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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
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
Table of Contents
iii
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
Table of Contents
iv
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
Table of Contents
v
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
Table of Contents
vi
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
Table of Contents
vii
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
Table of Contents
viii
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
Table of Contents
ix
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
Table of Contents
x
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
Table of Contents
xi
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
xii
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
xiii
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.
xiv
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
xv
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.
List of Tables
xvi
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
List of Tables
xvii
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
List of Figures
xviii
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
List of Figures
xix
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
List of Figures
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
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
List of Abbreviations
xxii
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
xxiii
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).
xxiv
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.
xxv
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.
xxvi
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.
Chapter 1. Panic Disorder
1
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).
Chapter 1. Panic Disorder
2
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).
Chapter 1. Panic Disorder
3
Figure 1. Physical and cognitive symptoms of panic disorder.
Chapter 1. Panic Disorder
4
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).
Chapter 1. Panic Disorder
5
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
Chapter 1. Panic Disorder
6
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).
Chapter 1. Panic Disorder
7
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.
Chapter 1. Panic Disorder
8
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
Chapter 1. Panic Disorder
9
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
Chapter 1. Panic Disorder
10
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 &
Chapter 1. Panic Disorder
11
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
Chapter 1. Panic Disorder
12
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).
Chapter 1. Panic Disorder
13
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).
Chapter 1. Panic Disorder
14
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
Chapter 1. Panic Disorder
15
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).
Chapter 1. Panic Disorder
16
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
Chapter 1. Panic Disorder
17
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
Chapter 1. Panic Disorder
18
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
Chapter 1. Panic Disorder
19
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).
Chapter 1. Panic Disorder
20
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
Chapter 1. Panic Disorder
21
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,
Chapter 1. Panic Disorder
22
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
Chapter 1. Panic Disorder
23
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
Chapter 1. Panic Disorder
24
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
Chapter 1. Panic Disorder
25
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).
Chapter 1. Panic Disorder
26
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
Chapter 1. Panic Disorder
27
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).
Chapter 1. Panic Disorder
28
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).
Chapter 1. Panic Disorder
29
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
Chapter 1. Panic Disorder
30
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,
Chapter 1. Panic Disorder
31
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
Chapter 1. Panic Disorder
32
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,
Chapter 1. Panic Disorder
33
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.
Chapter 1. Panic Disorder
34
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).
Chapter 1. Panic Disorder
35
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
Chapter 1. Panic Disorder
36
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
Chapter 1. Panic Disorder
37
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
Chapter 1. Panic Disorder
38
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
Chapter 1. Panic Disorder
39
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).
Chapter 1. Panic Disorder
40
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
Chapter 1. Panic Disorder
41
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).
Chapter 1. Panic Disorder
42
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
Chapter 1. Panic Disorder
43
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-
Chapter 1. Panic Disorder
44
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).
Chapter 1. Panic Disorder
45
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).
Chapter 1. Panic Disorder
46
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.
Chapter 1. Panic Disorder
47
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
Chapter 1. Panic Disorder
48
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).
Chapter 1. Panic Disorder
49
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.
Chapter 1. Panic Disorder
50
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
Chapter 1. Panic Disorder
51
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
Chapter 1. Panic Disorder
52
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;
Chapter 1. Panic Disorder
53
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
Chapter 1. Panic Disorder
54
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).
Chapter 1. Panic Disorder
55
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
Chapter 1. Panic Disorder
56
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
Chapter 1. Panic Disorder
57
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
Chapter 1. Panic Disorder
58
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).
Chapter 1. Panic Disorder
59
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.
Chapter 2. The Diving Response and its Applications
60
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).
Chapter 2. The Diving Response and its Applications
61
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
Chapter 2. The Diving Response and its Applications
62
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
Chapter 2. The Diving Response and its Applications
63
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.
Chapter 2. The Diving Response and its Applications
64
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
Chapter 2. The Diving Response and its Applications
65
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
Chapter 2. The Diving Response and its Applications
66
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
Chapter 2. The Diving Response and its Applications
67
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).
Chapter 2. The Diving Response and its Applications
68
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
Chapter 2. The Diving Response and its Applications
69
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
Chapter 2. The Diving Response and its Applications
70
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.
Chapter 2. The Diving Response and its Applications
71
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
Chapter 2. The Diving Response and its Applications
72
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
Chapter 2. The Diving Response and its Applications
73
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
Chapter 2. The Diving Response and its Applications
74
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
Chapter 2. The Diving Response and its Applications
75
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,
Chapter 2. The Diving Response and its Applications
76
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).
Chapter 2. The Diving Response and its Applications
77
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
Chapter 2. The Diving Response and its Applications
78
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
Chapter 2. The Diving Response and its Applications
79
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
Chapter 2. The Diving Response and its Applications
80
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
Chapter 2. The Diving Response and its Applications
81
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
Chapter 2. The Diving Response and its Applications
82
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).
Chapter 2. The Diving Response and its Applications
83
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
Chapter 2. The Diving Response and its Applications
84
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
Chapter 2. The Diving Response and its Applications
85
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
Chapter 2. The Diving Response and its Applications
86
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.,
Chapter 2. The Diving Response and its Applications
87
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.
Chapter 2. The Diving Response and its Applications
88
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).
Chapter 2. The Diving Response and its Applications
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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
Chapter 2. The Diving Response and its Applications
90
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
Chapter 2. The Diving Response and its Applications
91
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.
Chapter 3. Respiration and Panic Disorder
92
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).
Chapter 3. Respiration and Panic Disorder
93
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
Chapter 3. Respiration and Panic Disorder
94
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).
Chapter 3. Respiration and Panic Disorder
95
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).
Chapter 3. Respiration and Panic Disorder
96
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
Chapter 3. Respiration and Panic Disorder
97
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.
Chapter 3. Respiration and Panic Disorder
98
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
Chapter 3. Respiration and Panic Disorder
99
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
Chapter 3. Respiration and Panic Disorder
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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
Chapter 3. Respiration and Panic Disorder
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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).
Chapter 3. Respiration and Panic Disorder
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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
Chapter 3. Respiration and Panic Disorder
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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).
Chapter 3. Respiration and Panic Disorder
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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
Chapter 3. Respiration and Panic Disorder
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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
Chapter 3. Respiration and Panic Disorder
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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).
Chapter 3. Respiration and Panic Disorder
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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,
Chapter 3. Respiration and Panic Disorder
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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
Chapter 3. Respiration and Panic Disorder
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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
Chapter 3. Respiration and Panic Disorder
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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
Chapter 3. Respiration and Panic Disorder
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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.
Chapter 3. Respiration and Panic Disorder
119
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
Chapter 3. Respiration and Panic Disorder
120
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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121
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.
Chapter 4. Overall Methodology
123
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
Chapter 4. Overall Methodology
124
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.
Chapter 4. Overall Methodology
125
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.
Chapter 4. Overall Methodology
126
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.
Chapter 4. Overall Methodology
127
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-
Chapter 4. Overall Methodology
128
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.
Chapter 4. Overall Methodology
129
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
Chapter 4. Overall Methodology
130
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.
Chapter 4. Overall Methodology
131
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
Chapter 4. Overall Methodology
133
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
Chapter 4. Overall Methodology
134
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,
Chapter 4. Overall Methodology
135
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.
Chapter 4. Overall Methodology
136
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
Chapter 4. Overall Methodology
137
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,
Chapter 4. Overall Methodology
138
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.
Chapter 5. Respiratory Challenges and Cold Facial Immersion
139
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.
Chapter 5. Respiratory Challenges and Cold Facial Immersion
140
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.
Chapter 5. Respiratory Challenges and Cold Facial Immersion
141
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.
Chapter 5. Respiratory Challenges and Cold Facial Immersion
142
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.
Chapter 5. Respiratory Challenges and Cold Facial Immersion
143
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,
144
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
Chapter 4. Respiratory Challenges and Cold Facial Immersion
147
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;
Chapter 5. Respiratory Challenges and Cold Facial Immersion
167
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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170
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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171
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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173
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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174
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
Chapter 5. Respiratory Challenges and Cold Facial Immersion
179
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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183
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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184
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
Chapter 6. Cold Facial Immersion on CO2 Sensitivity
185
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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186
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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187
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.
188
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
Chapter 6. Cold Facial Immersion and CO2 Sensitivity
190
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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191
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).
Chapter 6. Cold Facial Immersion and CO2 Sensitivity
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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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194
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)
Chapter 6. Cold Facial Immersion and CO2 Sensitivity
195
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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196
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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197
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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198
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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199
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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200
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).
Chapter 6. Cold Facial Immersion and CO2 Sensitivity
201
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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202
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).
Chapter 6. Cold Facial Immersion and CO2 Sensitivity
203
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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204
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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205
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).
Chapter 6. Cold Facial Immersion and CO2 Sensitivity
206
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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207
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)
Chapter 6. Cold Facial Immersion and CO2 Sensitivity
208
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
Chapter 6. Cold Facial Immersion and CO2 Sensitivity
209
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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217
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.
224
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.
236
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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274
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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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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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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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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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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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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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.
282
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362
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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373
374
375
376
377
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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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380
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384
385
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Appendix D: Participant Information form and
Health Screening
388
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