pH and local variations in the concentrations of

Potassium (K+) and adenosine may also play a key part (Kandel et al., 2013). Several

studies have suggested a dysregulation of respiratory physiology in patients with PD

(Abelson, Weg, Nesse & Curtis, 2001; Gorman, Fyer & Goetz, 1988; Wilhelm,

Trabert & Roth, 2001).

Potassium (K+) is imperative for the homeostasis of the human organism.

Life threatening cardiac arrhythmias can be caused by the disruption of normal

electrical excitability caused by K+ falling or rising, and the cell membranes

becoming hyperpolarised or hypopolarised (McDonough & Youn, 2017). K+

channels are crucial in both excitable and non- excitable cells for the regulation of cell

volume, membrane potential, secretion of salt, hormones, and neurotransmitters

(Schwartz & Bauer, 2004). Multiple renal and extrarenal mechanisms regulate the K+

homeostasis within very tight parameters. Evidence suggests that acute challenges

such as hypercapnia and hypoxia are both detected through tandem acid sensitive

potassium channels which are located at carotid body chemoreceptor cells and plays a

central role in peripheral chemosensitivity (Trapp et al., 2008).

A recent meta-analysis (Grassi et al., 2014) demonstrated baseline respiratory

abnormalities in participants with PD compared to participants without PD.

Participants with PD in this study differed to participants in the social phobia and

generalised anxiety disorder group when compared, as the PD group demonstrated a

lower end-tidal CO2 pressure and a higher mean respiration rate at baseline.

Differences were also noted in venous CO2 pressure which was lower in the PD group

and in the bicarbonate ion concentrations which were higher in the PD group. It was

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concluded that these unique baseline respiratory abnormalities and the chronic

hyperventilation may be specific to PD pathophysiology as opposed to other anxiety

disorders. These findings are consistent with previous research (Colasanti et al.,

2008; Ramirez, 2014; Sikter, Frecska & Braun, 2007).

PD patients commonly report respiratory abnormalities. Chronic obstructive

pulmonary disease (COPD) has received the most attention (Kunik et al., 2005).

COPD is a severe lung disease which is characterised by airway restriction and

subsequent limitation of airflow and often presents with chronic bronchitis and/or

emphysema (Barrera, Grubbs, Kunik & Teng, 2014). Several studies have examined

the comorbidity of depression and anxiety symptomatology in COPD patients in a

number of pulmonary clinics as assessed by various self-report anxiety and depression

measures (Kunik et al., 2005). The prevalence of comorbid depression and anxiety

was increased in COPD patients (Bratek, Zawada, Barczyk, Sozanska & Krysta,

2013; Bratek et al., 2015) and in their spouses too (Kuhl, Schurmann & Rief, 2008).

Yohannes, Baldwin, and Connolly (2000), found that 37% of primary care outpatients

with COPD who had depressive symptoms also had anxiety symptoms.

Indeed respiratory disorders including (COPD) and asthma among patients

suffering from PD have a lifetime prevalence that is estimated to be 47% (Barrera et

al., 2014). There have also been reports of high comorbidity between PD and

respiratory abnormalities, which suggests that respiratory dysfunction plays a central

role in PD (Simon & Fischman, 2005). Furthermore, research implicates that there

may be a familial link between COPD and PD (van Beek, Schruers, & Griez, 2005).

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Hyperventilation has numerous empirical and theoretical associations to

anxiety and panic. Low CO2 levels can develop quite quickly even in the absence of

functional breathing disorders and this is because of the very high solubility of CO2

which is twenty times more soluble than O2 (Davies & Moore, 2003).

Hyperventilation can easily result from non-metabolic stimuli, including stress,

anxiety, or increased sensations of dyspnea, which in turn depletes CO2 and resultant

hypocapnia (Gotoh et al., 1965; Wilhelm, Gerlach & Roth, 2001). The effects of

hyperventilation and depletion of CO2 are pronounced and include increased neuronal

excitability and reduced cerebral blood flow (Papp, Klein & Gorman, 1993). It is

well understood that symptoms such as numbness, tingling sensations, dizziness, and

muscle hypertonicity could result from hyperventilation. These symptoms could be

attributed to hypocapnia and respiratory alkalosis, in which the body fluids have too

much base and too little acid, resulting from an increased gas exchange in the lungs

(Courtney, 2009). Intracellular pH (pHi) and cellular metabolism are impaired, as

well as the regulation of cerebrospinal fluid pressure (Freire & Nardi, 2012).

Hypocapnia produces bronchoconstriction in the lungs and vasoconstriction in the

blood vessels (Freire & Nardi, 2012). The depleted levels of CO2 cause alkalosis,

leading commonly to a reduction of cerebral oxygen metabolism, due to the Bohr

effect (Fried, 1987). Relative to the Bohr effect, the affinity of haemoglobin towards

oxygen is reduced and favours the oxyhaemoglobin dissociation when PaCO2

increases (Kandel et al., 2013). The oxyhaemoglobin dissociation curve has a strong

affinity to O2 so it ensures a stable oxygen delivery to the viscera, even under difficult

conditions (i.e., when engaging in strenuous physical activity) (Wilhelm, Gevirtz &

Roth, 2001). Adverse effects of hypocapnia can also result in reductions in blood

pressure, myocardial contractility, cardiac blood flow, and alterations in pH regulation

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and electrolyte balance. Given the widespread physiological effects of hypocapnia

and the consequences of respiratory alkalosis, it is not surprising that breathing

dysfunction has been associated with hyperventilation syndrome (Courtney, 2009)

and that hyperventilation theories have been used to explain panic.

In the general population the prevalence rate of dysfunctional breathing

characterised as breathing too fast and shallow has been as high as 5-11% (Fried,

1987; Hornsveld & Garrsen, 1997; Lum, 1981). In asthma sufferers, it is as high as

30% (Thomas, McKinly, Freeman & Froy, 2001) and in anxiety sufferers as high as

83% (Cowley & Roy-Burne, 1987). Consistent with previous findings, Freire et al.

(2013) reported the respiratory subtype correlated with high CO2 sensitivity (Biber &

Alkin, 1999; Nardi et al., 2006; Valenca, Nardi, Nascimento, Zin & Versiani, 2002).

Neuroanatomical Theories

Neuroimaging studies have been fruitful in demonstrating that anxiety

disorders such as PD which involve the fear circuitry, support the Deakin–Graeff

hypothesis which proposes that PD is characterised by underactivity in the prefrontal

cortex (PFC), which in turn decreases the amygdala inhibition (Deakin Graeff, 1991;

Berkowitz et al., 2007). Optogenetic and chemogenetic methods have been used in

animal models to study fear circuits involved in normal panic/fear as well as

pathological panic/fear (Pare & Quirk, 2017), however, the neural pathways involved

in initiating PAs in humans still remain poorly understood (Wiest, Lehner-

Baumgartner, & Baumgartner, 2006).

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Currently, a combination of complex fear circuitry and anxiety circuitry are

implicated in the functional aetiology of PD (Tovote, Fadok & Luthi, 2015). When

an individual perceives a stimulus as potentially threatening, a combination of

adaptive changes involving neurochemical, neuroendocrine and behavioural responses

are activated in an effort to maximise chances of survival. These neurobiological fear

responses comprise the fear circuitry and include the amygdala, thalamus,

hippocampus, insula and prefrontal cortex (Dias & Thuret, 2016).

The neuroanatomical theory of PD was first proposed by Gorman et al. (1989).

It was suggested that the dysfunctional integration of information and subsequent

discoordination of cortical and subcortical neural circuitry is involved in PD. Gorman

et al. (1989), initially proposed that PAs are resultant from increased activity of the

noradrenergic neurons of the locus coeruleus (LC), a nucleus in the pons of the

brainstem responsible for physiological responses to stress and panic. Furthermore, it

was suggested that anticipatory anxiety involves the limbic structures and that the

prefrontal cortex (PFC) is responsible for phobic avoidance (Canteras & Graeff,

2014). Based on this theory, Gorman and his colleagues hypothesised that

psychopharmacological interventions such as selective serotonin reuptake inhibitors

(SSRIs) may reduce PAs by decreasing the amygdala activity and by inhibiting

projections to subcortical sites including brainstem (Gorman et al., 2000).

Furthermore, Gorman et al. (2000) suggested that psychotherapies including CBT,

most likely act on the hippocampus by deconditioning contextual fear, decreasing

cognitive misappraisals, and disproportionate emotional reactions by reinforcing and

strengthening the ability of the medial PFC to inhibit the amygdala (Gorman et al.,

2000).

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In Gorman’s revised hypothesis, neuroanatomical pathways were

identified and mapped in humans, based on similarities between conditioned fear

responses in animals and PAs in humans (Le Doux, Cicchetti, Xagoraris & Romanski,

1990). In an attempt to explain panic and examine the fear circuits involved in the

brain, several neuroanatomical models have been proposed. It has been proposed that

hypersensitivity in the brainstem and the amygdala play a role in the pathogenesis of

PD (Gorman et al., 2000). Sub-cortical and cortical regions such as the amygdala,

thalamus, hypothalamus, insula cortex, and prefrontal cortex, are involved in the fear

network, which is predicted to be activated transiently in PD thus suggesting that PD

is best considered as a systems level abnormality.

The amygdala plays a significant role in the formation of memories as well as

in the elicitation of strong emotional responses (Kim & Jung, 2006; Maren, 2008;

Ziemann et al., 2009). Research conducted over the last several decades has revealed

that the amygdala is an important brain structure that is essential for learned and

innate fear and its function is pivotal to learning the association between conditioned

and unconditioned, aversive, fear-evoking stimuli (Kim & Jung, 2006; Maren, 2008;

Ziemann et al., 2008). The processing and directing of the inputs and outputs of fear

behaviours occur at the amygdala and therefore it is a key structure to fear behaviours

(Ziemann et al., 2008). It is well known that the amygdala incorporates sensory

inputs received from various brain structures in producing physiological and

behavioural expressions of fear (Wemmie, 2011; Ziemann et al., 2008). Whilst

Gorman’s panic amygdala model has gained popularity, it was discredited by studies

that found that patients suffering from the rare autosomal recessive Urbach–Wiethe

disease, who are lacking an amygdala, develop PAs spontaneously and in response to

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the 35% CO2 challenge (Feinstein et al., 2013). This has contradicted previous

findings that the amygdala is a key region in the initiation of panic attacks (PAs).

Similarly, Wiest, Lehner-Baumgartner, Baumgartner, (2006) in their study reported a

case study of a patient with bilateral selective lesions of the amygdala, experiencing

PAs, suggesting that the initial pathology is not necessarily restricted to fear circuits

such as the amygdala. However, in support of the role of the amygdala in fear

processing, there have been studies which have found that the amygdala in humans

with bilateral damage has notably impaired the processing of fearful facial

expressions (Adolphs, Tranel, Damasio & Damasio, 1995; Le Doux et al., 1990).

Deep brain stimulation studies have shed some light in deepening our

understanding of which areas are implicated in the induction of PAs and fear

responses (Rasche et al., 2006; Wilent et al., 2011). Meletti et al. (2006) in their

study, using intracerebral stimulation to stimulate the amygdala of 74 patients found

that 85% of the emotions elicited that were observed were associated with fear, whilst

11% were associated with pleasant-happy feelings and 4% elicited a sad response.

Their findings implicated that the medial temporal lobe structures are involved in fear

expression. Moreover, Meletti et al. (2003) in their study found that unilateral

damage in the amygdala can cause impairment in the recognition of facial

expressions. In brain stimulation studies involving humans, stimulating the tuberal

region of the hypothalamus (ventromedial/perifornical) region (Rasche et al., 2006;

Wilent et al., 2010, 2011) or the dorsal periaqueductal gray regions (DPAG) (Nashold

et al., 1969; Young, 1989) consistently elicits self-reports of dying, PAs, and anxiety

accompanied by autonomic symptoms associated with PAs. Similarly in rats

stimulation of the DPAG and hypothalamus evokes strong flight responses,

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autonomic responses and aversive anxiety associated behaviours in rats (Shekhar,

1993; Shekhar, Hingtgen & DiMicco, 1990; Shekhar, Keim, Simon & McBride, 1996;

Schenberg, 2010; Schenberg, Costa, Borges & Castro, 1990). The circa strike

defence which is activated by prominent sympathetic nervous system arousal and

active defensive behaviour also implicates the DPAG (Hamm et al., 2016; Le Doux ,

2012). A number of sites involved in the fear circuitry, including the prefrontal

cortex, insula, thalamus, septohippocampal system, as well as LC and RN have also

been implicated in the regulation of panic responses.

A regulatory dysfunction at any of the abovementioned key sites in this fear

network may lead to the development of PD symptoms (Dias & Thuret, 2016).

Furthermore, it has been found that different subsets of neurons in the dorsal raphe

nuclei (DRN) are activated by anxiety and panic, respectively and therefore it is also

implicated in the fear circuitry (Canteras & Graeff, 2014; Paul & Lowry, 2013;

Spiacci et al., 2012). According to Shekhar et al. (1999) amongst the critical

regulatory sites that elicit “panic-like” responses and are characterised by chronic

GABA dysfunction, is the dorsomedial hypothalamus and the anterior basolateral

amygdala which evoke physiological symptoms, and behavioural responses

associated with PAs resultant from the blockade of GABA receptors.

Summary

The biological theories have provided sound insights into understanding the

pathophysiology and aetiology of PD. Whilst biological theories have informed

psychopharmacological treatments that have been successful in treating PAs (Bonn et

al., 1984; Sheehan, 1982b), they have been limited in terms of their utility in the

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development of treatments outside of psychopharmacology. Several biological

theories have been proposed to explain the aetiology of PD including metabolic,

hormone, genetic, neurochemical and respiratory and hyperventilation theories.

Amongst the most popular are the neuroanatomical theories. Several brain

regions have been implicated to be involved in the fear circuitry and include the

amygdala, thalamus, hippocampus, insula and prefrontal cortex (Dias & Thuret,

2016). Numerous studies from clinical, provocation, neuroimaging,

psychophysiological and translational models of animal research in relation to PD

have contributed to our understanding and current knowledge of the fear circuitry in

the brain and the relevance of critical neuroanatomical sites involved in PD (Gorman,

Kent, Sullivan & Coplan, 2000; Gorman, Liebowitz, Fyer, & Stein, 1989; Klein,

1993; Ley, 1985; Perna, Caldirola, & Bellodi, 2004; Perna et al., 2014). However,

despite having a greater understanding about individual structures that are involved in

the pathophysiology of PD, much has yet to be determined about the functional

connectivity of the relevant structures involved in the fear circuitry and we are far

from having a satisfactory explanation of the causes and mechanisms of PD (Canteras

& Graeff, 2014; Dias & Thuret, 2016). Hence, more sophisticated translational

models are called for to determine what animal research is of empirical value to

humans and to further understand the molecular and neural systems involved in PD.

Moreover, with recent technological advances in neuroimaging techniques, more

human research needs to be carried out, to establish underpinnings and new insights

on the fear circuitry involved in PD and the variations between PD and other anxiety

disorders. These findings may in turn help to inform new treatments for PD patients,

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with the aim of restoring homeostatic parameters that have been compromised via the

activation of the brain’s fear circuitry.

Psychological theories have also been prominent. In terms of efficacy,

cognitive theories have gained increased acceptance as being superior in the treatment

and management of PD and have informed the development of psychologically-based

treatments, particularly cognitive behavioural therapy, (CBT) (Clark et al., 1985;

Salkovskis et al., 1986a). An individual’s susceptibility to developing PD is

influenced by a number of biological and psychological factors that create

vulnerabilities. Additionally, the catastrophic misinterpretation of somatic sensations

plays a key role in the maintenance of PD. Cognitive behavioural therapy and

biological approaches focusing on an interaction of physiological and psychological

factors are more likely to be equipped at integrating the relevant research findings that

complement the development of more efficacious treatments for PD.

Further understanding of the complex biological basis of PD needs to be

supported by scientific insights not solely concerned with biological factors of PD but

also genetic and epigenetic factors related to neurochemical, respiratory, endocrine,

cognitive and behavioural systems. A multifactorial approach and model for PD may

also help inform the development of novel treatments and combined interventions

targeting physiological, cognitive, and behavioural symptoms of anxiety and panic.

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PHYSIOLOGY OF PANIC

The human nervous system is made up of two anatomically separate systems:

the central nervous system (CNS) and the peripheral nervous system. Essentially, the

peripheral nervous system comprises twelve pairs of cranial nerves and thirty-one

pairs of spinal nerves, and their associated ganglia (Wood, 2012). The peripheral

nervous system is further divided into two main parts: an afferent (sensory) division

which transmits signals towards the CNS and an efferent (motor) division which

transmits signals away from the CNS. The efferent division can be further subdivided

into the somatic motor division which controls skeletal muscle and the visceral motor

division which is also referred to as the Autonomic Nervous System (ANS) (Wood,

2012). The vagal nerve which is the longest nerve in the body plays a key part in the

brain and viscera interplay within the ANS, as it is responsible for numerous

homeostatic regulations of visceral functions (Bonaz, Sinniger, & Pellissier, 2016).

The ANS is responsible for our basic life support systems that occur without

our conscious control. The ANS is involved in the unconscious regulation of visceral

functions and coordinates cardiovascular, respiratory, digestive, urinary and

reproductive functions without instructions or interference from the conscious mind

(Martini, Nath & Bartholomew, 2012). The ANS comprises sympathetic and

parasympathetic divisions. Parasympathetic activation conserves energy and

promotes a state of “rest and digest” as seen indigestion. The overall pattern of

parasympathetic nervous system (PNS) responses incorporate a decreased metabolic

rate, heart rate and blood pressure, increased secretion by salivary and digestive

glands, increased motility and blood flow in the digestive tract and stimulation of

urination and defecation (Martini et al., 2012).

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The sympathetic nervous system (SNS) is activated only during exertion,

stress or emergency, whilst the PNS predominates during resting conditions. The

SNS prepares the body for heightened activity and produces what is known as the

autonomic fight or flight response. More recently, the freeze response has also been

added to the fight or flight response and this is frequently observed when someone

becomes so overwhelmed by their fear and anxiety that they freeze and become

immobilised to act (Rothschild, 2017). In summary, the SNS activation is

characterised by heightened mental alertness, increased respiration and metabolic rate,

increased heart rate and blood pressure, activation of sweat glands, and reduced

urinary and digestive functions. When sympathetic activation occurs, which is what

happens during a panic attack (PA), an individual undergoes a number of

physiological changes designed to prepare them to cope with a stressful situation.

While the various symptoms of a PA may cause the person to feel that their body is

failing, it is, in fact, protecting itself from harm.

From a physiological perspective, the various symptoms of a PA can be

described as follows. Commonly PAs are characterised by a sudden onset of fear,

where there is little provoking stimulus. This is followed by a release of adrenaline

(epinephrine) and activation of the fight, flight or freeze response, which essentially

prepares one’s body for strenuous physical activity. Tachycardia and hyperventilation

are frequently reported to occur in PAs (Ley, 1992). Hyperventilation during a PA,

which may be a direct response to sympathetic activation or triggered by a subjective

difficulty in breathing results in a drop in carbon dioxide (CO2) levels in the lungs and

blood (Barlow, 2014). This, in turn, leads to changes in the blood pH levels

(respiratory alkalosis or hypocapnia) which can trigger various symptoms including

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numbness, tingling, dizziness and light headedness. The latter two of these symptoms

are also caused by vasoconstriction which results from the release of adrenaline

during a PA.

TREATMENTS OF PANIC DISORDER

Panic Disorder (PD) has been largely treated by psychopharmacological

interventions and cognitive behavioural therapy (CBT) alone or in conjunction. Prior

to 1980, biological theories dominated explanations regarding the aetiology and

treatment of PD. Since 1980, psychological explanations and theories including

conditioning and cognitive models have been developed to define PD and make its

treatments more efficacious (Sanchez-Meca, Rosa-Alcazar, Marin-Martinez, &

Gomez-Conesa, 2010).

According to Barlow, Allen and Choate (2016), while pharmacological and

psychological approaches have been shown to be equally effective treatments,

evidence implies that psychological treatments are more enduring after treatment

discontinuation. Research suggests that CBT or pharmacotherapy should be the

preferred strategy for treatment for PD (Chen & Tsai, 2016). Given that PD has

demonstrated to have more of a chronic phenomenological nature, combined

treatments are often more efficacious, Van Balkom et al. (1997), endorsed the

combination of in vivo exposure and antidepressant medication for the treatment of

PD, based on a meta-analysis of 106 studies. Bakker, van Balkom, Spinhoven,

Blaauw and van Dyck (1998) a year later published a review of 68 studies which

comprised an analysis of the long–term outcome of treatment. The researchers

concluded that the superiority of the combination of antidepressants and exposure

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therapy found earlier in Van Balkom et al. (1997), was confirmed at follow up.

Furukawa et al. (2007), in their Cochrane review, demonstrated that there was

sustained advantage for 6 to 24 months when psychotherapy and antidepressant

medication is combined over an antidepressant alone. This led them to conclude that

as a first line treatment combined therapy or psychotherapy alone should be

recommended. Benzodiazepines are not usually recommended in combination with

CBT as they are known to blunt the CBT treatment response (Watanabe, Churchill, &

Furukawa, 2007).

Chen and Tsai (2016) maintained that first line treatment should be CBT and

that the combination of CBT and pharmacotherapy should only be the second-line

treatment strategy for treatment-resistant PD. Individual characteristics of patients

with PD should be taken into consideration when choosing the most optimal treatment

strategy. For instance, patients that are unable to tolerate the side effects of

medication may benefit from CBT while pharmacotherapy may be more suited for

those experiencing more physical symptoms of PD rather than cognitive symptoms

(Chen & Tsai, 2016; Kircanski et al., 2009; Pattyn et al., 2015; Roshanaei-

Moghaddam et al., 2011; Roberson-Nay et al., 2012; Western & Morrison, 2001).

Patients with PD who possess effective self-control skills respond more successfully

to treatments using CBT (Chen & Tsai, 2016; Dusseldorp et al., 2007).

Besides increasing self-efficacy and decreasing AS, increasing patients’ sense

of controllability and predictability of events in one’s environment, and decreasing

avoidance and neurotic self-preoccupation are key mindsets that need to be developed

(Barlow, Allen & Choate, 2016). According to modern learning theory, anxiety too

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can become a conditioned stimulus, thus leading anxiety to initiate panic (Barlow,

Allen & Choate, 2016). Several treatment studies have also shown that behavioural

therapy which involves extensive exposure therapy in both the short term and the long

term, may be equally as effective as cognitive therapy in reducing PD (Margraf &

Schneider, 1995; Telch, 1995).

The efficacy of the treatment of PD has been well established in the literature

(Sanchez-Meca et al., 2010). In a meta-analysis of 65 studies between 1980 and

2006, 42 supported that when exposure therapy, relaxation training, and breathing

retraining are combined, it gave the most consistent evidence for treating PD

(Sanchez-Meca et al., 2010). Two treatments which have gained much attention that

fall under the CBT model include Barlow and his colleagues’ panic control treatment

(Barlow & Craske, 1989; Craske & Barlow, 2006) and cognitive therapy developed

by Clark and Salkovskis (Clark, 1997; Clark & Salkovskis, 1989).

In Barlow’s treatment model, exposure of the patient to interoceptive

sensations plays a key part. Feared sensations are elicited via exercises such as

visualisation of anxiety provoking scenes, over breathing and spinning (Barlow,

2014). Psychoeducation of panic and the factors that may affect its origin and

recurrence are further an important part of this treatment. Cognitive therapy is also

included in the treatment which focuses on modifying catastrophic misinterpretations

about panic and anxiety. Erroneous beliefs that overestimate the threat and danger

that the PAs represent are addressed. The program incorporates progressive muscle

relaxation which involves gradually tensing and relaxing various muscle groups

paying particular attention to the bodily sensations and inducing relaxation and

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warmth. Homework exercises are assigned to encourage client participation between

sessions (Sanchez-Meca et al., 2010).

The cognitive therapy developed by Clark and colleagues includes both an

educational and a cognitive component. The educational component focuses on

briefing the client on the causes and triggers of PAs. The cognitive component

focuses on identifying and challenging erroneous interpretations of the symptoms.

The program includes breathing retraining to correct abnormal habitual breathing

patterns such as hyperventilation, in order to alleviate fearful sensations.

Furthermore, behavioural experiments are implemented in order to expose the client

to their feared panic sensations and to encourage them to give up their safety

behaviours. When comparing the two approaches, Barlow’s approach is characterised

by an emphasis on exposing the clients to their interoceptive sensations whereas

Clark’s approach focuses more on the cognitive component (Sanchez-Meca et al.,

2010). Other treatment modalities have been applied in treating PD with some of the

more common ones being, eye movement desensitization and reprocessing (EMDR)

(Feske & Goldstein, 1997; Goldstein, de Beurs, Chambless & Wilson, 2000),

psychodynamic therapy (Milrod et al., 2007), emotion regulation therapy (Shear,

Houck, Greeno & Masters, 2001), breathing retraining (Meuret, Wilhelm, Ritz &

Roth, 2008), gestalt therapy (Chambless, Goldstein, Gallagher & Bright, 1986),

virtual reality exposure (Powers & Emmelkamp, 2008) and mindfulness based

approaches (Roemer & Orsillo, 2005) including acceptance and commitment therapy

(Forman et al., 2007).

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According to Cosci (2012), promoting recovery early in the treatment process

is seminal, given that PD often involves a staging process, implicating that the

disorder may worsen over time if left untreated. Fava and Mangelli (1999) proposed

a 4-stage model to describe the development of PD and agoraphobia. The first stage

is characterised by the interplay of several predisposing factors including genetic

vulnerability, personality features, anxiety sensitivity, health anxiety, and impaired

psychological well being. Stage 2 involves the onset of agoraphobia, whereby Stage

3 involves the acute phase of PD. Stage 4 is represented by a chronic phase of PD, in

which agoraphobia becomes more severe, and the risk of major depression is

increased. Support for the staging model of PD and agoraphobia has been implicated

by its utility to recognise PD early enough to be able to treat it successfully (McGorry

2007; Mc Gorry et al., 2007). The model may also be able to assist with the

development of therapeutic strategies for patients that are treatment resistant (Cosci,

2012).

The next section of the thesis will specifically explore cognitive behavioural

therapy (CBT), acceptance and commitment therapy (ACT), in vivo exposure with the

use of virtual reality, psychodynamic breathing retraining interventions and

psychopharmacological treatments, as these appear to be most frequently used in the

treatment of PD.

Cognitive Behavioural Therapy (CBT)

CBT for PD promotes the development of self-efficacy in which patients

develop their belief and confidence that they are capable of effectively coping with

panic-related symptoms. The role of the therapist in this process is to effectively

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discuss the true dangers of panic symptoms and encourage client’s ability to manage

with their symptoms of panic (Casey, Oei & Newcombe, 2004; Gallagher et al.,

2013). Studies conducted have revealed that severity of PD symptoms can be

predicted based on the self-efficacy beliefs of patients (Gallagher et al., 2013;

Richards, Richardson & Pier, 2002; Telch, Brouillard, Telch, Agras & Taylor, 1989).

According to Fentz et al. (2014), panic self-efficacy plays a vital role in determining

the outcome of treatment for PD. Research shows that misinterpretations of bodily

sensations experienced during PAs as well as lack of self-efficacy in managing and

dealing with PAs are significant factors that influence resistance to treatment for PD

(Fentz et al., 2013, 2014; Gallagher et al., 2013; Hoffart et al., 2016; Noda et al.,

2007; Teachman et al., 2010).

Hoffart et al. (2016) in their study found that catastrophic beliefs are a

mediating factor contributing to either remission or persistence of PD. Decreasing

catastrophic misinterpretations of bodily sensations using CBT has been demonstrated

to lead to an overall reduction in symptoms (Teachman et al., 2010). According to

Gallagher et al. (2013), the greatest changes occurring early in treatment was in AS,

while self-efficacy experienced notable changes towards the end of treatment.

CBT has demonstrated the greatest effect on AS which impacts changes in

panic symptoms early in the treatment process. The focus of therapy revolves around

providing psychoeducation, breathing retraining and cognitive restructuring which in

turn impacts subsequent panic symptom changes (Gallagher et al., 2013). Effective

and fast improvements have been observed in relation to patients’ fear of bodily

sensations using CBT for PD (Gallagher et al., 2013).

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Delivering psychoeducation about anxiety-related bodily sensations,

developing interoceptive distress tolerance, in vivo exposures exercises, and

restructuring of catastrophic appraisals of anxiety-related bodily sensations and

cognitions, all part of CBT for PD, have been shown to decrease AS in patients with

PD (Barlow, 1988, 2002; Craske & Barlow, 2013; Gallagher et al., 2013).

CBT is considered to be the preferred psychological treatment, given that is

the most researched form of psychological therapy. Moreover, no other

psychotherapies have systematically demonstrated that they are superior to CBT

(David, Cristea & Hofmann, 2018). The efficacy of CBT as a treatment for PD has

been demonstrated through large randomised controlled trials depicting evidence that

treatment effects of CBT are larger than that of placebo as CBT has greater durability

as well as producing similar outcomes to medication at post-treatment (Barlow,

Gorman, Shear & Woods, 2000; Gallagher et al., 2013). Meta-analyses conducted

(Mitte, 2005; Westen & Morrison, 2001) to date show that CBT has large effects on

PD (Gallagher et al., 2013). This has also been evidenced by studies without a control

condition, where patients despite being on a therapeutic dose of medication,

demonstrated improvement following the introduction of CBT (Heldt, et al, 2003;

Pollack et al., 1994).

Gallagher et al. (2013), emphasised the importance of correcting the

maladaptive perceptions of bodily sensations that patients have early in treatment to

facilitate positive outcomes. Increasing patients’ sense of mastery, self-efficacy and

personal agency in their ability to cope with the disorder has been demonstrated by

patients achieving an enhanced recovery. Evidence-based treatments are pointing to

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the constructs of self-efficacy and anxiety sensitivity (AS) as playing a key part in the

mechanisms of change of CBT for PD (Bouchard et al., 2007; Casey et al., 2005;

Gallagher et al., 2013; Reilly et al., 2005; Shear et al., 2001; Smits et al., 2004).

Research has demonstrated CBT’s efficacy in decreasing AS (Gallagher et al., 2013;

Shear, Houck, Greeno, & Masters, 2001; Smits, Berry, Tart, & Powers, 2008). The

importance of CBT’s efficacy in counteracting AS erroneous beliefs around is further

supported by evidence that AS has demonstrated to directly impact other anxiety-

related symptoms experienced by patients (Gallagher et al., 2013; Reilly, Gill, Dattilio

& Mc Cormick, 2005; Smits, Powers, Cho & Telch, 2004).

In summary, CBT approaches focus on directly changing the form, frequency

or validity of the context and function of psychological phenomena that includes

feelings, sensations and thoughts. ACT, on the other hand, emphasises these as the

target of change interventions (Blackedge, Ciarrochi & Deane, 2009; Hayes, 2004;

Hayes, Villatte, Levin & Hildebrandt, 2011; Swain, Hancock, Hainsworth &

Bowman, 2013).

Acceptance and Commitment Therapy (ACT)

According to Forman et al. (2007) amongst the new CBT approaches, ACT

has been the most well researched. There is expanding evidence as demonstrated by

meta-analysis, for the efficacy of ACT and anxiety disorders (Hayes, Luoma, Bond,

Masuda & Lillis, 2006). The main aim of ACT is to assist clients in developing

psychological flexibility for the purposes of adapting to novel potentially threatening

contexts. This is achieved through six core therapeutic processes that include

acceptance, cognitive defusion, mindfulness, values and committed action, and self-

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as-context (Hayes et al., 2006; Luoma et al., 2007; Swain et al., 2013). ACT

postulates that in order for clinical improvement to occur, patients are trained to feel

bodily sensations and emotions, without active avoidance or suppression, as well as to

focus on behaviour change in valued directions (Levitt et al., 2004). ACT aims to

increase willingness and behaviour control while reducing experiential avoidance and

attempts at internal control as it is believed that attempts at internal control and

regulating internal experiences may be the problem and not the solution to the

problem (Levitt et al., 2004).

Arch et al. (2009) conducted a study comparing 12 sessions of ACT to CBT

with 36 participants diagnosed with PD/agoraphobia, social anxiety disorder (SAD) or

specific phobia (SP). Results revealed that patients in the ACT group showed

significant decreases in clinician and self-report measures, with both ACT and CBT

showing similar reductions in clinician measures from moderate severity to

subclinical severity post-therapy (Arch et al., 2009). In another study by Arch et al.

(2012) comparing ACT and CBT in 128 participants with PD and/or agoraphobia,

obsessive-compulsive disorder, generalised anxiety disorder (GAD), SAD, SP, found

that both treatments produced equivalent reductions on both self-rated anxiety

measures and clinician rated anxiety measures. Results revealed that patients in the

ACT group showed significant decreases in clinician and self-report measures, with

both ACT and CBT producing equivalent and reliable change in clinician measures

from moderate severity to subclinical severity post-therapy (Arch et al., 2009).

Furthermore results revealed ACT was more effective than CBT based on clinician-

rated outcomes (Arch et al., 2012; Swain et al., 2013).

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Feldner et al. (2003), in their study, were the first to demonstrate that

experiential avoidance and emotion regulation strategies potentiate induced acute

emotional distress using inhalations of 20% CO2-enriched air which are typically

panicogenic under experimental conditions. Notably, such effects were largely

providing evidence that experiential avoidance, but not other psychological risk

factors for panic (e.g., anxiety sensitivity), tends to covary with a more exaggerated

panic response, even in non-panic counterparts (Karekla, Forsyth & Kelly, 2004).

Following several trials of CO2 inhalations, individuals high in experiential avoidance

exhibited more panic symptoms, increased panic cognitions, fear, panic, and loss of

control than their less avoidant counterparts (Forsyth, Barrios & Acheson, 2007).

Karekla (2004) in her dissertation study compared panic control treatment (PCT) with

ACT enhanced CBT in 22 participants. Results revealed that participants in the PCT

treatment group experienced more interference, agoraphobia severity and avoidance

compared to the ACT enhanced CBT treatment group.

Meuret and colleagues (2012) investigated the effectiveness of ACT-enhanced

exposure therapy for patients with PD with and without agoraphobia. Eleven

participants were provided with 4 sessions of ACT with a focus on acceptance,

defusion and value based behaviour which was followed by 6 sessions of exposure

therapy adapted from the ACT theoretical model (Meuret et al., 2012). In the initial

four sessions, participants reported significantly reduced agoraphobic cognitions,

decreased AS and increased mindfulness. Out of 11 participants in this study, 8

completed treatment and reported at least a 30% decrease in severity of their PD

(Bluett et al., 2014; Meuret et al., 2012).

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Levitt et al. (2004) examined the effects of acceptance as opposed to

suppression of emotions and thoughts during a 5.5% CO2 challenge in patients with

PD. The research revealed that compared to patients in the suppression group,

patients in the acceptance group reported less avoidance and subjective anxiety in a

second challenge (Levitt et al., 2004). While participants did not report changes to

experiencing panic sensations, their subjective anxiety and willingness to participate

in another challenge did differ among all three groups (suppression group, acceptance

group, and control group) (Levitt et al., 2004). The study also found that prior to a

CO2 challenge, a 10-minute acceptance intervention assisted in reducing participants’

subjective anxiety and avoidance. In summary, the results of this study indicate that

the two goals of acceptance based interventions were met, which include: (1)

encouraging patients to fully experience emotions while remaining non-judgemental

and (2) increasing willingness for participation in valued activities (Levitt et al.,

2004).

In reviewing the studies many of them lacked randomised controlled studies

and an active comparison group. Moreover, they did not compare ACT to standard

cognitive therapy and upon additional investigation, most of these controlled studies

which demonstrated efficacy in anxiety treatment were conducted by investigators

with an allegiance to ACT (Forman et al., 2007). According to Powers et al. (2009),

ACT did not outperform established treatments; hence, they concluded in their study

that there was no distinct advantage of using ACT over existing established

treatments.

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In Vivo Exposure and Virtual Reality Exposure

In vivo exposure has been a traditional a form of CBT that aims to reduce the

fear associated with the interoceptive and exteroceptive triggers (Barlow & Craske,

2014). In a meta-analysis of studies investigating the efficacy of pharmacological and

psychological interventions, results yielded support for the efficacy of cognitive

therapy and or in vivo exposure therapy which involves gradually exposing the client

to feared situations (Bakker, Balkom, Spinhoven, Blaauw & van Dyck, 1998;

Chambless & Gillis, 1993; Clum, Clum & Surls, 1993; Cox, Endler, Lee & Swinson,

1992; Gould, Otto & Pollack, 1995; Mattick, Andrews, Hadzi-Pavlovic &

Christensen, 1990; Mitte, 2005; Westen & Morrison, 2001). Meta-analyses that have

addressed the differential efficacy of psychological and pharmacological treatments

have revealed positive results for both of these treatments (Cox et al., 1992; Mitte,

2005; van Balkom et al., 1997; Wilkinson, Balestrieri, Ruggeri & Bellantuono, 1991).

The use of virtual reality (VR) as a tool for providing exposure is a relatively

recent development in the behavioural treatment of specific phobias (Powers &

Emmelkamp, 2008). Clients are exposed to virtual stimuli instead of being

confronted with real anxiety provoking stimuli (Powers & Emmelkamp, 2008). In

order to immerse patients in the generated virtual environment, VR integrates visual

displays, body tracking devices, real-time computer graphics, and other sensory input

devices (Powers & Emmelkamp, 2008).

The use of VR in treating more complex anxiety disorders such as panic

disorder with agoraphobia is scarce with only a few randomized control trials that

have been conducted to date (Meyerbroker & Paul, 2010). Agoraphobic avoidance

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behaviour and panic is the focus of treatment with particular emphasis on exposure to

agoraphobic avoidance behaviour which comprises exposing patients to feared

situations through virtual environments (Meyerbroker & Paul, 2010).

Choi et al. (2005) conducted a study comparing group experiential cognitive

therapy including VR exposure therapy, to a panic control program. Patients received

either twelve sessions of the panic control program (Craske & Barlow, 1994) or four

sessions of experiential cognitive therapy which consisted of relaxation training,

psychoeducation, VR exposure and interoceptive exposure). The study revealed that

both treatments were equally effective immediately following its completion, however

at six-months follow up, these results were not maintained with the panic control

group showing higher end-state functioning compared to the experiential cognitive

therapy group (Choi et al., 2005; Meyerbroker & Paul, 2010).

In a study by Botella et al. (2007), a comparison between nine treatment

sessions of CBT with VR exposure therapy, nine sessions of CBT plus exposure in

vivo and waiting list control condition was conducted. Results revealed that between

the two treatments conditions, no differences in effectiveness were found as both were

superior to the waiting list control. At 12-months post-treatment, results were

maintained. Some limitations noted with VR exposure therapy including challenges

with providing training for mental health providers in the use of VR exposure

behaviour therapy, and the lack of a standardised procedure in the delivery of

treatment (Botela et al., 2015).

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Penate et al. (2008) conducted a study comparing VR exposure therapy to

CBT in patients with PD. Eleven sessions of CBT or combined CBT and VR were

provided to patients who in conjunction took antidepressant medication. Results

demonstrated that both treatments were found to be effective at post-treatment. The

same research team who conducted a study investigating CBT with exposure in vivo

or a combination of CBT and VR exposure therapy for treating a diagnosis of PD and

agoraphobia in 27 patients found no differences between the two treatments at post-

treatment (Pitti et al., 2008). Results indicated that patients, however, favoured the

combined treatment over CBT alone (Pitti et al., 2008). The sole use of VR exposure

therapy in treating PD has not received much attention, with only Botella et al. (2007)

comparing VR exposure therapy and exposure in vivo found both to be equally

effective in treating PD (Meyerbroker & Paul, 2010).

The use of in vivo exposure and VR exposure are usually accompanied by

other psychological treatments. Many of the psychological treatments that are widely

used to treat PD encompass breathing training with an aim to mediate dysfunctional

habitual breathing patterns and to improve anxiety and general health. Barlow et al.

(1988) developed interoceptive exposure which was initially aimed at treating PD

with agoraphobia, as it was recognized that the context of anxiety and fear

experienced was external as well as internal (Barlow, 2016; Barlow, Allen & Choate,

2016). Pompoli et al. (2018) in their review postulated that CBT packages for PD

including face-to-face and interoceptive exposure components demonstrated

superiority over muscle relaxation and VR exposure components.

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Psychodynamic Therapy

Psychodynamic therapies have also been used to treat or to conceptualise PD.

Amongst the psychodynamic treatments that are specific to PD is the panic-focused

psychodynamic psychotherapy. This treatment modality is based on the theoretical

foundations that a PA can be understood as the consequence of intrapsychic conflict

arisen from unconscious fantasies that clash. One study randomised 49 patients to

either panic-focused psychodynamic psychotherapy or to an applied relaxation

treatment was used to evaluate the efficacy of panic-focused psychodynamic

psychotherapy (Milrod et al., 2007). Results demonstrated superior outcomes for the

group receiving panic focused psychodynamic therapy, as they reported a

significantly greater reduction in panic symptoms and higher than the group receiving

applied relaxation. However, it is less than clear if the applied relaxation treatment

actually was in accordance with the behavioural coping technique developed by Öst

(1987).

Breathing Training

A range of conditions including asthma, heart disease, depressive disorders

and anxiety are leaning towards breathing therapies given the growing body of

scientific evidence supporting their efficacy. Buteyko breathing techniques which

involve breath-holding in combination with reduced volume breathing have been

researched extensively for the efficacy on asthma with there being at least five

published clinical trials to date (Abramson et al., 2004; Bowler, Green & Mitchell,

1998; Cooper et al., 2003; Cowie, Underwood & Reader, 2008; McHugh, Aitcheson,

Duncan & Houghton, 2003; Opat, Cohen & Bailey, 2000; Slader et al., 2006). In

psychological conditions such as depression, stress and anxiety, breathing

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biofeedback and yoga based breathing techniques have been found to be effective

(Han, Stegen, De Valack, Clement & Vande Woestjine, 1995; Janakiramaiah et al.,

1998; Karavidas et al., 2007; Meuret, Wilhelm, Ritz & Roth, 2008; Murthy,

Janakiramaiah, Gangadhar & Subakrishna, 1998; Tweedale, Rowbottom & McHardy,

1994). Research in the field of respiratory psychophysiology and claims posited by

several eastern philosophies and traditions support the idea that emotional states are

largely dependent on breathing patterns, and that altering one’s breathing pattern

voluntarily can alter one’s emotional state (Boiten, 1998; Boiten, Frijda &Wientjes,

1994; Brown & Gerbarg, 2005; Grossman, 1983; Ley, 1999: Tweeddale, Rowbottom

& McHardy, 1994; Van Diest, Thayer, Vandeputte, Van de Woestijne &Van den

Bergh, 2006; Blom et al, 2014).

For this reason, motivated by a biological basis for panic, breathing training is

another common intervention used in the treatment of PD (Barlow, 2014; Courtney,

2009; Meuret et al., 2003). Breathing training derives its therapeutic effect through

correction of deranged respiratory patterns (i.e., thoracic breathing, hyperventilation)

(Klein, 1993; Ley, 1985). Hypocapnia (lower than normal levels of carbon dioxide) is

thought to be the primary cause of panic (Ley, 1985) or the secondary cause of panic

(Klein, 1993). Unpleasant bodily sensations experienced as a result of hypocapnia

(i.e., dizziness, numbness, tingling) may precipitate panic (Carr, Lehrer & Hochron,

1992; Chambless, Caputo, Bright & Gallagher, 1984), and hypocapnia in itself can

occur as a result of mental illnesses or due to intacranial hypertension and

hyperkalaemia (Laffey & Kavanagh, 2002; Meuret, Rosenfield, Seidel, Bhaskara, &

Hoffman, 2010). Changes in panic symptoms can be achieved through

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therapeutically increasing the partial pressure of carbon dioxide (PaCO2) (Meuret et

al., 2010).

Breathing Training Treatments

Capnometry-assisted respiratory training (CART) is a 4 week-training

program developed to systematically alter hypocapnia in PD patients (Meuret et al.,

2008). CART is an alternative breathing retraining method, as it assures the

manipulation and assessment of respiratory physiology (Meuret et al., 2003). CART

teaches patients to raise subnormal levels of PaCO2 through immediate feedback of

end-tidal PaCO2 that is monitored through a portable capnometer, in order to increase

patients’ control over dysfunctional gas exchange and the symptoms that develop

because of that (e.g., dizziness, shortness of breath) (Meuret, et al., 2010).

Meuret et al. (2008) conducted the first randomised controlled trial study

comparing CART to waitlist for patients with PD with agoraphobia. Results

demonstrated that 68% of patients achieved significant reductions in panic symptom

severity at post-treatment and at 2 and 12 months follow-up, 79% and 93% of such

patients showed significant reductions in severity of panic symptoms (Meuret et al.,

2008). Results yielded that patients were able to achieve sustained normalised levels

of PaCO2.

For several decades, respiratory abnormalities have been postulated as

significant factors in the development and maintenance of anxiety-related problems.

Breathing training/retraining has become a major therapeutic strategy in the treatment

of PD, often used as a component of a treatment package (Barlow & Craske, 1989;

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Telch, Shermis & Lucas, 1989; Wilhelm & Margraf, 1997) or as the sole component

of treatment (Clark, Salkovskis, & Chalkley, 1985; Han, Stegen, deValck, Clement, &

Van deWoestijne, 1996; Hibbert & Chan, 1989; Rapee, 1985; Salkovskis, Jones &

Clark, 1986). Breathing techniques are becoming increasingly popular given the

impact of dysfunctional breathing in common conditions including asthma,

cardiovascular disease, chronic pain, depression, anxiety and panic (Courtney, 2009).

In most panic treatment approaches, the reversal of the fight-or-flight response

is achieved by breathing retraining, which involves practicing controlled slow

breathing as well as various techniques which assist with relaxation, such as

progressive muscle relaxation and visualisation. The rationale of breathing training is

based on the hyperventilation theory of anxiety that supports a central role for

hypocapnia in panic symptom reduction (Ley, 1985, 1992). The essential aim of

these techniques is to terminate the positive feedback loop, the vicious panic cycle, by

reducing the respiratory rate and thus increase PaCO2 from hypocapnic to normal

levels (Clark, 1986). Cognitive theorists would emphasise that breathing control

techniques help clients learn to reinterpret somatic symptoms of hyperventilation as

being a normal physiological reaction rather than life-threatening. Wolpe and Rowan

(1988) assert that a feeling of immediate control over hyperventilation symptoms

should generally hinder the experience of anxiety and in particular panic.

Voluntary hyperventilation (VH) has been used as an educational tool to

simulate feared physical sensations and demonstrate the idea of the vicious cycle of

panic. Voluntary hyperventilation tests have been applied in the laboratory to

understand the physiological and psychological mechanisms involved that initiate and

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maintain anxiety. Moreover, they have been applied therapeutically in the treatment

of anxiety disorders. From the theoretical perspective of hyperventilation theories of

anxiety, voluntary hyperventilation is useful diagnostically to the clinician and

educationally to the patient. From the theoretical perspective of CBT, voluntary

hyperventilation is an alternative method to induce panic like sensations and to

activate catastrophic cognitions that need restructuring in PD patients (Barlow &

Craske, 2014).

Chronic emotional stress and states of hyperarousal have been found to alter

breathing patterns. Breathing irregularity is a common symptom in patients suffering

PD and other anxiety disorders. Dysregulation of normal breathing patterns are

observed and specific diaphragmatic changes are noted. Fluroscopic studies

demonstrated that the diaphragm becomes flat and is immobile in situations of

emotional stress. When a fight or flight response is activated, fast shallow and

thoracic breathing dominates. Increased levels of tonic contraction of respiratory

muscles expend a lot of energy and homeostatic functions necessary for renewal and

repair are compromised (Courtney, 2009). Controlled respiration aids the system to

return to a physiological rest state and appears to regulate neurological function which

assists with the decrease of SNS activity and increased PNS activity (Courtney, 2009).

Frequent and prolonged practice of several breathing techniques combining slow

diaphragmatic breathing, long breath retentions, alternate nostril breathing has been

known to benefit by resetting the autonomic balance and amplifying PNS responses

(Christoforidi et al., 2012; Mana, 2010; Pal, Velkumary, & Madanmohan, 2004).

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Meuret et al. (2003) identified nine studies as using breathing training (BT)

alone or in combination with other treatment modalities. The BT treatment took place

over the course of 2-4 weeks and comprised one to five sessions. The findings of most

of the nine studies revealed decreases in PA frequency, severity and self-reported

anxiety. Although some of these studies suggest that BT is effective alone or in

combination with other treatments, some studies suggest no greater efficacy compared

to other alternative treatments. Moreover, a number of limitations in these studies do

not warrant this to be a fruitful meta-analysis, including the extensive variation in

patient selection, study design, underlying rationales and BT techniques used. Meuret

et al. (2003) concluded that more studies are needed to test the efficacy of BT alone

and that the techniques used should take into consideration respiration rate and tidal

volume in the regulation of blood gases (PaCO2).

To date, there have been a large number of breathing techniques that have

been found to be effective in regulating mental and emotional states such as the

Buteyko breathing techniques (Abramson et al., 2004) and the Wim Hof breathing

method (Kox et al., 2014). The evidence for the ability of breathing therapies to

correct breathing dysfunctions is relatively sparse as research has largely focused on

psychological outcomes rather than examining the efficacy of breathing parameters.

Furthermore, breathing retraining has yielded mixed results and is not as effective as

CBT where the client is encouraged to stay with the sensations akin to “floating with

panic” or “riding the wave” (Barlow & Craske, 2014). Despite a number of studies

suggesting that breathing retraining is effective in reducing the frequency of panic

attacks (PAs), concerns have been raised about its regular use. Taylor (2010)

suggested that the routine use of breathing retraining may only be effective in patients

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who hyperventilate or breathe via the chest. Another concern raised is that breathing

retraining may prevent patients from learning that their catastrophic beliefs are

irrational, hence being counterproductive (Barlow & Craske, 2014; Taylor, 2010).

Pharmacological Treatments

A number of pharmacologic agents have demonstrated efficacy in the

treatment of PD. Selective serotonin reuptake inhibitors (SSRIs), selective

norepinephrine reuptake inhibitors (SNRIs), benzodiazepines, tricyclic and

heterocyclic antidepressants, and monoamine oxidase inhibitors (MAOIs) are

amongst the several classes of drugs that are used in the treatment of PD (Chen &

Tsai, 2016). Nowadays antidepressants which act on aminergic symptoms are used

more commonly to treat panic symptoms rather than benzodiazepines that potentiate

the effect of GABA, which is the principal inhibitory neurotransmitter in the central

nervous system (CNS) at various receptors (Taylor & Arnow, 1988). However, it is

now widely accepted that, although medications working on the GABA receptors are

highly effective, they come at a cost, as they are highly addictive and impact on

cognitive functioning (Andrews, Corry, Oakley-Browne & Shepherd, 2003).

Moreover, it is because of problems with side effects and safety concerns such as

sedation, dependence and tolerance that the benzodiazepines have been

contraindicated for long-term use (Baldwin et al., 2005; Bandelow et al., 2008; Garner

et al., 2009; Johnson, Federici & Shekhar, 2014; Petersson, 1994).

Nevertheless, despite the side effects commonly experienced by patients,

reports suggest that they are excellent anxiolytics and efficacious for the treatment of

PD (Graeff et al., 2003; Marks et al., 1993; Risborough, 2009). A systematic review

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and meta-analysis of 22 studies compared the efficacy of all the classes of

antidepressants against benzodiazepines and yielded support that benzodiazepine

trials were comparable or demonstrated greater improvements with fewer reported

adverse effects in PD or GAD patients, compared with newer class antidepressants

(Offidani, Guidi, Tomba & Fava, 2013). Some of the most common associated side

effects with the newer class antidepressants (SSRIs and SNRIs) have included sexual

dysfunction, weight gain and sleep disturbance (Ferguson, 2001; McHugh et al.,

2009), which have resulted in high rates of treatment discontinuation (Cowley et al.,

1997; Dewand & Anand, 1999) and greater attrition rates as compared to CBT in

clinical trials (Butler et al., 2006).

Nardi et al. (2012) in a randomised controlled naturalistic 8-week study

compared the safety and efficacy of treatment with clonazepam and paroxetine in PD

patients with or without agoraphobia. They found that the benzodiazepine was

superior to the antidepressant, as clonazepam resulted in fewer PAs at week 4 and

overall greater clinical improvements at week 8. Moreover, patients treated with

clonazepam reported fewer adverse symptoms than patients treated with paroxetine.

(Nardi, Valenca & Freire et al., 2011; Nardi et al., 2012). Notwithstanding, these

findings are compelling and have triggered some debate amongst the medical

community concerning preferences for first-line treatments, and their efficacy for

treating different anxiety disorders as well as relative adverse effects (Kaplan, 2013).

At present, SSRIs are typically, the preferred choice of psychotropic

medication used to treat PD and remain to date the first-line recommended

psychopharmacological treatment (Bandelow et al., 2008). Andrisano, Chiesa and

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Serreti (2013), in their meta-analysis found that there is a close link between serotonin

and PD and tryptophan depletion as evidenced by the increase of PAs and anxiety

symptoms in PD. Furthermore, their meta-analysis demonstrated higher anti-panic

efficacy in SSRI’s as compared to other medications. Burghhardt et al. (2007), in their

study, found that rats that were treated acutely by SSRI injections including

citalopram and fluoxetine demonstrated enhanced conditioned fear responses,

providing support that SSRIs become effective only after 2-3 weeks, of repeated

treatment. According to Klein (2013), serotonergic antidepressants are effective with

spontaneous and situationally predisposed PAs. To date, the mechanisms involved in

the therapeutic actions of the compounds in SSRIs remain largely unknown (Al-

Damluji, 2004).

SUMMARY OF CHAPTER

Panic research needs to continue to build on existing theories and on well

established evidence-based treatments and draw on advances in the disciplines of

psychology, physiology, neuroscience and psychiatry to further our understanding of

the complexities associated with panic and its pathophysiology. Amongst some of the

treatments for PD that yield positive therapeutic outcomes, are CBT, ACT, breathing

retraining, in vivo and virtual reality exposure, psychodynamic approaches and

pharmacological therapies. Despite a lot of other treatment modalities gaining

popularity, CBT appears to be the dominant modality of all the psychological

interventions and the preferred choice for a first line treatment. It is well established

that it is the gold standard treatment for PD in the literature and that a combination of

pharmacotherapy and CBT might be more appropriate as a second line treatment

(David, Cristea & Hofmann, 2018).

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In primary care and community health settings, anxiety disorders are too often,

not detected, or under recognised and hence not treated. Frequently, it is when a

patient demonstrates significant distress or experiences complications from the

disorder, that treatment is indicated. (Bandelow, Michaelis & Wedekind, 2017).

Psychopharmacological and psychological treatments can sometimes be lengthy, with

high drop-out rates and poor compliance (Ferguson, 2001). Hence there is a need for

the development of treatments that are more simple, and practical and cost-effective,

whereby treatment compliance and efficacy is improved.

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Chapter 2

The Diving Response and its Applications

BREATH-HOLDING (APNEA)

Breath-holding and controlled slow breathing are commonly used in the

treatment of panic both for exposure of interoceptive symptoms or sensations, and for

the reversal and prevention of anxiety and panic symptoms (Barlow, 2017). Breath-

hold (BH) training also known as apnea training has been used widely to enhance

sports performance in athletes and to train the body to adapt to the scarcity of oxygen

(Hutchinson, 2018). Cardiovascular adaptations such as the diving response (DR), are

induced during apnea (i.e. cessation of breathing or cooling of the face) and are

focused on reducing overall oxygen consumption (Breskovic et al., 1985; Guimard et

al., 2014).

THE DIVING RESPONSE (DR)

The DR, exhibited by all air-breathing vertebrates is a physiological

adaptation and reflex that optimises respiration, allowing humans to endure a lack of

oxygen underwater and remain underwater for extended periods of time.

Furthermore, this physiological response makes it possible for humans to dive to

depths thought potentially fatal by the medical profession for the human body to

survive. The current world record for breath-hold duration is 11.35 minutes and depth

of 214 metres (Ostrowski et al., 2012).

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For more than a century, the DR has been studied extensively in animals;

however human studies are limited (Shamsuzzaaman et al., 2014). It is elicited by

apnea (cessation of respiration) and stimulation of cold facial receptors (cold facial

immersion) (Foster & Steel, 2005). The DR is the most powerful autonomic reflex

characterised by bradycardia, peripheral vasoconstriction, blood centralization,

decreased cardiac output, increased arterial blood pressure and decreased arterial

oxygen saturation (SaO2) (Alboni, Alboni, & Gianfranchi, 2011; Andersson &

Schagatay, 1998; Foster & Sheel, 2005).

There are a number of factors that stimulate the DR, although the

contributions of each in eliciting the DR and the central mechanisms that control and

regulate these responses have not been fully determined (Baranova, Berlov &

Yanvareva, 2016). Factors activating the DR include, apnea, also known as breath-

holding (BH), cold facial immersion (CFI) and tactile stimulation of receptors of the

face, hypercapnic and hypoxic factors influencing chemoreceptors on the vascular

bed, carotid sinuses, medulla oblongata centres (i.e., respiratory, vasomotor)

(Andersson, Liner, Runow & Schagatay, 2002; Baranova et al., 2016). Upon

initiation of the DR, the physiological changes include: a decrease in heart rate

(bradycardia) (Asmussen & Kristiansson, 1968); constriction of blood vessels in

certain parts of the body (vascular constriction); reduced blood flow to peripheral

capillary beds (Leuenberger, Hardy, Herr, Gray & L.I., 2001) increased blood

pressure; and the spleen contracts to release more oxygen carrying red blood cells into

bloodstream (Ferrigno et al., 1997). There is also increased output in the volume of

blood being pumped out of the heart when the DR is activated (Ferrigno, Hickey,

Liner, & Lundgren, 1986). Anatomic differences between humans and diving animals

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point to the limitations of the human response to deep breath-hold diving (Ferrigno et

al., 1997).

According to a review by Ponganis, McDonald, Tift, and Williams (2017),

factors that may influence the intensity of the DR include baroreceptor reflexes,

pulmonary stretch receptor reflexes, trigeminal/glossopharyngeal nerve stimulation,

carotid body receptor responses, blood gases, volitional control and exercise (Angell-

James et al., 1978, 1981; Davis and Williams, 2012; de Burgh Daly et al., 1977;

Elsner, 1965; Elsner et al., 1977, 1964; Grinnell et al., 1942; Jobsis et al., 2001;

Ridgway et al., 1975; Signore & Jones, 1996 as cited by Ponganis et al., 2017). These

mechanisms are particularly exaggerated in breath-hold divers and assist in increasing

diving durations by temporarily reducing peripheral tissue oxygen uptake (Valic et al.,

2006).

During apnea, there are two distinct phases which contribute to the

physiological breaking point, at which rising concentration of CO2 in the blood

triggers “involuntary breathing movements” (Hentsch & Ulmer, 1984; Lin, 1982).

The first is the “easy-going ” phase and the second the “struggle phase”. During the

easy-going phase, the diver experiences reduced levels of breathing urges whilst

during the struggle phase, the diver experiences an urge to breathe followed by

progressive involuntary breathing movements and a final “fighting” phase usually

experienced by elite divers (Andersson & Schagatay, 2009; Dejours, 1995; Dujic &

Breskovic, 2012; Steinberg, Pixa, & Doppelmayr, 2012). The “individual breaking

point” marks the termination of apnea in which the need to breathe can no longer be

resisted voluntarily (Dejours, 1965). The length of the easy-going phase is primarily

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dependent on the accumulation of arterial PaCO2 and less dependent on arterial PaO2

(Andersson & Schagatay, 2009).

The DR has an oxygen conserving and dive prolonging effect (Schagatay &

Anderson, 1998). Initiated by apnea, the response is transmitted via either a decrease

in lung stretch receptor activity or direct contact between respiratory and

cardiovascular control centres (Elsner & Gooden, 1983). Several researchers

maintain that one’s breaking point can be postponed by changing the physiological

conditions in the blood or by increasing one’s tolerance to such conditions. Irving

(1963) who initially observed the diving response in humans, reported that the

bradycardia of trained free divers was more pronounced compared to that of untrained

subjects. Hong and Rahn (1967) in their study also reported pronounced bradycardia

in the Ama divers when compared to other participants.

Whilst the DR is involuntary, Schagatay and Andersson (1998) suggest that

the DR can be trained and can have positive effects on both HR reduction and apnoeic

duration. Training effects have been observed in pearl, shell and sponge divers as

well as athletes in the sport of free diving, which is the sport of diving on one breath.

Long term training of free diving is associated with a number of physiological

adaptations including a more exaggerated DR, and greater lung volume, lung O2 and

CO2 stores (Schagatay & Anderson, 1998; Ferretti & Costa, 2003). The HR of human

BH divers can decrease more than 50% whilst diving (Ferrigno et al. 1997).

Undoubtedly the training undertaken by professional free divers has contributed to

their exceptional breath-hold ability, as evidenced by the world record free diving

depths humans have been able to achieve.

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BREATH-HOLDING AND COLD FACIAL IMMERSION

Cold facial immersion (CFI) alone is sufficient in contributing to the oxygen-

conserving effect of the DR (Anderson et al., 2016; Lemaitre et al., 2008). During

CFI, receptors that are supplied by the trigeminal nerve transmit this information to

the brain and subsequently innervate the vagus nerve that is part of the ANS (Nepal,

Sharma, Mander & Kusma, 2015). The mechanisms underlying increases in blood

pressure due to CFI is likely the result of sympathetic nervous system (SNS)

activation. Increases in SNS activity elicits responses that include, vascular resistance

in the peripheral (Fisher et al., 2015; Heistad, Abbound & Eckstein, 1968), visceral

(Espersen et al., 2002; Patel, Mast, Sinoway & Muller, 2013) and cerebral (Brown,

Sanya & Hilz, 2003) vasculatures, all of which contribute to increases in blood

pressure (Fisher et al., 2015; Khurana & Wu, 2006; Patel et al., 2013; Shamsuzzaman

et al., 2014; Stemper, Hilz, Rauhut & Neundorfer, 2002). An increase in SNS activity

as a result of CFI is related to multiple mechanisms through which increases in stroke

volume occurs (Datta & Tipton, 2006; Gagnon et al., 2013; Gooden, 1994; Jay et al.,

2006; Paton et al., 2005; Schlader, Coleman, Sackett, Sarker & Johnson, 2016).

According to Nepal et al. (2015), exposing the peripheral skin to cold stimulus

is also sufficient in eliciting a DR, further stating that stimulation of the trigeminal

nerve around the facial region is not the only method in eliciting DR. A study by

Andersson et al. (2000) concluded that while HR reduction and selective

vasoconstriction brought about by BH without immersion were augmented by CFI,

forearm immersion in water as apnea begins had no effect on eliciting the DR. The

study also revealed that cold-water immersion augmented the reduction in skin

capillary blood flow, suggesting that cold stimulation is an effective method in

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provoking reflex vasoconstriction in the skin. Regardless of the site of stimulation,

cold stimulation leads to vasoconstriction in the skin vessels that is not affected or

augmented by concurrent cold stimulation to another part of the body (Andersson et

al., 2000).

The peripheral chemoreceptors’ primary purpose in humans is in detecting and

responding to an increase in partial pressure of carbon dioxide (PaCO2) and decreases

in pH or in PaO2 (Alboni et al., 2011). During apnea, peripheral chemoreceptors are

stimulated by the lack of consistent afferent stimuli directed from the pulmonary

stretch receptors leading to hypoxia. The response of the cardiovascular system

includes bradycardia, vasoconstriction, and secretion of suprarenal catecholamine.

Conversely, during facial or whole body immersion, the accompanying bradycardic

response is not attributed to the peripheral chemoreceptors, but instead is a

manifestation of the DR. In this instance, the arterial PaO2 and PaCO2 are within

normal range, hence the bradycardiac response is independent of chemoreceptor

stimulation and is triggered exclusively via breath-holding and through cutaneous

cold receptors. However, findings of previous research suggest that the

chemoreceptor stimulation during prolonged hypoxic dives may play a part in

accentuating bradycardia (Alboni et al., 2011).

Diving stimulates synergistic sympathetic and parasympathetic responses

responsible for the heightened cardiovascular reflexes in humans, which when

compared to cold facial stimulation and breath-holding alone, produce a greater

response than the sum of individual responses (Andersson et al., 2000;

Shamsuzzaman et al., 2014). The exact mechanisms by which the peripheral nervous

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system is activated by apnea remains undetermined. Potential explanations include

activation of baroreflex, activation of the lung inflation reflex and normalization of

blood gases, as well as hypoxia and hypercapnia playing an important part in the

stimulation of chemoreceptors (Foster & Sheel, 2005; Lemaitre, Buchheit, Joulia,

Fontanari & Tourny-Chollet, 2008). It is thought that the interplay of various

interacting factors such as baroreceptors, pulmonary stretch receptors, lung volume,

blood gases, pulmonary shunting and associated hydrostatic pressures influence the

bradycardiac effect of the DR (William et al., 2015).

Studies have demonstrated that decreases in heart rate are much greater with

facial immersion while breath-holding (Nepal et al., 2015; Andersson & Schagatay,

1998). This can be explained by the stimulation of the trigeminal nerve around the

facial and neck region. The cold sensation stimulates the afferent pathway of the

trigeminal nerve causing stimulation of the cardiac centre located in the medulla

resulting in bradycardia (Nepal et al., 2015). Apnea with face immersion producing

intense bradycardia and marked vasoconstriction can lead to lowered O2 consumption

and decreased CO2 (Andersson & Schagatay, 1998; Andersson et al., 2002). Due to

increased bradycardia, the metabolic demand for the cardiac muscle is lowered and

marked vasoconstriction leads to reduced O2 consumption by tissues, which during

apnea with cold facial immersion, results in a smaller degree of arterial haemoglobin

desaturation as compared to apnea in air (Andersson & Schagatay, 1998).

In a study by Andersson and Schagatay (1998), the level of arterial

haemoglobin desaturation observed was lower after apnea with face immersion, than

after apnea alone suggesting that O2 consumption was reduced due to a stronger DR

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elicited during apnea with face immersion. A study measuring neural and circulatory

responses during simulated diving in humans found that clear and significant

bradycardia was not evident during either facial immersion or apnea alone, suggesting

the importance of both these stimuli in eliciting “combined cardiac vagal outflow and

central sympathetic outflow” (Shamsuzzaman et al., 2014, p.77).

Whilst the DR is activated by apnea, it is significantly augmented by face

immersion in cold water in which cold-receptors in the upper facial region (forehead,

eyes, and nose) are stimulated (Gooden, 1994; Schagatay & Anderson, 1998). These

facial regions are supplied by the trigeminal nerve which when stimulated causes the

inhibition of respiration and stimulation of cardiac vagal motor neurones and

vasomotor centres (Elsner & Gooden,1983). The cardiovascular responses further

enhance the DR by reducing HR and vasoconstriction occurring during a dry BH

(Anderson, Liner, Runow & Schagatay, 2002). In particular, research indicates facial

cold receptors are more strongly innervated by immersion in water with a temperature

ranging 10 – 15 °C (Daly, 1997). Colder water temperatures 0-10 °C have

demonstrated to elicit a more pronounced bradycardiac effect, (Schagatay & Holm,

1996; Anderson et al., 2016), however lower temperatures are associated with more

physical discomfort (Manley, 1990). Water temperatures between 15 and 35°C have

been shown to have little effect (Asmussen & Kristiansson, 1968; Mukhtar & Patrick,

1986). More recently the difference between air ambient temperature and water

temperature has also been found to be an important determinant in the activation of

the DR. Diving bradycardia also develops in warm water however when the ambient

air temperature is higher and there is a marked gradient between air and water

(Schagatay, 2009).

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The DR has also been used as a laboratory procedure in experimental designs

and is also referred to as the simulated diving response. Given that the simulated DR

produces pronounced reflex bradycardia it has been used to treat paroxysmal atrial

tachycardia and has been utilised as a method to diagnose vagal dysfunction (Khurana

& Wu, 2006). Inputs from several sources including the trigeminal nerve,

chemoreceptors, arterial baroreceptors, cardiac and pulmonary receptors and higher

centres of the brain co-operate to elicit bradycardia. Relatively little is known about

the underlying mechanisms of the cold facial immersion task also known as the cold

facial test. It is thought that the trigeminal system and the brain stem are implicated

in the bradycardia response (Khurana & Wu, 2006).

It may be presumed that some of the neurobiological areas including the

chemoreceptors and baroreceptors which have been found to play an active role in

CO2 sensitivity, hypercapnia, and alkalosis, and Klein’s suffocation false alarm (SFA)

hypothesis in understanding the pathophysiology of panic may also be responsible for

the bradycardiac response in the cold facial immersion task. No research to date has

looked at whether the DR adaptation can be used to treat panic or any of the other

anxiety disorders. Given that most PD patients have respiratory abnormalities it

would be important to further explore the association between PD and

hypersensitivity to increased CO2 levels. The CO2 challenge should be considered

among the most valuable anxiogenic challenge test that can also be used as a

diagnostic tool, to identify patients with PD (Gorman et al., 1994).

During hyperventilation, there is a significant decrease in blood flow, due to

vascular constriction caused by hypocapnia. This accounts for many of the symptoms

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experienced during hyperventilation including lightheadedness, dizziness,

derealisation and anxiety (Gorman et al., 1994). In humans, the cerebral blood flow

reduction is observed to be between 5% and 15% (Edvinsson, 1982). Panic patients

have been noted to have more sympathetic stimulation in the periphery, which is

implicated by the reduction in the cerebral blood flow (Nesse et al., 1984). Reduced

cortical volume in the dorsal anterior cingulate cortex, as well as the rostral anterior

cingulate cortex, has been observed in PD patients (Asami et al., 2008). The anterior

cingulate cortex is responsible for regulating autonomic responses such as heart rate

and blood pressure, and it is involved in problem solving (Asami et al., 2008). On the

contrary, when the diving response (DR) is activated cerebral blood flow is increased

dramatically, in an attempt to conserve oxygen and ensure that the organs most

important for survival are oxygenated adequately, hence problem-solving ability may

increase. Elite divers have exhibited higher blood circulation in the brain and a more

accentuated DR (Joulia et al., 2009). Brain capillaries in divers are more dilated to

allow for increased blood flow, as a result of trained effects and prolonged exposure

to hypobaric conditions (Chavez et al., 2000).

Charles Darwin (1872) in his book the ‘Expression of Emotions in Man and

Animals’, wrote that “heart, guts and brain communicate intimately via the vagus

nerve the critical nerve involved in the expression and management of emotions in

both humans and animals”. When the mind is strongly excited, it instantly affects the

state of the viscera. Darwin described that expressions of emotions derived their

communicative value from the fact that they were outward manifestations of inner

state behaviour and that these served an advantageous purpose in natural selection

(Tooby & Cosmides, 1990). William James was strongly influenced by Darwinian

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ideas, and he proposed that emotions are simply sets of physiological changes that

result in response to emotive stimuli and that it is the perceived bodily changes that

evoke the feeling of an emotion (Friedman, 2010).

Approximately 80% of the fibres connecting the viscera to the vagus nerve are

afferent, meaning that the body communicates via sending signals to the brain through

this single direction (Martini et al., 2012). Stimulation of the vagus nerve has

important implications in inhibiting sympathetic nervous system (SNS) activity and

may enhance extinction in fear conditioning (O’Keane, Dinan, Scott & Corcoran,

2005; Porges, 2009). Noble et al. (2017) in their study found that stimulating the

vagal nerve in post-traumatic stress disorder (PTSD) rats, reduced PTSD symptoms

including re-experiencing fear, heightened anxiety, physiological arousal and social

withdrawal. Their findings suggest that vagal nerve stimulation may be an effective

adjunct to exposure therapy which may be used for PTSD and the anxiety disorders

that benefit from exposure-based treatments. In anxiety disorders such as PTSD and

PD which are characterised by more exaggerated fear and freezing responses, SNS

arousal increases metabolic output and inhibits peripheral nervous system /vagal tone

in an attempt to activate the fight or flight response. Alternative therapies that initiate

movement such as yoga and floating therapy that are thought to stimulate the vagal

nerve are becoming increasingly popular for disorders characterised by

immobilisation such as PTSD, PD and major depressive disorder (Cramer, Anheyer,

Saha & Dobos, 2018). Another alternative to stimulating the vagal nerve is using the

DR as it involves vagal-mediated activity and balances sympathetic and

parasympathetic nervous system responses in an attempt to conserve oxygen and

increase survival chances for the organism.

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FREE DIVING AND BREATH-HOLDING

Free diving, also known as breath-hold (BH) diving is the sport of diving on

one breath. It has been practiced for more than 2000 years in Greece, India, Japan,

Korea and Persia (Ferretti, 2001). Having evolved from the ancient traditions of

harvesting sponges, pearls and seafood, today, free diving is considered an extreme

sport in which competitors attempt to reach great depths on one breath without the

assistance of underwater breathing equipment. Humans are not natural breath-

holders, just like other birds and mammals and hence a lack of oxygen, even for short

periods can be detrimental. However, many diving birds, mammals (e.g., Weddell

seal) and humans have adapted to endure hypoxia or anoxia for extended periods

(Hermes-Lima & Zenteno-Savin, 2002).

Free divers are known to have exceptional breathing control, with higher brain

function being associated with a profound effect on the development of the DR

(Gooden, 1994). According to Mana (2010), free diving is able to improve the

neurovegetative system, specifically our breathing and respiratory rate, our heart and

lung function. Anecdotally, some of the benefits free divers claim they achieve from

regular free diving include mental clarity, relaxation, thoracic flexibility, and

emotional wellbeing. Free divers draw on a range of techniques to assist them to

attain greater depths underwater and both the dry training breathing techniques and

the breath-hold practice in the water stimulate the parasympathetic system and restore

the neurovegetative balance such as increased vagal tone (Christoforidi et al., 2012).

In particular, some of the breathing and relaxation techniques used in free diving have

been effective in activating the parasympathetic nervous system and slowing down

the heart rate (HR). More specifically, due to the exchanges of gases achieved by

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better breathing control, it promotes more efficacious cellular oxygenation which

extends to better functioning of the nervous system with general and deep body

revitalisation (Mana, 2010).

Extensive training of BH diving or apnea is associated with several

physiological adaptations including longer breath-holding dives, a more pronounced

diving response (DR), larger vital capacities and blunted hypocapnic response than

control participants which were non-divers (Andersson & Schagatay, 2009; Carey,

Schaefer & Alvis, 1956; Ferretti & Costa, 2003; Schagatay & Anderson, 1998). In a

more recent study, Schagatay, Johansson and Abrahamsson (2017) investigated

trained effects in 9 male Philippine Sama-Bajau divers and found that the DR was

more pronounced in divers as compared to non-divers. Although lung vital capacity

was comparable to non-divers, lung function effects were observed in divers.

Regular free diving practice brings physiological dynamism and builds

resistance to existing stress factors (Mana, 2010). Foster and Sheel (2005), stated that

healthy individuals that engage voluntarily in BH activities, display adaptations that

enable longer BH durations and a more pronounced DR. Ferretti (2001) in his study

found that trained BH divers will endure a breath-hold until PaO2 has fallen to 35

mmHg and PaCO2 has increased to 50 mmHg which is more adapted than in non BH

divers. There are also varying levels of CO2 tolerance and individual sensitivity to

CO2. Vagin and Zelenkova (2017) in their study, explored the physiological

mechanisms of hypoxia tolerance and physical endurance in free divers, basketball

players and untrained participants. The findings revealed that free divers possessed

the greatest tolerance to hypoxia and showed the highest physical work capacity

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compared to other groups in this study. Free divers were also observed to have had

the highest fall in oxygen saturation (SaO2) values and were the only group to perform

between three to eight breath-holds while still active on the cycle ergometer (Vagin &

Zelenkova, 2017). In their experiment, Baranova et al. (2016) discovered that

inhalation of 7% hypercapnic mixture led to variations in measures and magnitude of

changes of cerebral blood flow (CBF) indicating varying levels of sensitivities to

stimulus amongst participants.

Individual Determinants in Breath-Hold Diving

One area of contention is in establishing whether elite performance in BHD,

tolerance to CO2 and diminished respiratory drive under hypercapnia may be

hereditary or the result of an adaptation due to frequent short-term exposure to

hypercapnia (Walterspacher, Scholz, Tetzlaff & Sorichter, 2011). The world records

and boundaries of breath-holding and diving depths have been challenged and

“pushed further” in the last decade, exposing breath-hold divers to frequently severe

hypercapnia and hypoxic conditions (Walterspacher et al., 2011).

Ferringno et al. (1991) investigated the physiological responses to dives down

to 65 meters in 3 elite BH divers, all of whom were from the same family. Results

revealed that all three divers demonstrated marked bradycardia (20-25 beats per min)

compared to untrained controls. However, according to Ferrigno et al. (1997),

physiological observations obtained from the DR may not necessarily be the result of

physiological adaptation, but rather the expression of genetic factors (Ferrigno et al.,

1997). According to Alboni et al. (2011) studies have revealed that compared to

inexperienced divers, BH divers demonstrate more pronounced bradycardia. These

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notable differences between groups may be accounted for by the training and the

genetic differences between them.

In exploring the mechanisms of the DR, recent genetic studies suggest that the

intensity of vasoconstriction experienced during the activation of the DR is subject to

interpersonal differences. Baronova et al. (2017) in their study investigated the

genetic components of the vascular reactions in response to the DR and conducted a

genetic analysis of the polymorphisms of renin-angiotensin, kinin-bradykinin genes

and the gene β2-adrenoreceptor (ADRB2 48). They found that during the DR,

changes in blood pressure (BP) and vascular tone in participants were dependent on

their genotype. More specifically, this study found that participants with the most

pronounced peripheral vasoconstriction in response to diving had BDKRB2 (C/C),

ACE (D/D) and ADBR2 (G/G, G/A) genotypes. This study concluded that changes

experienced by participants in the vascular tone and BP were dependent on their

genotype (i.e., different combinations of alleles of the studied genes) (Baranova et al.,

2017).

Individual differences such as age and diving experience influence the extent

of DR. The diving bradycardia is pronounced in children between ages 4 and 12

months, as this may assist children in surviving through “hypoxic episodes proximal

to birth” (Lindholm & Lundgren, 2009, p. 285). With advancing age, the DR weakens

and is more pronounced in experienced and habitual BH divers than non-divers

(Lindholm & Lundgren, 2009; West et al., 2001). A study by West et al. (2001)

found that 11-14-year olds exhibited a greater reduction of HR after cold facial

immersion (CFI) as compared to adults, further stating that with advancing age, the

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extent of HR reduction weakens. This has also been confirmed in a study by Lee et

al. (2016) of elderly Korean women divers, or haenyeos, aged between 56 and 83 that

demonstrated lower mean HR with about 20% decrease rate in HR during dives as

compared to younger haenyeos in a previous study (Hong, Song, Kim & Suh, 1967)

that demonstrated reduction of 21% and 37% decrease in HR.

Psychological and physiological factors play a role in increased breath-holding

time (Andersson & Schagatay, 2009). Prolonged breath-holding not only elicits

extensive physiological changes, but also requires exceptional psychological states

and therefore breath-holding is thought to be a unique psycho-physiological state

(Steinberg, Pixa, & Doppelmayr, 2012; Schagatay, 2009). Besides physiological

capabilities, psychological factors are important aspects of BH diving, as mentally,

free divers need resilience to pain, physical exertion, withstanding extreme

environmental conditions, and coping with dangers to health and possible loss of life

(Ostrowski et al., 2012; Schagatay et al., 1999; Schagatay, van Kampen,

Emanuelsson, & Holm, 2000). Rodriguez-Zamora et al. (2014) suggest that an

interrelationship exists between psychological factors and physiological stress

experienced by synchronised swimmers during competitive events.

In trained apnea divers, duration of the easy-going phase is extended due to

training induced adaptations, while humans not trained in BH usually end apnea at the

start of the struggle phase (Steinberg et al., 2012). In the easy-phase of breath-

holding, physiological factors such as tolerance to increasing PaCO2, determines

duration of BH, while significant mental effort is necessary to maintain BH through

the discomfort of asphyxia in the struggle phase requiring motivation, stamina,

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emotion regulation and cognitive factors that includes inhibition and interoception

(Steinberg et al., 2012). Mental predispositions and psychological capacity to tolerate

the discomfort and urge to breathe strongly influences breath-holding durations in the

struggle phase (Ostrowski et al., 2012; Schagatay et al., 1999; Schagatay et al., 2012).

There is scant research on the characteristics of free divers; however, research

examining the characteristics of recreational scuba divers can provide some indication

into understanding free divers. Research indicates that the proportion of female and

males engaging in scuba diving activities is 29% and 71%, respectively (Morgan,

1987; Morgan, Lanphier, & Raglin, 1989). In the Morgan Study (1987), the average

age of both subgroups was 34 years, with the men averaging 7 years of diving

experience compared with 5 years average diving experience in women. Both

subgroups performed dives in a range of settings including fresh water, salt water,

cave, ice and shipwreck diving, with the average maximum depth being 34 m for

females and 36 m for males. Further examination of trait anxiety and mood states

indicated there were no significant differences in both trait anxiety and mood states

between males and females (Morgan, 1987; Morgan et al., 1989). There is a general

belief that recreational activities such as free diving and scuba diving can be stressful

and hence that these types of activities are characterised by high anxiety. However,

this assertion is not supported in the literature. On the contrary, it has been found that

students enrolled in beginner scuba classes have been found to report below the norm

on state and trait anxiety as measured by the State and Trait Anxiety Inventory (STAI)

(Griffiths, Steel, & Vaccaro, 1978).

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From an anxiety sensitivity (AS) perspective, panic disorder (PD) is associated

with an enduring trait-like characteristic in individuals which leads to cognitive

misappraisal of somatic symptoms as threatening (McNally, 1994; Reiss, 1991).

According to this theory and in line with the findings of Griffiths et al. (1978), it

would be expected that AS and trait anxiety would constitute characteristics that

differentiate free divers from individuals with PD. Free divers would be expected to

report low AS and trait anxiety as compared to high AS and high trait anxiety in

individuals with PD.

ADAPTIVE CHANGES DURING BREATH-HOLD AND

APNEA TRAINING

There have been numerous studies conducted on breath-holding over the

years, many of which have focused on the physiological aspects of breath-holding.

Yet despite constant improvements in the performance of elite free divers that are

capable of diving beyond depths imaginable, many questions regarding these

demonstrated performance increases are still unanswered (Steinberg, Pixa &

Dopplemayr, 2012). Indeed elite breath-hold divers are capable of such extraordinary

feats, however, the question is whether the abilities they possess are inherited or

developed through training? This section focuses on exploring the effects of short-

term and long-term breath-hold (BH) training and the adaptive changes associated

with it.

Improvements in performance and age differences between previous and

current world record holders point to the adaptive capabilities of humans, progress in

devices, training techniques, and technical progress (Ostrowski et al., 2012). There

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Stronger Diving

Response

Oxygen Conservation

Reduced Anaerobiosis

Reduced Chemo-

sensitivity

Reduced Respiration

Rate

Increased tolerance to

hypoxia

have been multiple studies (Adir et al., 2004, 2005; Andersson & Schagatay, 2009;

Breskovic et al., 2010; Delahoche et al., 2005; Engan et al., 2011; Gole et al., 2009;

Lemaitre et al., 2009; Lemaitre et al., 2010; Mourot et al., 2009; Schagatay et al.,

1999; Schagatay et al., 2000; Steinback et al., 2010; Vigetun – Haughey et al., 2015)

investigating the short-term and long-term training effects of the DR, with many

attributing short-term training effects to psychological and physiological factors. A

review by Konstantinidou and Chairopoulou (2017), reported several long-term

physiological adaptations resulting from apnea training effects. Figure 3 depicts how

long term apnea training may alter the diving response (DR).

Figure 3. Long-term training effects of the Diving Response (Konstandinou and

Chairopoulou, 2017).

Individuals that engaged in regular breath-hold training (BHT) had a stronger

DR, larger lungs and vital capacities, stronger respiratory muscles, haematological

variations such as an elevated haematocrit and haemoglobin, and reduced blood

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acidosis. Moreover, the apnea-trained individuals were observed to have reduced

chemosensitivity to hypoxia and hypocapnia, reduced respiratory drive and increased

blood circulation to the brain. Konstantinidou and Chairopoulou (2017), suggest that

most researchers, attribute the variations in physiological responses observed in apnea

trained individuals as compared to non-apnea trained individuals, to hypoxic

conditioning and the DR. Figure 4 depicts the characteristics and responses exhibited

by apnea trained individuals that may account for the increased tolerance to hypoxia

and potentially for their increased aerobic and anaerobic performance.

Figure 4. Long-term physiological adaptations in apnea-conditioned individuals

(Konstandinou and Chairopoulou, 2017).

Nevertheless, the mechanisms behind these adaptations have not yet been

completely clarified, and hence it is recommended that future research should clarify

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the physiological mechanisms involved that lead to altered responses to hypoxia

between apnea-trained and non-apnea trained individuals (Konstandinou &

Chairopoulou, 2017).

According to Tipton (2016), the most common questions regarding adaptation

includes, “how long does it take”, and more importantly, “how long does it last?” (p.

10). Two techniques are commonly used in inducing adaptations; the first being

repeated achievement of a constant physiological strain (e.g., deep body temperature,

heart level, level of exertion) or repeated exposure to a constant stimuli, while the

second aims to maintain the stimulus to adapt and delivers more effective

physiological adaptation (Taylor, 2014). Whilst the DR is involuntary, Schagatay and

Andersson (1998) suggest that the DR can be trained and it can have positive effects

on both heart rate reduction and apnoeic duration.

It has been well established in the literature that BH divers have more of a

pronounced DR. Coastalat et al. (2016) attributed this to simultaneous shifts in both

cardiac and peripheral hemodynamics taking place at the halfway point of the breath-

hold as measured by kinetics analysis. Structural changes have also been identified in

the heart, as evidenced by an increase in the size of heart chambers, resultant from

training effects and cardiovascular adaptive changes (Zelenkova & Chomahidze,

2016). In a study investigating cardiac autonomic activity in free diving (FD)

athletes, Christoforidi et al. (2012) revealed that when compared to an untrained

control group, free divers exhibited higher sympathetic and enhanced cardiac

parasympathetic tone four days after the last BH dive. This was the first study to

show that as a result of exercise training and repeated exposure to FD stimulus, the

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vagal tone and resting cardiac autonomic activity is significantly higher in FD

athletes. There is however a gap in the literature exploring long-term cardiac

autonomic adaptations in free divers.

Physical and apnea training are both vital components of active diving

performance. A study by Schagatay et al. (2000) demonstrated that of these two

modes of training, frequent exposure and performance of apnea is better at assisting in

increasing BH time by delaying the physiological breaking point and enhancing

bradycardia. Schagatay et al. (2000) demonstrated that two weeks of daily apnoeic

training increased both the DR and the duration of BH. In non-divers, even short term

repetitive breath-hold training (BHT) has demonstrated a positive effect on BH

duration without changing the magnitude of the DR, nor its oxygen-conserving effect

(Schagatay, van Kampen & Andersson, 1999). Adaptations of the cardiovascular

system to physical training results in increased O2 delivery to the muscles enabling

intense aerobic physical exercise, while adaptive changes are also exhibited at the

muscular level allowing increased extraction of O2 (Schagatay et al., 2000).

Short-term and long-term apnea training and physical training have

demonstrated adaptations to diving conditions and augmentation of arterial

compliance function. There are two major functions of the arterial system; the first is

the delivery of nutrients and oxygenated blood to organs and the second function is to

act as a buffer in softening pulsations from the heart to allow continuous capillary

blood flow (Steppan, Barodka, Berkowitz & Nyhan, 2011). Arterial compliance can

be defined as the relationship between changes in vessel dimension for a given change

in pressure or distending pressure (Anderson, 2006; Kinlay et al., 2001). There are

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several factors that can alter arterial circulation after a dive such as cold water

immersion and hyperoxic exposure, (Gole, Louge & Boussuges, 2007).

Biological aging and atherosclerosis are two contributing factors towards

arterial stiffness that are typically found in pathological conditions that include

diabetes, chronic kidney disease, isolated systolic hypertension and atherosclerosis

(London & Pannier, 2010). Tanaka et al. (2016) investigated the effects of chronic

diving manoeuvres on arterial elasticity, structure and function of Japanese female

pearl divers (Ama divers). The Ama divers were found to possess significantly lower

arterial stiffness and values in indices of arterial wave reflection, and higher

subendocardial perfusion as compared to non-Ama, which point to lower cardiac

activity. Based on the results of this study, it seems that regular diving manoeuvres

are associated with favourable adaptations in arterial elasticity, wave reflection, and

reduced risks of cardiovascular based diseases (Tanaka et al., 2016).

Vascular modifications induced as a result of physical training are dependent

on the training modalities (Gole et al., 2007). Increases in central arterial compliance

have been observed as a result of regular endurance exercise, which is attributed to

changes in vascular endothelium-derived factors (Cameron & Dart, 1994; Tanaka,

Dinenno & Monahan, 2000; Hayashi, Sugawara & Komine, 2005). According to

Gole et al. (2007), previous studies have shown that acute endothelial alteration can

be induced after a single dive. The endothelium plays a crucial role in maintaining

vascular homeostasis by achieving a balance between endothelium-derived

contracting and relaxing factors, and also through the release of paracrine factors that

act on platelets, inflammatory cells and the vessel walls (Anderson, 2006).

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Previous research has demonstrated a decrease in plasma concentrations of

endothelin-1 (vasoconstrictor peptide) produced by vascular endothelial cells in

endurance-trained men (Otsuki, Maeda & Lemitsu, 2007; Maeda, Miyauchi &

Kakiyama, 2001). Vascular endothelial function is important for the growth and

maintenance of the health of blood vessels, and for the regulation of immune

responses (Gole, Lounge & Boussuges, 2007). Endurance training has also been

associated with an increase in concentrations of nitric oxide, an important cellular

molecule that modulates vascular tone and reactivity (Anderson, 2006; Assumpção et

al., 2008). Nitric oxide is the product of synthesis from L-arginine and the enzyme

nitric oxide synthase (NOS) which has multiple functions such as insulin secretion

and vascular endothelial function by keeping the vessels flexible and dilated in order

to boost blood flow and regulate blood pressure. Furthermore, its functions extend to

protecting the arterial walls of blood vessels and inhibiting white cell and platelet

activation from adhering to the lining of the blood vessels, hence reducing the risk of

plaque development (Anderson, 2006; Assumpção et al., 2008; Kingwell, Sherrard &

Jennings, 1997; Maeda, Miyauchi & Kakiyama, 2001).

One of the benefits of training effects associated with repeated apneas is

prolonged breath-holding time as a result of blunted hypercapnic response (Andersson

& Schagatay, 2009; Roecker et al., 2014; Walterspacher et al., 2011). Grassi et al.

(1994), observed that divers exhibited a diminished ventilatory response to

hypercapnia. The hypercapnic ventilatory response curve measures CO2 sensitivity

(Andersson & Schagatay, 2009). In a variety of athletes, including elite endurance

and BH athletes, reduced chemosensitivity to progressive hypoxia and hypercapnia

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has been noted (Foster & Sheel, 2005). According to Andersson and Schagatay

(2009) reduced sensitivity to CO2 observed in divers is not a trait that is genetically

inherited; instead, it is caused by training of BH diving. Studies investigating

instructors working at a submarine escape training tank have provided evidence to

support this (Schaefer, 1965).

Ferretti and Costa (2003) postulated that the prolonged breath-holding time

demonstrated by trained divers may be due to a displaced threshold and reduced

sensitivity to CO2 as a result of frequent exposures to hypercapnia leading to a

reduced urge to breathe. Trained breath-hold (BH) divers will endure the human

diving response during a BH until PaO2 has fallen to 35 mmHg and PaCO2 has

increased to 50 mmHg whereas non-divers when engaging in BH activity, can

generally reduce their arterial partial pressure of oxygen (PaO2) as low as 60 mmHg

and their partial pressure of carbon dioxide (PaCO2) as high as 45 mmHg (Ferretti et

al., 2001). Tolerance to CO2 has also been demonstrated by trained synchronized

swimmers who can sustain a normoxic BH for approximately twice the BH time as

compared to non-diving controls (Bjurstrom & Schoene, 1987).

Studies have shown that only long-term exposures to hypercapnia results in

blunted hypercapnic ventilatory response as evidenced by trained breath-hold divers

(Costalat et al., 2014; Delapille et al., 2001; Grassi et al., 1994; Ivancev et al., 2007),

Ama divers (Masuda et al., 1982), and underwater hockey players (Davis et al., 1987),

while short-term training has no effect (Andersson & Schagatay, 2009). A study by

Schagatay and Andersson (2009) investigating whether short-term training reduces

the hypercapnic ventilatory response found that reduced CO2 sensitivity was not a

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contributing factor to the observed short-term apnea training effects. It has thus been

predicted that repeated and prolonged bouts of intermittent hypoxia/hypercapnia may

reset the chemosensitivities for both central and peripheral chemoreceptors, and

enhance chemoresponsiveness to hypoxia (Costalat et al., 2014). The time course for

the development of this adaptation to BH, that includes how many and how frequent

these exposures are needed has not yet been investigated (Andersson & Schagatay,

2009).

In a study by Andersson and Schagatay (2009), prolonged breath-holding time

observed as a result of short-term apnea training was attributed to changes in

hematocrit and hemoglobin concentrations, suggesting that changes in hematocrit and

hemoglobin concentration levels caused by splenic contractions could contribute to

the short-term training effects observed further stating that the changes in hematocrit

and hemoglobin concentration levels lead to a delay of the physiological breaking

point of apnea (Andersson & Schagatay, 2009; Schagatay et al, 2001; Bakovic et al.,

2003).

A study by Nygren-Bonnier et al. (2007a) investigated whether 6 weeks

training in glossopharyngeal pistoning, (a technique used in free diving with an aim to

piston more air into the lungs than able with maximum inspiratory capacity) would

increase vital capacity in healthy women. The researchers found that vital capacity

increased in the training group by 0.13 litres and the increase in vital capacity

persisted for twelve weeks post-training. The mean vital capacity increase in the

training group was by 3% after the six week training period (Nygren-Bonnier et al.,

2007a). Divers that have undergone long-term specialized training in BH have also

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demonstrated increases in the respiratory system’s functional parameters, which

during prolonged BH diving, assist in delaying respiratory muscle fatigue (Nygren-

Bonnier et al., 2007b). Bavis et al. (2007) draw on hypoxia research to suggest that

the human respiratory of BH divers has plasticity on several levels, including

increased lung capacity, diaphragmatic changes and biochemical shifts.

Joulia et al. (2009) postulated that apnea training provides hypoxic

preconditioning and hence it may be potentially used to optimise hypoxia protection

in various conditions such as hypobaric hypoxia exposure, chronic obstructive

pulmonary lung disease (COPD), and asthma. One may speculate, that this may be

further extended to respiratory abnormalities that involve a higher sensitivity to CO2,

including PD and sleep apnea. The exact underlying mechanism explaining increases

in vital capacity is undetermined. However, this phenomenon may be the result of an

increase in pulmonary compliance as a result of stretching experienced, thereby

allowing inspiratory muscles to inhale to a larger lung volume (Kang, 2000).

Longitudinal changes observed in divers by Carey et al. (1956) led to the

suggestion that training may be responsible for increases in lung volumes (as cited in

Schagatay et al., 2012). Frequent exposure to swimming or high altitudes may

account for an increase in lung volume capacities; however, this effect has not been

demonstrated in other sports (Gaultier & Crapo, 1997). Specific training protocols

and complex training programs developed by elite divers have also demonstrated

benefits in increasing lung volume (Schagatay et al., 2012). Long-term exercise alone

is not sufficient to enhance lung and respiratory capacities and requires underwater

exercise training where the lungs are exposed to greater water pressure (Lee et al.,

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2016). A study by Bachman and Hovarth (1968) demonstrated that participants that

undertook training as part of a four month swimming program demonstrated increased

lung and respiratory capacities compared to participants trained in a four month

wrestling program. According to Schagatay et al. (2000) similar to the concept of

specificity, training effects that are expressed are training-specific and dependent on

the type of training that was performed.

Breath-hold training (BHT) has also shown to induce adaptive metabolic

responses to repetitive periods of hypoxaemia. A longitudinal study by Joulia et al.

(2003) investigating the benefits of a 3-month training program of dynamic apnea

found that as a result of training, static apnea lengthened in duration along with

accentuated bradycardia. A decrease was also found in venous blood pH and an

increase in lactic acid concentration post-apnea. The study also showed the training

supressed oxidative stress following both static and dynamic apnea, increased

tolerance to hypoxemia independent of any genetic factor. According to Joulia et al.

(2003), exposure to intermittent asphyxia even in the short-term causes a sympathetic

activation that continues after the removal of the chemical stimuli, serving as an

explanation as to why the DR was accentuated after BHT. Results from this study

suggest that exposure to intermittent asphyxia during BHT enhances the mechanisms

protecting against membrane lipid peroxidation and reduced oxidative stress. The

adaptive mechanisms responsible for the protection of tissues against the harmful

effects of reactive oxygen species at rest requires prolonged exposures to hypoxemia.

The findings of Joulia et al. (2002), suggest that the tolerance to extended apnea

duration can be explained by post-training effects resulting in the reduction of lethal

cellular consequences of blood acidosis and oxygen free radicals production.

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Plasticity in the neural control of breathing is an important biological strategy

used to preserve optimal breathing control (Fuller, 2017). One can learn quickly to

voluntarily use their diaphragm and can readily achieve a habitual pattern of

diaphragmatic breathing (Demoule et al., 2008). Metaplasticity changes have

occurred as a result of training dependent plasticity on many levels including

corticospinal changes (Raux, 2007). New discoveries which have included the impact

of intermittent hypoxia on non-respiratory alpha motor neurons involved limb and

other motor functions (Dale et al., 2014) derived from the study of respiratory motor

plasticity has inspired new therapeutic strategies to treat motor deficits in multiple

clinical disorders that compromise movement.

Trained effects have also been evidenced in physiological changes in winter

swimmers. Whole body immersion in cold water also activates the DR and is

associated with reduced oxidative stress (Lubkowska et al., 2013; Mila-

Kierzenkowska et al., 2009), decreased levels of lipid peroxidation (Wozniak et al.,

2013), and increased stimulation of antioxidant capacity (Lubkowska,et al., 2013;

Sutkowy, Wozniak, Boraczynski, Mila- Kierzenkowska, Boraczynski, 2015). Cold

water exposure has been considered for centuries a traditional form of body

hardening, which is considered to build up resistance to infections and illness (Siems,

Brenke, Sommerburg & Grune, 1999).

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Clinical Implications of the Diving Response

While changes in physiology produced by activation of the DR has been

extensively explored and investigated, its clinical applications and implications need

to be further explored. Clinically, the breath-hold (BH) task has frequently been used

as a measure of distress (in) tolerance and self-regulatory strength (Steinberg, Pixa &

Doppelmayr, 2012; Sutterlin et al., 2013). BH duration in this task is correlated with

performance on neurobehavioural tests that quantify an individual’s ability in

maintaining emotional and behavioural control (Sutterlin et al., 2013). It is possible

that higher cognitive-control networks are involved in inhibiting the respiratory urge

to breathe during BH that includes maintaining stable emotional states, sustaining

motivation to reach BH goal while integrating unpleasant urges to breathe (Steinberg

et al., 2012).

Breathing irregularity is a common symptom in patients suffering from panic

disorder (PD) and other anxiety disorders. For some time now, it has been known that

PD symptoms such as numbness, tingling sensations, dizziness, muscle hypertonicity

could be brought on by hyperventilation and that these symptoms could be attributed

to hypocapnia and respiratory alkalosis (Courtney, 2009). Breathing techniques are

becoming increasingly popular and it has been found to be effective in regulating

mental and emotional states. In many ways, the physiological adaptations

experienced whilst free diving are the opposite of those triggered during a panic

attack. Breathing techniques used in free diving have been effective in activating the

parasympathetic system and slowing down the HR. Elevated HR is a common

symptom in anxiety and panic states and it has been established that effective

reductions in HR can provide substantial acute symptomatic relief for persons in such

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states (Meuret et al., 2003). Given that the key factors in both free diving and panic

attacks (PAs) are mental and breathing control, it is plausible that the diaphragmatic

breathing techniques already used to treat panic may benefit from drawing on the

physiological adaptions and techniques used in the sport of free diving.

A study by Yadav, Sule and Palekar (2017), which compared the effectiveness

of airflow and facial cooling stimulation versus controlled breathing exercise (i.e.,

diaphragmatic exercises) to reduce dyspnea in patients with COPD, reported that

facial cooling and airflow stimulation were more effective in relieving dyspnea.

Shortness of breathing or dyspnea is characterized by impaired breathing that requires

increased effort for breathing against increased resistance and in 85% of cases is the

result of asthma, pneumonia, COPD, congestive heart failure, or psychogenic causes

(i.e., PD, anxiety) (Yadav et al., 2017). Evidence suggests that the cold receptors

located in the upper airway may be responsible for the reduced breathlessness as a

result of facial cooling (Yadav et al., 2017). By detecting changes in temperature,

cold receptors that are innervated with vagus nerve are able to monitor changes of

flow in the upper airway (Yadav et al., 2017).

The DR has also been used in the treatment of paroxysmal supraventricular

tachycardia (PVST). While the clinical application of the DR in managing PVST has

gained acceptance in the medical community, evidence in the literature regarding its

effectiveness is limited and results between studies vary greatly (Lemaitre & Schaller,

2015; Smith, Morgans, McD Taylor & Cameron, 2012). However, in the Smith et al.

(2012) review, ten studies demonstrated that the human diving reflex is an effective

technique used to treat PVST. The reflex bradycardic response elicited by the DR and

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accompanying an increase in myocardial refractoriness “can be harnessed in a simple

and non-invasive manoeuvre for the termination of paroxysmal supraventricular

tachycardia (PVST)” (Smith et al., 2012, p. 611). The DR has also been utilized as a

therapeutic procedure for children, in order to interrupt PVST after catheter ablation

introduction, through facial immersion and is effective in 60-80% of cases (Mathew,

1981, as cited in Alboni et al., 2011). It can be difficult to distinguish between PVST

and PAs as both are characterised by similar clinical symptoms, specifically both

PVST and PAs present with rapid heart rate (Frommeyer, Eckardt & Breithardt,

2013).

Summary

The DR is an oxygen conserving adaptation allowing humans to hold their

breath that far beyond normal times. Training with breath-holding and the DR have

led elite free divers to achieve greater CO2 tolerance when breath–holding. Much has

yet to be determined about both the DR, its complex mechanisms involved, and the

short term and long term benefits of BHT. Future studies are needed to determine

whether the present physiological observations of the DR and adaptive training effects

can be useful as a behavioural therapeutic approach in treating or managing

psychological and physiological clinical conditions such as PD, COPD, asthma and

sleep apnea, which are frequently associated with respiratory irregularities. Further

investigation is needed in exploring the benefits of BHT and the treatment of PD.

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Chapter 3

Respiration and Panic Disorder

RESPIRATION

Respiration is vital for the survival of the human organism, with every organ

system relying on proper gas exchange (Wilhelm, et al., 2001). Respiration is an

important consideration when studying PD as air hunger, dyspnea, and rapid

breathing are common during PAs (Papp, Klein, & Gorman, 1993). Furthermore,

irregularities and abnormalities in breathing are well documented in studies of PD and

are important in understanding the pathophysiology of PD (Gorman et al., 1984;

Griez, Lousberg, Van den Hout & Van der Molen, 1987; Woods et al., 1986).

The respiratory system provides humans with the fundamental ability to

breathe, that is, to inhale and exhale air from the lungs. Breathing, also referred to as

respiration, is fundamental to our survival. Whilst we possess to some extent the

ability to consciously control the rate of breathing, it is a function that is instinctive

and occurs automatically, without us having to think about it (Rogers, 2010).

However, as simple as it is for us to inhale and exhale, respiration is a process

supported by a number of complex functions including muscular movements, and

cellular and chemical processes. Like any function of the body, breathing patterns

may become dysfunctional or disturbed because of stress or illness (Rogers, 2010).

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The term respiration includes two integrated processes including external

respiration and internal respiration. External respiration refers to all the processes

involved in the exchange of O2 and CO2 between the body’s interstitial fluids and the

external environment (Martini et al., 2012). The main purpose of external respiration

is to meet the respiratory demands of cells. Internal respiration is the absorption of O2

and the release of CO2 by those cells (Martini et al., 2012). Generally, the primary

function of the respiratory system and normal breathing is to provide O2 for the

production of energy, maintain balanced blood pH levels, and a balance of CO2 / O2,

for normal body functioning. An individual’s respiratory rate is defined as the

number of breaths they take each minute. The normal respiratory rate of a healthy

adult at rest ranges from 12 to 18 breaths each minute, which is roughly one breath for

every four heartbeats. Children breathe at a more rapid rate, approximately 18 – 20

breaths per minute (Martini et al., 2012).

The respiratory system also works closely with the brain and the central

nervous system. Both the diaphragm and chest muscles are stimulated by neurons

that connect to the brain regions, the pons and medulla oblongata. Both these regions

are intimately involved in the control of autonomic nervous activity and hence

involved in the regulation of internal organs in the absence of conscious recognition

or effort (Rogers, 2010). The most important input into the respiratory pattern

generator comes from chemoreceptors that sense O2 and CO2. Under normal

conditions, ventilation is primarily regulated by CO2 levels rather than O2. It is when

oxygen becomes sufficiently low, in the case of lung disease or high altitude, that

breathing is strongly stimulated and respiration increased. The peripheral

chemoreceptors in the aortic and carotid bodies respond principally to a decrease in

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blood oxygen. During hypoxia, the chemoreceptors also respond to the increased

acidity that results from an increase in CO2 (water and carbon dioxide combine to

form bicarbonate and hydrogen ions). Afferent fibres from peripheral chemoreceptors

travel in the glossopharyngeal and vagus nerves and communicate with neurons in the

DRG (Kandel, Schwartz, Jessell, Siegelbaum, & Hudspeth, 2013).

Central chemoreceptors in the brain stem respond to the decrease in the pH

induced by an increase in CO2 (hypercapnia) but do not respond to hypoxia.

Serotonergic neurons are central chemoreceptors that are activated and located here

due to their sensitivity to acidosis, and ability to sense hypercapnia in the blood. The

reflex control of breathing can be modified behaviourally by the cortex, which

receives information on respiratory movements and is able to alter ventilation by

sending signals to the bulbopontine respiratory neurons and to spinal motor neurons

(Feldman, 2011).

Respiratory sensations are affected both by respiratory movements and by

changes in chemoreceptor activity. Sensations increase with ventilation, particularly

with greater respiratory efforts per breath and also grow as the arterial PaCO2 rises.

This behavioural control which might act to modify ventilation and breathing patterns

to minimise respiratory sensations could help achieve an optimum compromise

between ventilation and PaCO2 (Cherniack, Lavietes, Tiersky & Natelson, 2001).

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Breathing and Chemosensitivity

The respiratory system’s basic functions are to transport O2 to the organs of

the body and to remove CO2 which is the waste product in cellular metabolism.

Although considered a waste product it plays a crucial role in maintaining acid-base

homeostasis within the internal milieu of the body (Wilhelm et al., 2001). Lung

ventilation which is determined by the rate and depth of breathing in humans is

largely dependent on the partial pressure of CO2 at normal levels of the partial

pressure of oxygen (PaO2) (>100 mmHg). When PaO2 drops to very low values

(<50mmHg) breathing is stimulated directly and is in turn more sensitive to an

increase in PaCO2 (Kandel et al., 2013).

To maintain homeostasis, physiological systems are subject to a number of

chemosensory feedback mechanisms. While O2 detection is taken care of by the

peripheral chemoreceptors, CO2 pH-sensitive chemoreceptors are found in the carotid

bodies, and central chemoreceptors (CCRS) in the brain (Lopez & Garcia, 2007).

Respiratory chemosensitivity enables the brain to detect changes in CO2 and alter

physiological systems to regulate its levels within tightly controlled parameters

(Huckstepp & Dale, 2011). Most of the sensitive CO2 cells are located in the brain,

whilst a smaller amount is found in the carotid bodies (Peers & Buckler, 1995). The

carotid body chemoreceptor cells are the sensory receptors responsible for hypoxia,

hypercapnia and acidosis detection (Gonzalez, Almaraz, Obeso & Rigual, 1994; Peers

& Buckler, 1995). CO2/pH signals are related to the blood and its acid-base status

and reflect the adequacy of breathing to metabolism (Lopez & Garcia, 2007).

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PaCO2 remains constant during physical exercise, and from well below to

above sea level until prolonged periods of time are spent there or extreme altitudes are

reached (e.g., a height greater than 762 metres). However, an increase in PaCO2 by

just 1 mm Hg causes a 20-30% increase in ventilation (Feldman, Mitchell, & Nattie,

2003) and increasing inspired CO2 to 4% increases ventilation by 177% (Haldane &

Priestley, 1905).

There are numerous physiological reflexes to protect against hypercapnia,

which can be a life-threatening condition that leads to dangerous changes in pH levels

and increased potential risk of asphyxiation. Better alveolar gas exchange may

counteract the effects of CO2 and improve with vasolidation and autoregulated organs

(i.e., the brain and kidney). Renal output alters when blood CO2 is high, which in turn

conserves bicarbonate ions which act as a buffer for pH changes caused by

hypercapnia (Huckstepp & Dale, 2011). Arousal from sleep and increased vigilance

are common responses to elevated CO2 ( Buchanana & Richerson, 2010; Haxhiu,

Toentino-Silva, Pete, Kc & Mack, 2001; Johnson et al., 2005; Williams et al., 2007)

that either ventilation is insufficient or that there is a dangerous build-up of CO2 that

has resulted. According to Papp, Klein and Gorman (1993), the association of

fear/anxiety to hypercapnia causes us to avoid or exit room areas where CO2 levels

exceed survivable limits.

Central chemoreceptors are found in the ventrolateral medulla, the nucleus of

the solitary tract; the ventral respiratory group, the locus coeruleus (LC), the caudal

medullary raphé; and the fastigial nucleus of the cerebellum (Nattie, 1999). Central

chemoreceptors in the medulla control ventilatory motor output to maintain normal

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blood CO2. Serotonergic neurons within the raphe nuclei of the medulla may play

this role by increasing the firing rate of the motor neurons when pH decreases because

of an increase in PaCO2. Serotonergic neurons are closely associated with large

arteries in the ventral medulla so they are able to detect local changes in PaCO2

(Kandel et al., 2013).

The level of respiratory chemosensitivity varies with developmental age,

(Putnam et al., 2005) and once fully established it remains constant throughout the

lifespan, at least in humans (Browne et al., 2003). Once in the extracellular fluid, CO2

combines with water facilitated by carbonic anhydrase (CA) to produce bicarbonate

ions and protons resulting in three possible acting chemosensory signals CO2, and

hydrogen (H+). For a number of years, the consensus was that CO2 is detected

entirely via its proxy, pH (Loeschcke, 1982). The effects of pH were initially deemed

as extracellular, although now changes in intracellular pH (pHi) are known to be

important. Although the term CO2 chemosensitivity commonly refers to the detection

of pH, it does not exclude other potential signalling molecules, the involvement of

direct detection of CO2 or has only recently gained attention. Different

chemosensitive cells respond to different stimuli consequently due to the

simultaneous adjustment of PaCO2 and pH (Filosa et al., 2002; Hartzler et al. 2008;

Huckstepp, Eason, Sachdev & Dale, 2010; Huckstepp, id Bihi et al., 2010; Mulkey et

al., 2004; Wang et al., 2002). Huckstepp and Dale (2011) emphasised the importance

of having a universal language in the cardiorespiratory physiology field to distinguish

between pH chemosensitivity, bicarbonate chemosensitivity and CO2

chemosensitivity as different chemosensitive cells respond accordingly to different

stimuli.

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Although modern neuroscience is making some advances, the identity of the

primary sensory cells constituting central chemoreceptors and of their neuronal

networks remain elusive. Neurons from many brain regions are excited or inhibited

by CO2/pH changes in vitro, which is in a controlled experimental environment rather

than within a living organism or natural setting. Hence it has been difficult to link in

vitro neuronal chemosensitivity to chemoreception in vivo, where investigations are

carried out within a living organism or a natural environment. Furthermore, it is

considered that central chemoreceptor locations are difficult to study, as they may

also contain neurons with multiple functions that are not distinct from chemosensitive

ones in their morphological or functional properties (Huckstepp & Dale 2011).

Quintero, Putnam and Cortovez (2018) in their study present an innovative ionic

model that reproduces electrophysiological activity of CO2/H+ sensitive neurons

located in the LC to study intrinsic chemosensitivity. Their findings highlight the

potential to study altered chemosensitivity in a variety of disorders including PD.

PHYSIOLOGICAL ABNORMALITIES AND

DISTURBANCES IN PANIC DISORDER

A number of environmental stressors including emotions, posture, alcohol,

medications, weather and chemicals can disrupt normal breathing patterns. The most

obvious symptom is usually the inability to breathe through the nose, comfortably,

with the mouth closed. Hyperventilation is characterised as a form of mouth

breathing. In consequence, the body’s response to hyperventilation is to restrict

breathing, by increasing mucus secretions, inducing swelling in the nasal passages,

tonsils and adenoids and result in spasm of the smooth muscle rings of the bronchi.

Professor Buteyko infers that mouth breathing and hyperventilation can lead to a

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number of health problems including asthma, chronic bronchitis, tonsilitis, sinusitis,

rhinitis, and nasal polyps (Adelola, Oosthuiven & Fenton, 2013).

People who hyperventilate rapidly respond to any decrease in levels of CO2

with increased respiration. Subsequently, levels of CO2 are further depleted and

increase respiratory symptoms. Disturbed breathing is often felt in the upper chest

with overuse of the secondary muscles of respiration. Rapid upper chest breathing is

typically observed during hyperventilation. Individuals who experience physical

exertion during exercise report dizziness, palpitations, breathlessness, chest tightness,

sudden fatigue, and many other symptoms, as a consequence of over breathing.

Increased lactic acid production not only affects their fitness levels but increases

hyperventilation. Low levels of CO2 makes our nervous system more excitable.

Brain wave patterns alter reflecting low uptake of O2 as a result of the increased CO2

levels (Martini et al., 2012). In summary, hyperventilation which is characterised by

a feeling of suffocation is usually superseded by the need to maintain blood gas

homeostasis, as even a small increase in CO2 produces severe air hunger or dyspnea.

The respiratory control system is a fascinating example of a brain stem pattern

that must be sufficiently stable to ensure survival yet flexible enough to accommodate

a wide variety of adaptations (Kandel et al., 2013; Davies & Moores, 2003). The

brainstem plays a crucial role in regulating homeostatic functions associated with PAs

(i.e., chemoreception, cardio-respiratory control) (Gorman et al., 2000; Perna et al.,

2014).

Neuroimaging studies conducted with PD patients have demonstrated that

homeostatic pH disturbances play a role in panic physiology (Vollmer, Strawn, &

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Sah, 2015). The nervous system’s function is to adapt and produce flexible

behavioural responses to a changing environment. The brain’s highly adaptive

defensive system reacts to threatening stimuli (e.g., predator, aversive stimulus)

through generating rapid autonomic and behavioural responses (Maren, 2009). These

behaviours are essential to survival and include securing food, shelter, water and most

importantly, defending against immediate and perceived threats (Maren, 2009).

Evidence suggests that expected PAs are triggered in response to external

triggers also known as exteroceptive threats (e.g., elevators, shopping malls). While,

interoceptive threats such as an imbalance of acid-base and related pH chemosensory

mechanisms are amongst some of the most significant internal homeostatic triggers

responsible for the pathogenesis of spontaneous PAs (Vollmer et al., 2015). Acid-

sensitivity serves differing functions (e.g., respiration, arousal, emotions) and is

present across a range of brain regions that detects changes/disturbances in brain pH

homeostasis, and depending on the level of threat, this system triggers a variety of

“primal” responses (e.g., breathlessness, panic) (Esquivel et al., 2009; Griez, et al.,

2007; Liotti, et al., 2001).

Respiratory sensations may also be affected by personality traits. Eysenck et

al. (2007), proposed that the state of anxiety alters the executive functioning, which

perpetuates and reinforces the appraisal of threat by the anxiety sufferer, thereby

maintaining the reduced inhibitory functioning in the pre-frontal cortex (PFC) region.

According to Cherniack et al. (2001) individuals who vary with psychological

characteristics like anxiety differ in the intensity of respiratory sensations (i.e., a

person with intensifying anxiety experiences dyspnea which leads to increased

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respiratory efforts). This appears to be in line with previous research (Pain, Biddle &

Tiller, 1989; Rushford, Tiller & Pain, 1989) postulating that PD may be inherently

linked to an unstable ANS mediated by cognitive distress. Pain et al. (1989) explain

the respiratory abnormalities found in PD, as adaptive and aimed at managing a

hypersensitive CO2 chemoreceptor system. Known common panicogens, for

example, CO2 and lactate stimulate the respiratory system by causing hyperventilation

and inducing panic symptoms. Catastrophic misinterpretations and misattributions

(i.e., bodily sensations and loss of control) may contribute to the exaggeration of

panic symptoms and contribute to the maintenance of PD (Pain et al., 1989).

Panic Disorder and hypersensitivity to Carbon Dioxide

Respiratory abnormalities are a physiological marker for PD (Hegel &

Ferguson, 1997; Holt & Andrews, 1998; Rapee, Brown, Antony & Barlow, 1992, Van

den Hout, et al., 1992; Wilhelm et al., 2001). Patients with PAs have been repeatedly

observed to have a vulnerability to CO2 inhalation (Bellodi & Perna, 1998; Freire &

Nardi, 2012; Gorman et al., 1984, 1989; Griez et al., 1990; Nardi et al., 1999, 2000;

Perna et al., 1995). Hypersensitivity to inhaled CO2 is one of the common

manifestations of these respiratory disturbances. Among some of the important

findings are reduced arterial and end-tidal CO2 level at rest (Papp, Martinez, Klein,

Coplan & Gorman, 1995; Papp et al., 1989). Moreover increased variability in tidal

volume and/or minute ventilation was observed in participants while awake in the

laboratory (Gorman et al., 1988; Papp et al., 1993) while asleep in the laboratory

(Stein et al., 1995) and asleep at home (Martinez et al., 1995). Other findings here

included, minute ventilation during PAs experienced in a laboratory setting (Goetz et

al., 1993), exaggerated brain blood flow (Gibbs, 1992) endogenous lactate responses

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to room air hyperventilation (Dager et al., 1995) and hypersensitivity to the effects of

inhaled CO2 (Battaglia & Perna, 1995; Gorman et al., 1994; Griez et al., 1987;

Sanderson & Wetzler, 1990). Papp et al. (1995) demonstrated in their study that

panic individuals exhibited irregularities in respiratory rhythms as characterised by

higher variance and lower correlations in respiratory rate and tidal volume as

compared to normal controls.

According to CO2 hypersensitivity theory of panic, when respiratory control

nuclei are stimulated during CO2 inhalation, dyspnea triggers a series of autonomic

arousal symptoms. Other respiratory challenges commonly used in laboratory

settings that induce panic include lactate, cholecystokinin (CCK) and caffeine (Papp

et al., 1992). Some studies have found that patients with PD have significant

physiological variations in response to breathing CO2, compared to normal controls

(Fishman, 1994; Gorman et al., 1988; Perna, Cocchi, Bertani, Arancio & Bellodi,

1995). Pain et al. (1988) found in their study that first-degree relatives of patients

with PD who are themselves free of PAs nevertheless have heightened anxiety in

response to the CO2 challenge, suggesting that the abnormal CO2 response could be a

genetic trait phenomenon. Gorman et al. (1997) established in their study that CO2

sensitivity in patients with PD can be reduced by anti-panic treatment such as

antidepressant medication.

Interestingly Briggs, Stretch and Brandon (1993) identified the respiratory

subtype of PD as characterised by PD sufferers with prominent respiratory symptoms.

Kircanski et al. (2009) in their theoretical review use Ley’s classification criteria to

identify the PD respiratory subtype. Ley (1992) proposed that patients need to have

four of the following five symptoms to fulfil the criteria. The symptoms include

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feelings of choking or smothering sensations, shortness of breath, chest pain or

discomfort, numbness and tingling and fear of dying. Patients in the respiratory

subgroup reportedly had more out of the blue PAs and responded better to

antidepressant medication such as imipramine. The other subgroup presented with

less prominent respiratory symptoms had more situational PAs and responded more

effectively to benzodiazepines such as alprazolam. Building on this notion Biber and

Alkin (1999) in their study found that the subgroup of PD patients with more

prominent respiratory symptoms were more sensitive to the CO2 challenge test, had

been suffering from PD longer, reported more severe panic and phobic symptoms, and

were more likely to be heavier smokers than patients with non-respiratory symptoms

(Freire & Nardi, 2012). Furthermore, it has been suggested that there is an altered

level of CO2 sensitivity in the respiratory PD subtype in response to panic provocation

challenges including the CO2 challenge and breath-holding (Nardi et al., 2004; Nardi

et al., 2006; Sardinha, Freire, Zin & Nardi, 2009). Research to support a respiratory

abnormality in PD is compelling (Abelson et al., 2001; Caldirola, Bellodi, Cammino,

& Perna, 2004; Stein, Millar, Larsen & Kryger, 1995; Yeragani, Radhakrishna,

Tancer & Uhde, 2002) and suggests that PAs are partly the result of respiratory

abnormalities rather than fear and anxiety alone.

The inhalation of CO2 is a useful paradigm to study panic/anxiety as it has

been established that breathing CO2 triggers PAs in patients with PD (Drury, 1918;

Klein, 1993; Papp et al., 1993; Sanderson et al., 1989). PD patients demonstrate an

increased sensitivity to CO2 inhalation (Papp et al., 1993; Rassovsky & Kushner,

2003; Rassovsky, Abrams & Kushner, 2006) and dysregulated brain pH (Friedman,

2006; Maddock, 2001). According to the CO2 hypersensitivity theory, PD patients

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have increased sensitivity of their chemical chemoreceptors (Klein, 1993). The

“Suffocation False Alarm” (SFA) theory proposed by Klein (1993), suggests that PAs

arise as a result of primitive defensive reactions to threats detected in the body’s

internal environment, which is different to that of fear responses (Klein, 1993; Perna

et al., 2014).

Klein (1993), postulated that activation of phylogenetically primitive brain

regions that include the brainstem areas may be associated with unexpected PAs,

while higher brain systems may be related to anticipatory and/or phobic avoidance

(Damasio, 2000). Although a disadvantage to Klein’s model of the suffocation false

alarm (SFA) system, is that anatomically or functionally no structure has been located

within the CNS. The best candidates to fulfil the function of a suffocation monitor are

the CNS structures linked to chemosensitive properties and the fear circuitry involved

in PD (Freire & Nardi, 2012). These areas are incorporated in the broad brainstem

respiratory network and include the nucleus tractus solitaries, the locus coeruleus, and

the raphe nuclei (Gorman et al., 2000; Griez & Perna, 2003).

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Carbon Dioxide and its role in Chemosensation

CO2 is constantly produced in the body as a result of end-product carbohydrate

metabolism and is processed by the bicarbonate system (Esquivel et al., 2009). CO2

and water interact to form carbonic acid (H2CO3), and the effect of CO2 on brain

tissue is facilitated by parallel increases in H+ ions that are present as a result of

dissociation of H2CO3, which plays a vital role in the bicarbonate buffer system aimed

at maintaining acid-base homeostasis (Cadoux-Hudson et al., 1990; Esquivel et al.,

2009; Jensen et al., 1988; Martoft et al., 2003).

Inhaling high concentrations of CO2 leads to a decrease in pH and an increase

in H+ across the blood-brain barrier and in body fluid compartments, which results in

respiratory acidosis (Esquivel et al., 2009). Increasing levels of CO2/H+ induces

dramatic physiological responses that serve as an adaptive panic/defence response and

include neuroendocrine, autonomic and behavioural responses (Johnson et al., 2011).

The blood-brain barrier is permeable to CO2 allowing variations in partial pressure of

CO2 (PaCO2) to influence brain pH. Once CO2 permeates the blood-brain barrier, the

resulting HCO3- and H+ of hydrolysed CO2 leads to temporary acidification of

extracellular brain fluids (Battaglia, 2017; Guyunet, 2014). When CO2 levels in the

body increase, a process mediated by CO2/H+ peripheral and central chemoreceptors,

ventilatory stimulation is subsequently elicited (Esquivel et al., 2009). Increased

ventilation to restore pH and partial pressure of oxygen (PaO2), increased arousal, and

anxiety are some responses through which mammals react to increased acidification

(Battaglia, 2017).

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According to Richerson (2004), serotonin-producing cells in the raphe nuclei

have been recognised as CO2 sensors and are thought to form the cellular link

between serotonin, chemoreception and panic. The serotonergic raphe neurons

located in the brain stem behave as pH regulators and are responsible for detecting

decreases in pH due to hypercapnia, and respond with stringent mechanisms such as

autonomic and behavioural responses to preserve pH homeostasis. These

serotonergic neurons which are strategically based near the large arteries to detect

CO2 levels rising in the blood have projections to the anterior limbic and pre-frontal

fear processing circuits and are implicated in the panic-like responses of CO2

(Severson, Wing, Pieribone, Dohle & Richerson, 2003). Buchanan and Richerson

(2009) found that when pH sensitive serotonergic neurons are silenced in mice, they

disrupt chemosensitive responses to CO2 inhalation, which impairs respiration.

Canteras and Graeff (2014), implicate that faulty serotonergic inhibition of the

DPAG and deficits in the autonomic medullary centres pose a vulnerability to PAs.

This in their view, may be associated with faulty opioid buffering mechanisms since

serotonin and opioids have been demonstrated to interact in the DPAG. Evidence

suggests that patients suffering from PD are more likely to experience PAs due to the

lack of effective 5-HT inhibition of neural networks that “integrate defensive

reactions to proximal danger” and an oversensitive suffocation false alarm system,

coupled with defective buffering of endogenous opioids (Graeff, 2012; Graeff, 2017).

Recently it was found that 5-HT interacts with endogenous opioids in the DPAG (the

structure that is vital for regulating PAs and proximal defence) (Graeff, 2012; Graeff,

2017). PD patients are likely to experience panic symptoms when they inhale a single

deep breath of CO2 as it stimulates the hypersensitive respiratory control nuclei,

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producing a subjective sense of dyspnea, which in turn triggers typical autonomic

symptoms (i.e., elevated heart rate) identified by PD patients as panic (Muhtz et al.,

2011; Verburg et al., 1998).

The nucleus tractus solitary, the medullary raphe, the locus coeruleus, the

nucleus ambiguous, and the ventrolateral medulla are brain regions that play a role in

ventilation and that have been found to contain CO2/H+ sensitive neurons (Equivel et

al., 2009; Putnam et al., 2004). Neurons sensitive to increases in levels of CO2 and

H+ multiply their rate of firing in response to detecting increased acid in the brain

(decreased pHi) increased CO2, and/or decreased extracellular pH (Esquivel et al.,

2009; Putnam et al., 2004). They also demonstrate a consistent reduction in pHi

during increased extracellular acid load (Esquivel et al., 2009; Putnam, 2001).

Furthermore, pH-sensitive ion channels mediate chemosensitive signalling and

sensitivity to acid (Esquivel et al., 2009). Esquivel et al. (2009) suggests that an

overlap exists between chemosensitive neurons that play a role in respiration and

neurons that provoke panic, as patients with PD, especially those that experience

spontaneous PAs, commonly experience respiratory symptoms (Briggs, et al., 1993;

Colasanti et al., 2008; Schruers et al., 2004). It has been suggested that brain regions

containing CO2/H+- sensitive neurons, such as the LC and hypothalamus, are

responsible for respiratory actions and autonomic defensive responses (Bailey et al.,

2003; Equivel et al., 2009; Putnam et al., 2004; Williams et al., 2007).

Evidence suggests PAs may be the result of abnormal respiratory regulation

and/or over sensitivity of the central neural network of CO2/H+ chemoreception

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(Esquivel et al., 2010; Grassi et al., 2013; Klein, 1993; Maddock et al., 2013; Perna et

al., 2004; Perna et al., 2014; van Duinen, Schruers, Maes & Griez, 2007).

Diaphragmatic changes have been noted in both disrupted and dysregulated breathing

patterns. When a fight/flight response is activated, rapid, shallow and thoracic

breathing dominates where high levels of tonic contraction of respiratory muscles

expand a lot of energy and homeostatic functions needed for repair and renewal are

impaired (Courtney, 2009).

Inhalations of CO2 can be life-threatening, hence why they initiate a fear

response that requires sensitive detection and action to ensure survival. Panicogenic

and anxiogenic effects induced by CO2 inhalations and evidence of hypersensitivity to

CO2 both point to a molecular and anatomical structure which acts as a chemosensor

that detects threats posed by CO2 and responds to these by activation of the SNS and

the fight and flight response (Muhtz et al., 2011).

The subject of CO2 chemosensitivity has developed considerably in recent

years. Central chemoreceptors play an important role in cardiorespiratory

homeostasis. One common mechanism for chemosensitivity is the direct activation of

ion channels by a drop in extracellular pH levels. The gating of many ion channels is

modulated by large changes in extracellular proton concentration (Hille, 2001).

Panic patients are considered to be on one end of the spectrum with high

sensitivity to rising CO2 levels, whereas on the other end of the spectrum, those that

have very low sensitivity to CO2 include individuals suffering from congenital central

hypoventilation syndrome and divers (Harper et al., 2005; Delapille et al., 2001).

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This led Harper et al. (2005) to believe that the central hypoventilation syndrome may

be the pathophysiological mirror picture of PD. Breath-hold (BH) divers have a lower

ventilatory response to CO2, which has been related to diving experience (Delahoche

et al., 2004).

Elite BH divers exhibit higher anaerobic metabolism (Ferretti, 2001) and

physiological adjustments to apnea that lead to lower acidosis (Joulia et al., 2002).

Joulia et al. (2003), found that repeated exposure to extended BHT increases the

body’s production of endogenous antioxidants. This, in turn, raises the anaerobic

threshold and the capacity to exercise at increased levels of exertion. A possible

explanation for this may be that given that the marker for breathing is the CO2 build-

up rather than the starvation of O2, BH athletes have developed trained effects and can

endure and tolerate a lot more CO2 build-up in the blood and tissues before they need

to take another breath). As described previously, respiratory control is very sensitive

to changes in PaCO2. The build-up of CO2 and lactic acid during prolonged apnea

results in progressive acidosis (Olsen, Fanestil, & Scholander, 1962). It is the

increases in PaCO2 that stimulate the central chemoreceptors in the brain, leading to

an increase in ventilation thus decreasing PaCO2 (Wood, 2012).

The DR has been observed to be more powerful in divers than in those of

untrained individuals, suggesting that divers are likely to store more lactate in

underperfused tissues (Rodriguez-Zamora et al., 2018; Schagatay & Andersson,

1998). Correspondingly, Joulia, Steinberg, Gavarry and James (2002), obtained lower

blood lactate levels in trained divers compared to their non-diver counterparts

following resting or working apneas and also following eupneic exercise. It is unclear

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whether these differences were induced by the diving training, but remarkably it was

noted that the non-divers had lower lactate accumulation after hand grip exercise with

apnea than without apnea. Although lactate is a common panicogenic that induces

panic attacks in individuals suffering from PD, in free divers it appears that they are

able to withstand more of a tolerance given that they are likely to accumulate more

lactate in underperfused tissues as a result of anaerobic metabolism. Schagatay

(2009) speculated that one of the necessary features for enduring prolonged apnea

may be the blood-buffering capacity for hydrogen ions from accumulating CO2 and

lactic acid. It is thought that the increased haemoglogin (Hb) resulting from apnea

training may lead to a number of changes, including increase of buffering capacity,

splenic contraction to add to this effect, and lung-volume expansion which has a

diluting effect on CO2 (Schagatay, 2009). Ferretti (2001) proposed that the overall

CO2 storage in divers was estimated to be twice that of non-divers. Schagatay (2009)

suggested, that this notion referred to as “lactate paradox of apnea” is of interest and

needs to be further researched with this unique group, that of free divers.

RESPIRATORY PROVOCATION TESTS

Carbon Dioxide (CO2)

Respiratory provocation tests have been fruitful in generating hypotheses

about panic disorder (PD). A common respiratory test is the 35% CO2 challenge

which involves taking one single deep inhalation of a gas mixture containing 35%

CO2 and 65% O2 or double breath inhalations. Under these conditions, healthy

individuals develop a brief respiratory response accompanied by neurovegetative

symptoms that largely overlap with symptoms commonly experienced during a panic

attack (PA) (Griez & Van den Hout, 1982; Nardi, Freire & Zin, 2009; Van den Hout

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& Griez, 1984). In individuals who suffer from PD, the CO2 challenge induces a

sharp and transitory rise in anxiety symptoms that have been compared to having a

PA (Griez et al., 1987; Nardi, Valenca, Nascimento, Mezzasalma & Zin, 2000; Perna,

Battaglia et al., 1994). Administered in a controlled laboratory setting, the 35% CO2

challenge is a brief test whose effects are completely vanished within seconds (Griez,

& van den Hout, 1982). Repeated studies have demonstrated that the 35% CO2

challenge is considered to be a safe and non-invasive procedure, devoid of unwanted

consequences both in short and long terms (Nardi et al., 2007; Perna, Cocchi, Allevi,

Bussi, & Bellodi, 1994). The CO2 challenge strongly suggests a relationship between

the pathophysiology of PD and breathing or respiratory disturbances. Some

abnormalities in respiration, such as enhanced CO2 sensitivity, have been observed in

individuals who suffer from PD. Muhtz et al. (2011), demonstrated in their study that

inhalation of a deep breath of 35% CO2 produced significant panicogenic and

anxiogenic effects in patients suffering from disorders such as PTSD and PD, in

which the fear centres and circuitry of the brain are involved. Previous studies

suggest common pathological processes in the noradrogenic /locus coeruleus system

in patients with PTSD and PD (Bailey, Argyropoulos, Lightman, & Nutt, 2003). A

study by Grillon et al. (2008) demonstrated that PTSD and PD patients have an

increased fear-potentiated startle response in an unpredictable aversive context as

opposed to a predictable situation when compared to healthy individuals. In a more

recent study, Grillon et al. (2017) identified that individuals with PAs demonstrated

hypersensitivity to unpredictable threatening situations. It has also been suggested

that common pathological processes in the noradrogenic /locus coeruleus system exist

in patients with PTSD and PD (Bailey, Argyropoulos, Lightman & Nutt, 2003;

Charney & Heninger, 1986; Charney et al., 1992).

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Hyperventilation

Hyperventilation has been reflected upon by researchers as a cause, correlate

and a consequence to panic attacks (PAs) and it has been studied extensively in PD in

comparison with other diagnoses (Nardi, Valenca, Nascimento & Zin, 2001; Papp,

Klein, & Gorman, 1998). Some authors support the causal relationship of

hyperventilation playing a key role in the development of PAs.

It is regarded that chronic hyperventilation in PD patients shifts to hypocapnic

alkalosis as a consequence of stress or anxiety induced acute hyperventilation thus

resulting in PAs. Freire and Nardi (2012) postulate that this hypothesis has been

formed based on three experimental pieces of evidence. First PAs and the

hyperventilation syndrome share common symptoms which include dyspnea,

palpitations, tremors, paresthesias and faintness. Second, the hyperventilation

syndrome has been reportedly overlapping with PD in 40% of patients (Nardi et al.,

2001). Third, the hyperventilation challenge test induces panic like symptoms in a

significant percentage of PD patients (Garssen, Van & Bloemink, 1983; Nardi et al.,

2004). Other respiratory challenges have included hyperventilation which involves

breathing fast and shallow and averaging approximately 30 breaths per minute. This

causes a significant drop in end-tidal CO2 (exhaled carbon dioxide) to conventionally

accepted levels of hypocapnia.

Breath-holding

Another common respiratory test to induce endogenous CO2 is breath-holding,

which is considered to be a natural and simple method (Van Der Does, 1997). Studies

that have utilised the breath-holding challenge to investigate panic have yielded

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mixed results. Zandbergen, Strahm, Pols and Griez (1992) examined whether breath-

holding durations can be used to diagnose panic disorder (PD). They established that

PD individuals in their study had shorter BH durations than normal individuals,

however similar to those of other anxiety disorders.

Asmundson and Stein (1994) in their study reported that patients diagnosed

with PD had significantly shorter BH durations relative to healthy participants as well

as participants suffering from social anxiety disorder. These findings are in line with

Klein’s (1993) theory of the suffocation false alarm (SFA) theory. Asmundson and

Stein (1994) suggest that PD participants terminate the breath-hold earlier in order to

avoid activation of the suffocation alarm. Freire and Nardi (2012), have hypothesised

that there is an integral abnormality in the physiological mechanisms that control

respiration in PD. In response to many of the common used respiratory challenge

tests, including the CO2 challenge, hyperventilation and breath-holding, PD patients

exhibit physiological and behavioural abnormal responses. They often report more

PAs and anxiety during respiratory challenges when compared to normal healthy

individuals (Gorman et al., 1994; Holt & Andrews, 1989; Papp et al., 1997).

Furthermore, it has been found that the respiratory group subtype is sensitive to the

BH challenge (Nardi, Valenca, Lopes, Nascimento & Mezzasalma, 2004; Nardi, et al.,

2006; Nardi, Valenca et al., 2006).

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IMPLICATIONS OF THE DIVING RESPONSE IN

TREATING PANIC DISORDER

Respiratory abnormalities and cardiovascular problems can be quite common

in patients suffering from PD, and many of the symptoms have an overlap with such

disturbances. Multiple susceptibility genes and their interplay with environmental

factors as well as chemosensitivity have been understood to play a significant role in

the aetiology of PD. A number of empirically supported risk factors for PD have been

identified and extend multiple levels of function including genetic, biological and

psychosocial factors) (Feldner et al. 2008; Zvolensky et al. 2006c). Although

advances and developments in the neurobiology of PD may be able to offer new

opportunities towards the treatment and prevention of PD, a greater understanding is

required of the link between respiratory abnormalities and PD. Particularly,

comprehending the mechanisms of chemosensation involved in respiration, and the

role that acid-sensing ion channels and tandem acid sensitive potassium channels play

in disrupting the homeostatic tight parameters of the brain pH levels may shed some

light in understanding the PD and its link with chemosensation. Indisputably, PD has

a very complex pathophysiology, and hence further research is required in

understanding what role pH regulation and pH-sensitive receptors play in its onset and

maintenance of symptoms. In view, understanding the molecular and cellular

biological and genetic influences involved in PD is fundamentally important in

gaining further insights. PD has been pivotal in research dealing with the respiratory

system and anxiety disorders (Gorman, Kent, Sullivan & Coplan, 2000a).

There is converging evidence from neuroimaging, genetic and animal studies

that support that respiratory provocation tests such as the CO2 challenge,

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hyperventilation and BH challenge disrupt pH homeostasis regulation, and underlying

abnormalities in chemosensation may play a role in panicogenesis. Specifically, acid-

chemosensory mechanisms involved in the fear circuitry may evoke fear and panic

responses to interoceptive stimuli resultant from respiratory provocation methods

(Vollmer et al., 2015). Hence, restoring the homeostasis regulatory mechanisms

within the interoceptive milieu may be the key to managing panic symptoms.

Correcting dysfunctional breathing has often been used to restore the balance in the

neurovegetative system however this has yielded mixed results (Wilhelm et al., 2001).

Although CBT is considered to be the most effective treatment modality

proposed to date for anxiety disorders, it is still far from optimal (Craske et al., 2014:

Hofmann & Smits, 2008). In the last few decades, neuroscience has contributed

vastly to our understanding of the human brain and psychological and biological

treatments have been influenced by developments in neuroscience. Kindt (2014)

argues that a neuroscientific approach can contribute to our understanding regarding

the mechanisms of change in the treatment of pathological anxiety and processes

involved in how one individual develops abnormal fear that stems from having

normal adaptive fear. Associative fear memory purportedly lies at the core of anxiety

and associated disorders (e.g., PD, PTSD, specific phobia), and given that the fear

circuitry is involved in the pathophysiology of PD, neurobiological and

neuroscientific research can complement cognitive behavioural treatment.

MacLean (1990) developed a groundbreaking theory of understanding brain

development called the “triune brain”. The triune brain is a model of development

which encompasses the reptilian complex, the paleomammilian complex and the

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neomamillian complex. MacLean contended that the reptilian brain is the first to

develop and is responsible for regulating automatic voluntary functions that are vital

for survival, including heart rate, breathing, blood pressure, and body temperature

regulation. It also handles motor planning and basic effects including physiological

aspects of aggression and anxiety. It comprises the brainstem, pons and diencephalon

(Kandel et al., 2013).

MacLean (1990) postulated that the paleomammalian complex, which houses

our emotions and is important for social emotions and expanded memory functions,

consists of the amygdala, hippocampus, thalamus, hypothalamus, septum and

cingulate cortex. MacLean termed this area as the limbic area and indicated that these

structures develop sequentially following the development of the reptilian complex.

The neomammalian complex which consists of the cerebral cortex, also known as the

neo-cortex is only found in mammals. MacLean (1990) maintained that in human

evolution, this is the most recent step conferring the ability for language, perception,

abstract cognitive processes, and sequential planning and organising. The neocortex

receives the most influence from its environment and is more adaptable and

malleable. Although to date there have been more sophisticated models put forward

explaining brain functioning, MacLean’s ideas have had a profound effect in

understanding the sequential pathogenesis of anxiety disorders and feared responses

in individuals (Newman, 2009).

Evolutionary pressures, and the driving motivations of any organism to

survive explains the need to maximise pleasure and minimise harm (Gordon et al.

2007; Öhman & Mineka, 2001). Therefore, stimuli such as the threat of CO2 that has

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been linked through evolution to danger are particularly salient (Kavaleris & Choleris,

2001; Lang & Davis, 2006). Moreover, threats can arise from within the organism

and can include detectable changes within the interoceptive milieu (Esquivel et al.

2010; McNaughton, 1989), cognitive misappraisals (Barlow, 2002), and imagined

threats (Bremmer, 2004).

It is commonly recognised that when an individual panics, the fear is

described as so imminent that a person cannot think clearly, nor challenge their

thoughts and it is because this fear is so prominent that it is quickly paired with

interoceptive and exteroceptive stimuli. The acceleration of the heart rate, or the

pounding of the heart is often one of the scariest symptoms reported by panic patients

and because the fear is so imminent, it is commonly misinterpreted as a sign that one

is having a heart attack. Furthermore, choking sensations and dyspnea are often

misattributed to suffocation.

Current exposure-based therapies are amongst the most popular and most

effective treatments for anxiety disorders aimed to reduce pathological fear.

According to Milad, Rosenbaum and Simon (2014), anxiety and trauma interventions

can be further improved by having a deeper understanding of the neurobiological

mechanisms of fear extinction to enhance initial and long-term outcomes. Mineka

and Zinbarg, (2006) proposed that the genesis of irrational fears originates from an

association between neutral and aversive stimuli. Hence, it may be imperative to

know that insight in the neurobiology of associative fear memory may contribute to

our understanding of the mechanisms of change in the treatment of anxiety and other

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related disorders (Hermans, Craske, Mineka & Lovibond, 2006; Kindt, 2014; Milad,

Rauch Pitman & Quirk, 2006).

Given MacLean’s (1990) and Newman’s (2009) ideas, based on the triune

model of the human brain evolution and recent neuroscientific advances in this fast

growing area, there is a need for science to develop simple treatments that employ a

bottom-up approach, where safety and primary needs are met prior to engaging in

cognitive interventions. During a state of panic, when experiencing exaggerated fear,

it is difficult to think rationally and hence challenge one’s irrational thinking. Based

on this assumption that these needs are initially met, one is then able to access

cognitive capacity and engage in cognitive restructuring more effectively.

Neurobiological insights support psychotherapeutic interventions that focus on

providing a supportive therapeutic environment that facilitates the safety needs of the

patient by prioritizing the stabilization of the autonomic nervous system when

dysregulated (Furmark et al. 2002; Grawe, 2007; LeDoux, 2002; Merzenich, 1983;

Newman, 2009; Rothschild, 2017; Sporns, 2011). One of the cardinal features of PD

when fear is elicited is a dysregulated ANS, characterised by sympathetic nervous

system (SNS) arousal. Many PD patients complain of heart palpitations or chest

pounding which are perceived as dangerous and which exaggerate their fear response.

One may anticipate that by reversing the accelerated heart rate and consequently the

SNS arousal, panic patients may be able to achieve stabilisation and increase their

perceived sense of safety and control. PD patients may be able to benefit from simple

and practical treatments aimed at regulating the ANS and reversing the fear response.

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One such strategy may be to activate the diving response (DR), the most

powerful autonomic reflex known to humans, which consequently reduces the heart

rate and initiates parasympathetic nervous system responses. Moreover, if

stabilisation is effectively achieved by reversing the accelerated heart rate and

stopping the palpitations, panic patients may benefit from repeated exposures of

simple practical strategies which activate the DR. Activating such an innate powerful

response, may down regulate the fear or panic response and prove to be an effective

novel treatment for PD. Furthermore, regular activation of the DR may assist with

unpairing aversive fear conditioned responses such as interoceptive and exteroceptive

stimuli. One known strategy that activates the DR, is the cold facial immersion (CFI)

which is routinely used in emergency departments for the treatment of atrial

tachycardia, to reset the elevated heart rate. The CFI task successfully activates

parasympathetic nervous system responses and slows down the heart rate

considerably.

According to Andersson & Schagatay (1998), frequent and extensive

exposures to hypercapnia (high CO2 levels in the blood) may reduce the sensitivity of

the central chemoreceptors, thereby reducing the urge to breathe which is stimulated

by hypercapnia. Furthermore, Andersson and Schagatay (1998) postulated that future

studies should investigate the time course for development of this adaptation to

breath-hold (BH), cold facial immersion (CFI) and or diving, (i.e., how many

exposures and how frequent exposures are needed to reduce CO2 sensitivity). As

discussed earlier, the training effects that free divers possess may be beneficial for

individuals suffering from panic attacks (PAs). Walterspacher, Scholz, Tetzlaff and

Sorichter (2011) proposed that one’s response to CO2 is largely determined by

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genetics and apnea training. Particularly, repetitive breath-hold (BH) training with

short recovery interval periods, have also demonstrated to increase the time in

withstanding the respiratory drive, and diminishing the ventilatory response to

hypercapnia, contributing to longer BH times (Schagatay et al., 1999).

In many ways, the physiological adaptations experienced whilst free diving

are the opposite of those triggered when an individual encounters a panic attack. Free

diving has been described as the feeling of “true ease and relaxation” under the water.

However, given the extreme nature of the sport, it is unlikely that individual’s with

PD would engage in free diving. Despite this, some of the techniques and

physiological adaptations used in free diving may be easily taught to PD patients and

utilised to counteract panic symptomatology. These may include breath-hold training

(BHT) and regular practice of the CFI task. Given that the key factors in both free

diving and PAs are mental and breathing control, it is plausible that the diaphragmatic

breathing techniques already used to treat panic may benefit from drawing on the

physiological adaptions and techniques used in the sport of free diving and in

particular the activation of the DR.

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RESEARCH AIMS

The overarching aims of this research are to examine the efficacy of cold

facial immersion and the diving response in treating panic disorder. Whilst the diving

response and cold facial immersion has been used in medical applications (i.e.

treatment of atrial tachycardia), this study is the first attempt to examine applications

of the diving response and cold facial immersion to treat panic symptoms.

As a preliminary investigation, this research examined the immediate effects

of apnea (breath-holding) and cold facial immersion on panic symptoms and

cognition. This preliminary study aims to examine the short-term effects of CFI on

physical and psychological symptoms of panic and examine differences between

individuals with panic compared with individuals healthy control participants.

Based on the findings of this literature review it was predicted:

1. That clinical participants will have shorter breath-hold durations

than healthy controls in both breath-hold challenges, in line with

Klein’s suffocation false alarm hypothesis.

2. That clinical and control participants will experience a heart rate

reduction in response to the cold facial immersion (CFI) tasks,

given the activation of the DR. Furthermore, it is predicted that

there will be no significant difference in heart rate reduction

between clinical and control participants.

3. That clinical participants will demonstrate increased heart rate and

respiration rate in response to the CO2 challenges when compared

to control participants.

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4. That clinical participants will report increased anxiety-related

symptoms when compared to control participants, in response to

the CO2 challenge.

5. That all participants will report significantly lower anxiety in

response to the CO2 challenge with Cold Facial Immersion when

compared to baseline measures and the CO2 challenge alone.

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Chapter 4

OVERALL METHODOLOGY

OVERVIEW OF METHODOLOGY

This chapter presents the overall methodology of the research conducted for

this thesis. The research studies are presented as three individual studies in the

following chapters (Chapters 5 – 7). As each of the chapters of these studies provides

a Method section which outlines methodological aspects that are relevant to each of

the studies, procedures and statistical analyses), the methodology which will be

described in this chapter is restricted to the elements that are common across all of the

studies.

ETHICS APPROVAL

Approval for this research was obtained from the Swinburne University

Human Research Ethics Committee (SUHREC 2014/010) on February 14th 2014.

Ethics was granted to conduct two studies: (1) preliminary study, and (2) an

investigation of the effects of cold facial immersion (CFI) on CO2 sensitivity. Both of

these studies were to be conducted with clinical participants, diagnosed with panic

disorder, and a group of healthy control participants. The initial design for the

preliminary investigation included a homework intervention whereby all participants

would practice three CFI tasks daily over a period of four weeks. The initial design

for the investigation of the effects of CFI on CO2 sensitivity included a comparison of

a six week CFI intervention (conducted at home by participants) with a six week

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online Cognitive Behavioural Therapy, where participants would be randomly

assigned to interventions. However, due to ethical and safety considerations with

regard to participant’s carrying out CFI tasks in their home, in a standardised and

supervised way, this original research design was not granted ethics approval. Hence

methodology for both the preliminary study and subsequent study investigating CFI

and its effects on CO2 was changed and ethics approval was granted for the research

which is reported in this thesis.

Throughout this research, amendments to ethics have been made in regards to

exclusion criteria, the location of the research, supervisory arrangements, changes to

the research protocol, and extension of the ethics approval period (see Appendix A for

ethics approvals and approved amendments granted by SUHREC 2014/010).

INFORMED CONSENT

As clinical and control participant groups underwent slightly different

screening procedures, they were provided with different Plain Language Statements

(PLS) and Consent Forms (see Appendix B and C for copies of the Plain Language

Statement and Consent Form for clinical and control participants for the two studies

conducted as part of this research). The PLS and consent forms outlined the aims and

requirements of the research study and provided participants with information

regarding their rights as research participants. These forms also provided information

regarding contact details for participants to contact should they require any further

information or have concerns about the research.

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Upon expressing interest in participating in the research, participants were

invited to a preliminary health screening and clinical interview. Prior to the

commencement of the health screening and clinical interview, participants were

provided with the PLS and consent form and asked to provide consent by completing

and signing the form. Following the consent process, the health screening and clinical

interview commenced.

CLINICAL PARTICIPANTS

Inclusion and Exclusion Criteria for participants with panic

disorder.

The key inclusion criterion for clinical participants was a primary diagnosis of

panic disorder with or without agoraphobia, according to the diagnostic criteria of

DSM-5 (APA, 2013). Participants who were using prescription medication, including

antidepressants and benzodiazepines were excluded from the study. Participants with

a first-degree biological relative with panic disorder were also excluded. Other

exclusion criteria for clinical participants included: a diagnosis of comorbidities to

Axis I mental health disorders according to the diagnostic criteria of DSM-5 (APA,

2013), psychotic disorders, substance abuse, known allergies to latex, asthma or

respiratory problems, cardiovascular problems, hypertension, hypotension, pregnancy,

and cerebrovascular problems including epilepsy, and organic brain disorder. In

summary, the inclusion and exclusion criteria were selected based on the medical

risks in relation to the CO2 challenge and our attempts to recruit a homogeneous

sample in order to reduce confounders.

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Recruitment of Clinical Participants

Clinical participants were recruited from a range of clinical and community

settings. Clinical sources included referrals from psychologists across three large

private psychology clinics based in Melbourne. Community sources included

referrals and self-referrals made by members of community based organisations such

as the Anxiety Disorders Association of Victoria, (ADAVIC), and the Anxiety

Recovery Centre Victoria (ARCvic). The study was predominantly advertised at

these locations as well through online social media platforms connected with these

organisations, as well as a neuropsychotherapy e-journal, a Melbourne based

newspaper, and at Swinburne University medical clinic and around the university

campus.

Potential participants who applied to participate in the study were invited to

undergo a clinical screening interview conducted by the principal researcher at

Swinburne University. Screening interviews ranged in duration from 40 minutes to

60 minutes. During the screening interview, the researcher provided potential

participants with information regarding the study. Health screening assessments were

carried out to establish medical eligibility to undergo the CO2 challenge. As part of

the health screening, all participants completed a demographic and health information

form (see Appendix D for Participant Information Form). Demographical data such

as age, gender, level of education completed, employment status were included in this

form. In addition, the demographical questionnaire included a health screening,

height and weight information, as well as fitness and exercise assessment which

included a physical activity index. Participants were also asked about their perceived

level of comfort with water.

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Furthermore, all participants were administered The Mini International

Neuropsychiatric Interview (M.I.N.I). The M.I.N.I is a short structured diagnostic

interview used to make diagnoses of Axis I disorders (DSM-IV) and has demonstrated

high reliability and validity (Sheehan, et al., 1997). The 5.0 version of the M.I.N.I

schedule was used to screen psychological disorders within the exclusion criteria and

identify individuals with PD (DSM-IV). Clinical participants were also assessed with

the structured clinical interview (SCID-I) for DSM-IV Axis I Disorders (SCID-I;

First, Spitzer, Gibbon & Williams, 1995) module for Panic Disorder and Agoraphobia

in order to confirm the diagnosis. The diagnostic assessment was conducted by the

researcher who is a clinical psychologist. The SCID-I is a comprehensive structured

interview that assesses for current episodes of anxiety disorders and allows

differential diagnosis among the DSM-IV anxiety disorders (First, Spitzer, Gibbon,

Williams, 1996). The SCID-I has demonstrated a high level of reliability (e.g.,

Kappas of at least .75 on symptoms and 90% accuracy in diagnosis) (Ventura, 1998).

Validity has been demonstrated via a number of studies that have used the SCID-I as

the “gold standard” in determining the accuracy of clinical diagnoses (e.g., Shear et

al., 2000; Steiner et al., 1995).

CONTROL PARTICIPANTS

Inclusion and Exclusion Criteria for Control Participants.

The key inclusion criterion for control participants was a negative diagnosis of

panic disorder or other mental illness, according to the diagnostic criteria of DSM-5

(APA, 2013). As per the exclusion criteria for clinical participants, control

participants who were using prescription medication, including antidepressants and

benzodiazepines were excluded from the study. Control participants with a first-

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degree biological relative with panic disorder were also excluded. Other exclusion

criteria for control participants included: a diagnosis of comorbidities to Axis I mental

health disorders according to the diagnostic criteria of DSM-V (APA, 2013),

psychotic disorders, substance abuse, known allergies to latex, asthma or respiratory

problems, cardiovascular problems, hypertension, hypotension, pregnancy, and

cerebrovascular problems including epilepsy, and organic brain disorder. In summary,

the inclusion and exclusion criteria were selected based on the medical risks in

relation to the CO2 challenge and our attempts to recruit a homogeneous sample in

order to reduce confounders.

Recruitment of Control Participants

The control participants in this study were recruited from various sources and

predominantly through snowball techniques through the researcher’s contacts through

Swinburne University and private practice settings. Social media platforms were also

used to advertise the research and attract control participants as well as advertising on

research notice boards throughout Swinburne University. Figure 5 depicts the process

of recruiting participants for this research study.

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Figure 5. Process for recruiting Clinical and Control participants and Control

participants.

As per the screening procedure for the clinical participants, potential control

participants who applied to partake in the study were invited to undergo a clinical

screening interview conducted by the principal researcher at Swinburne University.

Screening interviews ranged in duration from 30 minutes to 45 minutes. The

screening process for control participants was not as long as it was for the clinical

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participants. During the screening interview, the researcher provided potential

participants with information regarding the study. Health screening assessments were

carried out to establish medical eligibility to undergo the CO2 challenge. As part of

the health screening, all participants completed a demographic and health information

form (see Appendix D for Participant Information Form). Demographical data such

as age, gender, level of education completed, employment status were included in this

form. In addition, the demographical questionnaire included a health screening,

height and weight information, as well as fitness and exercise assessment which

included a physical activity index (PAI). Participants were also asked about their

perceived level of comfort with water.

Furthermore, participants were administered the Mini International

Neuropsychiatric Interview (M.I.N.I). The 5.0 version of the M.I.N.I schedule was

used to screen psychological disorders within the exclusion criteria and identify

individuals who did not meet the diagnostic criteria for PD or any other mental illness

according to the DSM-IV (APA, 2013).

OVERALL PROCEDURE

The following measures relate to the two quantitative studies reported in

chapter 5 and 6 respectively and include (1) Psychological Measures, (2)

Physiological Measures (3) CO2 Challenge, (4) Breath-hold challenge (5) Cold Facial

Immersion (CFI) Task. All participants completed the psychological measures as

well as the CO2 Challenge, Breath-hold challenge and CFI Task. These conditions

are discussed below.

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Psychological Measures

As part of the experimental procedure, all participants completed a battery of

psychological measures which comprised a number of self-report measures. The

battery of tests was administered a number of times throughout the experimental

studies. Chapters 5 and 6 provide further detail regarding the administration of this

battery of measures throughout the experimental process.

The Anxiety Sensitivity Index

Anxiety sensitivity was measured using the Anxiety Sensitivity Index (ASI).

The ASI is a 16-item self-report questionnaire that is designed to measure the

construct of anxiety sensitivity, which is defined as the tendency to fear the possible

consequences of somatic and cognitive anxiety symptoms (Peterson & Reiss, 1987).

Examples of the items include, “It scares me when my heart beats rapidly” and “It

scares me when I am short of breath”. The items of the ASI are rated on a 5-point

Likert scale ranging from 0 (very little) to 4 (very much). The ASI has demonstrated

adequate internal consistency (Telch, Shermis and Lucas, 1989) and test-retest

reliability (Mailer & Reiss, 1992). Moreover, the ASI appears to measure fear of

anxiety symptoms as opposed to state or trait anxiety (see McNally, 1994).

The Beck Anxiety Inventory

To measure overall anxiety, the Beck Anxiety Inventory (BAI) was used. The

BAI is a 21-item self-report questionnaire that assesses the degree that physical and

cognitive anxiety symptoms have affected an individual over the past month (Beck,

Epstein, Brown & Steer, 1988). Participants indicate the level to which they have

been bothered by anxiety symptoms over the past month. Examples of the symptoms

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measured include “Unable to relax”, “Numbness or tingling” and “Fear of losing

control”. The BAI is rated on a Likert scale ranging from 0 (Not at all) to 3

(Severely, it bothered me a lot) and raw scores ranging from 0 to 63. BAI scores are

classified into 4 categories including minimal anxiety (0 – 7), mild anxiety (8 – 15),

moderate anxiety (16 – 25) and severe anxiety (30 – 63). The BAI has demonstrated

high reliability and validity in a variety of studies both clinical samples (coefficient

alpha=0.82) and non-clinical samples (coefficient alpha=0.91) (Beck et al., 1998;

Borden, Peterson & Jackson, 1991).

The Discomfort Intolerance Scale

The Discomfort Intolerance Scale (DIS) is a 5-item self-report questionnaire

which measures the degree to which individuals are able to tolerate physical

discomfort including pain and bodily sensations. Items include “I have a high pain

threshold” and “I can tolerate a great deal of physical discomfort”. Participants

responded using a 7-item Likert Scale ranging from 0 (Not at all like me) to 6

(Extremely like me). The DIS has demonstrated sound reliability and validity

(Schmidt, Richey and Fitzpatrick, 2006).

The State-Trait Anxiety Inventory

The State/Trait Anxiety Inventory (STAI) is a self-report questionnaire

comprised of two 40-item scales designed to assess the intensity of feelings of anxiety

and distinguishes between state anxiety (a temporary condition experienced in

specific situations) and trait anxiety (a general tendency to perceive situations as

threatening) (Speilberger, Gorsuch and Lushene, 1970). The State Anxiety Scale

consists of 20 statements that evaluate how respondents feel “right now, at this

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moment”, for example, “I feel at ease”. Respondents self-rate on a 4 point scale: “not

at all”, “somewhat”, “moderately so”, and “very much so”. The Trait Anxiety Scale

consists of 20 statements that evaluate how respondents feel “generally”, i.e. “I am a

steady person”. Respondents indicate their responses on a 4 point scale: “almost

never”, “sometimes”, “often”, and “almost always”. Both state and trait anxiety

scales have adequate psychometric properties (Knight, Waal-Manning & Spears,

1983).

The Panic Attack Cognitions Questionnaire

The Panic Attack Cognitions Questionnaire (PACQ) assesses the degree of

preoccupation with 25 typical cognitions that occur during a panic attack. This scale

was used to measure participants’ severity of panic related cognitions. Respondents

are asked to rate each thought on a 4-point scale indicating their level of

preoccupation with that thought, from 0 = not at all, to 3=totally dominates my

thoughts. Examples of the 25 cognitions include, “I must have a brain tumor” and “I

will be paralyzed with fear”. The sum of the 25 item scores provides a total PACQ

score. The PACQ has demonstrated good internal consistency (Cronbach alpha .88)

and has shown to be a valid measure with discriminant function analysis indicating

the PACQ’s unique contribution in differentiating individuals with and without panic

attacks (Clum, 1990).

The Acute Panic Inventory

The Acute Panic Inventory (API) is a 17-item self-report inventory designed

to measure the severity of symptoms that typically occur during spontaneous panic

attacks in patients with PD (Liebowitz et al., 1984). Each of the 17 items on the scale

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represents one common symptom of a panic attack which respondents self-rate the

severity on a 4 point scale; where 0 = symptom not experienced, 1.0 = slight

experience, 2.0 = moderate experience, and 3.0 = severe experience of symptom.

Examples of the items include, “Are you fearful?” and “Do you have rapid or

difficulty breathing?” The API can be administered in minutes and yields a total

score ranging between 0 – 51. Respondents can be asked to respond to the API as if

they were (1) currently experiencing a panic attack, (2) currently experiencing a

period of marked stress, or (3) as they feel at the moment.

The Visual Analog Scale

The Visual Analog Scale (VAS) provides a simple technique for measuring

subjective experience. They have been established as valid and reliable in a range of

clinical and research applications (Carlsson, 1982). The scale consists of a 10 cm

horizontal line, anchored by the words “not at all anxious” on the extreme left hand

side, and the words “extremely anxious” on the extreme right hand side. Participants

are provided with the instructions, “Mark the line below with a vertical stroke to show

the level of anxiety you are feeling at the moment. A mark at the extreme right would

show that you are feeling the most anxious you could ever imagine. A mark near the

centre would show that you feel moderately anxious”. A higher score indicates

greater anxiety.

The Center for Epidemiological Studies Depression Scale

The Center for Epidemiological Studies Depression Scale (CES-D) measures

current depressive symptomatology related to major or clinical depression in adults

and adolescents. The CES-D comprises 20 items which tap into depressed mood,

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feelings of guilt, worthlessness and helplessness, psychomotor retardation, loss of

appetite and sleep difficulties. Internal consistency is excellent for the CES-D 20

(Cronbach’s α = .88-.91), and test-retest reliability is excellent (ICC = 0.87) (La

Chapelle, 2005, Miller et al., 2008). It has demonstrated ranges in validity from Pain

(Pearson’s r = 0.27) to Mental Health (Pearson’s r = 0.75) and adequate with the

Fatigue Severity Scale (Pearson’s r = 0.58) (Kuptniratsaikul et al, 2002, Miller et al,

2008, Anton et al., 2008).

Physiological Measures

As part of the experimental procedure for the first two studies, physiological

data, mainly heart rate, respiration rate and oxygen saturation (SaO2) levels were also

monitored and collected throughout.

Respiratory Challenges and Cold Facial Immersion Task

Breath-hold challenge

The breath-hold challenge was undertaken by all participants who were part of

the first study (Chapter 5). Participants wore a nose clip and were instructed to hold

their breath for as long as possible, following an exhalation. Upon completion of this

breath-hold challenge, they were given one minute rest period before being instructed

again to hold their breath after taking a maximum inhalation. Breath-hold time in

seconds was taken as a measure, and physiological measures including heart rate

(HR) and respiration rate were recorded as part of this challenge.

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Cold Facial Immersion Task

Upon provision of informed written consent, all participants took part in the

experimental study which involved a cold-facial immersion (CFI) task. This

experimental condition was present in both the first (Chapter 5) and the second study

(Chapter 6) reported in this thesis.

A sterilised container was filled with water and placed on the left side of a

medical bed which was cleared of any other apparatus. There was sufficient space

around the water container to allow participants room to rest their arms on each side

of the container whilst completing the task. Participants were instructed to take a

maximal vital capacity inhalation and then immerse their entire face in the water

(including the forehead), whilst holding their breath for thirty seconds. Participants

were informed that they could terminate the exercise at any time if they felt

discomfort or a strong urge to breathe. The researcher counted out aloud in intervals

of 5 seconds until 30 seconds was reached, at which point participants were asked to

lift their face from the water. The ambient air temperature was controlled at 22°C and

the water temperature was maintained between 7-12 °C. A thermometer was used to

ensure the water temperature was maintained within this range. A digital pulse

oximeter was also used with participants to measure oxygen saturation (SaO2) levels

during the CFI tasks, as the researchers were interested in seeing whether the SaO2

levels changed during the CFI task.

CO2 Challenge

For the CO2 challenge, participants were instructed to take in a single

inhalation of a 35% CO2 and 65% O2 gas mixture and to hold their breath for 4

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seconds before exhaling. Physiological measures including heart rate (HR) and

respiration rate (RR) were recorded using a Zephyr Bioharness which involved the

participant being fitted with a chest strap. Participants’ SaO2 levels were monitored

using a finger pulse oximeter. Upon completion of this task, participants were

required to complete a battery of self-report measures including; the ASI, BAI, STAI

(State), PACQ, API, and VAS (Participant). The researcher also completed the VAS

(Researcher) scale based on their perception of the participant’s anxiety to cross-

validate participant ratings.

Physiological Materials

Electrocardiogram (ECG)

A compact physiological monitoring system (Zephyr Bioharness), featuring a

chest strap and external multi recording and monitoring device was used to measure

heart rate, posture, breathing wave and respiration rate. Participants were connected

to the Zephyr Bioharness and measured throughout the experimental study.

Participant’s breath-hold ability was also measured during the experimental phase and

included breath-hold ability after exhalation, and breath-hold ability following

maximum inhalation.

Pulse Oximeter

A finger pulse oximeter was used to monitor the participants’ oxygen saturation

(SaO2) levels in the blood as well as pulse rate. The pulse oximeter was attached to

the participant’s fingers throughout the CO2 challenge and CFI exercises conducted in

the study. Part way through the study the use of the pulse oximeter was discontinued,

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as it was difficult for the researcher to record SaO2 levels on a second to second basis

and these measures were not the focus of the investigation in this study.

CO2 Inhalation Materials

For the CO2 challenge, a pre-mixed gas containing 35% CO2 and 65% O2 was

administered through a Douglas Bag. The CO2 challenge was administered by the

principal researcher who was trained to use the equipment. A medical specialist was

also available during the experimental study in case participants required medical

attention or in case of emergency. Equipment was sterilised prior to each use and a

one way valve was used to prevent cross contamination between participants.

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Chapter 5

PRELIMINARY INVESTIGATION:

RESPIRATORY CHALLENGES AND COLD

FACIAL IMMERSION

AIM

This preliminary study is the first of two studies which aim to investigate the

application of the diving response (DR), cold facial immersion (CFI) and breath-

holding, by examining the effects of this human adaptation on panic symptoms and

cognition in clinical participants and control participants. The present study

specifically aimed to investigate the immediate effects of breath-holding and cold

facial immersion (CFI) on panic symptoms and cognition. The objectives of the

present study were to (1) examine preliminary data on the short term effects of CFI on

physiological and psychological panic symptoms; (2) compare a group of PD

participants with a control in order to examine the magnitude of differences between

these groups. This study is the first attempt to examine applications of the DR and

CFI to treat panic symptoms.

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HYPOTHESES

Hypothesis 1

That clinical participants will have shorter breath-hold durations than

healthy controls in both breath-hold challenges in line with Klein’s suffocation

alarm hypothesis.

Hypothesis 2

That clinical and control participants will experience a heart rate reduction in

response to the cold facial immersion (CFI) tasks, as a result of the activation of the

diving response (DR). Furthermore, it is hypothesised that there will be no significant

difference in heart rate reduction between clinical and control participants.

Hypothesis 3

That clinical participants will demonstrate increased heart rate and respiration

rate in response to the CO2 challenges when compared to control participants.

Hypothesis 4

That clinical participants will report increased anxiety-related symptoms when

compared to control participants, in response to the CO2 challenge.

Hypothesis 5

It is hypothesised that all participants will report significantly lower anxiety in

response to the CO2 challenge with Cold Facial Immersion when compared to

baseline measures and the CO2 challenge alone.

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METHOD

Participants

A total of 38 participants were recruited to participate in this study. Of these,

six participants with PD were excluded from being able to participate as part of the

clinical group during the initial screening stage of the study. All six participants met

the criteria for a diagnosis of PD, however, three also had other co-morbidities that

were exclusion criteria, and three were taking medication and on this basis excluded

from the study.

In this exploratory study, we used a pragmatic approach of recruiting as many

participants as possible given time and budget constraints of this PhD research study.

To accurately estimate sample size we would have required variability data for the

outcomes of interest which were not available. The data from this study can be used

to estimate the variability in outcomes of interest and inform sample size calculations

in future studies.

Hence the final clinical and control groups comprised 32 participants; 16

patients with a primary diagnosis of panic disorder (PD) with or without agoraphobia

(DSM-V) (Clinical Group 1), and 16 normal controls who did not meet criteria for PD

or mental illness (Control Group 2). Of these 6 were male, and 26 were female. The

clinical group comprised 1 male and 15 females, and the control group comprised 5

males and 11 females. The participants in the clinical group had an average age of

36.43 years (SD = 2.82), whilst the participants in the control group had an average

age of 29.06 years (SD = 1.79). Demographic and clinical data for all participants are

reported in the results section of this chapter.

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Health Screening

The final 32 participants underwent health screening assessments and were

established as medically eligible to undergo the CO2 challenge.

Research Design

The experiment was conducted in a clinical setting. Participants took part in four

experimental challenges as outlined in Table 1. The order of the conditions was

randomly allocated to each participant.

Table 1

Experimental Conditions

Conditions Task

Condition A 2 Breath-hold challenges

Condition B Cold Facial Immersion (CFI) Task

Condition C CO2 Challenge

Condition D CO2 Challenge followed by CFI Task

Measures

All participants were required to complete a battery of psychological

assessments before, during and after the experimental study. Descriptions of the

psychological measures utilised in this study are described in Chapter 4. Table 2

provides a list of the battery of psychological measures and the various time points at

which these measures were administered throughout the experimental study.

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Physiological measures including heart rate, respiration rate and breath-hold

times in seconds were also recorded at various points throughout the experimental

study. Figure 6 displays the experimental procedure indicating when physiological

and psychological measures were collected as part of this study.

Table 2

Battery of Psychological Assessments Administered Before, During and After the

Experimental Study

Psychological Measures Administrations

1. Anxiety Sensitivity Index (ASI) Pre-Test, Condition C, Condition D

2. Beck Anxiety Inventory (BAI) Pre-Test, Condition C, Condition D

3. Discomfort Intolerance Scale (DIS) Pre-Test,

4. State/Trait Anxiety Inventory (STAI) (A-Trait) Pre-Test,

5. State/Trait Anxiety Inventory (STAI) (A-State) Pre-Test, Condition C, Condition D

6. Panic Attack Cognitions Questionnaire (PACQ) Pre-Test, Condition C, Condition D

7. Acute Panic Inventory (API) Pre-Test, Condition C, Condition D

8. Visual Analog Scale for Anxiety (VAS) – Participant &

Researcher Condtion C, Condition D (x2)

9. Center for Epidemiological Studies Depression Scale (CES-D) Pre-Test,

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Figure 6. Experimental procedure for data collection for Group 1 (Clinical) and Group 2 (Control) participants.

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Procedure

The study was held at a clinical room at Swinburne University which was

specifically set up for the research. Participants were asked to refrain from caffeine-

containing beverages including cola, and smoking for at least two hours prior to

testing. A compact physiological monitoring system (Zephyr Bioharness), featuring a

chest strap and external multi recording and monitoring device was used to measure

heart rate, posture, breathing wave and respiration rate. The PowerLab 7.0 version

data acquisition and analysis software was used as a multi-recording device and

recorded data were sampled at a frequency of 60hz (60 samples per minute). All

participants undertook all four conditions of the experimental study whilst wearing

the chest strap connected to the Zephyr Bioharness which was connected via

Bluetooth to a multi-recording and monitoring device (PowerLab).

Data Cleaning

Prior to statistical analysis, all variables were assessed for the presence of

missing data and univariate outliers. For demographic data, missing values were not

replaced. For all other data, the method for identifying and treating missing values

and outliers preceded as follows. Firstly, variables were inspected to identify any

cases of missing data. No missing data were identified in any of the psychological

measures or physiological measures collected during the pre-measure phase or

experimental phase. Variables with a known, finite range were inspected for the

presence of erroneous data. Data errors were checked against the original written data

source (self-report measures) and corrected. The distribution of each variable was

visually inspected for each group to be compared (this included Group 1 (clinical) and

Group 2 (control) to identify outliers that appeared to represent measurement error

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rather than true individual differences, in accordance with the recommendations of

(Tabachnick and Fidell, 2007). No outliers were identified in the clinical group or

control group of participants.

Prior to conducting statistical analyses, the distributions of all variables were

visually inspected to determine if they were normally distributed, a requirement of

parametric statistical analyses. In cases where data did not adequately meet the

assumptions of normality and could not be transformed to normalise their

distributions according to recommended procedures (Tabachnick & Fidell, 2007),

non-parametric analyses were conducted.

Statistical Analyses

Physiological data, including respiration rate (RR) and heart rate (RR) data,

satisfied the assumptions for parametric analysis. Hence t-tests and ANOVA analyses

were used to investigate the differences between the clinical group and control on the

experimental conditions. Examination of normal distribution revealed that scores

across all self-report psychological measures taken at Pre-test, after Condition C

(CO2), and after Condition D (CFI plus CO2) including API, ASI, BAI, PACQ, STAI,

VAS-R, and VAS-P were not normally distributed so non-parametric tests were

utilised. Spearman’s correlation coefficient was used to investigate the relationships

between psychological measures. Friedman’s test was used to examine differences in

the psychological measures collected across the experimental conditions. The

Statistical Package for Social Sciences version 22.0 was used for all analyses. The

alpha level was set at 0.05 for all parametric analyses. A Bonferroni adjustment was

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performed for parametric analyses, resulting in a significance level set at Alpha = p <

.016.

RESULTS

Overview of Analysis

The analysis of this study is presented in two sections. The first section

presents the comparison of demographic details between groups and correlations of

the pre-test measures. The second section presents the data analyses of study

measures in relation to the hypotheses.

Participant demographics and correlations between pre-measures

Age was significantly higher (p = .035) in the clinical group (M = 36.4 years;

SD = 11.3) compared with the control group (M = 29.1 years; SD = 7.2). Tables 3

and 4 provide the means on categorical demographic variables for the clinical and

control groups. No significant differences were found between the groups. Although

the groups were matched statistically, there were apparent differences in gender and

education that may not have been significant due to the small sample size.

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Table 3

Demographic Information Categorical Data

Group 1 (Clinical)

Group 2 (Control)

Variable Fisher’s z N % N % Gender

Male Female

p=.172 1 15

6.30

93.70

5

11

31.30 68.70

Education Level No University Degree University Degree

p=.156 11 5

69.00 31.00

6

10

37.60 62.40

Employment Status Employed Unemployed/Student

p=.479 10 6

62.50 37.50

7 9

43.80 56.30

Smoking Yes No

p=1.000 2 14

12.50 87.50

3

13

18.80 81.20

Drinking Yes No

p=1.000 13 3

81.30 18.80

14 2

87.50 12.50

Physical Fitness Poor/Fair Good/Very Good

p=1.000 7 9

43.75 56.25

7 9

43.75 56.25

Physical Activity at Work Sedentary Non-sedentary

p=.252 9 7

56.30 43.70

13 3

68.80 31.20

Employment status Unemployed Employed/Student

p= .479 1 15

6.30

93.70

2

14

12.50 87.50

Weekly Physical Exercise < 3 hrs >3 hrs

p= 1.000 12 4

75.00 25.00

12 4

75.00 25.00

Weekly Cycling None Some

p= 1.000 12 4

75.00 25.00

13 3

81.25 18.75

Weekly Walking < 3 hrs >3 hrs

p= .242 8 8

50.00 50.00

12 4

75.00 25.00

Weekly home duties < 3 hr >3 hrs

p= .273 4 12

25.00 75.00

8 8

50.00 50.00

Weekly gardening None Some

p= 1.000 11 5

68.75 31.25

10 6

62.50 37.50

Walking Pace Slow/Steady, average Brisk pace/Fast>6km

p= 1.000 4 12

25.00 75.00

5

11

31.25 68.75

Note. N = 32 (group 1: n =16, group 2: n = 16).Fisher’s exact test (2-sided).

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Table 4

Demographic Information Continuous Data

Panic Controls

M SD M SD

Water Comfort (Mann-Whitney,

p=.809)

(0 = Not at all comfortable - 10 =

Very comfortable)

7.31 2.68 7.94 1.53

Average No. of Glasses per week

(Mann-Whitney, p=.423)

3.00 2.88 2.00 1.63

No. Push Ups (Mann-Whitney,

p=.140)

9.40 8.32 16.81 14.19

Height (Mann-Whitney, p=.468) 167.25 7.46 169.12 8.30

Weight (Mann-Whitney, p=.564) 74.22 17.97 70.47 17.02

Note. p-values are based on Mann-Whitney test (2 sided).

The Spearman rank-order correlation coefficient was used as a nonparametric

measure to determine the strength and direction of association that exists between the

pre-measure assessments. Table 5 provides correlations between pre-measures.

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Table 5

Correlations between Pre-measure Assessments

API CESD DIS BAI ASI STAI T STAI S PACQ

API - .64** .27 .69 .60 .61 .60 .60

CESD - .18 .71** .84** .93** .83** .74**

DIS - .41 .46 .13 .12 .48

BAI - .84** .77** .62 .86**

ASI - .70 .62 .82**

STAI Trait - .82** .75**

STAI State - .64

PACQ -

Note. N = 30. ** p < .001

A series of t-tests for independent groups was employed to determine if

significant differences existed between the clinical and the control group on the scores

of all psychological measures at Time 1. The results of the analysis indicated that

there were significant differences (p < .05) across all psychological measures at pre-

test (Time 1), between the groups, except for the DIS (p > .05). The DIS is a measure

of discomfort intolerance rather than anxiety.

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Data Analyses

Differences between groups in Breath-hold durations (Condition A)

Two independent samples t-tests were conducted to compare the differences in

breath-hold durations between the clinical and control groups. See Table 6 for

descriptive statistics and t-test results for the breath-hold tasks for both groups.

Table 6

Results of t-test and Descriptive Statistics for breath-hold (BH) tasks for Clinical and

Control groups

Group 95% CI for

Mean Difference

Clinical (n = 16) Control (n = 16)

M SD M SD T Df p

BH p. max

inhalation

44.05 18.17 53.30 18.03 -22.31, 3.82 -1.45 30 .912

BH p. max

exhalation 24.18 9.84 26.32 15.53 -11.53, 7.25 -.465 30 .725

Results revealed there were no significant mean differences between the

clinical participants and control participants in their breath-hold times following a

maximum inhalation (p > .05). Furthermore, when comparing mean differences in

breath-hold times following a passive exhalation, no significant mean differences

were found between clinical participants and control participants (p > .05).

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Physiological Differences in response to Cold Facial Immersion Task

(Condition B)

Figure 7 shows the mean average HR measured just prior to the CFI task, and

the mean average HR measured upon completion of the CFI task. Simple main

effects analysis showed that prior to the CFI task and upon completion of the CFI

task, participants experienced a significant decrease in heart rate, (F = (1, 30) = 58.87,

p =.00, η2=.662). However there was no significant main effect of group, with clinical

and control participants experiencing similar reductions in heart rate as a result of the

CFI task (F(1, 30) = .127, p = .724, η2=.007).

Figure 7. Mean Heart rate for clinical group (n = 16) and control group (n= 16) before

and after cold facial immersion (CFI).

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Physiological Differences in response to the CO2 Challenge (Condition C)

Table 7 shows the Mean RR measured 30 seconds before the CO2 Challenge

(Time 1) and Mean RR measured 30 seconds after CO2 Challenge (Time 2). There

was no significant interaction between the effects of group and CO2 challenge task on

participants’ RR, (F = (1, 30) = .057, p = .814, η2= .002). Simple main effects analysis

showed that between 30 seconds prior to the CO2 challenge (Time 1) and 30 seconds

following the CO2 challenge (Time 2), participants experienced no significant increase

in respiration rate, (F = (1, 30) = .079 p =.780, η2=.003). No significant differences

between respiration rates were observed between the clinical and control groups, (F(1,

30) = 1.062, p = .311, η2=.034).

Table 7

Descriptive Statistics for Time 1 and Time 2 of the CO2 Challenge

Group

Clinical (n = 16) Control (n = 16)

M SD M SD

RR Time 1 14.09 3.52 13.29 4.18

RR Time 2 14.48 4.16 13.89 4.53

HR Time 1 92.33 15.13 85.83 12.72

HR Time 2 90.91 14.76 89.11 13.73

Furthermore, there was no significant interaction found between the effects of

group and CO2 on participants’ HR, (F = (1, 30) =.805, p =.377, η2=.026). Simple

main effects analysis showed that between 30 seconds prior to the CO2 challenge

(Time 1) and 30 seconds following the CO2 challenge (Time 2), participants

experienced no significant change in heart rate, (F = (1, 30) = .497, p =.486, η2=.016).

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In addition, no significant differences between heart rates were observed between the

clinical and control group, (F (1, 30) = .130, p = .721, η2=.004).

Physiological response pre and post CO2 administered prior to CFI

(Condition D)

Table 8 shows the mean heart rates and respiration rates for participants before

and after the CO2 Challenge. A mixed ANOVA was conducted to compare the

clinical and control group in terms of the effect of the CO2 challenge task and group

on participants’ RR and HR.

There was no significant interaction between the effects of group and CO2

challenge task on participants’ RR, (F = (1, 30) = .002, p = .966, η2= .000). Simple

main effects analysis showed that between 30 seconds prior to the CO2 challenge

(Time 1) and 30 seconds following the CO2 challenge (Time 2), participants

experienced no significant increase in respiration rate, (F = (1, 30) = 4.381, p = .045,

η2= .127). No significant differences between respiration rates were observed between

the panic and normal group, (F(1, 30) = .011, p = 9.19, η2=.000).

There was no significant interaction was found between the effects of group

and CO2 on participants’ HR, (F = (1, 30) = .074, p = .788, η2= .002). Simple main

effects analysis showed that between 30 seconds prior to the CO2 challenge (Time 1)

and 30 seconds following the CO2 challenge (Time 2), participants experienced no

significant change in heart rate, (F = (1, 30) = 1.861., p =.183, η2=.058). In addition,

no significant differences between heart rates were observed between the clinical and

control group, (F(1, 30) = .001, p = .970, η2=.000).

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Table 8

Descriptive Statistics for Heart Rate and Respiration rate before and after CO2

Challenge

Group

Clinical (n = 16) Control (n = 16)

M SD M SD

RR b CO2 15.80 3.60 15.93 3.03

RR p CO2 14.74 3.61 14.83 3.36

HR b CO 88.95 15.22 89.48 8.93

HR p CO2 91.16 15.11 90.96 12.31

Physiological response pre and post the CO2 + CFI task (Condition D)

Figure 8 shows the Mean HR at the start of the CFI following the CO2

challenge and the Mean HR at the completion of the CFI task. A mixed ANOVA was

conducted with the clinical and control group to examine the effect of CFI following

the CO2 Challenge on participants’ HR and examine whether differences between

groups were observed. There was no significant interaction between the effects of

group and CFI on participant’s HR, (F(1, 30) = .222, p = .641, η2=.007). Simple main

effects analysis showed that between Time 1 (start of CFI task following CO2

challenge) and Time 2 (end of CFI task), participants experienced a significant HR

reduction, (F(1, 30) = 58.878, p <0.01, η2=.662). This was a very large effect size.

However no significant differences between the clinical and control group were

observed, (F(1, 30) = .127, p = .724, η2=.004).

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Figure 8. Heart rate for clinical group (n = 16) and control group (n= 16) at the start

and completion of the cold facial immersion task following CO2 Challenge.

Psychological Measures and the effects of CO2 and CFI

Mann Whitney U test was used to examine differences in the psychological

measures collected across the three time periods. The PD group has significantly

higher scores compared to the control group on all psychological measures at Time 1

(Pre-test), Time 2 (CO2), and Time 3 (CFI after CO2) (p<0.05), with the exception of

the Discomfort Intolerance Scale (DIS) (p = .09). Table 9 provides means for all self-

report psychological measures taken at Time 1 (Pre-test), Time 2 (CO2), and Time 3

(CFI after CO2).

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Table 9

Medians, Minimum, Maximum and Interquartile Ranges for Psychological Measures

at Time 1, Time 2 and Time 3.

Mdn Min Max Interquartile Range

Acute Panic Inventory

Time 1 (Pre-test)

Time 2 (CO2 challenge)

Time 3 (CO2 with CFI)

2.5

11.5

1

0

0

0

28

45

39

6

17.25

6.5

Anxiety Sensitive Index

Time 1 (Pre-test)

Time 2 (CO2 challenge)

Time 3 (CO2 with CFI)

21.5

21.5

10

0

3

0

59

63

63

19

23

22.5

Beck Anxiety Inventory

Time 1 (Pre-test)

Time 2 (CO2 challenge)

Time 3 (CO2 with CFI)

11

17

3

0

2

0

47

60

62

28.1

27.25

9

Panic Cognitions

Questionnaire

Time 1 (Pre-test)

Time 2 (CO2 challenge)

Time 3 (CO2 with CFI)

17

7

0

0

0

0

45

68

69

27.75

18.25

5.5

State Anxiety Inventory

Time 1 (Pre-test)

Time 2 (CO2 challenge)

Time 3 (CO2 with CFI)

38

44.5

32

21

24

9

71

79

66

17.5

22

14.5

VAS – Participant

Time 1 (Pre-test)

Time 2 (CO2 challenge)

Time 3 (CO2 with CFI)

7

6

2

0

0

0

9

10

8

5.38

6.13

3.13

VAS – Researcher

Time 1 (Pre-test)

Time 2 (CO2 challenge)

Time 3 (CO2 with CFI)

7.25

7

2

0

1

0

10

10

7.5

4.75

6.25

2.75

Note. N = 32 (group 1: n =16, group 2: n = 16).

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Specifically, Friedman’s test was used to examine differences in the

psychological measures collected across the three time periods. API ratings were

significantly different across the three times, χ2(2) = 29.540, p <.01. Post-hoc

analysis with Wilcoxon signed-rank test was conducted with a Bonferroni correction

applied, resulting in a significance level set at Alpha = p < .016. The median API

ratings were 2.5 at Time 1, 11.5 at Time 2, and 1.0 at Time 3. A significant increase

was seen between Time 1 and Time 2, Z = -3.393, p >.001 .016 and a significant

decrease was observed between Time 2 and Time 3, Z = -4.407, p <.001. Figure 9

displays a box plot of participants’ API scores measured at baseline (Time 1),

following the CO2 challenge (Time 2), and after CO2 challenge followed by CFI task

(Time 3).

Figure 9. Median and interquartile range of API scores for all participants (clinical

group and control group (N= 32) at Time 1*, Time 2*, Time 3* (* p <.05)

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ASI ratings were significantly different across two times, χ2(2) = 22.252, p <

0.01. Post hoc analysis with Wilcoxon signed-rank tests was conducted with a

Bonferroni correction applied, resulting in a significance level set at Alpha = p <.016.

The median ASI ratings were 21.5 at Time 1, 21.5 at Time 2, and 10.0 at Time 3.

There were no significant differences between the participants’ baseline ASI measures

and those taken at time 2, following the CO2 challenge, Z = -.160, p=.016. A

statistically significant decrease was seen between Time 1 and Time 3, Z=3.911, p <

.001 and between Time 2 and Time 3, Z = 4.097, p <.001. Figure 10 displays a box

plot of participants’ API scores measured at baseline (Time 1), following the CO2

challenge (Time 2), and after CO2 challenge followed by CFI task (Time 3).

Figure 10. Median and interquartile range for ASI scores for all participants (clinical

and control groups) (N= 32) at Time 1*, Time 2*, Time 3* (* p < .05).

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BAI ratings were significantly different across the three times, χ2(2) = 19.820,

p < 0.01. Post-hoc analysis with Wilcoxon signed-rank test was conducted with a

Bonferroni correction applied, resulting in a significance level set at Alpha =p < .016.

The median BAI ratings were 11 at Time 1, 7 at Time 2, and 3 at Time 3. A

significant decrease was seen between baseline and Time 3, Z = 3.183, p =.001. A

significant decrease was observed between Time 2 and Time 3, Z = 4.436, p <.001.

Figure 11 displays a box plot of participants’ BAI scores measured at baseline (Time

1), following the CO2 challenge (Time 2), and after CO2 challenge followed by CFI

task (Time 3).

Figure 11. Median and interquartile range BAI scores for all participants (clinical

group and control group (N= 32) at Time 1*, Time 2*, Time 3* (* p < .05).

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PACQ ratings were found to be significantly different across the three times,

χ2(2) = 18.589, p < 0.01. Post-hoc analysis with Wilcoxon signed-rank test was

conducted with a Bonferroni correction applied, resulting in a significance level set at

Alpha = p < .016. The median PACQ ratings were 17 at Time 1, 7 at Time 2, and 1 at

Time 3. A significant decrease was seen between baseline and Time 3, Z = 2.950, p

=.003. A significant decrease was observed between time 2 and Time 3, Z = 4.069 p

<.0.01. Figure 12 displays a box plot of participants’ PACQ scores measured at

baseline (Time 1), following the CO2 challenge (Time 2), and after CO2 challenge

followed by CFI task (Time 3).

Figure 12. Median and interquartile range for PACQ scores for all participants

(clinical and control (N= 32) at Time 1*, Time 2*, Time 3* (* p < .05).

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STAI ratings were significantly different across the three times, χ2(2) =

17.758, p < 0.01. Post-hoc analysis with Wilcoxon signed-rank test was conducted

with a Bonferroni correction applied, resulting in a significance level set at Alpha = p

< .016. The median STAI ratings were 38 at Time 1, 44.5 at Time 2, and 32 at Time

3. A significant increase was seen between Time 1 and Time 2, Z = 2.334, p =.020,

whilst a significant decrease was noted between Time 1 and Time 3, Z = 2.402,

p=.016. A significant decrease was also observed between Time 2 and Time 3, Z =

3.951 p <.001. Figure 13 displays a box plot of participants’ STAI (State) scores

measured at baseline (Time 1), following the CO2 challenge (Time 2), and after CO2

challenge followed by CFI task (Time 3).

Figure 13. Median and interquartile range for STAI (State) scores for all participants

(clinical group and control group (N= 32) at Time 1*, Time 2*, Time 3* (* p < .05).

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VAS participant were significantly different across the three times, χ2(2) =

36.051, p < 0.01. Post-hoc analysis with Wilcoxon signed-rank test was conducted

with a Bonferroni correction applied, resulting in a significance level set at Alpha = p

< .016. The median VAS-P ratings were 7 at Time 1, 6 at Time 2, and 2 at Time 3. A

significant decrease was seen between Time 1 and Time 3, Z = 4.691, p =.001, and

between Time 2 and Time 3, Z = 4.767 p <.001.

Figure 14 displays a box plot of VAS- Participant scores measured at baseline

(Time 1), following the CO2 challenge (Time 2), and after CO2 challenge followed by

CFI task (Time 3).

Figure 14. Median and interquartile range for VAS-Participant scores for all

participants (clinical group and control group (N= 32) at Time 1*, Time 2*, Time 3*

(* p < .05).

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VAS Researcher ratings were also significantly different across the three

times, χ2(2) = 36.051, p < 0.01. Post-hoc analysis with Wilcoxon signed-rank test was

conducted with a Bonferroni correction applied, resulting in a significance level set at

Alpha = p < .016. The median VAS-R ratings were 7.25 at Time 1, 7 at Time 2, and 2

at Time 3. A significant decrease was seen between Time 1 and Time 3, Z = 4.507, p

=.001, and between Time 2 and Time 3, Z = 4.767 p <.001. Figure 15 displays a box

plot of participants’ VAS Researcher scores measured at baseline (Time 1), following

the CO2 challenge (Time 2), and after CO2 challenge followed by CFI task (Time 3).

Figure 15. Median and interquartile range for VAS-Researcher scores for all

participants (clinical group and control group (N= 32) at Time 1*, Time 2*, Time 3*

(* p < .05).

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DISCUSSION

The principal findings of the current investigation indicate that there were no

significant differences in breath-hold durations amongst the clinical and control

participants. Overall, the CO2 challenge evoked anxiety and panic symptoms as self-

reported by clinical participants and the cold facial immersion (CFI) task

demonstrated anxiolytic effects by reducing heart rate, as well as self-reported

symptoms of anxiety and panic in both the clinical and control group. The findings of

this preliminary study are discussed in light of each relevant hypothesis.

Hypothesis 1: There was no significant difference in breath-hold (BH) ability

between the clinical and control group. Whilst the means of the BH durations in both

the passive exhalation and the maximum deep inhalation BH tasks were slightly lower

for the clinical group as compared to the control group, these differences were not

significant. One possible explanation for this finding may have been the relatively

small sample size that comprised this study. Hence the findings of this study did not

support this hypothesis. Previous research which has tested this hypothesis have used

different methodologies and yielded varied findings (van der Does, 1997; Asmundson

& Stein, 1994; Roth et al., 1998; Zandbergen et al, 1992, Nardi et al, 2002). The

varied results found in previous studies may be explained by many of the studies

comprising small, heterogeneous samples, diverse inclusion and exclusion criteria,

and different criteria for assessing panic attacks (PA).

Furthermore, these findings do not provide support for Klein’s theory, which

suggests that the brain’s suffocation detector incorrectly signals a lack of useful air

and increases vulnerability to false suffocation alarms and PAs. Furthermore, these

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findings do not support the breath-hold challenge as a potential marker for CO2

hypersensitivity to CO2 induced panic. Hypersensitivity to CO2 may be more notable

in the PD respiratory subtype as suggested by (Biber &Alkin, 1999; Gorman et al.,

1994; Papp et al., 1995; Perna et al., 1995; Nardi et al., 2004, 2006; Sardinha et al.,

2009). The small sample in this study and our recruitment method (general rather

than selecting sub-groups) precluded subgroup analysis. According to Nardi et al.

(2002), respiratory symptoms may play a role in both PAs and CO2 induced panic.

Their study reported that with a single breath of 35% CO2/65% O2 inhalation

participants with PD reported significantly stronger symptoms of panic and anxiety

than the control group. These findings were in line with those of Griez et al. (1987)

and Perna et al. (1994).

Hypothesis 2: In this study, it was expected that clinical and control

participants will experience a reduced heart rate (HR) in response to the CFI task.

This is in line with previous research that has demonstrated that the diving response

(DR) elicits a strong autonomic response characterised by a pronounced HR reduction

and blood centralisation to the organs that are most in need of oxygen (i.e., heart,

lungs and brain) (Asmussen & Kristiansson, 1968; Ferringo et al., 1997; Foster &

Sheel, 2005; Hong & Rahn, 1967; Schagatay & Andersson, 1998; Schagatay et al.,

2000). The results of the current study support this hypothesis and found that both

clinical and control participants demonstrated a significant bradycardiac effect (a drop

of approximately 30-35 beats per minute) following the CFI task. Hiebert and Burch

(2003), and Reyners et al. (2000) in their studies reported an average HR reduction of

approximately 20 beats per minute. Most studies have demonstrated HR reductions

between 25%- 40% following cold facial immersion (Andersson et al., 2002, 2004;

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Lindholm et al., 1999, 2002) demonstrated a HR decrease between 33% and 35%. In

the current study, cold facial immersion bradycardia reached a peak within 20 to 30

seconds, which is consistent with previous research (Andersson & Schagatay, 1998;

Baranova et al., 2017; Sterba & Lundgren 1988; Gooden, 1994; Ferrigno et al., 1986;

Lindholm & Lundgren, 2009). No differences between groups were observed as both

groups had a comparable HR reduction, in response to the CFI task, regardless of how

they responded to the CO2 challenge. The findings of the current study suggest that

the DR is a powerful physiological adaptation that is innate to all humans. This is in

line with previous research that has found that the DR is augmented by the CFI task or

by facial cooling (Yadav et al., 2017; Khurana & Wu, 2006, Schagatay, 2009).

Hypothesis 3: It was hypothesised that clinical participants would demonstrate

higher CO2 sensitivity in response to the CO2 challenge as evidenced by increased HR

and RR when compared to control participants. No significant differences were found

between the clinical and control groups in heart rate in response to CO2. Previous

research has yielded mixed results with some CO2 studies reporting an increase in HR

(La Pierre et al., 1984, Liebowitz, et. al., 1985; Woods, et al., 1988; Charney et al.,

1987a; Poonai et al., 2000; Schmidt, Richey, Maner et al., 2006) and some reporting a

decrease or no change in HR (Nicolai et al., 2008; Gorman et al., 1990).

Furthermore, this study reported no significant difference in respiration rates

between the clinical and control group. Although previous research examining

respiration rate (RR) post CO2 has yielded mixed results, our findings lend support to

those of Griez and van det Hout (1983; 1986), Klein (1993), and Schimitel et al.

(2012) which reported no significant differences in respiration rates following CO2

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inhalation. Contrary, to the findings of van den Hout and Griez, (1984), the CO2

challenge did not induce a significant increase in RR in clinical and control

participants. Previous studies have reported that 50% of clinical panic participants

describe difficulties with taking a deep inhalation of CO2 and feeling breathlessness

(Perna et al., 2004b). This difficulty was also observed with the clinical group in this

study, with some participants reporting discomfort in breathing and with the bad

odour. Hence it is plausible that the full effects of CO2 were not observed as some

participants may not have taken a full inhalation of CO2. According to Griez and van

den Hout (1986) in order for the 35% CO2 test to be valid, a participant needs to

inhale at least 80% of their vital capacity.

Hypothesis 4: It was hypothesised that clinical participants would report

increased anxiety symptoms when compared to control participants, in response to the

CO2 challenge. The results of this study indicate that, compared to the controls, the

clinical participants reported experiencing more anxiety and panic symptoms

including panic cognitions and anxiety sensitivity in response to the CO2 challenge on

the following anxiety measures; Anxiety Sensitivity Index (ASI), Acute Panic

Inventory (API), State and Trait Anxiety Inventory (STAI), Panic Attack Cognitions

Questionnaire (PACQ), Beck Anxiety Inventory (BAI), Visual Analogue Scale

completed by the participant (VAS-P) and researcher (VAS-R). This finding is in line

with previous research which has reported increased anxiety symptoms as measured

by self-reports on anxiety measures and researcher observations following the CO2

challenge (Beck, Ohtake & Shipherd, 1999; Battaglia et al., 1995). In some studies,

healthy controls have reported a rise in anxiety symptoms, following the 35% CO2

challenge (Gorman et al., 2001; Griez & van den Hout, 1986; Harrison et al., 1989;

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Woods et al., 1988), however this is not comparable to PD participants who display

heightened anxiety and panic symptoms (Griez & Verburg, 1998; Papp et al., 1993;

Verburg et al., 1995). In a placebo controlled experiment the 35% CO2 challenge

provoked the interoceptions characteristic of panic attacks in healthy controls which

were observed to largely overlap with those reported by clinical participants (Griez, &

van den Hout, 1982; Harrison et al., 1989; van den Hout & Griez, 1984). Harrison et

al. (1989) in their study reported increases in the Acute Panic Inventory (API) and

anxiety ratings following the CO2 challenge in control participants. However despite

control participants experiencing anxiety, very rarely do they experience PAs in

response to the CO2 challenge (Perna et al., 1995).

The findings of the current study indicate that clinical participants reported

increased anxiety compared to control participants however this hypothesis was not

able to be completely tested due to limitations in the data. As the self-report measures

were not normally distributed, non-parametric statistics were used to examine the

effects of pre and post CO2 using repeated measures (Friedman’s and Wilcoxon

signed-rank tests). However, these statistics did not allow for a comparison of the pre

and post effects, and more specifically the increase in heart rate between groups for

the study conditions.

Furthermore, it appears that both groups may have experienced some

anticipatory anxiety with the clinical group, reporting elevated levels of anxiety at

Time 1. In relation to the CO2 challenge, the clinical group had more elevated anxiety

as measured by the anxiety measures administered at Time 2, as compared to the

control group. In the control group, although the ASI and the STAI scale scores were

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much lower than the clinical group, they were somewhat elevated as compared to all

the other anxiety measures at Time 1. A possible explanation could be that control

participants may have experienced some anticipatory anxiety with respect to the

experimental design.

Hypothesis 5: It was hypothesised that all participants will report significantly

lower anxiety in response to the CO2 challenge with Cold Facial Immersion (CFI)

when compared to baseline measures and the CO2 challenge alone. The findings of

this study support this hypothesis. All anxiety measures including the ASI, API,

STAI, PACQ, BAI, VAS-P, and VAS-R were lower at Time 3 (CO2 with CFI)

compared to Time 1 (baseline) with the exception of API. This makes sense as

control participants scored lower on the API, as they did not experience a PA in

response to the CO2 challenge. Furthermore, all participants reported a significant

decrease in anxiety symptoms across all of the measures between Time 2 (CO2

Challenge) and Time 3 (CO2 with CFI). The findings of this study lend support to the

application of the diving response and CFI in reducing panic cognitions and

symptoms of anxiety and panic. Furthermore, these results indicate some promise in

terms of the utility of CFI in assisting with the management and reduction of anxiety

and panic symptoms.

In view of the small sample size, the results of this study need to be interpreted

with caution. With regard to breath-hold (BH) durations, our findings were not in line

with the findings of Asmundson and Stein (1994) who found that patients diagnosed

with PD had significantly shorter BH durations than healthy participants. Our

findings were not in line with Klein’s (1993) theory of the suffocation false alarm

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theory, and the findings of Asmundson and Stein (1994), who suggested that

participants with PD terminate their BH earlier in order to avoid activation of the

suffocation alarm. A plausible explanation for why we did not yield the results we

expected may have been due to the relatively small sample size of the clinical group.

Future research of breath-hold durations between clinical and control groups should

look at investigation with a larger sample size that is adequately powered.

The current findings are consistent with Harrison et al. (1988), who found no

significant differences in HR changes between panic patients and controls following

the CO2 challenge, even though there was a trend for the heart rate increasing. It is

well established in the literature that CO2 induced hyperventilation, elicits a sudden

increase in ventilation accompanied with a surge of anxiety that mimics a PA (Klein,

1993; Griez & van det Hout, 1986) and triggers arousal of the conditioned fear

response in panic patients (Sinha et al., 2000; MacKinnon, Craighead & Hoehn-Saric,

2007). Woods, Charney, Goodman and Heninger (1988) in their study demonstrated

that the panic patients who experienced CO2-induced panic attacks (PAs) showed HR

responses to CO2 that were significantly greater than those of the non-panicking

patients, perhaps reflecting greater cardiac sympathetic stimulation by CO2.

Moreover, in response to the CO2 challenge, reports from the literature

indicate that patients tend to experience remarkable hyperventilation and subsequent

cognitive symptoms of anxiety (Klein, 1993). Both healthy and people diagnosed

with an anxiety disorder report feeling anxiety symptoms following CO2 inhalation

(Woods et al., 1986; Gorman et al., 1984; van det Hout & Griez, 1984). However, the

response in normal controls, as well as individuals suffering from generalised anxiety

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disorder (GAD), is generally much weaker than individuals suffering from PD (Griez,

Zandbergen, Pols & de Loof, 1990). Both healthy and anxious patients produce

anxiety following CO2 inhalation (Woods et al., 1986; Gorman et al., 1984; van det

Hout & Griez, 1984). However it is unlikely that CO2 evokes all 13 possible

symptoms of PD, and there is reported variability in the intensity of the symptoms

experienced (Perna et al., 1994). Individual sensitivity to the CO2 challenge and to

increased concentrations of CO2 may have accounted for some of the challenges with

the provocation study. Five out of ten studies reported greater increases in heart rate

(HR), of drug-induced panic, all of which involved the administration of sodium

lactate (La Pierre et al., 1984; Liebowitz, et al., 1985; Woods et al., 1988; Charney et

al., 1987a).

Hence the CO2 challenge may not be the best provocation method to induce

changes in HR. Notably, Kaye et al., (2004) found a significant decrease in HR

lasting 90 seconds post the CO2 challenge. This was in line with the findings of Griez

and van den Hout, (1983). On the contrary significant increases in HR post CO2 have

been noted (Poonai et al., 2000; Schmidt, Richey, Maner et al., 2006). The increase in

HR perhaps reflects greater sympathetic stimulation and noradrenergic neuronal

function (Woods et al., 1988). Research comparing PD with controls on their HR

response is limited, and two studies yielded no significant differences in neither of the

groups, in HR change from baseline to post CO2 inhalation (Nicolai et al., 2008;

Gorman et al., 1990).

A key finding of the study was that there was a significant increase in anxiety

symptomatology between Time 1 (baseline) and Time 2 (following CO2 challenge) on

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the following measures Acute Panic Inventory (API) and State Anxiety (STAI) as

reported by PD participants. This suggests that a number of clinical participants may

have experienced a panic attack or elevated anxiety levels induced by the CO2

inhalation. On the contrary, a number of participants may have had reduced panic

symptoms at Time 2, following the CO2 challenge, this was noted with the PACQ

measure. A plausible explanation for this may be that clinical participants at Time 1,

may have experienced more significant anticipatory anxiety in relation to the

experimental design as compared to Time 2.

In response to the CFI task, participants had significantly reduced self-

reported anxiety, as measured by the API, BAI, PACQ, STAI, at Time 3 (CO2 with

CFI) when compared to Time 1 (baseline). Also, there was a significant decrease in

both the VAS-P and VAS-R from Time 2 (CO2 Challenge) to Time 3 (CO2 with CFI).

This suggests that clinical participants following the CFI task reported minimal panic

or anxiety symptoms. The clinical group had significantly lower anxiety on all

anxiety measures (API, ASI, BAI, PACQ, STAI) following Time 3 (CO2 with CFI),

as compared to Time 2 (CO2 challenge). This is likely to be due to the activation of

the diving response (DR), a powerful autonomic reflex which initiates a bradycardiac

response.

These particular findings of this preliminary study may provide us with some

novel insights. It is of particular merit to note, that by activating the DR and

subsequently reducing one’s heart rate, one may observe reductions in both

physiological, and cognitive symptoms of panic and potentially in CO2 sensitivity.

One of the scariest symptoms, reported by sufferers of PD is the heart racing or

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pounding. Hence reducing the heart rate and the autonomic sympathetic nervous

system arousal may have a positive impact on self-reported anxiety. Another

common symptom reported by panic sufferers that are associated with fear are the

feelings of suffocation and dyspnea. On the contrary, when the DR is activated, it has

an oxygen conserving effect which extends the breath-hold with an aim to assist the

organism to survive. Hence, cold facial immersion may prove to be an effective

treatment for PD and other anxiety disorders. Furthermore, the DR can be easily

activated with cold moisture (i.e., ice pack) making it an easy to administer treatment.

Studies have demonstrated significant heart rate reductions, by the application of

cooling packs on the face (Brown, Sanya & Hilz, 2003) which too activate the DR.

Study Limitations

A limitation of this preliminary study was the recruitment of clinical

participants which proved difficult due to a number of constraints and challenges.

Specifically, the extensive list of exclusion criteria for individuals to be eligible to

participate in the study limited the sample. Many participants who were interested in

participating had other comorbidities or were taking prescribed medication. In the

current study, a number of participants were excluded based on their comorbidities.

Recruitment challenges also made it hard to match participants as closely as we had

planned. People with PD were significantly older on average than control participants

and this may have influenced the physiological and psychological outcomes in this

study.

Moreover, some candidates that expressed interest in participation did not

participate as they communicated to the researcher that they did not want to

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participate once informed of the experimental protocol due to their perceived fear that

the CO2 challenge may evoke a panic attack, and their perceived fear of losing

control. Some candidates that expressed interest in participation may have not

participated due to their perceived anxiety or discomfort involving the cold facial

immersion (CFI) task, and the breath-holding (BH) tasks. Furthermore, the

participants in the control group were mostly university students studying psychology,

and hence the results may not be truly representative of the normal population.

There were also there were some difficulties noted with the breathing

apparatus used for the CO2 challenge and with the provocation method as mentioned

previously. Although participants were instructed to take in a maximal vital capacity

inhalation during the CO2 challenge of a premixed gas comprising 35% CO2 and 65%

from the Douglas bag, some did not inhale deeply as instructed. Notably, this may

have affected the results; both the physiological response to the CO2 challenge as

measured by changes in heart rate and respiration rate and the psychological response

as measured by the anxiety measures. Moreover, not all participants were able to hold

their breath with the inhaled gas mixture for a period of 4 seconds before exhaling it,

as instructed. This was because some participants reported that they did not like the

taste, and some participants found the CO2 challenge elicited some symptoms that

made them reportedly anxious or panicky. Although participants were reassured that

is a completely safe procedure, and all they may experience is some transient

breathlessness, one may anticipate that the CO2 challenge may have evoked some

anxiety and hence they did not comply with the instructions of the task. This was

particularly observed in some PD participants who demonstrated some difficulty with

the inhalation of the CO2 challenge. The participants who were observed to have had

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difficulty doing this, may not have had a marked physiological response, following

the CO2 challenge, as they may not have had the transient breathlessness or the

elevated heart rate. Given that to be considered a valid test, participants need to

inhale at least 80% of their vital capacity of CO2 (Griez & van den Hout, 1986), our

results may have been impacted by the inability of some participants in achieving this.

Given the brevity of the task, it was not anticipated that participants would experience

difficulty in carrying out the CO2 challenge as per instructions. Future studies should

emphasise the importance of a maximum inhalation and maintaining the breath-hold

for 4 seconds to participants.

Another important limitation was that results were variable for each

individual. For example, some participants experienced transient breathlessness

immediately after the CO2 challenge, whereas with others there was a delay. For the

purposes of our statistical analysis, mean data were compared 30 seconds prior to the

CO2 challenge with 30 seconds post CO2 challenge, hence it was difficult to capture

unique differences in individual participants. However, when data were examined on

a case by case basis, a trend is depicted, characterised by a more elevated respiration

rate (RR) and heart rate (HR) in the clinical participants in response to the CO2

challenge, when compared to the control group. The data proved to be difficult to

interpret due to the increased variability in response to the CO2 challenge. Some

participants experienced an increase in RR immediately after the CO2 challenge,

whereas others had a delayed response up to a minute or two following the CO2

challenge. Furthermore, there was also variability in the HR increase following the

CO2 challenge, some participants had an increase in HR immediately after the CO2

challenge, whereas in others there was a delayed response. It was also observed that

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in some cases the increase in HR and RR was not concurrent following the CO2

challenge, but rather the increased responses in HR and RR were noted at different

time intervals. This was an important limitation of the study, as comparing 30

seconds of physiological data 30 seconds prior to the CO2 challenge to 30 seconds

following the CO2 challenge, did not provide us with an accurate reflection of the RR

and HR rate fluctuations. Previous research has yielded mixed results in regards to

RR and HR changes in response to the CO2 challenge, and found that RR and HR

changes are not always concurrent (La Pierre et al., 1984, Liebowitz et al., 1985;

Woods et al., 1988; Charney et al., 1987a; Poonai et al., 2000; Schmidt, Richey,

Maner et al., 2006; Klein, 1993 & Schmitel et al., 2012). Hence the statistical

analyses conducted did not take into consideration these cardiorespiratory fluctuations

post 30 seconds after the challenge, as this data was not available across all tasks.

FUTURE RESEARCH

Rationale for Study 2

The results of this preliminary study indicated that the cold facial immersion

(CFI) had a powerful autonomic response, evidenced by a significant reduction in

heart rate (HR) as well as a reduction in self-reported psychological and physiological

symptoms of anxiety. Upon the completion of this study, the main findings that

intrigued the researchers were that there was a marked reduction in anxiety and panic

symptoms reported on anxiety measures following the CO2 plus CFI task.

In designing Study 2, the researcher wanted to establish whether trained

effects of the CFI task could change individuals’ response to the CO2 challenge. The

proposed design put forward to the Ethics committee entailed both panic and control

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groups practising three daily CFI task administrations for a period of four weeks at

their own home. This design posed a number of ethical and safety considerations

regarding practicing the CFI task at home. Although we proposed that the CFI would

be practiced under supervision in participants’ own homes, the research ethics

committee were concerned that there may be public liability issues and safety, risks as

participants would not have appropriate supervision at home. Hence our submitted

ethics application was not approved by the Swinburne University Ethics Committee.

Consequently, as a result of ethical dilemmas and time constraints, ideas exploring

trained effects of the CFI were discontinued the design for the second study protocol

was reviewed.

The rationale for the next study resulted primarily from the CFI having such a

powerful response in terms of reducing panic and anxiety symptoms. The results

warranted further exploratory investigation of CFI and more specifically the

researcher thought it would be of merit to continue investigating the effects of CFI

with a clinical group compared to normal controls. In reviewing the findings of the

preliminary study, Condition D (CO2 challenge, plus CFI), appeared to elicit the most

notable changes in anxiety symptoms and physiological response. Hence examining

this relationship further was the core focus of the next study. It was conceptualised

that if Condition D is reversed and the CFI task is administered prior to the CO2

challenge, one may be able to make inferences about the effects of CFI, on an

individual’s response to the CO2 challenge, and more specifically to CO2 sensitivity.

Based on research on the trained effects of the diving response (Konstandinidou &

Chairopoulou 2017) and the findings of the preliminary study, there was value in

exploring whether CFI could be used as an intervention to reduce and prevent panic

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symptoms and panic attacks. Moreover, the genesis for the rationale of the second

study seemed to follow a logical sequence, given that it is well established in the

literature that patients with PD have higher CO2 sensitivity (Gorman et al., 2000;

Griez & Perna, 2003; Kent et al., 2001; Klein, 1993). Furthermore, the results of the

preliminary study indicated that the CFI task was able to reduce both physiological

symptoms and cognitive symptoms of anxiety and that this has not been researched

previously. Therefore, an experimental protocol was designed in an attempt to

explore this further.

It is of particular interest to preliminary investigate the CFI task, as a potential

intervention in order to further understand its utility, application and efficacy in

managing anxiety and panic symptoms. Given that the CO2 challenge was

administered before the CFI, the researchers wanted to determine whether

administering the CFI prior to the CO2 will change the response one has to the CO2

challenge by comparing the physiological response from the first administration

(baseline measure) to the second administration following the CFI. Furthermore, this

is the first study to look at the CFI as a potential treatment intervention, a combination

of qualitative research and quantitative research was decided upon to further

complement this preliminary investigation.

IMPROVEMENTS OF RESEARCH PROTOCOL

Physiological data were recorded at specific intervals for each of the study

conditions. In analyzing the respiration and heart rate data sets, it was noted there

was variability in the physiological outcomes observed at different times post the

interventions between participants, i.e., some participants had physiological changes

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later than others. Hence, it was difficult to determine the best way to analyse the data

set. Based on the available data recordings the data was compared 30 seconds prior to

the CO2 challenge to 30 seconds following the CO2 challenge to be able to allow the

researchers to compare the changes in mean heart rate. The sampling period prior to

CO2 was limited to 30 seconds for some participants because of technical issues,

hence this sampling period was applied consistently across the cohort. Individual data

for each participant was visually inspected and this also informed the time period over

which physiological data were measured pre and post the conditions. This was partly

informed by the literature, which suggests that the CO2 challenge elicits a brief but

strong respiratory response accompanied by neurovegetative symptoms (Griez et al.,

1987; Griez & van den Hout, 1982; van den Hout & Griez, 1984). Hence in the

second study investigating the effects of cold facial on CO2 sensitivity and

anxiety/panic symptoms, it was decided to extend the sampling period until 60

seconds post study conditions.

In the preliminary study, a pulse oximeter was used to measure oxygen

saturation (SaO2) levels in the blood. The pulse oximeter was worn on the index

finger, and samples at a frequency of 60hz (60 samples per minute). This was used

during the CFI task, however, this was discontinued as it was difficult to record the

SaO2 levels and the HR on a second to second basis from the pulse oximeter.

Recording SaO2 levels proved to be difficult and did not yield reductions in SaO2

during the CFI task which lasted approximately 30 seconds. Hence the use of the

pulse oximeter was ceased early on in the first study. Furthermore, the researchers

decided that SaO2 was beyond the scope of the research questions for the study and

hence did not warrant measuring. Based on the findings of the preliminary study, the

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second study had a slightly modified design, in an attempt to ameliorate the protocol

of the experimental design. The pulse oximeter in the second study was re-introduced

to verify the heart rate recorded on the Zephyr Bioharness, as a cross reference check

before undertaking each CO2 challenge and the CFI tasks. Whilst it was not intended

for SaO2 levels to be included in the data analysis, it was introduced as an aid for the

researcher to cross-reference that the equipment was properly secured on the

participants and recording accurately.

Another problem identified in the preliminary study was the difficulty some

participants experienced with taking a maximal deep inhalation during the CO2

challenge. Although participants were instructed to take a maximal deep inhalation

when breathing in the 35% CO2 and 65% O2 gas mixture, there were varying degrees

of inhalation observed between participants as discussed earlier. Given there were a

number of constraints including time, resources and equipment available at

Swinburne University, an alternative strategy was employed for the second study.

The participant’s in the second study were instructed participant to take a maximal

deep inhalation prior to the CO2 challenge, in order to compare if the maximal deep

inhalation taken during the CO2 challenge, is comparable to the previous maximal

deep inhalation breath taken.

In the preliminary study, the use of medication was exclusionary because

numerous antidepressant and anxiolytic drugs may significantly reduce the response

to the CO2 challenge. In order to improve the sample size in the second study, the

researcher proposed to the Ethics Committee to allow the intermittent use of

painkillers and anxiolytics such as benzodiazepines, as long as they have not taken

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any of these medications for at least 3 days prior to their participation in the research

study. If participants were not able to achieve 3 days of abstinence of the intermittent

use of medications, they were excluded or testing time was rescheduled.

Hence the main improvements for the next study included:

• Recording physiological data from 30 secs prior to 60 seconds post

conditions

• Clearer instructions for participants regarding taking in a maximal

inhalation prior to commencing the experimental conditions.

Participants were also required to practice one maximal inhalation

breathing in room air. This allowed the researcher to have a

comparison point and assess whether participants were having

difficulty in taking in the maximal inhalation of CO2.

• More flexible exclusion criteria to include some medications and

comorbidities of other anxiety disorders and depression. These

comorbidities resulted in potential participants being excluded in the

preliminary study.

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Chapter 6

STUDY 2. THE EFFECTS OF COLD FACIAL

IMMERSION ON CO2 SENSITIVITY

AIM

This study aims to further investigate the applications of the diving response

(DR) for panic disorder (PD) and more specifically determine whether CFI has a

preventative effect on panic-related symptoms and cognition. This study comprises

two phases, the first of which specifically examines the applications of the DR and

cold facial immersion (CFI) in altering CO2 sensitivity in participants with PD. The

second phase of this study is a qualitative exploration of the current strategies used by

clinical participants to manage anxiety and panic symptoms as well as the challenges

they experience in managing their symptoms. The qualitative study also explores all

participants’ experience of CFI as well as barriers and enablers to the therapeutic use

of this technique among people with PD. The qualitative exploration is presented in

Chapter 7.

HYPOTHESES

Hypothesis 1

Cold facial immersion (CFI) will reduce clinical and control participants’

sensitivity to CO2 as evidenced by heart rate (HR) and respiration rate (RR)

reductions following the subsequent CO2.

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Hypothesis 2

Participants in both groups will report a reduction in anxiety symptoms

following CFI and subsequent CO2 when compared to pre-measures and the CO2

administration without CFI.

METHOD

Participants

A total of 36 participants were recruited to participate in this study. Of these

three participants chose to discontinue, and three were excluded from being able to

participate as part of the clinical group during the initial screening stage of the study.

Of the participants that withdrew from the study out, two were screened into the

clinical group and one into the control group. The two clinical participants chose to

discontinue after experiencing discomfort with the CO2 inhalation, and the control

participant chose to discontinue after his partner in the clinical group withdrew from

the study. The other three participants who were excluded from the study met the

criteria for a diagnosis of PD, however one was taking medication within the

exclusion criteria, and two did not meet the criteria for PD and had other co-

morbidities, and hence on this basis, all three participants were excluded from the

study. Sample size calculations were not possible as the response to CO2 and CFI has

not previously been investigated among people with PD. Therefore, we recruited as

many participants as possible within the time and budget constraints of this PhD

research study. Due to difficulties with recruitment with regard to participants who

could meet the criteria for inclusion into the clinical group, 5 clinical participants who

participated in the preliminary and expressed interest in being involved in further

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research were invited back to participate in within the clinical group of this study.

Hence the final clinical and control samples for Study 2 comprised 30 participants: 15

participants with a primary diagnosis of panic disorder (PD) with or without

agoraphobia (DSM-V) (Clinical Group 1), and 15 controls who did not meet criteria

for PD or mental illness (Control Group 2). Of the 30 participants, 15 were male, and

15 were females. The participants in the clinical group had an average age of 36.3

years (SD = 13.8), whilst the participants in the control group had an average age of

33.1 years (SD = 7.7). Both groups comprised 6 males and 9 females. Given that

there were recruitment challenges, participants were matched as closely as possible.

Demographic and clinical data for all participants are reported in the results section of

this chapter.

Participant Sampling and Screening

Health screening assessments were carried out to establish medical eligibility

to undergo the CO2 challenge. Potential participants for both the clinical and control

groups also underwent a clinical interview to assess participants against the inclusion

and exclusion criteria as described in Chapter 4.

However, for the exclusion criteria regarding co-morbidities with Axis I

Disorders, as measured by the DSM-V (APA, 2013), was adjusted. The exclusion

criteria included all other comorbidities with the exception of another anxiety disorder

and depression being secondary to the panic disorder (PD). Depression, Generalised

Anxiety Disorder, and Social Anxiety Disorder were amongst the most popular

comorbidities found in our study, so it was decided that if these were secondary to

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PD, that they will be included. Such comorbid disorders were diagnosed by the

researcher who was a clinical psychologist that was secondary to PD.

Recruitment

Participants for both the clinical group and control group were recruited as

described in Chapter 4. To increase the likelihood of recruiting more clinical

participants, and to display a gesture of appreciation for the participation in the study,

two movie tickets were offered to participants upon completion of the study.

Measures

All participants were required to complete a battery of psychological

assessments at three time points throughout the study. Descriptions of the

psychological measures utilized in this study are described in Chapter 4. Table 10

provides a list of the batter of psychological measures and the time points at which the

measures were administered throughout the study. Physiological measures including

heart rate and respiration rate were also recorded at various points throughout the

study.

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Table 10.

Battery of Psychological Assessments Administered Before and During the Study

Psychological Measures Administrations

1. Anxiety Sensitivity Index (ASI) Time 1 (Baseline), Time 2, Time 3

2. Beck Anxiety Inventory (BAI) Time 1 (Baseline), Time 2, Time 3

3. Discomfort Intolerance Scale (DIS) Time 1 (Baseline)

4. State/Trait Anxiety Inventory (STAI) (A-Trait) Time 1 (Baseline)

5. State/Trait Anxiety Inventory (STAI) (A-State) Time 1 (Baseline), Time 2, Time 3

6. Panic Attack Cognitions Questionnaire (PACQ) Time 1 (Baseline), Time 2, Time 3

7. Acute Panic Inventory (API) Time 1 (Baseline), Time 2, Time 3

8. Visual Analog Scale for Anxiety (VAS) (Participant &

Researcher) Time 2, Time 3 (x 2)

9. Center for Epidemiological Studies Depression Scale

(CES-D) Time 1 (Baseline)

Research Design

Participants took part in two experimental challenges including the (1) CO2

Challenge, and (2) Cold Facial Immersion Task followed by CO2 Challenge. The

assignment of conditions was counterbalanced. Figure 16 displays the experimental

procedure indicating when physiological and psychological (cognitive) measures were

collected as part of this study.

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Figure 16. Experimental procedure for data collection for Group 1 (Clinical) and Group 2 (Control) participants.

ASSIGNMENT OF EXPERIMENTAL CODITIONS FOR

CLINICAL (GROUP 1) & CONTROL

(GROUP 2) PARTICIPANTS

WERE COUNTER -BALANCED

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Procedure

The experimental study was held at a clinical room at Swinburne University,

which was specifically set up for the research. A compact physiological monitoring

system (Zephyr Bioharness), featuring a chest strap and external multi-recording and

monitoring device was used to measure heart rate, posture, breathing wave and

respiration rate. All participants undertook the challenges involved in this study

whilst wearing the chest strap connected to the Zephyr Bioharness. Participants were

required to undertake Time 1 and Time 2 procedures on the same day. Participants

were scheduled to complete Time 3 tasks on a different day as ethics approval only

allowed for participant’s to complete one CO2 inhalation per day.

On completion of the experimental procedure for this study, participants were

invited to participate in an interview in which the researcher asked clinical

participants a number of qualitative questions regarding their experience of their

anxiety and panic symptoms. Both clinical and control participants were also asked

about their experience of the CFI task. The results of the Qualitative Study are

discussed in Chapter 7.

Data Cleaning

Prior to statistical analyses, all variables were assessed for the presence of

missing data and outliers, in accordance with the method described in Section 4.3.3.5.

The data revealed missing values and hence Little’s Missing Completely at Random

(MCAR) test was used to assess whether data were missing at random. Assumptions

for the MCAR test were assessed and fulfilled, χ2 (39) = 46.165, DF = 39, p > .005.

Missing values were replaced using the expectation-maximisation (EM) algorithm for

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imputation. Prior to conducting statistical analyses, the distributions of all variables

were visually inspected to determine if they met the assumption of normality of

distribution, a requirement of parametric statistical analyses. In cases where data did

not adequately meet the assumptions of normality and could not be transformed to

normalise their distributions according to recommended procedures (Tabachnick &

Fidell, 2007), non-parametric analyses were conducted.

Statistical Analyses

Prior to conducting parametric analyses, data were inspected to ensure they

met assumptions for such analyses. Physiological data, including respiration rate

(RR) and heart rate (HR) data, satisfied the assumptions for parametric analysis.

Hence t-tests and ANOVA analyses were employed to investigate the differences

between the clinical and control group on the experimental conditions. Examination

of normal distribution revealed that scores across all self-report psychological

measures taken at Pre-test, at Time 1 (CO2) and Time 2 (CFI plus CO2), including

API, ASI, BAI, PACQ, STAI, VAS-R, and VAS-P did not meet the assumptions of

normal distribution for parametric analyses. Hence non-parametric tests were utilised.

Spearman rank-order correlation coefficient was used to investigate the relationships

between the psychological measures. Friedman’s test was used to examine

differences in the psychological measures collected across the experimental

conditions. Demographic information was compared for Group 1 and Group 2 using

Fishers. The Statistical Package for Social Sciences version 22.0 was used for all

analyses.

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RESULTS

Overview of Analysis

The analysis of this study is presented in three sections. The first section

presents the comparison of demographic details between groups and the correlations

of the pre-test measures. The second section reports the examination of physiological

differences between the panic and control groups at Time 1 and 2. This section also

reports the results of mixed ANOVAs, examining the effects of Time 1 and Time 2

tasks on the participant’s physiological responses (HR and RR). The third section

examines the effects of the CO2 challenge and ultimately the effect of CFI on CO2

sensitivity across the anxiety measures. When outcomes were not normally

distributed Friedman tests were used instead of ANOVA tests and Wilcoxon signed–

rank tests were used instead of paired t-tests.

Correlations between Pre-measures

No significant differences (p = .44) in age were observed between the clinical

(M = 36.3 years, SD = 13.8) and control groups (M = 33.1 years, SD = 7.7). Tables

11 and 12 provide a comparison for the clinical and control groups. In examining the

demographic information in Study 2, significant differences were observed between

groups in education level and gardening. Participants were matched for age and

gender as closely as possible.

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Table 11

Demographic Information Categorical Data

Group 1 (Clincal) Group 2 (Controls)

Variable Fisher’s z, N % N %

Gender Male Female

p = 1.000 6 9

40

60.00

6 9

40.

60.00 Education Level p = .005

No University Degree 9 60.00 1 6.67 University Degree 6 40.00 14 93.33

Employment Status p =.008 Employed 8 53.33 7 46.77 Unemployed/Student 7 46.77 8 53.33

Smoking Yes No

p = .651 4 11

26.67 73.33

2 13

13.33 86.67

Drinking Yes No

p = .050 7 8

46.77 53.33

13 2

86.67 13.33

Physical Fitness p = .1000 Poor/Fair 5 25.00 6 40.00 Good/Very Good 10 75.00 9 60.00

Physical Activity at Work p = .715 Sedentary 9 60.00 7 46.77 Non-sedentary 6 40.00 8 53.33

Employment status p = 1.000 Unemployed 5 25.00 1 6.67 Employed/Student 10 75.00 14 93.33

Weekly Physical Exercise p = .206 < 3 hrs 10 75.00 11 73.33 >3 hrs 5 25.00 4 26.67

Weekly Cycling p = 1.000 None 15 100.00 14 93.33 Some 0 0.00 1 6.67

Weekly Walking p = 1.000 < 3 hrs 7 46.77 8 53.33 >3 hrs 8 53.33 7 46.77

Weekly home duties p = 1.000 < 1 hr 9 60.00 11 50.0 >3 hrs 6 40.00 4 50.0

Weekly gardening p = .035 None 8 53.33 14 93.33 Some 7 46.77 1 6.77

Walking Pace p = 1.000 Slow/Steady, average 6 40.00 5 25.00 Brisk pace/Fast>6km 9 60.00 10 75.00

Note. N = 30 (group 1: n =15, group 2: n = 15). p-values from Fisher’s exact test (2-sided).

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Table 12.

Demographic Information Continuous Data

Panic Controls

M SD M SD

Water Comfort

(Mann-Whitney, p=.933)

(0 = Not at all comfortable - 10 =

Very comfortable)

7.70 1.87 7.40 2.82

Average No. of Glasses per week

(Mann-Whitney, p=.270)

2.23 3.42 2.73 2.93

No. Push Ups (Mann-Whitney,

p=.443)

9.93 6.64 15.73 14.42

Height (Mann-Whitney, p=.406) 168.07 7.56 169.40 11.21

Weight (Mann-Whitney, p=.604) 71.40 11.78 71.33 22.96

Note. P-values are based on Mann-Whitney test (2 sided)

The Spearman rank-order correlation coefficient was used as a nonparametric

measure to determine the strength and direction of association that exists between the

pre-measure assessments. Correlation coefficients between pre-measure assessments

are presented in Table 13.

A series of t-tests for independent groups was employed to determine if

significant differences existed between the clinical and the control group on the scores

of all psychological measures at the pre-test stage. The results of the analysis

indicated that there were significant differences (p < .05) across all psychological

measures at pre-test with the exception of the DIS which was not significant at (p >

.05). The DIS is a measure of discomfort intolerance rather than anxiety.

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Table 13:

Correlations between Pre-measure Assessments

PACQ BAI CESD STAI-T ASI STAI_S API DIS

PACQ 1.00 .865** .760** .847 .792** .734** .656 .405

BAI 1.00 .719** .744** .813** .602 .663 .422

CESD 1.00 .847** .798** .734** .486 .219

STAI-

T

1.00 .745** .756** .678 .164

ASI 1.00 .734 .559 .331

STAI-

S

1.00 .726** .313

API 1.00 .403

DIS 1.00

Note. N = 30. ** p < .001

Physiological Differences at Time 2 (CO2 Challenge) and Time

3 (Cold Facial Immersion + CO2 Challenge)

A mixed, ANOVA was conducted to compare the panic and control group in

terms of the effect of the CO2 challenge task and group on participants’ RR. Table 14

shows respiration rate means and standard deviations for all participants before and

after the CO2 Challenge (Time 2) and before and after the CFI + CO2 Task (Time 3)

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Table 14

Descriptive Statistics for Respiration Rate (RR) before and after Time 2 (CO2) and

before and after Time 3 (CFI + CO2)

Group

Clinical (n = 15) Control (n = 15)

M SD M SD

RR Time 2 (b CO2) 14.60 3.08 15.90 3.59

RR Time 2 (p CO2) 15.30 3.03 16.95 3.59

RR Time 3 (b. CFI + CO2) 14.40 2.64 15.52 4.30

RR Time 3 (p. CFI + CO2) 14.34 2.41 16.32 4.21

There was no significant interaction between the effects of group and CO2

challenge task on participant’s RR, (F = (1, 28) = .706, p = 0.38, η2 =.005). Simple

main effects analysis showed that between 30 seconds prior to the CO2 challenge

(Time 2) and 60 seconds following the CO2 challenge (Time 3), participant’s

experienced no significant change in respiration rate, (F = (1, 28) = 3.549, p =.070, η2

=.112). There were no significant differences in respiration rates observed between

the clinical and control group, (F(1, 30) = 1.704, p = .20, η2 =.057).

A mixed, ANOVA was also conducted to compare the panic and control group

in terms of the effect of the CO2 challenge task and group on participants’ HR. Table

15 shows heart rate means and standard deviations for all participants before and after

the CO2 Challenge (Time 2) and before and after the CFI + CO2 Task (Time 3).

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Table 15

Descriptive Statistics for Heart Rate (HR) before and after Time 2 (CO2) and after

Time 3 (CFI + CO2)

Group

Clinical (n = 15) Control (n = 15)

M SD M SD

HR Time 2 (b CO2) 95.37 16.02 92.86 22.58

HR Time 2 (p CO2) 97.96 20.79 89.96 26.80

HR Time 3 (b. CFI + CO2) 100.31 19.08 87.84 19.59

HR Time 3 (p. CFI + CO2) 92.92 10.97 90.29 27.33

Furthermore, no significant interaction was found between the effects of group

and CO2 on participant’s HR, (F = (1, 28) =1.028, p =.319, η2=.035). Simple main

effects analysis showed that between 30 seconds prior to the CO2 challenge and 60

seconds following the CO2 challenge at Time 2, the participants experienced no

significant change in heart rate, (F = (1, 28) = .003, p = .955, η2=.000). There were

also no significant differences between heart rates observed between the clinical and

control group, (F(1, 28) = .489, p = .490, η2=.017).

Further mixed ANOVA analyses were conducted to compare the groups in

terms of the effects of CFI, specifically at Time 2 (CO2 challenge) and Time 3 (CFI

plus CO2 challenge), on participants’ heart rate (HR). A mixed ANOVA was

conducted with the clinical and control group to examine the effect of CFI on

participants’ HR and examine whether differences between groups were observed.

There were no significant interaction between the effects of group and CFI on

participant’s HR, (F(1, 28) = .074, p = .787, η2=.003). Simple main effects analysis

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showed that between at Time 3, at the start and end of the CFI task (prior to the CO2

Challenge), participant’s experienced a significant heart rate reduction, (F(1, 28) =

121.492, p =< 0.01, η2=.813) (see Figure 17). However no significant differences

between the clinical and control group were observed, (F(1, 28) = 2.902, p = .100,

η2=.094).

Figure 17. Mean Heart Rate (SE) for all participants (clinical n = 15, and control n =

15) pre and post the Cold Facial Immersion before CO2 at Time 3.

Psychological Measures and Effect of CFI on CO2 Sensitivity

Mann Whitney U test was used to examine differences in the psychological

measures collected across the three time periods. The clinical group has significantly

higher scores compared to the control group on all psychological measures at Time 1

(Pre-test) and Time 2 (CO2) (p<0.05). At Time 3 (CFI after CO2) the clinical group

was significantly higher on all psychological measures (p<0.05), with the exception of

the STAI (State) (p = .106), and VAS- Participant ratings (p= .116).

0

20

40

60

80

100

120

HR b CFI HR p. CFI

Mea

n H

eart

Rat

e

Cold Facial Immersion Task prior to CO2 Challenge (Time 3)

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Table 16 provides medians for all self-report psychological measures taken at

Time 1 (Pre-measures), Time 2 (CO2), and Time 3 (CFI plus CO2).

Table 16.

Medians, Minimum, Maximum and Interquartile Ranges for Psychological Measures

at Time 1, Time 2 and Time 3.

Mdn Min Max

Interquartile

Range

Acute Panic Inventory

Time 1 (Pre-test)

Time 2 (p. CO2)

Time 3 (p.CFI + CO2)

1

7.5

2.5

0

0

0

31

42

23

2.25

13.25

5.25

Anxiety Sensitivity Index

Time 1 (Pre-test)

Time 2 (p. CO2)

Time 3 (p. CFI + CO2)

33.5

34

27

17

16

17

73

80

63

28

27.5

24

Beck Anxiety Inventory

Time 1 (Pre-test)

Time 2 (p. CO2)

Time 3 (p. CFI + CO2)

11.5

19.5

6

0

0

0

61

62

34

23.75

21.5

11.25

Panic Cognitions Questionnaire

Time 1 (Pre-test)

Time 2 (p. CO2)

Time 3 (p. CFI + CO2)

10.5

4

2

0

0

0

68

75

27

31

18

12.25

State Anxiety Inventory

Time 1 (Pre-test)

Time 2 (p. CO2)

Time 3 (CFI + CO2)

28.5

39.5

30

20

20

20

61

74

68

21.25

28.25

20.5

VAS – Participant

Time 1 (p. CO2)

Time 2 (p. CO2 b. CFI)

Time 3 (p. CFI + CO2)

5

0.5

3

0

0

0

10

5

8

6

2.13

4.13

VAS – Researcher

Time 1 (p. CO2)

Time 2 (p. CO2 b. CFI)

Time 3 (p. CFI + CO2)

5

0

2.5

0

0

0

10

4

8

5.5

2

3

Note. N = 30 (group 1: n =15, group 2: n = 15).

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API ratings were significantly different across the three times, χ2(2) = 28.404,

p <.001. Post-hoc analysis with Wilcoxon signed-rank tests were conducted with a

Bonferroni correction applied, resulting in a significance level set at Alpha = p <

0.017. The median API ratings were 1.0 at Time 1, 7.5 at Time 2, and 2.5 at Time 3.

A significant increase was seen between Time 1 and Time 2, (Z = -4.401, p <.001). A

significant decrease was observed between Time 2 and Time 3, (Z = 3.235, p =.001).

There were no significant differences between the participants’ baseline API measures

and those taken at time 3 following the CO2 challenge, (Z = -.1651, p> .017). Figure

18 displays a box plot of participants’ API scores measured at baseline (Time 1),

following the CO2 challenge (Time 2), and after the CFI and CO2 challenge (Time 3).

Figure 18. Median and interquartile range for API scores for all participants (clinical

and control group (N=30) at Time 1*, Time 2*, and Time 3* (*p < .05).

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ASI ratings were significantly different across the three times, χ2(2) = 17.741,

p < 0.01. Post-hoc analysis with Wilcoxon signed-rank test was conducted with a

Bonferroni correction applied, resulting in a significance level set at Alpha = p < .016.

The median ASI ratings were 33.5 at Time 1, 34 at Time 2, and 27 at Time 3. No

significant difference was observed between baseline (Time 1) and Time 2, (Z =

0.520, p >.017), whilst a significant decrease was noted between Time 2 and Time 3,

(Z = 2.654, p =.008). A significant decrease was also observed between Time 1 and

Time 3, (Z = -3.019 p =.003). Figure 19 displays a box plot of participants’ ASI

scores measured at baseline (Time 1), following the CO2 challenge (Time 2), and after

the CFI and CO2 challenge (Time 3).

Figure 19. Median and interquartile range for ASI scores for all participants (clinical

and control group) (N=30) at Time 1*, Time 2*, and Time 3* (p < .05).

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BAI ratings were significantly different across the three times, χ2(2) = 14.131,

p = .001. Post-hoc analysis with Wilcoxon signed-rank test was conducted with a

Bonferroni correction applied, resulting in a significance level set at Alpha =p < .017.

The median BAI ratings were 11.51 at Time 1, 19.5 at Time 2, and 6.0 at Time 3. No

significant difference was noted between Time 1 and Time 2 (Z = -1.211, p > .017).

A significant decrease was seen between Time 1 and Time 3, (Z = -3.607, p < .001).

A significant decrease was observed between Time 1 and Time 3, (Z = -2.849, p =

.004). Figure 20 displays a box plot of participants’ BAI scores measured at baseline

(Time 1), following the CO2 challenge (Time 2), and after the CFI and CO2 challenge

(Time 3).

Figure 20. Median and interquartile range BAI scores for all participants (clinical and

control group (N=30) at Time 1*, Time 2*, and Time 3* (p < .05).

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PACQ ratings were significantly different across the three times, χ2(2) =

12.896, p = .002. Post-hoc analysis with Wilcoxon signed-rank test was conducted

with a Bonferroni correction applied, resulting in a significance level set at Alpha = p

< .017. The median PACQ ratings were 10.5 at Time 1, 4.0 at Time 2, and 2.0 at

Time 3. No significant differences were observed between baseline and time 2, (Z =

2.234, p > .017), and Time 2 and Time 3 (Z = -2.218, p >.017). A significant

decrease was observed between Time 1 and Time 3, (Z = 3.495, p < .001). Figure 21

displays a box plot of participants’ PACQ scores measured at baseline (Time 1),

following the CO2 challenge (Time 2), and after the CFI and CO2 challenge (Time 3).

Figure 21. Median and interquartile range for PACQ scores for all participants

(clinical and control group (N=30) at Time 1*, Time 2*, and Time 3* (p < .05).

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STAI ratings were significantly different across the three time periods, χ2(2) =

23.078, p < 0.01. Post hoc analysis with Wilcoxon signed-rank tests was conducted

with a Bonferroni correction applied, resulting in a significance level set at Alpha = p

< .017. The median STAI ratings were 28.5 at Time 1, 39.5 at Time 2, and 30.0 at

Time 3. There was a significant increase between the participants’ baseline STAI

measures and those taken at time 2, following the CO2 challenge, (Z = -.4.159, p <

.001). A statistically significant decrease was seen between Time 2 and Time 3, (Z =

-3.305, p = .001). There was no significant difference between Time 1 and Time 3, (Z

= -0.833, p > .017). Figure 22 displays a box plot of participants’ STAI-S scores

measured at baseline (Time 1), following the CO2 challenge (Time 2), and after the

CFI and CO2 challenge (Time 3).

Figure 22. Median and interquartile range for STAI scores for all participants (clinical

and control group (N=30) at Time 1*, Time 2*, and Time 3* (* p < .05).

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VAS Participant ratings were significantly different across the three times,

χ2(2) = 28.055, p < 0.01. Post-hoc analysis with Wilcoxon signed-rank test was

conducted with a Bonferroni correction applied, resulting in a significance level set at

Alpha = p < .017. The median VAS-P ratings were 5.0 at Time 1, 0.5 at Time 2, and

3.0 at Time 3. Significant decreases were observed between baseline and Time 2, (Z

= -4.363, p <. 001), and between Time 2 and Time 3, (Z = -3.782 p <. 001).

Furthermore, a significant decrease was seen between Time 1 and Time 3, (Z = -

2.801, p = .005). Figure 23 displays a box plot of participants’ VAS Participant

scores measured at baseline (Time 1), following the CO2 challenge (Time 2), and after

the CFI and CO2 challenge (Time 3).

Figure 23. Median and interquartile range for VAS – Participant scores for all

participants (clinical and control group (N=30) at Time 1*, Time 2*, and Time 3*

(p<.05)

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VAS Researcher ratings were significantly different across the three times,

χ2(2) = 39.086, p < 0.01. Post-hoc analysis with Wilcoxon signed-rank test was

conducted with a Bonferroni correction applied, resulting in a significance level set at

Alpha =p < .017. The median VAS-R ratings were 5.0 at Time 1, 0 at Time 2, and 2.5

at Time 3. A significant decrease was seen between baseline and Time 2, (Z = -4.462,

p < .001), and between Time 2 and Time 3, (Z = 4.178 p <.001). Furthermore, there

was a significant decrease between Time 1 and Time 3, (Z = -3.506, p < .001). Figure

24 displays a box plot of VAS Researcher scores measured at baseline (Time 1),

following the CO2 challenge (Time 2), and after the CFI and CO2 challenge (Time 3).

Figure 24. Median and interquartile range for VAS-Researcher scores for all

participants (clinical and control group (N=30) at Time 1*, Time 2*, and Time 3* (p

< .05).

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DISCUSSION

The principal findings of this study were that there were no differences in

heart rate (HR) and respiration rate (RR) within or between groups in response to the

CO2 challenge. Following the CO2 challenge, the clinical group was observed to have

more elevated anxiety and panic symptoms, as reported by the anxiety measures in

comparison to the control group. Furthermore, a significant reduction in anxiety

symptomatology was observed in both the clinical and control group following the

cold facial immersion (CFI). The results of this study are consistent with the finding

of the preliminary study and are discussed in light of the novel hypotheses in this

study.

Hypothesis 1: It was expected that the CFI task will reduce CO2 sensitivity as

evidenced by HR and RR reductions following the subsequent CO2 challenge in

clinical and control participants. The findings did not provide support for this

hypothesis as there was no significant difference found in participants’ HR and RR

between Time 2 (CO2 challenge) and Time 3 (CFI and CO2). However, the results

examining the effects of the CFI task (prior to the administration of CO2) indicate a

significant reduction in HR for both clinical and control participants. In line with the

preliminary study findings, these results indicate that CFI has anxiolytic effects.

However, despite its powerful response, it cannot be inferred that one single

administration of CFI can alter one’s sensitivity to CO2.

Hypothesis 2: It is hypothesised that following the CFI and subsequent CO2

challenge, all participants will report a reduction in anxiety in comparison to pre-

measures and the CO2 administration without CFI. This hypothesis was supported as

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there was a significant reduction noted between Time 1 (baseline pre-measures) and

Time 3 (CFI plus CO2) on the following anxiety measures Anxiety Sensitivity Index

(ASI), State and Trait Anxiety Inventory STAI, Panic Attack Cognitions

Questionnaire (PACQ), Beck Anxiety Inventory (BAI), Visual Analogue Scale

completed by the participant (VAS-P) and researcher (VAS-R), with the exception of

Acute Panic Inventory (API) for the both the clinical and control groups.

Furthermore, significant decreases in anxiety symptoms were reported from Time 2

(CO2) to Time 3 (CFI plus CO2) on the following measures; API, ASI, BAI, STAI,

VAS-R, and VAS-P, with the exception of the PACQ which was not found to change

significantly between Time 2 and 3. A possible explanation for this finding may have

been that control participants did not have panic cognitions in response to the CO2

challenge. Whilst the control group has minimal symptoms overall in response to the

CO2 challenge, they did report a reduction in symptoms and calming effects in

response to the CFI task. The clinical group reported a decrease in anxiety symptoms,

following exposure to the CFI task on all anxiety measures including the ASI, API,

STAI, PACQ, BAI, VAS-R and VAS-P. The reduction observed in anxiety

symptoms warrant further investigation to examine whether frequent exposure to the

CFI tasks and to breath-holding may be able to reduce CO2 sensitivity in PD patients

over time. Practicing breath-holding and activating the diving response (DR) through

free diving and CFI on a regular basis has been known to have trained effects,

subsequently reducing CO2 sensitivity (Konstandinidou & Chairopoulou 2017).

Reports in the literature have suggested that a blunted hypercapnic response and

prolonged breath-hold times have been associated with the benefits of trained effects

and repeated apneas (Andersson & Schagatay, 2009; Walterspacher et al., 2011;

Roecker et al., 2014, Grassi et al., 1994; Foster & Sheel, 2005). Goosens et al. (2014)

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in their study found that experienced divers displayed a decreased behavioural

response to CO2 as compared to clinical participants with PD and healthy controls.

This finding is also consistent with the research of Earing et al. (2014), who found

that experienced divers possess a lower ventilatory response to CO2 suggesting a

strong adaptation of central CO2 sensitivity.

Whilst the current study was unable to identify whether one single

administration of the CFI task can alter CO2 sensitivity, further investigation of this

novel intervention is warranted given the observed significant reductions in self-

reported anxiety symptoms and heart rate for both clinical and control participants.

Study Limitations

There were various limitations in the current study, with some similarities

shared with the preliminary study. Recruiting participants for the clinical group was

challenging due to a low number of participants applying. As a result, the researcher

invited five participants from the preliminary study to participate. These participants

had expressed interest in being involved in more research in this area. Despite having

more flexible exclusion criteria in this study, the recruitment of clinical participants

proved to be more difficult than the preliminary study. For example, in Study 2

participants with intermittent use of benzodiazepines, anxiolytics and painkillers were

allowed to participate in the study and we extended the age from 55 years of age to 60

years of age, in an attempt to recruit more participants. The low number of

participants made it difficult to compare groups. Furthermore, the participants in the

control group were again mostly university students studying psychology. Although

attempts were made in Study 2 to match participants and to recruit non-university

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students as controls, this was difficult to accomplish. Hence the results may not be

truly representative of what a normal population may look like.

Another limitation of the preliminary study may have been participant’s

reported comfort level with water. Participants who did not feel comfortable with

water may not have felt comfortable or relaxed during the CFI task. It is important to

consider this in future studies, or when determining with clients alternative ways to

activate the DR. This is something that we wanted to explore in the qualitative

interviews further to gain a better understanding of the different preferences and

possibilities of activating the DR.

A further limitation is that both the CO2 challenge and the CFI task elicit a

brief response. A drawback to this may be that participants may not accurately report

what they experience as by the time they complete the self –report anxiety measures

minutes later, their symptoms may have dissipated. Although the VAS-P and VAS-R

were used to try to capture how anxious participants felt following the tasks, an

improvement to consider would be to administer these tests at baseline before any

condition as a means of comparison. Other methodological considerations for future

studies investigating the CFI and the DR include improving the provocation of the

CO2 challenge, the continuous data acquisition during the experimental design, and

matching participants for age and gender.

Methodological Considerations for Future Research

An important methodological consideration for future research is to use the

standardized experimental equipment described by Schruers and colleagues (Schruers

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et al., 2011) and to include maximal vital capacity inhalations: one placebo condition

(normal room air) and one with CO2 enriched air. A stopcock used with two

positions, one for the normal air and one for the premixed CO2, is connected to either

the mouthpiece or the mask, in a way so the participant does not know which

condition is being administered (Hood et al., 2006). The odour or taste associated with

the CO2 is minimal, and as participants are not informed of the order of the conditions

they are being administered, placebo effects can be easily identified (O’Leary, 2000).

This method does not ensure a true blind as the participants do not usually respond

physiologically to the placebo, and the CO2 inhalation elicits immediate effects

(Ogliari et al., 2010).

The CO2 challenge proved to have some difficulties including individual

variability in response to the CO2 challenge. Some participants complained of the

taste and were not able to hold the inhaled gas mixture for a duration of 4 seconds

which they were instructed to do before exhalation. Clinical participants may have

also been fearful of the CO2 provocation method used and its potential to elicit a panic

attack, hence they approached the single breath inhalations with a degree of

apprehension. Furthermore, if they were unsuccessful in breathing in the CO2 by

taking in a maximal deep inhalation and holding the breath for a count of 4 seconds,

the researcher was unable to re-administer the CO2, as ethics approval was only

granted for one maximum CO2 inhalation per participant per day.

Furthermore, some participants reported difficulties with being able to breathe

in the CO2 properly, which resulted in an inability to take in a deep maximal

inhalation. Reports in the literature suggest that more sophisticated methods have

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been used, including standardised experimental equipment developed by Schruers and

colleagues (Schruers et al., 2011). This involves either a mask or a combination of a

mouthpiece and a nose clip which aids the participant to receive a maximal vital

capacity inhalation. Also recording devices such as the Finapress recorder are

commonly used to record continuous HR measurement (Vickers et al., 2012). In the

current study, the equipment we used was limited to that available at the university.

The provocation method used in our study may have been more appropriate

for investigating a more restricted, but perhaps more homogeneous, phenotype within

the wider clinical domain of PD syndromes (e.g., the respiratory subtype group of PD)

(Smoller & Tsuang, 1998). There is no consensus with some research favouring

(Battaglia, 2002; Battaglia, et al., 2001) and others questioning (Gorman et al., 2000)

the utility of CO2 in informing central nervous system mechanisms connected to

suffocation and PD. In this preliminary study, it would have been interesting to

recruit and compare both the respiratory and non-respiratory PD subtypes to

investigate differences in how the groups vary in their response to the provocation

methods (i.e., BH tasks, 35% CO2 challenge and CFI task). Future studies may

investigate differences between the respiratory and the non-respiratory clinical group.

Future research should consider gathering continuous cardiorespiratory data

recorded from start to finish, to include data between conditions, using a physiological

recording device such as the Zephyr Bioharness Bluetooth device, used in this study,

to capture the relevant data. This may assist with identifying at what time periods the

most significant cardiorespiratory changes occurred. Another consideration for future

studies may be for the researcher and the participant to complete the Visual Analog

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Scale (VAS) following each task of all conditions, which include both breath-hold

tasks, both CO2 challenges and following the CFI task, as a way of comparison. This

may yield important information regarding how anxious participants are likely to feel

following both breath-hold-tasks (Condition A) and following the CFI (Condition B).

This would allow for the (CFI) task (Condition B) to be compared with the CO2

Challenge + CFI task (Condition D), with respect to the VAS researcher and

participant ratings. Furthermore knowing how anxious or relaxed a participant is

feeling, following these abovementioned conditions, may yield important information

regarding how they may respond to the next randomly assigned challenge or task, as

well as information regarding their cardiorespiratory response.

Future Directions

Schagatay and Andersson (1998) suggested that the DR can be trained and that

it can elicit benefits on both HR reduction and apnoeic duration. It appears plausible

that PD individuals may have benefited from achieving trained effects of the DR

through the regular use of apnea training and CFI, as observed in free divers.

According to Christoforidi et al. (2012) the parasympathetic branch and resting

cardiac autonomic activity was increased in free divers compared to untrained

participants as evidenced by significantly lower minimum and mean heart rate. Vagal

tone and resting cardiac autonomic adaptation are different in free divers because of

known trained effects (Christoforidi et al., 2012). Park and Thayer (2014) posit that

cardiac vagal tone also known as heart rate variability facilitates effective emotion

regulation as it is associated with more “adaptive and functional top-down and

bottom-up cognitive modulation of emotional stimuli” (p.1). Free divers are a unique

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group that possess excellent mental control, and exceptional breathing control to be

able to reach depths that were beyond imaginable.

Furthermore, reports in the literature suggest a clear link between respiratory

disorders and PD (Biber & Alkin, 1999; Nardi et al., 2002, 2006a, 2006b; Freire et al.,

2008; Papp et al., 1989; Valenca et al., 2002). Joulia et al. (2009), postulated that

apnea training provided hypoxic preconditioning and hence it may be potentially used

to optimise hypoxia protection in patients with respiratory conditions such as chronic

obstructive pulmonary disease and asthma. Breathing exercises used by free divers

such as pranayama yoga, square and triangular breathing which involve inhaling,

exhaling and breath-hold (i.e., for 3 seconds each) have been associated with deeper

states of relaxation (Mana, 2010). Jerath et al. (2006) have demonstrated multiple

benefits including decreased oxygen consumption, heart rate, and blood pressure, as

well as increased theta wave amplitude in EEG recordings, and parasympathetic

activity as a result of regular use of pranayama yoga breathing. Experiences of

alertness and reinvigoration have also been reported by regular users (Jerath et al.,

2006).

A study by Schagatay et al. (2000) demonstrated that both frequent exposure

and apnea performance increase breath-hold (BH) time, by delaying the physiological

breaking point and enhancing bradycardia. According to Schagatay and Anderrson

(2009), future research should investigate the time course for the development of the

trained effects, specifically how frequent and how many apnea exposures are

required. This warrants further investigation, in order to explore the benefits of

breath-hold training (BHT) and CFI in the treatment of PD. Understanding the

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physiological adaptations of apnea training, and the techniques used in the sport of

freediving, including the activation of the DR, may shed some light into the

development of novel and innovative treatments used to treat and manage panic and

anxiety symptoms.

The CFI task may also be used as a diagnostic tool to inform the clinician of

the patient’s suffocation alarm system, and breathing irregularities. Imperatively, it

may also be used as a proposed intervention, psycho-educationally and as a

behavioural experiment with clinical participants to reduce panic symptoms and

cognitions. Moreover, in a behavioural experiment, the CFI task can be applied

following a hyperventilation challenge in an attempt to reverse the physiological

symptoms of anxiety and to help challenge and correct the erroneous beliefs and panic

cognitions. According to Barlow and Craske (2014), voluntary hyperventilation is a

way to expose patients with PD to sensations associated with panic and to activate

catastrophic cognitions that need restructuring. Given the calming effects of the CFI

and the reduction in physiological symptoms and cognitive symptoms of panic and

anxiety, the CFI may be used following a hyperventilation exercise to regulate the

autonomic nervous system and to counteract catastrophic cognitions.

CBT may also be able to draw on the adaptation of the DR to counteract

anxiety sensitivity erroneous beliefs. A large body of research has demonstrated a

relationship between anxiety sensitivity and panic-related psychopathology and have

suggested that anxiety sensitivity often precedes the development of PAs (Bouton et

al., 2001; Dixon, Sy, Kemp & Deacon, 2013; McNally, 1994, 2000; Reiss, 1991;

Poletti et al., 2015; Reiss & McNally, 1985, Scmidt, Lenew & Jackson, 1997; Taylor,

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1995). According to Barlow, (1988, 2002), Craske & Barlow, (2013) and Gallagher

et al. (2013) correcting erroneous beliefs via CBT interventions such as cognitive

restructuring and the use of behavioural experiments have demonstrated a reduction in

anxiety-related symptoms. The design and implementation of behavioural

experiments that activate the DR may have some merit here, in order to expose the

patient to their feared panic sensations and to encourage them to challenge erroneous

beliefs and give up their safety behaviours. Moreover, it would be really interesting

for future research to investigate whether the CFI task can reduce the intensity and

frequency of PAs by monitoring panic attack symptoms in the future, following CFI

exposures.

According to Gallagher (2013) increasing patients’ sense of mastery and

personal agency in their ability to cope with their symptoms, by correcting their

maladaptive perceptions of bodily sensations has been shown to enhance recovery.

Thus one proposed strategy to assist with increasing a patient’s sense of mastery, and

sense of control is to educate them on the physiology of the DR and to encourage

them to practice CFI regularly, as a way to reduce physiological and cognitive

symptoms of anxiety. Based on our findings and the trained effects perceived in free

divers, one may speculate that by practicing CFI on a regular basis, not only may one

be able to reverse physiological symptoms of anxiety and panic but potentially

prevent future PAs, something that warrants future investigation.

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Chapter 7

QUALITATIVE EXPLORATION OF PANIC

AND COLD FACIAL IMMERSION

RATIONALE FOR STUDY 2: QUALITATIVE

INVESTIGATION

According to Gallagher et al. (2013), the most important factor for promoting

recovery early in the treatment process involves correcting patients’ maladaptive

perceptions of bodily sensations. This may be accentuated by patient

psychoeducation on the diving response (DR) and its physiological adaptations and

benefits. This powerful autonomic response can also be activated by the cold facial

immersion (CFI) task or by other ways that may be regarded by the patient as more

practical, in order to correct one’s maladaptive perceptions of bodily sensations or

panic cognitions. Self-efficacy and anxiety sensitivity according to evidence may be

the mechanisms of change of CBT for PD (Bouchard et al., 2007; Casey et al., 2005;

Reilly et al., 2005; Shear et al., 2001; Smits et al., 2004; Gallagher et al., 2013).

Incorporating the DR in the existing treatments may complement already existing

CBT treatments. The pronounced bradycardia experienced during the activation of

the DR can help mediate catastrophic beliefs or misinterpretations. Hoffart et al.

(2016) in his study found that catastrophic belief is a mediating factor contributing to

either remission or persistence of PD. Decreasing catastrophic misinterpretations of

bodily sensations using CBT can lead to overall changes in symptoms (Teachman et

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al., 2010). According to Gallagher et al. (2013), the greatest changes occurring early

in treatment was in anxiety sensitivity, while self-efficacy experienced greatest

changes towards the end of treatment.

Evidence shows that CBT has the greatest effect on anxiety sensitivity which

impacts changes in panic symptoms early in the treatment process when the focus of

therapy revolves around providing psychoeducation, breathing retraining and

cognitive restructuring which in turn impacts subsequent panic symptom changes

(Gallagher et al., 2013). Effective and fast improvements have been observed in

relation to patients’ fear of bodily sensations using CBT for PD (Gallagher et al.,

2013).

Research has demonstrated CBT’s efficacy in decreasing anxiety sensitivity

(Shear, Houck, Greeno, & Masters, 2001; Smits, Berry, Tart, & Powers, 2008;

Gallagher et al., 2013) and further evidence reveals that anxiety sensitivity may be an

important mechanism of change of CBT for PD that directly impacts other anxiety-

related symptoms experienced (Reilly, Gill, Dattilio & Mc Cormick, 2005; Smits,

Powers, Cho & Telch, 2004; Gallagher et al., 2013).

Delivering psychoeducation about anxiety-related bodily sensations, assisting

patients develop a tolerance to these sensations, interoceptive and in vivo exposures

exercises, and cognitive restructuring of catastrophic appraisals of anxiety-related

bodily sensations, all part of CBT for PD, have been shown to decrease anxiety

sensitivity in patients with PD (Barlow, 1988, 2002; Craske & Barlow, 2013;

Gallagher et al., 2013).

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AIM

This study aims to explore the current strategies used by clinical participants

to manage anxiety and panic symptoms as well as understanding the key challenges

experienced by individuals with PD in managing their symptoms. Furthermore, this

study aims to explore the experience of CFI for clinical and control participants, as

well as the challenges participants identify with using CFI and views around its utility

as a treatment for managing anxiety and panic symptoms. Preferences of practical

strategies to activate the DR are explored, and challenges discussed with the CFI task.

METHOD

Participants

A total of 30 participants, of whom 15 were males and 15 were females

participated in this phase of Study 2. As per Study 2 reported in Chapter 6, 15

participants had a primary diagnosis of panic disorder with or without agoraphobia

(PD) (DSM – 5), and 15 participants who did not meet criteria for PD or mental

illness were recruited into the control group. The participants in the clinical group

had an average age of 36.3 years (SD = 13.8), whilst the participants in the control

group had an average age of 33.1 years (SD = 7.7). Both groups comprised 6 males

and 9 females.

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Materials

Appendix E includes the qualitative questionnaire that was used to interview

participants from Group 1 and 2. Figure 25 provides an overview of the experimental

procedure for this qualitative study.

Figure 25. Experimental procedure for the qualitative interviews for Group 1

(clinical) and Group 2 (control) participants.

Procedure

Two lists of questions were developed and agreed upon for the researcher to

ask participants at Time 3 of Study 2. The first list of questions exploring challenges

experienced and strategies used in managing anxiety and panic symptoms and

thoughts. The second list of questions explored the participants’ experience of cold

facial immersion and their views around its utility as an intervention to assist in

managing anxiety/panic thoughts and symptoms. Participants of this study were

recruited as part of Study 2 (see Chapter 6). Participants were required to complete a

consent form, and consent to participate in an interview (see Appendix C for Plain

Language Statement and Consent Form). Interviews were conducted face to face

following the completion of the Time 3 task of Study 2 Phase 1. They were on

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average 30 minutes in length. Clinical participants were asked both sets of questions,

regarding their experience of their anxiety and panic symptoms, and their experience

of the CFI task. For example, participants were asked, What are the challenges you

face in managing your anxiety/panic symptoms? Participants in the control group

were asked only the question in relation to their experience of the CFI task. For

example, they were asked, How would you describe your experience of cold facial

immersion? Demographic data such as age, gender, and current employment status

was gathered as part of Study 2, Phase 1. The interviews were recorded and written

verbatim and de-identified for data analysis.

Data Analysis

A thematic analysis of the 30 transcripts was undertaken. Initially, interview

transcripts were grouped and analysed according to the type of questions (i.e.,

Anxiety/panic questions and CFI questions) and by group (clinical and control group).

This resulted in 3 sets of data for analysis: Anxiety/panic related questions for the

clinical group (15 transcripts), CFI experience questions for the clinical group (15

transcripts), and CFI experience questions for the clinical group control group (30

transcripts). For the analysis, an inductive approach was applied, where the identified

categories and themes emerged from the data. Transcripts were read several times

and a list of broad categories was developed and expanded as the analysis progressed.

When allocating data to specific categories the “unit of meaning” was selected as the

unit of coding (Dey 1993). Using this method, a unit of meaning is conveyed by

content rather than form. As participants in qualitative interviews vary in the manner

in which they express themselves, some succinctly and some more in-depth,

consideration is not given to the number of words but rather to the meaning conveyed.

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Once thematic categories were established from the initial exploratory research

questions and coding was done using the QSR NVivo qualitative data analysis

software package. The transcripts were initially coded to 23 broad categories

identified in the data. Once the transcripts had been coded with the broad categories,

text within categories was read and analysed to identify themes within categories. To

establish sufficient reliability to proceed with the analysis and interpretation of the

data, a second researcher familiar with the aims and objectives of the research

reviewed the data, categories and themes within categories. This is known as the

double coding method (Boyatzis, 1998). Discussions were held between the two

researchers to reach agreement over the final categories and themes within categories.

For the questions relating to challenges experienced in managing

panic/anxiety thoughts and symptoms for the clinical group refinement of an initial 13

categories (whereby categories were expanded, combined or renamed) resulted in five

broad categories established. The five categories relating to challenges experienced in

managing anxiety/panic included: cognitive disruption, disability burden, debilitating

fear, debilitating symptoms, unhelpful thinking.

For the questions relating to strategies commonly used by clinical participants

to manage anxiety/panic thoughts and symptoms for the clinical group refinement of

an initial 10 categories (whereby categories were expanded, combined or renamed)

resulted in three categories established. The three categories relating to strategies

used in managing anxiety/panic included: Cognitive Strategies, Physical strategies,

Mindfulness Strategies.

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For the CFI experience questions for the clinical group refinement of an initial

16 categories (whereby categories were expanded, combined or renamed) resulted in

5 broad categories established. The five broad categories related to the clinical

group’s CFI experience included: initial experience of CFI, post experience of CFI,

practising CFI, perceived challenges with practicing CFI, and utility of CFI in

assisting with panic and anxiety.

For the CFI experience questions for the control group refinement of an initial

14 categories (whereby categories were expanded, combined or renamed) resulted in

4 broad categories established. The four broad categories related to the control

group’s CFI experience included: initial experience of CFI, positive experience after

practicing CFI, perceived challenges with practicing CFI, and utility of CFI in

assisting with panic and anxiety.

RESULTS

All 30 participants in Study 2 Phase 2 participated in the interviews result in

30 interview transcripts. The results of this study are presented in four parts. The

first part reports the results of the thematic analysis of 15 transcripts relating to panic

participant’s challenges in managing anxiety and panic thoughts and symptoms. The

second part reports the results of the thematic analysis of 15 transcripts relating to

strategies used by clinical participants to manage anxiety and panic thoughts and

symptoms. The third section presents the results of the thematic analysis of 15

interview transcripts related to panic participant’s experience with the cold facial

immersion (CFI) intervention. The fourth section reports the results of the thematic

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analysis of 15 interview transcripts related to the control group’s experience of the

CFI task.

Section 1. Challenges experienced in managing anxiety and

panic thoughts and symptoms

The final categories and themes from the thematic analysis of the

anxiety/panic qualitative questions administered to Group 1 appear in Table 17. The

themes are described in further detail and individual quotes from participants are used

for illustrative purposes. Participants identified a range of factors that challenge them

in managing their anxiety/panic.

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Table 17.

Themes and Categories in relation to Panic Cognitions and Symptoms for Group 1 (Clinical Participants)

Category Themes within categories Participant Quotes

Cognitive Disruption Derealisation or Depersonalisation Difficulty Thinking

You become detached, and everything becomes hazy. I can’t think clearly.

Disability Burden Avoidance Escape Behaviour Impact on daily functioning

I try and avoid situations that will bring it on. I usually stay by myself to feel better with the sensations, or flee or run away. With work, finding it hard to work, hard to stay in a job.

Anxiety and panic-related fear Dying Fainting Loss of control Uncertainty

I think I might die because my chest is moving up and down Well I’m scared of fainting …symptoms come on and persist, I feel anxious and not in control The uncertainty and the fear is a challenge

Panic Cognitions Predictive & Catastrophic Thinking Racing Thoughts Worrying

….think about things which might go wrong when the onset of the panic attack is occurring, I usually the mind is racing continual probably worrisome thought process that leads eventually to a panic attack

Physiological Symptoms Cardiorespiratory Symptoms Vestibular Symptoms

Struggling to breathe, I don’t realise that I’m not breathing at all. If I am having a panic attack it’s usually I get hot flushes.

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Cognitive Disruption experienced during anxiety and panic

Derealisation or Depersonalisation

When asked what challenges participants experience in managing anxiety or

panic symptoms many discussed feeling a sense of being so overwhelmed by their

symptoms that they lose touch with reality:

…you lose a sense of reality…

You become very detached.

Difficulty Thinking

When asked what challenges participants experience in managing anxiety or

panic thoughts many discussed difficulty in ordering their thoughts:

…anxiety and panic thoughts are entangled, can’t separate them from one

another, makes it more difficult…

I can’t think clearly.

Disability Burden of panic and anxiety

Avoidance Behaviour

When asked what challenges participants experience in managing anxiety or

panic thoughts many discussed having to avoid situations that might trigger anxiety or

panic:

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On a plane for example, I do not travel if I do not get an aisle seat. There is no

way that I will be able to travel on a plane if I have to sit between people or

you know there’s no way out.

.. in a back seat of a car I will never sit in between and if there’s a crowded

train I will never get on it..

Escape Behaviour

When asked what challenges participants experience in managing anxiety or

panic thoughts many discussed feeling a strong need to escape situations:

I get a strong feeling or need to escape.

Disruption to daily functioning

When asked what challenges participants experience in managing anxiety or

panic thoughts many how their symptoms and thoughts impact their ability to engage

in everyday life:

With work, finding it hard to find work, hard to stay in a job

And if I need to do something then I will spend a lot of time preparing and

informing myself.

Anxiety and panic-related fear

Fear of Dying

Catastrophic thinking and in particular a fear of dying was evident in many of

the clinical participants:

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Difficulty with fear of death, I think I might die because chest is moving up

and down.

Initially it was a huge challenge. I didn’t understand what was happening. So

you really believe those symptoms that you’re going to die; that you’re going

to have a stroke that you need to call an ambulance…

Fear of Fainting

A fear of fainting was also discussed by a couple of clinical participants:

well I’m scared of fainting

I have thoughts around feeling faint, thinking that I would pass out

Loss of control

A sense of losing control or not being in control was a challenge that many

clinical participants discussed in relation to managing both symptoms and thoughts

related to panic and anxiety:

Difficult to control thoughts in beginning try to stay calm symptoms come on

and persist I feel anxious and not in control

I feel something is wrong with me, I can’t control the symptoms because I’m

overwhelmed by them.

.

Fear of uncertainty

A sense of not knowing what is happening was also discussed as a challenge

in relation to managing anxiety and panic:

Being unsure of what is happening

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…how long is it going to last? Is it going to be a lengthy one? Is it going to go

fast? That uncertainty and the fear is a challenge

Anxiety and panic cognitions

Predictive and catastrophic thinking

The majority of clinical participants reported a preoccupation with predictive

or catastrophic thoughts that contributed to their challenge in managing anxiety and

panic:

…thinking about things which might go wrong

…trying to predict what can happen you know, or is it happening right now

I think I might die because my chest is moving up and down.

Racing thoughts

Trying to manage racing thoughts associated with anxiety and panic was

described as a significant challenge for clinical participants:

When the onset of the panic attack is occurring, usually the mind is racing..

Thoughts, yeah thoughts can race…. I can leap around from some different

subject matters randomly, they’re not linked at all.

Worrying

General worrying was also discussed by clinical participants as a contributor

to the challenge of managing panic and anxiety thoughts and symptoms:

..continual probably worrisome thought process that leads eventually to a

panic attack..

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I worry about things which might go wrong

Physiological Symptoms

Respiratory Symptoms

Coping with respiratory symptoms associated with anxiety and panic were

described as major challenges for clinical participants:

Struggling to breathe, I don’t realise that I’m not breathing at all

Challenges are more breathing, like I know that… When I’m anxious I don’t

breathe well.

Vestibular Symptoms

Participants also described difficulties in coping with the following vestibular

symptoms:

Shakiness that I feel that’s challenging, feeling somewhat disorientated.

the most challenging thing and my trembling…and of course the trembling

gets to the point that everyone notices, that disturbs me a lot

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Section 2. Strategies used to manage anxiety and panic thoughts

and symptoms

The final categories and themes from the thematic analysis relating to

strategies used by clinical participants to manage anxiety/panic thoughts and

symptoms appear in Table 18. The themes are described in further detail and

individual quotes from participants are used for illustrative purposes. Participants

identified a range of strategies they use to assist them in managing their anxiety/panic.

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Table 18.

Themes and Categories relating to panic management strategies for Group 1

(Clinical participants)

Category Themes within categories Participant Quotes

Cognitive Strategies

Thought Stopping Self talk and Reassurance Psychoeducation Distraction and Refocus

Stop yourself from generating negative….. panicky thoughts I started to tell myself, I started to self-talk myself out go it. I did a lot of reading, and that helped me understand. Yeah I will find distractions, things that I can really concentrate on, like a singular thing.

Physical Strategies

Breathing techniques Physical activity

I would concentrate on the breathing which is a good distraction so it helps the anxiety to pass I try to do a bit of stretching….because I get a lot of muscle tension.

Mindfulness Strategies

Mindfulness and Acceptance techniques Meditation

I would just relax and take a breath, and before this I would just let the anxiety do its thing, let the panic attack happen I use prayer meditation

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Cognitive Strategies used to manage anxiety and panic

Thought Stopping

A common strategy discussed by clinical participants was trying to put a stop

to thoughts that were contributing to their panic and anxiety:

…stop yourself from thinking

Stop yourself from generating negative….. panicky thoughts

Self- talk and Reassurance

When asked what strategies they employed to assist them in managing panic

and anxiety symptoms, many discussed using self-talk and reassurance:

…… you just tell yourself it will pass. And that’s what you keep telling

yourself. You’re not going to die, you’re not having a stroke.

Yeah, you almost have to tell yourself it isn’t real it isn’t happening especially

when you’re in that really heightened state of panic.

Psychoeducation

Among the strategies discussed, clinical participants mentioned educating

themselves on their conditions and learning about themselves as helpful in managing

their panic and anxiety:

So the way I did, because my personality is that type, I started to research and

investigate it myself. So I did a lot of reading, and that helped me understand.

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Distraction and Refocus

Many clinical participants described the use of distraction techniques and

trying to refocus their thoughts:

I would concentrate on the breathing which is a good distraction so it helps

the anxiety to pass

trying to focus more on thoughts on one single thing.

refocusing the thoughts correctly

Also, and I try not to do this too much, but I do find other things to do as a

form of distraction. Such as playing an instrument, or reading a book, messing

around on the computer.

Physical Strategies

Breathing Techniques

When asked what challenges participants experience in managing anxiety or

panic symptoms many discussed feeling a sense of being so overwhelmed by their

symptoms that they lose touch with reality:

Breathing... yes I try but it doesn’t help me I try whenever I feel that I might

get a panic attack….I do breathing exercises before… but I’m not too sure

whether that works to be honest

I have also practiced breathing techniques, taking deep breaths. With long

pauses. And then you try and do those deep breaths….

I’ve tried mindfulness and relaxation, and controlled breathing, but it’s not as

effective as I would like it to be

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Physical Activity

Another strategy discussed by clinical participants, was exercising and trying

to keep physically active:

I feel like… that I… needed to go for a run

I’ve been trying to incorporate some form of exercise as well but I have very

limited energy for each day... I try to do a bit of stretching as well, because I

get a lot of muscle tension.

Mindfulness Strategies

Mindfulness and Acceptance

Using the practices of mindfulness and acceptance were discussed by many

clinical participants as a strategy that they employ to assist in the management of

anxiety and panic symptoms:

I would just relax and take a breath, and before this I would just let the

anxiety do its thing, let the panic attack happen

I stay with the sensations or my thoughts and just notice them. Sometimes it

may be helpful to sit with the emotions and thoughts and just watch them.

Mindfulness, that’s something that when I do think of it, I then focus on things,

I focus on things that I smell or what I’m looking at…

Mindfulness, controlled breathing, relaxation, challenging and distracting

myself, re-adjusting my thinking process from obsessing about health concerns

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Meditation

Whilst mindfulness was most commonly discussed, some clinical participants

specifically identified meditation as a strategy to manage anxiety and panic

symptoms:

I use prayer meditation

Doing those sorts of things it’s a bit of like meditation where, you, kind of,

focussing on one area, and that, I found that can help, a lot.

Section 3. Experience with cold facial immersion task for

clinical participants

The final categories and themes from the thematic analysis relating to the

experience of cold facial immersion and views around its utility in helping manage

anxiety/ panic for clinical participants appear in Table 19. The themes are described

in further detail and individual quotes from participants are used for illustrative

purposes. Participants described their experience and perceptions of the cold facial

immersion task and its utility as an intervention.

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Table 19.

Themes and Categories regarding Participants Experiences of the Cold Facial Immersion Task for Group 1

Category Themes within categories Participant Quotes

Initial experience with CFI Relaxed state Calm effect Physical Discomfort Anticipatory Anxiety

I…felt relaxed while my face was immersed I felt, a rush of calmness while …my face was in there I felt sinus pain… above the bridge of the nose… it was just like pressure I felt scared to begin with but knew things were under control

Experience post CFI Relaxed state Calming effect Mindful state Reduced panic symptoms and cognitions Confidence and Empowerment

I was surprisingly really relaxed My thoughts went away felt frozen at the moment. Really present. …easier to focus on the here and now I didn’t have the thoughts, sensations and symptoms of anxiety that I usually have Once it’s done you get this feeling of accomplishment.

Practicing CFI Motivation to practice CFI Predicted regularity of practice Practice during panic

I want to practice CFI, as hopefully it will help I definitely would practice it on a regular basis. Very likely, to practice it in a panic attack, because found it helpful

Perceived challenges with practicing CFI Time challenges Physical challenges Accessibility and convenience Social Acceptance

…it’s more finding the time… cos I’m pretty busy Only challenge is lasting 30 seconds, and increasing the capacity for breath-hold. the only challenge I see is access to the cold water when out, it’s kind of you know weird to do it in public

Utility of CFI in assisting panic/anxiety Simplicity and practicality Reducing panic symptoms and thoughts Effectiveness as an intervention

I think it’s great… something so simple, that can calm you.. It reduces panic symptoms and negative thoughts…very helpful I think it would be beneficial, it would be effective for most people

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Initial experience with the cold facial immersion (CFI) task

Relaxed state

Many clinical participants described a general state of relaxation in the initial

stages of the cold facial immersion task:

… felt comfortable after 10 seconds. Felt relaxed by the end of it. I was

stressed that I won’t last 30 seconds but I got through it.

I…actually felt relaxed while my face was immersed

… when I put my face into the cold water I just thought like the temperature

just brought my heart rate down

Calm effect

When describing their initial experience clinical participants also discussed

feeling calm as a result of the cold facial immersion task:

I felt, a rush of calmness while my face was in there

… when I realized how calming it all was I allowed, myself to experience that

calmness and embrace it. So when I came up, I was still in that, calm level.

Physical Discomfort

Although some clinical participants described feelings of relaxation and calm,

it was evident that some participants’ experience of the cold facial immersion task

involved some physical discomfort:

I felt a bit dizzy…or not dizzy but disoriented …from the cold water

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… apart from getting a bit of pain in the sinus area because the water was

cold…but turned out I had some sort of cold coming on

Anticipatory Anxiety

Some participants talked about a general feeling of uncertainty and feeling

fearful and nervous in the lead up and/or at the beginning of the cold facial immersion

task:

I felt scared to begin with but knew things were under control.

Initially I was petrified..

Yeah. I was more anxious before

Feeling anxious before the CO2 challenge was an experience described by

some of the participants:

I didn’t have an immediate… anxiety, until…shortly after once everything

went back to room temperature, right before I inhaled the mixture, there was, I

started to feel some, worry thoughts I think that was more to do with the fact

that I was about to inhale; knowing what was coming next; or what I was

supposed to do next

A lack of belief in being able to hold their breath for the duration of the CFI

task also raised some concerns among some of the participants:

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… I didn’t know what to expect. I didn’t think I would be able to hold my

breath for 30 seconds. The shock of the water, didn’t think I would last 30

seconds.

I was actually worrying about… if I could actually hold my breath long

enough and not spoil the experiment.

Experience after completing with the cold facial immersion (CFI) task

Relaxed state after CFI

Following completion of the CFI task, many of the clinical participants

described a state of relaxation:

Once I came out of the water, felt relaxed. Felt good that I lasted 30 seconds.

And relaxed after.

I was quite surprised I could hold my breath for that long, and really was

quite relaxing to be honest.

I was surprisingly really relaxed.

Some participants also described the experience of a lowered, more relaxed

heart rate:

I noticed the relaxing heart rate, I felt mellow, relaxed, and wasn’t as fearful

of taking a breath of the CO2. So it was easier following the CFI

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Calming effect

When asked how they felt following the CFI task, many clinical participants also

reported feeling a state of calm:

I did not feel too tense…after I did the cold water immersion. If you ask me

about you know how tense I felt I think I felt relatively calm… after immersion

There was no surprises, there was no funny sensations through my body or my

mind…[I felt] perfectly calm you know…

I certainly felt calm from the cold water.

Mindful State

Some clinical participants also reported a state of mindfulness following

completion of the CFI task:

Thoughts went away felt frozen at the moment. Really present.

…easier to focus on the here and now

The CFI distracts everything, distracts my thinking, because I was

concentrating on getting to the 30 seconds and the breath-holding

Reduced panic symptoms and cognitions

Many of the clinical participants described having reduced or the absence of

panic thoughts and symptoms following completion of the CFI task:

It reduced my panic yes because I felt it reduced anxiety, because before I had

a lot of high anxiety which is anticipatory

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The cold water got rid of fear or anxiety or panic thoughts. Felt no anxiety or

panic.

I didn’t have the thoughts, sensations and symptoms of anxiety that I usually

have

I didn’t have any worrying thoughts at all, I think because I was so surprised

how pleasant the experience

Some participants went beyond describing an absence of panic cognitions and

symptoms to reporting positive and optimistic thinking:

Following the CFI, thoughts were positive, I have more of a positive mindset,

because it was relaxing it cleared my mind and thoughts

My optimistic thinking improved…

Confidence and Empowerment

Clinical participants described a sense of confidence and accomplishment at

being able to complete the CFI task:

So it was easier following the CFI. I felt empowered about managing my

symptoms, I feel more confident now. The CFI distracts everything, distracts

my thinking because if I get through something difficult I feel more confident,

and the next time I don’t think about it as much

…once it’s done you get this feeling of accomplishment.

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Practicing CFI

Motivation to practice CFI

Participants were asked about the likelihood they would practice CFI and

more specifically how motivated they would be in using CFI as a strategy to assist

with management of panic and anxiety thoughts and symptoms. Many described it

being a good strategy and feeling motivated to practice it if they needed:

It would definitely help me out. I wouldn’t be scared at home alone. It’s a

good strategy, it teaches you to relax and calm down. As you calm down so

quickly, it’s very effective.

I see it as an excellent strategy to reduce symptoms. I could keep calm, walk to

bathroom, put cold water in face when having a panic attack, this would relax

me.

I want to practice CFI, as hopefully it will help, very hopeful, it did help in the

lab but that was in a controlled setting. Should do it when panic sensations

coming on.

Hopeful as I wasn’t fearful when I was practicing the cold facial immersion.

Perceived challenges with practicing CFI

Time challenges

Some clinical participants identified that finding the time to set up and practice

CFI as a challenge:

Yeah it’s more finding the time… cos I’m pretty busy.

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Partly the time to set it up but also the fact that, I would be constantly

distracted. Due to the fact that I have young children. It’ll be a different story

when they’re at school.

Physical challenges

Challenges with breath-holding and water temperature were among some of

the physical challenges identified by clinical participants:

… taking a deep breath, and if not in control, if I was to take a deep breath, it

would help, as it would calm my symptoms so I think it would be a win-win.

… lasting 30 seconds, and increasing the capacity for breath-hold. I think it

would help me particularly with my anxiety and panic, as I hyperventilate and

need to take deeper breaths.

Accessibility and convenience

Clinical participants also discussed convenience of practicing CFI in certain

situations, and being able to access water as potential challenges to practicing CFI:

Only challenge is finding ice or access to cold water when out

Well obviously access to water, a container where you can… submerge your

face, that’s obviously not always available, and you know something that you

need to organise when it happens…

I’m in a truck all day so… it’s not like I can find the nearest bucket to fill

water up… that’s going to be a challenge, it’ll be hard if I can’t use it if I’m at

work or anywhere else.

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Social Acceptance

Challenges with practicing CFI in public places or whilst out were also

identified as potential barriers to practicing CFI:

I don’t see any challenges, other than being in public in front of others. That’s

the only challenge as I would feel embarrassed sometimes, depending on

where I am and who I am with.

You are going to look silly if you’ve got all wet hair coming out of the [water].

Predicted regularity of practice

Following on from motivation to practice CFI, participants were asked how

regularly they could see themselves using CFI. Many of them indicated it would be a

practice they would use regularly:

…whatever I find effective, I use on a regular basis

…if I found that it was effective you know of course I would, I would really do

anything to try and help out you know the onset of an anxiety or panic attack,

because it’s not a nice experience to go through

Some participants also commented on the likelihood that they would use it

whilst having a panic attack:

Very likely, to practice it in a panic attack, because found it helpful, I don’t

see any challenges with it. It’s a strategy that I have to do more often

…it’s…difficult when I’m ...out but if I’m at home…I can like just wash my

face with some cold water in the sink

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Utility of CFI in assisting panic/anxiety

Simplicity and practicality

When considering the usefulness of cold facial immersion as a strategy for

managing anxiety and panic some clinical participants commented on the simplicity

and practicality of CFI:

I’ve gone to a psychologist...to help me with my panic attacks…the programs

are almost…impossible to follow. By using this which is a very simple

technique … I think I would feel much better

Depending on results I think…it would be the most….easiest technique for

someone who has…if you want to treat panic disorders it requires.. breathing

exercises, you know thrice a day, then muscle exercise twice a day... you know

you have to follow it very strictly…so it is difficult…. this technique will be

very easy, you can do that, in the shower…

I can see it rolling it out as an intervention, each time you have anxiety putting

your face in cold water as this is a very easy to use method and practical.

Some clinical participants also discussed the utility of using CFI to reduce

panic symptoms and thoughts during panic attacks:

It reduces panic symptoms and negative thoughts, I think it would be very

helpful

I want to practice CFI, as hopefully it will help, very hopeful, it did help in the

lab but that was in a controlled setting. Should do it when panic sensations

coming on.

Well it can help me relax and forget about the anxiety.

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Effectiveness as an intervention

When considering its long term use, some participants considered CFI to be a

potentially useful intervention for managing panic and anxiety thoughts and

symptoms:

It would definitely help me out. I wouldn’t be scared at home alone. It’s a

good strategy, it teaches you to relax and calm down. As you calm down so

quickly, it’s very effective. I see it as an excellent strategy to reduce symptoms.

I could keep calm, walk to bathroom, put cold water in face when having a

panic attack, this would relax me.

From what I’ve learnt I think it would be very beneficial. So I even think that if

I ever start to get into a state of panic I might actually a bucket of water and

just throw my face into it. I think that would be very beneficial. Definitely.

… I would see it, well in the future in would be a very good intervention, like a

very good technique to help people… who have anxiety and panic disorders.

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Section 4. Experience with cold facial immersion task for

control participants

The final categories and themes from the thematic analysis relating to the

experience of cold facial immersion and views around its utility in helping manage

anxiety/ panic for control participants appear in Table 20. The themes are described

in further detail and individual quotes from participants are used for illustrative

purposes. Participants identified a range of strategies they use to assist them in

managing their anxiety/panic.

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Table 20.

Themes and Categories regarding Participants Experiences of the Cold Facial

Immersion Task for Group 2

Category Themes within categories Participant Quotes Initial experience of CFI

Mindful calming effect Relaxed state Reduced Heart rate Anticipatory Anxiety Discomfort with cold water

I felt the coldness calmed me down Relaxing, could feel tension in facial muscles reduced I felt the heart rate was going down Yeah I was a bit nervous holding my breath… … it was difficult to hold my breath for that long, 30 seconds

Positive experience after practicing CFI

State of Mindfulness Relaxed state and reduced heart rate Reduced anxiety symptoms and thoughts Sense of confidence and accomplishment

I think they [thoughts] were really reduced on the moment straight away I could definitely feel my heart..beating slower Could feel anxiety go down… I felt like I had more self confidence

Perceived challenges with practicing CFI

Accessibility and convenience Social Acceptance Physical discomfort with water

Having access to cold water if I’m outside somewhere. …it’s kind of you know weird to do it in public some people don’t feel as comfortable with their face under water

Utility of CFI in assisting panic/anxiety

Effective stress and anxiety relief Induce mindfulness and relaxation Simplicity and practicality Useful for people that suffer anxiety Likelihood of practicing CFI

Well it can help me relax and forget about the anxiety I find being in cold water relaxing It’s easy and practical to use…people can practice this quite easily I would also recommend it to people who are going towards panic attacks I would recommend it to friends and family. I would practice it more often

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Initial experience of CFI

Mindful calming effect

Many control participants described a mindful and calm state in in the initial

stages of the cold facial immersion task:

It was refreshing

It was really good, it was calming in the sense that, yeah, you just couldn’t

hear anything and it was just everything was blocked out for a bit.

.. the calming effect within one or two seconds I could feel myself slowing

down.

Relaxed state

Many control participants also described feeling relaxed during the initial

stage of the CFI task:

Relaxing, could feel tension in facial muscles reduced,

Relaxing..

…when I took my head out I actually felt quite refreshed and felt quite nice

actually

Reduced Heart rate

Some of the control participants also reported feeling a reduction in their heart

rate in the initial stages of the CFI task:

Well… when I put my face into the cold water I just thought like the

temperature just brought my heart rate down

I felt the heart rate was going down

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Anticipatory Anxiety

Some control participants described experiencing anticipatory anxiety before

and in the initial stages of the CFI task, particularly with regard to being able to hold

their breath for 30 seconds:

Yeah I was a bit nervous holding my breath…

I guess before the face immersion, I probably had a little bit of anxiety,

because I even asked “Do I have to hold my breath for 30 seconds?” Because

I questioned it, and I thought I don’t know if I can…like I don’t know I’ve

never tried this before, I haven’t been underwater before, like scuba diving

and I’m uncomfortable with water…

Discomfort with cold water

Furthermore some control participants reported some level of discomfort in

the initial stages of the CFI task:

…I felt a little hot after a few seconds

I felt cold towards the end of 30 seconds,

I felt dizzy and jittery

Positive experience after practicing CFI

State of Mindfulness

Many control participants discussed feeling a state of mindfulness following

the completion of the CFI task:

..calm…similar to like doing, like meditating or yoga or something, just

calming…

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I guess it just completely clears your mind, I wasn’t really thinking of

anything..

Oh yeah I think they [thoughts] were really reduced on the moment

Relaxed state and reduced heart rate

Following completion of the CFI task, many of the control participants

described a state of relaxation:

The feeling that I had afterwards it was like…when you go for a swim in the

ocean, and then afterwards… you kind of feel relief and refreshed…

I feel like straight after [CFI] it was just such a relaxing sensation, I kind of

wanted to stay like that but obviously it didn’t last that long…

Reduced anxiety symptoms and thoughts

When asked how they felt following the CFI task, many control participants

also reported experiencing reduced anxiety symptoms and thoughts:

I was a bit nervous going into it, and then like, I don’t really remember what I

was thinking…

I was just kind of like waiting for what was gonna happen but I just felt calm

and just kind of relieved…

My optimistic thinking improved

Sense of confidence and accomplishment

Some control participants also reported feeling a sense of confidence and

accomplishment upon completing the CFI task:

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And I could say it was.. I felt like I had more self confidence

I had more self confidence

I was surprised I could hold my breath for thirty seconds without really having

trained for it.

Perceived challenges with practicing CFI

Accessibility and convenience

Some control participants identified that accessibility to water and

convenience were some of the potential challenges with practicing CFI:

I was thinking maybe time…. if I had to get ready to go for work, it’s not ideal

time, ….but maybe like, I don’t know like… as soon as you wake up, it would

be good…

Access to the bucket or cold water that you can actually immerse your face in.

Another possible challenge would be that when I’m actually in a situation

where I’m experiencing panic or anxiety, I think it would be difficult to

prepare all the things needed for CFI, for example the pale and cold water.

Social Acceptance

Some control participants identified that accessibility to water and

convenience were some of the potential challenges with practicing CFI:

I don’t know…in your house it’s more practical, there isn’t no other

persons…I guess with me personally embarrassment in public

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if I was out no, and for me I think when I’m feeling anxious it’s more so when

I’m out, you know more like social anxiety. So in that sense probably not so

practical.

Physical discomfort with water

Some control participants also mentioned physical discomfort with water as a

potential barrier for practicing CFI:

You know, some people don’t feel as comfortable with their face under water.

I taught a ‘learn to swim’ program and you know, half of the system is just

teaching people to keep their face in the water. So that might be a difficulty.

But for your every day average person who doesn’t mind it – I think it will be

fine.

Utility of CFI in assisting panic/anxiety

Effective stress and anxiety relief

When asked about the usefulness of CFI in assisting in the management of

anxiety and panic, many control participants identified discussed its use as a form of

stress and anxiety relief:

If I ever felt that I was anxious I think it would help it..because it helps relax.

So it would definitely help relax the situation.

It could really assist me if I have anxiety as I felt refreshed and this may help

with stress and anxiety.

I think it would be a great way to help control many of the physical symptoms

of anxiety, as the CFI has a very calming effect.

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Induce mindfulness and relaxation

Another common benefit identified by control participants as adding to the

effectiveness of CFI in assisting the management of anxiety and panic was that it

induced mindfulness and relaxation from their experience:

It's also very good distraction. It's a very mindful experience I can see this

calming me and my anxiety and stress and in terms of thinking as well

Its like …going swimming in the ocean, it’s like … almost like refreshing…

and like you’re putting something in the past and then kind of looking at

something in a different way. I don’t know how to explain that…

It will definitely lower the heart rate, bringing down anxiety, it will be

beneficial definitely. Blood flow to the head is relaxing following the cold

facial immersion, that will definitely help me relax. With panic and anxiety

thoughts, I think it will help because of the shock to the system, and because of

the thoughts stopping

Simplicity and practicality

Many control participants also emphasised the simplicity and ease with which

you can practice CFI as another benefit in its effectiveness to assist individuals in

managing anxiety and panic:

I think a combination with other things, even if you were to do this regularly at

home, as such, I think you know if you’re you know a place where you cant

really you know excuse yourself for a few minutes to go and do that, then you

could use other techniques

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This would impact me in a positive way. I would let other people know about

this technique because it's easy and practical to use, and people can practice

this quite easily.

Useful for people that suffer anxiety

Many control participants discussed CFI specifically in terms of its usefulness

in assisting individuals that suffer from anxiety:

Yeah pretty positive like it seems to be helping…I think it’s positive, I think it

would be helpful and not many people would have probably considered

something like this so… like I haven’t considered it until the start of the

research I suppose

It’d be a positive impact and I would then also recommend it to other people.

I guess if it’s been proven to work, then the fact that can also lend support to,

when you’re describing it to the person to give them confidence, well it’s been

tested and it actually works

Likelihood of practicing CFI

When asked about whether participants were likely to practice CFI, many

participants indicated it would be something they would consider practicing:

It could really assist me if I have anxiety as I felt refreshed and this may help

with stress and anxiety. It's also very good distraction. It's a very mindful

experience I can see this calming me and my anxiety and stress and in terms of

thinking as well

If it had more of an empirical basis, I would be more likely to practice, and it

will have a positive impact

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DISCUSSION

The aims of the current study were to identify the current challenges which

clinical participants have managing their panic and anxiety symptoms and thoughts,

as well as the participants’ experience of cold facial immersion (CFI) and their views

around its utility as an intervention to assist in managing anxiety/panic thoughts and

symptoms. The results from this qualitative study proved to be a rich source of data,

enabling the illumination of some valuable information. They will be discussed in

two parts, firstly the current challenges will be discussed and then the experience and

application of the CFI task.

Challenges with the management of anxiety and panic thoughts

and symptoms

The key factors identified related to anxiety/panic management of thoughts

and symptoms included: cognitive disruption, disability burden, anxiety and panic-

related fear and panic cognitions. Cognitive disruption entailed challenges like

derealisation and depersonalisation themes, and difficulty thinking and concentrating.

There is an obvious manifestation of cognitive disruption in both state and clinical

anxiety (Vytal et al., 2013). Cognitive functions such as spatial working memory

(Lavric et al., 2003, Shackman et al., 2006) and particularly verbal working memory

respectively may be disrupted by anxious apprehension and anxious arousal. Verbal

working memory processes may share more neural circuitry with anxious

apprehension and anxious arousal hence accounting for the exaggerated disruption

(Vytal et al., 2013). The cognitive disruption experienced by Panic Disorder (PD)

sufferers characterised by difficulty concentrating and feeling easily distracted, has

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been undoubtedly linked to their disability burden as it can negatively impact their

performance at work and interpersonal relationships (Vytal et al., 2013).

Disability burden was a key factor found to be a challenge in managing

anxiety symptoms and thoughts by the clinical participants. The themes identified

comprised avoidance/escape behaviours and impact on daily functioning which depict

the magnitude of one’s perceived experience of feeling debilitated. PD is among the

anxiety disorders that can have a significant impact on peoples’ lives. Our findings

correspond with previous research that reported that PD accounted for high levels of

social, marital, occupational and physical disability (Klerman et al., 1991; Ettigi et al.,

1997) and in the primary health-care and community settings, PD is regarded as one

of the most costly mental health conditions (Meuret et al., 2017; Kessler et al., 2005),

being potentially more of a disability burden than even the severe mental disorders

(Baxter, Vos, Scott, Ferrai & Whiteford, 2010; Kessler, et al., 2006, Kennedy &

Schwabb, 1997).

Avoidance and escape behaviours which were identified as themes associated

to the disability burden may occur in response to perceived threat and anxiety, and in

turn, may drive to maintain the perceived threat and anxious beliefs (Funuyama et al.,

2013). According to Forsyth, Barrios and Acheson, (2007) following several trials of

CO2 inhalations individuals high in experiential avoidance, present with more panic

symptoms, panic cognitions, fear, and loss of control than their less avoidant

counterparts.

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Salkovskis, Clark and Hackmann, (1991) proposed that exposure therapy

although effective in the treatment of phobias can be compromised by the

implementation of in-situation safety behaviours, and/or subtle avoidance strategies

aimed to prevent the perceived threat or feared catastrophe while remaining in the

feared situation. Such safety behaviours and avoidance strategies that are applied in

phobic situations by the anxiety sufferer prevents him/her from experiencing an

unambiguous disconfirmation of their erroneous beliefs, regarding feared catastrophes

(Salkovskis et al., 1991; Salkovskis, Clark & Gelder, 1996).

Impact on daily functioning was notable as an important theme, playing a role

in contributing to the disability burden of clinical participants in Study 2. PD is often

considered to have a chronic course which has been associated with having significant

life impairment, including substance abuse, and increased likelihood of suicide

attempts, unemployment, frequent absenteeism, early retirement and regular use of

health care services (Ettigi et al., 1997). This impact on daily functioning caused by

the chronic nature of the symptoms, the avoidance and escape behaviours and the

debilitating physiological and cognitive symptoms reported generally by PD patients

impact pose a significant challenge in managing anxiety symptoms, and panic and

anxiety thoughts.

According to Cosci (2012) promoting recovery early in the treatment process

is important, given that PD often involves a staging process, implicating that the

disorder often gradually worsens over time if left untreated. Support for the staging

model of PD and agoraphobia has been implicated by its utility to recognise PD early

enough to be able to treat it successfully (Fava et al., 1999; McGorry 2007; Mc Gorry

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et al., 2007). The model may also be able to assist with the development of

therapeutic strategies for patients that are treatment resistant (Cosci, 2012).

Anxiety and panic-related fear was another key area identified which

encompassed the following themes: fears of dying, fainting, losing control and

uncertainty. All these themes pose significant challenges given that fear is very much

accentuated in the abovementioned perceived threats. These fears may be quite

common in anxiety provoking situations in anxiety sufferers, however in PD sufferers

they are more vast and scary given that individuals fear their own bodily symptoms,

losing control and uncertainty. These are more exaggerated in the PD group given

that PD is characterised by recurrent and spontaneous panic attacks (PAs). Clinical

participants reported fears and exaggerated anxiety to the unlikely prospect that they

may faint, pass out, die, or have a heart attack.

Loss of control and fear of uncertainty were a challenge that many clinical

participants discussed in relation to managing both symptoms and thoughts related to

panic and anxiety. Particularly participants described having difficulty controlling

their thoughts and anxiety/panic, as their symptoms are often exaggerated due to

disproportionate fear experienced and the uncertainty of not knowing when the PA

will cease. Participants reported having difficulty with the uncertainty, i.e., whether

they will be able to cope, how long the PA will last e.t.c. PD individuals have

difficulty managing symptoms such as loss of control and uncertainty. Often these

symptoms may be exacerbated by the lack of perceived locus of control, an

accentuated fear response and a perceived threat to either interoceptive or

exteroceptive stimuli. This heightened anxiety in panic sufferers may be an

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antecedent to catastrophic misinterpretation which leads to the exacerbation and

maintenance of the vicious cycle of panic (Barlow & Craske, 2007).

Anxiety and panic cognitions were also factors identified by the qualitative

study which comprised the following themes: predictive and catastrophic thinking,

racing thoughts and worrying. There is considerable evidence that panic cognitions

and catastrophic cognitions facilitate the maintenance of PD (Clark, 1988; Bouton et

al., 2001; Salkovskis et al., 1996). Participants reported a preoccupation with

overthinking and worrying about things potentially going wrong, predicting what is

about to happen and thinking the worst. Furthermore, they reported difficulties with

managing the racing thoughts before and during the onset of a PA. Tangential

thinking and predictive, catastrophic thinking was identified as challenging, by PD

participants. These cognitive symptoms are often experienced during the PA and are

often reported concurrently with mind racing by PD individuals. Worrying was

another significant contributing factor to their PAs which clinical participants

identified as challenging when managing their panic thoughts and anxiety symptoms.

Some clinical participants reported that excessive worrying could initiate a PA or

exacerbate one that has already taken place. Our findings support those of Raffa,

White and Barlow (2010) who proposed that cognitions play a central role in PD.

Khawaja and Oei (1998) in their systematic review provided substantial empirical

evidence in support of the cardinal role catastrophic cognitions play in the

maintenance of PD and agoraphobia. This provides compelling evidence for the

cognitive theory models which propose that symptoms are maintained by the

catastrophic misinterpretation of both internal and external cues made by patients

(Craske & Barlow, 2007).

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According to modern learning theory anxiety is seen as a distinct construct to

panic, where anxiety is characterized by apprehension, worry and tension whilst panic

is accompanied by strong autonomic arousal, extreme fear and fight or flight response

tendencies (Barlow, 1988; Bouton et al., 2001; Craske, 1999). According to this

perspective, a central factor in the development of PD is the interaction of anxiety and

panic. Anxiety may manifest as anticipatory anxiety and thus contributes to PD

maintenance via a positive feedback loop of anxiety and panic (Barlow, 2000; Öhman

et al., 2001). In the current study clinical participants reported experiencing

challenges with managing cognitive symptoms of anxiety as well as physiological

symptoms of anxiety, hence the ongoing interaction of these two constructs

(panic/anxiety) during a PA or in the anticipation of it, appears to be challenging for

PD sufferers.

Physiological symptoms of anxiety are another contributing factor that

comprises cardiorespiratory symptoms and vestibular symptoms. Coping with

cardiorespiratory symptoms associated with anxiety and panic were described as

major challenges by clinical participants. Specifically, difficulties with breathing,

choking sensations, heart racing or chest pounding, numbness and tingling sensations

were amongst some of the symptoms participants reported having difficulty

managing. Amongst some of the vestibular symptoms which were commonly

reported as being difficult to manage were feelings of faintness, dizziness, hot flushes,

shakiness and trembling. PD sufferers have difficulty managing these symptoms as

they are likely to perceive these symptoms as threatening and are likely to think that

something is terribly wrong with them. These findings support previous research that

has found the construct of anxiety sensitivity to be related to PD (McNally, 1994;

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Reiss, 1991). Anxiety sensitivity posits that cognitive misappraisals is central to the

provocation of anxiety. Individuals who score high on anxiety sensitivity attribute the

abovementioned cardiorespiratory and vestibular symptoms experienced by the

participants as being dangerous and having inherent beliefs about the possible harm

such symptoms to their body or to their mental health (McNally, 1994; Reiss, 1991;

Schmidt et al., 1997, 1999; Weems, Hayward, Killen & Taylor, 2002, Dixon et al.,

2013). Furthermore, PD participants that reported respiratory symptoms, such as

breathing difficulties, choking sensations, heart racing or chest pounding, numbness

and tingling sensations, experienced challenges with managing these symptoms. This

is consistent with previous findings (Freire et al., 2013; Nardi et al., 2006; Valenca,

Nardi, Nascimento, Zin & Versiani, 2002).

Strategies used to manage anxiety and panic thoughts and

symptoms

Cognitive strategies are a key theme used to manage anxiety and panic

thoughts and symptoms, comprising the following categories: thought stopping, self-

talk and reassurance, psychoeducation, distraction and refocus strategies. Thought

stopping techniques are amongst one of the most common strategies that are

reportedly used to stop the mind racing or the negative spiralling of the anxious

thoughts. Such strategies have included dismissing or disputing negative catastrophic

thoughts. Participants expressed having some difficulty with thought stopping

techniques, when they are having a panic attack, suggesting that they are merely

effective.

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Self-talk and reassurance were other strategies participants employed to assist

them in managing anxiety and panic symptoms. Participants reported practicing

positive self-talk, reassuring the self that nothing bad will happen or telling the self

that it will pass. Using repeated self-talk that is comforting, and reiterating to the self

that it will be okay and that there is nothing to worry about, and to ride the wave are

amongst some of the techniques that fall under this category. The strategies used by

the participants in Study 2 are amongst the techniques commonly applied in many of

the cognitive treatments (Leahy, Holland & McGinn, 2011). In depressed patients

with comorbid panic attacks (PAs), Goldberg (2011) proposed that they are given

advice about not leaving the place immediately where the panic attack occurred.

Furthermore, they were encouraged to practice helpful self-talk and to remind

themselves that they have had PAs previously and that they will pass. Reassurance

was a strategy used, as well as counteracting negative thoughts with more comforting

thoughts, to make the PAs easier to deal with, and less likely to become worse

(Goldberg, 2011). Similarly, positive self-talk was reportedly used in a similar way

by the participants in Study 2.

Among the strategies discussed, clinical participants mentioned

psychoeducation to be helpful, which involved learning about their conditions and

themselves as helpful in managing their panic and anxiety. Psychoeducation is a key

component of cognitive behavioural therapy and breathing retraining (Craske et al.,

2014). Participants reported that educating themselves about the symptoms and that

the symptoms are not dangerous is common in the management of anxiety and panic

symptoms.

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Many clinical participants described the use of distraction techniques and

trying to refocus their thoughts. Distraction techniques, included changing one’s

environment or having someone distract them, trying to focus on something else, on a

single thought or on breathing. These strategies were reportedly used to distract the

self from the mind racing and from focusing on catastrophic thinking and panic

symptoms. Common distraction techniques included: playing an instrument, or

reading a book, messing around on the computer, drawing, colouring and zoning out.

The qualitative data supported the notion that although some of the CBT strategies

used to assist with the management of panic and anxiety symptoms, they remain quite

limited. This appears to be in line with the ideas of Craske et al. (2014) and Hoffman

and Smits (2008) who proposed that CBT is still far from optimal.

Physical Strategies

Breathing techniques were amongst the physical strategies used to manage

anxiety or panic symptoms. Many participants reported feeling a sense of being so

overwhelmed by their symptoms that they lose touch with reality. Practicing deep

diaphragmatic breathing yielded mixed results, with some participants finding it

helpful and with others noting the limitations of breathing exercises to assist with

their panic symptoms. Breathing retraining has proven to be effective however it

needs to be practiced as a preventative strategy on a regular basis, rather than on the

onset of panic to reverse the symptoms (Garssen, de Ruiter & van Dyck, 1992; Lum,

1983; Grossman et al., 1985). It was difficult to determine whether participants in our

study practice deep breathing on a regular basis, as this was not explored in the

interview.

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Breathing retraining is commonly used in the treatment of panic disorder to

purposefully reduce anxious arousal (Barlow & Craske, 2007). Although several

studies suggest that this intervention is effective in reducing both panic frequency,

and severity (Clark, Salkovskis & Chalkley, 1985; Rapee, 1985; Salkovskis, Jones &

Clark, 1986), concerns have been raised about its efficacy when used routinely (Bonn,

Readhead & Timmons 1984; Barlow, 2002; Schmidt et al., 2000; Taylor, 2001).

Some theorists have cautioned against the regular use of breathing retraining,

postulating that it is counterproductive as it can take on the role of a safety cue or an

aid, to the extent that it prevents patients from learning that their catastrophic beliefs

are irrational (Taylor, 2010). Safety behaviours are thought to maintain clinical

anxiety by exacerbating or maintaining hypervigilance toward threat and increasing

the perception that exposure to anxiety-related body sensations is dangerous (Telch et

al. 2008). Numerous reports in the literature support the notion that treatment

response is improved by the identification and elimination of safety behaviours (e.g.,

Morgan & Raffle, 1999; Salkovskis, Clark, Hackmann, Wells & Gelder 1999;

Schmidt, Richey, Maner & Woolaway-Bickel, 2006; Wells et al., 1995) hence

cautioning against breathing retraining. Furthermore, in the one single placebo study

conducted by Hibbert and Chan (1989), the effects of breathing retraining on panic

attack (PA) frequency and severity were not demonstrated to exceed those produced

by a credible placebo. This may be due to the challenges of not knowing the effects

of more commonly applied breathing retraining techniques and that the distinction

between safety behaviours and coping aids is difficult to determine in clinical practice

(Thwaites & Freeston, 2005).

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According to numerous theorists, breathing retraining may be an effective

intervention for reducing anxious arousal (Clark et al., 1985; Meuret et al., 2008;

Rapee, 1985; Salkovskis et al., 1986). Growing evidence has been pointing to

capnometry assisted respiratory training, aimed at gaining respiratory control, as

showing more promise (e.g., Meuret, Wilhelm, Ritz & Roth, 2008). Both breathing

retraining and capnometry assisted respiratory training (CART) are thought to

increase perceptions of control in anxiety sufferers, with CART yielding more

consistent results (Sanderson et al., 1989).

According to Lickel et al. (2010), the addition of breathing retraining when

compared to psychoeducation alone did not improve anxiety sensitivity symptoms,

nor add to the gains observed on measures of coping (e.g., perceived control). Our

findings from the qualitative interviews suggest that although breathing retraining

may be commonly applied by participants, both during a PA and/or routinely as a

preventative strategy, there were mixed reports of whether they found the breathing

retraining to be helpful. Some of the perceived challenges included that breathing

was difficult to practice and that it didn’t always work. Also, it is quite common to

experience relaxation-induced anxiety when people with anxiety sensitivity practice

breathing exercises and relaxation techniques (Wells, 1990).

Physical activity was another strategy discussed by clinical participants, that

was used to manage panic and anxiety symptoms. Participants reported exercising

and trying to keep physically active which included walking, pacing, running and

stretching. Reports in the literature have demonstrated that people who are regarded

to be physically active, and engage in regular physical exercise (2-3 times per week)

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have decreased prevalence of anxiety disorders (Goodwin, 2003; Muhsen, Lipsitz,

Garty-Sandalon, Gross & Green, 2008; Ströhle et al., 2007; ten Have, de Graaf &

Monshouwer, 2011). Although physical exercise has been demonstrated to reduce

anxiety symptoms in participants with elevated anxiety levels (Petruzzello, Landers,

Hatfield, Kubitz & Salazar, 1991), few studies have explored the use of physical

exercise as a treatment for PD (Martinsen, Sandvik & Kolbjørnsrud, 1989; Broocks,

et al., 1998; Hovland et al., 2012). A number of studies have demonstrated that

physical exercise can have acute anti-panic effects, reducing the risk of PAs in not

only healthy individuals (Esquivel, Schruers, Kuipers, & Griez, 2002; Smits et al.,

2009; Ströhle et al., 2005) but in patients with high anxiety sensitivity (Broman-Fulks,

Berman, Rabian & Webster, 2004; Broman-Fulks & Storey, 2008; Smits et al., 2008)

and in patients with PD (Esquivel et al., 2008; Ströhle et al., 2009) with limited

prescribed physical exercise. Hovland et al. (2012) compared physical exercise in

groups to group cognitive behaviour therapy (CBT) as a treatment for PD in a

randomised clinical trial (RCT) and found CBT to be superior yielding significantly

better long-term effects than physical exercise which still displayed relatively large

effect sizes. Our findings suggest that although physical exercise was used by the PD

participants as a strategy to aid their symptoms, they explicated that exercise was still

quite limited in terms of its efficacy and utility. Moreover, participants reported that

it was difficult to find the time and to maintain the exercise routine.

Mindfulness Strategies

Using the practices of mindfulness and acceptance were discussed by many

clinical participants as a strategy that they employ to assist in the management of

anxiety and panic symptoms. Observing and noticing thoughts, bodily sensations and

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feelings, practicing mindfulness breathing, relaxation and acceptance were amongst

the strategies used by participants in this category. Some participants described riding

the wave and allowing anxiety to do its thing whilst others reported practicing self–

talk in a mindful way whilst pushing through and persevering. Focusing on things on

the external environment as well as bodily sensations in a mindful way were also

strategies used when experiencing panic or anxiety. The consensus in our clinical

group was that some participants found it helpful whereas others practiced but did not

find the mindfulness strategies as helpful.

Insights from our qualitative interviews were in line with those documented in

the literature as the clinical participants experienced mindfulness without active

avoidance and suppression (Levitt et al., 2004) but rather trying to fully experience

the emotions of anxiety during a PA in a non-judgemental way. Although some

reported finding these strategies beneficial, many reported experiencing challenges

with mindfulness in managing their symptoms. This appears to be in line with reports

in the literature that suggest that mindfulness strategies and ACT were no better than

established treatments (Powers et al., 2009).

Whilst mindfulness was most commonly discussed, some clinical participants

in our second study specifically identified meditation as a strategy to manage anxiety

and panic symptoms. Prayer meditation and more general meditation were amongst

the techniques reportedly used by the participants in Study 2. Meditation practices

such as prayer meditation, gratitude meditation, and self-compassion meditation are

becoming more increasingly popular, however, there are some limitations with these

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strategies, as during a PA it is difficult to engage in these. More empirical evidence is

needed for meditation strategies.

Experience of the Cold facial Immersion

The initial experience of CFI was described as positive by both clinical and

control participants. Although there was some anticipatory anxiety or discomfort

related to the breath-hold, and the temperature of the cold water, participants in both

groups described a feeling of calmness and relaxed feelings associated with the CFI.

A number of participants reported that they relaxed so much that they felt that their

heart reduced. Similarly, both groups had similar experiences post CFI, describing it

as a pleasant mindful experience that elicited feelings of calmness, relaxation, and

stillness. A number of participants described feeling surprised at how relaxed they

felt, and how the mind and the anxious thoughts had cleared. From the data gathered

from the qualitative interviews, the CFI task was referred to as a mindful experience

that was rejuvenating. Interestingly, this is consistent with anecdotal evidence that

suggests that free diving is a mindful experience, one that’s characterised as being

fully present, and feeling invigorated, energised, calm and relaxed.

In regards to practicing CFI on a regular basis, participants in the clinical group

expressed that they were hopeful that the CFI would help with their anxiety.

Moreover, many of the participants did suggest that they would practice this on a

regular basis, given that they found the CFI was beneficial in reducing their panic and

anxiety symptoms when practiced during the experimental study. Both groups felt

they had a reduction of anxiety as a result of the CFI and described that they felt a

sense of confidence and feeling of empowerment by completing the CFI, particularly

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when they surprised themselves that they could hold their breath for that 30 seconds

and with feeling so relaxed.

When asked about perceived challenges accessibility and convenience including

trying to access water and being worried about what other people think, or feeling

embarrassed to use the CFI task in front of others, were amongst the most common

barriers explained by both groups. The clinical group differed in the responses as

they identified more physical challenges such as not being able to hold breath for 30

seconds, or water being too cold. Time challenges were also identified as a potential

barrier, partly the time taken to set up the CFI task, as that may take on average a few

to several minutes, as well as time taken to practice. A number of clinical participants

perceived the time taken to set up the CFI task as a positive factor as it may be

considered a distraction from the panic symptoms. Despite the abovementioned

challenges that both groups could foresee with the CFI task most participants were

willing to practice it when having a PA.

In respect to the utility of CFI task, both the clinical and control group

participants emphasised overall the simplicity and practicality of the CFI, its ability to

induce a mindful, invigorating and relaxed state, and its potential to be an effective

intervention for anxiety and stress management. Given its practicality, participants

stated that they would recommend it to friends and family, given that it is easily

applied and so immediately beneficial.

Both clinical and control participants in the study were also asked which ways

they would prefer to activate the DR. Amongst some of the most frequent responses

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of preferences in how to activate the DR included CFI, splashing cold water in face,

having a cold shower, applying an ice pack on the face, and wearing a specially

designed facial mask that activates the DR. Participants suggested that a facial mask

would be more accessible, something that one can carry with them wherever they go.

When one experiences a PA, they could wear the facial mask and activate it so it

cools the sensitive areas of the face that activate the DR.

Study Limitations

A limitation of the qualitative study was that the interviews were quite short

ranging from 10-20 minutes. This was initially because some participants did not

answer the questions of the interview in length, and did not elaborate on their answers

much when probed. The researchers were also mindful of the time the participants

dedicated to this research study and did not want to take too long with the interviews,

as this would have exceeded the time that we informed participants it is likely to take.

Another noted limitation is that the cold water in both our studies was

regulated between 7 ˚C - 12˚C whilst maintaining the room temperature at a constant

22˚C. Although reports in the literature suggest that lower water temperatures (0˚C -

10˚C) increases both minute ventilation and elicit more pronounced bradycardia as

compared to warmer water (Schagatay & Holm, 1996; Anderson et al., 2016), reports

that water was too cold or that it created physical discomfort were discussed by

participants. Reports of physical discomfort caused by the cold water temperature

have also been noted in the literature (Manley, 1990). An improvement for future

studies may be to use cold water temperature ranging 10°C – 15 °C as research

indicates facial cold receptors are strongly stimulated by immersion in water with this

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temperature range (Daly, 1997; Jay, Christensen & White, 2007). This warrants

further investigation to identify if you can elicit the same bradycardiac response in

10°C – 15 °C water without participants experiencing pain and physical discomfort.

Furthermore, control participants were asked the same questions as the clinical

group. The questions regarding panic and anxiety symptoms and cognitions did not

yield useful information as control participants did not suffer from panic symptoms.

Future methodological considerations for the acquisition of the qualitative data

may include more in-depth and comprehensive interviews, and reconsideration of

whether to interview control participants. The inclusion of the control group in the

interview process, may not be required given that we are more interested in responses

that elicit information about panic symptoms experienced by the clinical participants

and the utility and application of the CFI task to assist a PD patient with managing

panic symptoms. Furthermore, more questions exploring the strategies that are

currently being used by clinical participants to manage their symptoms, i.e., how

frequently are they practicing the strategies? how effective are they?, and what are the

challenges with practicing these strategies? Furthermore, collecting more information

about the application of the DR and CFI, and preferences of how and when to use it

may assist us further with gathering more comprehensive information about its utility

and potentially future directions as a new treatment approach.

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Implications and Conclusions

The findings of the qualitative exploration indicate that CFI induces calming,

relaxing and anxiolytic effects in both panic and control participants. This is likely to

be the case, as CFI activates the DR which is an innate human adaptation that has an

oxygen conserving effect and has the ability to reduce the heart rate considerably and

to redistribute blood to the most vital organs for survival, including heart and brain.

The CFI is also described as a mindful experience, that is very still, and participants

reported feeling very present and focused during the task, and invigorated and

rejuvenated once they complete the CFI. Participants reported that it is easy to use

and practical and that they are likely to use it on a regular basis particularly if it is

effective. Although there were some perceived challenges around accessibility, the

majority of participants were intrigued regarding its subsequent calming effects and

its practicality, and ease of applicability. Moreover, participants were intrigued about

the alternative methods one could use to activate the DR. Hence they reported that

they are likely to use it, given that they reported that it was surprisingly beneficial.

This appears to demonstrate promise as an anxiety management technique and

warrants further investigation.

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Chapter 8

OVERALL CONCLUSIONS

The present research was presented in three parts, preliminary study, an

investigation of cold facial immersion (CFI) and its effects on CO2 sensitivity, and

qualitative exploration of panic and CFI. The preliminary study examined the

differences in anxiety and panic symptoms, and cardiorespiratory measurements

between the control and clinical participants in a number of challenges, including two

breath-hold challenges, a CO2 challenge, a CFI task, and a CO2 challenge followed by

a CFI task. The second study investigated the effects of CFI on CO2, particularly

whether CO2 sensitivity may be altered by one single administration of CFI. The

qualitative investigation gathered qualitative data via face to face interviews from the

same participants given that this is a preliminary investigation on determining

whether the DR activated by the CFI warrants further investigation as a potential new

treatment or strategy used to manage panic and anxiety symptoms in individuals

suffering from panic disorder (PD). The final section of this chapter brings together

the findings from the abovementioned studies and discusses their implications for PD

research and clinical practice.

In the preliminary study, the key findings were that both clinical and control

participants experienced a reduced heart rate (HR) in response to the CFI task.

Furthermore, both clinical and control participants experienced a significant heart rate

(HR) reduction in response to the CFI task, with the clinical participants experiencing

a greater reduction in HR during the CFI task, immediately after the CO2 challenge

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than the control cohort. This suggests that the DR is a powerful physiological

adaptation. This is in line with previous research that has found that the DR is

augmented by the CFI task or by facial cooling (Yadav et al., 2017; Khurana & Wu,

2006, Schagatay, 2009). Finally, the preliminary study found that activating the DR

via the CFI task, reduced panic cognitions and physiological symptoms of anxiety and

panic. This demonstrates some promise in terms of the CFI’s utility to assist with the

management and reduction of anxiety and panic symptoms.

There was no significant difference noted in breath-hold (BH) ability between

the clinical and the control group. Although the means of the BH durations were

slightly shorter for the clinical participants as compared to control participants, in

both the passive exhalation BH and the maximum deep inhalation BH, the difference

was not significant. Previous studies have yielded varied findings (van der Does,

1997; Asmundson & Stein, 1994; Roth et al., 1998; Zandbergen et al, 1992, Nardi et

al, 2002). The inconsistent results found in previous studies may be explained by

many of the studies comprising small, heterogeneous samples, diverse inclusion and

exclusion criteria, and different PA criteria. It is inconclusive whether our data

support Klein’s theory and whether our findings support that the BH challenge may

be a marker for CO2 hypersensitivity to CO2 induced panic. Hypersensitivity to CO2

may be more notable in the PD respiratory subtype, something our study could not

investigate due to the limitation of having a small sample. The preliminary study

reported no significant differences between the clinical and control group, however,

an increase was noted in HR in both the clinical group and the control group.

Furthermore, the preliminary study reported no significant difference in respiration

rates were observed between the clinical group and the control group in response to

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Chapter 8. Overall Conclusion

276

the CO2 challenge. Although previous research examining RR post CO2 has yielded

mixed findings, our findings do not lend support to those of Griez &Van det Hout,

(1983; 1986), Klein, (1993), and Schimitel et al. (2012) as our hypothesis was not

supported.

The preliminary study findings indicated that the clinical and control

participants reported experiencing more anxiety and panic symptoms in response to

the CO2 challenge on the following anxiety measures PACQ, ASI, API, BAI, STAI

and VAS –P participant and VAS-R researcher ratings. This appears to be in line

with previous research which has reported increased anxiety symptoms following the

CO2 challenge (Beck, Ohtake & Shipherd, 1999; Battaglia et al., 1995).

The results of the investigation of the effects of CFI on CO2 sensitivity found

there were no differences in the physiological response of the CO2 challenge, as

measured by changes in HR and RR. Although appropriate steps and measures were

taken to improve the experimental design, it appears that there continued to be some

difficulties in this study, particularly with the provocation challenge. It was observed

during the procedure in both studies that clinical participants had difficulty with not

only taking a maximal deep inhalation of 35% CO2 and 65% O2 but also with holding

the breath for 4 seconds before exhalation.

Another important finding of the second study was that there was a significant

reduction in reported symptoms in the anxiety measures, in both the clinical and the

control group. These findings were of particular interest. Although the current study

was unable to identify whether one single administration of the CFI task can reduce

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Chapter 8. Overall Conclusion

277

CO2 sensitivity, it appears promising as an intervention given that it was able to

significantly reduce self-reported anxiety symptoms in both groups, particularly in the

clinical group. Whilst the control group has minimal symptoms overall in response to

the CO2 challenge, they also report a reduction in symptoms and calming effects in

response to the CFI task. The clinical group demonstrated a reduction in anxiety

symptoms, following exposure to the CFI task on all anxiety measures including the

ASI, API, STAI, PACQ, BAI, VAS-R and VAS-P. Given these results have been

demonstrated from one exposure to the CFI, it is plausible to infer that frequent

exposure to the CFI tasks and to breath-holding may be able to reduce CO2 sensitivity

in PD patients over time. Practicing breath-holding and activating the DR through

free diving and CFI on a regular basis has been known to have trained effects, and

subsequently the capacity to reduce CO2 sensitivity (Konstandinidou & Chairopoulou,

2017). Reports in the literature have suggested that a blunted hypercapnic response

and prolonged breath-hold times have been associated with the benefits of trained

effects and repeated apneas (Andersson & Schagatay, 2009; Walterspacher et al.,

2011; Roecker et al., 2014, Grassi et al., 1994; Foster & Sheel, 2005).

Another principal finding of the investigation of CFI effects on CO2 sensitivity

was that there was no significant difference found in HR nor RR following the CO2

challenge. In many ways, the results of this study correspond with the results of the

preliminary study. In the second CO2 challenge we expected that the clinical group

will demonstrate a blunted response following the CO2 administration. Our results

were not significant and hence, it cannot be inferred that one single administration of

CFI can alter one’s sensitivity to CO2. Also as anticipated and consistent with the

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Chapter 8. Overall Conclusion

278

findings of the preliminary study, both the panic and control group had a significant

HR reduction as a result of the CFI.

The results of the qualitative research are consistent with our main findings

from the preliminary and second study. That is, that CFI has calming and relaxing

effects and that it reduced panic/anxiety symptoms, anxiety sensitivity, panic thoughts

and cognitions. The CFI task was able to reverse panic symptoms in clinical

participants, that were elicited by the CO2 challenge. This was evidenced by the

significant reductions in self-reported anxiety measures as reported by the clinical

participants as well from feedback from the qualitative interviews. Among the

themes of the qualitative research is that CFI is described as a mindful and a pleasant

experience and that it is easy to use and practical. Both control and clinical

participants described this to be beneficial and reported that they are likely to use it on

a regular basis and recommend to others. Although there were some perceived

challenges around accessibility, the majority of participants were intrigued regarding

its subsequent calming effects and reported that they are likely to use it on a regular

basis and tell their family and friends about it that suffer from anxiety. This appears

to demonstrate promise as an anxiety management technique and warrants further

investigation.

A key feature in anxiety disorders is the failure to appropriately extinguish the

fear (Hermans et al., 2006; Milad et al., 2006; Pitman, Hin & Rauch, 2001).

Individuals suffering from debilitating anxiety disorders have a tendency to avoid fear

provoking situations, or stimuli, or to tolerate them with great difficulty, by

employing a range of safety behaviours which further maintain PD symptoms and

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Chapter 8. Overall Conclusion

279

prevent fear extinction (Lovibond et al., 2008: 2009). Avoidance and the use of

safety behaviours may hold patients back from overcoming their fears and from

challenging unrealistic beliefs related to their fear (Lovibond et al., 2009). According

to Breier, Charney and Heninger (1986), PD with agoraphobia is a fear-based

disorder. Research examining the potential differences in fear extinction processes

across all anxiety disorders and particularly in the fear based disorders is lacking

(Milad et al., 2014). Furthermore, more human and animal research is needed to

understand the neural mechanisms involved in fear generalisation and fear extinction,

as this may aid exposure-based treatments. Future research should aim to develop

innovative and effective behavioural techniques to promote the generalisation of fear

extinction in humans, to better inform translational models for the treatment of

psychiatric disorders characterised by excessive fear, and anxiety (Dunsmoor & Paz,

2015). Hence longitudinal studies are needed to investigate both the clinical

applicability and likely practice effects of CFI in exposure-based treatments aimed to

reduce fear generalisation and promote fear extinction.

These findings may help to inform new treatments for PD patients. The CFI

task may have significant merit in its applicability to downregulate the fear, given that

it reduces the heart rate significantly, and increases in heart rate are among of the

scariest of panic symptoms reported by PD sufferers. It is common to use in hospital

emergency departments to counteract atrial tachycardia, and the results from our

studies point to the CFI task and the DR to being worthy of further investigation in

terms of exploring its efficacy in the management or treatment of PAs and PD.

Furthermore, the CFI task may be used psycho-educationally and as a behavioural

experiment, following a hyperventilation challenge in an attempt to reverse the

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Chapter 8. Overall Conclusion

280

physiological symptoms of anxiety and the panic cognitions. Moreover, it may be

used as an exercise to demonstrate to panic and anxiety sufferers how not only can

someone habituate to the cold water with the facial immersion task, but that they may

also be able to habituate to the feared response.

Although in the first study we did not achieve the differences in breath-hold

(BH) durations that we anticipated this warrants further investigation. A large sample

size needs to be recruited in order to investigate differences in BH duration between

the clinical and the control group. Furthermore, given that repetitive breath-hold

training (BHT) with short recovery interval periods, has been associated with longer

BH times due to the increased time in withstanding the respiratory drive, and

diminishing the ventilatory response to hypercapnia (Schagatay et al., 1999), BHT

requires further investigation to determine its efficacy as a potential treatment for PD.

Future studies should consider looking at whether BHT can change the duration of

BH times in PD patients, and potentially changing the CO2 sensitivity in this patient

group.

In summary, the CFI may be a useful tool diagnostically and therapeutically.

The findings from both studies first and foremost indicate the need for further

research. The applications of the DR may provide scope for a more effective and

robust treatment for PD, given its practicality, and ease of application, when

combined with existing treatments such as CBT. Therapies that focus on exposure to

feared bodily sensations may be complemented by this powerful autonomic reflex, the

DR. Potentially, there may be scope to introduce the DR and CFI applications in self-

help, or guided self-help treatments, as a viable combination to provide additional

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Chapter 8. Overall Conclusion

281

treatment as well as effective and cost-effective treatment for PD. The feasibility,

practicality, and efficacy of such a combination may yield important insights and

improved interventions for PD and anxiety sufferers, something future studies will

assist to determine.

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282

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Appendix A: Ethics Approval

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From: Ann Gaeth <[email protected]> Date: Friday, February 14, 2014 Subject: SUHREC 2014/010 Ethics clearance To: Michael Kyrios <[email protected]>, Peter Kyriakoulis <[email protected]> Cc: RES Ethics <[email protected]>

Dear Michael and Peter, SUHREC Project 2014/010 The efficacy of cold facial immersion and the diving response in treating panic disorder Prof M Kyrios, Mr P Kyriakoulis et al Approved Duration: 14/02/2014 To 01/12/2016 I refer to the ethical review of the above project protocol undertaken by Swinburne’s Human Research Ethics Committee (SUHREC). Your responses to the review were put to a SUHREC delegate for consideration and accords with the feedback. I am pleased to advise that, as submitted to date, the project must commence in line with standard on-going ethics clearance conditions here outlined.

- All human research activity undertaken under Swinburne auspices must conform to Swinburne and external regulatory standards, including the National Statement on Ethical Conduct in Human Research and with respect to secure data use, retention and disposal. - The named Swinburne Chief Investigator/Supervisor remains responsible for any personnel appointed to or associated with the project being made aware of ethics clearance conditions, including research and consent procedures or instruments approved. Any change in chief investigator/supervisor requires timely notification and SUHREC endorsement. - The above project has been approved as submitted for ethical review by or on behalf of SUHREC. Amendments to approved procedures or instruments ordinarily require prior ethical appraisal/ clearance. SUHREC must be notified immediately or as soon as possible thereafter of (a) any serious or unexpected adverse effects on participants and any redress measures; (b) proposed changes in protocols; and (c) unforeseen events which might affect continued ethical acceptability of the project. - At a minimum, an annual report on the progress of the project is required as well as at the conclusion (or abandonment) of the project. - A duly authorised external or internal audit of the project may be undertaken at any time. Please contact the Research Ethics Office if you have any queries about on-going ethics

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clearance, citing the SUHREC project number. Copies of clearance emails should be retained as part of project record-keeping. Best wishes for the project. Kind regards, Ann _____________________________________ Dr Ann Gaeth Executive Officer (Research) Swinburne Research (H68) Swinburne University of Technology P O Box 218 HAWTHORN VIC 3122 Ph +61 3 9214 8356

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From: Ann Gaeth Sent: Monday, 24 March 2014 4:02 PM To: Michael Kyrios; Peter Kyriakoulis Cc: RES Ethics Subject: SUHREC 2014/010 Ethics clearance for modification (1) Dear Michael and Peter, SUHREC Project 2014/010 The efficacy of cold facial immersion and the diving response in treating panic disorder Prof M Kyrios, Mr P Kyriakoulis et al Approved Duration: 14/02/2014 To 01/12/2016 Project Modification: Mar 2014 I refer to your request, as e-mailed on 24 March 2014 with attachments, regarding a modification request replace one module with another. I am pleased to advise that, as submitted to date, the modified extended project/protocol may continue in line with standard ethics clearance conditions previously communicated and reprinted below. Please contact me if you have any queries about on-going ethics clearance, citing the SUHREC project number. Copies of clearance emails should be retained as part of project record-keeping. As before, best wishes for the project. Regards Ann _____________________________________ Dr Ann Gaeth Executive Officer (Research) Swinburne Research (H68) Swinburne University of Technology P O Box 218 HAWTHORN VIC 3122 Ph +61 3 9214 8356

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From: Keith Wilkins Sent: Thursday, 22 May 2014 9:52 AM To: Michael Kyrios; Peter Kyriakoulis ([email protected]); Peter Kyriakoulis Cc: David Liley; Mark Schier; RES Ethics Subject: SHR Project 2014/010 Ethics Clearance for Modifications (1 2) [Correction] To: Prof Michael Kyrios/Mr Peter Kyriakoulis, FHAD Dear Mike and Peter SHR Project 2014/010 The efficacy of cold facial immersion and the diving response in treating panic disorder Prof M Kyrios, FHAD; Mr P Kyriakoulis, Prof D Liley, Dr M Schier Approved Duration: 14/02/2014 To 01/12/2016 [Modified May 2014] I refer to your request concerning a modification to the above project approved protocol re a change of location for testing and confidential data management. The request, as emailed on 20 May 2014, was put to a SUHREC delegate for consideration. I am pleased to advise that, as modified to date, the project may continue in line with ethics clearance conditions previously communicated and reprinted below. Please contact the Research Ethics Office if you have any queries about on-going ethics clearance, citing the project number. A copy of this email should be retained as part of project record-keeping. As before, best wishes for the project. Yours sincerely Keith --------------------------------------------------------------------- Keith Wilkins Secretary, SUHREC & Research Ethics Officer Swinburne Research (H68) Swinburne University of Technology P O Box 218 HAWTHORN VIC 3122 Tel +61 3 9214 5218 Fax +61 3 9214 5267

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From: Keith Wilkins Sent: Friday, 15 August 2014 5:09 PM To: David Liley; Peter Kyriakoulis Cc: Peter Kyriakoulis ([email protected]); Mark Schier; Astrid Nordmann; RES Ethics Subject: SHR Project 2014/010 Ethics Clearance for Modifications (3) To: Prof David Liley/Mr Peter Kyriakoulis, FHAD Dear David and Peter SHR Project 2014/010 The efficacy of cold facial immersion and the diving response in treating panic disorder Prof D Liley, FHAD; Mr P Kyriakoulis, Dr M Schier, Prof M Kyrios Approved Duration: 14/02/2014 To 01/12/2016 [Modified: March 2014, May 2014, August 2014] I refer to your request, concerning modifications to the above project approved protocol, as emailed on 24 July 2014 with attachments. The request (re changes to inclusion criteria, research and consent arrangements and also changed supervisory arrangements) was put to SUHREC delegates for consideration and feedback sent to you on 11 August 2014. I acknowledge your response, emailed today, accepting the feedback was regards what has been approved in relation to the modification request. I am pleased to advise that, as modified and approved to date, the project may continue in line with ethics clearance conditions previously communicated and reprinted below. Please contact the Research Ethics Office if you have any queries about on-going ethics clearance, citing the project number. A copy of this email should be retained as part of project record-keeping. As before, best wishes for the project. Yours sincerely Keith --------------------------------------------------------------------- Keith Wilkins Secretary, SUHREC & Research Ethics Officer Swinburne Research (H68) Swinburne University of Technology P O Box 218 HAWTHORN VIC 3122 Tel +61 3 9214 5218 Fax +61 3 9214 5267

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From: RES Ethics Date:21/12/2015 16:46 (GMT+10:00) To: David Liley , Peter Kyriakoulis Cc: [email protected], RES Ethics Subject: SHR Project 2014/010 Ethics Clearance for Modifications/Extensions (4)

To: Prof David Liley/Mr Peter Kyriakoulis, FHAD Dear David and Peter SHR Project 2014/010 The efficacy of cold facial immersion and the diving response in treating panic disorder Prof D Liley, FHAD; Mr P Kyriakoulis, Dr M Schier, Prof M Kyrios Approved Duration: 14/02/2014 To 01/12/2016 Modifications/Extensions: March 2014, May 2014, August 2014, December 2015. I refer to your request, concerning modifications to the above project approved protocol, as emailed on 16 December 2015 with attachments. The request documentation, re Study 2 and including consent instruments for Study 2, was put to a SUHREC delegate for consideration. I am pleased to advise that, as modified and approved to date, the project may continue in line with ethics clearance conditions previously communicated and reprinted below. (Information on project self-auditing, reporting and modifications/additions can now be found on the Research Intranet.) Please contact the Research Ethics Office if you have any queries about on-going ethics clearance, citing the project number. A copy of this email should be retained as part of project record-keeping. As before, best wishes for the project. Yours sincerely Keith --------------------------------------------------------------------- Keith Wilkins Secretary, SUHREC & Research Ethics Officer Swinburne Research (H68) Swinburne University of Technology P O Box 218 HAWTHORN VIC 3122 Tel +61 3 9214 5218 Fax +61 3 9214 5267

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Appendix B: Plain Language Statement and Consent

Forms Group 1 (Clinical) and Group 2 (Control) for

the Preliminary Study

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Appendix C: Plain Language Statement and

Consent Forms Group 1 (Clinical) and Group 2

(Control) for Study 2

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Appendix D: Participant Information form and

Health Screening

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Date: _________________________

Background Information

1. Name: ____________________________________________ 2. Age (to nearest year): ____ / ____ / ____

3. Sex: □ Male □ Female 4. Phone: ________________________________

5. Education

What is the highest degree or level of school you have completed? If currently enrolled, mark the previous grade or highest degree received.

□ No schooling completed

□ Primary school to Year 8

□ Some high school

□ High school graduate – VCE or equivalent

□ Some tertiary education, no degree

□ Trade /technical/vocational training □ Bachelor’s degree

□ Master's degree

□ Professional degree

□ Doctorate degree

6. Employment.

Are you currently…..?

□ Employed for wages

□ Self-employed

□ Out of work and looking for work

□ Out of work but not currently looking for work

□ A homemaker

□ A student

□ Retired

□ Unable to work

If employed what is your current occupation / title _____________________________________________________

Comfort with water

How would you rate your perceived level of comfort in water? (Please circle one)

0 1 2 3 4 5 6 7 8 9 10 Extremely Uncomfotable Extremely

Comfortable

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7. Health Screening If female, please indicate if you are pregnant

□ Definitely not pregnant □ Not sure □ Definitely pregnant

Do you have a history of / suffer or have suffered from:

Heart disease □ Yes □ No Diabetes □ Yes □ No

A family history of Coronary Heart Disease □ Yes □ No Substance abuse □ Yes □ No

Angina □ Yes □ No Psychotic symptoms □ Yes □ No

Other chest pain/discomfort □ Yes □ No Asthma or other respiratory conditions □ Yes □ No

High blood pressure (Hypertension) □ Yes □ No Allergies, including latex or rubber □ Yes □ No

Low blood pressure (Hypotension) □ Yes □ No Epilepsy □ Yes □ No Increased or high cholesterol □ Yes □ No Renal disease □ Yes □ No Stroke, brain haemorrhage or aneurisms □ Yes □ No First degree relative with Panic Disorder □ Yes □ No

If yes to any of the above please specify:

_________________________________________________________________________________________

_________________________________________________________________________________________

Do you smoke? □ Yes □ No Do you drink alcohol? □ Yes □ No

How many cigarettes per day ( ) How many glasses per week ( )

Do you ever feel faint, have spells of dizziness or have ever lost consciousness? □ Yes □ No Is your doctor currently prescribing you drugs/medication/oral contraceptives? □ Yes □ No

If yes to drugs/medication/oral contraceptives please specify:

_________________________________________________________________________________________ _________________________________________________________________________________________ How regularly do you take the above mentioned drugs/medication/oral contraceptives? Do you know of any other reason why you should not participate in a programme of physical activity? □ Yes □ No

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If yes please specify:

_________________________________________________________________________________________

_________________________________________________________________________________________

8. Fitness and Exercise

How many push ups can you do at the moment? _____________

What is your height? _______________(cm) What is your current weight? ______________(kg)

How would you rate your current physical fitness compared with others your age? (Circle one answer)

Poor Fair Good Very Good

Excellent

Please let us know the type and amount of physical activity involved in your work: (Tick one box)

□ I am not in employment (eg. retired, retired for health reasons, unemployed, full-time carer etc.)

□ I spend most of my time at work sitting (such as in an office)

□ I spend most of my time at work standing or walking. However my work does not require much intense physical effort (eg. shop assistant, hairdresser, security guard, childminder etc.)

□ My work involves definite physical effort including handling of heavy objects and use of tools (eg. plumber, electrician, carpenter, cleaner, hospital nurse, gardener, postal delivery workers etc.)

□ My work involves vigorous physical activity including handling of very heavy objects (e.g. scaffolder, construction worker, refuse collector, etc.)

During the last week, how many hours did you spend on each of the following activities? Please answer whether you are in employment or not:

Physical exercise such as swimming, jogging, aerobics, football, tennis, gym, workout, etc.

None Some but < 1 hr

1 hr but < 3 hrs

3 hrs +

Cycling (including cycling to work) and during leisure time. None Some but < 1

hr 1 hr but <

3 hrs 3 hrs +

Walking (including walking to work), shopping etc. None Some but < 1

hr 1 hr but <

3 hrs 3 hrs +

Housework or childcare None Some but < 1

hr 1 hr but <

3 hrs 3 hrs +

Gardening or DIY None Some but < 1 hr

1 hr but < 3 hrs

3 hrs +

How would you describe your usual walking pace? (Circle one answer)

Slow Steady average pace Brisk pace Fast pace (over 6km)

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Appendix E: Qualitative Questions

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Qualitative Questions

1) What are the challenges you face in managing your anxiety/panic symptoms?

2) What are the challenges you face in managing your anxiety/panic thoughts?

3) How would you describe your experience of cold facial immersion?

4) Describe any changes you experienced in your anxiety/panic symptoms following

cold facial immersion?

5) Describe any changes you experienced in your anxiety/panic thoughts following the

cold facial immersion?

6) What current strategies do you use to help manage your anxiety/panic symptoms?

What strategies do you use to manage your thoughts?

7) How could cold facial immersion assist you in managing your anxiety/panic

symptoms and thoughts?

8) If you found that CFI assisted you in managing your anxiety/panic symptoms and/or

thoughts how likely would you be to practice CFI during a panic attack? Are there

any challenges that might prevent you from using CFI?

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9) If you found that CFI assisted you in preventing your anxiety/panic, how likely would

you be to practice CFI on a regular basis? Are there any challenges that might prevent

you from using CFI?

10) If this research was to demonstrate that CFI is an effective intervention in assisting the

management of anxiety/panic how would this impact you?

11) What other challenges do you forsee with using CFI to help manage your

anxiety/panic?

12) Which of the following methods would you consider using to mimic cold facial

immersion and activate the diving response:

a) ice pack /frozen vegetable packet applied to the face

b) specially designed waterproof facial mask

c) splashing cold water to your face

d) taking up swimming as a sport/exercise

e) other

13) If the activation of the diving response was to be used as an intervention for

managing anxiety symptoms how do you see this developing into an intervention?

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PUBLICATIONS AND AWARDS ARISING FROM THIS WORK

Conference Presentations

Kyriakoulis, Kyrios, Liley & Schier (2014). The efficacy of the diving response in treating

Panic Disorder . Poster Presentation at the International Behavioural Neuroscience Society

(IBNS) Meeting. Las Vegas, United States of America.

Kyriakoulis, Kyrios, Liley & Schier (2015). The diving response and its applicability in Panic

Disorder. The 9th Annual International Conference on Psychology Conference. Athens,

Greece.

Kyriakoulis, Liley, Schier, Kyrios & Murray (2016). The implications of the diving response

in reducing panic symptoms. Poster Presentation at the European Conference of Positive

Psychology (ECPP). Angers, France.

Kyriakoulis, Liley, Schier, Kyrios & Murray (2016). The implications of the diving response

in reducing panic symptoms and cognitions. World CBT Congress. Melbourne, Australia.

Kyriakoulis, Liley, Schier, Kyrios & Murray (2017). The implications of the diving response

in changing CO2 sensitivity in individuals diagnosed with Panic Disorder. International

Conference of Neuropsychotherapy. Brisbane, Australia.

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Kyriakoulis, Liley, Schier, Kyrios & Murray (2018). The implications of the diving response

in reducing panic symptoms and cognitions. 2nd International Conference of

Neuropsychotherapy. Melbourne, Australia.

Kyriakoulis, Liley, Schier, Kyrios & Murray (2018). The implications of the diving response

in reducing panic symptoms and cognitions. 28th Euro Congress of Psychiatry and

Psychology. Vienna, Austria.

Publications

Kyriakoulis (2014). A neuropsychotherapy approach to panic disorder and complex

psychopathology. In P. JRossouw (EDs.). Neuropsychotherapy: Theoretical underpinnings

and Clinical Applications (pp.371-390). Brisbane, QLD, Mediros Pty. Ltd.

Kyriakoulis (Dec 2017-Jan2018). Panic Disorder as a Treatment of Panic Disorder.

Neuropsychotherapy e-journal, Issue 47 (pp. 2-4).

Awards

Amplify Ignite Finalist 2018- Excellence in Doctoral Research