analgesic effects of eeg alpha-wave entrainment on acute and chronic pain

223 Pages·2014·5.55 MB·English

by  Katharina Ecsy

ANALGESIC EFFECTS OF EEG
ALPHA-WAVE ENTRAINMENT ON
ACUTE AND CHRONIC PAIN

A thesis submitted to The University of Manchester for the degree of
Doctor of Philosophy
in the Faculty of Medical and Human Sciences

2014

K E
ATHARINA CSY

SCHOOL OF MEDICINE
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CONTENTS PAGE

LIST OF FIGURES ................................................................................................... 6
LIST OF TABLES ..................................................................................................... 7
LIST OF ABBREVIATIONS....................................................................................... 8
ABSTRACT ........................................................................................................... 10
DECLARATION..................................................................................................... 11
COPYRIGHT STATEMENT .................................................................................... 11
DEDICATION ....................................................................................................... 12
ACKNOWLEDGEMENTS ...................................................................................... 12
PROLOGUE ......................................................................................................... 13
CHAPTER 1 Introduction .................................................................................... 14
1. Overview ................................................................................................ 15
2. The Sensation of Pain ............................................................................. 16
3. Nociception and Nociceptive Signal Transmission ................................ 17
4. Acute and Chronic .................................................................................. 20
5. The Pain Matrix ...................................................................................... 21
5.1 Medial and Lateral Pain Matrix ........................................................ 22
6. Neural Oscillations ................................................................................. 23
6.1. Alpha ............................................................................................... 24
6.1.1. Alpha Subdivisions ................................................................... 25
6.1.2. Alpha Changes in Pain .............................................................. 26
6.2. SMR ................................................................................................. 27
6.2.1. Changes in Pain ........................................................................ 28
6.3. Theta ............................................................................................... 28
6.3.1. Theta Changes in Pain .............................................................. 29
6.4. Gamma ............................................................................................ 30
6.4.1. Gamma changes in Pain ........................................................... 30
7. Altered Pain Perception ......................................................................... 31
7.1. Changes in the Peripheral and Central Nervous Systems ............... 31
7.2. Psychological Modulation of Pain and Pain Control ....................... 34
7.2.1. Neural Oscillations in the Psychological Modulation of Pain .. 37
8. Manipulating Pain .................................................................................. 37
8.1. Pharmacological modulation of Pain Perception ............................ 38
8.1.1. Neural Oscillations in Pharmacologically induced Analgesia ... 38
9. Analgesic Neuro-modulation ................................................................. 39
9.1. Mindfulness Meditation .................................................................. 39
9.1.1. Neural Oscillations in Mindfulness Meditation ....................... 40
9.2. Biofeedback ..................................................................................... 42
9.3. Neurofeedback ................................................................................ 43
9.3.1. Learning through EEG-Neurofeedback .................................... 43
9.3.2. Neurofeedback Training for Chronic Pain ................................ 44
9.4. Entrainment .................................................................................... 46
9.4.1. Visual Entrainment ................................................................... 47
9.4.2. Auditory Entrainment .............................................................. 47
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10. Thesis Aims and Objectives .................................................................. 48
11. Thesis Hypotheses ................................................................................ 49
CHAPTER 2 Methodology ................................................................................... 51
1. Introduction ........................................................................................... 52
2. Experimental Pain .................................................................................. 52
2.1. Mechanical Stimulation .................................................................. 53
2.2. Electrical Stimulation ...................................................................... 54
2.3. Thermal Stimulation ........................................................................ 55
3. Pain Assessment ..................................................................................... 56
3.1. Behavioural Pain Assessment ......................................................... 56
3.2. Neurophysiological Measures of Pain ............................................. 58
3.2.1. Electroencephalography (EEG) ................................................ 58
4. Behavioural Associations with Pain and Alpha Activity ......................... 64
4.1. Profile of Mood States (POMS) ....................................................... 65
4.2. State-Trait Anxiety Inventory (STAI) ............................................... 65
4.3. Karolinska Sleepiness Scale (KSS) .................................................... 66
4.4. Pain Catastrophising Scale (PCS) ..................................................... 66
4.5. The Pain Anxiety Symptoms Scale (PASS) ....................................... 67
4.6. The Patient Health Questionnaire 9-item (PHQ-9) ......................... 67
5. Statistical Approaches ............................................................................ 67
6. Sample Size Calculation .......................................................................... 69
CHAPTER 3 Pilot Study: Neural Entrainment of an Alpha Rhythm Flicker ............ 71
1. Abstract .................................................................................................. 72
2. Introduction ........................................................................................... 73
3. Materials and Methods .......................................................................... 74
3.1.1. Ethics Statement ...................................................................... 74
3.1.2. Participants .............................................................................. 74
3.1.3. Procedure ................................................................................. 75
3.1.4. Electrophysiological Recordings .............................................. 76
3.1.5. Alpha Power Analysis ............................................................... 76
4. Results .................................................................................................... 78
4.1.1. 10Hz Alpha Entrainment .......................................................... 79
4.1.2. 11Hz Alpha Entrainment .......................................................... 83
5. Discussion ............................................................................................... 87
CHAPTER 4 Visual and Auditory Alpha Stimulation reduces Pain Perception ....... 91
1. Abstract .................................................................................................. 92
2. Introduction ........................................................................................... 93
3. Methods ................................................................................................. 94
3.1.1. Ethics statement ...................................................................... 96
3.1.2. Participants .............................................................................. 96
3.1.3. Pre-experimental Psychophysics procedure ............................ 97
3.1.4. Pre-experimental Questionnaires ............................................ 98
3.1.5. Profile of Mood States (POMS) ................................................ 98
3.1.6. State-Trait Anxiety Inventory (STAI) ........................................ 99
3.1.7. Karolinska Sleepiness Scale (KSS) ............................................. 99
3.1.8. Pre-experimental trial ............................................................ 100
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3.1.9. Auditory entrainment ............................................................ 100
3.1.10. Visual entrainment ............................................................... 101
3.1.11. Behavioural Data Analysis .................................................... 101
4. Result .................................................................................................... 102
4.1.1. Pain Ratings – Auditory Entrainment Group .......................... 102
4.1.2. Pain Ratings – Visual Entrainment Group .............................. 103
4.1.3. Questionnaire Results ............................................................ 104
5. Discussion ............................................................................................. 105
CHAPTER 5 Alpha Analgesia: modulating Pain Perception through Binaural Beat
Entrainment .................................................................................................... 112
1. Abstract ................................................................................................ 113
2. Introduction ......................................................................................... 114
3. Methods ............................................................................................... 115
3.1.1. Ethics statement .................................................................... 115
3.1.2. Participants ............................................................................ 115
3.1.3. The Pain Stimulus ................................................................... 115
3.1.4. Pre-experimental Psychophysics procedure .......................... 116
3.1.5. Pre-experimental Questionnaires .......................................... 116
3.1.6. Pre-experimental trial ............................................................ 117
3.1.7. Entrainment ........................................................................... 118
3.1.8. EEG Recording ........................................................................ 118
3.2. EEG Data Analysis .......................................................................... 119
3.2.1. Event-Related Potentials ........................................................ 119
3.2.2. Spectral Analysis..................................................................... 120
3.2.3. Source Localisation Analysis .................................................. 120
3.2.4. Statistical Analysis .................................................................. 121
4. Results .................................................................................................. 122
4.1.1. Pain Ratings ............................................................................ 122
4.2. EEG Results .................................................................................... 123
4.2.1. Laser Evoked Potential (LEP) .................................................. 123
4.2.2. N2-P2 Components ................................................................ 124
4.2.3. Alpha Power ........................................................................... 125
4.2.4. Source Analysis (LORETA)....................................................... 130
5. Discussion ............................................................................................. 131
CHAPTER 6 Visual Alpha-Band Entrainment reduces the Behavioural and
Electrophysiological Pain Response .................................................................. 139
1. Abstract ................................................................................................ 140
2. Introduction ......................................................................................... 141
3. Materials and Methods ........................................................................ 142
3.1.1. Ethics Statement .................................................................... 142
3.1.2. Participants ............................................................................ 143
3.1.3. The Painful Stimulus ............................................................... 143
3.1.4. Psychophysics Procedure (Pre-experimental) ....................... 143
3.1.5. Questionnaires (pre-experimental) ....................................... 144
3.1.6. Baseline Pain Ratings ............................................................. 145
3.1.7. Visual Entrainment ................................................................. 145
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3.1.8. Acquisition of EEG Data.......................................................... 145
3.2. Quantitative Electrophysiological Analysis ................................... 146
3.2.1. Laser-Evoked Potentials (LEPs) .............................................. 146
3.2.2. Spectral Analysis..................................................................... 147
3.2.3. Source Localisation ................................................................ 147
3.3. Statistical Analysis ......................................................................... 148
4. Results .................................................................................................. 150
4.1.1. Behavioural Pain Ratings ........................................................ 150
4.1.2. Correlation Analysis ............................................................... 151
4.1.3. Alpha Activity ......................................................................... 151
4.1.4. Laser-Evoked Potentials ......................................................... 155
4.1.5. Sources of Laser-Evoked Potentials ....................................... 156
4.1.6. Source Analysis of Alpha Activity ........................................... 158
5. Discussion ............................................................................................. 160
CHAPTER 7 Modulating Pain through Visual Alpha Stimulation in Osteoarthritis
Patients: a role for the Insula Cortex ................................................................ 167
1. Abstract ................................................................................................ 168
2. Introduction ......................................................................................... 169
3. Materials and Methods ........................................................................ 170
3.1.1. Ethics statement .................................................................... 170
3.1.2. Study Participants .................................................................. 171
3.1.3. Pre-experimental questionnaires .......................................... 171
3.1.4. Experimental Procedure ........................................................ 172
3.1.5. Acquisition of EEG Data.......................................................... 173
3.1.6. Pre-processing of EEG data .................................................... 174
3.1.7. Spectral Analysis..................................................................... 174
3.1.8. Source Localisation ................................................................ 175
3.1.9. Statistical Analysis .................................................................. 175
4. Results .................................................................................................. 177
4.1.1. Behavioural Results ................................................................ 177
4.1.2. Clinical Pain Ratings ............................................................... 178
4.1.3. Anxiety and Sleepiness ........................................................... 179
4.1.4. Electrophysiological Results ................................................... 180
4.1.5. Alpha Activity ......................................................................... 181
4.1.6. LORETA ................................................................................... 184
5. Discussion ............................................................................................. 185
CHAPTER 8 General Discussion ......................................................................... 192
1. Introduction to Chapter 8 .................................................................... 193
2. Addressing Hypotheses: ....................................................................... 193
3. Clinical Implications of the Results ...................................................... 202
4. Limitations and Future Directions ........................................................ 203
5. Final Conclusions .................................................................................. 206
6. References: ........................................................................................... 207

Total number of words in main text: 52,295
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LIST OF FIGURES

Figure 1.1. C and A - Fibre Afferents .......................................................................... 17
Figure 1.2 Ascending Pathways .................................................................................. 19
Figure 1.3 Ascending Pathways and the Pain Matrix ................................................. 22
Figure 2.1 Numeric Pain Scale .................................................................................... 57
Figure 2.2 Generating evoked-potential responses from continuous EEG data. ...... 61
Figure 3.1 Experimental Entrainment Procedure ...................................................... 75
Figure 3.2 Electrode Scalp Regions ............................................................................ 77
Figure 3.3 Alpha Power .............................................................................................. 78
Figure 3.4 Topographical Maps .................................................................................. 79
Figure 3.5 Anterior to Posterior Effects ..................................................................... 81
Figure 3.6. Left to Right Effect ................................................................................... 82
Figure 3.7 Anterior to Posterior Effects ..................................................................... 85
Figure 3.8 Left to Right Effects ................................................................................... 86
Figure 4.1 Procedure in the Auditory Entrainment Group ........................................ 95
Figure 4.2 Procedure in the Visual Entrainment Group ............................................. 96
Figure 4.3 Auditory Group - Change in Pain Ratings ................................................ 103
Figure 4.4 Visual Group - Change in Pain Ratings .................................................... 104
Figure 5.1 Experimental Paradigm of Auditory Binaural Beat Entrainment ............ 117
Figure 5.2 Map of Electrode Scalp Regions .............................................................. 122
Figure 5.3 Laser-Evoked Potential over Middle Central Electrodes ........................ 124
Figure 5.4 N2P2 Topographies ................................................................................. 125
Figure 5.5 Alpha Power across Scalp Regions .......................................................... 128
Figure 5.6 Alpha Band Topographies ....................................................................... 129
Figure 5.7 LORETA P2 Results .................................................................................. 130
Figure 5.8 LORETA Alpha Results ............................................................................. 131
Figure 6.1 Experimental Procedures ........................................................................ 144
Figure 6.2 Map of Scalp Electrode Regions .............................................................. 149
Figure 6.3 Change in Pain Ratings from Baseline ..................................................... 150
Figure 6.4 Global Alpha Power Post Visual Entrainment ......................................... 152
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Figure 6.5 Alpha Power across Scalp Regions .......................................................... 153
Figure 6.6 Alpha Band Topographies ....................................................................... 154
Figure 6.7 Laser-Evoked Potentials over Middle Central Electrodes ....................... 155
Figure 6.8 N2 and P2 Peak Topographies ................................................................ 156
Figure 6.9 LORETA P2 Results .................................................................................. 158
Figure 6.10 LORETA Alpha Power Results ................................................................ 159
Figure 7.1 Experimental Procedure ......................................................................... 173
Figure 7.2 Map of Scalp Electrode Regions .............................................................. 176
Figure 7.3 Changes in Pain Ratings .......................................................................... 178
Figure 7.4 Changes in Clinical Pain ........................................................................... 179
Figure 7.5 Laser-Evoked Potentials in the Central Middle Electrodes ..................... 180
Figure 7.6 Topographies of LEPs .............................................................................. 181
Figure 7.7 Alpha Power across Scalp Regions .......................................................... 182
Figure 7.8 Alpha Band Topographies ....................................................................... 183
Figure 7.9 LORETA Results of P2 Peaks .................................................................... 184

LIST OF TABLES
Table 3.1 Condition Effects of Scalp Electrode Region Entrainment at 10Hz. ........... 80
Table 3.2 Follow-up Paired t-test of Anterior-to-Posterior Interaction following 10Hz
Entrainment ............................................................................................................... 83
Table 3.3 Condition Effects of Scalp Electrode Region Entrainment at 11Hz ............ 84
Table 5.1 Paired t-test comparing activity in LA, LM and LP regions to control at
10Hz .......................................................................................................................... 126
Table 5.2 Paired t-test comparing activity in LA, LM and LP regions to control at
10Hz .......................................................................................................................... 127
Table 6.1 LORETA P2 Results .................................................................................... 157
Table 6.2 LORETA Alpha Power Results ................................................................... 159
Table 7.1 Numeric Pain Ratings ............................................................................... 177
Table 7.2 Clinical Pain ............................................................................................... 179
Table 7.3 LORETA Results of P2 Peaks ..................................................................... 185
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LIST OF ABBREVIATIONS

ACC Anterior cingulate cortex
ANOVA Analysis of variance
BA Brodmann’s area
BCI Brain–Computer Interface
BF Biofeedback
CNS Central nervous system
CO Carbon dioxide
2
DC Direct current
DLPT Dorsolateral Pontine Tegmentum
DRG Dorsal root ganglion
EEG Electroencephalography
EOG Electro-oculogram
ERD Event-related desynchronisation
ERP Event-related potential
FIQ Fibromyalgia Impact Questionnaire
FFT Fast Fourier Transform
fMRI Functional magnetic resonance imaging
FM/FMS Fibromyalgia syndrome
HAQ -DI Health Assessment Questionnaire – Disability Index
Hz Hertz
IAF Individual Alpha Frequency
IASP International Association for the Study of Pain
ICA Independent components analysis
KSS Karolinska Sleepiness Scale
LORETA Low resolution electromagnetic tomography
LEP Laser-evoked potential
MCC Midcingulate cortex
MEG Magnetoencephalography
NCF Nucleus Cuneiforms
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NRS Numeric Rating Scale
NSAID Non-steroidal anti-inflammatory drug
OA Osteoarthritis
PAG Peri-aqueductal grey
PASS Pain Anxiety Symptoms Scale
PCS Pain Catastrophising Scale
PCC Posterior cingulate cortex
PET Positron emission tomography
PHQ - 9 Participant Health Questionnaire - 9
POMS Profile of mood states
RA Rheumatoid arthritis
RVM Rostroventral medulla
SI/S1 Primary somatosensory cortex
SII/S2 Secondary somatosensory cortex
SFC/G Superior frontal cortex/gyrus
SMR Sensorimotor Rhythm
STAI State and Train Anxiety Inventory
VAS Visual Analogue Scale
WOMAC Western Ontario and McMaster Universities Arthritis Index
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ABSTRACT

Pharmacological treatments for pain show limited analgesic benefits when
compared with placebo. Neuro-modulatory approaches, such as mindfulness
meditation and neurofeedback training show more promising effects, but are time
consuming and difficult to complete. Neural entrainment provides an almost
instantaneous increase in EEG power of the stimulated frequency, achieved with
minimal effort through visual flicker stimuli or auditory binaural beats. EEG
recorded alpha power displays a reproducible inverse relationship with pain
perception. Hence, the main objective of this PhD thesis was to develop an
analgesic alpha entrainment intervention: increasing alpha power with the aim to
reduce the perception of acute pain in healthy volunteers and chronic pain
patients.

Prior to attempting to modulate pain, pilot work assessing the ability to entrain
alpha power is reported in Chapter 3. A checkerboard stimulus was used to visually
entrain frequencies across the alpha band from 7Hz – 14Hz, resulting in a significant
power increase at 10Hz and 11Hz. With the goal to reduce behavioural and
electrophysiological responses to a moderately painful stimulus, EEG alpha
entrainment at 8Hz, 10Hz and 12Hz through auditory binaural beats (in Chapters 4
and 5), and visual flashing LED goggles (in Chapters 4, 6 and 7) was then attempted.
A significant reduction of pain ratings was found following both the visual and the
auditory alpha stimulation across all three frequencies in Chapters 4,5 and 6.
Chapter 5 revealed a significant alpha power increase following 10Hz and 12Hz
auditory stimulation. The laser-evoked potential’s (LEP) N2 peak reduced
significantly following 10Hz auditory entrainment and the P2 peak reduced
significantly across all auditory entrainment conditions.

In Chapter 6, alpha power entrained significantly at 8Hz and 10Hz. The P2 peak
reduced significantly following the 10Hz visual stimulation. Source analysis showed
the precuneus and posterior cingulate cortex might mediate alpha entrainment-
induced reductions in LEPs and pain ratings. The paradigm used in Chapter 6 was
repeated in osteoarthritic patients in Chapter 7. Significant reductions in pain
ratings were observed following all three alpha stimulation sessions, despite a lack
of alpha power increase. A significantly reduced response in the P2 peak was also
observed following the 12Hz visual stimulation. Decreases in P2 source activity in
the posterior insula suggest a functional role in the reduction of pain intensity
triggered by alpha stimulation.

A significant reduction in the electrophysiological response and the perception of
moderately painful stimuli can be achieved through visual or auditory entrainment
across the alpha band range, in both healthy volunteers and osteoarthritic patients.
The findings from this PhD thesis provide a solid foundation for further
investigation of alpha based neuro-modulation as an analgesic intervention.