Paired Transcranial Direct Current Stimulation/ Dorsal Root Ganglion Stimulation Trial
Phase: NA
Conditions: Chronic Pain
Sponsor: University of Oxford

 
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Study Title: The cerebral signature for pain perception and its modula-
tion 
REC Ref: 13/SC/0298 
Date and Version No: Version 7  28/05/2018 
 
Chief Investigator:  
Mr Alexander L Green, FRCS (SN),MD, BSc (Hons), MB BS 
Department of Neurosurgery, John Radcliffe Hospital 
Investigators:  
Professor Tipu Aziz, FRCS(SN), MD, Department of Neurosurgery, John Rad-
cliffe Hospital; Dr Sandra Boccard, PhD, Nuffield Department of Clinical 
Neuroscience; Dr Mark Stokes, PhD, Oxford Centre for Human Brain Activ-
ity; ; Mr James Fitzgerald FRCS(SN) PhD Department of Neurosurgery, John 
Radcliffe Hospital; Dr Yrsa Sverrisdóttir, PhD, Cardiovascular Clinical Re-
search Facility, Radcliffe Department of Medicine, Oxford; Mr Laurie 
Pycroft, MSc, Nuffield Department of Surgical Sciences; Dr Marko Bogda-
novic, MD, MRCP, Neurology Department, Royal Berkshire Hospital; Dr 
Tariq Parker, MBBS, Msc, Nuffield Department of Surgical Sciences; Dr 
Yongzhi Huang, PhD, Nuffield Department of Surgical Sciences; Dr John Erai-
fej, BSc (Hons), MBChB, Nuffield Department of Surgical Sciences. 
Sponsor:  
University of Oxford 
Funder: 
The late Prof Francis John Gillingham Legacy Grant  
Signatures:  
Mr Alexander L Green, FRCS (SN), MD, BSc (Hons), MB BS 
 
 
 
The investigators declared there is no conflict of interest in this research. 

 
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Table of Contents 
STUDY TITLE: THE CEREBRAL SIGNATURE FOR PAIN PERCEPTION AND ITS MODULATION 
1 
ETHICS REF: 
1 
DATE AND VERSION NO: 
1 
SYNOPSIS                                                                           5             
ABBREVIATIONS 
7 
Background and Rationale                                                       9 
OBJECTIVES 
10 
PRIMARY OBJECTIVE 
10 
SECONDARY OBJECTIVES 
10 
STUDY DESIGN 
10 
SUMMARY OF STUDY DESIGN 
11 
PRIMARY AND SECONDARY ENDPOINTS/OUTCOME MEASURES 
11 
STUDY PARTICIPANTS 
12 
OVERALL DESCRIPTION OF STUDY PARTICIPANTS 
12 
INCLUSION CRITERIA 
12 
EXCLUSION CRITERIA 
12 
STUDY PROCEDURES 
14 
STUDY PROTOCOL 
14 
INFORMED CONSENT 
20 
DEFINITION OF END OF STUDY 
20 
INTERVENTIONS 
20 
SAFETY 
21 
DEFINITION OF SERIOUS ADVERSE EVENTS 
21 
REPORTING PROCEDURES FOR SERIOUS ADVERSE EVENTS 
21 
STATISTICS AND ANALYSIS 
21 
NUMBER OF PARTICIPANTS 
21 
ANALYSIS OF ENDPOINTS 
22 
ETHICS 
22 
PARTICIPANT CONFIDENTIALITY 
22 

 
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OTHER ETHICAL CONSIDERATIONS 
23 
DATA HANDLING AND RECORD KEEPING 
23 
FINANCING AND INSURANCE 
23 
FUNDING 
23 
NEGLIGENT HARM 
23 
NON-NEGLIGENT HARM 
23 
REFERENCES 
24 
APPENDIX A: FUNDING STATEMENT 
26 
APPENDIX B: FLOWCHART OF PATIENT MOVEMENT IN THE HOSPITAL                                27 
FLOWCHART OF HEALTHY VOLUNTEER EVENTS  
 
 
   
    28 
 
APPENDIX C: AMENDMENT HISTORY                                                                29 
 

 
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SYNOPSIS 
Study Title 
The cerebral signature for pain perception and its modulation 
Study Design 
Prospective study 
Intervention Group 
All chronic neuropathic pain patients treated with deep brain  
Stimulation, Spinal Cord Stimulation including targeted stimulation of 
the Dorsal Root Ganglion, and noninvasive neurostimulation. 
Number in Intervention 
Group  
Approximately 50 patients minimum 
Control Group 
Healthy volunteers with no history of chronic pain, no acute pain, no 
previous neurosurgery and , no neurological/psychiatric comorbidities.
Number in Control Group 
Approximately 50 minimum 
Planned Study Period 
September 2013 to December 2019 
Primary Objective 
To determine whether there is cerebral pain signature  
Secondary Objectives 
To understand how the cerebral pain matrix, including brainstem, an-
terior cingulate cortex, thalamus and cerebral cortex interact with one 
another and with the spinal cord and dorsal root ganglia for pain per-
ception and its modulation. Also, to determine whether stimulation 
has an effect on the autonomic nervous  
system. 
Primary Endpoint 
Differences of LFPs of various cerebral nuclei induced by  
endogenous pain modulation and DBS in chronic pain compared to 
healthy controls 

 
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Secondary Endpoints 
Differences of LFPs of various cerebral nuclei induced by  
Analgesics, Difference in Muscle Sympathetic Nerve Activity (MSNA), 
Magnetoencephalographic (MEG) or Electroencephalographic (EEG) 
signals on and off stimulation and other autonomic parameters 
Intervention (s) 
Quantitative Sensory Testing, and patients’ everyday analgesics, Micro-
neurography, EMG, and LFP, EEG or MEG recording of brain or DRG, 
Non-invasive brain stimulation (TMS/tDCS) in chronic pain compared 
to healthy controls  

 
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ABBREVIATIONS 
ACC 
Anterior Cingulate Cortex 
DBS 
Deep Brain Stimulation 
DRG 
Dorsal Root Ganglion 
EEG 
Electroencephalogram 
EMG 
Electromyography 
GCP 
Good Clinical Practice 
IPG 
Internal Pulse Generator 
ICF 
Informed Consent Form 
LFPs 
Local Field Potentials 
MEG 
Magnetoencephalography 
MRI 
Magnetic Resonance Imaging 
MSNA 
Muscle Sympathetic Nerve Activity 
PAG 
Periaqueductal Grey 
PIL 
Participant/ Patient Information Leaflet 
QST 
Quantitative Sensory Testing 
R&D 
NHS Trust R&D Department 

 
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REC 
Research Ethics Committee 
SCS 
Spinal Cord Stimulation 
SOP 
Standard Operating Procedure 
tDCS 
Transcranial Direct Current Stimulation 
TMS 
Transcranial Magnetic Stimulation 
VPL 
Ventral Posterolateral thalamic nucleus 
VPM 
Ventral Posteromedial thalamic nucleus 

 
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BACKGROUND AND RATIONALE 
 
We want to know whether there is a brain signature of pain. Pain perception is very subjective, 
but if we can find a pain signature, we can detect the objective pain feeling of patients, and we 
can modulate it to relieve patients’ chronic pain.  
 
Besides this, we also want to study the endogenous pain modulation pathway. The more we un-
derstand it, the more effective pain treatment we can provide. Pain perception can be altered, 
and abundant evidence has demonstrated that stimulation of the brainstem (ventrolateral col-
umn of the PAG) can activate the endogenous pain modulation pathway to inhibit the pain signal 
input at the level of the spinal cord1-5. Richardson and Akil 6,7, and Hosobuchi and colleagues 8 
translated this body of knowledge to clinical use and reported pain relief in patients given chronic 
stimulation of the PAG. Since then, deep brain stimulation (DBS) of the PAG has been successfully 
carried out all over the world and has been proved as an effective treatment for pain relief in 
chronic medicine-refractory pain patients 9,10. 
 
Even though the aforementioned mechanism is well-studied, it is still unclear whether the PAG 
may exert its pain-modulation effect by alternative pathways in addition. Animal studies have 
shown that the PAG has direct projections to the thalamus in many species 11,12. Likewise imaging 
studies in humans have demonstrated direct connections between the PAG and the thalamus 13. 
Therefore, it is reasonable to suggest that the PAG may affect the thalamus to modulate pain 
perception, and the thalamus, traditionally regarded as a sensory relay centre, may also be able 
to project to the PAG to modulate pain. However, much less attention has been paid to this sug-
gestion. 
 
In this human study, we take advantage of the DBS of various cerebral nuclei related to pain 
perception, and use a mental task to induce patients’ endogenous pain modulation, to determine 
whether there is cerebral signature of pain, and to test our two hypotheses: 1. that the PAG 
modulates pain perception not only via its pathway to the spinal cord, but also via more direct 
ascending connections to the thalamus; 2. that the thalamus can also affect the PAG to modulate 
pain, rather than being merely a relay centre.   
 
In addition to these questions, we would also like to investigate the effects of stimulation on the 
autonomic nervous system to see whether modulation of this system is responsible (at least in 
part) for the effects of stimulation on pain relief. We have previously shown that stimulation can 
alter sympathetic nerve activity1 but would like to investigate this further, especially looking at 
the peripheral part of the system (dorsal root ganglion (DRG)). 
 

 
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Previous unpublished data suggests that the left side of the brain may modulate pain differently 
than the right side. In order to ascertain these differences we would utilize the high temporal and 
spatial resolution of MEG to compare brain signals in various patient states. 
 
In order to validate the clinical significance of MEG-identified signatures, we intend to recruit 
healthy controls for comparison of neural signatures in pain-free individuals. Furthermore, we 
wish to evaluate this objectively identified pain signature by localizing the brain structures in-
volved from MRI scans and conducting non-invasive targeted inhibition of these signal with 
TMS/tDCS to evaluate its impact on pain relief and cognitive function.   
 
OBJECTIVES 
 
Primary Objective  
To determine whether there is a cerebral pain signature  
Secondary Objectives  
To understand how the cerebral pain matrix, including brainstem, anterior cingulate cortex, thal-
amus and cerebral cortex interact with one another, and with the spinal cord and peripheral 
nervous system, for pain perception and its modulation. 
To determine whether stimulation of the DRG, Spinal Cord, Brain, or periphery alter sympathetic 
nervous system activity and whether these changes (if present) are related to pain relief. 
STUDY DESIGN 
This is a prospective study. Participants are chronic pain patients admitted to the John Radcliffe 
Hospital to receive deep brain stimulation, spinal cord stimulation, DRG stimulation, or noninva-
sive stimulation treatment for pain relief. Their standard clinical treatment involves two opera-
tions: stage 1 operation for deep brain or spinal electrode implantation, and stage 2 for pulse 
generator implantation, which is usually performed one week after stage one operation (for 
DBS/SCS/DRG patients). The baseline Quantitative Sensory Testing (QST), EEG, MEG, EMG, and 
Microneurography will take place pre-operatively, within 6 weeks post-operatively and at 6 
months. LFP recording will take place between stage 1 and 2 (where appropriate). None of the 
tests will interfere with the patient’s usual treatment. 
 
In addition, a control cohort of healthy subjects that have not experienced chronic pain will be 
recruited as a comparator group to observe the cerebral signature during non-painful states. 
 

 
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Summary of Study Design 
  
Pre-operatively, before 6 weeks post-operatively and at 6 months post-operatively, patients will 
undergo standard Quantitative Sensory Testing (QST), EEG, MEG, EMG, microneurography and 
measurement of autonomic parameters (heart rate, 24 hour ambulatory blood pressure, ECG 
and galvanic skin response). These sessions will not last longer than 2 hours each.  
 
Patients with externalized electrodes are expected to spend one hour a day for 2 days during 
their stay in the hospital or will be tested intraoperatively. We use computer-based mental tasks 
to distract patients from their pain, decreasing their pain perception. We record their brain, spi-
nal or DRG electrophysiological signals - local field potentials - to analyse what happens to their 
nervous system when pain decreases. We will also use electrical, thermal and pressure/ pin prick 
stimulation on patients’ limbs, producing graded painful feeling, and record and analyse their 
signals during the time to see what kind of signals are related to pain.  
 
A control cohort of healthy age-matched subjects that have not experienced chronic pain will be 
recruited as a comparator group to observe the normal cerebral signature during unaffected by 
chronic pain. 
 
Primary and Secondary Endpoints/Outcome Measures 
In the intervention group, we will observe the changes of LFPs of various cerebral, spinal and DRG 
nuclei induced by endogenous pain modulation, therapeutic DBS and TMS/tDCS. We will also 
investigate the differences of LFPs of various nuclei induced by medications. 
 
Cortical signatures of pain will be recorded to identify global changes in neural excitation under 
chronic pain and therapeutic states. This will be identified using MRI, MEG/EEG recordings and 
Quantitative sensory testing (QST). In the intervention group, this will be undertaken during en-
dogenous pain modulation, therapeutic DBS, SCS, DRGS and TMS/tDCS. We will also observe 
changes in autonomic parameters induced by stimulation. 
 
In the control group, we will identify the brain wave patterns via MEG/EEG during quantitative 
sensory testing (QST), TMS/tDCS and during cognitive tasks in order to compare the chronic pain 
cerebral patterns with that of the healthy brain.  
 

 
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STUDY PARTICIPANTS 
Overall Description of Study Participants 
Patients with chronic medicine-refractory neuropathic pain that are referred to the Department 
of Neurological Surgery for DBS, SCS or DRG treatment, or for treatment with noninvasive elec-
trical/radio wave stimulation. Controls will also be recruited. 
 
Chronic pain patients: 
Inclusion Criteria 
Patients who are willing and able to give consent to the study. 
Male or Female, aged 18 years or above. 
Treatment includes DBS of ACC, PAG or sensory thalamus (VPL or VPM), SCS or DRG stim-
ulation, or peripheral analgesic stimulation. 
Exclusion Criteria 
Patients may not enter the study if any of the following applies: 
Patients who do not wish to be in the study. 
Patients with extreme language barrier that cannot understand the purpose of the study 
despite the use of an interpreter. 
(see below for non-invasive stimulation-specific exclusion criteria) 
 
Controls: 
Inclusion Criteria 
Patients who are willing and able to give consent to the study. 
Male or Female, aged 18 years or above. 
Exclusion Criteria 
Participants may not enter the study if any of the following applies: 
Participants who do not wish to be in the study. 
Patients with extreme language barrier that cannot understand the purpose of the study 
despite the use of an interpreter. 
Participants with a history of neurological disorders. 
Participants with a history of psychiatric disorders. 
Participants who have chronic pain. 
Participants who have acute pain. 
Participants who had ever undergone neurosurgery. 
 
Participant recruitment: 
The intervention group will be recruited from neurosurgery clinics lists of patients with known 
DBS, spinal or DRG electrodes implanted. They will be invited to participate in the study either in 

 
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person at clinic appointments or by telephone. Participant information leaflets will be given to 
patients ahead of participation in the study to allow for informed consent for participation. 
 
To recruit an appropriately age and sex-matched control group, spouses and partners of partici-
pants within the intervention group will simultaneously be invited to participate and will receive 
the relevant participant information sheet. Participants will also be recruited by word-of-mouth18 
as a passive recruitment strategy. This will allow willing members of the participants’ community 
to self-identify interest in partaking in the study. Exclusion criteria can be found above. 

 
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STUDY PROCEDURES 
Experimental protocol  
Participants 
Participants will be patients who have suffered from chronic pain, and undergone insertion of 
DBS electrodes into various cerebral areas, including the ACC, sensory thalamus and PAG or Spi-
nal Cord Stimulation including targeted stimulation of the Dorsal Root Ganglion (DRG stimula-
tion), or who have been offered noninvasive analgesic stimulation, such as transcutaneous elec-
trical nerve stimulation (TENS) or pulsed shortwave therapy (PSWT). 
Procedure: 
Intervention Group: 
Pre-operatively and post-operatively (<6 weeks and 6 months), participants will undergo a full 
Quantitative Sensory Testing (QST) protocol and Autonomic protocol including microneurogra-
phy. Participants will also undergo EEG/MEG recording and pre-operative MRI at the Oxford Cen-
tre for Human Brain Activity (OHBA) if this has not been done prior to recruitment.  
During their inpatient stay, participants will perform a distraction mental task four times. Each 
time they will be in an ‘assigned’ state, such as ‘resting’, with therapeutic stimulation (DBS, SCS, 
DRG, or noninvasive stimulation), with ‘medication’ or with ‘painful stimulation’. Local field po-
tentials are recorded from the electrodes whilst doing the mental task. Cortical activity will also 
be recorded using EEG. The order of the patients’ states will be randomised. Any experiments in 
the off medication state will be after 24 hours off analgesics such as paracetamol and codeine-
based drugs, making sure that the drug effect has vanished. 
Participants will also perform a short computer-based task to measure cognitive performance, 
including attention, working memory and task-switching. Each subtask is less than 5 minutes, and 
participants will perform no more than 6 such tasks in succession. 
Control Group: 
In the control group, participants will undergo a full Quantitative Sensory Testing (QST) protocol 
and Autonomic protocol including microneurography. Participants will also undergo MRI, 
EEG/MEG analysis at the Oxford Centre for Human Brain Activity (OHBA) and TMS/tDCS at the 
John Radcliffe Hospital. 

 
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During EEG/MEG recordings, participants will perform a short computer-based task to measure 
cognitive performance, including attention, working memory and task-switching. Each subtask is 
less than 5 minutes, and participants will perform no more than 6 such tasks in succession. 
MRI 
Once contraindications to magnetic resonance imaging are excluded by use of the facility’s 
screening forms, the risks of undergoing a scan are minimal.  A trained scanner operator or ra-
diographer will go through a list of possible risks with the participant before scanning.  The MRI 
scanner consists of a large powerful magnet.  Magnetic resonance imaging uses no ionising ra-
diation.  There are, however, potential hazards associated with MRI and the scanning of partic-
ipants including the presence of surgical implants, participants’ clothing, jewellery (such as body 
piercings) bodily habitus, or medical conditions.  A comprehensive list of potential risks has 
been compiled, and the participant should be checked against this by the operator, prior to en-
tering the controlled areas of the MRI scanners.  During the actual scanning procedure, the 
scanner produces loud banging noises and the participant will be given suitable hearing protec-
tion (earplugs).  There is a small mirror that will allow them to see out of the scanner.  During 
the experiment, the participant will be able to communicate with the operator in the control 
room.  In addition, they will be given a call button, which allows them to alert the operator at 
any time.  People with a history of claustrophobia may be excluded from participation in the 
study.  All participants will still be introduced carefully to the scanner and allowed to leave at 
any stage, should they wish to do so.  Once in the scanner, participants will be able to indicate 
immediately if they wish the scanning to cease by pressing a call button in their hands 

 
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Rationales behind this protocol 
In order to be able to determine whether LFP ‘signatures’ are related to pain states per se, we 
need to be able to look at the LFPs during modulation of those pain states. If a particular signature 
correlates with the degree of pain (measured using a visual analogue score), we can only show 
cause and effect by either endogenous modulation (distraction mental task) or exogenous mod-
ulation (increasing or decreasing the pain using painful stimulation or analgesia respectively). The 
rationale behind the QST is to precisely define the pain characteristics for each patient. The au-
tonomic parameters need to be tested before the intervention and after acute and chronic stim-
ulation to look at possible plasticity effects 
Microneurography 
This technique entails insertion of two very fine needles (microelectrodes, 30-40 microns in di-
ameter, less than the diameter of a human hair) below the knee. The first will record directly 
from the common peroneal nerve whilst the second will lie subcutaneously as a reference. We 
will perform this bilaterally. This is an established technique and the only one enabling direct 
measure of peripheral sympathetic nerve activity. Neurograms will be recorded with stimulation 
On and then Off during the same sitting. The maximum time the needle will remain within the 
tissue will be 45 minutes. We will measure galvanic skin response (sweating), continuous non-
invasive blood pressure, ECG and tilt table testing during the same sitting. In some patients, we 
will measure ambulatory blood pressure for 24 hours (whilst at home).  
Quantitative Sensory Testing 
A standard battery of tests (e.g. the German Research Network on Neuropathic Pain (DFNS) pro-
tocol will be used. This consists of measurements of pain threshold and sensation using heat, 
pressure, pin prick, vibration, and electrical stimuli. Proprioception will be tested by measure-
ment of tendon reflexes and surface electromyography. We will use a Somedic Sensebox and 
ThermoTest equipment. QST has been used in a number of studies involving neuromodulation 
and spinal cord stimulation in particular15. The rationale for its use is that we are looking for an 
‘objective’ measure of pain which can be provided by looking at pain thresholds etc. whereas 
simply monitoring ‘visual analogue score’ will not validate our cerebral signature as an objective 
measure as it is subject to reporting bias. 
Magnetoencephalography 

 
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This procedure is a non-invasive method of detecting changes in the magnetic fields around the 
scalp which correspond to underlying neural activity. The protocol would involve recording these 
signals from both hemispheres of the brain, during “on” and “off” stimulation periods to deter-
mine if there is a difference in laterality of brain processing during dorsal root ganglion stimula-
tion. We will simultaneously evaluate the aforementioned vital sign evaluations (ECG, blood pres-
sure) and QST to determine the differences between stimulation-induced brain signals and sen-
sory signals and how they correlate with autonomic nervous system function. For those patients 
who have not undergone MRI Brain pre-operatively, this will be facilitated at the time of MEG 
recruitment for purposes of pain signal localization. 
Non-invasive Brain Stimulation 
Transcranial Magnetic Stimulation (TMS) and Transcranial Direct Current Stimulation (tDCS) have 
arisen as novel non-invasive brain stimulation (NIBS) techniques used in experimental and ther-
apeutic applications for a variety of neurologic disorders. Depending on the placement of anode 
and cathode, they have been found to produce intracortical facilitation and inhibition, which pro-
vides a unique opportunity to identify causal relationships between brain region activity and clin-
ical/behavioural effects. 
Studies have shown that anodal tDCS to primary motor cortex (M1) and dorsolateral prefrontal 
cortex (dlPFC) can result in short-term and long-term relief of neuropathic pain [Ngyernam et al, 
2013]. Possible mechanisms of this pain relief are posited to occur via restoration of defective 
intracortical inhibition at M1 in patients suffering from neuropathic pain [Portilla et al, 2013]. The 
goal of the proposed experiment would be to investigate the effect of intracortical inhibition of 
the identified MEG pain signals, or, intracortical facilitation of pain relief centres, to validate 
whether they are representative of pain signalling or a cortical epiphenomenon of neurostimu-
lation. The following treatment groups: 
M1 NIBS-SCS/DRG Stim(positive control)         vs.    MEG signal-targeted NIBS-SCS/DRG 
Stim   vs.       sham NIBS-SCS/DRG Stim (negative control) 
Would be evaluated before and after 30 minutes of stimulation with Visual Analogue Scale (VAS), 
Neuropathic Pain Symptom Inventory (NPSI) and EuroQol 5D (EQ-5D) as primary, secondary and 
tertiary endpoints for evaluation of the effect of cortical facilitation/inhibition on spinal/dorsal 
root ganglion stimulation. Each participant will undergo a maximum of 5 sessions, each session 
taking place at least one day apart. 

 
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Whereas non-invasive brain stimulation has been used safely in patients with spinal cord stimu-
lators (Schlaier et al., 2007) this technology has not been explored for safety in patients with 
metallic head/brain implants, and as such, tDCS will not be implemented in patients treated with 
Deep Brain Stimulation. 
The seizure risk from rTMS is usually during low frequency (<0.1%), whereas therapeutic pain 
relief has been shown with high frequency TMS19,20. Nevertheless, prior to TMS participants will 
be excluded from participation if they are sleep deprived prior to study, have a family history of 
seizures, have a significant history of alcohol use or previous neurological condition, factors 
which may increase the risk of TMS-induced seizure. 
Distraction mental task 
The task includes 15 sections, including 5 rest, 5 easy and 5 difficult ones. Each section lasts 
around one minute. The sequence of these sections will be randomised.   
In the rest section patients will just need to concentrate on their pain, and after the section pa-
tients will choose a score on the visual analogue scale on the screen, indicating how their pain is 
during the section.   
In the easy task section patients will need to remember the colour of the T-shape figure shown 
on the screen before starting the easy section. When the section begins, the screen will show 
many T-shape figures, one by one, with various colours. Whenever seeing the correct colour, as 
shown before the section, patients need to push a button of the computer’s keyboard. After the 
section patients will choose a score on the visual analogue scale, indicating how their pain is 
during the task section. 
In the difficult task section patients will need to remember the colour and the orientation of the 
T-shape figure shown on the screen before starting of the section. When the section begins, the 
screen will show many T-shape figures, one by one, with various colours and orientations. When-
ever seeing the figure with the correct colour and orientation patients need to push a button of 
the computer’s keyboard. After the section patients will choose a score on the visual analogue 
scale, indicating how their pain is during the task section. 
Various patients’ states  
State 1 – resting state, without stimulation or drugs 
Participants will do the mental task when their stimulator is off. In addition, they will not take their eve-
ryday pain medications for at least 24 hours before the task 

 
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State 2 – Therapeutic stimulation state, with stimulation on  
Participants will do the mental task when their stimulators are on and at the stimulation parameters pro-
ducing the most pain relief.  
State 3 – medication state, with patients’ everyday medications for pain relief 
Participants will do the mental task with their usual pain medications. Their stimulators will be turned off 
too. 
State 4 – pain stimulation state, with peripheral stimulation to induce patients’ pain symptom 
Participants will do the mental task when their stimulator is turned off. We will use peripheral stimulation 
to induce pain when they are doing the task. This peripheral stimulation will take the form of a Somedic 
Thermotest or equivalent heat stimulus, an electrical stimulus, or a mechanical stimulus, just above the 
pre-measured pain threshold.  
Summary of the possible combinations of participants’ experimental states and the mental task they 
are having, and the questions that each combination can address (explained below) 
 
 
               
State 
Task 
Resting
Therapeutic Stim-
ulation on 
Medication
Pain stimulation
Rest
 
Rest LFPs
Neuro modula-
tion effect 
Drug effects on 
the target 
Effect of painful 
stimulus on tar-
gets 
Easy
 
Endogenous pain 
modulation 
Stim + endoge-
nous pain modu-
lation effect 
Drug + endoge-
nous pain modu-
lation effect 
Effect of endoge-
nous modulation 
on pain signa-
tures induced by 
painful stimulus 
Difficult
 
Endogenous pain 
modulation 
Stim + endoge-
nous pain modu-
lation effect 
Drug + endoge-
nous pain modu-
lation effect 
Effect of endoge-
nous modulation 
on pain signa-
tures induced by 
painful stimulus 
 

 
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Questions that each state of the experiment could address 
Resting state 
1. Brain signals (MEG/EEG/LFPs) recorded during rest sections of the task: the baseline of targets’ 
local field potentials and patients’ pain scale. 
2. Signals recorded during easy task sections: the response of the targets to the endogenous pain 
modulation (compared with baseline signals). 
3. Signals recorded during difficult task sections: the response of the targets to the endogenous pain 
modulation (compared with baseline signals) 
4. The change of targets’ brain signals with different degrees of pain modulation (easy versus  dif-
ficult task 
Therapeutic Stimulation state 
1. Brain signals recorded during rest sections of the task: Stimulation effect on the targets  
2. Brain signals recorded during easy and difficult sections of the mental task: compared with the 
data gathered in resting state, we can see if stimulation can enhance the endogenous pain mod-
ulation or have no effect on it. 
Medication state 
1. Brain signals recorded during rest sections of the mental task: Drug effects on the targets 
2. Brain signals recorded during easy and difficult sections of the mental task: compared with the 
data gathered from resting state, we can see if medications can enhance endogenous pain mod-
ulation or have no effect on it. 
Pain stimulation state 
1. Brain signals recorded during rest sections of the mental task: pain signatures of the targets in-
duced by painful stimulus 
2. Brain signals recorded during easy and difficult sections of the mental task: we can investigate 
how endogenous pain modulation affects the pain signatures induced by painful stimulus 
 
Informed Consent 
Informed consent to this study will be obtained prior to the participants’ inclusion in the study. 
In addition, verbal consent will also be acquired at the point of each research intervention. The 
patients will be supplied with Patient Information Sheets in advance of the surgery while partici-
pants will be provided with the Healthy Volunteer Information Sheet at least 2 weeks prior to 
involvement in any imaging or testing. Consent will be taken by the pain nurse or someone else 
independent of the direct care team. 
 
Definition of End of Study  
The end of study is the date of the last research experiment of the last participant. 

 
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INTERVENTIONS  
Pre-operatively and Post-operatively we will perform microneurography, QST, tilt table tests, 
ECG, ambulatory blood pressure, and GSR. 
 
During the distraction and MEG/LFP experiments we will measure patients’ ECG, blood pressure 
and respiratory rate. We will also record their LFPs, MEG, EEG and visual analog scale of pain.   
In order to know the neural signature for pain, we will use painful stimulation to induce patients’ 
pain perception. This stimulation will take the form of Contact Heat-Evoked Potential Stimula-
tion, electrical stimulation, or mechanical stimulation, with selective stimulation of A-Delta & C-
fibers.  
SAFETY 
There is no risk that participants are exposed to other than they may experience more pain or a 
different type of pain to their usual pain. Patients will be given the ability to stop the experiment 
at any time should they feel uncomfortable. 
Definition of Serious Adverse Events 
A serious adverse event is any untoward medical occurrence that: 
 Results in death, 
 Is life-threatening, 
Requires inpatient hospitalisation or prolongation of existing hospitalisation, 
Results in persistent or significant disability / incapacity, or 
Is a congenital anomaly / birth defect. 
Other important medical events.* 
  
NOTE: The term "life-threatening" in the definition of "serious" refers to an event in which the 
participant was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe.  
 
*Other events that may not result in death, are not life threatening, or do not require hospitali-
sation, may be considered a serious adverse event when, based upon appropriate medical judge-
ment, the event may jeopardise the participant and may require medical or surgical intervention 
to prevent one of the outcomes listed above. 
Reporting Procedures for Serious Adverse Events 
A serious adverse event (SAE) occurring to a participant should be reported to the REC that gave 
a favourable opinion of the study where in the opinion of the Chief Investigator the event was 
‘related’ (resulted from administration of any of the research procedures) and ‘unexpected’ (the 
type of event is not listed in the protocol as an expected occurrence). Reports of related and 
unexpected SAEs should be submitted within 15 days of the Chief Investigator becoming aware 
of the event, using the NRES report of serious adverse event form (see IRAS/NRES website). 

 
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STATISTICS AND ANALYSIS 
Number of Participants 
The expected number of participants involved in this study is approximately 50. This is based on 
the annual number of neuromodulation operations for pain relief at the John Radcliffe Hospital. 
Analysis of Outcome Measures 
Outcome measures of both intervention group and control group (QST, EEG/MEG) will be ana-
lysed using statistical analysis software and MATLAB. All participant data will be utilized in anal-
ysis unless they have withdrawn consent. 
Analysis of Endpoints  
The endpoint analysis will be performed using statistical analysis software and mathematical 
computational modeling licensed by the University of Oxford. The analysis involves complex sig-
nals analysis techniques where significant difference in power at certain frequencies can be de-
termined using custom-made software (based on MATLAB®).  
ETHICAL AND REGULATORY CONSIDERATIONS 
 
Declaration of Helsinki 
The Investigator will ensure that this study is conducted in accordance with the principles of the 
Declaration of Helsinki  
Guidelines for Good Clinical Practice 
The Investigator will ensure that this study is conducted in accordance with relevant regulations 
and with Good Clinical Practice. 
Approvals 
The protocol, informed consent form, participant information sheet and any proposed advertis-
ing material will be submitted to an appropriate Research Ethics Committee (REC), and HRA for 
written approval. 
The Investigator will submit and, where necessary, obtain approval from the above parties for 
all substantial amendments to the original approved documents. 
Reporting 
The CI shall submit once a year throughout the study, or on request, an Annual Progress report to the 
REC Committee, HRA (where required) host organisation and Sponsor. In addition, an End of Study noti-
fication and final report will be submitted to the same parties 

 
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Participant Confidentiality 
The study staff will ensure that the participants’ anonymity is maintained. The participants will 
be identified only by initials and a participants ID number on the CRF and any electronic database. 
All documents will be stored securely and only accessible by study staff and authorised person-
nel. The study will comply with the Data Protection Act which requires data to be anonymised 
when it is practical to do so.   
Expenses and Benefits 
Reasonable travel expenses for any visits additional to normal care will be reimbursed on production of 
receipts, or a mileage allowance provided as appropriate. 
Other Ethical Considerations 
This study does not require any involvement of vulnerable participants, participants who are un-
able to consent for themselves or indemnity provision.  
In the unlikely event of seeing any structural abnormalities on an MRI scan, the scan will be 
checked by a clinical specialist.  If the specialist feels that the abnormality was medically im-
portant, they will discuss the implications with the participant and arrange for further investiga-
tions as necessary.  Participants will not be informed unless the doctor considers the finding 
has clear implications for their current or future health.  It is important to note that scans are 
not carried out for diagnostic purposes, and therefore the scans are not a substitute for a clini-
cal appointment. Rather, the scans are intended for research purposes only. 
 
DATA HANDLING AND RECORD KEEPING 
The participants will be identified by a study specific participant number. The name and any other 
identifying detail will NOT be included in any study data electronic file. 
Publication Policy 
The investigators will be involved in reviewing drafts of the manuscripts, abstracts, press releases 
and any other publications arising from the study. Authorship will be determined in accordance 
with the ICMJE guidelines and other contributors will be acknowledged. 
FINANCE AND INSURANCE 
Funding 
The late Prof Francis John Gillingham Legacy Grant as attached. 

 
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Insurance 
The University has a specialist insurance policy in place which would operate in the event of any 
participant suffering harm as a result of their involvement in the research (Newline Underwrit-
ing Management Ltd, at Lloyd’s of London). NHS indemnity operates in respect of the clinical 
treatment that is provided. 
 
REFERENCES 
 
1 Basbaum, A. I. & Fields, H. L. Annual Review of Neuroscience 7, 309-338, (1984). 
2 Budai, D., Harasawa, I. & Fields, H. L. Journal of Neurophysiology 80, 2244-2254 (1998). 
3 Heinricher, M. M., Tavares, I., Leith, J. L. & Lumb, B. M. Brain Research Reviews 60, 214-
225, (2009). 
4 Millan, M. J. Progress in Neurobiology 66, 355-474, (2002). 
5 Bandler, R. & Shipley, M. T. Trends in Neurosciences 17, 379-389, (1994). 
6 Richardson, D. E. & Akil, H. Journal of Neurosurgery 47, 178-183, (1977). 
7 Richardson, D. E. & Akil, H. Journal of Neurosurgery 47, 184-194, (1977). 
8 Hosobuchi, Y., Adams, J. E. & Linchitz, R. Science 197, 183-186, (1977). 
9 Bittar, R. G. et al. Journal of Clinical Neuroscience 12, 515-519, (2005). 
10 Levy, R., Deer, T. R. & Henderson, J. Pain Physician 13, 157-165 (2010). 
11 Krout, K. E. & Loewy, A. D. Journal of Comparative Neurology 424, 111-141, (2000). 
12 Benarroch, E. E. Neurology 78, 210-217 (2012). 
13 Sillery, E. et al. Journal of Neurosurgery 103, 1030-1034, (2005). 
14 Sverrisdottir Y et al. Hypertension 63(5):1000-10 (2014) 
15 Rasche D, et al. Neuromodulation. 2006 ;9(3):239-47. 

 
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16 Ngernyam N et al (2013) Transcranial Direct Current Stimulation in Neuropathic Pain. J 
pain Reli Suppl 3 
17 Portilla AS et al (2013) A feasibility study assessing cortical plasticity in chronic neuro-
pathic pain following burn injury. J Burn care Res 34:48–52  
18 Raynor HA, Osterholt KM, Hart CN, Jelalian E, Vivier P, Wing RR (2009) Evaluation of ac-
tive and passive recruitment methods used in randomized controlled trials targeting pediat-
ric obesity. Int J Pediatr Obes 4:224–232 Available at: https://onlineli-
brary.wiley.com/doi/pdf/10.3109/17477160802596189 [Accessed June 18, 2018]. 
19 Dobek CE, Blumberger DM, Downar J, Daskalakis ZJ, Vila-Rodriguez F (2015) Risk of sei-
zures in transcranial magnetic stimulation: a clinical review to inform consent process fo-
cused on bupropion. Neuropsychiatr Dis Treat 11:2975–2987 Available at: 
http://www.ncbi.nlm.nih.gov/pubmed/26664122 [Accessed June 18, 2018]. 
20 Klein MM, Treister R, Raij T, Pascual-Leone A, Park L, Nurmikko T, Lenz F, Lefaucheur J-P, 
Lang M, Hallett M, Fox M, Cudkowicz M, Costello A, Carr DB, Ayache SS, Oaklander AL 
(2015) Transcranial magnetic stimulation of the brain: guidelines for pain treatment re-
search. Pain 156:1601–1614 Available at: http://www.ncbi.nlm.nih.gov/pubmed/25919472 
[Accessed June 18, 2018]. 
 
 
 
 
 
 
 
 

 
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APPENDIX A: Funding Statement 
 
 

 
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APPENDIX B: Flowchart of patient events 
 
 
 
Pre-
operative
•MEG/ EEG, MRI, Microneurography  and QST. Ambulatory BP (24 hours) and Tilt table testing in those who 
consent
Stage 1 
operatio
n
•Admission to hospital
•Receive stage 1 DBS or SCS or DRG operation
Program
ming
•During the first 2-3 post-operation days, pain nurses will program your stimulator to get the best setting reducing 
your pain.
Study
•Having obtained best settings of your stimulator, pain nurses will refer you, with your consent,  to the research 
team for pain study.
•The study will be held in two days between the two operations you will receive in hospital
Stage 2 
operation
•Received stage 2 operation
•Discharge from hospital
Immediate 
Post-op
•Within 6 weeks: MEG/EEG, Microneurography and QST
6 months 
Post-op
•MEG/EEG, Microneurography and QST
6-12 months 
post-op
•Pre-tDCS EEG, VAS, NPSI, EQ-5D - 30 minutes tDCS stimulation - Post-tDCS EEG, VAS, NPSI, EQ-5D 

 
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Flowchart of Healthy volunteer events 
 
 
 
 
 
 
 
 
 
 
Recruitment
•Age-matched controls will be screened for inclusion and exclusion criteria
Pre-testing
•MRI conducted at the Oxford Centre for Human Brain Activity (OHBA)
Testing
•EEG, QST, Microneurography and non-invasive brain stimulation conducted at 
the John Radcliffe Hospital 
•MEG conducted at the OHBA
•Cognitive tasks conducted at both sites during testing

 
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APPENDIX C:  AMENDMENT HISTORY 
 
Amend-
ment No. 
Protocol 
Version 
No. 
Date issued
Author(s) of changes 
Details of Changes 
made 
7 
7 
28/01/2018
Tariq Parker, John Eraifej 
This amendment 
makes provision for 
the recruitment of a 
healthy control group, 
acquisition of a pre-
operative MRI in 
chronic pain partici-
pants, as well as the 
use of non-invasive 
brain stimulation 
(TMS/tDCS).