fhg – Zentrum für Gesundheitsberufe Tirol GmbH / University of Applied Sciences Tyrol

Lehrgang zur Weiterbildung §14a FHStG Osteopathie Neurovegetative Reactions of Spinal

Manipulations and Mobilizations in

Manual Therapy, Chiropractic and

Osteopathic Medicine

A literature review Master Thesis

Author: Koen Groot Zwaaftink, D.O.

Supervisor: Johan Schelpe, D.O. - MSc.Ost.Med

Gent, July 2016

Preface and Acknowledgements

This thesis is made as a completion of the Master of Science in

Osteopathy education. The thesis is original, unpublished work by the

author, K.H.Groot Zwaaftink.

The first time I heard about neurovegetative reactions and segmental

processes following a spinal manipulation or mobilization was during my

physiotherapy education. I wondered how it was possible that a local

technique changes general physiologic parameters so widely spread in

our body. Because of the distant physiologic effects I started searching

in literature for treatment options and possibilities how to use this

phenomenon to my therapeutic advantage. During the osteopathic

education some of my questions were answered, but my interest in the

real effects of spinal manipulation and mobilization and the best

technique to choose was awakened.

I would like to thank my family for all the love, understanding and time

they gave me to complete this thesis. Especially my girlfriend Inge and

the kids who missed their father in the evenings and weekends the last

months. I thank my promotor Johan Schelpe for his excellent guidance

and support during the process. I ‘am grateful to Ronald van Oers for

finding some full-text articles and always responding quickly. Also my

parents and parents-in-law deserve a special thanks for their wise

counsel and kind words which kept me motivated.

Koen Groot Zwaaftink

June 22, 2016

Enschede

Dedication

This thesis is dedicated to:

My girlfriend Inge

She has given me love and inner peace to complete th is thesis

Gwen & Kai

Their presence and smiles kept me focussed

My parents

Who give me confidence and all the possibilities

Table of contents

1. Introduction 9

2. Spinal manipulation and mobilization techniques 13

2.1 Spinal Manipulation 13

2.2 Spinal Mobilization 13

2.3 Neurophysiological Mechanisms 14

3. Neurovegetative Nervous System 17

3.1 Definition and homeostasis 17

3.2 Neurovegetative Nervous System and SMT 18

3.2.1 Vasomotor System 18

3.2.2 Sudomotor System 19

3.2.3 Visceral System 20

4. Method 22

4.1 Literature search 22

4.2 Eligibility criteria 22

4.2.1. Inclusion criteria 22

4.2.2. Exclusion criteria 23

4.3 Types of manual intervention 23

4.4 Types of outcome measures 23

4.5 Data extraction 24

4.6 PEDro Quality Rating 24

5. Results 25

5.1 Study Characteristics 28

- Table 1. Results from data extraction 30

- Table 2. Quality Assessment PEDro Scale 35

5.2 Peripheral Reactions Neurovegatative Nervous System 36

5.3 Reactions on SNS in relation to Pain Perception 38

5.4 Visceral Reactions of Neurovegatative Nervous System 40

5.5 Types of manipulation/mobilization techniques 41

- Table 3. Spinal manipulation versus mobilization 42

5.6 Synthesis of results 44

6. Discussion 45

7. Conclusion 56

- Funding 56

- Competing interests 56

- Author contributions 56

- Author details 56

8. Bibliography 57

9. List of abbreviations 69

10. Appendices 70

10.1 Table Literature search strategy 70

10.2 Table first selection of literature search 73

10.3 PEDro Quality Assessment Scale 78

Curriculum Vitae 81

Affidavit 82

Abstract Neurovegetative Reactions of Spinal Manipulations and Mobilizations in Manual Therapy, Chiropractic and Osteopathic Medicine

A literature review Author: Koen Groot Zwaaftink D.O. Supervisor: Johan Schelpe D.O.-MSc.Ost.Med.

Master of Science in Osteopathy, University of Applied Sciences Tyrol

Introduction: Spinal manipulation and mobilization are commonly used for musculoskeletal and spine problems. Evidence about neurophysiological reactions indicates that spinal manipulation and mobilization initiate neurovegetative responses. Reports are about effects of separate manual techniques and neurophysiological effects following a manipulation or a mobil ization. No research is done which analyses general neurovegetative reactions following spinal manipulation and mobilization. There are no studies been done on spinal technique efficiencies, outcome differences concerning neurovegetative reactions. Research Questions: Primary research question: ‘Which significant changes in neurovegetative physiological parameters occur after manual sp inal manipulation and mobilization in symptomatic and a-symptomatic adults in manual therapy, chiropractic or osteopathic medicine?’ and secondary research question: ‘Are there differences between manual spinal manipulation and mobilization on the objective changes in neurovegeta tive physiological parameters in symptomatic and a-symptomatic adults in manual therapy, chiropractic or osteopathic medicine?’ Objective: The objective of this literature review is to analyse evidence on

neurovegetative responses following spinal manipulation and mob ilization compared to a

sham or control group. The secondary objective is to establish level of neurovegetative

change and differences between manual spinal techniques.

Method: A systematic search in MEDLINE and Cochrane Library with (MeSH)terms: ‘spinal manipulation’, ‘chiropractic manipulation’, ‘osteopathic manipulative treatment’, ‘manual therapy’, ‘sympathetic nervous system’, ‘parasympathetic nervous system’, ‘autonomic nervous system’, ‘enteric nervous system’, blood supply’, ‘vasomotor system’, ‘blood flow velocity’, ‘sweat glands’, ‘viscera’, ‘visceral pain’, ‘piloerection’, ‘skin temperature’ and ‘pain’ for eligible RCTs and systematic reviews between 2000 and May 2016. Data were extracted and analysed. Quality of the studies is assessed according to the PEDro scale. Findings: 13 RCTs were included. Statistically significant changes were seen with increased skin conductance, increased pressure pain thresholds, increased breathing rate, decreased pain on Visual Analog Scale, decreased local allodynia,hyperalgesia and changes in heart rate and heart rate variability. Inconsistent changes are seen in skin temperature. No significant changes are seen in thermal pain thresholds , pupillary reactions and cutaneous blood flow. No clear differences in spinal manual technique efficiency. Discussion/conclusion: In conclusion, this literature review provide evidence that spinal manipulation and mobilization evoke neurovegetative reactions. Some parameters are consistent, but in other parameters there is an inconsistency in neurovegetative effect. Despite the evidence, neurophysiological mechanisms are still relatively unclear. Due to the unequal distribution of the number of mobilization repetitions, number of sessions, different measurement methods and treatment locations, it is not possible to make concrete statements which technique is superior. Long-term effects of multi-technique sessions and multiple sessions are too scarce to draw clear practical conclusions. There is a need of high quality, large sample RCTs on selective symptomatic subjects with a multi -technique or intersession design. Only then is a representative therapeutic outcome measurable of strong clinical importance. Keywords: neurovegetative nervous system, autonomic nervous system, spinal

manipulation, spinal mobilization, osteopathy, chiropractic, manual therapy.

Abstract in German

Neurovegetative Reaktionen auf Manipulationen und Mobilisationen

der Wirbelsäule in der manuellen Therapie, Chiropraktik und

Osteopathie

Eine Literaturstudie

Autor: Koen Groot Zwaaftink D.O. Supervisor: Johan Schelpe D.O.-MSc.Ost.Med.

Master of Science in Osteopathy, University of Applied Sciences Tyrol

Einleitung: Manipulationen und Mobilisationen der Wirbelsäule werden häufig eingesetzt bei muskuloskelettalen Beschwerden und Wirbelsäulenproblemen. Wissenschaftliche Untersuchungen zeigen das Manipulationen und Mobilisationen der Wirbelsäule eine neurovegetative Reaktion erzeugen. Es gibt Berichte über den Effekt verschied ener manueller Techniken und neurophysiologischer Effekte, die nach einer Manipulation oder Mobilisation auftreten. Bisher ist noch nicht untersucht worden, welche generelle neurovegetative Reaktion eine Manipulation oder Mobilisation der Wirbelsäule verursachen kann. Es bestehen keine Studien über die Effizienz einer Behandlungstechnik an der Wirbelsäule und die verschiedenes Effekte im Bezug auf neurovegetative Reaktionen. Fragestellung: 1. „Welche signifikanten Veränderungen der neurovegetativen physiologischen Parameter treten in der Manuellen Therapie, der Osteopathie und der Chiropraktik nach einer manuellen Manipulation oder Mobilisation der Wirbelsäule bei Erwachsenen mit Symptomen und bei Erwachsenen ohne Symptomen auf?“ 2. „Gibt es Unterschiede zwischen manuellen Manipulationen und Mobilisationen der Wirbelsäule im Bezug auf eine objektive Veränderung der neurovegetativen physiologischen Parameter bei Erwachsenen mit Symptomen und bei Erwachsenen ohne Symptome in der manuellen Therapie, der Osteopathie und der Chiropraktik?“ Ziele: Das Ziel dieser Literaturstudie ist es, wissenschaftliche Untersuchungen über den neurovegetativen Effekt, der durch eine Manipulation oder Mobilisation der Wirbelsäule verursacht wird, zu analysieren und diesen mit einer Kontrollgruppe zu vergleichen. Desweiteren sollen die neurovegetativen Veränderungen analysiert werden, die durch verschiedene Behandlungstechniken der Wirbelsäule verursacht werden. Methoden: Eine systematische Suche in MEDLINE und der Cochrane Biblio thek nach geeigneten RCT’s und „Systematic Reviews“ mit folgenden (MeSH) Termen: ‘spinal manipulation’, ‘chiropractic manipulation’, ‘osteopathic manipulative treatment’, ‘manual therapy’, ‘sympathetic nervous system’, ‘parasympathetic nervous system’, ‘a utonomic nervous system’, ‘enteric nervous system’, blood supply’, ‘vasomotor system’, ‘blood flow velocity’, ‘sweat glands’, ‘viscera’, ‘visceral pain’, ‘piloerection’, ‘skin temperature’ and ‘pain’ aus dem Zeitraum von 2000 bis Mai 2016. Die Daten wurden ausgewählt und analysiert. Die Qualität der Studien wurde anhand der PEDro Skala überprüft. Ergebnisse: Es wurden 13 RCT’s einbezogen. Statistisch signifikante Veränderungen treten auf im Bezug auf zugenommen Hautwiderstand, eine erhöhte Schmerzgrenze bei Druck, zugenommene Atemfrequenz, Abnahme der Schmerzen auf der ‚Visual Analog Scale‘, Abnahme der lokalen allodynie, hyperalgesie und Veränderungen der Herzfrequenz und der Herzrythmus- Variabilität. Die Aussagen zur Veränderungen der Hauttemperatur sind Widersprüchlich. Es gibt keine signifikante Veränderung der thermischen Schmerzgrenze, Pupille Reaction und der Durchblutung der Haut. Deutliche Unterschiede der Effizienz der verschiednen manuellen Techniken zur Behandlung der Wirbelsäule treten nicht hervor. Endergebnis und Diskussion: Zusammenfassend ist zu sagen, dass diese Literaturstudie beweist, dass Manipulationen und Mobilisationen der Wirbelsäule eine neurovegetative Reaktion hervorrufen. Einige Parameter sind gleichbleibend, andere Parameter zeigen eine Unstimmigkeit des neurovegetativen Effekts. Trotz der wissenschaftlichen Untersuchungen ist der neurophysiologische Mechanismus noch recht undeutlich. Es ist nicht möglich zu sagen, welche Behandlungstechnik die beste ist,

da die Angaben zur Anzahl der Wiederholungen der Mobili sationen, sowie die Anzahl der Behandlungen, die Behandlungsorte und auch die Testmethoden unterschiedlich sind. Der Langzeiteffekt einer Behandlung mit verschiedenen Behandlungsmethoden und mehreren Behandlungen ist noch nicht ausreichend untersucht, um h ierzu eine Aussage für die Praxis machen zu können. Es werden mehr RCT’s mit guter Qualität und großen Untersuchungsgruppen benötigt, die sich auf selektive Zielgruppen beziehen, die mit verschiedenen Techniken behandelt werden oder mehrere Behandlungen be kommen, um ein repräsentatives therapeutisches Ergebnis mit wichtiger klinischer Bedeutung zu erzielen. Schlüsselwörter: neurovegetatives Nervensystem, autonomes Nervensystem, Manipulation der Wirbelsäule, Mobilisation der Wirbelsäule, Osteopathie, Chiro praktik, Manuelle Therapie

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1. Introduction

Spinal manipulation is generally accepted as a treatment option in

management of musculoskeletal disorders. The effectiveness of spinal

manipulative therapy to treat musculoskeletal disorders and spinal pain has

been confirmed in several studies [46,136,4]. Evidence report that spinal

manipulative therapy provides greater improvement for pain and function

than a placebo or no treatment [4,46]. A systematic review of Michaleff et al.

found that SMT is a cost-effective treatment to manage spinal pain when

used alone or in combination with general practice care, like mobilization

[106]. Spinal manipulative therapy (spinal manipulation and mobilization) is

usually provided by manual therapists, osteopaths and chiropractic doctors

or therapists. Approximately 26% of the people worldwide visit a doctor or

therapist for spinal manipulative therapie [38].

Despite studies supporting the effectiveness of SMT, neurophysiological

mechanisms of SMT are not fully understood. As result that the National

Institutes of Health specially addresses the lack of a clear

neurophysiological explanation as a scientific problem [56].

Manipulation and mobilization effects cannot be solely biomechanically

explained. First, scientists believe that biomechanical changes following

SMT are only transient on range of motion, but no lasting structural

changes occur [165,54]. Second, improvement and effects following SMT are

reported not only locally, but also remote of the treated area [24,169]. Several

studies have shown that effects of spinal manipulation and mobilization are

beyond biomechanical changes only [10,15,37,126,159,121,118,91]. In the current

literature there is no clear explanation for some spinal manipulation and

mobilization effects [9]. Researchers proposed hypotheses on mechanical,

neurophysiological and psychological grounds. They think that extra-

biomechanical changes are supra-spinal modulated and partly caused by

the neurovegetative nervous system [9,10,37,50,126,138,147,178,168,184]. There is

evidence that manipulation and mobilization causes a sympathoexcitatory

effect and that the reaction is not only local but also segmentally and

supra-segmentally reactions are possible [18,20,80,86,91,121,150,154,159,171].

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Bialosky et al. and Vicenzino et al. demonstrated a sympathoexcitatory and

hypoalgesic effect following manipulation and mobilization in areas that are

segmentally related [10,169,171]. Other studies provide evidence that the

hypoalgesic effect is not only segmentally coordinated, but also supra-

segmental [168,159,111].

Within the nervous system the somatic and neurovegetative nervous

system work together, with an interaction between both systems. By

treating or stimulating the somatic nervous system the neurovegetative

nervous system can be influenced [7,6,19,125,139,140,141,142,143]. Scientists have

found that in several regions nervous system there is an interaction

between the somatic and neurovegetative nervous system. Areas are

identified in the periphery, dorsal horn of spinal cord, brainstem and the

brain [7,150, 187]. After spinal manipulation and mobilization there are

changes in the neurovegetative nervous system reported. Significant

changes in peripheral skin temperature (ST), skin conductance (SC),

cutaneous blood flow (CBF) and pain perception is seen in several

studies.[159,91,122,123,134,111,113,80,170,171,172] Most of the performed studies

demonstrate significant neurovegetative changes in sympathetic nervous

system (SNS) [159,91,122,123,134,111,113,80].

Results of the studies are not always consistent and the outcome values

differ between the studies. Studies often used different manual techniques

and performed treatments on not the same spine region, making it difficult

to draw conclusions about efficacy for the practice. Studies on spinal

techniques and neurovegetative effects are focussed on a single region of

the spine (cervical, thoracic or lumbar spine) and effects are locally

measured (face, upper or lower extremity). There are a few systematic

reviews that combined the neurovegetative outcomes of the upper and

lower extremity, but analysed solely manipulation or mobilization effects.

Most of the studies investigate peripheral neurovegetative reactions

following spinal manipulation or mobilization and only a few examined

visceral reactions. Most researchers measure a single manual intervention

(mobilization or manipulation) and hardly any analyses outcomes and

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differences of the various spinal techniques. A literature review on

neurovegetative reactions following a spinal manipulation or mobilization of

the total body, peripheral and visceral has not been done. No literature

review has been published that investigates the differences in

neurovegetative outcomes between various spinal manipulation and

mobilization techniques. Because of this the following research questions

have been drawn up.

The primary research question of the literature review is:

- Which significant changes in neurovegetative physiological

parameters occur after manual spinal manipulation and mobilization

of symptomatic and a-symptomatic adults in manual therapy,

chiropractic or osteopathic medicine?

Secondary research question:

- Is there a difference between manual spinal manipulation and

mobilization on neurovegetative physiological parameters of

symptomatic and a-symptomatic adults in manual therapy,

chiropractic or osteopathic medicine?

In order to answer the research questions a literature review between 2000

and May 2016 is done in MEDLINE and Cochrane Library with the following

MeSH-terms: ‘spinal manipulation’, ‘chiropractic manipulation’, ‘osteopathic

manipulative treatment’, ‘manual therapy’, ‘sympathetic nervous system’,

‘parasympathetic nervous system’, ‘autonomic nervous system’, ‘enteric

nervous system’, blood supply’, ‘vasomotor system’, ‘blood flow velocity’,

‘sweat glands’, ‘viscera’, ‘visceral pain’, ‘piloerection’, ‘skin temperature’

and ‘pain’. Afterwards the data is extracted and analysed. The quality of the

studies is assessed according to the PEDro scale.

The thesis shows general information and explanatory models on spinal

manipulation or mobilization and the neurovegetative nervous system. It

describes outcomes in the neurovegetative nervous system (sympathetic,

parasympathetic and enteric nervous system) of skin conductance (SC),

skin temperature (ST), cutaneous blood flow (CBF), pain perception (VAS

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and pressure pain thresholds) and visceral changes. In the discussion

section the results following spinal manipulation or mobilization are

discussed as well as the used study methods and clinical relevance.

The thesis is orginized in 4 sections. The thesis starts with a short

theoretical section, spinal manipulation and mobilization are described and

current neurophysiological explanatory models are presented. Then

methodology and search strategy are described, followed by results and

discussion. Abbreviations, appendices, curriculum vitae of the author and

affidavit are listed at the end of the thesis.

This literature review should provide valuable information for manual

therapists, osteopaths and chiropractic practitioners about neurovegetative

reactions following spinal manipulation and mobilization. Information which

has an direct effect on the practice for all therapists and physicians who

uses spinal manipulative treatments. More understanding leads to better

desision-making and quality in health care.

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2. Spinal manipulation and mobilization techniques

2.1 Spinal manipulation

Spinal manipulation can be described as: A therapeutic intervention

performed on spinal articulations which are synovial jo ints. These

articulations in the spine that are amenable to spinal manipulative therapy

include the zygapophyseal joints, the atlanto-occipital, atlanto-axial, lumbo-

sacral, sacroiliac, costotransverse and costovertebral joints [87]. Gross et

al. defined a spinal manipulation as “a localized force of high velocity and

low amplitude directed at the spinal joints” [46]. Manipulation is known by

several other names. Chiropractors usually refer to manipulation of a spinal

joint as an ‘adjustment’ and following the labeling system by Maitland a

manipulation is synonymous with a grade V mobilization [98,99]. Manipulation

has distinct biomechanics and can be distinguished from other spinal

manual techniques such as mobilizations [50,37,51]. Because of this

biomechanics the term high velocity low amplitude thrust (HVLAT) is

normally used.

2.2 Spinal mobilization

The definition of a spinal mobilization is; a type of passive movement of a

spinal segment or region and can be described as a gentle, often

oscillatory, passive movement applied to a spinal region or segment to

increase the passive range of motion of that segment or region ” [17,107].

Mobilizations use a low grade-velocity, small or large amplitude, passive

movement within the patient ’s range of spinal motion and control [46]. Some

researchers refer to spinal manipulative therapy (SMT), including both

manipulation and mobilization techniques. Also the term osteopathic

manipulative treatment (OMT) is used in several studies. This is a core set

of spinal (HVLAT and mobilization) and non-spinal (myofascial, muscle

energy, strain-counterstrain, vascular) techniques. In this literature review

with a spinal manipulation is meant a HVLAT technique and with a spinal

mobilization a low grade-velocity, small or large amplitude, passive

movement within the patient’s range of spinal motion and control . With SMT

in this literature review is meant spinal manipulation and/or mobilization.

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2.3 Neurophysiological mechanisms

Evidence indicates that SMT techniques work through biomechanical and

neurophysiological mechanisms. Despite the evidence supporting the

effectiveness of SMT [46,136,4], neurophysiological mechanisms of SMT are

not fully understood. Studies suggest that in addition to the biomechanical

effects other neurophysiological mechanisms are present [126,9,37,184]. They

suggest that a mechanical force (manipulation or mobilization) is necessary

to initiate a chain of neurophysiological responses which are responsible

for the local and central effects following SMT [9,184]. Theories on

neurophysiological processes likely find the origin from a peripheral

mechanism, spinal cord mechanism and supra-spinal mechanisms.

Evidence for a peripheral mechanism is reported by studies that measure a

local change, like hypoalgesia and reflex changes, following SMT [9,109,184].

Peripheral lesions induce a local inflammatory response which stimulate

healing processes and produces local hyperalgesia. Inflammatory

mediators and peripheral nociceptors react due to the inflammatory

response and spinal manipulation and mobilization directly can affect this

process. Studies report a significant reduction of cytokines level in blood or

serum, changes in blood level of beta-endorphin, anandamide, N-

palmitoylethanolamide, serotonin and endogenous cannabinoids in subjects

that received SMT [162,29,104]. Studies have found anatomical vascular

connections between peripheral nociceptors and sympathetic neurons at

the terminal axons and within the spinal ganglion [157]. Local lesions

stimulate interconnection and makes primary afferent neurons more

sympathetic sensitive due to increase of adrenergic receptors [157].

Evidence report an increase sympathetic activity following SMT

[10,159,91,121,171], or the sympathoexcitation has an influence on the micro-

vascularization between primary afferents and sympathetic fibers is not

known.

SMT has an effect on spinal processes and decreases activation of the

dorsal horn [14,126,184]. The result of SMT is an increased activation of

muscle spindles, capsule receptors and Golgi tendon organs which

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influences pain transmission in the dorsal horn [14,126]. Direct evidence

comes from a study of Malisza et al. were decreased dorsal horn

excitability was seen by functional MRI following SMT [100]. Indirect

evidence for spinal mechanisms is reported in several studies. SMT is

associated with hypoalgesia [109,171,172,91], afferent discharge [27], motoric

function [21,31] and changes in muscle activity [52,161]. In addition to the

mentioned somatic changes, there are also changes described in visceral

and humeral function following SMT [15,137,43,138,18,19,91]. Also evidence

indicates that SMT has a postulated effect in visceral disorders, such as

asthma [5] and hypertension [128].

Spinal changes have been shown to occur in caudal dermatomes to the

treated area [12]. The presence or absence of cavitation during thrust

manipulation was not associated with differences in outcome [10].

Supra-spinal reactions after SMT are reported due to changes in insular

cortex oxygenation, dorsal periaqueductal grey matter (dPAG) and

participant’s expectation (placebo). Oxygenation changes in insular cortex

are seen by functional magnetic resonance imaging (fMRI) after SMT [156]. It

shows a significant relationship between reduced oxygenation and reduced

pain ratings immediately after thrust manipulation in a-symptomatic

subjects. These findings are consistent with the results of Malisza et al.

who also found supra-spinal changes with fMRI following SMT [100]. Other

studies demonstrate that these supra-spinal changes are associated with

neurovegetative changes [170,171,111,159,186].

Ogura et al. demonstrated that SMT elicits sympathetic inhibition in part of

the brain [118]. A study using positron emission tomography (PET) found a

reduced activation in the cerebellar vermis and increased activation in parts

of the limbic system. Several studies have showed that spinal mobilization

produced a hypoalgesic effect [152,91,109,159,121,171,172]. This effect could be

due to descending serotoninergic or noradrenergic inhibitory mechanisms

via corticospinal projects of the dPAG. Scientists relate to noradrenaline, a

dPAG neurotransmitter more effective in inhibiting mechanical nociception

than thermal nociception which is serotoninergic regulated [89,90].

Researchers think that SMT produces the right stimulus for dPAG regulated

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nonopioid analgesia, hypoalgesia and sympathoexcitatory effects

[159,121,171].

Additionally psychological factors and placebo may be inseparable with

SMT effects [36,82,8,12]. Expectation for the effectiveness of SMT can

significantly influence the result [12]. This may support the hypothesis that

the psychological and emotional factors from the cortex influence the

descending anti-nociceptive pathways from the dPAG [12,8].

Some scientists claim that the biomechanical effects associated with spinal

techniques are non-specific and not related to the type of manual technique

[51,133,105]. Another claim is that the biomechanical effects are transitory and

without structural changes [165,49]. Bialosky et al. described that the

biomechanical input applied during manipulations and mobilizations is the

provocative factor for a cascade of neurophysiological reactions and that

the spinal techniques are imprecise [9]. Through this neurophysiological

cascade changes on peripheral, spinal and supra-spinal level are possible.

This indicates that we probably have to change our vision about

manipulations and mobilizations of the spine. Maybe we have to approach it

from a less technical, biomechanical point of view and have to shift more to

a neurophysiological explanation.

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3. Neurovegetative Nervous System

3.1 Definition and homeostasis

Langley described the neurovegetative nervous system as “a system of

nerves that regulate the function of all innervated tissues and organs

throughout the vertebrate body except striated muscle fibers; that is, the

innervation of the viscera, vasculature, glands and some other tissues” [59].

The neurovegetative nervous system consists out of three parts: the

parasympathetic nervous system, the sympathetic nervous system and the

enteric nervous system” [59]. Spinal manipulation and mobilization can

affect the neurovegetative nervous system on a local, spinal and supra-

spinal level. A part of the interconnection of the somatic (spine) and

neurovegetatve system is formed by neurological spinal reflexes. According

to Pickar et al. the spinal reflexes are “a type of neurological circuit that

functionally connects the biomechanical and chemical environment of the

musculoskeletal tissues with the non-musculoskeletal tissues” [126]. This

circuit consists of primary afferents which carry mechanical, chemical and

thermal stimuli to the central nervous system. An interaction in the central

nervous system (spinal or supra-spinal) and an efferent neurovegetative

reaction [126]. An important function of these reflexes is body protection and

spinal regulation of maintaining the homeostasis and allostasis of the body

[78]. The concept of homeostasis is formulated by Walter B. Cannon in 1929

and it means the maintenance of physiological parameters such as

concentration of ions, blood glucose, arterial blood gases, core-

temperature in a narrow range. Allostasis is described as stabilizing the

internal milieu during changes of the body and during activity [78].

Homeostatic and allostatic regulation involves the neurovegetative nervous

system, the endocrine system, the central nervous system and the

respiratory system [59].

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3.2 Neurovegetative Nervous System and SMT

Studies demonstrated that SMT can alter physiological processes and

affect the neurovegetative nervous system

[159,91,122,123,134,111,113,80,170,171,172,83,109,122,123] . Effects after spinal

manipulation and mobilization are reported in physiological changes of skin

temperature (ST), skin conductance (SC), cutaneous blood flow (CBF),

visceral activity, pressure pain threshold (PPT) and pain intensity

[159,91,122,123,134,111,113,80,170,171,172]. There are different types of spinal reflex

pathways between the somatic (spine) and neurovegetative nervous system

[65,91,126,139,140,141,142,143,67]. Spinal reflex pathways are modulated and

controlled by supra-spinal structures, like lower brain stem, telencephalon,

limbic system and hypothalamus [67,61]. For measuring the peripheral activity

of the SNS, the SC and ST are commonly used. SC and ST are

measurements values of the sudomotor and skin vasomotor function and

are dependent on the sympathetic activity.

3.2.1 Vasomotor system

Stimulation of the SNS results in vasoconstriction of the artero-venous

anastomoses in the skin, which results in a decreased cutaneous blood

flow, leading to a decrease of ST [23]. Animal experimental studies report

that low-threshold mechanoreceptive afferents out of the skin leads to

excitation of the skin vasoconstrictor neurons [65]. The opposite reaction

happens by stimulation skin nociceptors [69]. In the human skin the majority

of the vasomotor neurons are sympathetic vasoconstrictor neurons, but in

some parts there are also sympathetic vasodilator neurons [64]. Experiments

report that active sympathetic vasodilatation occur in the proximal skin of

the extremities due to vasodilator neurons [75,79]. It is unclear of distinct

populations of skin vasodilator neurons are active stimulated or are

generated in association of sudomotor neurons [70]. Evidence of existence

of skin vasodilator neurons is indirect and is still debated [75,79]. Animal

studies reported that the skin vasoconstrictor neurons differ according the

section of the vascular bed they innervated and according to the

localisation and type of skin (glabrous or hairy skin) [64]. It is expected that

the activity pattern of the skin vasomotor neurons is not uniform and

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dependent on the above mentioned differences [66]. Skin vasoconstrictor

neurons are thermo-sensitive and react on arterial chemo- and

baroreceptors [66,68]. Activity of the supra-spinal level and cardiovascular

and respiratory reflexes also play an important role in regulation skin

vasoconstrictor neurons [66,67]. The baroreceptive spinal reflexes are

respiratory and cardiovascular controlled and skin vasomotor changes are

seen by deep breaths, body position changes and altered heart frequencies

[66,67]. The hairy skin vasoconstrictor neurons are more sensitive for

baroreceptor reflexes than the glabrous skin vasoconstrictor neurons (palm

of the hands) [68]. Thermal stimuli are the most specific stimuli and result in

increased or decreased activity in the distal skin vasoconstrictor neurons.

All or most distal extremity skin vasoconstrictor neurons are involved in

thermoregulation [66,45]. Vasoconstrictor neuron activity is also dependent

on the mental state, arousal because they are supra-spinal mediated by

cerebral cortex and limbic system [67]. Arousal, emotional stimuli and

hyperventilation has an excitatory effect on the skin vasoconstrictor

neurons [67].

3.2.2 Sudomotor system

Increased activity of the SNS also results in an increased sudomotor

function, via the cholinergic neurons, which results in increased sweat

gland activity. The increased sudomotor function leads to a subsequent

decrease of skin resistance potential and an increase skin conductance

(SC) [2]. This reaction is a result of a primitive ‘fight or flight’ mechanism

whereby blood flow is sent to the muscles and heart and is redirected away

from the cutaneous surface. This reaction is combined with increased

sweating of the palmar area of the hands and feet in order to strengthen

the grasp or grip for escape and to play a role in thermoregulation by

physical activity [2]. Sudomotor neurons are active in high ambient

temperatures and silent at low ambient temperatures [73].

Observed single sudomotor neuron action potentials are followed by fast

transient skin potential changes. This indicates that sudomotor neurons

discharge synchronously [71]. Sudomotor neuron and skin vasoconstrictor

neuron recordings in animal studies reveal that the both neurons not react

2 0

simultaneously in the glabrous skin [71]. Studies on cats reported that

sudomotor neurons are reciprocally organized to the vasoconstrictor

neurons. When afferent stimulation sudomotor neurons inhibits, skin

vasoconstrictor neurons are excited [73]. Sudomotor neurons react on

nociception, arterial chemoreceptors, arousal states and emotional stimuli

[61]. At high temperatures sudomotor neurons are rhythmic activated with

the arterial pressure wave [73]. Changes in arousal, emotional stimuli and

deep breathing alters sudomotor activity in the glabrous skin of hands, feet,

armpits and some parts of the face [61]. Activation of the sympathetic

pathway to the sudomotor neurons of the extremities is initiated from the

frontal cortex and demonstrates that spinal level is regulated by supra-

spinal processes [61]. Stimulation of arterial baroreceptors has no effect on

sudomotor neurons [72]. In cats a vibration stimulus and cutaneous

mechanoreceptors stimulus did not lead to a change in activity in

sudomotor neurons [72]. Sudomotor neurons thresholds are location and

skin type dependent [73]. Proximal hairy skin sudomotor neurons have other

thermal thresholds than in the glabrous skin [61].

Animal studies have reported that regulation of the neurovegetative

nervous system is regulated by segmentally organized reflexes in response

to stimulation of skin, muscles and various paraspinal tissues [139,140,141,142].

Depending on the type of stimulus or which visceral organ responses can

be dominant sympathetic or parasympathetic. Some responses have

propiospinal and segmental characteristics, while others have supra-spinal

characteristics [139]. Animal studies have reported that muscle spindle

activation can elicit responses of the neurovegetative nervous system [141].

Stimulation of muscle spindles due to spinal manipulation and mobilization

can trigger these responses. Especially the cervical region is of importance

because it histologically contains a high density of muscles spindles and

Golgi tendon organs [102].

3.2.3 Visceral system

There is evidence that SMT has a positive effect on certain visceral

disorders [15,5,115,128]. Studies report positive effects on the cardiovascular

2 1

system, gynecological problems and asthma [15,5,115,128]. Primary afferents

for skin, deep somatic tissues and viscera form spinal reflex circuits with

neurovegetative preganglionic neurons [76]. Spinal neurovegetative circuits

regulate the efferent activity to target organs. Spinal neurovegetative

outflow is dependent on the spinal neurovegetative circuits which are the

result of peripheral (visceral and somatic) afference and supra-spinal

descending control [77]. McLachlan and Deuchars demonstrate that

preganglionic neurovegetative neurons have synaptic connections with

peripheral somatic afferents [77]. Sato et al. have seen that the cutaneous

group II afferents did not change the heart rate and blood pressure in

animal experiments [141,142]. The cutaneous group III and IV led to an

increased cardiovascular system [141,142]. Volleys in the group I and II

muscle afferents were not effective. Stimulation of the muscle group III

afferents elicited a not consistent response, in some cases a bradycardiac

(40%) and in other cases a tachycardiac (30%) response. Triggering the

muscle IV afferents always led to an increase in heart rate [141,142]. Sato et

al. reported in another animal study that stimulation of the thoracic and

lumbar spine with forces of 0.5-3.0 kg lateral glide on the segment blood

pressure decreases 29.8(±3.1)mmHg and a decrease of 6.1(±1.6) beats per

minute (BPM) [140]. Also an increased adrenal nerve activity was seen,

which was attributed to baroreceptor effects, since bilateral dissection of

the vagus nerve and carotid sinus nerve (glossopharyngeal nerve)

abolished the reaction [140]. In a study of Camelleri et al. on the gastric

motility is reported that the location of the stimulus is not primary important

and that a non-dermatomal skin stimulation with transcutaneous electrical

nerve stimulation (TENS) can also elicit visceral responses [22]. Because of

the similarity of the gastric responses on different locations of the skin it is

suggested that the induced somatovisceral reaction relays predominantly at

the supra-spinal level [22]. The spinal cord has an integrative function and

controls different spinal neurovegetative reflex pathways. Peripheral

neurovegetative reactions are spinally mediated and receive synaptic input

from supra-spinal structures and primary afferents (somatic and visceral).

Supra-spinal structures can regulate and change the sensitivity of the

spinal reflex mechanisms [63].

2 2

4. Methodology

4.1 Literature search

The following electronic databases were searched for eligible articles.

MEDLINE and Cochrane Library were searched for articles between 2000

and May 2016. The search was conducted from October 2015 to May 2016.

The following search terms and Medical Subject Headings (MeSH) were

used:

Spinal Manipulation Sympathetic nervous system

Chiropractic Manipulation

Osteopathic Manipulative

Treatment

Manual Therapy

Blood Supply

Vasomotor System

Blood Flow Velocity

Sweat Glands

Parasympathetic nervous system

Autonomic nervous system

Enteric nervous system

Viscera

Visceral pain

Piloerection

Skin Temperature

Pain

For search strategy and the exact combinations of MeSH-terms see 10.1: Appendix 1

Citations and reference lists were also examined to identify any relevant

articles not captured in the electronic databases search. The search was

restricted to randomized controlled trials (RCTs) and systematic reviews

that were reported in English language.

4.2 Eligibility criteria

4.2.1 Inclusion criteria

- Articles in the English language

- Publication date 2000 – May 2016

- Randomized Controlled Trials and Systematic Reviews

- Adult (>18 years) and human (male and female)

- A-Symptomatic and Symptomatic subjects

2 3

- Manual spinal technique intervention (manipulation or mobilization)

- Objective measurement of at least one neurovegetative outcome

(autonomic, sympathetic, parasympathetic or enteric nervous system)

4.2.2 Exclusion criteria

- Articles in another language than English

- Studies other than RCTs and systematic reviews

- Studies on medicinal uses, chirurgical studies and molecular studies

- Neurologic diseases or neurologic pathologies

- Studies with no objective measurable neurovegetative outcome

(autonomic, sympathetic, parasympathetic or enteric nervous system)

- Neuro-adrenal/humeral reactions or reactions caused by the

hypothalamic-pituitary-adrenal axis

- Studies with no reproducible treatment, no studies with patients need

based treatment (Black Box)

- Studies which use a spinal correction device (Activator) as intervention

- Studies where the intervention do not consists only of manipulation or

mobilization techniques (spinal techniques combined with non-spinal

techniques)

4.3 Types of manual intervention

Studies that are included in this literature review use manual spinal

manipulation and/or mobilization techniques as an intervention. All general

or specific manual spinal manipulation and mobilization techniques used in

manual therapy, chiropractic and osteopathic medicine are included.

4.4 Types of outcome measures

This review will focus on the neurovegetative outcomes in three systems:

the peripheral system, the visceral system and the specific sympathetic

pain system. This includes outcomes for the peripheral system: skin

conductance, skin temperature, skin/local blood flow, blood supply, blood

flow velocity, piloerection, pupillary diameter.

2 4

For the visceral system: heart rate variability, heart rate, systolic and

diastolic blood pressure, respiratory rate, visceral motility/contractions,

filtration rate.

For the sympathetic nervous system in relation to pain: pressure pain

threshold, thermal pain threshold, pain intensity on Visual Analog Scale

(VAS).

4.5 Data extraction

The data are extracted from the studies and characteristics are summarized

and presented in table 1. The included studies were examined and

classified using the PEDro Quality Assessment Scale to identify

methodological quality (table 2). Citavi5 was used to create a bibliographic

database to manage the search results.

4.6 Quality Rating

To assess the risk of bias all included studies are examined and classified

using the PEDro Quality Assessment Scale (table 2). The PEDro Scale is

based on the Delphi list developed by Verhagen et al. [167]. It is an 11-item

scale designed for rating methodological quality of RCTs (appendix 10.3).

The PEDro Scale contains the 3-point Jadad Scale and the 9-item Delphi

list and is according to Maher et al. reliable for reviewing RCTs [97].

2 5

5. Results

The search strategies were first developed in MEDLINE and subsequently

adapted to the Cochrane Library database. The search in MEDLINE and

Cochrane Library yielded 259 articles (appendix 10.1). The first search with

MeSH-terms in MEDLINE resulted in 101 articles with 35 duplicate articles.

The second search with MeSH-terms in Cochrane Library resulted in 158

articles with 60 duplicates (duplicate articles within search MEDLINE and

Cochrane Library together). After the first selection the combined database

search in MEDLINE (n=19) and Cochrane Library (n=6) yielded 25 results

(for first selection strategy, see appendix 10.2). Searching the reference

lists of keys articles between 2000 and 2016 yielded a further article from

Win et al. [117] that was not captured in the electronic search.

22 Randomized Controlled Trials (RCTs) and 4 systematic reviews were

analysed in full-text. 12 RCTs and 2 systematic reviews were excluded

because they did not meet the eligibility criteria, leaving 12 primary studies

in this literature review. 10 RCTs and 2 systematic reviews. Because the

systematic reviews selected other inclusion criteria the results cannot be

extrapolated. Described studies in the systematic reviews were separate

analysed on the author’s criteria. From the studies that were examined in

the systematic review 3 studies met the inclusion criteria [154,134,20].

Finally there were 13 RCTs included in the qualitative syntheses. The

process of the study selection is shown in figure 1.

During full-text screening on eligibility criteria the following articles are

excluded; The record from Maclean et al.[103] is screened on eligibility

criteria and is excluded because of a non-spinal mobilization. The reason

for exclusion from Ogura et al.[118], Roy et al. [135] and Zhang et al.[186] was

that they didn’t use a manual technique. They tested the effect of a cervical

manipulation by correction of an Activator or pressure device. The study of

Ruffini et al.[137] is excluded because the osteopathic manipulative

treatment consisted of a patient’s need based treatment, no pre-determined

protocol was applied and thus the treatment is not reproducible. Giles et

2 6

al.[43] and Licciardone et al.[95] are excluded because they used a combined

intervention and not solely a spinal manipulation or mobilization technique.

Precise conclusions from a combined intervention cannot be drawn. The

reason for exclusion of Karason et al.[83] and Dimmick et al.[30] is because of

no randomization of the groups. The article of Gibbons et al. [42] and Win et

al. [177] are excluded on account of no control group. Amatuzzi’s et al. [1]

study is excluded because no full-text document was available in

MEDLINE, Cochrane Library, Science Direct, ResearchGate or Google

Scholar search and no personal reaction after e-mail.

The database search yielded 4 systematic reviews; Kingston [86], Schmid

[147], Bolton [15] and Proctor [129]. Because the systematic reviews selected

other inclusion criteria, the described studies in the systematic reviews

were analysed on the inclusion criteria. Kingston et al. [86] performed a

systematic review on spinal mobilizations and the SNS. 7 studies were

included in the systematic review of Kingston. From the 7 studies, 4 studies

were excluded in this literature search due to publication date. The

remaining 3 studies are duplicates of the database search. The systematic

review of Schmid et al. [147] examined the response to passive cervical joint

mobilization on the central nervous system. From the 15 studies, 1 study of

Soon et al.[154] is obtained in full-text. 14 studies were excluded (1

duplicate, 3 studies with no neurovegetative outcome and 11 studies are

performed before 2000). Bolton et al. [15] performed a systematic review on

visceral reactions due to spinal manipulation and mobilization. Bolton et al.

searched MEDLINE and Index to Chiropractic Literature Databases without

date limitations and included studies that examined visceral responses by

spinal manipulation and mobilization on healthy subjects. Total of 18

articles were reviewed on the cardiovascular function. 2 of the articles met

the inclusion criteria and were obtained in full-text.[20,134] Reason of

exclusion of 16 studies was; 11 studies were performed before 2000, 2

studies with non-randomization, 1 study had no control group and 2

duplicates. The review of Bolton et al. conducted 3 studies which

measured the respiratory function. The study of Engel et al. [35] is reviewed

in full-text and is excluded because no neurovegetative outcome is tested;

2 7

the other 2 studies were excluded because of publication date. On

gastrointestinal function 2 studies were described and both were excluded

because of date and non-control design. The studies selected by Bolton et

al. on somato-autonomic function (n=5) yielded no new studies. There is 1

study excluded on publication date; the remaining 4 are duplicates. The

systematic review of Proctor et al. [129] is excluded because of date

intervention; all 3 studies are performed before 2000.

Figure 1: Study Selection

Table 1 summarises the studies, including author and publication year,

inclusion and exclusion criteria, participant characteristics, measurements,

type of intervention, type of sham and/or control group, type of outcome

measures, results and PEDro Quality Assessment Scale.

Search

•Records identified througt database search on keywords and date (n=259)

•Additional records identified through other sources (n=1)

•Total records identified (n=260)

Screening

• Records after duplicates removed (n=166)1

•Records after screened for eligibility criteria on title and abstract (n=26)1

Eligibility

•Full-text RCTs (n=22) and systematic reviews (n=4) assessed

•Full-text RCTs excluded (n=12)

•Full-text systematic reviews excluded (n=4) systematic review RCTs included (n=3)

Included •Randomized Controled Trials included in qualitative synthesis (n=13)

2 8

5.1 Study Characteristics The electronic search yielded 13 RCTs

[113,159,123,122,80,91,150,18,134,20,154,109,111]. From the 13 RCTs 7 studies

[113,123,122,80,91,150,134] performed a parallel group design and 6 studies

[159,18,20,154,109,111] performed a cross-over or within subjects design. All 13

studies examined neurovegetative reactions of spinal manipulation and

mobilization in adults. 4 studies included symptomatic adults [159,91,134,150]

and 9 studies investigated a-symptomatic adults [11,123,122,80,18,20,154,109,111].

Sterling et al. [159] and Sillevis et al. [150] examined subjects with chronic

cervical pain and La Touche et al. [91] included subjects with chronic

craniofacial pain. Roy et al. performed a study on patients with acute low

back pain [134].The total sample sizes from the examined studies ranged

from 16 to 100 subjects per study and for the different groups from 15 to 50

subjects. The search resulted in 7 RCTs which examined the effect of a

spinal mobilization [113,159,122,80,91,154,111] and 6 RCTs of a spinal

manipulation [123,150,134,18,20,109] 4 of the 13 studies included in this review

applied spinal techniques to lumbosacral spine [122,123,134,113], 4 to the upper

thoracic spine [80,150,20,109], 3 to the lower cervical spine [159,154,111] and 2 to

the upper cervical spine [91,18].

5 studies performed as a sham procedure manual contact that is identical

as the treatment technique, but with no movement and as control procedure

no physical contact. [113,159,122,154,111] La Touche et al. [91] uses the same

sham procedure (identical contact on the technique site) but with no control

measurements. In 3 spinal manipulation studies the sham procedure

contains the same starting position as the manipulation technique, but

without thrust [134,150,109]. In 2 of the 4 studies pressure without thrust is

added in the manipulation position [134,150]. Budgell et al. [20] conducted in 1

of his 2 studies single, light brief impulse on the treatment site as a sham

procedure and in the other study a sham manipulation with thrust [18].

Jowsey et al. mimics the treatment position and physical contact and uses

manual pressure as sham procedure [80]. In 2 studies treatment and sham

procedure involve active movements in the same direction [113,111]. Perry et

al. (2011) is the only study which analyses the outcomes between 2

common treatment techniques [123]. A spinal manipulation technique is

2 9

compared to a statically postero-anteriorly technique with active lumbar

extension exercises. 1 study used a multi-session design [91]. La Touche et

al. performed 3 sessions within 2 weeks. Other studies measured a single

application and immediate or short-term results

[113,159,123,122,80,150,18,134,20,154,109,111].

Assessment of the quality of the RCTs is performed with the PEDro Scale.

Table 2 summarizes the PEDro ratings for the different studies. The overall

quality of the 13 RCTs was good. 11 of the 13 RCTs received 6-8 points out

of 10 points and are classified as good [113,159,123,80,91,150,18,134,20,154,111],

Perry et al. (2009) [122] received 5 out of 10 points and is classified as fair

quality and Mohammadian et al. [109] is classified with 9 out of 10 points as

very good quality. The quality of the studies was mostly downgraded due to

the lack of therapist blinding, assessor blinding and because of insufficient

reports about the number of subjects that completed the study or subject

dropouts.

3 0

Table 1: Data extracted from studies reviewed

Author /Year - Design

Inclusion-Exclusion Criteria

Participant charact / Measurements

Intervention Control Outcome Results PEDro Scale

Moutzouri M. et al. (2012) -Prospective, single blind, randomized, parallel group 3-arm design

Exclusion: LBP past 6 months, spinal deformity or fracture, previous lumbar surgery or trauma, neuromuscular joint or skin disease.

Inclusion: healthy volunteers

N=45 healthy subjects (male & female) -8 min stab period-3 min baseline measurements-application-3 min

measurements

Sustained central joint glide L4 with flexion/ SNAGS (sustained natural apophyseal glides) (n=15)

-3 sets of 6 rep. full active lumbar flexion sitt ing

Sham: hand contact L4-L5 no glide with active lumbar flexion. 3 sets of 6 rep.(n=15) Control : seated

without contact or glide(n=15)

Bilateral lower limb SC, second and third toes

-Sign diff between SNAG and control group for both right (P = .044) and left side (P = .004). -No sign diff between SNAG and sham. -SNAG increase SC 10.60% ± 7.5% and 11.19% ± 7.85% for the right and left limb -no sign diff between intervention periods

-control group no sign diff. - sham group SC 6.54% R and 7.44% L. no sign effect.

8/10

Sterling M. et al. (2001) -Double blind, randomized, placebo-controlled, within subjects design.

Exclusion: history of trauma or surgery to the cervical spine, evidence of referred arm pain or

radiculopathy, headache, dizziness or other cervical spine symptoms, diabetes or peripheral vascular disease Inclusion: history of mid to lower cervical spine pain of insidious onset, >3 months, symptoms primarily from C5-C6 segment

N=30 symptomatic subjects. (F=16 and M=14) mean y= 35.77(±14.92)

-3 different days with at least 24 hours between sessions. -VAS-PPT-TPT recorded immediately before and after application. -SC and ST 2 min baseline measurement and during application

Passive grade III postero-anterior mobilization C5-C6 symptomatic side

3 times, 1 min application with 1 min interval. Total length 6 min. Treatment group characteristics not reported

Sham: manual contact C5-C6 no movement Control: no physical

contact. Sham and control group characteristics not reported

-SC distal palmar index and middle finger bilaterally -ST palmar

thumb bilaterally -Pressure pain thresholds (PPT) symptomatic segment -Thermal pain thresholds (TPT) symptomatic segment -VAS at rest

-Resting VAS intervention-VAS control sign diff 0.044.Resting VAS intervention-VAS placebo not sign diff 0.091. Decrease resting VAS 0.335 ±0.02 cm.

-No sign effect VAS end ROM cervical rotation -PPT side of treatment sign diff with placebo p=0.0002 and control p=0.0001. mean increase 22.55 ±2.4% treatment vs. baseline -TPT no sign diff p=0.669. -SC sign diff treatment vs. placebo and sign diff treatment vs. control. -Baseline-SC AUC 16±2.96%. Baseline-SC MAX 114±10.5% -ST sign diff treatment vs. placebo ST MIN and sign diff treatment vs.

control ST AUC-ST MIN. . Baseline-ST AUC -1.3±0.4%. Baseline-ST MIN -2.5±0.5%. - No sign diff side of treatment or interaction effect.

6/10

Perry J. et al. (2011) Prospective, quasi-experimental, randomized, independent subjects design

Inclusion: naivety any form of manual physiotherapy.

Exclusion: prohibition of any strenuous activity, intake of caffeine, nicotine or other drug in the four hours prior to the experiment. The maintenance of regular patterns of exercise, diet and sleep over the experiment period were also required.

n=50 healthy a-symptomatic non-smoking, student-staff

at Coventry University -10min stabilization period-2min baseline measurements-application, last 2min of the application period measurements-10min final rest, last 2min of final rest period measurements

Single HVLA grade V segmental rotation technique (L4/5) in

either right or left side-lying, computer generated random allocation left or right side. Technique protocol described in Maitland

and Herzog

N= 25 y=36.9(±8.27) M=11 F=14

Exercise: A postero-anteriorly techn statically proc.spin

L4/5 and actively 3 sets of 10 rep. lumbar extension exercises (McKenzie, 2003). 1 min rest between the 3 sets. N= 25 y=37.7(±8.28) M=10 F=15

Continuously SC second and third toes bilaterally

-HVLA baseline-intervention SC76% increased p=0.0005/HVLA intervention-final rest SC p=0.0005

HVLA baseline-final rest SC 12.9% increased p=0.0001 -lumbar extensions baseline-intervention SC 36% increased p=0.0005 / lumbar extensions intervention-final rest SC p=0.0005 -lumbar extensions baseline-final rest SC 2.7% increased p=0.137 -SC HVLA vs.lumbar exercises intervention p=0.001 HVLA +40.61% -SC HVLA vs.lumbar exercises final rest p=0.0048 HVLA +10.22% - no sign diff opening-closing facet

5/10

3 1

Author /Year - Design

Inclusion-Exclusion Criteria

Participant charact / Measurements

Intervention Control Outcome Results PEDro Scale

Perry J. et al. (2008) -Double blind, randomized, independent group, between subjects experimental design

Inclusion: naivety any form

of manual physiotherapy. Exclusion: prohibition of any strenuous activity, intake of caffeine, nicotine or other drug in the four hours prior to the experiment. The maintenance of regular patterns of exercise, diet and sleep over the experiment period were also required.

N=45 healthy

a-symptomatic, non-smoking -10 min stabilization period-2min baseline measurements-5min application period-final rest period and measurements 5min

Unilaterally grade III

osci llatory mobilization 2Hz left L4-L5 facet joint. N=15 y=21.4 (±1.88) Treatment: 3 t imes 1min, with 1min rest between, total 5min.

-Sham: contact

identical as technique but with light tough, minimal pressure no movement. N=15 y=21.5(±1.85) 3 times 1min, with 1min rest between -Control: identical positioning no contact or movement. N=15 y=21.4(±1.88).

SC dorsum

second and third toes bilaterally

-sign diff treatment group vs. sham during

intervention for L side p=0.005 13.47%(±20.26) increased. Side specific sign effect. - no sign diff treatment group during intervention for R side 4.11%(±10.65) -no sign diff in final rest period

8/10

Jowsey P. et al. (2010) -double blind, randomized, placebo controlled, independent group design

Inclusion: healthy individuals 18-35 years. A-symptomatic of thoracic spine, neck and upper limb pain. Exclusion: no alcohol consumption <24h, no caffeine/nicotine and

physical activity <4h prior experiment, medication that influences SNS activity

N=36 healthy subjects, M=13 F=23 mean y=22.7(±5.2) -8min stabilizing period-2min baseline measurements-5min application period-

5min post-application measurements

-Grade III rotatory postero-anterior intervertebral T4 mobilization in 3 directions: postero-anterior, cranio-caudaal and lateral. The technique was

performed 0.5 Hz. -3 sets of 1min, with 1min rest between sets. N=18 y=23.44(±6.11)

Sham: Postero-anterior rotatory pressure on T4 no oscillation. Statically pressure 1min, 3 set with 1min intervals. N= 18 y=22.00(±5.26)

SC index and middle fingers bilaterally

-during treatment no sign diff between intervention and sham. -post-treatment sign diff intervention vs. sham on the R hand p=0.034.side specific. -L hand p=0.052 trend towards bilateral effect but no sign diff. - during intervention treatment vs.

sham SC changes +5.74% and +16.85% post-intervention R hand. - during intervention treatment vs. sham SC changes 4.95% and +10.56% post-intervention L hand.

7/10

La Touche R. et al. (2012) Randomized, double blind placebo-controlled design

Inclusion: subjects were selected if they met all the following criteria 1. Primary diagnosis

myofascial pain 2. Bilateral pain masseter, temporalis, upper trapezius and suboccipital muscles 3. Pain >3 months 4. Pain average VAS >30mm on a 100mm VAS 5. Neck-shoulder pain provoked by neck posture or movement 6. Neck Disabili ty Index (NDI) ≥15 points 7. Bilateral trigger points in masseter,

temporalis, upper trapezius and subocciptal muscles.

N=32 patients with chronic craniofacial pain of myofascial origin.

-10min stabilizing period-baseline measurements-application period-immediately after application measurements-5min post-application measurements

Passive anterior-posterior C0-C3 cervical mobilization at 0.5 Hz (1 osci llation per 2 sec) 3 intervals in 2 weeks of 3 times 2min mobilization, with 30sec rest in between. Total 7min. N=16 mean y=33.19(±9.49)

Sham: same contact no movement. 3 intervals in 2 weeks of 2min contact, with 30sec rest in between. Total 7min. N=16 mean y=34.56(±7.84)

-SC tip of second and third fingers on the left hand.

-ST tip of the fourth fingers left hand. -Heart rate (HR) anterior radial aspect wrists -Breathing rate (BR) sensor placed around the chest -Pressure Pain Thresholds (PPT) digital

algometer bilaterally 2 points in

-VAS: sign diff treatment group p=<0.001, no sign diff sham group p=0.3. -VAS Sign diff between groups

-Decrease VAS was maintained between the sessions, total decrease 41.7% or 29.13mm in 3 sessions. -PPT sign diff between 3 sessions treatment group P=<0.001. no sign diff sham group p=>0.05 for all craniofacial points. PPT revealed a sign effect of time factor, but not for side factor. PPT sign diff for L and R side craniofacial points. A maintained increase over the 3 sessions.

-PPT sign diff between groups -SC sign diff treatment group p=<0.001, but not for sham group

8/10

3 2

Exclusion: signs, symptoms or history of the following disease: intra-articulair temporomandibular disk replacement, osteoarthrosis or arthritis temporomandibular joint. History of traumatic

injuries, systemic diseases, neurological disorders, concominant diagnosis of a primary headache, unilateral neck pain, cervical spine surgery, cervical radiculopathy or myelopathy, history of previous physical therapy intervention for cervical region.

masseter, 2 points in temporalis, suboccipital muscles, C5 zygapophyseal joint, upper trapezius - VAS 100mm

horizontal line

p=0.73. increase of 83.75% -SC sign group diff p=0.003 -SC no sign intersessions diff or group by intersession diff. -BR sign diff treatment group p=0.02, but not for sham group p=0.08. increase 10.8% -HR sign diff in treatment group p=<0.001 and sham group

p=<0.001. increase +6.06% treatment group, -5.5% decrease in sham group. -ST no sign diff between groups. An effect of SC-BR-HR changed after each session, but reversed and was not maintained between the 3 sessions. SNS values returned to a normal state of SNS activity.

Sillevis R. et al. (2010) Randomized, placebo-controlled design

Inclusion: 18-65 years and able to speak and read the English language. Exclusion: medication that influences autonomic nervous system <24h before participating or <12h before participating caffeine, smoke or eating, autonomic diseases,

history of concurrent neurological, ocular, and/or retinal disease, >2 alcoholic beverages daily, or trained for endurance sports.

N= 100 patients with chronic neck pain -3min stabilizing period-measurement 60sec-application-post-application measurement for 60sec.

High velocity mid-range postero-anterior force T3-T4 segment in supine position (technique Hartman)

[48]

-N= 50 M=10 F=40

Mean y=42.7 Mean VAS=38mm Mean duration

symptoms 23.3 months. -baseline-treatment/sham-measurement 1- after 4 min measurement 2

Placebo: open-hand placement T4 in combination deep inhalation followed by an exhalation and light 3sec compression (sham technique described by Cleland)

[26]

N= 50 M=13 F=37 Mean y=46.48 Mean VAS=33mm Mean duration symptoms 25.3 months

-Pain VAS 100mm line -automated pupillometry right eye continuously for 60sec (Friedman’s test)

-no sign diff pupil diameter intervention group. - sign diff in mean pupil diameter placebo group among the 3 time points p=<0.022. Pupil diameter decreased over time for placebo group. Pupil was sign more dilated before intervention compared to post1 and post2 measurements.

-Pain VAS: no sign diff between groups p=0.961. Sign reduction VAS for both groups. Concluded that thrust manipulation did not result in immediate pain reduction.

6/10

Budgell B. et al. (2001) Single blind, placebo-controlled, randomized, cross-over design

Inclusion: normotensive

Exclusion: history of cervical surgery, fracture or dislocation, cervical anatomical abnormality, history of cervical trauma <3 months or persistent symptoms from earlier trauma, history of cancer, stroke, positional vertigo, current anticoagulant or steroid therapy, history of chronic or recurrent inflammatory disease,

current li tigation for spinal injury.

N= 24 healthy

subjects. M=20 F=5 mean y= 28.5(±6) -measurement process not reported

C1 supine cervical rotatory adjustment HVLAT. Single technique. Intervention in 5sec. Cross-over design with 1 week washout period. Treatment group characteristics not reported

Sham: subject’s

head at the limit of rotation without extension, contact with skin of the neck and applying thrust along the plane of the skin. Sham in 5 sec, single technique Sham group characteristics not reported

-heart rate with

electro-cardiogram ECG -HRV with electro-cardiogram ECG, records analysed with HRV software - 5 minute pre- and post-stimulation

measurements

-sign diff between manipulation -3.36 bpm

and sham -2.13 bpm HR decline pre- and poststimulation p=0.0496 -manipulation sign increases in absolute- p=0.0310 and normalized low frequency component p=0.0061 levels of the low-frequency component of the lower spectrum and in the ratio of low- to high frequency components p=0.0037 - no sign diff in low-frequency or high-frequency components of the power spectrum, nor in the ratio of the two.

7/10

3 3

Author /Year - Design

Inclusion-Exclusion Criteria

Participant charact / Measurements

Intervention Control Outcome Results PEDro Scale

Roy R. et al. (2010) Single blinded, randomized, placebo-controlled design

Inclusion: free of any

underlying pathologic conditions (acute or chronic diseases, cold and/or any thermogenic disease Exclusion: <2h before intervention coffee or any other beverages with caffeine, smoking, chewing tobacco, female subjects having their menses.

-N= 20 acute low

back pain M=8 F=12 -sign diff between groups in age p=0.04, weight p=0.04 and BMI p=0.02 -stabilization period 8min-baseline measurement- immediately after application and after 1-3-5-10 minutes

measurements

HVLAT lumbar roll

L5 in sode posture N=10 y= 35.7 (±11.73) Measurements: 8 minute stabilization period before spinal manipulation. Immediately after and 1-3-5-10 minutes after spinal

manipulation

Sham: 5 second

pressure with no thrust in side posture N= 10 y=44.7(±9.8)

-Cutaneous skin

temperature (ST) with handheld infrared camera half inch away from the skin lateral of the processus spinosus at L5.

-ST between groups non-sign p=0.238.

-Sign diff ST in treatment group ipsilateral- compared with heterolateral side. Sham group no diff between ipsilateral and heterolateral side.

7/10

Budgell B. et al. (2006) Single blind, Placebo-controlled, randomized cross-over design

Inclusion: healthy adults. Exclusion: current neck and upper back pain. History of cervicothoracic surgery, fracture or dislocation, a known anatomical abnormality in the cervicothoracic region,

history of cervicothoracic trauma < 3 months or persistent symptoms from an earlier trauma, history of cancer, stroke, positional vertigo or chronic or recurrent inflammatory disease, receiving anticoagulant or a steroid therapy or i f they were currently engaged in litigation for spinal injury. Immediately for each

intervention blood pressure was measured, systolic pressure >140 mmHg or diastolic pressure > 90 mmHg

N=28 healthy adults M=23 F=5 y=29(±7) -5min pre-application and 5min post-application ECG records analysed for HRV

- Continuously ECG recording, during applying the application the ECG records are excluded

HVLAT cross-bilateral adjustment T1-T4 in prone position and a combination adjustment of T1-T4

Contact hands on scapulae bilaterally, end exhalation single light brief impulse with both hands

-HR ECG -HRV ECG - Blood pressure - 5 minute pre- and post-stimulation measurements

-Blood pressure no sign diff before and after treatment -no sign diff between groups in decline of HR p=0.7450. - both groups sign decline of HR. manipulation group 2.45(±2.5) bpm and 2.7(±2.4) bpm comparing with 5 minute resting period.

-sign increases in absolute (LF) 195.6(±146.8) to 275.1(±202.9) p=0.0098 and normalized (LF/total power) levels of the LF component of the power spectrum increased from 40.25(±18.55) to 46.66(±20.35) p=0.201 as well as in the LF/HF ratio increased to 0.9562(±0.9192) to 1.304(±1.118) p=0.0030. - no sign diff LF or HF component of the power spectrum, neither was in ratio of the two.

8/10

Soon B. et al. (2010) -double blind, controlled, randomized, within subjects crossover design

Exclusion: histroy of neck or back pain <6 months, previous experience with

spinal manipulative therapy, any history of musculoskeletal or rheumatological conditions, any kind of spinal surgery, dizziness, previous trauma cervical spine and neurologic sign and symptoms.

N=24 asymptomatic subjects with history of neck or back pain

<6 months, previous experience with spinal manipulative therapy M=13 F=11 Y=34(±12) -measurements immediately before and after application

Passive cervical mobilization, osci llatory 2 Hz

grade III unilateral postero-anterior mobilization left C5-C6 segment (Maitland)

[98,99]

- 3 periods of 1 minute applications, resting period of 1 minute

Sham: manual contact left C5-C6 segment, no

movement. 3 periods of 1 minute applications, resting period of 1 minute. Control: noncontact. 5 minute resting in treatment position.

PPT electronic digital algometer on posterior

aspect of the left and right C5-C6 articular pillar in prone position.

-no sign mean effect PPT p=0.846

7/10

3 4

Author /Year - Design

Inclusion-Exclusion Criteria

Participant charact / Measurements

Intervention Control Outcome Results PEDro Scale

Mohammadian P. et al. (2004) Single blind, randomized, placebo-controlled, within subjects design

Inclusion: healthy subjects. Exclusion: <7 days prior experiment drugs, <8h before experiment drinking caffeine or alcohol-containing beverages, chiropractic treatment <30 days before experiment.

N=20 healthy subjects M=14 F=6 Y=27 -baseline measurements-application-immediately after application measurements

-15 minute short-lever pre-stressed, high-velocity, low-amplitude sustained thrust on thoracic vertebral subluxation sites. Spinal Manipulative Treatment (SMT) -2 experimental sessions 60 minute duration, separate

at least 7 days. -Capsaicin cream right or left forearm 20 mintes.

Sham: same contact without thrust. Non-Spinal Manipulative Treatment (N-SMT)

-stroking allodynia application site using swab -hyperalgesia application site using Frey hair -skin blood flow application site and 2cm from edge application site by Laser

doppler Flowmeter -Spontaneous pain: VAS scale

- sign decrease of mean values of hyperalgesia p=0.007 and allodynia p=0.003 following SMT compared with N-SMT. Opposite effect recorded by N-SMT group. - intensity of spontaneous pain after SMT sign lower than N-SMT p=0.014. In the N-SMT group spontaneous pain was more painful. - no sign diff in blood flow for both groups. -no statements about inter-session effects.

9/10

Moulson A. et al. (2006) single, blind, randomized, within subject, repeated measures design

Inclusion: asymptomatic subjects. Exclusion: previous neuromusculoskeletal dysfunctions affecting the

cervical spine and upper quadrant, previous experience of SMT and any subjects with contraindications of manual therapy, <1h prior experiment smoking, participating in strenuous exercise and consuming alcohol or caffeine.

N=16 asymptomatic subjects M=5 F=11 y=23.06(±5.35) -8min stabilization

period-2min baseline measurements-application-immediately after application 2min measurements

-sustained natural apophyseal glides (SNAG) C5-C6 intervertebral joint and simultaneously

turned their head to the right. The direction of the SNAG was parallel to the plane of the joint (Mull igan, 1999) -3 times cervical rotation, mean treatment time 22 sec(±3.6) -8 minute stabilization period-

2 minute baseline measurements-after intervention 2 minute measurements

Sham: same procedure and contact as intervention with no accessory glide

SNAG technique. Control: no contact, looking forward during recording.

-bilateral upper limb SC and ST simultaneously recorded before, during and after

intervention. First, second and third palmar digits.

-no sign diff for SC and ST between left and right for treatment, sham and control group at any phase of the intervention. -ST no sign diff between independent variables.

- sign increase SC in treatment and sham group vs. control for pre-treatment compared with treatment phase - sign diff treatment and sham vs. control group for pre-treatment phase compared with post-treatment phase. - sign increase SC for treatment vs. sham group for pre-treatment phase compared with post-treatment. -sign diff treatment group in SC once the treatment has finished.

7/10

L=left R=right CBF=cutaneous blood flow SC=skin conductance ST=skin temperature HR=heart rate BR=breathing rate PPT=pressure pain thresholds VAS=Visual Analog Scale HRV=heart rate variability LF=low frequency HF=high frequency AUC=area under curve MAX=maximum MIN=minimum HVLAT=high velocit y low amplitude thrust (manipulation) TPT=temperature pain thresholds SMT=spinal manipulative treatment N -SMT=non-spinal manipulative treatment BPM=beats per minute SNAG= sustained natural apophyseal glides

3 5

Table 2: PEDro Scale scores for each study

References Criteria 1* Criteria 2 Criteria 3 Criteria 4 Criteria 5 Criteria 6 Criteria 7 Criteria 8 Criteria 9 Criteria 10 Criteria 11 Total

Moutzouri M.

et al. (2012)

Y

Y

Y

Y

Y

N

N

Y

Y

Y

Y

8/10 (good)

Sterling M. et

al. (2001)

Y

Y

N

Y

Y

N

Y

N

N

Y

Y

6/10 (good)

Perry J. et al.

(2011)

Y

Y

N

Y

Y

N

N

N

N

Y

Y

5/10 (fair)

Perry J. et al.

(2008)

Y

Y

Y

Y

Y

N

Y

Y

N

Y

Y

8/10 (good)

Jowsey P. et

al. (2010)

Y

Y

N

Y

Y

N

Y

Y

N

Y

Y

7/10 (good)

La Touche R.

et al. (2012)

Y

Y

Y

Y

Y

N

Y

Y

N

Y

Y

8/10 (good)

Sillevis R. et

al. (2010)

Y

Y

Y

Y

N

N

N

Y

N

Y

Y

6/10 (good)

Budgell B. et

al. (2001)

Y

Y

Y

Y

Y

N

Y

N

N

Y

Y

7/10 (good)

Roy R. et al.

(2010)

Y

Y

Y

Y

Y

N

Y

N

N

Y

Y

7/10 (good)

Budgell B. et

al. (2006)

Y

Y

Y

Y

Y

N

N

Y

Y

Y

Y

8/10 (good)

Soon B. et al.

(2010)

Y

Y

Y

Y

Y

N

Y

N

N

Y

Y

7/10 (good)

Mohammadian

P. et al. (2004)

Y

Y

Y

Y

Y

N

Y

Y

Y

Y

Y

9/10 (very

good)

Moulson A. et

al. (2006)

Y

Y

Y

Y

N

N

N

Y

Y

Y

Y

7/10 (good)

For PEDro Scale scores and criteria see appendix 10.3 *= Criteria 1 (Eligibility criteria) is not added to the calculate the PEDro score

3 6

5.2 Peripheral reactions of the neurovegetative nervous system

Skin Conductance

7 included studies measure skin conductance (SC) as reaction of the

neurovegetative nervous system on a manipulation or mobilization

[159,123,113,122,80,91,111]. All the studies measures significant differences in SC

between intervention and sham or control group. In the study of Perry et

al.(2008)[122] there was only a significant difference during treatment and

Jowsey et al.[80] found only significant differences post-intervention period.

Moulson et al. found a significant difference intervention versus control group,

but no significant difference between intervention versus sham group [111]. The

other studies found a significant difference between intervention and sham or

control group.

SC increases in all studies and rates vary between 10.6% and 83.75%. Sterling

et al.[159] used a different measurement technique for SC and in the study of

Moulson et al. [111] no SC percentages are reported.

Results of side-specific changes are not consistent. 6 out of 7 studies did side

specific measurements [159,123,113,122,80,111]. Bilateral changes are found in the

majority of the studies. In 2 studies side specific changes are reported [122,80].

Perry et al.(2008)[122] found during a unilateral grade III oscillatory 2 Hz

mobilization at the left L4-L5 facet joint a significant difference during treatment

only at the left side and Jowsey et al. [80] performed a grade III rotatory postero-

anterior intervertebral T4 mobilization and reported post-treatment a significant

effect only at the right side. 6 out of 7 studies examined SC changes during and

after spinal mobilization [159,113,122,80,91,111] and 1 study reported SC changes after

spinal manipulation [123]. 5 studies included a-symptomatic subjects

[123,113,122,80,111] and 2 studies symptomatic subjects. Sterling et al. [159] examined

chronic cervical pain patients and La Touche et al. [91] examined patients with

chronic craniofacial pain of myofascial origin. No consistent differences are

reported in results between a-symptomatic and symptomatic subjects. All studies

except the study of La Touche et al. [91] analysed a single-intervention and short-

term results. La Touche et al. performed 3 intervals of 2 minute upper cervical

mobilizations in 2 weeks. SC reversed after each session and is not maintained

between the 3 sessions. This effect is also seen in the study of Perry et al.(2011)

3 7

[123], SC increases 76% during treatment and 10 minutes post-treatment SC is

descreased to 12.9%. Effect measurements in other studies are till 2-5 minutes

post-intervention. No statements are done about long-term effects.

Skin temperature

4 of the 13 RCTs measured skin temperature (ST) [159,91,134,111] and 1 RCT

measured cutaneous blood flow (CBF) [109]. Reports on ST effects are not

consistent. 3 of the 4 studies report no significant differences in ST between

groups [91,134,111]. Only the study of Sterling et al. [159] found significant differences

after a passive grade III postero-anterior mobilization from C5-C6 between

intervention versus sham group for ST minimum (MIN) and between intervention

versus control group for ST area under curve (AUC) -1.3% and ST MIN -2.5%. 3

of the 4 studies examined reactions by symptomatic subjects. Sterling et al. [159]

included patients with chronic cervical spine pain, La Touche et al. [91] patients

with chronic craniofacial pain of myofascial origin and Roy et al. [134] acute low

back pain patients requiring chiropractic care. ST is measured in 3 of the 4

studies at the palmar surface of the hands [159,91,111]. Sterling et al.[159] and

Moulson et al. [111] measures at the thumb or digits and La Touche et al. [91]

measures at the left fourth digit. The study of Roy et al. measures the ST

paravertebral, lateral of the processus spinosus at L5 [134]. The studies of

Sterling et al.[159], Moulson et al. [111] and Roy et al. [134] measures bilaterally and

La Touche et al. [91] measures unilateral on the left side. Only Roy et al. reported

side specific differences paravertebral L5 after a lumbar HVLAT manipulation

[134]. No significant differences were found between groups. Significant

differences within treatment group were reported between ipsilateral and

heterolateral side, these differences were not side significant between groups.

Immediately after adjustment the ST at the ipsilateral side cooled down -0.46ºF

and 10 minutes after adjustment the ST was 0.49 ºF warmer compared to

baseline measures. The heterolateral side cooled down the entire period and 10

minutes after adjustment the ST was -0.17 ºF cooler than baseline values. All the

studies except La Touche et al. analysed a single-intervention and short-term (2-

5 minutes post-intervention) results [91].

3 8

Cutaneous blood flow

Mohammadian et al. examined cutaneous blood flow (CBF) after experimental

induced inflammatory reaction with capsaicin cream on the forearm [109]. 20

healthy, a-symptomatic subjects were treated with a short lever pre-stressed

HVLAT manipulation of the thoracic spine or with sham treatment. Outcomes

were measured with Laser Doppler Flowmeter on the site of the forearm. No

significant changes in CBF in the groups after 15 minutes adjustments, high

velocity low amplitude sustained thrust manipulation at the thoracic spine were

found.

Pupillary reactions

1 included study examined pupillary reactions after a high velocity mid-range

postero-anterior T3-T4 manipulation [150]. Right eye is continuously measured

with fully automated pupillometry. There was a significant difference in the mean

pupil diameter within the sham group, no significant difference in the treatment

group. The pupil diameter constricted over time for the sham group. The pupil

was significantly more dilated before sham compared to both post-intervention

measures. Immediate post-intervention measurement reported 4.28mm pupillary

constriction and 4 minutes later post-intervention 2 measurement reported

3.89mm pupillary constriction, compared with 1.68mm pupillary dilatation and

1.23mm pupillary dilatation for the treatment group. Between the 2 post-

intervention measures there was no significant difference. No statements are

reported about significance between groups. No conclusions can be done

regarding long-term effects.

5.3 Reactions of sympathetic nervous system in relation to pain perception

Sympathetic pain related outcomes that are measured in the included studies

are; pressure pain thresholds (PPT), thermal pain thresholds (TPT), allodynia,

hyperalgesia and pain intensity on the Visual Analog Scale (VAS). Pain threshold

is defined as “the least stimulus intensity at which a subject perceives pain” as

stated by the International Association for The Study of Pain [57]. 3 studies

measured PPT after a spinal technique [159,91,154]. Changes of the PPT in the 3

studies are not consistent. Sterling et al.[159] did a passive grade III postero-

anterior mobilization of C5-C6 at the symptomatic side by chronic cervical pain

3 9

patients and found significant ipsilateral differences between mobilization and

sham or control group. The PPT at the symptomatic cervical segment increased

22.55%. La Touche et al. performed 3 passive antero-posterior C0-C3 cervical

mobilization at 0.5Hz over 2 weeks by chronic craniofacial pain patients and

reported a significant bilateral effect on all craniofacial PPT and all cerv ical PPT

[91]. Namely a PPT increase of 64-77% for masseter, 38-59% for temporalis and

47-79% for all cervical points. Post hoc testing revealed significant differences

between the 3 sessions for the treatment group, which is indicative of a

maintained increase over the sessions. Soon et al. examined a-symptomatic

subjects with a passive grade III unilateral postero-anterior C5-C6 mobilization at

the left zygapophyseal joint at 2 Hz [154]. PPT at the posterior aspect of the left

and right C5-C6 articular pillar did not change significantly.

TPT is only measured in the study of Sterling et al. at the symptomatic cervical

segment [159]. After a passive grade III postero-anterior mobilization of C5-C6

there were no significant differences in TPT.

A not consistent change in VAS-scores is seen in 4 studies [159,91,150,109]. Sterling

et al. found a significant difference between VAS intervention and VAS control

group and no significant difference between VAS intervention and VAS sham

group [159]. In the study VAS-scores decreased 3.35mm [159]. The study of La

Touche et al. described a significant decrease in VAS between groups [91]. Post

hoc analysis revealed significant differences in the treatment group and no

significant differences in the sham group. The decrease of VAS in the treatment

group was maintained between the 3 sessions over the 2 weeks, with a total

decrease of 41.71% or 29.11mm on the VAS-scale. Sillevis et al. reported no

significant differences between intervention and sham group for VAS-scores [150].

Mohammadian et al. found that spontaneous pain (experimental induced

inflammatory reaction and pain with capsaicin cream) measured with the VAS-

scale, decreases significant after 15 minutes of multiple short lever pre-stressed

HVLAT of thoracic vertebral subluxation sites compared with sham group [109].

Spontaneous VAS rate in the sham group increases after sham treatment. In the

same study researchers also found significant decreases of hyperalgesia and

allodynia on the capsaicin site following HVLAT compared with the sham group.

In the sham group the intensity of the hyperalgesia and allodynia increases

following sham application.

4 0

La Touche et al. performed multiple sessions, 3 sessions in 2 weeks [91].

Significant changes in PPT and VAS-scores are maintained during the 2 weeks

experimental period. Other studies performed short-term measurements and no

statements are reported about long-term or maintained pain-reducing or

hypoalgesic effect.

5.4 Visceral reactions of the neurovegetative nervous system

3 studies examine visceral reactions after a spinal mobilization or manipulation

[91,18,20]. 2 studies [18,20] are included that measures heart rate (HR) and heart

rate variability (HRV) and 1 study [91] that examined HR and breathing rate (BR)

after a spinal technique. 1 study reports next to HR and HRV also effects on

blood pressure (BP) [20]. Bugell et al. performed 2 studies which analysed HR

and HRV with electrocardiogram (ECG) [18,20]. Both studies included a-

symptomatic subjects and tested cardiovascular reactions after a spinal

manipulation. In the first study in 2001 Budgell et al. performed a C1 cervical

rotatory HVLAT adjustment and reported a significant difference between HVLAT

and sham treatment on HR and some HRV frequencies [18]. HR declined -3.36

BPM after HVLAT and -2.13 BPM after sham treatment pre- and post-stimulation.

HRV changes after HVLAT of C1 significant with increase of the absolute (+67.9)

and normalized low frequency (+6.7) component levels of low frequency

component of the lower spectrum and in the ratio of low and high frequency

components (+0.43). In the second study in 2006 Budgell et al. found no

significant changes in HR and blood pressure after a cross-bilateral HVLAT

adjustment of T1-T4 compared to a sham treatment [20]. In both groups the HR

declined significantly. HRV changed significant at some levels following a HVLAT

at T1-T4. Significant increase of HRV levels are reported for absolute (195.6 to

275.1) and normalized levels (40.25 to 46.7) of the low frequency component of

the power spectrum and low frequency versus high frequency ratio increased

from 0.9562 to 1.304. No significant differences are described for the low

frequency of high frequency component of the power spectrum, neither for the

ratio of the two. This indicates as an increase in sympathetic output to the heart

and a shift in the balance of sympathetic and parasympathetic cardiac output in

favor of the sympathetic component. La Touche et al. measured the breathing

rate and heart rate after 3 sessions of passive anterior -posterior mobilization at

4 1

0.5Hz of C0-C3 [91]. Breathing rate increased significant with 10.8% in the

intervention group compared to the sham group. Also the HR changed significant

following mobilization compared with the sham group. HR increase 6.06% and in

the sham group HR declined -5.05%. No significant maintained or intersession

differences for both variables are seen.

5.5 Types of manipulation and mobilization techniques and outcomes

The different types of spinal techniques, intervention process and specific results

are listed in table 3. The study included 6 different types of mobilization

techniques [113,159,122,80,91,154,111] and 6 different types of manipulation techniques

[123,150,18,134,20,109]. Perry et al.(2011) [123] and Soon et al. [154] analysed the same

mobilization technique, namely a unilateral grade III oscillatory mobilization at 2

Hz. Side specific changes are seen in 3 studies [122,80,134] , other studies found

bilateral effects [113,159,91,154,111,123,150,18,20,109]. Perry et al.(2011) [123] used a

unilateral grade III oscillatory 2Hz technique, Jowsey et al. [80] a rotatory postero-

anterior 0.5Hz technique and Roy et al. a HVLAT lumbar roll. No side specific

effects are reported by similar rotatory, HVLAT and oscillatory techniques. No

superior effects are seen by oscillatory techniques, results of 2Hz or 0.5Hz

oscillatory techniques are similar as non-oscillatory techniques.

SC increased following a manipulation with 76% [122], due to mobilization SC

increases in range of 10.56% to 16.85% and an outlying value of 83.75% in the

study of La Touche et al [113,159,80,91,111,123]. Sterling et al. [159] reported a VAS

score reduction of 3.35mm after 3 times, 1 minute passive grade III postero -

anterior mobilization C5-C6 and La Touche et al. [91] described a VAS score

reduction of 29.13mm after 3 sessions of 3 times, 2 minutes passive anterior-

posterior C0-C3 mobilization 0.5Hz. Sterling et al. [159] reported after 1 session

an increase of 22.5% for PPT and La Touche et al. [91] described after 3 sessions

a maintained intersession main increase for the craniofacial and cervical PPT of

60%. Contradictory HR reactions are measured between 2 studies following an

upper cervical technique [91,18]. After a passive posterior-anterior C0-C3

mobilization of 0.5Hz HR increased with 6.06% BPM and following a C1 rotatory

HVLAT HR declined with -3.36 BPM [91]. Budgell et al. reported after 2 different

types of manipulation techniques at the thoracic and cervical spine similar

changes in HRV. A T1-T4 cross-bilateral HVLAT manipulation and a C1 rotatory

4 2

HVLAT manipulation have similar effects on HRV [18,20]. La Touche et al.

performed multiple sessions, 3 sessions in 2 weeks [91]. All studies except one,

measured short-term or immediate effects. Maintained inter-sessions effects up

to 2 weeks are described by La Touche et al. for VAS scores and PPT [91]. SC,

BR and HR reversed after each session and no maintained effects are

measured. On account of a single study, it is unknown whether spinal

manipulation or mobilization has long-term neurovegetative effects. Due to the

unequal distribution of the number of mobilization repetitions, number of

sessions, different measurement methods/locations and treatment regions; it is

not possible to make concrete statements which technique is superior.

Table 3: Type of spinal techniques and outcomes

Author /Year Type of subjects

Intervention Single or multi technique-

intervention

Results*

Side

specif ic

MAN-MOB

Short-long-term effects

Moutzouri M. et al.

(2012)

a-symptomatic

subjects

Sustained central joint glide L4 with full active lumbar flexion sitting

3 sets of 6 repetitions

SC L side +11.19% R side +10.60%

NO MOB unknown

Sterling M. et al.

(2001)

Chronic cervical pain

Passive grade III postero-anterior mobilization C5-C6 symptomatic side

3 times, 1 min application with 1 min interval.

-resting VAS -3.35mm -PPT mean + 22.55% -SC AUC +16% MAX +114% - ST AUC -1.3% ST

MIN -2.5%

NO MOB unknown

Perry J. et al. (2011)

a-symptomatic

subjects

HVLA grade V segmental rotation technique L4/5 in side-lying (Technique described by Maitland

and

Herzog)

Single technique -HVLAT baseline-intervention SC +76% -HVLAT baseline-final rest SC +12.9% - HVLAT vs. sham SC +10.22%

NO MAN unknown

Perry J. et al. (2008)

a-symptomatic

subjects

Unilaterally grade III osci llatory mobilization 2 Hz left L4-L5 facet joint

3 times, 1 min application with 1 min interval.

-L side during intervention SC +13.47%

YES MOB unknown

Jowsey P. et al. (2010)

a-symptomatic

subjects

Grade III rotatory postero-anterior intervertebral T4 mobilization 0.5 Hz

in 3 directions: postero-anterior, cranio-caudaal and lateral.

3 sets of 1min, with 1min rest between sets.

-SC post-treatment R

side 16.85%

YES trend

towards bilateral

changes

MOB unknown

La Touche R. et al. (2012) Chronic craniofacial pain

Passive anterior-posterior C0-C3 cervical mobilization at 0.5 Hz

3 intervals in 2 weeks of 3 times 2min mobilization,

with 30sec rest in between.

-VAS -41.7% or 29.13mm maintained intersession -PPT masseter +64%-

+77% / temporalis +38%-+59% / cervical +47%-+79% maintained intersession -SC +83.75% not maintained intersession - BR +10.8% not maintained intersession - HR +6.06% not maintained

intersession

NO MOB VAS-PPT maintaind intersession measured

up to 2 weeks SC-BR-HR reversed after each session

4 3

Sillevis R. et al. (2010)

Chronic cervical pain

High velocity mid-range postero-anterior force T3-T4 segment in supine position (technique Hartman)

[48]

Single technique -sham group mean constriction R eye post-1 4.28mm and post-2 3.89mm

Unknown/ Unilateral Measure-

ments

MAN unknown

Budgell B. et al.

(2001)

a-symptomatic

subjects

C1 supine cervical rotary HVLAT

Single technique -HR decline -3.36 BPM -HRV absolute LF +67.9/normalized LF +6.7/LF-HF +0.43

Inapplicable MAN unknown

Roy R. et al.(2010)

Acute low back pain

HVLAT lumbar roll L5 in side posture

Single technique -ST ipsilateral side 0.66ºF warmer compared to sham

YES MAN unknown

Budgell B. et al.

(2006)

a-symptomatic

subjects

HVLAT cross-bilateral and a combination adjustment T1-T4

Multi technique, 1 session

-HRV absolute LF +79.5/normalized LF +6.41/LF-HF +0.348

Inapplicable MAN unknown

Soon B. et al. (2010) Passive oscillatory 2 Hz grade III unilateral postero-anterior mobilization left C5-C6 segment (Maitland)

3 periods of 1 minute applications, resting period of 1 minute

-PPT C5-C6: none

Inapplicable MOB unknown

Mohammadian P. et

al. (2004)

a-symptomatic

subjects

15 minute short-lever pre-stressed, high-velocity, low-amplitude sustained thrust on thoracic vertebral subluxation sites

15 minute multiple short lever pre-stressed HVLAT

-mean values decrease hyperalgesia and allodynia -VAS spontaneous decrease (no percentages or absolute numbers are reported)

Not

reported

MAN unknown

Moulson A. et al.

(2006)

a-symptomatic

subjects

Sustained natural apophyseal glides (SNAG) C5-C6 intervertebral joint and simultaneously turned their head to the right. (Mulligan, 1999)

3 times cervical rotation

-pre-treatment compared with treatment phase SC 0.131 µmho (treatment vs. control) and SC 0.095 µmho (treatment vs. sham) -pre-treatment compared with post-

treatment phase SC 0.009 µmho (treatment vs. control) and SC 0.108 µmho (treatment vs. sham) -No percentages are reported

NO MOB unknown

*= Only significant results are listed MAN=manipulation MOB=mobil ization L=left R=right CBF=cutaneous blood flow SC=skin conductance ST -skin temperature HR=heart rate BR=breathing rate PPT=pressure pain thresholds VAS=Visual Analog Scale HRV=heart rate variabil ity LF=low frequency HF=high frequency AUC=area under curve MAX=max imum MIN=minimum HVLAT=high velocity low amplitude thrust (manipulation) BPM=beats per minute

4 4

5.6 Synthesis of results

The overall quality of the included studies is fair till good; the majority received

6-8/10 points on the PEDro scale and is categorized as good quality. SC

[113,159,123,122,80,91,111] and BR [91] increased significantly following spinal

manipulation or mobilization. 2 of the 3 studies confirmed a significant increase

in PPT [159,91]. Not consistent results are found for ST. Studies found no

significant effects in ST between intervention and sham group [91,134,111]. One

study reported significant ST effects between intervention and control group [159].

Except one study [150] VAS scores decreased significantly when intervention is

compared to control group [159,91,109] and 2 of the 4 studies found a significant

decrease of VAS scores between intervention versus sham group [91,109]. No

significant effects are reported on TPT [159], cutaneous blood flow [109] and

pupillary reactions [150]. For HR are inconsistent and contradictory effects

reported [18,20,91]. Almost all significant effects were excitatory for SNS in nature.

An increase of SC, PPT, BR, HR, changes in HRV and a decrease of ST and

VAS scores. Only Budgell et al.(2006) reported following a C1 HVLAT a

decrease in HR [20]. For VAS scores and PPT are maintained (up to 2 weeks)

results described [91]. Reversed, not maintained inter-session changes in SC, BR

and HR are reported [91]. Except one study [91] short-term or immediate effects

are measured. There is no solid evidence that neurovegetative effects persist

following spinal manipulation or mobilization. No concrete differences in the

magnitude of effects are found between symptomatic versus a-symptomatic

subjects. Reports on side specific reactions are inconsistent. Due to the unequal

distribution of the number of mobilization repetitions, number of sessions,

different measurement methods and treatment locations, it is not possible to

make concrete statements which technique is superior.

4 5

6. Discussion

To answer the primary research question; Which significant changes in

neurovegetative physiological parameters occur after manual spinal manipulation

and mobilization of symptomatic and a-symptomatic adults in manual therapy,

chiropractic or osteopathic medicine? the literature review included 13 fair to

high quality RCTs [113,159,123,122,80,91,150,18,134,20,154,109,111]. 11 of the 13 included

studies established a significant change in neurovegetative outcome following a

spinal manipulation or mobilization compared to control or sham treatment

[113,159,123,122,80,91,18,134,20,109,111]. SNS responses are demonstrated by measures

of different physiological parameters, but mostly SC, ST and pain associated

SNS reactions (VAS scores and PPT). The included studies measured

neurovegetative modulated physiological parameters. Outcome measures are

SC, ST, PPT, TPT, VAS scores, CBF, BR, HR, HRV and pupillary reactions. All

except one study [20] report effects due to sympathetic excitation

[113,159,123,122,80,91,150,18,134,154,109,111].

Inconsistent side specific changes are reported by SC. Perry et al. [122] describe

a significant side specific, unilateral effect during intervention and Jowsey et al.

[80] describe a significant side specific, unilateral effect post-intervention.

According to the authors the side specific effects are due to the oscillatory

nature of the technique. This is in contradiction with the findings of La Touche et

al. [91] and Soon et al. [154] who found no side specific effects by oscillatory

techniques. A study in 2011 Perry et al. reported that further group analysis

revealed that side specific changes are not dependent on closing or opening of

the joint [123]. There were no significant differences p=0.76 between the opening

and closing facet joint and sympathetic effects. Analysis has shown that side

specific changes are not dependent on the unilateral nature of the technique,

because similar unilateral techniques are used in other studies with no side

specific results. Findings of Lovick [96], Wright [178], Zusman [187] and Bialosky [10]

support a more general bilateral central response to a local spinal applied

technique. Findings suggest that sympathetic excitation is mediated via the

dPAG in the midbrain, through neural descending pathways. Manipulation and

mobilization of the spine stimulates capsule, muscle, tendon and connective

4 6

tissue receptors which are capable of directly or indirectly activate dPAG

mechanisms [159,37,126,147]. Some authors believe that side specific effects are

possible by specific mediation within the dPAG reactions [159,151]. They report that

dPAG has a somatotopic distribution and can centrally generate side specific

responses. Mouton et al. examined dPAG in cats and saw that dPAG regions are

modulated in medullary control nuclei with either unilateral or bilateral

anatomical projections [112]. Other researchers report local biomechanical

explanatory models for side specific changes [159,88,37]. Activation of local

sympathetic fibers is possible due to the unilateral vertebral movement caused

by spinal manipulation and mobilization. This local biomechanical theory is

inconsistent with bilateral findings in studies which uses similar unilateral spinal

manipulation and mobilization techniques and reports bilateral findings. The

unilateral nature of a spinal technique is questionable. Anterior-posterior,

posterior-anterior and rotatory techniques stress the ipsilateral facet joint and

indirectly also the heterolateral facet joint. Side specific effects are not

consistent and cannot be explained by type of technique or oscillatory nature.

About the exact neurophysiological processes and pathway is debated.

SC has been proposed as a valid method to investigate SNS responses for

outcome greater than 4.6% change from baseline [123]. Besides Moulson et al.

[111] (no percentages reported), all studies measure a greater effect than 4.6%

compared to baseline. All the studies measure SC at the hands (palmar index

and middle finger) and the feet (second and third toes). Because sudomotor

neurons distribution is skin type and localisation dependent, it is not possible the

compare hand SC outcomes with feet SC outcomes [74]. In the under extremity

the mobilization techniques increased SC 10.6-13.47% [113,122]. The manipulation

technique increased SC 76% [123]. This seems to be in favour of the manipulation

technique. In the upper extremity SC varies between a 10.56% and 83.75%

increase [80,91]. This consistent with previous studies performed on SC [23,124,153].

Sterling et al. used a different measurement technique for SC; this makes it

impossible to compare the values [159]. Previous studies used data analysis using

AUC-MAX and MIN SC values to illustrate results [23,171,172]. However this

process has been statistically questioned [173]. In the study of Moulson et al. no

SC percentages are reported, so according to Perry et al. (2011) no conclusions

4 7

can be drawn about the validity of the measurement [111]. All spinal techniques of

the upper extremity are mobilizations, so no comparison can be made between

manipulation and mobilization techniques. The high percentages after

mobilization (83.75%) in the study of La Touche et al. are a outlier and probably

explained by a longer treatment session [91]. 3 times, 2 minutes mobilization

compared to 3 times, 1 minute mobilization in most studies. Several studies

examined the relationship between duration, dose of SMT and the SNS activity

[23,155]. Results of studies demonstrated that frequency and duration of treatment

time has a significant effect on the response of SC and ST [23,155]. Some

researchers cautioned the uses of SC measurements on the palm of the hands

[144,34,53]. They say that the SC on the palm of the hands is solely controlled by

psychological and emotional centres and may measure only a psycho-emotional

reaction. The SC on the palm of the hands is regulated by numerous control

centres in the central nervous system [144,34,53]. This psycho-emotional reaction

causes an outcome inaccuracy and may be the reason why some sham

treatments have significant effects on SC. Significant changes in sham group in

the study of Perry et al.(2008) following McKenzie exercises can be explained by

active nature of the exercises [122]. The exercises cause a vertical movement of

the heart and as reaction altered SNS activity, cardio-vascular and orthostatic

changes [153].

The majority of the included studies describe no significant difference for ST

[91,134,111]. This is consistent with previous studies of Chiu and Wright [23] and

Peterson et al. [124]. They have identified that ST is often smaller and more

inconsistent compared to SC. Thermometric measures of ST is a reliable and

valid manner for measuring the vascularization in the cutaneous skin [114,120].

Owens et al. reported that, for an accurate and reproducible measurement, an 8-

16 minute stabilization period and a stable room temperature 22ºC (±1.0ºC) is

needed [120]. A guideline from Chui and Wright describe that the room

temperature and humidity needed to be constant for all experiments varied by a

maximum of 2% [23]. All 4 studies controlled temperature [91,134,111,159], only 2 of

the 4 studies controlled humidity [159,111]. In 2 studies temperature is reported,

21.95ºC and 25ºC [91,134]. The room temperature in the study of La Touche et al.

(25ºC) does not match the guideline which requires 22ºC [91]. Jänig et al.

4 8

describe that activity of skin vasoconstrictor neurons are dependent on

temperature [68]. Because of the room temperature differs in the studies, it is

possible that the sudomotor neurons react physiological differently. Evidence

indicates that ST reactions are dependent on body mass index and age. Dufour

et al. demonstrated that older subjects and middle-aged subjects have a higher

ST than younger subjects [33]. This is in contrast to a study of Wilson et al. who

describe an inability to prevent heat loss via the skin by cutaneous

vasoconstrictor dysfunction by older subjects [176]. In the study of Roy et al.

participant characteristics significant differ between groups in age, weight and

BMI [134]. This makes it hard to draw statistically correct conclusions. La Touche

et al. described group characteristics in age and gender, no group data abou t

weight or BMI is reported [91]. The other 2 studies performed a within subjects

design [159,111]. Roy et al. used measurements in the local ST direct after a spinal

technique can be through heat transfer of the hand of the researcher [134]. It is

also possible that direct ST reactions after a spinal technique are a result of a

reactive hyperemia that is caused by compression of local tissues. 2 of the 4

studies uses mobilization movements of the head compared to a no movement

sham application [159,91]. Skin vasoconstrictor neurons are centrally mediated and

are responsive for baroreceptor reflexes, cardiovascular reflexes, respiratory

reflexes and changes of body position [66]. Evidence demonstrated that vestibular

stimulation (movement of head) can elicit cardiovascular reflexes [179,180,181,182].

These cardiovascular reflexes can influence skin vasoconstrictor neurons by

head movements. Yates et al. described an inhibitory vestibule-sympathetic

reflex mediated by neurons in the ventrolateral medulla [179,180,181,182]. The

neurons in the ventrolateral medulla respond to vestibular stimuli, but also on

carotid sinus stimulation. Suggesting a role in cardiovascular regulation. Low-

amplitude accelerations of the head can produce responses in heart rate, with

the latency of the response prolonged in subjects with vestibular dysfunction

[130]. Additionally, there is evidence from animals studies with cats that cervical

mechanoreceptors stimuli interacts in an antagonistic manner with input from the

vestibulum to modify the activity of the SNS [16]. Because skin vasoconstrictor

neurons differ according type, localization of skin and the section of the vascular

bed they innervate, studies results on different body locations cannot be

compared [64,185]. Roy et al. [134] measured paravertebral and in other studies the

4 9

hands [159,91,111]. On the exact physiological reaction of blood vessels is debated.

Perry et al. (2008) [122] suspect a supra-spinal mediation from the ventral

periaqueductal grey matter (vasoconstriction) and the dorsal periaqueductal grey

matter (vasodilatation) [185,122]. Other possible theories are, release of cytokines

and pro- and anti-inflammatory mediators, immunologic reactions and neurologic

neurovegetative effects. From the included studies we cannot draw conclusions

regarding long-term results.

There is limited evidence concerns visceral reactions following spinal

manipulation or mobilization. 3 of the 13 studies measured and reported

significant visceral changes [18,20,91]. Differences are seen in HR, BR and HRV.

Surprisingly there are contradictory results following upper cervical treatment. La

Touche et al. [91] report a significant increase of HR (+6.06%) and Budgell et al.

(2001) [18] demonstrated a significant decline of HR (-3.36). This could be

explained by the nature and duration of the technique. La Touche et al. [91]

performed a 3 times, 2 minutes C0-C3 mobilization and Budgell et al.(2001) [18]

did a single C1 HVLAT in 5 seconds. 6 minutes of repetitive C0-C3 mobilizations

evokes more cervical proprioception and vestibular-sympathetic reflex stimuli,

than a single HVLAT. About the exact neurophysiological pathway is debated. Or

the manipulation and mobilization technique stimulate local sympathetic fibers

from superior cervical ganglion or does it influences the cervico-trigeminal

complex, vestibular-sympathetic reflexes and supra-spinal structures is not

known. Both studies of Budgell et al. saw significant changes in HRV [18,20]. With

an increase of sympathetic outflow in direction of the heart and a shift in balance

between parasympathetic and sympathetic cardiac output in favour of the

sympathetic component. The same outcome in HRV is surprisingly, because in

the first study C1 is manipulated and in the second study T1-T4. Neuro-

anatomical is suspected that a C1 region influences the PSNS and the T1-T4

region affects the SNS. Possible explanations of results may be supra-spinal

mediating, vestibule-sympathetic reflexes (C0-C3) and hemodynamic

alternations due to the thoracic thrust (thoracic thrust compression has direct

mechanical effect on the heart and great blood vessels, influence on blood

pressure and cardiovascular mechanoreceptors).

5 0

The majority of the studies reported significant differences in PPT and VAS

between intervention and sham or control group [159,91,109]. These positive

foundings are similar as previous studies [171,44,121,152]. Nociceptic mechanisms of

pain are known to be complex, involving bi-directional interactions between

peripheral nociceptors, spinal cord and supra-spinal centers [10,12,116].

Nociception is centrally regulated by, dorsal horn neurons and dPAG activity

[92,93,164]. Also local nociceptors threshold and local mediators play an important

role in processing from nociception. The SNS has the possibility to influence

nociception on a peripheral, local or central level. Evidence has shown that

spinal manipulation and mobilization has an effect on the descending pain

inhibitory systems upon short-term hypoalgesic effect [159,91,109,147,178,171].

Vincenzino et al. reported a hypoalgesic affect following a cervical manipulation

[169]. The hypoalgesia was significantly correlated with sympathoexcitation

[169,171]. Skyba et al. supported this theory in an animal study; mobilization of a

hyperalgesic knee joint in rats had a hypoalgesic effect [152]. This effect could be

possible due to descending serotoninergic or noradrenergic inhibitory

mechanisms via corticospinal pathways from the dPAG [96, 9,178,187]. A

noradrenergic effect is most likely because, this dPAG neurotransmitter is more

effective in inhibiting mechanical nociception than thermal nociception, which is

serotoninergically mediated [89,90]. This explains the significant difference in PPT

and the non-significant difference in TPT in the study of Sterling et al. [159]. These

reports are consistent with previous studies which found significant changes in

PPT and no significant changes in TPT following manipulation or mobilization

[171,172,121]. Studies have shown that manipulation or mobilization might be the

perfect stimulus for dPAG regulated nonopioid hypoalgesia and

sympathoexcitatory effects [171,172,10,159,91]. Or these effects segmental or extra-

segmental occur is still debated. Some included studies measured bilateral

effects in the related segment [159,123,113,122,111] however other studies have

shown to changes values distal to the treated segment; that is, manipulation of

the thoracic spine has positive effects on arm or cervical pain [80,109] and cervical

application influences cardiac outcomes and face [18,91,20]. Unfortunately the

studies which found segmental differences only measured in the related

segmental [159,123,113,122,111], hereby no conclusions can be drawn about extra-

segmental effects. Most of the segmental related effects are bilaterally, which

5 1

assumes that these are probably extra-segmentally coordinated. Also is the

somatic segmental distribution more accurate segmented than the

neurovegetative or SNS segmental distribution. Because of the difference in the

segmental distribution it is difficult to draw conclusions.

Immediately hypoalgesia effects can also be described to dorsal horn modulat ion

[9,10,14]. Researchers suggest that manipulation inhibit pain at the dorsal horn

through alternations of the neuroplastic changes [14]. They think that a

manipulation and mobilization stimulus closes the ‘gate’ for C-fiber mediated

nociception [159,126,171,169,178].

Statistically significant changes are dependent of the minimal clinically important

difference (MCID). The MCID is the smallest change in outcome perceived as

important and beneficial for the patients management [175]. Todd et al. reported

that a minimal VAS change of -13mm is clinically significant [163]. Bird et al. say

that the minimal clinically significant change in VAS depends on the baseline

VAS of the participant [11,32]. They have calculated that a change of -13mm in

VAS would be clinically significant for a baseline VAS <34mm, a change of -

17mm VAS for a baseline VAS between 34mm and 67mm and a change of -

28mm VAS for a baseline VAS >67mm [11,32]. According to Todd and Bird et al.

the VAS changes in the study of Sterling et al. [159] (3.35mm) has no clinical

value. La Touche et al. [91] found a change of 29.13mm and is clinically

important. Mohammadian et al. reported no mean or absolute VAS values, only a

bar graph [109]. According to the bar graph the VAS decreases +/-15mm (45mm-

30mm) following spinal manipulation. According the opinion of Todd et al. it is a

significant decrease (>13mm) and in opinion of Bird et al. it is not (<17mm).

3 included studies examined PPT. 2 studies found significant differences.

Sterling et al. [159] found a 22.55% increase of PPT and La Touche et al. [91]

found an increase of 64-77% for masseter, 38-59% for temporalis and 47-79%

for all cervical PPT point. Significant results are consistent with previous studies.

Vicenzino et al. [171] reported an increase of 25%, Yeo and Wright [183] an

increase of 23% following an accessory ankle dorsiflexion mobilization, Moss et

al. [110] an increase of 27.3% following an anterior-posterior mobilization of

osteoarthritic knee joints and Paungmali et al. [121] an 15.4% increase after a

mobilization with movement of the elbow. The increase found by La Touche et al.

5 2

clearly exceeds the other studies [91]. La Touche et al. performed 3 treatment

sessions in 2 weeks of 3 times 2 minutes C0-C3 mobilization [91]. The duration

and number of treatment sessions is similar as in the studies of Paungmali et al.

[121] and Moss et al. [110]. La Touche et al. [91] found a maintained carry-over

effect of PPT and VAS between the sessions; this is not found in the study of

Moss et al. [110]. A explanation could be that Paungmali et al. [121] and Moss et al.

[110] treated peripheral joints and La Touche et al. [91] performed a mobilization

technique on a cervical vertebrae, which has a higher density of proprioceptors

[102,132] and a greater central neurological connection (cervico-trigeminale

interaction and different specialist tracts) [91,85,13]. Previous research has

demonstrated the reliability and validity of PPT measures in pain-free individuals

[117]. Also a study of Ohrbach et al. suggest PPT-validity between groups data of

pain vs. no-pain subjects [119]. Findings in a study of Bird et al. and Gallagher et

al. suggest that a change of at least 15% in PPT is needed for a clinically

significant difference [11,40]. Both studies, Sterling et al. and La Touche et al.

exceed 15% and have a clinically significant effect [159,91]. Prior to the study of

Sterling et al. the reliability of the PPT measurement was determined on 10

subjects (5 male and 5 female) [159]. The intra-examiner reliability was excellent

with intraclass correlation coefficients of 0.923 for the right and 0.912 for the left

articular pillars of C5-C6 vertebral segment. Standard error of measurements

(SEM) was 1.41 kPa for the right and 1.62 kPa for the left side. Indicating small

variability in mean PPT values.

Regarding to SC, ST and CBF, no minimal clinically important difference or

clinically significant values are published. As result it is not clear if the found

differences in SC, ST and CBF are clinically important for our practice.

It is unknown whether neurovegetative changes provoke a significant reaction in

the body or produce lasting results. There is limited evidence on long-term

effects. 1 included study measured inter-session carry-over effects over 2 weeks

[91]. Only PPT and VAS scores had a maintained intersession effect and changes

in SC, BR and HR reversed after each session. Vincenzino et al. reported a

22mm pain reduction on the VAS score 24 hours after cervical manipulation on

lateral epicondylalgia [169].

5 3

By far the majority of the included interventions provoked sympathoexcitatory

responses. This reaction was irrespective of the region of the spine. This finding

is consistent with the findings of the majority of the high-quality RCTs. This

review revealed convincing evidence that sympathetic reactions can be evoked

by spinal manipulation and mobilization techniques and is excitatory of nature.

Andreassi et al. describe that there might be a difference in sympathetic

response between a-symptomatic and symptomatic subjects. They describe a

sympathetic ‘rebound effect’ by symptomatic subjects [2]. Pain changes the

activity of the SNS and an increased SNS due to pain returns to levels below

their pre-stimulus values following spinal manipulation and mobilization [2]. Other

studies report no differences in SNS changes following spinal manipulation and

mobilization between a-symptomatic and symptomatic subjects [10,9]. Probably it

is dependent on the type of lesion and how the SNS is involved. Also a-

symptomatic participants may have spine dysfunctions that could affect

neurophysiological processes [9,126]. Future studies on a large scale in various

types of symptomatic participants are necessary in order to draw concrete

conclusions.

It is not possible to answer the secondary research question; Is there a

difference between manual spinal manipulation and mobilizat ion on

neurovegetative physiological parameters of symptomatic and a-symptomatic

adults in manual therapy, chiropractic or osteopathic medicine? This because of

the differences in duration, number of sessions, location of application on the

spine and measurement methods. Also not every physiological parameter is

examined following spinal manipulation and mobilization. As result, a comparison

between spinal manipulation and mobilization for these parameters is not

possible. Results in BR and PPT are solely reported following spinal mobilization

[91,159,154] and pupillary [150] and HRV changes [18,20] are solely measured after

spinal manipulation. Regarding to SC changes it appears that manipulation [123]

have better results than mobilization [113,159,122,111,91], but on account of a single

study it is not advisable to draw conclusions. Given the overall good results in

the study of La Touche et al. it seems like multiple sessions for some

physiological parameters (PPT-VAS) have beneficial effects [91]. Also the

duration of the application seems to be of interest. Studies demonstrated a

5 4

relationship between SNS results and duration and dose [23,155]. They reported

that frequency and duration of application time has a significant effect on the

response of SNS. Also here the results should be handled with caution because

there is limited evidence on multiple- or inter-session neurovegetative effects.

General, due to the unequal distribution of the number of mobilization

repetitions, number of sessions, different measurement methods/locations and

treatment regions, it is not possible to make concrete statements which

technique is superior.

Despite the evidence, neurophysiological mechanisms are still relatively unclear.

Future research should consider investigating multi -technique, inter-session

effects on different populations. Multi-techniques settings are more therapeutic

representative and results have practical relevance. Inter-session or long-term

measurements give valuable information about time related effects. Evidence

showed that some effects are maintained and other are only short -term [91].

Knowledge about time related effects has practical importance and provides

information about the therapeutic possibilities. The majority of the studies

included have a sample size less than 25 and primary a-symptomatic subjects.

Due to the low number of subjects the significant ‘power’ of the results is

questionable. There is a need for studies with a high ‘power’, sufficient number

of a-symptomatic and selective symptomatic subjects. All except one study

measure neurophysiological, short-term or immediate effects of a single

technique which makes the long-term effects and clinical importance hard to

predict. Effects of multi-technique sessions and multiple sessions are to scare to

drawn concrete conclusions. Multi-technique and multi-session, high-quality

study designs need to be done to measure real clinical importance and

applicability. During the last years there is a paradigm shift in spinal

manipulative therapy and therapists search for scientific answers to

neurophysiological effects due to spinal manipulation. Answers to these

questions are important since spinal manipulations and mobilizations are a

multidisciplinary non-invasive technique, worldwide used and economically

interesting. There is a need of high quality, large sample RCTs on selective

symptomatic subjects with a multi-technique or intersession design. Only than is

a representative therapeutic outcome measurable of strong clinical importance.

5 5

Results will provide important information for all therapists which lead to more

understanding about neurophysiological effects following spinal manipulation or

mobilization what will in the end benefit patients.

Limitations

The results of this literature review should be interpreted with some limitations.

First, the goal of the database search is inclusion current studies. No studies

before 2000 are included in this review. The review may have missed potentially

relevant studies published prior to 2000. Second, this review searched solely in

MEDLINE and Cochrane Library to find selective, high quality studies. A search

in other databases like Google Scholar, EMBASE and CINAHL will result in more

studies. Third, this review may miss some relevant studies despite the broad

search with multiple MeSH-term, adding more MeSH-term probably provide new

studies. Also this study selected only studies in the English language, which may

have excluded some relevant studies. However this is not likely, because the

majority of the RCTs are published in English. Finally, this review is conducted

by a single researcher, search and study analyses performed by 2 or more

researchers provide probably a more accurate and broad vision on this topic.

5 6

7. Conclusion

In conclusion; this review provides evidence that spinal manipulation and

mobilization evoke significant neurovegetative reactions in SC [159,123,122,80,91,111],

PPT [159,91], VAS [91,109], local allodynia and hyperalgesia [109], BR [91], HR [91,18]

and HRV [18,20]. Inconsistent results are found for ST [134,111,109,159,91] and no

significant differences are found for TPT [159], cutaneous blood flow [109], blood

pressure [20] and pupillary reactions [150]. There is no concrete difference in

outcome and efficiency between different types of manual spinal techniques and

between a-symptomatic and symptomatic subjects. Some parameters are

consistent, but in other parameters there is an inconsistency in neurovegetative

effects between studies following spinal manipulation or mobilization. Due to the

unequal distribution of the number of mobilization repetitions, number of

sessions, different measurement methods and treatment locations, it is not

possible to make clear statements which technique is superior. Despite the

evidence, neurophysiological mechanisms are still relatively unclear.

Funding sources and potential conflicts of interest The author declares to have received no funding sources or conflicts of interest for

this review.

Author contributions

All process elements; literature search, analyses and writing are performed by the

author.

Author Details

Koen Groot Zwaaftink is Osteopath at an Osteopathic clinic in Albergen (The

Netherlands). He was awarded with a Bachelor degree in Physiotherapy in 2004

from the University of Applied Sciences of Enschede (The Netherlands). He earned

his Diploma in Osteopathy (D.O.) in 2009 from the International Academy of

Osteopathy (Gent, Belgium). From 2010 he is a teacher in Clinical Neurology and

Cranial Nerves at the International Academy of Osteopathy.

5 7

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2. Andreassi John L. Psychophysiology: human behaviour and physiological response. 3rd ed. London: Erlbaum; 1995. p. 166-370. [Chapters 9-16].

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160. Sterling, Michele, et al. "Cervical lateral glide increases nociceptive flexion reflex

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161. Symons, Bruce P., et al. "Reflex responses associated with activator treatment."

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162. Teodorczyk-Injeyan, Julita A., H. Stephen Injeyan, and Richard Ruegg. "Spinal

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163. Todd, Knox H., and Joseph P. Funk. "The minimum clinically important difference

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164. Torebjörk, H. E., L. E. Lundberg, and R. H. LaMotte. "Central changes in

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165. Tullberg, Tycho, et al. "Manipulation does not alter the position of the sacroiliac

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6 7

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6 8

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6 9

9. List of Abbrevations BP – Blood Pressure

BPM – Beats Per Minute

BR – Breathing Rate

CBF – Cutaneous Blood Flow

CT- Cutaneous Skin Temperature

dPAG – dorsal Peri-Aquaductal Gray Matter

fMRI - functional Magnetic Resonance Imaging

HR – Heart Rate

HRV – Heart Rate Variability

HVLA – High Velocity Low Amplitude

HVLAT – High Velocity Low Amplitude Thrust (Manipulation)

MRI - Magnetic Resonance Imaging

OMT – Osteopathic Manipulative Treatment

PPT – Pressure Pain Threshold

PSNS – Parasympathetic Nervous System

RR – Blood Pressure

SC – Skin Conductance

SMT – Spinal Manipulative Treatment

SNAG – Sustained Natural Apophyseal Glides

SNS – Sympathetic Nervous System

ST – Skin Temperature

TENS - Transcutaneous Electrical Nerve Stimulation

TPT – Thermal Pain Threshold

VAS – Visual Analoge Scale

7 0

10. Appendices

10.1 Appendix 1: Specific search strategy Search terms and Medical Subject Headings (MeSH) Database Results

Spinal Manipulation OR Osteopathic Manipulative Treatment OR

Manual Therapy OR Chiropractic Manipulation AND Sympathetic

Nervous System

Spinal Manipulation OR Osteopathic Manipulative Treatment OR

Manual Therapy OR Chiropractic Manipulation AND Parasympathetic

Nervous System

Spinal Manipulation OR Osteopathic Manipulative Treatment OR

Manual Therapy OR Chiropractic Manipulation AND Enteric Nervous

System

Spinal Manipulation OR Osteopathic Manipulative Treatment OR

Manual Therapy OR Chiropractic Manipulation AND Autonomic

Nervous System

Spinal Manipulation OR Osteopathic Manipulative Treatment OR

Manual Therapy OR Chiropractic Manipulation AND Viscera

Spinal Manipulation OR Osteopathic Manipulative Treatment OR

Manual Therapy OR Chiropractic Manipulation AND Visceral Pain

Spinal Manipulation OR Osteopathic Manipulative Treatment OR

Manual Therapy OR Chiropractic Manipulation AND Pain AND

Sympathetic Nervous System

Spinal Manipulation OR Osteopathic Manipulative Treatment OR

Manual Therapy OR Chiropractic Manipulation AND Blood Supply

Spinal Manipulation OR Osteopathic Manipulative Treatment OR

Manual Therapy OR Chiropractic Manipulation AND Vasomotor

System

Spinal Manipulation OR Osteopathic Manipulative Treatment OR

Manual Therapy OR Chiropractic Manipulation AND Blood Flow

Velocity

Spinal Manipulation OR Osteopathic Manipulative Treatment OR

Manual Therapy OR Chiropractic Manipulation AND Piloerection

Spinal Manipulation OR Osteopathic Manipulative Treatment OR

Manual Therapy OR Chiropractic Manipulation AND Sweat Glands

Spinal Manipulation OR Osteopathic Manipulative Treatment OR

Manual Therapy OR Chiropractic Manipulation AND Skin Temperature

MEDLINE

MEDLINE

MEDLINE

MEDLINE

MEDLINE

MEDLINE

MEDLINE

MEDLINE

MEDLINE

MEDLINE

MEDLINE

MEDLINE

MEDLINE

14

5

0

37

1

0

5

21

0

9

0

0

9

Spinal Manipulation OR Osteopathic Manipulative Treatment (OMT)

OR Manual Therapy OR Chiropractic AND Sympathetic Nervous

System1

Cochrane

Library

7 1

Spinal Manipulation AND Sympathetic Nervous System

OMT AND Sympathetic Nervous System

Manual AND Sympathetic Nervous System2

Chiropractic AND Sympathetic Nervous System5

Spinal Manipulation OR Osteopathic Manipulative Treatment (OMT)

OR Manual Therapy OR Chiropractic AND Parasympathetic Nervous

System1

Spinal Manipulation AND Parasympathetic Nervous System

OMT AND Parasympathetic Nervous System

Manual AND Parasympathetic Nervous System2

Chiropractic AND Parasympathetic Nervous System5

Spinal Manipulation OR Osteopathic Manipulative Treatment (OMT)

OR Manual Therapy OR Chiropractic AND Enteric Nervous System1

Spinal Manipulation AND Enteric Nervous System

OMT AND Enteric Nervous System

Manual AND Enteric Nervous System2

Chiropractic AND Enteric Nervous System5

Spinal Manipulation OR Osteopathic Manipulative Treatment (OMT)

OR Manual Therapy OR Chiropractic AND Autonomic Nervous

System1

Spinal Manipulation AND Autonomic Nervous System

OMT AND Autonomic Nervous System

Manual AND Autonomic Nervous System2

Chiropractic AND Autonomic Nervous System5

Spinal Manipulation OR Osteopathic Manipulative Treatment OR

Manual Therapy OR Chiropractic AND Visceral1-3

Spinal Manipulation AND Visceral

OMT AND Autonomic Visceral

Manual AND Visceral2

Chiropractic AND Visceral5

Spinal Manipulation OR Osteopathic Manipulative Treatment OR

Manual Therapy OR Chiropractic AND Visceral Pain1

Spinal Manipulation AND Visceral Pain

OMT AND Autonomic Visceral Pain

Manual AND Visceral Pain2

Chiropractic AND Visceral Pain5

Spinal Manipulation OR Osteopathic Manipulative Treatment OR

Manual Therapy OR Chiropractic AND Pain1

Spinal Manipulation AND Pain AND Sympathetic Nervous System

OMT AND Pain AND Sympathetic Nervous System

Manual AND Pain AND Sympathetic Nervous System2

Chiropractic AND Pain AND Sympathetic Nervous System5

Spinal Manipulation OR Osteopathic Manipulative Treatment OR

Manual Therapy OR Chiropractic AND Blood Supply1

Cochrane

Library

Cochrane

Library

Cochrane

Library

Cochrane

Library

Cochrane

Library

Cochrane

Library

Cochrane

Library

1

1

16

0

1

2

2

1

0

0

0

0

3

7

15

4

3

0

20

7

0

0

0

0

1

0

11

0

7 2

Spinal Manipulation AND Blood Supply

OMT AND Autonomic Blood Supply

Manual AND Blood Supply2

Chiropractic AND Blood Supply5

Spinal Manipulation OR Osteopathic Manipulative Treatment OR

Manual Therapy OR Chiropractic AND Vasomotor System1

Spinal Manipulation AND Vasomotor System

OMT AND Vasomotor System

Manual AND Vasomotor System2

Chiropractic AND Vasomotor System5

Spinal Manipulation OR Osteopathic Manipulative Treatment OR

Manual Therapy OR Chiropractic AND Blood Flow Velocity1

Spinal Manipulation AND Blood Flow Velocity

OMT AND Blood Flow Velocity

Manual AND Blood Flow Velocity2

Chiropractic AND Blood Flow Velocity5

Spinal Manipulation OR Osteopathic Manipulative Treatment OR

Manual Therapy OR Chiropractic AND Piloerection1

Spinal Manipulation AND Piloerection

OMT AND Piloerection

Manual AND Piloerection2

Chiropractic AND Piloerection5

Spinal Manipulation OR Osteopathic Manipulative Treatment OR

Manual Therapy OR Chiropractic AND Sweat Gland1-4

Spinal Manipulation AND Sweat Gland

OMT AND Sweat Gland

Manual AND Sweat Gland2

Chiropractic AND Sweat Gland5

Spinal Manipulation OR Osteopathic Manipulative Treatment OR

Manual Therapy OR Chiropractic AND Skin Temperature1

Spinal Manipulation AND Skin Temperature

OMT AND Skin Temperature

Manual AND Skin Temperature2

Chiropractic AND Skin Temperature5

Cochrane

Library

Cochrane

Library

Cochrane

Library

Cochrane

Library

Cochrane

Library

2

0

24

4

0

0

1

0

1

0

10

1

0

0

0

0

0

0

2

1

2

0

12

3

1. Cochrane Library, best specific results only 2 separate search terms inserted

2. Cochrane Library, “manual therapy” do not exist, searched with “manual”

3. Cochrane Library, “Viscera” term do not exist, searched with “visceral”

4. Cochrane Library, “Sweat Glands” do not exist, searched with “Sweat Gland”

5. Cochrane Library, “Chiropractic Manipulation” do not exist, searched with “Chiropractic”

7 3

10.2 Appendix 2: Specific search strategy / First study selection Search terms and Medical Subject Headings (MeSH) Database Results

Spinal Manipulation OR Osteopathic Manipulative Treatment OR

Manual Therapy OR Chiropractic Manipulation AND Sympathetic

Nervous System

[Excluded: 2 studies on preterm infants or children with cerebral palsy. 1

study because of medicinal uses, 2 study no spinal technique]

Spinal Manipulation OR Osteopathic Manipulative Treatment OR

Manual Therapy OR Chiropractic Manipulation AND

Parasympathetic Nervous System

[Excluded: 3 studies on preterm infants. 4 studies no spinal manipulation or

mobilization techniques]

Spinal Manipulation OR Osteopathic Manipulative Treatment OR

Manual Therapy OR Chiropractic Manipulation AND Enteric

Nervous System

Spinal Manipulation OR Osteopathic Manipulative Treatment OR

Manual Therapy OR Chiropractic Manipulation AND Autonomic

Nervous System

[Excluded: Duplicates 22 studies. 8 studies no manipulation or mobilization

technique. 2 studies on preterm infants ]

Spinal Manipulation OR Osteopathic Manipulative Treatment OR

Manual Therapy OR Chiropractic Manipulation AND Viscera

[Excluded: none]

Spinal Manipulation OR Osteopathic Manipulative Treatment OR

Manual Therapy OR Chiropractic Manipulation AND Visceral Pain

Spinal Manipulation OR Osteopathic Manipulative Treatment OR

Manual Therapy OR Chiropractic Manipulation AND Pain AND

Sympathetic Nervous System

[Excluded: 5 duplicates]

Spinal Manipulation OR Osteopathic Manipulative Treatment OR

Manual Therapy OR Chiropractic Manipulation AND Blood Supply

[Excluded: 2 duplicates. 3 diagnostic studies. 2 studies in Chinese

language. 12 studies no manipulat ion or mobilization technique]

Spinal Manipulation OR Osteopathic Manipulative Treatment OR

Manual Therapy OR Chiropractic Manipulation AND Vasomotor

System

Spinal Manipulation OR Osteopathic Manipulative Treatment OR

Manual Therapy OR Chiropractic Manipulation AND Blood Flow

Velocity

[Excluded: 3 duplicates. 1 study on medicinal uses. 4 studies no

manipulation or mobilization technique, 2 studies in Chinese]

Spinal Manipulation OR Osteopathic Manipulative Treatment OR

Manual Therapy OR Chiropractic Manipulation AND Piloerection

MEDLINE

Relevant

MEDLINE

Relevant

MEDLINE

MEDLINE

Relevant

MEDLINE

Relevant

MEDLINE

MEDLINE

Relevant

MEDLINE

Relevant

MEDLINE

MEDLINE

Relevant

MEDLINE

14

9

8

1

0

37

5

1

1

0

5

0

21

2

0

9

0

0

7 4

Spinal Manipulation OR Osteopathic Manipulative Treatment OR

Manual Therapy OR Chiropractic Manipulation AND Sweat Glands

Spinal Manipulation OR Osteopathic Manipulative Treatment OR

Manual Therapy OR Chiropractic Manipulation AND Skin

Temperature

[Excluded: 3 duplicates. 5 studies no manipulat ion or mobilization

technique]

MEDLINE

MEDLINE

Relevant

0

9

1

Spinal Manipulation OR Osteopathic Manipulative Treatment (OMT)

OR Manual Therapy OR Chiropractic AND Sympathetic Nervous

System1

Spinal Manipulation AND Sympathetic Nervous System

[Excluded: study duplicate]

OMT AND Sympathetic Nervous System

[Excluded: study duplicate]

Manual AND Sympathetic Nervous System2

[Excluded: 8 duplicates.4 studies no manipulation or mobilization

technique. 1 diagnostic study. 1 study on medicinal uses. 2 studies no

neurovegetative outcome]

Chiropractic AND Sympathetic Nervous System5

Spinal Manipulation OR Osteopathic Manipulative Treatment (OMT)

OR Manual Therapy OR Chiropractic AND Parasympathetic

Nervous System1

Spinal Manipulation AND Parasympathetic Nervous System

[Excluded: study duplicate]

OMT AND Parasympathetic Nervous System

[Excluded: 2 study duplicates]

Manual AND Parasympathetic Nervous System2

[Excluded: 2 studies no manipulation or mobilization technique]

Chiropractic AND Parasympathetic Nervous System5

[Excluded: study duplicate]

Spinal Manipulation OR Osteopathic Manipulative Treatment (OMT)

OR Manual Therapy OR Chiropractic AND Enteric Nervous System1

Spinal Manipulation AND Enteric Nervous System

OMT AND Enteric Nervous System

Manual AND Enteric Nervous System2

Chiropractic AND Enteric Nervous System5

Spinal Manipulation OR Osteopathic Manipulative Treatment (OMT)

OR Manual Therapy OR Chiropractic AND Autonomic Nervous

System1

Spinal Manipulation AND Autonomic Nervous System

[Excluded: 3 duplicates]

OMT AND Autonomic Nervous System

Cochrane

Library

Relevant

Relevant

Relevant

New studies

Cochrane

Library

Relevant

Relevant

Relevant

Relevant

New studies

Cochrane

Library

Cochrane

Library

Relevant

Total 18

1

0

1

0

16

0

0

0

Total 6

1

0

2

0

2

0

1

0

0

Total 0

0

0

0

0

Total 29

3

0

7

7 5

[Excluded:4 duplicates]

Manual AND Autonomic Nervous System2

[Excluded: 1 study no neurovegetative outcome. 14 studies no

manipulation or mobilization technique]

Chiropractic AND Autonomic Nervous System5

[Excluded: 2 duplicate. 1 study no manipulation or mobilization technique]

Spinal Manipulation OR Osteopathic Manipulative Treatment OR

Manual Therapy OR Chiropractic AND Visceral1-3

Spinal Manipulation AND Visceral

[Excluded: 4 duplicates. 2 studies with no neurovegetative outcome. 1

study before year 2000]

OMT AND Autonomic Visceral

Manual AND Visceral2

[Excluded: 2 duplicates. 3 studies with no neurovegetative outcome.15

studies no manipulation or mobilization technique]

Chiropractic AND Visceral5

[Excluded: 2 duplicates.4 studies with no neurovegetative outcome. 1 study

treatment technique unclear]

Spinal Manipulation OR Osteopathic Manipulative Treatment OR

Manual Therapy OR Chiropractic AND Visceral Pain1

Spinal Manipulation AND Visceral Pain

OMT AND Autonomic Visceral Pain

Manual AND Visceral Pain2

Chiropractic AND Visceral Pain5

Spinal Manipulation OR Osteopathic Manipulative Treatment OR

Manual Therapy OR Chiropractic AND Pain1

Spinal Manipulation AND Pain AND Sympathetic Nervous System

[Excluded: study duplicate]

OMT AND Pain AND Sympathetic Nervous System

Manual AND Pain AND Sympathetic Nervous System2

[Excluded: 6 duplicates. 2 study with no neurovegetative outcome. 3

studies no manipulation or mobilization technique. 1 study before year

2000]

Chiropractic AND Pain AND Sympathetic Nervous System5

Spinal Manipulation OR Osteopathic Manipulative Treatment OR

Manual Therapy OR Chiropractic AND Blood Supply1

Spinal Manipulation AND Blood Supply

[Excluded: 2 duplicates]

OMT AND Autonomic Blood Supply

Manual AND Blood Supply2

[Excluded: 22 studies no manipulation or mobilization technique. 5 studies

on medicinal bases. 1 diagnostic study. 1 prevalence study]

Chiropractic AND Blood Supply5

[Excluded: 2 duplicates]

Relevant

Relevant

Relevant

New studies

Cochrane

Library

Relevant

Relevant

Relevant

New studies

Cochrane

Library

Cochrane

Library

Relevant

Relevant

New studies

Cochrane

Library

Relevant

Relevant

Relevant

3

15

0

4

1

4

Total 30

3

0

0

20

0

7

0

0

Total 0

0

0

0

0

Total 12

1

0

0

12

0

0

0

Total 35

2

0

0

29

0

4

2

7 6

Spinal Manipulation OR Osteopathic Manipulative Treatment OR

Manual Therapy OR Chiropractic AND Vasomotor System1

Spinal Manipulation AND Vasomotor System

OMT AND Vasomotor System

Manual AND Vasomotor System2

[Excluded: 1 duplicate. 1 study before year 2000]

Chiropractic AND Vasomotor System5

Spinal Manipulation OR Osteopathic Manipulative Treatment OR

Manual Therapy OR Chiropractic AND Blood Flow Velocity1

Spinal Manipulation AND Blood Flow Velocity

[Excluded: 2 duplicates. 1 study no manipulation or mobilization technique.

1 study no neurovegetative outcome]

OMT AND Blood Flow Velocity

Manual AND Blood Flow Velocity2

[Excluded: all studies no manipulation or mobilization technique]

Chiropractic AND Blood Flow Velocity5

[Excluded:3 duplicates]

Spinal Manipulation OR Osteopathic Manipulative Treatment OR

Manual Therapy OR Chiropractic AND Piloerection1

Spinal Manipulation AND Piloerection

OMT AND Piloerection

Manual AND Piloerection2

Chiropractic AND Piloerection5

Spinal Manipulation OR Osteopathic Manipulative Treatment OR

Manual Therapy OR Chiropractic AND Sweat Gland1-4

Spinal Manipulation AND Sweat Gland

OMT AND Sweat Gland

Manual AND Sweat Gland2

[Excluded: 1 duplicate. 1 study no manipulation or mobilization technique]

Chiropractic AND Sweat Gland5

[Excluded no manipulation or mobilization technique]

Spinal Manipulation OR Osteopathic Manipulative Treatment OR

Manual Therapy OR Chiropractic AND Skin Temperature1

Spinal Manipulation AND Skin Temperature

[Excluded:3 duplicates. 1 study no manipulation or mobilization technique]

OMT AND Skin Temperature

Manual AND Skin Temperature2

[Excluded:2 duplicates. 12 studies no manipulation or mobilization

technique]

Chiropractic AND Skin Temperature5

[Excluded:4 duplicates]

New studies

Cochrane

Library

Relevant

New studies

Cochrane

Library

Relevant

Relevant

Relevant

New studies

Cochrane

Library

Cochrane

Library

Relevant

Relevant

New studies

Cochrane

Library

Relevant

Relevant

Relevant

New studies

2

Total 1

0

0

1

0

0

0

Total 19

4

0

0

12

0

3

0

0

Total 0

0

0

0

0

Total 3

0

0

2

0

1

0

0

Total 22

4

0

0

14

0

4

0

0

1. Cochrane Library, best specific results only 2 separate search terms inserted

7 7

2. Cochrane Library, “manual therapy” do not exist, searched with “manual”

3. Cochrane Library, “Viscera” term do not exist, searched with “visceral”

4. Cochrane Library, “Sweat Glands” do not exist, searched with “Sweat Gland”

5. Cochrane Library, “Chiropractic Manipulation” do not exist, searched with “Chiropractic”

7 8

10.3 Appendix 3: PEDro Scale and criteria

1. eligibility criteria were specified no yes where:

2. subjects were randomly allocated to groups (in a crossover study, subjects were randomly allocated an order in which treatments were received) no yes where:

3. allocation was concealed no yes where:

4. the groups were similar at baseline regarding the most important prognostic indicators no yes where:

5. there was blinding of all subjects no yes where:

6. there was blinding of all therapists who administered the therapy no yes where:

7. there was blinding of all assessors who measured at least one key outcome no yes where:

8. measures of at least one key outcome were obtained from more than 85% of the subjects initially allocated to groups no yes where:

9. all subjects for whom outcome measures were available received the treatment or control condition as allocated or, where this was not the case, data for at least one key outcome was analysed by “intention to treat” no yes where:

10. the results of between-group statistical comparisons are reported for at least one key outcome no yes where:

11. the study provides both point measures and measures of variability for at least one key outcome no yes where:

The PEDro scale is based on the Delphi list developed by Verhagen and colleagues at the Department of

Epidemiology, University of Maastricht (Verhagen AP et al (1998). The Delphi list: a criteria list for

quality assessment of randomised clinical trials for conducting systematic reviews developed by Delphi

consensus. Journal of Clinical Epidemiology, 51(12):1235-41). The list is based on "expert consensus"

not, for the most part, on empirical data. Two additional items not on the Delphi list (PEDro scale items 8

and 10) have been included in the PEDro scale. As more empirical data comes to hand it may be come

possible to "weight" scale items so that the PEDro score reflects the importance of individual scale items.

The purpose of the PEDro scale is to help the users of the PEDro database rapidly identify which of the

known or suspected randomised clinical trials (ie RCTs or CCTs) archived on the PEDro database are

likely to be internally valid (criteria 2-9), and could have sufficient statistical information to make their

results interpretable (criteria 10-11). An additional criterion (criterion 1) that relates to the external

validity (or “generalisability” or “applicability” of the trial) has been retained so that the Delphi list is

complete, but this criterion will not be used to calculate the PEDro score reported on the PEDro web site.

The PEDro scale should not be used as a measure of the “validity” of a study’s conclusions. In particular,

we caution users of the PEDro scale that studies which show significant treatment effects and which

score highly on the PEDro scale do not necessarily provide evidence that the treatment is clinically

useful. Additional considerations include whether the treatment effect was big enough to be clinically

worthwhile, whether the positive effects of the treatment outweigh its negative effects, and the cost -

effectiveness of the treatment. The scale should not be used to compare the "quality" of trials performed

in different areas of therapy, primarily because it is not possible to satisfy all scale items in some areas

of physiotherapy practice.

7 9

Notes on administration of the PEDro scale:

All criteria Points are only awarded when a criterion is clearly satisfied . If on a literal

reading of the trial report it is possible that a criterion was not satisfied, a point

should not be awarded for that criterion.

Criterion 1 This criterion is satisfied if the report describes the source of subjects and a list of

criteria used to determine who was eligible to participate in the study.

Criterion 2 A study is considered to have used random allocation if the report states that

allocation was random. The precise method of randomisation need not be

specified. Procedures such as coin-tossing and dice-rolling should be considered

random. Quasi-randomisation allocation procedures such as allocation by hospital

record number or birth date, or alternation, do not satisfy this criterion.

Criterion 3 Concealed allocation means that the person who determined if a subject was

eligible for inclusion in the trial was unaware, when this decision was made, of

which group the subject would be allocated to. A point is awarded for this criteria,

even if it is not stated that allocation was concealed, when the report states that

allocation was by sealed opaque envelopes or that allocation involved contacting

the holder of the allocation schedule who was “off -site”.

Criterion 4 At a minimum, in studies of therapeutic interventions, the report must describe at

least one measure of the severity of the condition being treated and at least one

(different) key outcome measure at baseline. The rater must be satisfied that the

groups’ outcomes would not be expected to differ, on the basis of baseline

differences in prognostic variables alone, by a clinically significant amount. This

criterion is satisfied even if only baseline data of study completers are presented.

Criteria 4, 7-11 Key outcomes are those outcomes which provide the primary measure of the

effectiveness (or lack of effectiveness) of the therapy. In most studies, more than

one variable is used as an outcome measure.

Criterion 5-7 Blinding means the person in question (subject, therapist or assessor) did not

know which group the subject had been allocated to. In addition, subjects and

therapists are only considered to be “blind” if it could be expected that the y would

have been unable to distinguish between the treatments applied to different

groups. In trials in which key outcomes are self -reported (eg, visual analogue

scale, pain diary), the assessor is considered to be blind if the subject was blind.

Criterion 8 This criterion is only satisfied if the report explicitly states both the number of

subjects initially allocated to groups and the number of subjects from whom key

outcome measures were obtained. In trials in which outcomes are measured at

several points in time, a key outcome must have been measured in more than

85% of subjects at one of those points in time.

Criterion 9 An intention to treat analysis means that, where subjects did not receive treatment

(or the control condition) as allocated, and where measures of outcomes were

available, the analysis was performed as if subjects received the treatment (or

control condition) they were allocated to. This criterion is satisfied, even if there is

no mention of analysis by intention to treat, if the report explicitly states that all

subjects received treatment or control conditions as allocated.

Criterion 10 A between-group statistical comparison involves statistical comparison of one

group with another. Depending on the design of the study, this may involv e

comparison of two or more treatments, or comparison of treatment with a control

condition. The analysis may be a simple comparison of outcomes measured after

the treatment was administered, or a comparison of the change in one group with

the change in another (when a factorial analysis of variance has been used to

analyse the data, the latter is often reported as a group time interaction). The

comparison may be in the form hypothesis testing (which provides a “p” value,

describing the probability that the groups differed only by chance) or in the form of

an estimate (for example, the mean or median difference, or a differ ence in

8 0

proportions, or number needed to treat, or a relative risk or hazard ratio) and its

confidence interval.

Criterion 11 A point measure is a measure of the size of the treatment effect. The treatment

effect may be described as a difference in group outcomes, or as the outcome in

(each of) all groups. Measures of variability include standard deviations, standard

errors, confidence intervals, interquartile ranges (or other quantile ranges), and

ranges. Point measures and/or measures of variability may be provided

graphically (for example, SDs may be given as error bars in a Figure) as long as it

is clear what is being graphed (for example, as long as it is clear whether error

bars represent SDs or SEs). Where outcomes are categorical, this criterion is

considered to have been met if the number of subjects in each category is given

for each group.

8 1

Curriculum Vitae

K.H. (Koen) Groot Zwaaftink D.O.-MRO

Personal Details

Address: Pathmossingel 49 7513 CB Enschede The Netherlands

Phone: +31641557330 Date of birth: 13 May 1983 Place of birth: Oldenzaal

Nationality: Dutch E-mail: koengz@hotmail.com

Present Position

Osteopath in a privite practise, OsteoCura - Albergen

Teacher International Academy of Osteopathy - Clinical Neurology and Cranial Nerves

Education

2013-present Osteopathy MSc. - University of Applied Sciences, Innsbruck

2004-2009 Osteopathy D.O. - International Academy of Osteopathy, Gent

2005-2006 Ultrasound of the Musculoskeletal System - Fysus Communications, Delft

2000-2004 Physiotherapy Bac.- Saxion University of Applied Sciences, Enschede

Courses

2015 Das vegetative Nervensystem – Osteopathie Schule Deutschland, Hamburg

2013 Shoulder Plus – Saxion University of Applied Sciences, Enschede

2013 Shoulder Basic – Saxion University of Applied Sciences, Enschede

2012 Mobilisation of the Nervous System – Paramedic Institute, Papendal

2011 Manipulations-Functional Techniques of the Spine – Panta Rhei, Hoeven

2011 Visceral Manipulations – Panta Rhei, Hoeven

2011 Kneeproblems - Saxion University of Applied Sciences, Enschede

2010 Musculoskeletal Ultrasound – Specialists Course, Amersfoort

2008 Musculoskeletal Ultrasound – Specialists Course, Amersfoort

2007 Musculoskeletal Ultrasound – Specialists Course Shoulder, Amersfoort

2007 Medical Taping – Fysiotape Courses, Alphen aan de Rijn

2004 Functional Taping - Saxion University of Applied Sciences, Enschede

Professional Experience

2004-2009 Physical therapist in a private practice

2009-present Osteopath in a private practice

2009-present Teacher International Academy of Osteopathy

Membership of Professional Association

Dutch Association for Osteopathy (NVO)

Dutch Register of Osteopathy (NRO)

Language Skills

Dutch, English and German

8 2

Declaration of originality

o

Affidavit concerning

Master's thesis

I hereby deciare that the present paper is entirely my own work and that I have not used any

sourees and/or resources other than those specified in the bibliography. AII quotes taken literally or

analogously from any works either published or as yet unpublished or taken from the Internet are

indicated as such in accordance with the rules of academie writing.

The present work has never been submitted as part of another examination procedure, in either this or a similar form, and neither have any excerpts from it ever been used in such a procedur

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