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A NOVEL HAPTIC DEVICE TO TEST THE EFFICACY OF MUSICAL

VIBROACUPUNCTURE IN PAIN RELIEF

AUGUSTO WEBER

A thesis submitted in partial fulfillment of the requirements of the University of

Brighton for the degree of Doctor of Philosophy

MAY 2024

i

In memory of my father

ii

Abstract

The motivation behind this PhD was to use the concept of vibrotactile music applied

to acupoints and test its effects on pain relief. The contribution of multiple and

simultaneous vibrational frequencies (vibrochords) to stimulating acupoints has

received little attention in the field.

The thesis involved three phases: The first was to validate the technique of multiple

frequencies in healthy participants using the cold pressor test as a pain model. The

second was to design and develop a new voice coil actuator with a greater

magnitude of stimulus and a more balanced response at multiple frequencies than

the previous version. The third phase tested and compared the efficacy of the

revised actuator against the original one in healthy participants with musculoskeletal

soreness provoked by recent sports activity.

The study did not focus on the cognitive aspect of music; instead, the purpose is to

use a non-cognitive approach using vibration according to musical harmony to

stimulate a composite of acupoints due to their pain-relieving qualities. The

prototype device developed for the study allows primary melodic intervals, such as

the octave and fifth, to influence the body through voice coil actuators attached to

the skin. The study confirms that a combination of frequencies leads to increased

tolerance pain levels compared to a single frequency and sham group, which was

statistically significant, demonstrated by the cold pressor test.

The second aim was to design and validate a more powerful vibration actuator with

a flatter response at multiple frequencies. This aim was carried out in response to

exposed limitations from the original actuator, especially regarding the stimulus's

intensity and an unbalance at multiple frequencies. Thus, the second study focused

on providing a detailed physical description of the musical haptic device used in

previous studies and the design and validation of a custom-built vibration actuator.

These aspects are described in more detail, and novel data is presented in an

improved actuator plus test trials against the original model. An accelerometer was

utilised to measure the acceleration RMS values for each actuator at 32, 48, and 64

Hz to evaluate the correlation between the original and revised actuators. The force,

magnetic field strength, and magnetic field interaction were computed for both

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actuators. Results from the test trials indicate that the new actuator provides a more

potent stimulus and more balanced response across all frequencies compared to

the original actuator.

Finally, the third stage of the study tested and compared the efficacy of the new

actuators against the initial prototype in a population of healthy individuals with

recent musculoskeletal soreness provoked by sports activity. To attain this goal, an

experimental randomised and controlled trial in collaboration with the University of

Brighton and the Medical and Research Acupuncture clinic was conducted. After

obtaining informed consent, each participant was asked to perform three

procedures: multiple frequencies on a combination of acupoints, a single frequency

on the same points, and a sham procedure, which was considered the control group.

The results demonstrated that the revised actuator presents a better pain relief

effect than the original actuator in participants with recent musculoskeletal pain.

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Declaration

I declare that the research contained in this thesis, unless otherwise formally

indicated within the text, is the author’s original work. The idea has not been

previously submitted to this or any other university for a degree and does need to

incorporate any already submitted for a degree.

Signed

Date 21/01/2024

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Acknowledgements

First, I would like to thank my family; without their support, I would never have been

able to study in the UK. Thanks to my wife, Maria Lucia, and my sons, Fabiola,

Matheus, Paula, and Gabriela, for being patient, understanding, and supportive

throughout my studies. A big thank you to my supervisor, Dr Simon Busbridge,

whose unwavering support and expert advice on the engineering aspects of this

project would not have come to fruition. Thanks also to my co-supervisor, Dr Ricardo

Governo, for his expert advice on neuroscience and pain-related elements of the

study. His constructive criticism has improved the quality of this thesis. I would

especially like to thank Professor Neil Ravenscroft for his support and being the first

to believe in this PhD. Many thanks to Luiz Henrique Heinz Bueno for your crucial

assistance and suggestions in developing the hardware for the vibration device. I

would also especially like to thank all the teachers from the Brighton Language

Institute who were essential to improving my language skills. Many thanks to all the

technicians, especially Tony Brown and Terry Murphy, who have always been

supportive. Lastly, thanks to all the volunteers for their selfless participation in the

experiments. With their time, patience, and belief in the advancement of science,

this was achievable.

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TABLE OF CONTENTS

Abstract ……………………………………………………………………………………ii

Declaration………………………………………………………………………………..iv

Acknowledgements……………………………………………………………………….v

Contents…………………………………………………………………………………...vi

List of Figures…………………………………………………………………………….xv

List of Tables…………………………………………………………………………….xvii

List of Equations ………………………………………………………………………...xix

Acronyms…………………………………………………………………………………xx

Chapter 1………………………………………………………………………………….1

Non-Pharmaceutical Approaches to Pain Relief - An Overview and Account of the

Nociceptive Nervous System…………………………………………………………….1

1.1 General introduction………………………………………………………………….1

1.2 Literature review……………………………………………………………………...2

1.2.1 Introduction……………………………………………………………………..2

1.2.2 Historical background………………………………………………………....2

1.2.2.1 Acupuncture: Tradition and historical perspective…………………..3

1.2.3 Mechanisms of acupuncture…………………………………………………5

1.2.4 Types of acupuncture currently used in clinical pain conditions…………7

1.2.4.1 Manual acupuncture……………………………………………………8

1.2.4.2 Electroacupuncture…………………………………………………….9

1.2.4.3 TENS…………………………………………………………………...11

1.2.4.4 Acupuncture likeTENS………………………………………………..13

1.2.4.5 Musical electroacupuncture…………………………………………13

1.2.4.6 Vibroacupuncture……………………………………………………..13

1.2.5 The use of music during an acupuncture session………………………..14

1.2.5.1 Five element music therapy…………………………………………..15

1.2.5.1.1 The music of elements……………………………………….....16

1.2.6 Vibroacoustic stimulation…………………………………………………...16

1.2.6.1 Vibroacoustic therapy………………………………………………...17

1.2.6.2 Music vibration table…………………………………………………..17

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1.2.6.3 Low-frequency sound stimulation……………………………………18

1.2.6.4 Physioacoustic stimulation…………………………………………...18

1.2.6.5 Whole body vibration………………………………………………….19

1.2.7 The somatosensory system………………………………………………..19

1.2.7.1 Mechanical stimuli: touch and proprioception……………………..20

1.2.7.1.1 Tactile and auditory systems similarities…………………….24

1.2.7.1.2 The four-channel theory/Critical band model……………….25

1.2.7.2 Thermoception and nociception…………………………………….26

1.2.8 Anatomy of the nervous system…………………………………………..27

1.2.8.1 Peripheral afferents and the dorsal root ganglion………………….29

1.2.8.1.1 Cutaneous receptors that mediate pain signals……………..30

1.2.8.2 The spinal cord………………………………………………………...31

1.2.8.3 Ascending pathways………………………………………………….33

1.2.8.3.1 Neospinothalamic tract………………………………………...34

1.2.8.3.2 Paleospinothalamic tract………………………………………34

1.2.8.3.3 The central role of the thalamus in somatosensory

sensation…………………………………………………………………...35

1.2.8.4 Descending pathways……………………………………………….35

1.2.8.4.1 Pain modulation at higher brain levels………………………35

1.2.8.4.2 Analgesia system in the brain and spinal cord……………..36

1.2.9 Neurochemistry involved in pain modulation……………………………..37

1.2.9.1 Opioids…………………………………………………………………37

1.2.9.2 GABA and glycine……………………………………………………39

1.2.9.3 Serotonin (5-HT)………………………………………………………40

1.2.9.4 Dopamine……………………………………………………………...40

1.2.9.5 Cannabinoids………………………………………………………….41

1.2.10 The Pain system: classification, presentation and management……..42

1.2.10.1 Introduction…………………………………………………………..42

1.2.10.2 Pain types……………………………………………………………42

1.2.10.3 Pain Theories: Specificity, Pattern and Gate Control……………44

1.2.10.4 Pain Models: Neuromatrix, Biopsychosocial and Palliative care.47

1.2.10.5 Clinical pain conditions………………………………………………48

1.2.10.6 Pain generating stimuli……………………………………………...49

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1.2.11 Pain management…………………………………………………………..50

1.2.11.1 Pharmacological……………………………………………………..51

1.2.11.2 Surgical………………………………………………………………51

1.2.11.3 Non-pharmacological…………………………………...................51

1.2.12 Cutaneous receptors that mediate vibration signals………………….........52

1.2.13 Sensory pathways for vibration signals into the central nervous system…56

1.2.14 Characteristics of the dorsal column – Medial lemniscus system..............57

1.2.15 Anatomy of the dorsal column-medial lemniscal system…………………..57

1.2.16 Differences between the dorsal column and spinothalamic system………58

1.3 The triad of: Music, acupuncture and endorphins………………………………59

1.3.1 The musical brain…………………………………………………………...........61

1.3.2 Biological rhythms and dissipative structures………………………………….63

1.3.3 The brain as a dissipative structure…………………………………………….65

1.3.4 Rhythms of the brain …………………………………………………………….67

1.3.4.1 Gamma waves……………………………………………………………...68

1.3.4.2 Beta waves………………………………………………………………….68

1.3.4.3 Alpha waves………………………………………………………………...68

1.3.4.4 Theta waves………………………………………………………………...69

1.3.4.5 Delta waves…………………………………………………………………69

1.4 Conclusions………………………………………………………………………….69

1.5 Hypothesis…………………………………………………………………………...70

1.6 Aims…………………………………………………………………………………..70

Chapter 2………………………………………………………………………………...71

Results 1: Evaluation of the Efficacy of Musical Vibroacupuncture on Experimental

(Cold Pressor) Induced Pain…………………………………………………………....71

2.1 Introduction…………………………………………………………………………..71

2.1.1 Aim, objectives, and hypothesis……………………………………………73

2.1.2 Research questions…………………………………………………………74

2.2 Materials and methods……………………………………………………………...74

2.2.1 Participants, recruitment, and screening………………………………...74

2.2.2 The device…………………………………………………………………..75

2.2.3 The procedure……………………………………………………………....76

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2.2.4 The cold pressor test………………………………………………………79

2.2.5 Data acquisition…………………………………………………………….80

2.2.6 Data analysis………………………………………………………………..81

2.3 Results ……………………………………………………………………………….81

2.3.1 Demographics………………………………………………………………...81

2.3.2 The cold pressor test and the effect of skin vibration on pain

perception……………………………………………………………………………82

2.3.3 Pain threshold and tolerance across trials……………………………......82

2.3.4 Effect of MVA, VA or SP on Numerical Rating Scale (NRS), Short-Form

McGill Pain questionnaire (SF-MPQ) and STAI Form Y-1 (STATE) (STAI)

scores ………………………………………………………………………………..83

2.4 Discussion …………………………………………………………………………...83

2.4.1 Study limitations………………………………………………………………90

2.4.2 Identified risks…………………………………………………………………90

2.5 Conclusion ………………………………………………………………………….91

Chapter 3………………………………………………………………………………...92

Results 2: Design and Characterisation of an Acoustic Transducer for Use on

Acupuncture Points Commonly Used to Relieve Pain……………………………….92

3.1 Introduction…………………………………………………………………………..92

3.2 Literature review……………………………………………………………………..93

3.2.1 Physics of music, sound and vibration………………………………………93

3.2.1.1 Wave…………………………………………………………………….94

3.2.1.2 Classification of waves………………………………………………...95

3.2.1.2.1 Mechanical and non-mechanical waves……………………..95

3.2.1.2.2 Transversal and longitudinal waves…………………………..95

3.2.1.2.3 Periodic and non-periodic waves……………………………...95

3.2.1.2.4 Standing or progressive waves………………………………..96

3.2.2 Sound wave ………………………………………………………………....96

3.2.2.1 Definition and characteristics………………………………………...96

3.2.2.1.1 Amplitude (sound pressure), intensity (loudness)…………..96

3.2.2.1.2 Frequency (pitch)………………………………………………97

3.2.2.1.3 Pulse (rhythm)………………………………………………….98

3.2.2.1.4 Phase (consonance/dissonance)…………………………….98

3.2.2.1.5 Resonance...........................................................................99

3.2.2.1.6 Timbre (tone)……..............................................................101

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3.2.3 The harmonic series / Harmonics………………………………………..102

3.2.4 Analysis and synthesis of complex waves..........................................105

3.2.5 The harmonic series as a model for the symmetrical relations of

the human body…………………………………………………………………..105

3.3 Principles of music intervals and chords………………………………………..109

3.3.1 Musical intervals…………………........................................................109

3.3.2 The meaning and qualities of musical intervals..................................110

3.3.2.1 Octave………………………………………………………………...111

3.3.2.2 Fifth…………………………………………………………………....111

3.3.2.3 Fourth………………………………………………………………....112

3.3.2.4 Major third/ minor third………………………………………………112

3.3.2.5 Second………………………………………………………………..113

3.3.2.6 Sixth……………………………………………………………………113

3.3.2.7 Seventh……………………………………………………………….113

3.3.2.8 Fourth augmented (Tritone)…………………………………………114

3.3.3 Musical chord (Harmony)………………………………………………..115

3.3.4 Musical scale (Melody)......................................................................115

3.4 Technology applied to music, sound, and vibration…………………………….116

3.4.1 Transducer definition…........................................................................116

3.4.2 Vibrotactile actuators………………………………………………………117

3.4.3 The use of voice coil actuators in acupuncture…………………………117

3.4.4 Magnetism…………………………………………..................................119

3.4.5 Effects of sound and electromagnetic fields on the peripheral and

central nervous system…………………………………………………………...120

3.5 Material and methods……………………………………………………………. 120

3.5.1 The apparatus………………………………………………………………120

3.5.1.1 A general overview of the apparatus……………………………...121

3.5.1.2 Operational device aspects……………………………………….123

3.5.1.3 Program paradigm………………………………………………….124

3.5.1.4 Musical tones and vibrochords used in program software/Technical

specifications…………………………………………………………………124

3.5.2 Design and description of the original actuator………………………….126

3.5.3 Design, modelling and testing the new voice coil acoustic actuator....128

3.5.4 Data acquisition…………………………………………………………….131

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3.5.5 Measuring the vibration magnitude of the actuators……………………132

3.5.5.1 Measuring RMS power using a gyroscope accelerometer……..133

3.5.5.2 Measuring the force and the magnetic field strength for the original

and revised actuators………………………………………………………...133

3.5.5.3 Measuring the magnetic field interaction between the magnet

and the solenoid for the original and revised actuators…………………..135

3.6 Results……………………………………………………………………………..136

3.6.1 Data analysis of the first measurement (accelerometer attached

directly to the bottom of the actuator) ............................................................136

3.6.2 Data analysis from the second measurement (accelerometer

attached to a silicone base) ……………………………………………………..137

3.6.3 Calculating the force in newtons (N) and the magnetic field strength (H)

for the original and revised actuators……………………………………………138

3.6.3.1 Calculating the magnetic field strength of the magnetic poles for

the original and revised actuators…………………………………….........138

3.6.4 Force (F) and current (A) comparison between the original and

revised actuators…………………………………………………………………139

3.6.5 Calculating the magnetic field interaction between the magnet and

the solenoid for the original and revised actuators…………………………….140

3.6.6 Measuring the temperature of the actuators…………………………….141

3.7 Discussion………………………………………………………………………….141

3.7.1 Study limitations……………………………………………………………..145

3.8 Conclusion………………………………………………………………………….145

Chapter 4……………………………………………………………………………….147

Results 3: Evaluation and Comparison of the Efficacy of Musical Vibroacupuncture

on Musculoskeletal Soreness for the Original and Revised Actuators.................147

4.1 Introduction…………………………………………………………………………147

4.1.1 Research question………………………………………………………... 149

4.1.2 Hypothesis…………………………………………………………………...149

4.1.3 Primary and secondary aims………………………………………………149

4.2 Musical haptics and acupuncture………………………………………………..150

4.2.1 Vibrotactile music applied to acupuncture treatment……………………151

4.3 Materials and methods…………………………………………………………….153

4.3.1 Randomisation and blinding………………………………………………..153

4.3.2 The device……………………………………………………………………153

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4.3.3 Participants…………………………………………………………………..154

4.3.4 The procedure……………………………………………………………….154

4.3.5 Data acquisition……………………………………………………………..155

4.3.6 Data analysis………………………………………………………………..155

4.4 Results……………………………………………………………………………..155

4.4.1 Demographics………………………………………………………………156

4.4.2 MSK pain trials testing the original actuator (Trial 1)……..…………….156

4.4.2.1 NRS scores comparison between baseline, MVA, VA, and

SP……………………………………………………………………………156

4.4.2.2 SF-MPQ (Sensory) scores comparison between baseline, MVA,

VA and SP…………………………………………………………………..157

4.4.2.3 SF-MPQ (Affective) scores comparison between baseline, MVA,

VA, and SP………………………………………………………………….158

4.4.2.4 SF-MPQ (PPI) scores comparison between baseline, MVA, VA

and SP……………………………………………………………………….158

4.4.2.5 STAY Form Y-1 (STATE) questionnaire scores comparison

between baseline, MVA, VA and SP……………………………………...159

4.4.3 MSK pain trials testing the revised actuators (Trial 2)……………....161

4.4.3.1 NRS questionnaire scores comparison between MVA, VA, and

SP…………………………………………………………………..........161

4.4.3.2 SF-MPQ (Sensory) questionnaire scores comparison

between MVA, VA and SP…………………………………………….162

4.4.3.3 SF-MPQ (Affective) questionnaire scores comparison between

MVA, VA and SP………………………………………………………...163

4.4.3.4 SF-MPQ (PPI) scores comparison between baseline, MVA,

VA and SP……………………………………………………………….164

4.4.3.5 STAY Form Y-1 (STATE) questionnaire scores comparison

between MVA, VA and SP……………………………………………..165

4.5 Discussion………………………………………………………………………….167

4.5.1 Study limitations………………………………………………………….....172

4.5.2 Identified risks……………………………………………………………….172

4.6 Conclusion…………………………………………………………….…………...172

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Chapter 5……………………………………………………………………………….173

Music and Science/Music in Medicine: Insight into the future……………………..173

5.1 Introduction…………………………………………………………………………173

5.2 Music and science…………………………………………………………………173

5.3 Music in medicine…………………………………………………………………177

5.3.1 Historical perspective……………………………………………………...178

5.4 Medicinal properties of sound/vibration and music……………………………188

5.4.1 Hemodynamic effects……………………………………………………..188

5.4.2 Neurological effects………………………………………………………..188

5.4.2.1 Effects of music on the brain………………………………...........189

5.4.2.2 Effects of music on the skin………………………………………..190

5.4.3 Musculoskeletal effects…………………………………………………..191

5.4.4 Emotional regulation effects……………………………………………..192

5.4.5 Pain relief effects ………………………………………………………....193

5.4.6 The harmful and beneficial effects of vibration……………………......194

5.5 Discussion………………………………………………………………………….196

5.6 Conclusion………………………………………………………………………….198

5.6.1 Future work………………………………………………………………….199

5.7 Summary…………………………………………………………………………...199

References…………………………………………………………………………….201

Appendix A

Ethical approval processes…………………………………………………………...230

Appendix B

Symbols Used in Equations…………………………………………………………..231

Appendix C

CPT values on pain threshold and tolerance vs. treatment……………………….232

Appendix D

Effects of CPT-induced NRS scores before (b) and after (a) treatment for Baseline,

MVA, VA and SP…………………………………………………………...................233

Appendix E

Effects of CPT-induced SF-MPQ scores before (b) and after (a) treatment for

baseline, MVA, VA and SP……………………………………………………………234

Appendix F

Effects of CPT in STAI questionnaire before (b) and after (a) treatment for Baseline,

MVA, VA and SP…………………………………………………………...................237

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Appendix G

NRS values in MSK soreness for Baseline, MVA, VA, and SP in the original

actuator…………………………………………………………………………………..239

Appendix H

SF-MPQ values in MSK soreness for Baseline, Chord, Tone, and Control Group in

the original actuator…………………………………………………………………….240

Appendix I

STAI values in MSK soreness for Baseline, Chord, Tone, and Control Group in the

original actuator…………………………………………………………………………242

Appendix J

NRS values in MSK soreness for Baseline, Chord, Tone, and Control Group in the

revised actuator…………………………………………………………………………243

Appendix K

SF-MPQ values in MSK soreness for Baseline, MVA, VA and SP in the revised

actuator………………………………………………………………………………….244

Appendix L

STAI values in MSK soreness for Baseline, MVA, VA, and SP in the revised

actuator………………………………………………………………………………….246

Appendix M

Participation Information Sheet (PIS)………………………………………………...247

Appendix N

Participant Consent Declaration………………………………………………………251

Appendix O

Advertisement…………………………………………………………………………. 252

Appendix P

Participant Consent Form……………………………………………………………..253

Appendix Q

Published articles………………………………………………………………………254

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List of Figures

Chapter 1

Figure 1.1. The electroacupuncture device……………………………………………10

Figure 1.2. The main touch pathways…………………………………………………21

Figure 1.3. The vestibular system...........................................................................22

Figure 1.4. Nerve fibres classification………………………………………………….28

Figure 1.5. Spinal cord Rexed laminae………………………………………………...31

Figure 1.6. Schematic diagram of the GCT of pain by Melzack and Wall ………..46

Figure 1.7. The system of the dorsal column – medial lemniscus………………….58

Figure 1.8. Human brain waves………………………………………………………...67

Chapter 2

Figure 2.1. The Apparatus.……………………………………………………………..76

Figure 2.2. The experimental setup……………………………………………………77

Figure 2.3. The transducer on point LI-4………………………………………………78

Figure 2.4. Effects of CPT-induced NRS scores before and after Baseline, musical

vibroacupuncture (MVA), vibroacupuncture (VA), and sham procedure…………..80

Figure 2.5. Effects of CPT on pain threshold (top) and tolerance versus treatment.85

Chapter 3

Figure 3.1. Sinusoidal wave signal……………………………………………………101

Figure 3.2. The harmonics of a musical note on a vibrating string……………….101

Figure 3.3. The fundamental components of the harmonic series for clamped-ended

systems…………………………………………………………………………………103

Figure 3.4. The first harmonic………………………………………………………...104

Figure 3.5. The second harmonic…………………………………………………….104

Figure 3.6. The third harmonic………………………………………………………..104

Figure 3.7. The harmonic series and the human body’s anatomic symmetries...106

Figure 3.8. Musical interval of an octave…………………………………………… 111

Figure 3.9. Schematic representation of Figure 2.1…………………………………121

Figure 3.10. Components and measures of the original actuator…………………127

Figure 3.11. Components and measures of the revised actuators……………….129

Figure 3.12. The original and revised actuators ……………………………………130

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Figure 3.13. (a) an accelerometer is attached to the actuator’s bottom. (b) an

accelerometer attached to a silicone base…………………………………………...132

Figure 3.14. Acceleration RMS values compare original and revised actuators with

the accelerometer attached to the bottom of the actuator…………………………136

Figure 3.15. Acceleration RMS values compare original and revised actuators with

the accelerometer attached to a silicone base………………………………………137

Figure 3.16. (a) The magnet’s magnetic field strength is for the original and revised

actuators. (b) the solenoid magnetic field strength for the original and revised

actuators………………………………………………………………………………..139

Figure 3.17. Force and current values comparison between the original and revised

actuators………………………………………………………………………………..140

Figure 3.18. Magnetic field interaction values compare the magnet and the solenoid

for the original and revised actuators…………………………………………………141

Chapter 5

Figure 5.1. The circle of fifths …………………………………………………………180

Figure 5.2. The points of the N�ndeva Indians (Tupi-Guarani), The art of

Mimby…………………………………………………………………………………...181

Figure 5.3. The Chakras ………………………………………………………..........182

Figure 5.4. The divine monochord. …………………………………………………..184

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List of Tables

Chapter 1

Table 1.1. The Rexed Laminae…………………………………………………………32

Chapter 2

Table 2.1. Tukey’s multiple comparison tests for post-trial NRS scores between

baseline and following MVA, VA, or SP………………………………………………..82

Table 2.2. Tukey’s multiple comparison test for pain tolerance between baseline and

following MVA, VA, or SP........................................................................................83

Chapter 3

Table 3.1. Psychological aspects of harmonic musical intervals…………………..114

Table 3.2. Two octaves range of frequencies for equal-tempered scale…………123

Table 3.3. Vibrochords frequencies in the software device………………………...125

Table 3.4. Specifications and parameters comparison between the original and

revised actuators……………………………………………………………………….130

Chapter 4

Table 4.1. Trial 1, procedures comparison for differences in NRS questionnaire

scores in the original actuator………………………………………………………...156

Table 4.2. Procedures pairwise comparison scores in the NRS questionnaire for the

original actuator………………………………………………………………………...157

Table 4.3. Procedures comparison for differences in the sensory component of the

SF-MPQ scores for the original actuator…………………………………………….157

Table 4.4. Procedures pairwise comparison scores in the sensory component of the

SF-MPQ for the original actuator……………………………………………………..158

Table 4.5. Procedures comparison for differences in SF-MPQ (PPI) scores for the

original actuator………………………………………………………………………...158

Table 4.6. Procedures pairwise comparison for differences in the SF-MPQ (PPI)

scores for the original actuator……………………………………………………….159

Table 4.7. Procedures comparison for differences in the STAI Form Y (STATE)

questionnaire scores between all trials for the original actuator………………….159

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Table 4.8. Procedures pairwise comparison for differences in the STAI form Y

(STATE) questionnaire scores for the original actuator……………………………160

Table 4.9. Descriptive statistical analysis for trial 1 (original actuator)……………160

Table 4.10. Summary of intertrial comparison in the original actuator for all

questionnaires………………………………………………………………………….161

Table 4.11. Trial 2, procedures comparison of score differences in the NRS

questionnaire for the revised actuator……………………………………………….162

Table 4.12. Procedurespairwise comparison scores differences in the NRS

questionnaire for the revised actuator……………………………………………….162

Table 4.13. Procedures comparison for differences in SF-MPQ (Sensory) scores for

the revised actuator……………………………………………………………………163

Table 4.14. Procedures pairwise comparison for differences in SF-MPQ (Sensory)

scores for the revised actuator……………………………………………………….163

Table 4.15. Procedures comparison for differences in SF-MPQ (Affective)

questionnaire scores for the revised actuator………………………………………163

Table 4.16. Procedures pairwise comparison for differences in SF-MPQ (Affective)

scores for the revised actuator………………………………………………………..164

Table 4.17. Procedures comparison for differences in SF-MPQ (PPI) scores for the

revised actuator………………………………………………………………………..164

Table 4.18. Procedures pairwise comparison for differences in SF-MPQ (PPI)

scores for the revised actuator………………………………………………………..165

Table 4.19. Procedures comparison for differences in STAI Form Y questionnaire

scores for the revised actuator………………………………………………………..165

Table 4.20. Procedures pairwise comparison for differences in STAI form Y (STATE)

questionnaire scores for the revised actuator……………………………………….165

Table 4.21. Descriptive statistical analysis for trial 2 (revised actuator)………….166

Table 4.22. Procedures score pairwise comparison in the revised actuator for NRS,

SF-MPQ, and STAI questionnaires………………………………………….............167

xix

List of Equations

Chapter 3

(1) Simple wave equation……………………………………………………………….94

(2) The Fourier theorem equation…………………………………………………….105

(3) Lorentz force equation……………………………………………………………..118

(4) The RMS corresponding equation for a continuous function or waveform…..133

(5) The Coulomb equation for magnetism……………………………………………134

(6) The magnetic field strength equation for the magnet (m1) in amperes per metre

(A/m)…………………………………………………………………………………….134

(7) The magnetic field strength equation for the solenoid (m2) in amperes per metre

(A/m)…………………………………………………………………………………….134

(8) The equation to calculate the area of the magnet and the solenoid………….135

(9) The magnetic interaction forces between the magnet and the solenoid

equation…………………………………………………………………………………135

xx

Acronyms

AL-TENS: Acupuncture-like TENS

ANOVA: Analysis of Variance

CNS: Central Nervous System

CPT: Cold Pressor Test

CT: Tactile C-Fibres

DRG: Dorsal Root Ganglia

EA: Electroacupuncture

EEG: Electroencephalogram

EMF: Electromagnetic Field

FDA: Federal Drug Administration

FM: Fibromyalgia

fMRI: Functional Magnetic Resonance Imaging

GABA: γ-Amino Butyric Acid

GCT: Gate Control Theory

HTMRs: High-Threshold Mechanoreceptors

IDE: Integrated Development Environmental

LTMRs: Low-Threshold Mechanoreceptors

LFSS: Low-Frequency Sound Stimulation

MA: Manual Acupuncture

MEA: Musical Electroacupuncture

MEG: Magnetoencephalogram

MSK: Musculoskeletal

MVA: Musical Vibroacupuncture

MVT: Music Vibration Table

NM: Neuromatrix Theory of Pain

NRM: Nucleus Raphe Magnus

NRS: Numerical Rating Scale

PAG: Periaqueductal Gray

PC: Pacinian Corpuscle

PENS: Percutaneous Electrical Nerve Stimulation

PIS: Participant Information Sheet

PNS: Peripheral Nervous System

PPI: Present Pain Intensity

xxi

RA I: Rapidly-Adapting I

RA II: Rapidly-Adapting II

RCT: Randomized and Controlled Trial

RMN: Raphe Magnus Nucleus

RMS: Root Mean Square

SA I: Slowly Adapting Type I

SA II: Slowly Adapting Type II

SC: Spinal Cord

SD: Standard Deviation

SG: Substantia Gelatinosa

SP: Sham Procedure

SF-MPQ: Short-Form McGill Pain Questionnaire

STAI: State-Trait Anxiety Inventory Form Y-1

TMS: Transcranial Magnetic Stimulation

TCM: Traditional Chinese Medicine

TENS: Trans Electric Nerve Stimulation

VA: Vibroacupuncture

VAT: Vibroacoustic Therapy

VCA: Voice Coil Actuator

VCAs: Voice Coil Actuators

WBV: Whole Body Vibration

WDR: Wide Dynamic Range

1

Chapter 1

Non-Pharmaceutical Approaches to Pain Relief - An Overview and Account

of the Nociceptive Nervous System

1.1 General introduction

The role of acupuncture as a non-pharmacological approach to relieving pain has

received increased attention in Western countries in recent decades. This technique

originated in China and forms part of traditional Chinese medicine (TCM), which has

been used to relieve pain for centuries. According to TCM, acupuncture involves

stimulating specific points on the skin using various techniques, including needles,

cups, burning herbs (known as moxibustion), electricity, magnetism, and light or

sound vibration, the latter of which was the technique of choice behind this thesis.

Over the past few decades, research has provided evidence of acupuncture's

effectiveness in pain relief, whereby acupuncture is reported to significantly affect

pain relief compared to placebo stimulation (Linde, 2016; Vickers et al., 2018;

Nielsen & Wieland, 2019). Some mechanisms proposed to mediate this response

include the gate control spinal cord system, descending inhibitory pathways such as

the diffuse noxious inhibitory control, release of opioids or top-down effects such as

expectations and placebo effects (Hui et al., 2010; Chae & Olausson, 2016; Lim et

al., 2018). Other mechanisms include oscillatory coherence and synchronisation of

the brain wave patterns activated by acupuncture procedures (Hauck et al., 2017).

Additionally, there has been growing interest in using sound frequencies to alleviate

pain in recent years, a technique known as vibroacoustic stimulation. Research has

shown that this method can effectively reduce pain (Chesky et al., 1997; Staud et

al., 2011; Weber et al., 2015; Campbell et al., 2019). The specific mechanisms

activated by these methods may vary depending on the stimulus's intensity, rhythm,

location and frequency. Furthermore, music, which comprises vibrations at different

frequencies, can also relieve pain by applying it to specific acupoints via vibrotactile

chords. This non-cognitive approach to music is very much unexplored in

acupuncture and is the paradigm used in the present study.

2

In this context, the non-cognitive method involves using musical frequencies to

stimulate the skin (acupoints) rather than the auditory system, which is considered

a cognitive perception. Music has the ability to evoke emotions and memories

through the cognitive perception of sound, which occurs through the processing of

various frequencies and rhythms by the auditory system. On the other hand, non-

cognitive perception of music refers to the physical vibrations or waves that music

produces, influencing our bodies, specifically through the skin or tactile system.

These mechanical sensations can be experienced as a physical response to music,

independent of any emotional or cognitive associations that we may have with it.

1.2 Literature review

1.2.1 Introduction

The following section will provide a comprehensive review of non-pharmacological

methods used for pain relief. It will start with a historical background of techniques

employed to stimulate the skin, ranging from traditional acupuncture needles to

more recent vibroacoustic methods. This section will also reexamine the target of

these techniques, from the anatomy of the somatosensory system recapitulating

pain concepts and related neurochemistry to providing examples of some treatment

options.

1.2.2 Historical background

The ancient world observed that stimuli produced by acupuncture needles, hot cups

applied to the skin, or a jolt of electricity from stepping on electric eels relieved aches

and pains (Melzack & Wall, 1988). Indeed, historical records reveal that in Roman

times, electric eels were used to treat various painful conditions. At the same time,

healers from that period administered herbs to perform cuts or burns, often

combining rhythmic sounds, hypnotic chants, musical instruments, or prayers

alongside these healing techniques to instil an unquestioned expectation of relief

from pain (Melzack & Wall, 1988). One example is the N�ndeva (Tupi-Guarani)

Indians from Brazil, which used the sound produced by bamboo flutes to stimulate

specific points on the skin during healing rituals (Pereira, 1995). Interestingly, these

3

points correspond to those used in Chinese medicine (Weber et al., 2015). The

Guaranis believe that each part of the body has its own unique frequency. To

stimulate these regions or cutaneous points, the Shaman would play his flute with

the correct intonation. These points were tuned using ascending fifth intervals,

similar to how Chinese music is tuned. This suggests that Brazilian Indians used a

form of "Musical Acupuncture" centuries ago. They could vibrate and resonate with

different body regions by playing specific notes on the bamboo flute (Pereira, 1995).

1.2.2.1 Acupuncture and music: Tradition and historical perspective

The practice of acupuncture is part of a complex, enticing theory of medicine in

which all diseases and somatic disturbs are considered to be due to disharmony

between Yin (blood) and Yang (“Qi”), which flow in channels called “meridians”.

Acupuncture charts are complex and consist of 361 points on 12 meridians, most

named according to internal organs such as the large intestine, heart, or kidneys.

These points chosen for treating a given malady are subtly influenced by other

variables, including the time of day, weather, temperature or emotions.

The ancient Chinese believed in the unity of the universe and the human body as a

whole. These recognised two fundamental forces - Yang and Yin – that worked

together in balance. In the human body, this duality is reflected in the circulation of

“Qi” (Yang) and blood (Yin) as distinct but complementary systems. The concept of

“Qi” is similar to the Greek notion of pneuma and represents a subtle, refined

manifestation of energy. Unlike blood, which is pumped by the heart through the

body's visible pathways, “Qi” originates in the lungs and flows through invisible Jing-

Luo meridians or channels. (Needham, 1976).

The meridians are an occidental translation attempting to describe Jing-Luo as

having multi-functions in analogy with the earth’s electromagnetic field,

astronomical cycles or terrestrial longitude. Thus, meridians are the conductive

pathways of a network sustaining the flowing of "Qi." The blood and "Qi" are

interconnected, mutually supportive, or counterbalancing as Yin and Yang. These

two forces are essential concepts in TCM underlying physiology and pathology,

along with the meridians and the five elements.

4

The theory of the five elements, i.e. metal, wood, water, fire and earth, is one of the

most basic philosophic foundations in TCM. In Yellow Emperor’s Inner Classic, a

connection between the five elements of organs, emotions, tones and musical

scales has been established (Zhang & Lai, 2017). The five organs, the spleen, lungs,

liver, heart and kidneys, correspond to the tones Gong, Shang, Jue, Zhi, and Yu,

respectively, as described in Nei-Jing Ling Shu (Wong, 1995). These five elements

or phases are considered descriptive labels for meridians associated with organs

which resonate with the corresponding tones and different types of music.

A reciprocal relationship of promotion and suppression is necessary to maintain

balance among the five fundamental elements. This balance ensures that all

elements are in harmony: earth promotes metal, metal promotes water, water

promotes wood, wood promotes fire, and fire promotes earth. However, earth

suppresses water, water suppresses fire, fire suppresses metal, metal suppresses

wood, and wood suppresses earth. This creates a complex dynamic among all five

elements and the meridians, which are used for clinical diagnosis and therapy in

TCM (Leung, 2011). For example, if the liver has excess, it is necessary to reinforce

the spleen and stomach because the liver suppresses them. In this case, earth and

metal music are recommended because earth is suppressed by wood, and metal

suppresses wood. Alternatively, if a person has anxiety or insomnia, which

corresponds in TCM to an excess of fire, it is essential to nourish the water (kidneys)

and reinforce the metal (lungs). To achieve this goal, water and metal music should

be played in a sequence of songs for approximately 20 to 40 minutes. However,

starting the song sequence with fire music is crucial because it resonates easily with

the fire temperament. After this, the sequence should subtly modulate as a target to

water and metal music (see Chapter 1, subsection 1.2.5.1). TCM suggests that

different types of music can influence emotions and the meridian system where the

acupoints are located (Wong, 1995).

The meridian system's function also promotes a regular distribution of the blood and

"Qi" so that the vital essentials originating from food can replenish the Yin and Yang,

support the muscles, ligaments, and bones, and lubricate the joints. In disease, the

“Qi and blood did not circulate properly in the meridians, which is suggested as the

principal cause of pain. According to TCM, pain is caused by obstructing the flow of

“Qi” and blood in the meridians. The principle of treatment is to promote the free

5

flow of “Qi” and blood in the channels and collaterals that can be obtained by

stimulating certain points on the skin using tiny needles or other stimuli such cups,

pressure (cups), heat (moxa), electricity (EA,) or sound vibration. According to TCM,

needles are used to move “Qi”, cups are more indicated to move blood and moxa is

indicated to fortify the Yang.

Needham (1976) described meridians as systems that transport energy to all tissues

around the body. Several points on the body's surface related to organs and viscera

are along the meridians. Three hundred sixty-five were numbered (probably

consonant to the calendar days) in the 1st century BC and over 400 in the late 20th

century. However, fewer than 50 points are usually employed for practical purposes

(Yang et al., 2011).

1.2.3 Principles and mechanisms of acupuncture

As detailed in Chapter 1, section 1.2.2, the ancient Chinese believed that maladies

resulted from an imbalance between the essential forces, such as pain from

obstruction of both “Qi” and blood along the meridians. Thus, acupuncture originated

from the belief that targeting specific points along these meridians could resolve

symptoms.

From a neurobiologic perspective, acupuncture can be considered a somatic

stimulation therapy that uses a sequence of neuroinformation input signals (Qin et

al., 2011). The precise mechanisms are not fully explained but may include gate

control at the level of the spinal cord (SC) (see subsection 1.2.8.2) or the diffuse

noxious inhibitory control, which involves the release of neurotransmitters such as

endogenous opioids (Han, 2003) described in section 1.2.9) or via changes in pain-

related neuronal oscillations (Ploner et al.,2006; Bartel et al., 2017). Previous

studies also demonstrate that acupuncture may interact with the cortical sensory,

limbic networks and the autonomic nervous system to modulate pain (Hui et al.,

2010; Hauck et al., 2017; Vickers et al., 2018).

It is now well established that primary afferent nerve fibres mediate peripheral

sensory transmission elicited by external stimuli such as acupuncture. The

acupuncture method itself generates several stimuli. Firstly, the skin is stimulated

6

through touch before inserting the needle, which activates a large A-beta fibres,

described further in section 1.2.8. Secondly, when the needle is inserted, it

stimulates C and A-delta fibres (described in section 1.2.8). The A-delta fibre is

responsible for fast transmitting stimuli and promotes the "Deqi" sensation caused

by needle stimulation.

"Deqi" is described as a distinct needling sensation upon insertion, often

exacerbated by manipulating the needle (e.g., twisting), and activates different brain

regions, such as cerebro-cerebellar and limbic system as demonstrated in functional

magnetic resonance imaging (fMRI) (Hui et al., 2005; Zhu et al., 2013). These

findings support the notion that central effects play a pivotal role in the analgesic

effect of acupuncture. Acupuncture has been demonstrated to initiate other events,

such as anti-inflammatory actions, through releases of proinflammatory mediators

(interleukins and chemokines) at the needling site and neurotransmitter modulation

systems, such as serotonin and endorphin release (Leung, 2012). In addition, it is

reported that local point stimulation acts through peripheral and segmental

inhibition, whereas distant point stimulation involves central mechanisms such as

opioid-mediated pain inhibition (Carlsson, 2002).

The above supports the notion that the effect of acupuncture analgesia is not reliant

on one single mechanism. However, these do support the idea that a multiplicity of

events are involved and that acupuncture could help treat various disorders. The

extensive evidence on acupuncture analgesia and the gradual decoding of

underlying mechanisms support the analgesic capacity and clinical use (Wang, Yan,

& Xu, 2012; Baeumler et al., 2014).

Other mechanisms influenced by acupuncture treatment include brain patterns and

neuronal oscillations (Hauck et al., 2017). According to this view, pain is associated

with neuronal oscillations and synchrony at different frequencies within the brain,

which can suppress natural brain rhythms (Ploner et al., 2006; Ploner, Sorg, &

Gross, 2017). Neuronal oscillations and synchrony brain rhythms refer to the

rhythmic fluctuations of neural mass signals recorded by electroencephalogram

(EEG) and magnetoencephalography (MEG). Brain oscillations are most prominent

between 1 and 100 Hz (Busz�ki & Dragun, 2004). Pain-related neuronal oscillations

7

at different frequencies have been observed, ranging from delta (0.1- 3 Hz), theta

(4–7 Hz), alpha (8–13 Hz), beta (14–29 Hz) to gamma (30–100 Hz) oscillations

(Ploner, Sorg, & Gross, 2017) which will be described in more detail in section 1.3.4.

Acupuncture has been found to drive oscillatory coherence, contributing to the

brain's regulation, reset, or circuit connectivity (Hauck et al., 2017).

The resting human brain experiences spontaneous oscillatory activity dominated by

the primary visual, somatosensory, and motor areas. A higher amplitude of

oscillatory activity indicates an idling state, while a lower amplitude is linked to

activation and higher excitability of the specific system. According to Ploner et al.

(2006), painful stimulus suppresses spontaneous oscillations in somatosensory,

motor, and visual areas, demonstrating that pain induces a widespread change in

cortical function and excitability. This change in excitability may reflect the alerting

function of pain, which opens the gates for processing and reacting to stimuli of

existential relevance.

1.2.4 Types of acupuncture used in clinical pain conditions

This section will thoroughly explore the different types of acupuncture commonly

utilised in clinical settings, with manual acupuncture (MA) and electroacupuncture

(EA) being the most prevalent types. With MA, the acupuncture needles are inserted

into the skin and twisted in various directions and rhythms according to previously

defined practices specific to the therapeutic aim (as reviewed by Leung, 2012). In

contrast, EA also involves the insertion of a needle, but instead of manual

stimulation, an electrical impulse is sent through the needle at different frequencies,

pulse widths, magnitudes, or pulse intervals according to a particular treatment goal

(Ulett, Han, & Han, 1998; Napadow et al., 2005).

Indeed, applying frequencies to the skin forms the basis of standard treatment

techniques, specifically EA and trans-electric nerve stimulation (TENS). The action

activated by EA or TENS is suggested to differ according to the stimulation

frequency (Lin et al., 2002; Han, 2003; Han, 2004; Kimura et al., 2015). The

mechanism by which these techniques produce antinociception is still debatable.

Still, most authors attribute the effect to the gate control mechanisms involving the

8

release of neurotransmitters and endogenous opioids (Lim et al., 2018). Moreover,

electrical impulses have been proven to increase the efficiency of the various

stimulation points used in acupuncture and favour external stimulation with

conventional MA (Napadow et al., 2005). This evidence opens for exploration into

other modalities, such as vibroacoustic and musical methods used in the present

study that, when applied to MA, may raise effectiveness in managing pain. In 1979,

the World Health Organization reinforced the use of acupuncture to treat 43

symptoms (Naik et al., 2014). Since then, substantial research has been realised to

clarify the mechanisms and the possible use of acupuncture in modern medicine

and pain management (Ma, 2004; Mayhew & Ernst, 2007; Zhao, 2008; Baeumler et

al., 2014). The limitations are a need for more consensus on proper control groups,

relatively small sample sizes, and a severe lack of long-term follow-up effects of

acupuncture. Several reviews warrant more extensive, well-designed trials

elucidating acupuncture's analgesic effect (Cao, Bourchier, & Liu, 2012; Naik et al.,

2014; Linde et al., 2016).

1.2.4.1 Manual acupuncture (MA)

MA consists of inserting tiny needles into acupuncture points and manipulating them

by twisting, lifting, and pushing the needle (Plaster et al., 2014). This procedure is

suggested to stimulate all types of afferent fibres.

Since the early classical texts, many acupuncturists have considered this approach

essential for acupuncture treatment. According to these texts, a needling sensation

called “Deqi” is a combination of impressions decoded as the flow of “Qi” or "the

coming of vital energy. It originates from the theory of TCM, which states that

acupuncture is successful only when “Deqi” is experienced (Lundeberg, 2013). Both

patient and acupuncturist experience the phenomenon of eliciting “Qi” with needles.

Patients experience "Deqi" as various sensations at the needle site and around the

site of needle manipulation. In unison, acupuncturists feel changes in the tissues'

mechanical behaviour surrounding the needle (needle grasp). This conversion is

described as tense, tight, and full, like "a fish biting onto the bait" (Lundeberg, 2013).

9

Langevin (2001) points out that the mechanical coupling between the needle and

connective tissue, with a convolution of tissue around the needle during needle

rotation and manipulation, transmits a mechanical signal to connective tissue cells.

The initial action of acupuncture is mechanical, not neural or electrical. In any case,

the mechanistic role provides a model to explain MA (Yang et al., 2011). Hui and

coworkers (2005) have shown that MA stimulation induces limbic system

deactivation and somatosensory brain region activation.

Evidence suggests that the different outcomes experienced between MA and EA

pertain to a diverse network of brain regions being activated. In addition, in the

clinical setting, there is a continuo between both methods because, in the EA

method (jacks inserted at the needle's cable), the needles are previously inserted

and obtain the “Deqi” sensation by the manual technique. Previous studies also

demonstrated that EA elicits a more widespread brain region activation than MA

(Kong et al., 2002; Napadow et al., 2005). This effect suggests that conventional

MA can be enhanced centrally by combining external stimuli with acupuncture

needles. Nonetheless, both types of acupuncture are reported to effectively reduce

pain in many common acute and chronic pain syndromes (as reviewed by Chen et

al., 2010).

1.2.4.2 Electroacupuncture (EA)

EA is a technique based on traditional acupuncture combined with modern

electrotherapy (Liu, 2015). This technique uses small crocodile clips to acupuncture

needle cables after acupuncture points are applied by an EA device providing

electric stimulations (Qi et al., 2016), as shown in Figure 1.1.

10

Figure 1.1. The EA device. The crocodile clips are fixed at the needle's cable and

inserted at the shu dorsal points on a low back pain treatment (source: Weber, 2015)

The fundamental difference between EA and TENS-related techniques is that the

former uses penetration of needles in the skin. In contrast, the latter is administered

via non-penetrating electrostimulation, usually by electrodes attached to the skin.

One of the main benefits of using EA and TENS in clinical practice or research is to

set the stimulation frequency and the current intensity objectively and quantifiably

(Plaster et al., 2014).

The last few decades have seen a noticeable increase in the number of preclinical

investigations using EA on persistent tissue injury (inflammatory), nerve injury

(neuropathic), cancer or visceral pain (Ma, 2004; Wang, Yang, & Xu, 2012). The

mechanism through which EA promotes antinociception is still a matter of

controversy. However, most authors attribute the effect to the release of

endogenous opiates (Han, 2003) and activation of the descending pain inhibitory

system, originating in the brainstem and terminating at the SC (Fleckenstein, 2013;

Lv et al., 2019).

One crucial question to be addressed in EA and TENS research is the optimal

stimulation frequency for pain control. Individual studies have used low, high, or

mixed frequencies, and the effectiveness varies from study to study (Lee et al.,

2017). According to many studies, the EA mechanism is suggested to differ

according to the frequency of stimulation (Lin et al., 2002; Han, 2003; Han, 2004;

Kimura, 2015). For example, low-frequency EA (<15 Hz) increases the spinal

release of opioids, including met-enkephalin, endomorphin, and beta-endorphin. On

the other hand, high-frequency EA (15 to 100 Hz) is suggested to trigger spinal

dynorphin release (Han, 2003; Lin and Chen, 2009). Therefore, a mixed

combination of low and high frequencies (2/100 Hz EA) is reported to release

11

various opioid peptides, creating a synergetic effect that improves antinociceptive

effects (Huang et al., 1987; Han, 2003; Lee et al., 2017). These effects might be

explained because using a single frequency facilitates neuronal accommodation of

the stimulus, reducing its therapeutic effect. Therefore, using two or more

frequencies generates a movement or tension, which avoids the system

accommodation.

In addition, stimulation at a single frequency, whether low or high, would not elicit a

full release of all four kinds of opioid peptides: endorphins, enkephalins, dynorphins,

and nociceptins. These neuropeptides comprise a highly complex neurobiological

system acting through four opioid receptor systems: Mu, Delta, Kappa, and the

nociceptin opioid peptide receptor (Conway, Mikati,& Al-Hasani, 2022).

It has also been shown that the analgesic effect of low-frequency stimulation is

naloxone-reversible, while high-frequency stimulation is not (Lin et al., 2002).

Naloxone is an opioid antagonist, which suggests that opioids mediate the effect of

low-frequency acupuncture. Ultimately, the fact that EA induces the release of

endogenous opioids to inhibit pain has clinical usefulness. For example, EA added

to opioid therapy might decrease the dosages required for pain control (Coura et al.,

2011; Fan et al., 2017), thereby reducing the impact of adverse side effects from

opioids.

1.2.4.3 Trans electric nerve stimulation (TENS)

TENS is a variant of peripheral nerve stimulation that sends an electrical current

through the skin to reduce acute or chronic pain associated with various etiologies

(Sluka & Walsh, 2003). TENS efficacy was demonstrated in several pain models,

including pressure, intense experimental, or thermal (Gibson et al., 2019).

Technological advances have since provided various TENS devices capable of

various stimulation parameters that clinicians and patients can choose from (e.g.,

frequency, amplitude, duration of stimulus or electrode placement site). In general,

the effect of TENS is conveyed using either high frequency (>50 Hz) or low

frequency (<10 Hz) (Vance et al., 2012). The conventional method requires high

frequency (100 Hz) with low-intensity stimulations. Low-frequency (2Hz) TENS, in

turn, are often used at higher intensities to elicit motor contraction (Sluka & Walsh,

12

2003), which is denominated EA. Consequently, TENS is described according to

these technical characteristics as either high frequency / low intensity (conventional

TENS) or low frequency / high intensity (acupuncture-like TENS, shortened to AL-

TENS or Acu-TENS). A crucial aspect related to stimulation parameters is the

intensity of a stimulus. This element is fundamental to TENS efficacy. Thus, TENS

should be delivered at a robust, no-painful intensity level to produce maximum pain

relief. Studies have shown that solid but comfortable intensity significantly reduces

pain (Choi et al., 2016). For example, a survey by AminiSaman et al. (2018)

demonstrated that using TENS on acupuncture points could decrease pain and

opioid consumption in intubated patients under a mechanical ventilator. On the other

hand, some studies show limited effects of TENS in labour pain (Bedwell et al.,

2011).

While intensity is an essential element, as is the stimulation frequency, ultimately,

the outcome depends on the type of pain. In a study of rheumatoid arthritis, for

instance, high-frequency (70Hz) stimulation was observed to be more effective than

low-frequency (3Hz) (Sluka & Walsh, 2003). It is not yet possible to predict the

optimal frequencies or intensities of stimulation for each pain source type. However,

it is clear that a high proportion is helped by appropriate stimulation, that TENS is

more effective than any other form of treatment for many patients, and that the ratio

may become higher when the correct type of stimulation is found for each pain

syndrome, probably for each patient (Melzack & Wall, 1988). For the operator, the

physiological target when applying conventional TENS is to activate selectively non-

noxious low threshold afferent nerve fibres in the skin (see section 1.2.8), which are

in charge of inhibiting transmission of nociceptive information at the level of the

spinal cord (SC), i.e. segmental modulation (DeSantana et al., 2008). Research

suggests different TENS frequencies may operate through various neurotransmitter

systems, specifically opioids in the central nervous system (CNS). For instance,

Sluka and colleagues demonstrated that low-frequency TENS induced anti-

hyperalgesia (decreased sensitivity to pain), mediated by activation of serotonin and

mu-opioid receptors (see sections 1.2.9.1 and 1.2.9.3). In contrast, high-frequency

TENS activates delta-opioid receptors (Kalra, Urban, & Sluka, 2001) and promotes

the release of dynorphin acting on the kappa receptor. Low-frequency stimulation (2

Hz), in turn, releases enkephalins and beta-endorphins (Han, 2003). Thus, the

13

choice of frequency from TENS acts via different analgesic pathways. Finally, some

researchers defend that an alternating stimulation frequency of TENS could produce

optimal analgesic effects. According to Law and Cheing (2004), an alternating mode

of low (2 Hz) and high (100 Hz) frequencies in TENS generates a synergistic

interaction of dynorphin and enkephalin, which would have a more substantial

analgesic effect compared to a fixed frequency of stimulation (Sluka & Walsh, 2003).

1.2.4.4 Acupuncture-like TENS (Al-TENS)

Acupuncture-like TENS (AL-TENS), or Acu-TENS, is the technique of selecting the

points according to TCM (Han, 2003) followed by the administration of low-

frequency, high-intensity but non-painful currents over muscles (Francis, Marchant,

& Johnson, 2011). The physiological aim of AL-TENS is to induce muscular

twitching, which is believed to increase activity in tiny diameter cutaneous afferent

A-delta fibres and muscles (Group III) (see section1.2.8), leading to activation of

descending pain inhibitory pathways described in section 1.2.8.4.

1.2.4.5 Musical electroacupuncture (MEA)

MEA combines music therapy and EA. The technique converts music into electric

waves that are relayed through the needle. This form of music EA device involves

middle frequency, biphasic, sinusoidal or alternating current in 1 mA, 5-10V output

(Tekeoglu, 1994), and switching waveforms and frequencies in rhythmic patterns.

According to Nakatani and Yamashita (1977), mechanical sound waves of music

converted into electric signals may be used to stimulate acupuncture needles to

improve the efficacy of EA. However, MEA has an additional advantage over

classical EA (Hongsheng, Hao, & Guiron, 2005; Jiang et al., 2016). The constant

changing of frequency intrinsic within music prevents neurological accommodation

and adaptation of the skin mechanoreceptors, which are reported to significantly

reduce the analgesic effect of EA (Hongsheng, Hao, & Guiron, 2005).

1.2.4.6 Vibroacupuncture (VA)

VA is a novel technique applied to acupuncture that uses a small vibration motor

connected to the acupuncture needles with a metal clip and produces vibration of

100 Hz and amplitudes from 0 to 200 �m. This device transmits waves into the deep

14

muscle, normally to the same acupoints normally targeted in MA. The technique

combines acupuncture and vibration stimuli, thereby conducting high-frequency

vibration into the deep tissue (Wang et al., 2016).

1.2.5 The use of music during an acupuncture session

The application of music and sounds can form two approaches during an

acupuncture session. The first uses musical sequences according to TCM’s five

elements theory for around thirty minutes, or close to an acupuncture session's

average duration. This Chinese medicine five-element music is designed and

produced based on the relationship between the elements (wood, fire, earth, metal,

and water) and the five tones (Jue, Zhi, Gong, Shang, and Yu). It aims to balance

the yin and yang, regulate “Qi” and blood, and maintain the human body in a state

of dynamic homeostasis, thus keeping the individual in good health (Liao et al.,

2013).

The second is using the five musical tones directly on acupoints (Kim, Jeong and

Lee, 2004). A variant of this method, which was used in the actual study, is the use

of consonant frequencies (vibrochords) directly on a combination of acupoints (Kim,

Jeong & Lee, 2004; Weber, 2004; Weber, 2010; Weber et al., 2015; Weber,

Busbridge, & Governo 2020).

According to TCM, music and sounds can be classified as Yang or Yin. In this

context, Yang's music is represented by high-frequency sounds and fast rhythms

and evokes dynamic and optimistic emotions, for example, an Allegro by Mozart.

On the other hand, Yin music corresponds to low frequencies and slow rhythms and

elicits more impressionist feelings, for instance, Clair de Lune by Debussy, Chopin's

Nocturne or a Bossa Nova song by Jo�o Gilberto. So, Yin music is targeted at

individuals with an excess of Yang. However, it is essential to start listening to Yang

music because it is easier for the subject to resonate and gradually modulate to slow

and intimate music (Yin music). On the other hand, Yang music is targeted to

subjects with an excess of Yin. In this case, it is indicated that we should start using

Yin music and subtle modulate to more intense and energetic music (Yang music).

Chinese medicine places great importance on studying the pulse, which is likened

to the rhythm of music. If the pulse is fast (between 80 and 120 bpm), it is

15

recommended to begin the session with energetic Yang music, such as an allegro

(120-140 bpm) or vivace (140-160 bpm). As the session progresses, the rhythm

should gradually slow down to Yin music, such as an andante (75-107 bpm) or largo

(40-50 bpm). Conversely, if the pulse is slow, it is recommended to start with slow

Yin music, such as a largo (40-50 bpm) or adagio (55-65 bpm), and gradually

increase the rhythm to more dynamic Yang music, such as an allegro or presto.

Moreover, Yin is located below in space, while Yang is situated above. This means

that the former is better for stimulating areas below the navel, while the latter is more

suitable for stimulating areas above. This approach was explored prior to and during

the main investigation of this thesis (Weber et al., 2015; Weber, Busbridge, &

Governo, 2020). The points were standardised as follows: the first and second

transducers fixed in the foot (acupoint LR3) and three fingers below the navel

(acupoint CV4) related to the lower frequencies. The acupoint located at the tip of

the chest's xiphoid appendices (CV14), in turn, corresponds to the music interval of

the fifth. Finally, the two last acupoints, which are located on the hand between the

metacarpi (IG4) and the forehead (Yintang), correspond to the musical interval of

an octave, which contains the musical scale, from the fundamental (low frequency)

to the octave (high frequency).

1.2.5.1 Five elements of music therapy

Music therapy of the five elements is the term designated for using music for

therapeutic purposes in TCM, using the five elements theory. Music is classified into

wood, fire, earth, metal and water. Each element relates to a human organ, season,

emotion, temperament, note and musical scale, and rhythms and musical

instruments. Accordingly, music awakens emotions, which need symbols to become

intelligible. The number five indicates two movements and a return to the centre: the

horizontal movement, the vertical movement and the intersection of the two. In

Chinese, the ideogram used for the word man shows the five points of the figure of

a man with open arms. The five positions are left to right, top and bottom, and centre.

Represented by the organs heart, lung, liver, kidneys and pancreas/spleen.

16

1.2.5.1.1 The music of the elements

• Wood: This music is indicated for wood temperament and is characterised

by vigorous, optimistic, melodious, cheerful, and bright. So, it is called the

music of the spring. The organ related is the liver, the emotion is anger, and

the musical note is Jue (C).

• Fire: This music is indicated for fire temperament and is characterised by

warmth, energy, intensity, passion and contagiousness. It is called the music

of the summer. The organ is related to the heart, the emotion is joy, and the

musical note is Zhi (G).

• Earth: This type of music is best suited for those with an earth temperament.

It is known for its calming, stable, solemn, and mellow qualities and is often

called "late summer music". The associated organ is the spleen, the emotion

it evokes is worry, and the musical note is Gong (E).

• Metal: This music is indicated for the metal temperament and is

characterised by impressionist, melancholic, resounding, and sorrowful tones.

So, it is called the music of autumn. The organ is the lungs, the emotion is

sadness, and the musical note is Shang (D).

• Water: This type of music is suited for those with a water temperament and

is known for its pure, subtle, meditative, plaintive, mysterious, and profound

qualities. It is often referred to as winter music. The organ associated with it

is the kidneys, the emotion it evokes is fear, and the musical note is Yu (A).

In the upcoming review, other non-pharmacologic approaches to pain relief that

have gained popularity in recent decades will be described. Specifically,

vibroacoustic stimulation will be examined in more detail.

1.2.6 Vibroacoustic Stimulation

The field of vibroacoustic stimulation has been known for a long time to possess

analgesic effects. Various vibration techniques, such as therapy tools and

vibrotactile displays, have been developed for numerous conditions, including pain

relief. Such studies have shown that multiple superficial and deep-lying receptors

are susceptible to vibration, both slowly and fast adapting mechanoreceptors. These

receptors are mainly associated with A-beta fibres and react to vibration over a

17

broad extent of frequencies (1 to 400 Hz), even when the amplitudes are very low.

Muscle receptors are also stimulated by vibration, and microneurographic studies in

humans have shown that the primary muscle spindle endings (la) are highly

vibration-sensitive, usually at frequencies of up to 100-150 Hz (Guieu, Tardy-Gervet,

& Roll, 1991). The following topics provide a brief overview of currently available

vibroacoustic methods in treatment.

1.2.6.1 Vibroacoustic therapy (VAT)

VAT is a vibroacoustic technique based on the combined effects of music and low-

frequency sound vibration (R��tel, 2002) that impresses the human body in a non-

invasive approach and is part of musical therapy used worldwide (Punkanen & Ala-

Ruona, 2012). This therapy was pioneered by Olav Skille in 1982 and employs 30-

120 Hz rhythmic sinusoidal sounds accompanied by music for therapy purposes

(Skille,1991). The set uses six loudspeakers as transducers in a chair, with two

positioned to face the legs, another two at the seating area, and the final ones at the

neck and back (Skille, Wigran, & Weeks 1989; Hooper, 2001). Skille hypothesised

that VAT would effectively reduce pain and other stress-related symptoms. Further

studies showed that vibration delivered through chairs or beds specially fitted with

low-frequency transducers improved mobility and increased circulation (Karkkainen

& Mitsui, 2006), decreased low-density lipoprotein levels and blood pressure (Zheng

et al., 2009) and helped decrease pain (Karkainen, 2006; Zheng et al., 2009). Also,

studies involving VAT have examined specific pain conditions such as polyarthritis

in the hand and chest using 40 Hz (Wigran, 1995) and low back pain using 52 Hz

(Skille,1989).

1.2.6.2 Music vibration table (MVT)

The MVT method developed by Chesky et al.(1997) used a range of frequencies

between 60 to 600 Hz. This frequency range is known to stimulate the Pacini

corpuscle (PC), which plays a crucial function in pain perception (Lundeberg,

Nordemar, & Ottoson,1984; Chesky et al., 1997; Boyd-Brewer & McCaffrey, 2004).

The technique combines music listening with the physiological effects of

transcutaneously applied musically fluctuating vibration (Chesky et al., 1997). Most

music delivers the frequency bandwidth needed to excite PC receptors and

18

transduce into mechanical vibration via a bed or table for applications to the body.

The use of music is considered to be essential because it promotes variation in the

vibration. While periods of vibration stimulation at a single frequency and amplitude

might quickly give rise to habituation and fatigue in vibrotactile sensitivity and central

processing, such effects may be avoided by variations in the amplitude-frequency

of sustained excitation. The MVT was designed to stimulate the body surface with

a controlled level of vibration derived from the same music used for listening. It also

consists of a control unit with three independently controlled sub-modules, all

housed on a typical medical procedural stretcher. In each sub-module, signals from

the music source first pass through a computer-controlled filter, then an amplifier,

and finally to a vibration stimulus generator positioned on the bed or table. MVT has

been used extensively, with many studies reporting its pain relief qualities (Chesky

& Michel, 1991; Chesky, Rubin & Frische,1992; Chesky et al.,1997).

1.2.6.3 Low-frequency sound stimulation (LFSS)

This technique is usually delivered through low-frequency transducers adapted to

chairs or beds, and this technique is also being reported to relieve pain. Studies

involving LFSS have examined specific pain conditions: rheumatoid arthritis using

40 Hz, polyarthritis in hands and chest using 40 Hz, or low back pain using 52 Hz

(Nahgdi et al., 2015). When the 40 Hz sound is processed by transducers installed

in a chair, the effect is felt as vibrotactile and can drive a response from the

somatosensory system.

1.2.6.4 Physioacoustic stimulation (scanning pitches stimulation)

The physio-acoustic method developed in 1970 by Petri Lehikoinen is based on

scanning the body with a sinusoidal sound between 27 to 113 Hz, including specially

selected listening music. The scanning technique's theory is that each muscle

resonates to a specific frequency. In this method, the desired frequency is

stimulated many times in a single vibroacoustic session. The theory is based on the

physics principle of sympathetic resonance (Boyd-Brewer, 2003).

1.2.6.5 Whole-body vibration (WBV)

WBV treatments are usually performed with the user standing on a motor-driven

vibrating plate. The vibration transmitted to the body via the plate constitutes the

19

vibration exposure to the user (Rauch et al., 2010). In recent years, WBV has been

used extensively in sports, physiotherapy and physiatry or as an adjuvant in pain

relief (Alev et al., 2017). The primary mechanism involved is the stimulus-induced

activation of mechanical receptors via the afferent pathway in myelinated sensory

axons (A-beta-fibres), which can interact with the nociceptors inhibiting the tiny

presynaptic pain fibres in the dorsal horn of the SC. WBV is applied through a

vibrating surface that supports the subject. Commonly, WBV apparatus delivers

vibrations in a range of 15-60 Hz and displacement from < 1mm to 10 mm. The

acceleration can reach 15 g (1 g is due to the Earth's gravitational field or 9.81 m/s2).

The current technology offers a vast array of amplitude and frequency combinations

for producing whole-body vibration (WBV) devices and protocols for humans.

According to Cardinale and Wakeling (2005), these protocols and devices provide

benefits such as muscle activation and neuromuscular performance, which

effectively mitigate the impact of ageing on musculoskeletal structures.

1.2.7 The somatosensory system

A detailed account of the somatosensory system, the collection of anatomical

structures that together subserve the body’s senses, is necessary to better

understand the effect of the multitude of tools described in previous sections.

The somatosensory system plays a crucial role in various physiological functions.

For the purpose of this thesis, the focus will be on touch, proprioception, and

nociception. Proprioception refers to the ability to perceive one's body position in

space and is linked to balance and equilibrium. On the other hand, nociception is a

neural process that involves the transduction and transmission of harmful stimuli to

the brain (Steeds, 2016). These functions are carried out by mechanosensory

neurons that respond to pressure and force (Delmas, Hao, & Rodat-Despoix, 2011).

From the viewpoint of evolution, the somatosensory system developed before all

other senses. Mechanotransduction, which refers to the ability to convert

mechanical stimuli into electrical signals, is observed in simple organisms such as

eubacteria, archaea and eukarya kingdoms, confirming its early origin. Although the

first mechanosensitive channels in bacteria and archaea were developed for cell

20

protection and survival, these eventually evolved into more complex structures for

organismal specialisation.

The skin is an essential part of the somatosensory system and comprises almost

two square metres on average, making it the largest sensory organ in the human

body (Geffeney & Goodman, 2012). It contains a particular structure called the

acupuncture point, considered a polymodal sense that can be stimulated by various

stimuli, including meteorological, electromagnetic, barometric, luminous, sound, or

vibration (Limansky, 1990).

The elements of the somatosensory system can also be subdivided into three

distinct types: (1) the mechanoreceptive somatic senses, including touch and

proprioception; (2) the thermal senses, which perceive heat and cold; and (3) the

pain sensation; activated by factors that can potentially damage the tissues.

1.2.7.1 Mechanical stimuli: touch and proprioception

The sense of touch is considered the most extensive and heaviest sense organs. It

encodes a broad spectrum of sensations, such as the sound emitted by music or

the “Deqi” sensation provoked by the acupuncture needle. It is also crucial for social

contact or sexuality (Moriwaki & Yuge, 1999; Kleggetveit & Jorum, 2010).

Specialised receptors, termed mechanoreceptors, are located in both the glabrous

(hairless) or hairy skin and are traditionally classified based on the types of

stimulation to which each responds, the receptive field size or adaptation rates.

21

Figure 1.2. The main touch pathways ( Kim, 2021)

As shown in Figure 1.2, the mechanosensory receptors at the periphery ascend

from the lower and upper parts of the body, reach the SC, and ascend to the Gracile

and Cuneate nuclei, respectively. From this dorsal nucleus, the information is

relayed to the brain via the medial lemniscus, brainstem and ventral posterior lateral

nucleus of the thalamus, where info is processed and finally, at the somatosensory

area of the cortex, where the information is consciously perceived.

The mechanoreceptors (proprioceptors) encode the phenomenon of proprioception,

which means the perception of the body in space. This system processes

information about alterations in the position of joints and limbs and controls posture,

equilibrium, and movement. Both the proprioceptors and mechanoreceptors have

an anatomical basis on the skin, joints and inner ear at the vestibule. Tomatis (1996)

states that skin sensitivity is related to the proprioceptive system. This complex

system involves the vestibule, VIII cranial nerve (vestibulocochlear), brain steam

22

(olivary nucleus), SC, and CNS pathways terminating within the ventral

posterolateral nucleus of the thalamus and cerebral cortex (Gilman, 2002).

Mechanosensory neurons located in the skin, commonly denominated Meissner’s

and Pacini corpuscles (PC), Merkel disks, Ruffini endings, Golgi tendon organs and

joints are the peripheral elements of this system. Thus, empirical evidence suggests

that the skin and the inner ear are intrinsically connected.

The vestibular apparatus (see Figure 1.3), which contains the semicircular canals,

is located at the labyrinth's centre, a crucial part of the inner ear. It is associated

with the bone wall that separates the middle ear from the inner ear and contains

the oval vestibule and cochlea windows. Both of these are filled with membranes.

The vestibule consists of a bony labyrinth that contains a functional membranous

labyrinth, which includes the cochlear duct, three semicircular canals, and two

large chambers, the utricle and saccule. The cochlear duct is responsible for

hearing, while the utricle, saccule, and semicircular canals play a vital role in

maintaining balance (Guyton, 1977).

Figure 1.3. The vestibular system (based on Lent, 2001)

Figure 1.3 shows the vestibular apparatus, which encloses the cochlea, three

semicircular canals, and two large chambers, the utricle and saccule, located at

the labyrinth's centre. The tympanic membrane divides the external ear to the

23

middle ear, which includes the small bones denominated incus, stapes and

malleus

Embryologically, the brain and all sensory systems, such as hearing, sight or touch,

originate from the same embryonic leaflet, the ectoderm. In addition, hearing can

be divided into cognitive and non-cognitive aspects. The cochlea represents the

former, directly linked to musical language and deciphering sounds in the brain. The

latter, called the vestibular hearing, is related to balance, proprioception, skin

sensitivity (Tomatis, 1996) or motor control, which is connected to the rhythm of

music and dance.

It should be noted that many biological structures share a common ancestry. For

instance, mammals' organs responsible for balance and hearing are believed to

have evolved from the lateral line organs found in all aquatic vertebrates (Popper,

Platt & Edds, 1992; Streit, 2001). Also, the lateral line and inner ear can detect

changes in pressure, making this the most commonly used method for identifying

sound sources among vertebrates. It is also believed to be the most primitive mode

of detecting sound sources (Braun & Coombs, 2000). The lateral lines consist of

small pits or tubes along the side surface of a fish. Each tube contains clusters of

hair cells whose cilia protrude into a gelatinous substance that opens in the animal

swims water. The function of the lateral lines in many animals is to detect vibrations

or changes in water pressure. In some cases, sensitivity to temperature or electric

fields also occurs. Certain fish have electroreceptors sensitive to variations in the

electric field in the surrounding environment, and others have magnetoreceptors

sensitive to the Earth's magnetic field, as is the case with hammerhead sharks.

While the lateral lines disappeared during the reptile evolution, the hair cell's

particular mechanical sensitivity was adopted and adapted for use in structures of

the inner ear derived from the lateral line (Braun & Coombs, 2000). Previous studies

by Li et al.(2008) and Wang et al. (2015) reported that the lateral line presents a

linear arrangement of receptors on the body surface, similar to acupoints and

meridians described in the human body in Chinese medicine.

24

1.2.7.1.1 Tactile and auditory systems similarities

Research into the sense of touch has found similarities in how the skin and ear

respond to mechanical vibrating stimuli. B�k�sy's extensive work (1955, 1957,

1959, 1961) on this topic suggested that studying the skin could improve

understanding of the ear and the sense of hearing. B�k�sy pointed out that the skin

and the basilar membrane are spatially extended and perceive mechanical waves

caused by sound and music.

The basilar membrane is around 3.5 cm long and contains roughly 30.000 nerve

endings, often called hair cells due to their physical appearance, distributed

relatively uniformly along its length. Electrical impulses from these hair cell nerve

endings are transmitted to the brain, which interprets the signals as words, music or

noise. Along the basilar membrane is Corti's organ, which contains the nerve

endings that convert the mechanical waves to electrical impulses relayed to the

auditory cortex system. This structure was named after the Italian anatomist Alfonso

Corti, the first to recognise it in 1851. The Corti’s organ is the most developed,

intricate and sensitive aspect of the hearing system components. Although only

about 4 mm long, it is a gelatinous mass that comprises almost 7,500 interrelated

parts, which relay to the brain the full range of frequencies audible to humans. This

delicate mechanism is one of the best-protected points on the body, embedded

within the cochlea and located within the temporal bone, the hardest in the body

(Nomura, 1989).

The Corti�s organ performs two essential functions: to convert mechanical energy

into electrical energy and then relay it to the brain to code a version of the original

sound. This information is not only about the frequencies but also the intensity and

timbre of the sound received. Deciphering all these informative fragments allows

those who listen to an orchestra to distinguish the sounds of violin, piano or flute

separately. Embryologically, Corti's organ proceeds as a specialised piece of skin

(Gillespie & Muller, 2009). Just as a touch on the skin produces a spatial sensation

that seems localised in a particular place of the body, a "touch" on the inner ear's

sensitive cells produces a temporal and subjective feeling denominated by music.

25

From an evolutionary perspective, the ear originates from the organ of balance in

primitive fish, consisting of lines and points along the sides of the fish body

containing ciliated cells that specialised in detecting vibrations (Streit, 2001). It has

been speculated that acupuncture channels or meridians, where acupuncture points

are located, may have evolved from these lateral lines (Weber, 2004; Li et al., 2008).

Another study by Wilson et al. (2009) states that the auditory and tactile systems

are integrated into a common neural pathway. In this sense, both systems could

represent a continuum of detectable frequencies, from the low frequencies (3-1000

Hz), detected mainly by the tactile system, and the high frequencies (20 Hz -20 kHz)

perceived by the auditory system. Other studies, including Tomatis (1996), point out

that the senses of touch and hearing are intimately related, the link being the

vestibular system responsible for balance and skin sensitivity. Beyond its hearing

functions, the inner ear comprises the semicircular canals that detect gravitational

fields and acceleration. These structures play an important role in balance and the

perception of the body in space (Berg & Storck, 2011). Frenzel et al. (2012) reported

that the tactile and auditory systems have common genes and that individuals with

a good sense of hearing also have an excellent bodily sense.

Other similarities include the phenomenon of beats and the frequencies or intensity

of a stimulus. Rothenberg and Verrillo (1976) investigated the effect of frequency,

determining that the skin vibrotactile frequency response range is roughly 20-1000

Hz, with maximal sensitivity occurring around 250 Hz in PC and around 40 Hz for

the Meissner system. Concerning the intensity of the stimulus, the skin range

reaches about 55 dB above the detection threshold, beyond which vibrations may

become unpleasant or painful (Gunther & O�Modhrain, 2003).

1.2.7.1.2 The four-channel theory/Critical band model

One of the most established models in vibrotactile perception is the four-channel

theory. According to the critical band model, glabrous (non-hairy) human skin

contains four types of mechanoreceptors (Bolanowski et al., 1988). Each of these

four touch-sensing channels uniquely responds to specific types of mechanical

stimuli. Hairy skin has unique characteristics, including a hair follicle receptor, lower

PC density, and relatively unknown neurophysiology and psychophysical basis.

26

The thresholds of vibrotactile stimuli in the tactile perception channels strongly

depend on the vibration frequency. This hypothesis for the somatosensory system

postulated by Verrillo (1963) and later by Talbot et al. (1968) in the context of

vibration led to an extensive series of studies that culminated in the four-channel

model for touch, as proposed by Bolanowski and others (Verrillo,1963; Verrillo &

Gescheider,1975,1977; Gescheider, Malley, & Verillo, 1983; Verillo et al.,1983;

Gescheider et al.,1985). Interestingly, this channel hypothesis resembles Chinese

medicine's channels or meridians theory. The theory argues that the touch system

could have two possible analogues to four channels. The first uses B�k�si’s

observations (1955) that the basilar membrane is spatially extended, similar to the

skin. A second possible analogue is to map sound frequency directly to vibration

frequency. According to Verrillo (1963), at least two receptor systems mediate

touch, especially the sensation of vibration. The first system displays considerable

temporal and spatial integration. It responds most readily to skin vibration at

frequencies around 250 Hz and, therefore, for convenience, is called the “high-

frequency system” (Wilson, Reed, & Braido, 2010). A second system displays little

temporal or spatial integration. When sensitivity is tested with large contactors, this

system responds uniformly to signals over 20-40 Hz. This system is called the “low-

frequency” system. Based on these pieces of evidence, some authors suggest

expanding the tactile critical band model that includes musical stimuli and

hypothesise that the integration at the cortical level of cutaneous signals among

tactile critical bands provides somatosensory perceptions resembling acoustic

timbre (Fontana et al., 2019).

1.2.7.2 Thermoception and nociception

Thermoception is the perception of cold and heat, while nociception is the neural

process involving the transduction and transmitting a noxious stimulus to the brain

via a pain pathway (Steeds, 2016). Cutaneous thermosensation is translated by

various primary afferent nerve fibres that transduce, codify and convey thermal

information (Schepers and Ringkamp, 2010). These nerve fibres provide a

thermoregulatory afferent signal for homeostatic mechanisms, which keep the body

at an optimal working temperature and detect potentially noxious thermal stimuli that

could threaten the tegument integrity (Schepers and Ringkamp, 2010). Noxious cold

27

and noxious heat stimuli are detected by A-delta and C fibre nociceptors, which are

polymodal, i.e., sensitive to mechanical and thermic stimuli. In the mammalian

peripheral nervous system (PNS), warmth receptors are thought to

be unmyelinated C-fibres (low conduction velocity), while those responding to cold

have both C-fibres and thinly myelinated A-delta fibres (faster conduction velocity)

(Smith et al., 1979).

Nociceptors are receptors in tissues that are activated by painful stimuli. The

receptors send this information from the periphery to the CNS. In addition, there are

two types of nociceptors: (1) high-threshold mechanoreceptors, which respond to

mechanical deformation, and (2) polymodal nociceptors, which respond to various

tissue-damaging inputs.

1.2.8 Anatomy of the nervous system

The nervous system is distinctly divided into two parts: the CNS and the PNS. The

CNS comprises the brain, brainstem, cerebellum and SC, while the PNS comprises

nerve fibres with cell bodies outside the CNS and cutaneous receptors on the skin,

joints and internal organs. The system has two types of nerve fibres: afferent and

efferent. Afferent fibres transmit signals towards the brain, such as those related to

injury or damage from inside or outside the body. Efferent fibres, on the other hand,

carry signals away from the CNS. These fibres are further classified into four main

types of primary sensory neurons, summarised below and illustrated in Figure 1.4:

• A-alpha (Aα): A-alpha fibres (Group I), which are heavily myelinated,

represent motor fibres connected to voluntary muscles and include sensory

fibres that communicate position sensation from skeletal muscles and are

intrinsically related to the proprioception sense.

• A-beta (Aβ): A-beta fibres (Group II), which are myelinated, conduct non-

noxious stimuli and transmit the sensations of touch, vibration, and pressure

on the skin.

• A-delta (Aδ): The A-delta fibre (Group III) is myelinated, permits fast impulse

transmission, and produces sharp and well-localised pain.

• C fibre: The unmyelinated C fibre (Group IV) is slow in transmission and

28

generates dull or burning pain, and the exact location is dispersed and poorly

localized.

Figure 1.4. Nerve fibre classification (based on Lent, 2001)

As displayed in Figure 1.4, nerve fibres associated with low and high-threshold

mechanoreceptors are classified as A-beta, A-delta, or C-fibres based on their

action potential conduction velocities. C fibres are unmyelinated and have the

slowest conduction velocities (0.5-2 m/s), whereas A-delta, A-beta and A-alpha

fibres are lightly and heavily myelinated, respectively, exhibiting intermediate (5-30

m/s) and rapid (35-75 m/s), (80-120 m/s) velocities, respectively.

The peripheral afferent receptors can also be classified into two groups: 1. low-

threshold mechanoreceptors (LTMRs) that respond to pressure or vibration and 2.

high-threshold mechanoreceptors (HTMRs) that react to noxious mechanical

stimulation. LTMRs and HTMRs cell bodies reside within the dorsal root ganglia

(DRG) or cranial ganglia (trigeminal ganglia). LTMRs are also labelled as slowly or

rapidly adapting responses (SA and RA-LTMRs) according to their adaptation rates

to a sustained mechanical stimulus (Roudaut et al., 2012).

29

1.2.8.1 Peripheral afferents and the dorsal root ganglion

As described in section 1.2.8, the first degree of any somatosensory perception

involves activating primary sensory neurons in the skin. The cell bodies of these

sensory receptors occupy the DRG and cranial sensory ganglia. Other ramifications

penetrate the SC and form synapses upon second-order neurons in the SC, grey

matter and the dorsal column nuclei of the brainstem.

Dedicated nociceptors in the somatosensory system convert harmful stimuli into

neural signals that travel along the nervous system, reaching consciousness and

eliciting an appropriate response. These receptors are spread widely in the skin's

superficial layers and specific internal tissues like the periosteum, arterial walls,

joints and falx plus tentorium in the cranial vault (Hall, 2016). These nerve fibres are

of several known subtypes activated by specific painful stimuli: cold, heat, toxins,

and various stimuli. Once activated, these open receptor channels allow positive

ions to enter, resulting in the initial firing of signals from nociceptive fibres. These

receptors are classed primarily by the unmyelinated C-fibres but occasionally

involve the faster-conducting A-delta fibres. C-fibre activation produces the

prolonged burning sensation commonly felt following a painful experience (Hall,

2016). Activation of the A-delta type fibres, in turn, is suggested to produce sharp or

intense sensations such as the “Deqi” phenomenon in acupuncture (see section

1.2.4.1).

A characteristic feature of pain receptors is very poor to no adaption to a stimulus.

Under some conditions, excitation of pain fibres becomes progressively higher,

especially for slow-aching-nauseous pain, as the pain stimulus persists. This

improvement in pain receptor sensitivity is denominated as hyperalgesia. It is

suggested that this inability to adapt by the pain receptors is a necessary

preservation mechanism since the persistence of pain enforces awareness of the

potential tissue lesion (Melzack & Wall, 1988).

The receptor's capacity to detect mechanical information depends on the

mechanotransducer ion channels that convert mechanical energy into electrical

signals. This local depolarisation, called receptor potential, can originate action

30

potentials propagating towards the CNS (Roudaut et al., 2012). Other cutaneous

receptors, such as chemoreceptors and nociceptors, send signals along a sensory

nerve to the SC, where other neurons may process and relay these signals to

the brain for further processing. The representation of the body in the brain is

called somatotopy and is referred to as cortical homunculus. This brain-surface map

is not immutable; however, dramatic shifts can occur due to stroke or injury.

The following section will outline these elements that relay and enhance pain

perception, from the class of peripheral receptors to the principal nerve subtypes,

generally transmitting nociceptive stimuli, SC mechanisms and high brain areas

devoted to pain perception.

1.2.8.1.1 Cutaneous receptors that mediate pain signals

Pain receptors are classified as free-nerve endings HTMRs and free-nerve endings

LTMRs (Roudaut et al., 2012).

• Free-nerve endings HTMRs: HTMRs include mechano-nociceptors activated

by noxious mechanical stimuli and polymodal nociceptors that respond to

harmful heat and exogenous chemicals (Perl, 1996). HTMR afferent fibres

terminate on projection neurons in the dorsal horn of the SC. A-delta-HTMRs

contact the SC’s second-order neurons in laminae I and V, whereas C-

HTMRs terminate in lamina II. Here, second-order nociceptive neurons

project to the white matter in the contralateral side of the SC, forming the

anterolateral system. These neurons terminate mainly in the thalamus.

• Free-nerve endings LMTRs: Generally, C-fibres-free endings in the skin are

HTMRs. However, a subpopulation of tactile C-fibres (CT) does not make a

response to noxious touch. These CT afferents denote a distinct type of

unmyelinated, low-threshold mechanoreceptors located in the hairy skin but

not the glabrous skin of humans and mammals (Valbo, Olausson &

Wessberg,1999). CT is usually related to the perception of pleasant tactile

stimulation in body contact (McGlone, 2007). CT fibre activation may function

in pain inhibition, however, and it has recently been suggested that

31

inflammation or trauma may alter the sensation conveyed by CT-fibre LMTRs

from pleasant touch to pain (Olausson et al., 2010).

1.2.8.2 The spinal cord (SC)

The SC is considered an integrative centre processing all bodily sensations

previously described. It is constituted of a long, tubular structure of nervous tissue,

which spreads from the medulla oblongata in the brainstem to the lumbar column

region and is formed mainly of grey and white matter. The white matter is constituted

chiefly of longitudinally running axons but also contains glial cells. The grey matter,

in turn, consists of nine distinct cellular layers (Rexed laminae), as first defined by

Rexed (1952), forming a butterfly shape, as shown in Figure 1.5. Thus, laminae I-VI

comprises the SC dorsal horn; lamina VII is the intermediate grey matter, while

laminae VIII and IX represent the ventral horn. Finally, area X corresponds to the

area surrounding the central canal. Regarding the processing of nociceptive

information, A-delta or C nociceptors, although occasionally A-beta

mechanoreceptors, enter the dorsal horn of the SC and terminate at the superficial

layers of the dorsal horn (lamina II) known as the substantia gelatinosa (SG). Then,

nociceptive information ascends in the neospinothalamic tract towards the thalamus

ventroposterolateral nucleus and finally to the brain somatosensory cortex, where

nociceptive input is perceived as pain.

Figure 1.5. Spinal cord Rexed laminae (grey matter). The ten Rexed laminae

classification in Italian numerals is on the left (Source: Creative Commons)

32

Table 1.1. Classification and characteristics of Rexed laminae

Lamina I

• Located at the apex of the dorsal horn. Cells respond to

noxious or thermal stimuli conducted by C and delta fibres.

Convey info to the brain by the contralateral spinothalamic

tract

Lamina II

• Corresponds to SG. Implicated in the sensation of noxious

and non-noxious stimuli and modulating the sensory input of

signals as painful or not. It is related to slow pain

transmission. Sends information to laminae III and IV

Lamina III

• Implicated in proprioception and sensation of light touch

• Cells in this layer connect with cells in layers IV, V and VI

Lamina IV

• Involved in processing non-noxious sensory information

• Cells connect with those in lamina II

Lamina V

• Relays sensory and nociceptive info to the brain by the

contralateral spinothalamic tracts. Enter information from the

brain via the corticospinal and rubrospinal tracts

Lamina VI

• Contains interneurons involved in spinal reflexes

• Receives sensory information from muscle spindles

implicated in proprioception. Sends information to the brain

by the ipsilateral spinocerebellar pathways

Lamina VII

• The large, heterogenous zone that varies through the length

of the SC.Receives information from laminae II to VI and

from viscera. Convey motor info to the viscera. It gives rise

to cells implicated in the autonomic system

Lamina VIII

• Most prominent in cervical and lumbar regions. Cells are in

charge of modulating motor output to skeletal muscles

Lamina IX

• Size and shapes vary between SC levels. Correspond to

distinct groups of motor neurons that innervate skeletal

muscles

Lamina X

• Surrounds the central canal (the grey commissure). Axons

cross over (decussate) from one side to the other side of SC

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Numerous connections exist between the laminae, each containing physiological,

histochemical or cytoarchitectonic characteristics. For instance, C fibres terminate

in lamina II, while A-delta fibres terminate primarily in laminae I and V. On the other

hand, A-beta fibres (encoding light touch and vibration) penetrate the cord medial

to the dorsal horn and cross without forming synapses onto the SC dorsal columns

but emitting collateral branches to laminae III and V. These branches also synapse

with endings of unmyelinated C fibres in lamina II. Both laminae II and V are

considered areas for the modulation and localisation of pain (Steeds, 2016).

However, layer V polymodal nonspecific neurons also receive non-nociceptive

external input, albeit these neurons respond to peripheral nociceptors. These

nonspecific neurons project centrally via the palaeospinothalamic tract. This tract

contains crossed and uncrossed fibres that travel towards the hindbrain, forming

synapses in this region in areas such as periaqueductal grey (PAG) or tegmentum

reticular formation before targeting the thalamus, secondary somatosensory cortex,

cingulate and insula in the brain.

1.2.8.3 Ascending pathways

Nociceptive information is relayed to the brain via ascending pathways that target

two main areas. Generally, some inputs target the thalamus and neocortex sensory

regions while others reach the limbic region, such as the amygdala, contributing to

the pain experience's affective and emotional aspects (Basbaum & Woolf,1999). SC

pathways implicated in ascending nociceptive signals transmission towards the

brain is via the anterolateral system, which is comprised of four tracts: the

spinothalamic tract, spinoreticular tract, spinomesencephalic tract, and post-

synaptic dorsal column tract. The spinothalamic tract is the most readily associated

with nociceptive transmission and is divided into the anterior and lateral pathways.

The anterior pathway conveys sensory input related to crude touch, while the lateral

pathway sends signals about temperature and pain. Nonetheless, the two divisions

of the spinothalamic tract can be viewed as a single pathway (Al-Chalabi and Reddy,

2020).

In general, this tract pathway is responsible for transmitting sensory signals from the

SC to the brain that do not require high signal localisation or discrimination of subtle

34

degrees of intensity stimulus. These signals include sensations such as heat, cold,

rough tactile, tickle, itch, sexual sensations or pain. On the other hand, the dorsal

column system, which conveys vibrotactile stimulation, requires a more sensitive

system. Prior to reaching the brain, the spinothalamic tract divides into

neospinothalamic and paleospinothalamic tracts, explained in more detail below

(Hall, 2016):

1.2.8.3.1 Neospinothalamic tract

To recap, fast pain travels from the periphery via A-delta fibres to within the SC

dorsal horn (Laminae I and V), whereby these fibres synapse onto dendrites of

neurons that form the neospinothalamic tract. The neuron's axons then cross the

midline and decussate through the anterior white commissure ascending

contralaterally along with the anterolateral columns. Fast pain is a sharp, acute,

prickling pain perceived in response to mechanical and thermal stimulation (Hall,

2016). A few fibres of the neospinothalamic tract that carry tactile sensation project

to the brainstem reticular areas, bypassing the thalamus without synapsing and

terminating in the ventrobasal complex and the dorsal column medial lemniscal

tract. Others, however, target the posterior nuclear group of the thalamus. The

signals are transmitted from these thalamic areas to other basal regions of the brain

and, ultimately, the somatosensory cortex (Hall, 2016).

1.2.8.3.2 Paleospinothalamic tract

Slow pain is conducted via slower type C fibres at the periphery (skin or viscera) to

laminae II and III of the SC. Impulses are also transmitted by nerve fibres that

terminate in lamina V. These synapse with neurons that form the fast pathway,

crossing to the opposite side by the anterior white commissure and projecting

upwards through the anterolateral route. The slow-chronic paleospinothalamic

pathway targets several areas of the brain stem. Only one-tenth to one-fourth of

these travel to the thalamus. Most terminate in one of three areas: (1) reticular nuclei

of the medulla, pons and mesencephalon; (2) tectal area of the mesencephalon

(superior and inferior colliculi); and (3) the PAG region encircling the aqueduct of

Sylvius (Hall, 2016). These brain regions are essential for processing the

35

phenomenon of suffering secondary to pain. From these brain stem areas, multiple

short-fibre neurons then relay pain signals to the intralaminar and ventrolateral

nuclei of the thalamus and other basal regions of the brain, including the

hypothalamus. The localisation of pain transmitted by the paleospinothalamic

pathway is imprecise. For example, slow-chronic pain can usually be localised only

to a significant body region, such as an arm or leg but not to a particular point on

the arm or leg (Hall, 2016).

1.2.8.3.3 The central role of the Thalamus in somatosensory sensation

The thalamus is considered a key player in processing somatosensory information.

Axons within the lateral and medial spinothalamic tracts end in the medial and lateral

nuclei of the thalamus. Here, neurons project to the primary and secondary

somatosensory cortices, insula, anterior cingulate, and prefrontal cortex. This

network is considered key in how pain is perceived, but equally in promoting motor

and emotional responses through interactions with other brain areas such as the

cerebellum and basal ganglia. The latter is more readily associated with motor

function rather than pain (Steeds, 2016). It is remarked that damage to the

somatosensory cortex has little impact on the awareness of pain perception and has

a moderate impact on the sense of temperature. These sensibilities emerge early in

animals' phylogenetic development, whereas the subtle tactile aptitudes and the

somatosensory cortex were late developments (Hall, 2016).

1.2.8.4 Descending pathways

1.2.8.4.1 Pain modulation at higher brain levels

Pathways activated by painful stimuli connect to many brain areas involved in fear,

anxiety, mood, and autonomic responses. These areas include the limbic system,

thalamus and somatosensory regions. In turn, activity from descending fibres

originating in supraspinal regions projects to the SC to modulate these pain signals.

The study of these facilitatory and inhibitory pathways has improved knowledge of

the mechanisms of drugs used to relieve pain, such as antidepressants or

36

neuromodulation therapies and also comprehension of events underlying pain

states (Dickenson, 2016).

Descending pain inhibition is crucial to translating physiological and pathological

pain (Sirucek et al., 2023). It is generally accepted that the descending pain

modulatory system and multiple supraspinal sites exert potent effects on the

nociceptive message's inhibitory response at the spinal level (Ma, 2004).

The two crucial brainstem areas in the descending pain modulatory system are the

PAG and the nucleus raphe magnus (NRM). These brain areas are responsible for

analgesia, and injection of morphine in these sites produced a far more significant

analgesic effect than injections elsewhere in the CNS. The PAG has inputs from the

thalamus, hypothalamus, cortex and collaterals from the spinothalamic tract. The

NRM, in turn, is situated in the medulla's raphe nuclei and, like the noradrenalin-

containing neurons, its axons synapse on cells in lamina II and III. Stimulation of the

raphe nuclei is reported to generate a potent analgesic effect via serotonergic

neurons activating inhibitory interneurons responsible for ablating pain transmission

(Steeds, 2016).

The main neurotransmitters within the descending pain control system are

monoamines like noradrenaline, GABA or serotonin, although the opioidergic

system is also involved. Although opioid receptors are found throughout the CNS,

these neuropeptides also have a specific analgesic effect through descending

pathways (Bagley & Ingram, 2020).

1.2.8.4.2 Analgesia system in the brain and spinal cord

The level to which an individual reacts to pain varies enormously. This fact depends

partially on the brain's ability to suppress pain signals' input to the nervous system

by operating a pain control system called the analgesia system (Hall, 2016). This

network is classified into three major components: (1) The PAG and periventricular

areas of the mesencephalon, upper pons around the aqueduct of Sylvius, and parts

of the third and fourth ventricles. (2) The raphe magnus nucleus (RMN), plus the

37

nucleus reticularis paragigantocellularis, is positioned laterally in the medulla. (3) A

pain inhibitory network within the SC dorsal horns.

1.2.9 Neurochemistry involved in pain modulation

This section will discuss the biological agents responsible for transmitting or

regulating pain perception. Pain modulation involves different neurotransmitters,

some of which have an excitatory effect while others have an inhibitory effect. The

most commonly known excitatory neurotransmitters are glutamate, epinephrine,

dopamine or aspartate, while the most commonly known inhibitory

neurotransmitters are opioids, GABA, glycine, serotonin, adenosine or

cannabinoids.

Neurotransmitters are chemical substances that mediate the transmission of

impulses across the synapses initiated from the presynaptic neuron. The binding of

neurotransmitters to its receptor on the postsynaptic membrane influences pain

transmission in either an inhibitory or excitatory way. These neurotransmitters can

be characterised based on function (excitatory or inhibitory), molecular size (small

molecules, including amino acids and monoamines, or large molecules, including

peptides), or type (inflammatory mediators, such as prostaglandins, adenosine

triphosphate (ATP), histamine, glutamate, and nitric oxide or non-inflammatory

mediators, including GABA, glycine or cannabinoids) (Yam et al., 2018). In addition,

glial cells, such as microglia and astrocytes, can also release various

neurotransmitters that contribute to the development and maintenance of pain

states by activating or deactivating nociceptive neurons in the CNS (Ji, Berta and

Nedergaard, 2013).

The following subsections will discuss in detail only the most relevant

neurotransmitters to this thesis for simplicity.

1.2.9.1 Opioids

Among the many neurotransmitters involved in pain modulation, opioids are the

most relevant. The endogenous opioid peptide system, comprised of enkephalins,

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endorphins, dynorphins, and nociceptin, is a highly complex neurobiological system

(Conway, Mikati & Al-Hasani, 2022). These neuropeptides are also suggested as

the mechanisms of action by acupuncture and/or music. Endogenous opioids are

fundamental mediators in the descending pain suppression pathways. Additionally,

monoaminergic neurotransmitters such as norepinephrine, serotonin and dopamine

positively or negatively modulate pain signalling, depending on receptor type and

location (Argoff, 2011).

More than 50 years ago, it was observed that injection of morphine into the PAG

created an extreme degree of analgesia (Loyd & Murphy, 2009; Hall 2016). In later

studies, it has been found that morphine-like agents, primarily opiates, act in many

other areas in the analgesia system, including the SC dorsal horns (Kirkpatrick et

al., 2015; Steeds, 2016). Because most drugs that alter the excitability of neurons

act on synaptic receptors, it was presumed that the morphine receptors of the

analgesia complex must be receptors for any morphine-like neurotransmitter

naturally released in the brain. Many opiate-like substances have been found in

different areas of the nervous system. The most critical opioid substances are beta-

endorphin, met-enkephalin, leu-enkephalin, and dynorphin (Hall, 2016).

Enkephalins originate in the brain stem and SC, as well as other regions of the

analgesia system; beta-endorphin is present in the hypothalamus and the pituitary

gland, while dynorphin is merged primarily in the same regions as the enkephalins

but in a lower proportion. Although the brain opioid system details are still to be fully

understood, activating the analgesia system by neuronal signals penetrating the

PAG and periventricular areas or inhibiting pain pathways by morphine-like drugs

can suppress pain signals in the peripheral nerves.

In the last few decades, various clinical proceedings have been developed for

inhibiting pain by electrical, magnetic or vibroacoustic stimulation of afferent neural

pathways—surveys of the extensively used TENS, for instance, have suggested that

most patients experience analgesia soon after the technique is implemented, but

fewer can obtain prolonged relief. Notwithstanding this ambiguous data, the safety of

the noninvasive techniques and the observation that some patients benefit

significantly from even temporary relief justify the therapeutic trials selected. The

electrodes are placed directly on specific skin areas, implanted over the SC to

39

stimulate the dorsal sensory columns, or placed in the thalamus or the periventricular

and PAG area of the diencephalon or adapted to chairs, tables or platforms in

techniques such as vibroacoustic stimulation which uses mechanical waves instead

of electrical waves most commonly used in EA or TENS.

However, the precise effect of these frequencies, especially concerning the

frequency spectrum or combination of frequencies, is a hotly debated topic.

Previous studies have suggested that the mechanism activated by EA and TENS

may differ according to the stimulation frequency (Han, 2003; Han, 2004; Plaster et

al., 2014; Kimura et., 2015; Lee et al., 2017).

It is important to note that low-frequency EA (2 Hz) is highly effective in increasing

the release of opioids such as met-enkephalin, endomorphin, or beta-endorphin,

which are particularly useful in relieving neuropathic pain (Han, 2003; Kimura et al.,

2015). On the other hand, high-frequency EA (100 Hz) is more effective in releasing

spinal dynorphin, which is better suited for inflammatory pain and muscle spasms.

If the goal is to stimulate the simultaneous release of multiple opioids, it is

recommended to apply alternate frequencies (2/100 Hz EA), as this cannot be

achieved with a single frequency (Kimura et al., 2015).

1.2.9.2 GABA and glycine

GABA is a crucial inhibitory transmitter in the mammalian CNS, making up

approximately 40% of brain synapses. It is present in interneurons throughout the

SC, neocortex, and cerebellum and is produced by GABAergic neurons mainly

located in the brain (Watanabe et al., 2002). GABA is the primary inhibitory

neurotransmitter in higher CNS levels, while glycine is more prevalent at spinal

levels. Both are vital for inhibiting the somatosensory system, and most modulatory

projections in the CNS are GABAergic or glycinergic (Kirkpatrick et al., 2015).

Research shows that GABA and glycine receptors facilitate the rapid conductance

of Cl- ions in laminae I-III (Todd et al., 1996). Additionally, dysfunction in these

systems can contribute to neuropathic and inflammatory pain (Vandenberg et al.,

2014). In addition, GABA is critical in reducing neuron excitement levels in the CNS

and regulating muscle tone. Its activation of receptors in specific areas can also

40

impact pain levels by blocking the release of other neurotransmitters. However, It is

worth noting that conditions like chronic inflammation or nerve damage can cause

GABA receptors to malfunction, leading to heightened sensitivity and increased pain

(Yang and Chang, 2019).

1.2.9.3 Serotonin (5-HT)

Serotonin (5-hydroxytryptamine, 5-HT) is a monoamine widely distributed at the

periphery and in the CNS. Among monoamine neurotransmitters, serotonin is

known to play complex modulatory roles in pain signalling mechanisms since the

first reports, about forty years ago, on its essentially pro-nociceptive effects at the

periphery and anti-nociceptive effects when injected directly at the SC level (Viguier

et al., 2013). Serotonin in brain descending pathways predominantly originates in

the raphe nuclei in the midline from the medulla to the midbrain. These descending

projections of the NRM provide the main serotonergic innervation of the SC,

whereas the midbrain dorsal raphe nucleus provides ascending serotonergic

innervation to the cerebral cortex. To date, seven classes of 5-HT receptors (5-HT1–

5-HT7) have been identified that comprise at least 15 subtypes responsible for the

differing effects of serotonin modulation. Most of the studies concerning 5-HT have

focused on two central pain control levels: the SC's dorsal horn and the midbrain,

which are anatomically and functionally interconnected (Viguier et al., 2013). In

addition, serotonin is also associated with an increase in alpha-brain wave activity,

which is related to relaxation (Puig and Gener, 2015). The diffuse projection of 5-

HT neurons to many brain regions and the remarkable influence of 5-HT on neuronal

activity suggest that the serotonergic system is a major modulator of brain rhythms

(Puig and Gener, 2015). Additional information regarding the function of brain

rhythms will be expanded in the upcoming sections.

1.2.9.4 Dopamine

Dopamine, like serotonin, is a monoamine which exerts an important role in the

regulation of several aspects of behaviour, such as motivation, reinforcement,

mood, movement, and cognitive functions (Martikainen et al., 2018) or activation of

brain reward circuits as well as pleasure (Mitsi and Zachariou, 2016). Like opioids,

dopamine acts in the reward pathway and can influence "wanting" (Kirkpatrick et al.,

41

2015). In addition, individuals with dopamine-related diseases, such as Parkinson's

and restless leg syndrome, are more susceptible to pain disorders (Kirkpatrick et

al., 2015; Martikainen et al., 2018). Dopamine also plays a critical role in fear and

anxiety, affecting the amygdala and pain processing (Kirkpatrick et al., 2015).

Clinical and preclinical research suggests that the brain reward centre plays a

crucial part in regulating nociception and that changes in dopaminergic circuitry may

impact various sensory and emotional aspects of pain syndromes (Mitsi &

Zachariou, 2016). According to Lohani et al. (2019), dopamine increases oscillatory

activity at the gamma brain wave range. High and low gamma oscillations are

implicated in dopamine-dependent cognitive processes, such as working memory

and attention. Research by Chanda and Levitin (2013) suggests that music can

positively impact health and well-being by activating neurochemical systems linked

to reward, motivation, and pleasure. Extensive research conducted by Boso et al.

(2006) and Chanda and Levitin (2013) has established that the release of dopamine

and endogenous opioids in the midbrain structure plays a crucial role in shaping the

perception of music. Some studies on vibration therapy also indicate that vibration

can enhance dopamine levels in the brain (Mosabbir, Almeida, and Ahonen, 2020).

This effect may explain why some people with Parkinson's disease have reported

improvements in their symptoms after trying various forms of vibrations, such as

locally applied vibrations, whole-body vibrations, and physioacoustic low-frequency

vibrations (Mosabbir, Almeida, and Ahonen, 2020).

1.2.9.5 Cannabinoids

Cannabis cultivation for spiritual, recreational, and medicinal purposes has been

practised for thousands of years worldwide. However, the mid-20th century's

cannabis prohibition brought research on cannabis to a halt. Nowadays, there is a

growing debate on the use of cannabis for medical purposes with the guidance of a

physician. This involves using the cannabis plant and its components, known as

cannabinoids, to treat diseases or alleviate symptoms. Medical cannabis is

commonly used for pain relief, and cannabinoids act on cannabinoid receptors while

also impacting multiple other receptors, ion channels, and enzymes (Vučkovic et al.,

2018). Cannabinoids have various mechanisms of action to alleviate pain, which

include inhibiting the release of neurotransmitters and neuropeptides from

42

presynaptic nerve endings, modulating postsynaptic neuron excitability, activating

descending inhibitory pain pathways, and reducing neural inflammation (Vučkovic

et al., 2018).

Cannabis has a historical association with different music genres, including jazz,

bossa nova, reggae or rock and has been linked to a heightened appreciation of

music. This connection may be due to shared effects on the reward system between

drug and non-drug rewards (Freeman et al., 2018). The endocannabinoid system

contains cannabinoid receptors, endogenous cannabinoids (endocannabinoids),

proteins, and enzymes responsible for synthesising or breaking down

endocannabinoids (Vučkovic et al., 2018). Many brain regions involved in reward

are characterised by a high density of cannabinoid receptors (Curran et al., 2016).

1.2.10 The Pain system: classification, presentation and management

1.2.10.1 Introduction

According to Tracey and Mantyh (2007), pain is a subjective experience influenced

by various factors such as memories, emotions, genetics, pathology, and cognitive

processes. It is essentially an interpretation of the nociceptive input.

Pain's ultimate perception involves inhibitory or facilitatory mechanisms that can

alter a nociceptive stimulus as painful or non-painful or even affect its perceived

intensity (Argoff, 2011).

The following subsections will review the features of the most common pain types

commonly observed in the acupuncture clinical setting.

1.2.10.2 Pain Types

• Acute pain: Acute pain is an unpleasant, complex, dynamic

psychophysiological response to tissue trauma and related acute

inflammatory processes. Usually, severe pain is self-limiting and confined to

a given period. It arises in response to tissue injury, disease, or inflammation.

Acute pain serves a protective biological function that minimises behaviours

that incur risk and fosters tissue healing. Although severe pain promotes

43

survival in a primitive environment, in medical settings such as recovery from

surgery, the physiological processes accompanying acute pain, if

uncontrolled, can exert deleterious influences on health and generate chronic

pain syndromes (Chapman & Vierck, 2017). According to Melzack (2001),

acute pains evoked by brief noxious inputs and their sensory transmission

mechanisms are generally well understood. In contrast, chronic pain

syndromes, often characterised by severe pain associated with little or no

discernible injury or pathology, remain a mystery.

• Chronic pain: Chronic pain due to musculoskeletal conditions relies on pain

chronicity (more than three months duration) and widespread distribution,

referring to both sides of the body, including the axial skeleton (Cimmino,

Ferrone, & Cutolo, 2011). In recent years, one significant progress in pain

research has been identifying that chronic, persistent pain is a distinct

medical entity different from acute pain in many respects (Melzack, 2001;

Dickenson, 2016; Vickers et al., 2018). Melzack and Wall (1988) have

established that pain serves several protective purposes. Memories

associated with pain can help prevent future dangerous situations while

ensuring that an injured body rests after a severe injury or illness, thus

promoting healing. However, some aspects of pain remain a mystery and are

difficult to comprehend. Chronic pain is not a mere indication of physical

injury or illness but rather a disease resulting from a dysfunctional neural

mechanism (Melzack & Wall, 1988). It becomes a pain syndrome – a medical

problem in its own right, and medications generally adequate for acute pain

are insufficient for chronic pain. Patients are afflicted with a sense of

helplessness, hopelessness, and meaninglessness. The pain becomes

unbearable and serves no proper function. Medicine must solve two salient

challenges: understanding chronic pain and new relieving methods (Melzack

& Wall, 1988).

• Neuropathic pain: Neuropathic pain is generated by a direct result of an

injury or disease affecting the somatosensory system ( Haanp�� et al., 2011).

• Inflammatory pain: This pain results from tissue damage and local chemical

release, resulting in inflammation (e.g., postoperative pain, trauma, arthritis).

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1.2.10.3 Pain theories: Specificity, pattern and gate control

A plurality of theories have been proposed to define mechanisms related to pain

perception. These theories date back many centuries and even millennia. In Ancient

Greece, Plato and Aristotle stated that pain is an emotional rather than a sensory

experience, something experienced by the human soul. Aristotle believed it to be

like a spirit that enters the body through an injury. In 1664, Rene Descartes wrote

the Treatise of Man, which outlines the pain pathway. His comprehension was that

perceived pain in the brain was transmitted in only one route - the same way used

by other sensations (Seth & Gray, 2016). The character of pain has been the subject

of severe discussion since the turn of the 20th century. The most significant pain

theories comprise the specificity, pattern, gate control theory (GCT), neuromatrix

theory of pain (NM), and biopsychosocial pain model.

• Specificity theory

According to this theory, pain is considered a distinct modality, much like vision or

hearing, complete with its own central and peripheral apparatus (Moayedi & Davis,

2013). This theory posits that pain is generated by pain receptors in free nerve

endings, transmitting pain impulses through A-delta and C fibres in peripheral

nerves, ultimately reaching the lateral spinothalamic tract in the spinal cord and the

pain centre in the thalamus.

• Pattern theory

The pattern theory suggests the nature of a rapid conduction fibre system that

inhibits synaptic transmission in a more slow conduction system that transmits pain

signals. These systems are epicritic and protopathic (fast and slow transmission

signals, phylogenetically new and old, and myelinated and unmyelinated fibre

systems). In painful situations, the slow system maintains dominance over the fast,

resulting in a protopathic sensation, diffuse burning pain, and hyperalgesia (Melzack

& Wall, 1965).

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• The GCT of pain

The first formulation of GCT proposed by Melzack and Wall in 1965 states that the

perception of pain assembled by SC signalling to the brain relies on a balance of

activity generated in large and small diameter primary afferent fibres. The theory

suggests that activation of the large-diameter afferent fibres ‘‘closes’’ the gate of

pain by triggering a superficial dorsal horn interneuron that inhibits the excitation of

projection neurons. Thus, pain-control gates appear to consist of inhibitory neurons

in the SC activated by tactile stimulation concomitantly with pain information input

(Melzack & Wall, 1965). After its publication, the GCT had a prominent influence on

pain treatment. Its emphasis on a dynamic balance between excitatory and

inhibitory influences, including feedback interactions between spinal and brain

levels, has been the basis of a new conceptual approach to pain therapy and has

suggested new treatment forms.

In recent years, the GCT has introduced new techniques to modulate sensory input.

It suggests pain control may be achieved by enhancing normal physiological

activities rather than disrupting destructive, irreversible lesions. Fewer surgeries,

such as rhizotomies or cordotomies, are now being carried out, and neurosurgeons

are turning increasingly to non-destructive approaches, such as using devices to

electrically stimulate nerves, the SC and specific areas of the brain.

According to the GCT, stimulation of the skin produces nerve impulses that are

disseminated to three SC systems: (1) cells of the SG in the dorsal horn, (2) the

dorsal-column fibres that project toward the brain, and (3) the first central

transmission (T) cells in the dorsal horn. The SG is a gate control process that

modulates the afferent patterns before influencing the T cells. The afferent patterns

in the dorsal column horns perform as a central control, which activates selective

brain processes that affect the gate control system's modulating properties. The T

cells activate neural mechanisms, including the action system responsible for

response and perception. The GCT proposes that pain is determined by interactions

among these three systems (Melzack & Wall, 1965).

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Figure 1.6. Schematic diagram of the GCT of pain by Melzack and Wall

(Melzack & Wall, Science, 1965,150,971-979)

Figure 1.6 demonstrates that the stimulation of skin triggers nerve impulses that

travel to three spinal cord systems: the substantia gelatinosa (SG) cells located in

the dorsal horn, the dorsal-column fibres, and the first central transmission (T) cells

in the dorsal horn. SG cells serve as a gate control system that regulates the

synaptic transmission of nerve impulses from peripheral fibres to central cells.

Afferent fibres of both large (L) and small-diameter (S) project to SG and T cells.

SG's inhibitory effect (-) on afferent terminals is enhanced (+) by L fibre activity and

reduced by S fibre activity. Additionally, a specialised L fibre system known as the

central control trigger activates particular cognitive processes that influence the

spinal gating mechanism modulating properties through descending fibres.

The GCT is the main theory that explains how EA or vibroacoustic-related

techniques act to produce its effects. GCT vibration activates fibres of all diameters

but enables a more significant proportion of A-beta-fibres since these fibres tend to

adapt during constant stimulation, whereas C-fibre firing is maintained. Vibration,

therefore, sets the gate in a more closed position. When sensitive information

reaches a threshold that surpasses the inhibition promoted, it “opens the gate” and

mobilises pathways that lead to the experience of pain and its associated

behaviours. Therefore, the GCT provided a neural basis that helped harmonise the

divergence among the pattern and specificity theories of pain (Moayedi & Davis,

2013).

47

In summary, the model's therapeutic implications suggest that pain control may be

achieved by selectively influencing the large, rapidly conducting fibres. The gate

may be closed by decreasing the small fibre input and enhancing the large fibre

input (Melzack & Wall, 1965).

1.2.10.4 Pain models: Neuromatrix, biopsychosocial and palliative care

• Neuromatrix theory of pain (NM)

The NM theory infers that pain is a multidimensional event created by

idiosyncratic “neuro signature” patterns of nerve impulses initiated by an

extensive widespread neural network – the “body-self neuromatrix”- in the

brain (Melzack, 2001). Sensory inputs may activate these neuro signature

patterns but may also originate autonomously. The NM proposes that the

output patterns of the body-self neuromatrix trigger perceptual, homeostatic,

and behavioural programs after injury, disease, or chronic stress. Pain is

generated by the output of a broadly disseminated neural network in the brain

rather than directly by sensory input enhanced by trauma, inflammation, or

other disturbances. The NM is genetically determined and modified by

sensory experience, the primary mechanism that generates the neural

pattern that produces pain (Melzack, 2001). The NM led experts away from

the Cartesian theory of pain as a sensation created by trauma, inflammation,

or other tissue pathology and onto the notion of pain as a multidimensional

experience generated by multiple influences (Moayedi & Davis,

2013). Genetic characteristics of synaptic configuration could influence the

advancement of chronic pain syndromes.

• Biopsychosocial model

Comprehending the biopsychosocial model is essential to understand the

difference between nociception and pain. Nociception is the stimulation of

nerves conveying information about tissue damage to the brain. Pain refers

to the subjective experience resulting from transduction, transmission and

modulation of nociception and its complex interactions with genetics,

previous history of pain, current mood state and surrounding socio-cultural

48

environment (Seth & Gray, 2016). George Engel (1981) credited and

introduced the biopsychosocial model of illness. In contrast to the biomedical

model, Engel states that illness results from a complex interaction between

various biological, psychological and social factors. These factors culminated

in a biopsychosocial interdisciplinary care model, incorporating physical

treatment with cognitive, behavioural, environmental, and emotional

interventions. From this emerged four dimensions of pain: nociception, pain,

suffering, and pain behaviour (Engel, 1981).

• Palliative care

Palliative care is an interdisciplinary speciality focused on boosting the quality

of life for persons with severe illness and their families. Over the past decade,

the field has substantially grown and increased public and professional

awareness (Kelley & Morrison, 2015). According to the World Health

Organization (2017), palliative care is a method that increases the capacity

the life span of patients and their families who are confronted with severe

disease through the prevention and consolation of suffering by employing

early identification and impeccable assessment of physical, psychosocial,

and spiritual problems. In current usage, palliative care has a connotation of

uselessness and ineffectiveness; however, it is the only treatment that is truly

useful to patients with chronic pain and who are in the last stages of their life

or are dying (Perrin & Kazanowski, 2015).

1.2.10.5 Clinical pain conditions

One of the most common painful conditions is musculoskeletal (MSK) pain which is

defined as acute or chronic pain affecting bones, muscles, ligaments, tendons and

nerves, including many different pain syndromes, ranging from local to neuropathic

pain (El-Tallawy et al., 2021). MSK pain has many symptoms and causes. Some of

the more common are exemplified as follows:

• Bone Pain: Usually deep, penetrating, or dull. It results from injury or

diseases such as bone cancer.

• Muscle Pain: Muscle pain can be produced by an injury, an autoimmune

reaction, an infection, or a tumour. The pain includes muscle spasms and

49

cramps.

• Tendon and Ligament Pain: Injuries, including sprains, often provoke pains

in the tendons or ligaments. MSK pain turns worse when the affected area is

stretched or moved.

• Joint Pain: Joint injuries and diseases generally produce stiff, aching

soreness. The pain spectrum varies from mild to severe and worsens when

moving the joint. Joint inflammation (arthritis) is the usual cause of pain.

• Tunnel Syndromes: These refer to musculoskeletal disorders that originate

from pain due to nerve constriction. Examples include carpal tunnel

syndrome, cubital tunnel syndrome, and tarsal tunnel syndrome. The pain

spreads along the path supplied by the nerve and may feel like burning.

These disorders are often caused by overuse.

• Fibromyalgia: Fibromyalgia (FM) is a syndrome distinguished by chronic

MSK pain and a multifactorial dysfunction that presents with sleep disorders,

fatigue, muscular stiffness, anxiety, and depression (Wolfe et al., 2010). FM

affects two per cent of the population and attacks more females than males

(7:1). The dysfunction is believed to be caused by increased sensitivity of the

CNS, amplifying pain perception, including central sensitisation and

inadequate pain inhibition (Staud, 2006; Desmeules et al., 2003). It is well

known that continuous or sharp nociception can produce neuroplastic

changes in the SC and brain. This mechanism represents a hallmark of FM

and many other chronic pain syndromes (Staud, 2006).

1.2.10.6 Pain generating stimuli

Various types of stimuli can elicit MSK pain. These distinct stimuli are categorised

as mechanical, thermal or chemical. In general, the mechanical and thermal types

of stimuli produce fast pain, whereas all three types can elicit slow pain. The most

common chemical stimuli are bradykinin, serotonin, histamine, potassium ions,

acetylcholine, and proteolytic enzymes that promote the chemical type of pain. Also,

prostaglandins and substance P enhance the sensitivity of pain endings. The

chemical substances stimulate the slow, suffering pain after tissue injury. However,

many pains arise from tissue damage, such as trauma, surgery, and arthritis.

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1.2.11 Pain management

There have been three main approaches to combat pain: medication, sensory-

modulation techniques and psychological procedures. Regarding the former, early

historical records demonstrate the use of poppy juice (opium) to treat various

illnesses. Various drugs and sensory-modulation methods evolved in communion

with powerful psychological suggestions in all cultures and countries. The herbs,

cuts, and burns were administered by the healers of the time, who often combined

rhythmic, hypnotic chants, musical instruments, and prayers alongside medication

and instilled an unquestioned expectation of pain relief (Melzack & Wall, 1988).

Regarding sensory-modulation techniques, the neuromodulation field for intractable

and chronic pain was developed after Wall and Melzack's GCT of pain in 1965. Wall

and Sweet's (1967) study was the first reference to pain relief using electric

stimulation on eight participants with chronic neuropathic pain. The stimulation

consisted of 0.1 ms pulses at a rate of 100 Hz for two minutes, with the voltage

adjusted until patients reported a tingling sensation in the affected area. Since then,

various methods have been implemented in peripheral nerve stimulation, including

sound technologies, trans and percutaneous implantation techniques, smaller

devices, and rechargeable and larger-capacity batteries (Nayak & Banik, 2018).

Peripheral nerve stimulation also includes other different methods, such as SC

stimulation, occipital nerve stimulation, and vagal nerve stimulation, which have

been used to treat pain conditions such as inflammatory and peripheral nerve

disorders, complex regional pain syndrome, and cranial neuralgias (Nayak & Banik,

2018). A new generation of peripheral nerve stimulation devices has been

developed, allowing pulse generators to transmit impulses wirelessly to the

implanted electrode with a less invasive action.

To corroborate these new developments, previous studies on the mechanisms of

action of acupuncture, for instance, have denoted that endogenous opioid peptides

in the CNS play a fundamental role in mediating the MA and EA analgesic effect

(Han, 2003; Han, 2004). Further studies have shown that EA releases different

neuropeptides with distinct frequencies. For example, EA of 2 Hz improves the

release of enkephalin, beta-endorphin and endomorphin, while 100 Hz increases

dynorphin release (Han, 2003). Combining two frequencies generates a

51

synchronous release of all four opioid peptides, culminating in a maximal therapeutic

action. This finding has been testified in clinical studies with patients with chronic

low back pain and diabetic neuropathic pain (Han, 2003; Han, 2004; Kimura et al.,

2015).

The following subsections will list briefly pharmacological and non-pharmacological

methods in pain management.

1.2.11.1 Pharmacological

Drugs used to treat pain can be divided into three broad categories: nonsteroidal

anti-inflammatory drugs, adjuvant analgesics, and opioids, as cited below:

• Nonsteroidal anti-inflammatory drugs: Acetaminophen, Aspirin, Ibuprofen,

Naproxen, Diclofenac, and Piroxicam.

• Adjuvant analgesics: Antidepressants (Amitriptyline, Fluoxetine,

Paroxetine), Anticonvulsants (Carbamazepine, Gabapentin), Oral local

anaesthetics (Mexiletine), Neuroleptics (Haloperidol), Muscle relaxants

(Orphenadrine), Antihistamines (Hydroxyzine), Alpha-2 adrenergic agonists

(Clonidine), Benzodiazepines (Diazepam, Mizadolan), Drugs for

sympathetically maintained pain (Prazosin).

• Opioid analgesics: Morphine, Codeine, Methadone, Fentanyl.

1.2.11.2 Surgical

• Cordotomy, lobotomy, neural blockade and intraspinal infusional modalities.

1.2.11.3 Non-pharmacological

• Psychologic approaches such as cognitive and behavioural therapies

• Peripheric, electric or magnetic stimulation (MA, EA, TENS, transcranial

magnetic stimulation (TMS)): These methods can be delivered via electrodes

placed on the skin, known as TENS, or by a probe inserted through the skin

into the tissue called percutaneous electrical nerve stimulation (PENS). If the

local stimulation is based on traditional acupuncture therapy and a jack is

52

fixed on the needle cable inserted into the skin, the method is denominated

EA (Han, 2003).

• Vibroacoustic approaches (VAT, MVT, LFSS, WBV): Vibroacoustic methods

stimulate the body by using vibration produced by transducers fixed on

chairs, tables, or platforms (described in section 1.2.6).

Understanding how this wide variety of methods and technologies affect the human

brain and body is crucial. Given that the current study uses vibration to stimulate

acupoints, the following topic will delve into the essential components of the

structures responsible for detecting vibroacoustic stimuli in the human body,

including their neurophysiology and anatomy.

1.2.12 Cutaneous receptors that mediate vibration signals

The receptors on the skin that detect sensations such as a light breeze or touch are

also involved in perceiving sound and vibrations. To fully understand how vibrations

affect the human body, it is essential to understand the basic structures called

mechanoreceptors, which will be discussed in the following section. These

mechanoreceptors are as follows:

• Pacini Corpuscles (PC)

PC is the skin's deeper mechanoreceptor and its most sensitive

encapsulated cutaneous mechanoreceptor. These large corpuscles (1 mm in

length) have an ovoid structure made of lamellae of connective tissue and

fibroblasts aligned by flat modified Schwann cells located in the deep dermis

(Johnson, 2001). A fluid-filled cavity called the inner bulb in the corpuscle

centre terminates one A beta afferent fibre. PC exhibits rapid adaptation in

response to the skin's indentation and is considered rapidly adapting II (RA

II) mechanoreceptors. The receptors can detect changes in the intensity and

rhythm of the stimulus, specifically in response to vibrations. Even faraway

events can be detected through transmitted vibrations, as noted by

Mendelson and Lowenstein (1964), making these receptors extremely

efficient and reliable. In addition these cutaneous receptors have a high

53

sensitivity to vibrations, especially within the range of 0.5 Hz up to

approximately 1000 Hz (Bolanowski et al., 1988), 20-1000 Hz (Bolanowski &

Zwislocki, 1984), 30-1000 Hz (Morley & Rowe,1990), 40-1000 Hz (Talbot et

al., 1968; Bell, Bolanowski, & Holmes, 1994; 60-300 Hz (Chesky et al., 1997).

It was speculated that PC signals might suppress nociceptive transmission

via adenosine acting on P1- P1-purinergic receptors at the SC level (Salter

& Henry 1987). In a study by Lundeberg (1984), the fundamental frequency

for reducing pain was between 50 and 200 Hz. According to Ottoson (1981),

vibratory stimulation at 100 Hz could be a helpful procedure in relieving pain

in patients with acute or chronic orofacial pain and acute or chronic pain of

musculoskeletal origin. Other studies have examined pain conditions like

rheumatoid arthritis using 40 Hz (Chesky,1992), sports injuries and low back

pain using 52 Hz (Skille, Wigran, & Weeks, 1989; Wigram, 1995). According

to Skille (1991), frequencies between 30 Hz and 120 Hz are therapeutic, with

the most beneficial being those between 40 and 80 Hz. Chesky (1997) found

that 60 Hz to 300 Hz vibroacoustic frequencies provided optimal pain relief

because this frequency range stimulated PC.

• Meissner corpuscles

Meissner corpuscles anatomically consist of an encapsulated nerve ending

in the dermal papillae on the glabrous skin, primarily situated in hand palms

and foot soles, lips, tongue, face, nipples, and genitals. The capsule

comprises flattened cells aligned as horizontal lamellae embedded in

connective tissue. Each corpuscle is exclusively connected to a distinct nerve,

specifically an A-beta afferent. If the corpuscle undergoes any physical

alteration, it triggers a flurry of action potentials that cease shortly after that.

These receptors are classified as rapidly adapting receptors. When the

stimulus is withdrawn, the corpuscle regains shape and produces another

volley of action potential. Due to their superficial position in the dermis, these

corpuscles react to skin motion, tactile slip detection, and low-frequency

vibrations (20-40 Hz). Meissner’s corpuscles also adapt in a fraction of a

second after being stimulated, making these receptors susceptible to moving

objects over the skin's surface and low-frequency vibration (Vega et al., 2009).

54

Third, fingertips and other areas containing many Meissner’s corpuscles

usually include large quantities of Merkel’s discs. The Meissner corpuscle is

unique to glabrous skin and is a multi-afferent end organ with three distinct

types of innervation. In addition to innervation consistent with its

mechanoreceptive properties (alpha and beta fibres), the Meissner corpuscle

has two kinds of C-fibre innervation, typically implicated in nociception (Par�

et al., 2001).

• Merkel cell-neurite complexes

Merkel cell-neurite complexes are abundant in the skin, especially in touch-

sensitive areas like the epidermis basal level, mainly in fingers, lips, and

genitals. These cutaneous receptors also exist in hairy skin at a reduced

density. Anatomically, the Merkel cell-neurite complex comprises a Merkel

cell in apposition to an enlarged nerve from a single myelinated A beta fibre.

Stimulation of Merkel cell-neurite complex results in slowly-adapting Type I

(SA I) responses, originating from punctuated responsive fields with sharp

borders mechanoreceptors. There is no spontaneous discharge. These

complexes respond to the skin indentation and have the cutaneous

mechanoreceptors' highest spatial resolution (0.5 mm). The receptors

transmit precise spatial information about tactile sensations and play a crucial

role in distinguishing shapes and textures. Merkel cells are keratinocyte-

derived epidermal cells (Morrison, 2009), which are essential in the normal

functioning of the Merkel cell-neurite complex. Any mechanical stimulus on

the skin is transmitted through keratinocytes that form the epidermis. These

ubiquitous cells may perform signalling functions and have supportive or

protective roles. Merkel’s discs are often grouped in the Iggo dome

receptor, extending upward against the skin epithelium base. This receptor

engenders the epithelium at this point to protrude outer, thus generating a

dome and constituting a very sensitive receptor. Merkel’s disc's whole group

is innervated by a large myelinated nerve fibre type A beta. These receptors,

along with the Meissners corpuscles, are more sensitive to low-frequency

vibrations (<5 Hz for the former and 40 Hz for the latter) (Choi &

Kuchenbecker, 2013).

55

• Ruffini endings

Ruffini terminations are thin encapsulated sensory endings connected to A-

Beta nerve termination. These endings are tiny connective tissue arranged

along dermal collagen strands supplied by one to three myelinated nerve

fibres. Structurally, Ruffini endings are analogous to Golgi tendon organs.

These cutaneous receptors are widely located in the dermis and have been

distinguished as the slowly adapting type II (SA II) cutaneous

mechanoreceptors. SA II responses originate from large receptive fields with

vague borders. These receptors also occur in joint capsules, help detect the

degree of joint rotation, and are essential to the perception of object motion's

direction through skin stretch patterns (Roudaut et al., 2012).

• Hair follicle

The hair follicles are characterised by hair shaft-producing mini-organs that

perceive light touch. Fibres related to hair follicles react to hair movement

and direction by generating trains of action potentials at the start and

removing the stimulus. These cutaneous receptors are considered rapidly

adapting receptors. The sensory fibres of a hair follicle are located below the

sebaceous gland and are attributed to A beta or A-delta fibres. Also, the three

hair follicle types exhibit different shapes, sizes and cellular compositions and

likely have distinct vibrational tuning properties (Roudaut et al., 2012). A

tender displacement of any skin hair on the body stimulates a nerve fibre

entwining its base. Thus, each hair and its basal nerve fibre, denominated

the hair end-organ, are also touch receptors. A receptor adapts quickly and,

like Meissner’s corpuscles, detects mainly (a) the motion of objects on the

surface of the body or (b) initial contact with the skin surface (Roudaut et al.,

2012).

• Adaptation of receptors and mechanism of receptor adaptation

A further characteristic of all sensory receptors which detect vibration signals

is that these receptors adapt partially or entirely to any constant stimulus after

56

some time. When a sustained sensory stimulus is generated, the receptor

reacts at a high impulse level at first and then progressively slower until the

rate of action potentials decreases very few or often to none. The mechanism

of receptor adaptation is distinct for each receptor type in much the same

way the development of a receptor potential is individual property. The

mechanoreceptor studied in the most considerable detail is the PC.

Adaptation happens in this mechanoreceptor in two modes. Firstly, the PC is

a viscoelastic structure, so when a distorting force is applied to the corpuscle,

this force is immediately conducted by the viscous element of the corpuscle

directly to the nerve fibre, thus producing a receptor potential. The second

mechanism of receptor adaptation results from a process-denominated

accommodation. In this case, even the central core fibre should continue to

be distorted; the tip of the nerve fibre itself gradually becomes

“accommodated” to the stimulus. This accommodation probably results from

progressive “inactivation” of the sodium channels in the nerve fibre

membrane, an effect that seems to occur for all or most cell membrane

sodium channels. Presumably, these two general adaptation mechanisms

apply to other types of mechanoreceptors (Hall, 2016). Different receptors

can be stimulated in many ways to produce receptor potentials: (1) the

mechanical modification of the receptor, which extends the receptor

membrane and opens ion channels; (2) by utilisation of a chemical to the

membrane, which opens ion channels; (3) by variation of the temperature of

the layer, which changes the permeability of the membrane; of (4) by the

action of acoustic or electromagnetic radiation, such as sound and light,

which alters the receptor membrane and allows ions to flow through

membrane channels.

1.2.13 Sensory pathways for vibration signals into the CNS

Projections of the A-beta-LTMRs in the SC are divided into two branches. The

central branch rises to the cervical level in the SC (ipsilateral dorsal columns).

Secondary ramifications finish in laminae IV of the dorsal horn (see Table 1) and

influence pain transmission as part of the gate control mechanism of pain (Basbaum

& Woolf, 1999). At the cervical levels, axons of the main branch divide into two

tracts: the midline tract embraces the gracile fascicle, sending signals from the lower

57

half of the body (legs and trunk), and the outer tract contains the cuneate fascicle,

transmitting information from the upper half of the body. The present study

specifically selected acupoints IG4 and Yintang on the upper half of the body, along

with LR3 and VC4 on the lower half, to activate both the cuneatus and gracile

fascicles.

1.2.14 Characteristics of the dorsal column – medial lemniscus system

• Touch sensations need a high degree of localisation of the stimulus

• Touch sensations requiring the transmission of subtle gradations of

intensity

• Phasic sensations, such as vibratory sensations

• Position sensations from the joints

• Pressure sensations related to quality degrees of a judgment of pressure

intensity

1.2.15 Anatomy of the dorsal column-medial lemniscus system

The large myelinated fibres from specialised mechanoreceptors at the skin enter the

SC through the DRG and divide into medial and lateral branches. In Fig 1.7 (dorsal

column system), nerve fibres entering the dorsal columns pass continuously to the

dorsal medulla, where these nerves synapse in the cuneate and the gracile nucleus.

After that, second-order neurons immediately decussate to the brain stem's

opposite side and continue upward through the medial lemniscus to the thalamus.

Additional fibres join each medial lemniscus from the trigeminal nerve's sensory

nuclei through the brain stem. These fibres support the head's same sensory

functions that the dorsal column fibres serve for the body. In the thalamus, the

medial lemniscus fibres end in the thalamic sensory area, called the thalamus's

ventrobasal complex. From the ventrobasal complex, third-order nerve fibres project

to the postcentral gyrus of the brain, denominated somatic sensory area I. These

fibres project to the lateral parietal cortex, denominated somatic sensory area II. In

addition, primary tactile afferents like the PC form their first synapse with second-

order neurons at the medulla, where fibres from each tract synapse in the gracile

and cuneate nucleus.

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Figure 1.7. The system of the dorsal column – medial lemniscus (based on

Purves et al. (2001)

The transduction process, including cutaneous skin and joint receptors, begins at

the periphery, as shown in Figure 1.7. The stimulus then travels to the dorsal horn

of the SC and ascends through the posterior column, gracile and cuneate nuclei.

These tracts decussate and project to the ponds, medial lemniscus, ventral

posterolateral nucleus of the thalamus, and ultimately to the primary sensory cortex

1.2.16 Differences between the dorsal column and spinothalamic systems

The dorsal column-medial lemniscus system carries signals to the brain, mainly in

the cord's dorsal columns. Then, the signals synapse to the opposite side in the

medulla and continue upward through the brain stem and the thalamus through the

medial lemniscus. Differently, signals in the anterolateral system entering the SC

59

from the dorsal spinal nerve roots synapse in the spinal grey matter within the dorsal

horn and then go across to the opposite edge of the cord and rise over the SC's

anterior and lateral white columns. These nerves end at the lower brain stem and

thalamus. Another aspect is that the dorsal column-medial lemniscal system

comprises large, myelinated nerve fibres conveying signals at 30 to 110 m/sec

velocities. In contrast, the anterolateral system comprises smaller myelinated fibres

that transmit signals ranging from metres per second up to 40 m/sec. A further

distinction between the two systems is that the dorsal column medial lemniscal

system has a high spatial orientation of the nerve fibres concerning their source. In

contrast, the anterolateral system has reduced spatial orientation. These

distinctions characterise the types of sensory information that the two systems can

conduct. Sensory information that must be communicated rapidly and with temporal

and spatial fidelity is transmitted principally in the dorsal column medial lemniscal

system. On the other hand, information that does not need to be conveyed rapidly

or with high spatial fidelity is carried mainly in the anterolateral system. The

anterolateral system has a particular capability that the dorsal system does not

have: transmit a broad spectrum of sensory modalities, including pain, warmth, cold,

and crude tactile sensations. The dorsal system is related to different

mechanoreceptive sensations involving more subtle stimuli such as music or sound

vibration.

1.3 The triad of music, acupuncture, and endorphins

Although music and acupuncture seem unrelated to the first view, these two distinct

practices are very similar in many ways. The acupuncturist combines points to cover

the case, like a musician combinates tones to create music. A single point used in

acupuncture is an analogue to a musical note, and a combination of points

corresponds to chords and harmony in music. The musical notes sequence

(melody) corresponds to the order of points used during the acupuncture procedure.

Also, the technique manipulation and the practitioner's movements during the

acupuncture procedure are related to the rhythm. The acupoints can be understood

like notes of the cutaneous keyboard, from the fundamental note of the chord (the

lowest) in the lower limbs and feet to the octave (the highest) in the upper limbs and

head. In addition, the mechanisms of action of acupuncture and music are related

60

to the release of endogenous opioids. These hormones promote intense and vital

effects on the human organism and explain a large amount of information regarding

brain functioning. They are currently the most significant evidence in studies

concerning acupuncture and music neurophysiological mechanisms.

From early records, it is known that music has soporific and hypnagogic effects

similar to those of opioids. Morphine, a word derived from the Greek god of sleep

and dreams, Morpheus, is a derivative of opium obtained from poppy, whose

euphoric and analgesic actions have long been appreciated by musicians and

doctors (Hutchison, 1986). In the 1970s, it was reasoned that the

neuropharmacological effect of morphine could only exist if there were

corresponding molecular receptors in the brain. This logical reasoning was

confirmed, and the use of radioactive opioids identified specific receptors in many

brain regions, and the search for natural opioids soon found enkephalins,

endorphins, and dynorphins. As reviewed in 1.2.9, most opioid receptors are found

in brain areas related to the autonomic nervous system and emotional behaviour,

such as the thalamus and limbic system, specifically in regions such as the PAG,

NRM, and the SC dorsal horn. This fact is significant because it is known that most

drugs used in psychiatry to treat behavioural and affective disorders act by

modifying the content of brain monoamines (Guyton, 1977).

The connection between music, acupuncture and endorphins is undeniable, as

many people feel intense emotional reactions and get goosebumps when listening

to certain melodies. According to Goldstein's research in 1980, endorphins play a

role in causing this emotional state. Participants were allowed to choose music that

produced chills to test this theory. This experimental state was then identified and

charted. The participants were organised into two groups: one group was injected

with naloxone, an endorphin antagonist, and another was injected with a placebo in

a double-blind situation. What was found is that naloxone blocked or interrupted the

emotional state in many individuals. This experiment suggests that the musical state

is mediated by releasing endorphins in music response. Similar mechanisms occur

in acupuncture treatment. Han (2003) points out that the acupuncture procedure,

including EA at different frequencies, affects the release of other opioids, such as

beta-endorphins using 2 Hz or dynorphin with 100 Hz frequencies. These

61

experiments suggest that acupuncture and the emotional response to music are

mediated by the release of endogenous opioids ( endorphins), which would explain

the soporific, hypnagogic, and analgesic nature of certain songs and the state of

relaxation and well-being, which some subjects referred after an acupuncture

procedure. The fact that endorphins reward this type of emotional response

indicates that aesthetic involvement, including music, art, philosophy, and the

perception of beauty, is beneficial and perhaps essential for emotional and

intellectual growth and health (Hutchison, 1986; Mathis, 2015). These findings open

new ways of stimulating acupuncture points, such as music, sound and vibration, to

enhance treatment efficacy (Han, 2003; Han, 2004; Vickers et al., 2018).

1.3.1 The musical brain

The nervous system comprises two major cell types: neurons and glia. Glial cells

originate from the Greek word for glue and constitute ninety per cent of cells in the

human brain (He & Sun, 2007). Histologists have considered that neuroglia cells

(gliocytes) would play a role in aggregating and sustaining neurons (Lent, 2001).

However, some studies have reported that glial cells play a more active and

essential role in brain development and brain function than previously

acknowledged (He & Sun, 2007; Allen & Barres, 2005). According to Cullen and

Young (2016), glial cells are electrically sensitive, acting like liquid crystals and

resonating with surrounding electric fields. This means that glial cells serve as

semiconductors, enhancing nerve impulses in the nervous system like transistors

amplifying electrical signals. So, while neurons can send signals through networks

of interconnected cells, the signals are amplified and circulated through the brain

through glial cells, perceived by any neuron, tuned with the appropriate frequency,

or resonating with the environment. In addition, there is substantial experimental

confirmation that collections of neurons may operate as oscillators, and the

synchronisation of oscillators may play a vital role in transmitting information within

the CNS (Haddad, Hui & Bailey, 2014). According to Lent (2001), neurons work

cooperatively, with several subpopulations joined through a network of millions of

cells and each subpopulation responding to vibrations at specific frequencies, like a

crystal glass resonating to a particular tone. By stimulating specific neural centres

or neuro populations of neurons with the appropriate frequency, waveform (timbre),

62

rhythms, or beats, it is possible to tune the brain and body just as a musician tunes

an instrument or conductor tunes an orchestra.

The reports of many studies carried out in the last decades regarding brain

functioning, including EEG studies of thousands of people, led to a growing

understanding of human brain functioning. One of the conclusions is that the brain

is vastly influenced by hearing (Tomatis, 1996) and that the ear has the function of

listening and an essential function in the processes of cortical recharge and,

therefore, regeneration and improvement of brain functions. As previously cited, the

proprioception system has an anatomical basis in the inner ear and another at the

mechanoreceptors on the skin and joints. Thus, there is a link between the auditory

and somatosensory systems mediated by the vestibular system. In addition, Pack

and Pawson (2010) point out that the cells of the organ of Corti in the inner ear are

a highly specialised form of glia and influence auditory responses indirectly by

helping determine the mechanical properties of the sensory epithelium.

Another important aspect related to music that has increased the curiosity of

researchers for many centuries is the phenomenon of consonance, an attribute of

musical sounds. It was observed as early as Pythagoras that pleasant (i.e.,

consonant musical intervals) are produced when the frequencies of two vibrating

tones formed simple integer ratios (e.g., 1:2 corresponding to the musical interval of

the octave or 2:3 corresponds to the perfect fifth). On the other hand, unpleasant

sounds (dissonant musical intervals, 16:15) produced “harsh”- or “rough”- sounding

tones (Bidelman & Krishnan, 2009). These authors found that consonant musical

intervals were characterised by more robust neural pattern responses, which yielded

stronger neural pitch salience than dissonant intervals. Preference for consonant

sounds has been found in newborns from deaf parents (Masataka, 2006) and in

animals (Watanabe, Uozumi & Tanaka, 2005), bringing researchers to search for

universal explanations involving, for instance, geometrical symmetries existing in

chords (Tymoczko, 2006) or symmetrical relations between acupuncture points

(Schroeder et al., 2012). The explanation for this phenomenon lies in the variation

of pitches between intervals, ultimately leading to the creation of beats that affect

the brain's activity. The outcome of this process is the establishment of oscillatory

coherence and synchrony.

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These facts evidence a neurobiological predisposition for simple consonant

intervals and may explain why composers and listeners have favoured such pitch

combinations for centuries (Bidelman & Krishnan, 2009). Mcdermott and Oxenham

(2008) argued that the arrangement of musical notes into a hierarchical structure,

as evidenced by the harmonic series (see section 3.2.3), might result in certain pitch

combinations striking a deep chord with the architecture of the nervous system.

1.3.2 Biological rhythms and dissipative structures

The “Dissipative Structures theory", developed by the Belgian physicist Ilya

Prigogine, states that living systems remain away from stability and equilibrium. This

situation is very different from the phenomena described by classical science.

According to the dissipative structure theory, a living organism is characterised by a

continuous flow and change in its metabolism, involving thousands of chemical

reactions (Doll, 1986). In other words, a balanced organism is a dead organism.

Living organisms are continually kept away from equilibrium, which is the state of

life (Goldbeter, 2017). Prigogine's theory links the main characteristics of living

forms in a coherent conceptual and mathematical framework, which implies a

reconceptualisation of many fundamental ideas associated with structure - a shift in

perception from stability to instability, from order to disorder, the balance for non-

equilibrium, from being to becoming, just like in the Taoist view. In the words of

Prigogine and Stengers, "The flow of energy that crosses an organism is somewhat

similar to the flow of a river that, in general, flows smoothly, but from time to time, it

falls into a fall that releases part of the water-energy it contains” (Doll, 1986).

Interestingly, this idea corroborated the notion of the origin and circulation of “Qi”

on acupuncture meridians and, in general, with the natural rational thought used in

TCM.

In the words of Prigogine, a system or structure to become dissipative must be:

• Open: A dissipative structure must remain open to the interchangeable flow of

matter and energy with the environment.

• Far from Equilibrium: A high-energy medium with a constant flow of new energies is

always in unstable equilibrium. This process is necessary for self-organisation,

exposing the system to fluctuations and permitting it to dissipate the resulting

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entropy in the environment. Close to equilibrium, the system can become a closed

system.

The human brain fulfils these requirements because it is an open system where

energy and matter continually circulate in light, sound, electricity, oxygen, nutrients,

sensations, and emotions. The brain is only about two per cent of total body weight

and uses over twenty per cent of all oxygen in the body, making the brain the most

consumer and transformer of energy (Hutchison, 1986). Unlike systems at

equilibrium or close to equilibrium, the brain is clearly out of balance. Instead of

exact, defined parts with fixed functions, the brain is flexible, continually

transforming itself, with its neural chains moving and changing with experience and

response to energies circulating through the system (Hutchison, 1986). By

responding coherently to the disturbance, a dissipative structure, in this case, the

human brain, can move to greater functional complexity due to organisational

improvement. Paradoxically, an imbalance or disease seems necessary for a better

organisation (health) of the human body's dissipative structure.

Prigogine’s theory of dissipative structures involves temporal oscillations and

enables us to integrate the rhythms at different levels of biological organisation.

(Goldbeter, 2017). Besides oscillations and stationary spatial structures, often called

Turing patterns, spatiotemporal structures may also develop in the mode of

propagating waves (Goldbeter, 2017). The main reason rhythmic behaviour is so

frequently encountered in biological systems is related to feedback processes,

which control the dynamics of organisms at the cellular and supracellular levels.

Oscillations are a systemic property associated with regulatory interactions between

the constitutive elements of biological systems, which may range from metabolic

and genetic networks to cell and animal populations. Dysfunction of many biological

rhythms is associated with many physiological disorders, including cardiac

arrhythmias and diseases related to altered oscillatory behaviour exemplified by

epileptic seizures, Parkinson's and Alzheimer's diseases. (Goldbeter, 2017).

65

1.3.3 The brain as a dissipative structure

The brain is a rhythmic organ producing oscillations over various frequencies

(Buzs�ki, 2006). Brain waves, like sound waves, are valued in Hertz, representing

all oscillatory electrical activity composed of millions of neurons responding to a

particular frequency. Studies revealed that even a single neuron could resonate and

oscillate at specific frequencies (Buzsaki & Draghun, 2004).

The body's reaction to vibration and sound frequencies is called resonance

(Campbell et al., 2019). However, this applies to the body's and the brain's resonant

oscillations, defined as the steady-state response evoked by rhythmic stimulation

(Ross et al., 2013). It has been reported that external rhythms could influence these

brain patterns (Bartel et al., 2017; Ploner, Sorg, & Gross, 2017). Brain electrical

activity results from millions of interconnected neurons in a synchronous activity.

Evidence suggests that this electrical brain activity is related to releasing different

neurotransmitters, including norepinephrine, endorphins, serotonin, or dopamine.

Thus, if the brain wave pattern changes, the brain chemistry is also altered.

Synchronising sensory stimulation parameters with intrinsic EEG oscillating

frequencies is appropriate to enhance various sensory stimulation treatments

(Salansky, Fedotchev, & Bondar, 1998). The brain harmonises or aligns its wave

pulses with outer pulses; the phenomenon is known as "brain wave acoustic

entrainment." Research has shown that different states of mind can be induced by

hearing pulses of sound (binaural beats) that equal brain wave speed (Oster, 1973).

When the brain reacts to these pulses, it aligns with these wave patterns, inducing

an appropriate brain wave activity state. A characteristic of relaxation is the rapid

change in brain wave oscillation models from low amplitude (fast gamma and beta

waves) to high amplitude (slow alpha, theta, and delta waves). These brain waves

do not represent individual neurons' electrical activity. Instead, these may reflect

cooperative electrical models of millions of neurons. Beta waves are low amplitude,

meaning there is little difference between high and low peaks. The slow rhythmic

alpha and theta waves are of high amplitude, which indicates a more significant

difference between their ups and downs. Beta waves characteristic of external

attention and a normal state of consciousness do not show fluctuations. On the other

hand, the high amplitude of alpha and theta waves indicates large brain fluctuation

66

areas. This phenomenon is similar to fluctuations or disturbances that lead to

changes in the organisation of dissipative structures (see section 1.3.2). Another

way to exemplify this phenomenon is the result of thousands of people walking

across a bridge. If each person walks at their own pace, the sound of the steps will

be continuous (i.e., high frequency), and the vibrations on the bridge will be very

light. Otherwise, if thousands of people cross the bridge at a single pace, the sound

of the steps will be a series of separate steps (i.e., low frequency); the bridge

vibrations will be rhythmic and tend to become more significant. As the alpha and

theta brain waves, the bridge fluctuations will be low frequency / high amplitude.

Ultimately, these disturbances can powerfully destabilise the bridge that cannot

dissipate entropy and transform it into a new organisation model. In the case of the

bridge, this escape or transformation could mean a collapse; in the brain, it can imply

a reorganisation at a high level of order, coherence, and complexity (Hutchison,

1986).

A remarkable effect when multiple instruments or voices, such as Tibetan, African,

Indigenous or Gregorian chants, sing together in unison is that the subjects tend to

hear a wah-wah effect, the wave's vibrating effect, the voices or instruments are in

unison (musical interval of an octave) and then subtly drift out of original tone. Thus,

the tones start to generate beats. When the tones are in unison, the beat becomes

slow; when the tones drift more and more out of the tone, the pulse becomes faster

(Helmholtz, 1954; Hutchison, 1986).

Wide fluctuations in the brain do not occur in the everyday, typical state of

consciousness when the brain produces beta brain waves. Wide fluctuations occur

during relaxation, meditation, creative pursuits, dreams, trance, or deep inner

contemplation. The common denominator is that each technique increases cerebral

fluctuation by increasing the brain wave amplitude and decreasing the brain wave

frequency (Hutchison, 1986).

1.3.4 Rhythms of the brain

Brain rhythms or wave patterns oscillations refer to rhythmic fluctuations of neural

mass signals recorded by field potential, EEG or MEG and are most prominent at

67

frequencies between 1 and 100 Hz (Buzs�ki & Draguhn, 2004; Ploner, Sorg, &

Gross, 2017). An increasing amount of research suggests that oscillatory activity in

specific frequency bands is correlated with the secretion of various

neurotransmitters, including opioids, serotonin, and dopamine (Lohani et al., 2019).

Moreover, these neurotransmitters are involved in a range of cognitive, sensory-

motor, and perceptual processes, including the perception of pain, which is linked

to neural synchronisation and oscillations at different frequencies (Ploner, Sorg, &

Gross, 2017). Additionally, pain has been found to inhibit spontaneous brain

rhythms (Ploner et al., 2006).

Figure 1.8. Human brain wave activity (Hossan and Chowdhury, 2016)

Figure 1.8 depicts the amplitude (μV) and time in seconds (s) of brain wave patterns.

Gamma and beta waves have low amplitude and high frequency, while alpha, theta,

and delta waves have high amplitude and low frequency. These waves are

associated with human brain oscillatory activity.

As shown in Figure 1.8, the oscillatory brain signals or brainwave patterns are

usually categorised into five frequency bands, which are as follows:

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1.3.4.1 Gamma waves (40-100 Hz)

Gamma electrical activity refers to EEG oscillation at around 40-100 Hz in specific

neural pathways. This electrical activity has been associated with many sensory and

cognitive functions. Studies suggest that interneuron networks respond most to 40

Hz (Mcdermott et al., 2018). In a survey by Lohani et al. (2019), these authors found

a causative relationship between gamma oscillations and dopamine activity in the

brain. High and low gamma oscillations are implicated in dopamine-dependent

cognitive processes, such as working memory and attention (Salansky, Fedotchev,

& Bondar, 1998; Puig & Gener, 2015; Lohani et al., 2019). Recently, studies suggest

that acupuncture analgesia encompasses the modulation of pain-induced gamma

oscillations and cortical connectivity (Hauck et al., 2017). Many techniques from the

field of acupuncture and vibroacoustic stimulation use these frequency ranges in

their procedures, including EA (2-100 Hz), TENS (100 Hz) or VAT (30-120 Hz).

1.3.4.2 Beta waves (14-30 Hz)

This frequency range relates to alert awareness, attention, and concentration. The

beta state is also associated with linear thinking and mental activity. This state

usually occurs during daily activities such as driving, walking, reading, and talking.

In the beta state, the mind is generally concentrated on just one thing, so

concentration is focused. The neurotransmitter associated with this brain wave

pattern is dopamine.

1.3.4.3 Alpha waves (9-13 Hz)

Alpha waves are linked to a peaceful, contemplative, and introspective mental state.

During this state, the mind takes in the entire painting. This state of mind is the focus

of most meditation practices. Moreover, alpha waves function as a natural mood

enhancer by increasing the release of neurotransmitters such as serotonin and

GABA (Puig & Gener, 2015).

1.3.4.4 Theta waves (4-8 Hz)

Theta waves are related to deep relaxation, meditation, mental images, learning,

creativity and listening to pleasant music (Kabuto, Kageyama & Nitta, 1993). Theta

69

brain waves are present during both the waking and sleeping states. During sleep,

these waves are linked to the experience of dreams, whereas in the waking state,

they are associated with imagination, visualisation, and problem-solving. Theta

brain waves are particularly prevalent in children. This emotional state can enable

catharsis and aid in overcoming specific behavioural or defence barriers during

therapy.

1.3.4.5 Delta waves (1-3 Hz)

Delta brain waves are associated with sleep, dreams, unconsciousness, coma or

opioid-induced brain states (Salansky, Fedotchev & Bondar, 1998). Delta sleep is

the most profound sleep state, with the lowest metabolic rate, blood pressure, body

temperature, and heart rate. This is also the state of the fastest recovery from

physical health.

1.4 Conclusions

Pain is a ubiquitous and debilitating malady that has afflicted humanity throughout

history. To counter this suffering, humans have developed a means of relieving this

symptom using pharmacological or non-pharmacological approaches. While the

former has prevailed to become commonplace, it is not without adverse side effects

or occasionally ineffective. The latter, in turn, has given rise to multiple techniques,

such as acupuncture, that have provided an effective alternative for centuries.

Common to both, however, is that, to date, its precise mechanism of action remains

an open question. To address this, it is necessary to review the system's anatomy,

which is responsible for detecting and processing nociceptive information, from the

receptor terminals located at the periphery to the SC and, finally, the higher centres.

Alongside this line of inquiry is an investigation of music and frequency vibration

affecting the neuromatrix encoding pain perception. This thesis has combined these

two discrete bodies of knowledge to investigate if multiple frequencies, applied at

acupoints known to relieve the symptom of pain, produce the same outcome.

1.5 Hypothesis

This investigation hypothesises that healthy individuals suffering from muscle

soreness or subjected to the cold pressor test perceive less pain when subjected to

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multiple and simultaneous frequencies on a combination of acupoints compared to

a single frequency in the same points and sham procedure.

1.6 Aims

This research aims to validate a novel technique that involves applying vibration

according to musical harmony through vibrotactile actuators attached to a composite

of acupoints. MVA means stimulating a combination of acupuncture points using

frequencies within a musical chord. Unlike vibroacoustic methods, which use

transducers adapted to individual chairs or beds, or EA and TENS, which use

electrical waves, MVA uses vibration transducers attached directly to a specific

acupoint. The short-term benefit is developing a working protocol for future studies

with MSK (musculoskeletal) pain participants. The long-term goal is to reduce the

overuse of medications, confirm the effectiveness of this technique as an adjuvant in

an acupuncture session, and improve the quality of life of individuals with MSK pain.

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Chapter 2

Results 1: Evaluation of the Efficacy of Musical Vibroacupuncture on

Experimental (Cold Pressor) Induced Pain

2.1 Introduction

Pain affects many people worldwide and is a cause of suffering and significant social

and economic losses (Henschke, Kamper, & Maher, 2015). The International

Association for the Study of Pain (IASP) has described pain as an unpleasant

sensory and emotional experience related to actual or potential tissue damage

(Trovin & Perrot, 2019). This definition means pain is a subjective neural and

affective phenomenon influenced by physiological and emotional processes (Renn

& Dorsey, 2005). While opioids, or the like, are the first line of treatment for pain,

there are several examples where alternatives are sought, such as the medication

not being entirely beneficial for a particular condition (e.g., back pain) or carrying

adverse side effects (Sanger et al., 2019; Martel et al., 2015).

One of the most advantageous non-pharmacologic treatments for pain relief that

has received renewed attention over recent decades is acupuncture. This procedure

has traditionally relied on skin needles and is generally employed to alleviate many

conditions, although more commonly, non-specific MSK pain, chronic pain,

osteoarthritis, or headache (Vickers et al., 2018). Recently, other forms have arisen,

such as EA, TENS, or MEA, which converts music into electric signals, switching

waveforms and frequencies in rhythmic patterns (Tekeoglu, 1995) (see Chapter 1,

subsection 1.2.4.5). The potential quality of sound, music, or vibration in pain relief

is not novel (Lundeberg, Nordemar, & Ottoson, 1984; Chesky et al., 1997; Hollins,

Mcdermott & Harper, 2014; Hole et al., 2015; Lunde et al., 2019). In the brain, slow

rhythms are reported to modulate the magnitude oscillations of the brain waves

(Buzs�ki & Draguhn, 2004; Herbst & Landau, 2016), and the rhythmic stimulation of

music, rather than the melody is proposed to modulate pain perception at this level

effectively (Chanda & Levitin, 2013).

However, the mechanical sound waves can also have a non-cognitive influence,

and indeed, MEA has a more significant analgesic effect over classical EA

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(Hongshen, Hao, & Guiron, 2005; Jiang et al., 2016) as a result of the continually

changing frequency that prevents neurological accommodation and adaptation of

the mechanoreceptors from the skin.

These two lines of evidence raise the question of whether the pain-relieving qualities

of musical harmony or acupuncture could be combined by employing

electromagnetic transducers that vibrate at frequencies found in a musical chord

rather than needles or electricity. This was addressed by conducting a pilot

investigation on healthy participants subjected to experimental pain by comparing a

composite of consonant frequencies versus a single frequency.

In music, a chord tone or musical chord is defined as the combination of three or

more consonant tones sounding together and simultaneously, which needs to be

done more research in the context of pain relief. It is proposed that the mechanism

would involve large-diameter afferents from low threshold rapidly adapting receptors

PC and Meissner corpuscles, which are already described as having a high

sensitivity to vibration in the range of 40-800 Hz and 20-40 Hz, respectively

(Bensma�a, Hollins & Yau, 2005; Hollins, Corsi & Sloan, 2017). Thus, vibration is

much more selective than EA or TENS, activating a more substantial portion of A-

beta fibres responsible for closing the "gate of pain" (Melzack & Wall, 1965). Also,

this would involve frequencies known to reduce pain, ranging between 30-200 Hz

(Lundeberg, Nordemar & Ottoson, 1984; Skille, 1989), although mainly focusing on

those termed gamma oscillations – 40-100 Hz – that are reported to induce

oscillatory activity in the brain (McDermott et al., 2018; Janzen et al., 2019). These

are the range of frequencies commonly used in the majority of vibroacoustic

techniques, including VAT, MVT or WBV, which is delivered through the body via

chairs, beds, tables or platforms fitted with low-frequency transducers (Janzen et

al., 2019). EA and TENS commonly use a single or alternate frequency range of 2-

100 Hz.

The majority of these studies generally resort to employing a single frequency. In

addition, only a few studies use a combination of frequencies according to musical

principles or how the effects compare to a single frequency (Weber et al., 2015;

Weber, Busbridge, & Governo, 2020). The hypothesis is that vibrational frequencies

73

emitted simultaneously (vibrochord) on a combination of acupuncture points would

be more effective than just a single frequency in alleviating pain perception, using

the cold pressor test (CPT) as an experimental pain model.

This pilot work is relevant because it is necessary to develop new approaches to

pain relief. Music and vibration are renewable and clean forms of energy without

side effects and could be integrated with leading medical treatments. Just as pain

has several causes, treatment should also be multifaceted. Medications cannot

solve the numerous symptoms that the patient presents. The drug interaction and

high doses, sometimes necessary to control the symptoms, often generate multiple

side effects with few long-term results. Thus, alternative procedures that can relieve

pain must be encouraged and studied to complement the therapeutic arsenal.

The primary objective of this research was to verify the effectiveness of a non-

pharmaceutical method that employs vibration on acupuncture points relying on

musical harmony as a viable substitute to invasive procedures for mitigating pain.

To this end, a novel appliance that provided vibratory stimulation using harmonic

frequencies was tested on a composite of acupuncture points. In addition, the device

can be connected to an audio player, mixing music with the appliance frequencies.

However, this possibility was not used in the current study. The equipment has

hardware, firmware, and a display for configuring the machine and monitoring its

status. The tool can be used by the medical acupuncturist, music therapist, or the

nursing service in patient care at the bedside and can also be integrated into

palliative care.

2.1.1 Aim, objectives, and hypothesis

• Aim: To validate the novel technique of applying vibration on acupuncture

points according to musical harmony and its possible effects on pain relief.

• Objectives: (a) Perform a pilot study using healthy individuals subjected to

experimental cutaneous pain (CPT) to assess device efficacy. (b)

Compare the vibromusical stimulus (multiple frequencies) with the

vibratory stimulus (single frequency) and sham procedure (control) in a

combination of acupuncture points as a means of assessing the

74

effectiveness of follow-up studies using participants with

musculocutaneous pain. (c) To design and build five electromagnetic

vibration actuators to be used on a combination of acupoints and test their

efficacy in pain relief.

• Hypothesis: A vibrotactile chord on a combination of acupoints will reduce

pain perception in healthy individuals undergoing short-term cutaneous pain

stimulus. The null hypothesis is that the vibrotactile chord on a combination

of acupoints will not reduce pain perception in healthy individuals submitted

to the cold pressor test.

2.1.2 Research questions

• To what extent could a vibrotactile chord on a combination of acupuncture

points be helpful in pain relief?

• To what extent could vibromusical stimulation on acupuncture points be

helpful in musculoskeletal soreness?

2.2 Materials and methods

MVA (musical vibroacupuncture) versus VA (vibroacupuncture) and SP (sham

procedure) effects were investigated in a randomised controlled trial on pain-free

healthy human volunteers between March and September 2018. The study was

authorised by the College Research Ethics Committee of the University of Brighton,

and all participants signed informed consent. All procedures were conducted in a

research-dedicated room at the University of Brighton.

2.2.1 Participants, recruitment, and screening

Study participation was open to both genders through advertisements on the

Brighton University campus. Volunteers expressing interest were invited to attend a

pre-study familiarisation session, provided with a participant information sheet, and

briefed about the nature of the study and the CPT procedure. Volunteers were

screened against eligibility criteria: 18 to 45 years, not revealing a history or

symptoms of any significant disease such as peripheral vascular abnormalities,

hypertension/hypotension, peripheral neuropathies, recent trauma, depression,

75

pregnant women or those taking regular contraception, diabetes or epilepsy. Also,

anyone exhibiting or reporting suffering from skin allergy was abstained from

participation. The vibration efficacy depends on normally functioning nerves in the

skin, which are responsible for detecting the vibroacoustic stimulus, so regular skin

sensation was an inclusion criterion. Also, only volunteers who reported not taking

any medication were recruited. Each participant underwent all three procedures:

MVA, VA, and SP, the latter corresponding to the control group. Each procedure

was conducted on alternate days with an interval of one day between sessions, and

its order was randomised. Randomisation was achieved by creating three cards

corresponding to the three methods that the participant picked at each session.

However, the study paradigm, including the choice of trial, was hidden to ensure

that the study participants remained blinded to the proceedings.

2.2.2 The device

This study operated the same vibromusic stimulator device used previously to

stimulate acupuncture points with vibration (Weber et al., 2015). The hardware

comprises a programmable circuit with a display for configuring the machine and

monitoring its status and input/output ports linked to five micro speakers used as

transducers placed on a combination of acupoints. Its software was developed

purposely for this study to deliver various musical tones and chords within a

frequency range from 32 Hz to 128 Hz, with amplitude signals around 60 dB

delivered as square waves. These frequencies could be distributed through

headphones and mixed with music (Figure 2.1). The participant could hear and feel

the same frequencies in the same amplitude (Weber et al., 2015). However, in the

actual study, music was not used in the sense of hearing; instead, is performed a

non-cognitive approach using consonant sound vibrations through five small

transducers fixed to a combination of acupuncture points to test its effects in pain

relief.

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Figure 2.1. The Apparatus. Original prototype and interfaces, including five

transducers used in previous trials (source: Weber, 2015)

As shown in Figure 2.1, the two transducers on the left side emit the lowest tone (32

Hz), the fundamental frequency of the chord, inserted on acupuncture points located

below the pelvis (CV-4) and on the dorsum of the left foot (LR-3). The transducer in

the middle emits the fifth (48 Hz), attached to an acupoint located at a 2:3 ratio at

the thorax level (CV-15), and the two transducers on the right side are related to the

octave (64 Hz), attached to acupoints located at higher levels (head- Yintang, and

in the dorsum of the right hand (LI-4). The same chord frequencies felt on the skin

could be heard through headphones and mixed with music and psychoacoustic

approaches such as binaural beats, creating a synchronic audio-tactile-visual

stimulus

2.2.3 The procedure

Each procedure began by recording the participants' pain and emotional status by

filling in the numerical rating scale questionnaire (NRS), short-form McGill pain

questionnaire (SF-MPQ) and State-trait anxiety inventory (STAI) Form Y-1 (STATE).

This stage was followed by asking the participant to lie in the dorsal decubitus

position on a gurney and put on blindfolds (opaque glasses) plus headphones to

isolate external sounds. The transducers were then placed symmetrically on five

locations traditionally used in acupuncture for the treatment of pain (LI 4, LR3) and

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anxiety (YINTANG, CV 15, CV4) (Ross,1995), according to the following

frequencies, as shown in Figure 2.2.

• LI 4 (Hegu) on the right hand between the two metacarpi (64 Hz, Figure 2.3)

• YINTANG on the glabella between the eyes (64 Hz)

• CV 15 (Jiuwei) on the tip of the xiphoid appendix (48 Hz)

• CV 4 (Guanyuan) on the pelvis, 4 inches below the navel (32Hz)

•

LR 3 (Taichong) on the left foot between the two metatarsi (32 Hz) (Xinnong,1987).

Figure 2.2. Experimental set-up. Acupoints, location, and frequencies. LI 4

(Hegu) on the right hand between the two metacarpi (64 Hz), YINTANG on the

glabella in the forehead (64 Hz), CV 15 (Jiuwei) on the tip of the xiphoid

process (48 Hz), CV 4 (Guanyuan) on the pelvis, 4 inches below the navel

(32Hz), LR 3 (Taichong) on the left foot between the two metatarsi (32 Hz)

(source: Weber, 2015)

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Figure 2.3. The transducer on point LI-4 (source: Weber, 2015)

The first reason behind the choice of a range of frequencies (32, 48, 64 Hz) is that

these correspond to the range of frequencies perceived by the Meissner corpuscles,

between 20-40 Hz, and PC corpuscles that are responsible for the perception of

frequencies between 50-800 Hz (Bensmaia & Hollins, 2005; Hollins, Corsi, & Sloan,

2017) as cited previously. According to Ferrington, Nail and Rowe (1977) and

Verrillo et al. (1983), the 30 Hz frequency corresponds to the breakpoint between

the two systems and could be used to ensure sufficient isolation of PC and non-

Pacinian activation.

The second reason is that this range of frequencies corresponds to the gamma-

oscillations between 40 and 100 Hz. Dysfunction of the gamma oscillations could

induce chronic pain states (Mcdermott et al., 2018). The third reason is that these

frequencies correspond to the frequencies of the monochromatic musical scale

starting at the C1 of piano (32 Hz), G1 (48 Hz), and C2 (64 Hz), which together form

the major chord. This chord generated by the first musical intervals from the

overtone series, a natural vibroacoustic phenomenon, is used as a model to

represent the harmony-symmetry of the human body. In this sense, the feet

correspond to the root or fundamental (lowest note of the chord, 32Hz) with a ratio

of 1:1; the head corresponds to the octave (highest note, 64 Hz), a ratio of 1:2,

inserted at the forehead (YINTANG) acupoint, and the middle frequency of the chord

corresponding to the second harmonic (the fifth-48 Hz) with a ratio of 3:2, is applied

at the tip of xyphoid process (CV 15) acupoint on the thorax.

79

For the VA procedure, 32 Hz was used at all points, while for the SP, the identical

transducers were employed but without producing a vibratory stimulus on the skin.

Instead, a buzzing sound was provided by a sensor attached to a table nearby to

give an impression of treatment. Also, the stimulus duration was intermittent (e.g.,1

minute "on" followed by 10 seconds "off"). Although periods of vibratory stimulation

invariably during 20 minutes could lead to habituation and fatigue in vibrotactile

sensitivity and central processing, this aspect was prevented by varying the time of

sustained excitation and the variety of frequencies used. The choice of 20 minutes

was based on an acupuncture session's typical duration, ranging between 15 and

45 minutes. It was calculated that the stimulus should be longer than the minimum

but simultaneously to avoid boredom, adding 5 minutes to the minimum. The

vibratory stimulation period was set for 20 minutes, after which the participants were

transferred to a chair and underwent the CPT. The latter began when the participant

submerged the hand in chilled water at seven �C. The participant was explained to

inform the experimenter when the pain was perceived, translating to the time interval

corresponding to the "pain threshold." The participants were also instructed to

withdraw at the point at which the pain became "unbearable." this time interval

corresponded to "pain tolerance" (Modir & Wallace, 2010). Using a stopwatch, the

latencies in seconds between the initial pain sensation (pain threshold) and the

intolerable pain (pain tolerance) were measured. Once the participant withdrew the

hand, thus terminating the CPT, the study required filling out the NRS, SF-MPQ,

and the STAI-Form Y-1 (STATE) questionnaire, after which the trial ended.

2.2.4 The CPT

The CPT is commonly used in pain studies to induce a significant and consistent

painful stimulus (La Cesa et al., 2014; Koenig et al., 2014; Lovallo, 1975) but is

equally considered safe. The CPT apparatus itself consisted of an eight-litre bucket

half-filled with ice. Cold water was poured over the ice until it filled deep enough to

cover the participant's hand. The test replicated previously described methods (La

Cesa et al., 2014).

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Figure 2.4. Effects of CPT-induced NRS scores before (bef) and after (aft)

treatment for baseline, musical vibroacupuncture (MVA), vibroacupuncture

(VA), and sham procedure (SP)

As shown in Figure 2.4, the analysis of post-treatment (aft) scores revealed a

significant difference between baseline vs MVA (p=0.007) and MVA vs SHAM

(p=0.027), but not for VA. The significance of these results is that the MVA

paradigm, which includes multiple frequencies on a combination of acupoints,

demonstrates a better efficacy in pain intensity (NRS values) compared to baseline,

VA and Sham procedures, although not significant compared to the VA.

2.2.5 Data acquisition

SF-MPQ and STAI-Form Y data were recorded to assess the pain experience's

sensorial, affective, and psychological aspects. It was deemed crucial to investigate

if the participant's mood or emotion across the different study days impacted the trial

effect and the means of ensuring that the participant was pain-free before each trial.

The SF-MPQ comprise 15 descriptors (11 sensory; 4 affective) scored on an

intensity scale as 0=none, 1=mild, 2=moderate or 3=severe (Hawker et al., 2011).

The STAI-Form Y questionnaire form, in turn, evaluates the current state of anxiety,

asking how respondents feel "right now." It consists of 20 items that measure

subjective feelings of apprehension, tension, nervousness, worry, and

activation/arousal of the autonomic nervous system. All items are scored on a 4-

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point scale (�not at all�, �somewhat�, �moderately so�, �very much so�), with a higher

score indicating more considerable anxiety (Julian, 2011). The participant's

perception of pain was acquired continuously throughout the CPT using the self-

reporting numeric rating scale (NRS). The NRS is a segmented numeric version of

the visual analogue scale (VAS) in which a respondent chooses a whole number

(0–10 integers) that most demonstrates the intensity of pain, with higher scores

suggesting greater pain intensity (Hawker, 2011). The NRS is used extensively in

pain studies, thus regarded as the standard and essential to ensure consistency

throughout the data acquisition.

2.2.6 Data analysis

All data analyses were conducted using the Prism Graph Pad software. Data

distribution was initially investigated using the Shapiro-Wilk normality test

(significance set at p < 0.05). NRS data comparing procedures were analysed using

a mixed-effects model, followed by Tukey's multiple comparisons test. In turn,

analysis of either pain threshold or tolerance between trials and all baseline data

between all procedures was achieved using the RM one-way ANOVA with Tukey's

multiple comparison test. Finally, the Student’s paired t-Test was compared

between two trials within the same treatment. A p-value smaller than 0.05 was

deemed to represent significance for all analyses.

2.3 Results

2.3.1 Demographics

This pilot study recruited 13 participants, eight women and five men, with a mean

(SD) age of 29 (11) years. All participants completed the three procedures

successfully without being required to withdraw from the study. However, analysis

of the output data revealed that one of the participants rated baseline pain

perception before one of the trials as four out of ten, which represented an outlier

and was withdrawn from the study analysis. The following, therefore, pertains to a

number of 12.

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2.3.2 The CPT and the effect of skin vibration on pain perception

Analysis of all NRS scores obtained before each trial averaged (SD) 0.3 (0.67),

which falls below the generally accepted threshold of pain experience of NRS above

1. Also, there was no significant difference between trials (F (3,11) = 0.712, p = 0.49;

one-way ANOVA; Figure 2.4). A direct comparison of post-trial scores against the

respective pre-trial data demonstrated that the impact of CPT on pain perception

was significant (p < 0.001 for all comparisons, paired t-Test). A more in-depth,

mixed-effect analysis comparing baseline with MVA, VA, or SP showed a significant

effect from treatment (p = 0.0082). The post-test output is summarised in Table 2.1.

The effect of MVA on post-trial NRS scores differed significantly from the baseline

(P=0.007) or SP (p=0.027) trials but not for VA (Tukey's multiple comparisons test).

The latter, although, did not compare significantly against baseline or SP.

Table 2.1. Tukey’s multiple comparison test for post-trial NRS scores between

baseline and following MVA, VA or SP (Asterisks depict statistically significant

values: *p<0.05, **p<0.01)

2.3.3 Pain threshold or tolerance across trials

Pain threshold is the minimum point at which a person perceives pain, while pain

tolerance is the maximum level of pain a person can withstand. Both periods, were

investigated in parallel to the above analysis (Figure 2.5). Output was normally

distributed between participants (Shapiro-Wilk test, data not shown). Results

showed that the pain threshold did not vary significantly between the three treatment

trials or against baseline (one-way ANOVA). Differently, there was a significant

Groups comparison p-value

Baseline vs MVA

Baseline vs VA

Baseline vs SP

MVA vs VA

MVA vs SP

VA vs SP

0.007**

ns

ns

ns

0.027*

ns

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effect of treatment for pain tolerance (F(3,11) = 8.17, p = 0.002; one-way ANOVA).

The subsequent post-test analysis is summarised in Table 2.2, whereby the output

replicated the results described above, where pain tolerance following MVA scores

differed significantly against the times obtained from the baseline (p=0.0043) or SP

(p=0.006) trials but not for VA (Tukey's multiple comparisons test). The latter also

did not compare significantly against baseline or SP.

Table 2.2. Tukey’s multiple comparison test for pain tolerance between

baseline and following MVA, VA or SP (Asterisks depict statistically significant

values: *p<0.05; **p<0.01)

2.3.4 Effect of MVA, VA or SP on SF-MPQ or STAI Form Y-1 (STATE) scores

The participant's mood state, trait, and baseline pain were explored between trial

days or even as a result of the trial, so data were pooled for each study day. The

data passed the normality test for all categories, and all pre-trial scores were not

significantly different (F (3,13) = 3.171, p = 0.09; one-way ANOVA with Tukey's

multiple comparisons test). Direct pre- to post-trial comparisons also revealed no

significant differences for all measures tested, albeit very close for the affective

component in the MVA trial (p = 0.054; paired t-test).

2.4 Discussion

This pilot study was projected to test the efficacy of MVA compared to VA and SP

on experimentally induced thermal pain in healthy human participants. Healthy

participants and the CPT as the pain model were chosen for many reasons instead

of testing this procedure directly on pain patients. First, experimental pain is

Groups comparison p-value

Baseline vs MVA

Baseline vs VA

Baseline vs SP

MVA vs VA

MVA vs SP

VA vs SP

0.0043**

ns

ns

ns

0.006**

ns

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reproducible and more easily controlled than clinical pain. Secondly, healthy

subjects are generally unaffected by the extensive myriad of factors that can colour

the ultimate pain experience, such as emotion, context, or experience, as reviewed

by Tracey (2007). Third, the CPT procedure has several advantages, including

being safe, ethically acceptable, and reliable for pain threshold or tolerance (Modir

& Wallace, 2010). In addition, the CPT was opted for this specific experimental pain

model since this pain model elicits an acute and tonic noxious cold pain stimulus by

activating peripheral nociceptors (cold-sensitive C and A-delta fibres) (see Chapter

1, subsection 1.2.7.2) and central pain systems, which is often accompanied by an

autonomic response (Lovallo, 1975). This study was built on previous work,

demonstrating that music and vibration can have an analgesic effect on CPT-

induced pain (Choi, Park, & Lee, 2018; Staud et al., 2011).

Turning to the topic of the musical notes used in the chord, the frequencies chosen

correspond to fractions of the whole numbers in concordance with the Pythagorean

tuning system (A4= 432 Hz), which is a tuning based on perfect fifths. The rationale

was that it provided simple natural frequency ratios, which correspond to the

fundamental note of the chord (the lowest) with a ratio of (1:1), the octave (2:1), and

the fifth (3:2), which are considered the most stable and consonant intervals

corresponding to the first intervals from the overtones series (Martineau, 2010).

According to Ball (2011), the brain prefers frequencies in simple ratios because

these generate more robust and synchronous neural responses. Consonant and

dissonant intervals, for example, generate different patterns of neural activity in the

auditory cortex of both monkeys and humans, leading some researchers to believe

that it involves separate neuron populations (Bidelman & Krishnan, 2009).

Considering then the backdrop for this study, as detailed earlier, the inherent quality

attributed to music and vibration in alleviating pain is already well-known (Lunde et

al., 2019; Hole et al., 2015; Hollins, McDermott, & Harper, 2014; Chesky et al., 1997;

Lundeberg, Nordermar, & Ottoson, 1984), which includes sound captured by the

auditory system and vibrations captivated by the somatosensory system (see

Chapter 1, subsection 1.2.7.1.1). However, although music is readily identified as a

cognitive experience, this study was more interested in its non-cognitive quality,

specifically the vibratory effects produced on the skin. This investigation tested if the

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pain-relieving qualities of music could be experienced via skin vibration, using

acupuncture points as the starting point, given its reported impact on pain

perception.

Figure 2.5. Effects of CPT on pain threshold (top) and tolerance versus

treatment. There were no significant changes in pain thresholds compared

with all groups, including baseline. Pain tolerance significantly affected MVA

compared with baseline (p=0.0043**) and SP(p=0.006**)

Of note, in a review by Lunde and colleagues (2019), the analgesic property of music

is suggested to target primarily the higher centres, where factors such as

expectation, placebo, or distraction are known to influence pain experience

Baseline

MVA (vms)

VA (vs)

Sham (sp)

0

10

20

30

40

50

Trial

S

e

c

o

n

d

s

Pain Threshold

Bas

MVA

VA (

Sha

Baseline

MVA (vms)

VA (vs)

Sham (sp)

0

50

100

150

200

250

Trial

S

e

c

o

n

d

s

Pain Tolerance

Bas

MVA

VA (

Sha

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(Villarreal et al., 2012; Perlini & Viita, 1996; Bingel et al., 2011), through opioid or

dopamine release. These features are reinforced by neuroimaging studies that have

observed activity in both the limbic and brain nuclei that form part of the descending

pain-modulation pathways from listening to consonant and pleasurable music

(Dobek et al., 2014). However, it is also suggested that sound perception involves

different cutaneous afferents within the somatosensory system, such as the

proprioceptive or vestibular inputs (Huang et al., 2012). It should also be mentioned

that specific musical frequencies can stimulate the brain through auditory and

vibrotactile pathways and consequently contribute to regulating oscillatory activity in

the brain (Bartel et al., 2017). It is reported that vibration applied to acupuncture

affects driving oscillatory coherence and contributes to regulation or reset or circuit

connectivity (Hauck et al., 2017).

The body's response to sound frequencies and vibration is called resonance

(Campbell et al., 2019). Nevertheless, this applies to the body and the resonant

oscillations within the brain, defined as the steady-state response evoked by

rhythmic stimulation (Ross et al., 2013). In addition, the effect of external pulses of

sound and rhythm patterns could also influence brain activity directly, generating

oscillations in responsive brain areas (Bartel et al., 2017). Brain natural oscillations

are most prominent at frequencies between 1 and 100 Hz (Buzs�ki & Wang, 2012),

ranging from 1-3 Hz (delta), 4-7 Hz (theta), 8-13 (alpha), 14-30 Hz (beta) and 40-

100 Hz (gamma) oscillations (Ploner, Sorg, & Gross, 2017), (see Chapter 1,

subsection 1.3.4). It has been reported that external rhythms could influence the

activity of these brain patterns (Bartel et al., 2017; Ploner, Sorg, & Gross, 2017). As

predicted, skin vibration employing multiple frequencies had a unique and significant

impact on both pain perceptions compared to no skin vibration (baseline), which

was not the case for either VA or SP.

Given that pain is a complex phenomenon promoted by a network of neurons

(Melzack, 2001), generating neural oscillations in different brain areas (Nickel et

al., 2020), one possible explanation for the significant results in MVA when

compared to baseline and SP, is that the differences between frequencies generate

beats, which might increase the effect of entrainment of the oscillatory activity in the

brain (Yang, Tippey, & Ferris, 2014).

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In therapy, a commonality between electro-pulsation and rhythmic mechanical

pulsation is that both techniques use pulses and rhythm patterns to stimulate the

body. However, these differ because electrical waves do not need a medium to

propagate, whereas mechanical waves do. Secondly, the mechanisms of action are

different according to the receptor types of each target. Electrical waves activate a

more substantial portion of C fibres and A-delta fibres than vibration, which activates

a proportion of A-beta. Ultimately, the biggest advantage of vibration over EA in

therapy is that the latter is more invasive and produces pain or shocks. On the other

hand, vibration is more pleasurable for the patients and can activate the analgesia

system more effectively than electricity. Finally, vibration is more relatable to sound

and music than electrical waves.

Despite the evidence above, the post-procedure scores for the SF-MPQ and STAI

questionnaires revealed no significant differences between procedures, albeit very

close regarding the affective component in the MVA (p = 0.054). This data suggests

that pain perception and tolerance reduction more likely arose from skin vibration

using a combination of frequencies than through an affective response alone.

Again, that is not to say that the reduction in the reported pain score obtained in this

study was limited to changes occurring at the periphery. Indeed, the Hollins group

presents a compelling analysis of the more likely predictors that explain the process

of vibratory analgesia (Hollins, McDermott & Harper, 2014). These authors suggest

that pain suppression does involve higher centres, albeit not necessarily from the

more generally accepted contributors, such as distraction, but from interactions

within specific regions of the somatosensory cortex. This aspect confirms previous

findings that argue that vibrotactile stimulation has a more significant impact than a

distraction in alleviating experimental pain (Villarreal et al., 2012).

Based on this line of evidence, the effect obtained from MVA could likely be

mimicking the phenomenon of vibrotactile analgesia that these sources describe as

the actuation of low-threshold A-beta mechanoreceptors, a.k.a. Pacinian corpuscles

(Bensmaia & Hollins, 2005; Hollins, McDermott, & Harper, 2014; Hollins, Corsi, &

Sloan, 2017) (as described in Chapter 1, subsection 1.2.12). If the latter is correct,

one possible mechanism responsible for reducing pain is reported by Salter and

Henry (1990), who reported that the actuation of large-diameter A-beta fibres

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through vibration effectively inhibited nociceptive-specific neurons at the spinal

dorsal horn (Salter & Henry, 1990). Also, within many tactile receptors that innervate

the skin, the Pacinian and Meissner receptors are suggested to have a direct role in

modulating vibratory-mediated pain transmission (Bensmaia et al., 2005; Hollins,

Corsi, & Sloan, 2017). Moreover, these studies revealed that these receptors are

involved in the perception of high (40-800 Hz) and low frequencies (20-40 Hz),

respectively, and can adapt during constant stimulation (Bensmaia et al., 2005).

Otherwise, the results could elicit a similar response as observed with EA and

TENS, which also report a spinal locum of action in controlling pain, albeit via a

different method (Han, 2003). Indeed, these authors observed that peripheral

electrical stimulation triggers the top-down facilitation of neuropeptides released into

the SC. This facilitation was also seen as frequency-dependent, similar to different

brain substrates, and different neuropeptides were released according to specific

frequencies. Low-frequency EA (2 Hz), for example, is said to increase the spinal

release of opioids, including met-enkephalin, endomorphin, or beta-endorphin,

which have a better analgesic effect on neuropathic pain (Han, 2003; Kimura et al.,

2015). On the other hand, high-frequency EA (100 Hz) is proposed to trigger spinal

dynorphin release, which has a better analgesic effect on inflammatory pain and

muscle spasms. More notable was the observation that applying alternate

frequencies (2/100 Hz EA) stimulated the simultaneous release of multiple opioids,

a phenomenon that did not occur when employing a single frequency (Kimura et al.,

2015).

The above only represents a minimal number of possible explanations for the results

obtained in this study. However, the remit of this pilot work was not so much to

identify which mechanisms are actuated by MVA but to focus on the greater picture,

that of investigating any potential overlap between the auditory and somatosensory

systems by building on demonstrable evidence (Wilson, Reed, & Braida, 2010;

Anmirante, Patel, & Russo, 2016; Hopkins et al., 2016). In particular, Wilson's group

(2010) revealed that hearing and tactile systems detect different frequencies, each

being more sensitive to high and low frequencies, respectively. While it is feasible

to hear frequencies within 20 Hz to 20 kHz, frequencies can only be ‘felt’ up to 1000

Hz (Karam et al., 2009). Also, receptors on the skin are suggested to respond to

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sounds like the cochlea of the inner ear (B�k�sy, 1959), with contrasting regions

devoted to perceiving specific frequencies (Han, 2003). At the same time, the pitch

is proposed to entail a particular intrinsic elevation, with higher-frequency sounds

that tend to be perceived as coming from above, while lower-frequency sounds are

speculated to originate from below (Parise, Knorre, & Ernst, 2014).

Like the keys of a piano, the basilar membrane's nerve cells inside the cochlea are

positioned from the lowest to the highest pitch. It is speculated that a similar

organization occurs on the skin, with regions of the body specifically devoted to

resonating to high or low frequencies of the musical scale. In addition, the human

body may resonate to the musical scale from the lowest frequency (fundamental or

root, ratio 1:1, acupoints on feet and pelvis) to the highest frequency of the scale

(the octave – 64 Hz; ratio 2:1, acupoints in hand and head). This supposition's

premise follows work demonstrating that higher-frequency pitches were associated

with right/up locations while lower-frequency pitches were assigned to left/down

locations (Rusconi et al., 2006). This is why was opted to apply 64 Hz on the right

hand, 32 Hz on the left foot, 64 Hz, 48 Hz, and 32 Hz on the body's vertical line from

the head to the foot, as outlined in the methods section. This is supported by work

undertaken by Karam et al. (2009), which uses the model human cochlea (MHC) as

a design metaphor to translate the music into vibration signals displayed along the

body (Karam et al., 2009; Karam, Russo, & Fels, 2009). Thus, the vibrotactile stimuli

were conveyed by placing low-frequency transducers on the lower back and higher

vibrational signals on the upper back of the chair, considering the concepts of pitch

height and spatial orientation of the body (Brange et al., 2010). This setup also dealt

with the standard music notation maps that pitch to vertical locations, whereby notes

corresponding to higher pitches are represented with a higher spatial location on the

musical notation sheet (Rusconi et al., 2006). In other words, this study sought to

follow a cognitive system map pitch onto a mental representation of space as

described (Rusconi et al., 2006).

Musical intervals, like geometrical proportions and combinations of acupuncture

points, always involve two or more elements in a relationship. In acupuncture, the

combination of points is an essential feature to improve efficacy in treatment. An

effective combination of points involved symmetrical relations between the

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acupoints and regions of the body (Schroeder et al., 2012). This spatial arrangement

and study paradigm prompted a perception akin to listening to a musical chord

instead of a single-frequency vibration, which lowered pain perception through a

tactile vibro-stimulation mechanism.

2.4.1 Study limitations

As this study represented a pilot investigation, it was subjected to restrictions

dictated by ethics, such as limiting the number of participants, which lowered

statistical power. While post-procedure NRS scores differed significantly between

MVA and the remaining procedures, this limitation could explain the lack of

significance in the questionnaire data. Also, this cross-over study was not

successfully double-blinded, so the participants' expectations and the tester's

subjective tendency could impact the results. This study would also benefit

significantly if it could investigate whether gender or age has a say on MVA-related

pain control for this paradigm. Regarding the former, it is known that pain perception

differs among genders, with women demonstrating lower pain thresholds than men

(Dahlin et al., 2006; Stening et al., 2007). Another limiting factor was the lack of

long-term efficacy observation or follow-up. However, the initial data is promising

and will serve as the basis for a follow-on study to implement MVA on healthy

individuals experiencing musculoskeletal soreness as an acute pain model. If

successful, the ultimate goal would be to translate this paradigm into the clinical

setting, which will seek to employ MVA on patients suffering from pain.

2.4.2 Identified risks

There were no risks to the participants from participating in this study. The

frequencies and amplitude were safe and not predicted to produce adverse side

effects. The participants felt a slight vibration on the skin produced by the

transducers. The procedure was executed by an expert acupuncturist with

considerable experience in patient selection and handling, thus ensuring participant

safety and well-being. Moreover, the procedures and data acquisition were

monitored by qualified supervisors, and the University approved the protocol of the

Brighton ethics board. However, since this is a pain study, some issues were

considered, and measures were implemented for safety reasons. First, participants

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were informed about the study elements, that participation is entirely voluntary, and

the right to be taken away at any stage without providing a reason. Before each pain

trial session, this information was reminded to gauge whether the participant was

still happy to remain involved. Also, the researcher continuously monitored the

participant's moods throughout the study. Nonetheless, should the repeated pain

trial trigger a novel emotive response hitherto unknown and of concern to the

experimenter, it was discussed in the first instance with the research supervisor. If

clinically relevant, the participant was offered a recommendation of withdrawal from

the study and to seek appropriate medical guidance. Although some emotional

symptoms precede an acupuncture session, these are considerably less intense

and immediately reversible. The experimenter was adequately trained to conduct

the pain trial and monitor the participants' emotional states. All participants were

informed that if the study's participation significantly affected the work or any other

day-to-day function, the participant was advised to withdraw from the study. Finally,

the experimenter could discuss any participants' concerns outside of trial days.

2.5 Conclusion

In conclusion, MVA effectively reduced CPT-induced pain perception compared to

VA or SP. These results are suggested to arise from the actuation of skin receptors

instead of higher centres since the sensory or affective aspects of pain perception

are not significantly affected by MVA (although the latter was very close). However,

the i