Technology Development for Closed-loop Deep Brain Stimulation to Treat Refractory Neuropathic Pain
Phase: NA
Conditions: Chronic Pain, Post Stroke Pain, Phantom Limb Pain, Spinal Cord Injuries
Sponsor: Prasad Shirvalkar, MD, PhD

v 10.01.2019 
CLINICAL PROTOCOL 
(version 10.01.2019) 
 
 
Title: 
Deep brain stimulation (DBS) in patients with refractory chronic 
neuropathic pain 
 
Protocol: 
NCT03029884  
 
Study Sponsors/ 
Investigators: 
 
Dr. Edward F. Chang MD 
Associate Professor of Neurological Surgery 
University of California, San Francisco 
513 Parnassus Ave, Med Sci 
San Francisco, CA 94143 
Phone: 415-502-7346 
Fax: 415-502-7332 
E-mail: Edward.Chang@ucsf.edu 
 
 
Co-Investigator: 
Prasad Shirvalkar M.D., Ph.D. 
Assistant Professor of Anesthesiology and Neurology 
University of California, San Francisco 
2255 Post Street, San Francisco, CA 94143 
Phone: 415-502-7346 Fax: 415-502-7332 
Prasad.Shirvalkar@ucsf.edu 
 
Other: 
Philip Starr M.D., Ph.D.  
Professor of Neurological Surgery  
University of California, San Francisco  
779 Moffitt, 505 Parnassus Ave San Francisco, CA 94143 
Phone: 415.502.2885 Fax: 415.353.2889  
Philip.Starr@ucsf.edu  
 
Contact: Prasad Shirvalkar MD, PhD 
Prasad.Shirvalkar@ucsf.edu 
 
 

 
 
V10.01.2019 
2 
Protocol Synopsis 
 
Title 
Deep brain stimulation (DBS) in patients with refractory chronic 
neuropathic pain 
Study Phase 
Phase I 
Device(s) 
Device Information:  Devices to be used in this study are grouped 
below according to FDA approval.  All are Medtronic Devices.     
Investigational 
• 
Activa PC+S implantable pulse generator, Model 37604 
• 
Sensing Programmer Model 8181 for Activa PC+S 
• 
Sensing Programmer Software Model 8180 for Activa PC+S 
• 
Intercept Patient Programmer, model 37441  
• 
Lead extension Model 37087 
• 
Nexus-D (vD3) / E Systems 
• 
Nexus-D Application Programming Interfaces (v1.5) 
• 
Nexus-E Activator Model 4NR005 
 
Approved for other indications 
• 
Medtronic Resume II paddle electrode model 3587A 
• 
Medtronic Resume II paddle electrode model 031930 
• 
N'Vision Clinical Programmer Model 8840 
• 
Clinician Programmer Software Model 8870 
• 
Patient Programmer Model 37642  
• 
Patient Programmer Antenna Model 37092 
• 
Medtronic Lead Model 3389S/ 3387S / 3391S 
• 
External Neurostimulator 37022 
• 
Lead extension model 37086 
Indication 
Adults with refractory chronic neuropathic pain, specific to phantom 
limb, spinal cord injury or post-stroke, who have failed standard medical 
pain management (e.g. more than two pain medications from different 
classes, spinal injections) for one year or more.   
Sponsor Contact 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Edward F. Chang MD 
Associate Professor of Neurological Surgery 
University of California, San Francisco 
513 Parnassus Ave, Med Sci 
San Francisco, CA 94143 
Phone: 415-502-7346 
Fax: 415-502-7332 
E-mail: Edward.Chang@ucsf.edu 
Prasad Shirvalkar M.D., Ph.D. 
Assistant Professor of Anesthesiology and Neurology 
University of California, San Francisco 
2255 Post Street, San Francisco, CA 94143 
Phone: 415-502-7346  
Fax: 415-502-7332  
Email: Prasad.Shirvalkar@ucsf.edu 
 
Other: 
Philip Starr M.D., Ph.D.  
Professor of Neurological Surgery  
University of California, San Francisco  

 
 
V10.01.2019 
3 
 
779 Moffitt, 505 Parnassus Ave 
San Francisco, CA 94143 
Phone 415.502.2885  
Fax: 415.353.2889  
Philip.Starr@ucsf.edu  
Data 
Safety 
Monitor Board 
(DSMB) 
Dr. Line Jacques, MD, a neurosurgeon and chief of peripheral nerve and 
pain surgery at UCSF, not directly involved in this study, will lead the 
DSMB that will review the study data and provide guidance on a regular 
basis. 
Dr. Line Jacques, MD, UCSF, 505 Parnassus Ave. Rm. M779, San 
Francisco, CA 94143-0112 
Treatment 
Deep-brain stimulation of paired brain regions related to neuropathic 
pain, cingulate cortex and orbital frontal cortex. 
Study Sites 
University of California, San Francisco 
505 Parnassus Ave               675 Nelson Rising Lane 
San Francisco, CA 94143    San Francisco, CA 94143 
 
Study Design 
This is a single-center study of the effectiveness of open- and closed-loop 
DBS paradigms in the treatment of chronic neuropathic pain disorders 
that are refractory to current treatment options (e.g. two or more pain 
medications from different classes, spinal injections).   
 
Our primary objectives are to: 
1) Determine the neural correlates of increased pain states in 
patients with chronic pain in order to enable targeted DBS 
treatment 
2) Provide pain relief with neural stimulation  
3) Establish the efficacy of open-loop and closed-loop DBS 
paradigms. 
 
DBS electrodes will be inserted into regions of the brain related to pain 
processing. After implantation of electrodes, study patients will undergo 
three phases of assessment.   
 
In phase 1, patients will undergo ambulatory monitoring (~6 months) of 
their pain states linked to recordings of local field potentials (LFPs) in 
pain-processing regions.   Stimulation will not be enabled during this 
period.   This phase will be conducted in both the outpatient office 
setting and the patient’s home environment. Throughout this period, 
data will be analyzed to develop a predictive model of increased pain 
states and to guide precision DBS treatment.   
 
In phase 2, we will determine the stimulation parameters that optimally 
reduce the level of pain for each patient, in clinic daily, for 1-2 weeks.  
We will then randomly assign patients to 3-week periods of stimulation 
ON / stimulation OFF. We anticipate this phase will last approximately 6 
months and that stimulation will be conducted in the office as well as the 
home setting. Patients will be under close monitoring, with frequent in-
clinic appointments. 
 

 
 
V10.01.2019 
4 
In phase 3, we will determine differences in pain relief efficacy for at-
home open-loop versus closed-loop stimulation parameters (single-
blind study). Patients will be under close monitoring, with frequent in-
clinic appointments.  
 
In phase 1, if data of sufficiently high quality is collected before the 6 
month phase period ends, and a predictive biomarker is found before 
the 6-month phase period ends, the patient can accelerate to the next 
phases of the study to help ensure a rapid positive clinical outcome. 
Similarly, the patient may accelerate from phase 2 to phase 3 before the 
6-month period ends to ensure rapid positive clinical outcomes. 
 
Objectives 
In ten patients with chronic pain refractory to standard medical 
treatment, we will implant DBS electrodes in brain regions related to 
pain processing (phantom limb, spinal cord injury and post-stroke pain 
patients implanted in cingulate and orbital frontal cortex). We will 
connect these electrodes to an implantable pulse generator that stores 
field potential data in addition to delivering stimulation (Medtronic 
Activa PC+S).  At multiple time points post-implantation (in our clinic 
and the patient home), we will record LFP data in conjunction with data 
regarding pain states. We will also record LFP data in conjunction with 
quantitative sensory testing (QST) of pain thresholds. Together, these 
data collections will allow us to identify neurophysiological correlates of 
pain and then use these signals to set stimulation parameters to disrupt 
pain-related neural activity, thereby reducing pain states for patients. 
 
Hypotheses: 
1) Local field potentials recorded using DBS electrodes can predict 
the transition to an elevated pain state. 
2) Open-loop stimulation in response to elevated pain states will 
reduce duration and/or intensity of the pain state. 
3) Closed-loop stimulation may be more effective in treating pain 
symptoms than open-loop stimulation owing to temporal 
targeting and avoidance of potential side effects. 
Patient 
Population 
Study subjects will be adults with refractory chronic neuropathic pain. 
 
Inclusion Criteria. 
• 
Age ≥ 21 years 
• 
Clinical diagnosis of post-stroke pain (thalamic pain), spinal cord 
injury or phantom limb pain with allodynia or dysesthesia with 
pinprick anesthesia or hypoesthesia on the affected hemibody or 
limb (anesthesia dolorosa). 
• 
For Post-Stroke Pain: Stroke of ischemic etiology only. MRI done 
within one year of the first visit showing a lesion that involves the 
contralateral brainstem, thalamus or cortex. The lesion will involve 
cortical-subcortical areas in topography consistent with sensory 
thalamocortical connections. This will include patients with infarcts 
in the territory of the middle cerebral artery or those with 
cavernous malformations. A more recent MRI may be required if 
the patient's condition changed within the previous year. 

 
 
V10.01.2019 
5 
• 
For Phantom limb pain: MRI done within one year not showing any 
contraindication to surgery such as mass, lesion, hemorrhage or 
other abnormality near target 
• 
For Spinal Cord Injury pain: MRI done within one year not showing 
contraindication to surgery such as mass, lesion, hemorrhage or 
other abnormality near target 
• 
One year or more of medically refractory severe pain (see below) 
• 
Average daily pain for the past 30 days reported as >5 on a 0-10 
numeric rating scale (NRS) 
• 
Failure to respond adequately to at least one antidepressant, one 
anti-seizure medication and one oral narcotic with current stable 
doses of medications. 
• 
Ability to speak / read English 
• 
Capable of understanding and providing informed consent 
• 
Stable doses of pain medications (e.g. anticonvulsant drug, anti-
depressants, and opioids etc.) 
• 
Women of childbearing age must be on regular use of an accepted 
contraceptive method(s). 
 
Exclusion Criteria. 
• 
Pregnancy or breast feeding 
• 
Inability to speak and / or read English 
• 
Inability to give informed consent 
• 
Significant cognitive impairment or Dementia (MoCA < 25) 
• 
Aphasia severe enough to limit the consent process or 
communication between the investigators and the patient. Patients 
with mild or recovering aphasia may be considered candidates at 
the discretion of the PI. 
• 
Active depression (BDI > 20) or other untreated or uncontrolled 
psychiatric illness (active general anxiety disorder, schizophrenia, 
bipolar disorder, obsessive-compulsive disorder (OCD), or 
personality disorders (e.g. multiple personality disorder, 
borderline personality disorder, etc.) or other neuropsychiatric 
conditions that evaluating psychiatrist would recommend 
exclusion of patient after neuropsychiatric evaluation.  
• 
Suicide attempt </= 12 months or imminent suicide risk 
• 
History of substance abuse in past 3 years. 
• 
Major medical co-morbidities increasing the risk of surgery 
including uncontrolled hypertension, severe diabetes, major organ 
system failure, history of hemorrhagic stroke, need for chronic 
anticoagulation other than aspirin, active infection, 
immunocompromised state or malignancy with < 5 years life 
expectancy 
• 
Inability to stop Coumadin or platelet anti-aggregation therapy for 
surgery and after surgery. Patients taking these medications will 
need to discuss the need/risk of continuing these medications with 
their physicians and the PI or study personnel may contact the 
treating physician(s) as well to discuss the risks of anticoagulation 
/ antiaggregation therapy discontinuation. 
• 
Coagulopathy. Patients will be excluded unless assessed and 
cleared by hematology. 

 
 
V10.01.2019 
6 
• 
MRI (done within one year of the first visit) with significant 
abnormalities other than those associated with the neurological 
disorder causing chronic pain. 
• 
Implantable hardware not compatible with MRI or with the study. 
• 
Inability to comply with study follow-up visits 
• 
Previous ablative intracranial surgery for the management of the 
thalamic pain syndrome. 
• 
Previously implanted with deep brain stimulation system or any 
previously implanted device treatment involving brain stimulation 
• 
Major neurological disorder other than the one that led to the 
chronic pain including epilepsy, neurodegenerative condition or 
any history of seizure 
• 
Requires diathermy, electroconvulsive therapy (ECT) or 
transcranial magnetic stimulation (TMS) to treat a chronic 
condition 
• 
Has an implanted electronic device such as a neurostimulator, 
cardiac pacemaker or medication pump  
• 
Allergies or known hypersensitivity to materials in the Activa PC+S 
system (i.e. titanium, polyurethane, silicone, polyetherimide, 
stainless steel). 
• 
Pregnancy or lack of regular use of contraceptives. Patients who 
become pregnant after enrollment may be excluded from the study. 
Patients who become pregnant prior to the surgical implantation of 
the DBS systems will be excluded from the study. 
• 
Patients may be excluded from enrollment due to a condition that, 
in the judgment of the PI, significantly increases risk or reduces 
significantly the likelihood of benefit from DBS. 
Sample Size 
 10 patients 
Efficacy 
Assessments 
Primary Endpoints 
• 
Pain intensity / relief visual analog scale  
• 
Thermal pain threshold testing with QST 
Secondary Endpoints 
• 
Neuropathic Pain Questionnaire 
• 
NIH PROMIS Global health and physical function scales 
• 
SF-36 
Safety 
Assessments 
• 
Physical examination at specified study visits (see Section 6.0) 
• 
Check of pulse generator stimulation parameters, impedance 
measurements, and battery voltage at all study visits 
• 
Surgical or nonsurgical protocol-defined adverse events as recorded 
on adverse events case report forms 
• 
Assessment of suicidality using the Columbia Suicide Severity Rating 
Scale, and assessment of changes in depression and anxiety using the 
Beck Depression and Anxiety Inventories, at all protocol-defined 
outpatient visits 
• 
Daily visits for up to 2 weeks at start of Phase 2 for optimizing 
stimulation parameters. 
 
*Abbreviations: C-SSRS=Columbia Suicide Severity Rating Scale; BDI=Beck Depression 
Inventory; BAI=Beck Anxiety Inventory.  

 
 
V10.01.2019 
7 
Table of Contents 
 
 
Title Page 
1. 
Investigational Plan 
2. 
Patient Eligibility 
3. 
Study Device 
4. 
Study Procedure 
5. 
Clinical Measurements and Procedures 
6. 
Data Management 
7. 
Statistical Methods and Data Analysis 
8. 
Regulatory Requirements 
9. 
References 
10. Appendices  

 
 
V10.01.2019 
8 
1.0 
Investigational Plan 
 
This is a single-center study of the neurophysiology of neuropathic pain disorders with several 
goals: (1) define the electrophysiological correlates of elevated pain states (i.e. abnormal LFP 
oscillatory activity), [120] determine the DBS parameters that can disrupt such abnormal 
oscillatory activity and acutely reduce this pain state, (3) integrate that biomarker of pain in a 
closed-loop DBS paradigm and (4) compare success rates of pain remediation for stimulation 
across pain etiologies.   
 
In a cohort of 10 subjects, we aim to assess the feasibility of disrupting pain states using deep 
brain stimulation.  Bilateral or unilateral surgical implantation of electrodes will be dependent 
on the etiology and specific clinical presentation of the patient’s chronic neuropathic pain. For 
instance, chronic neuropathic pain patients with unilateral pain syndromes may only require 
unilateral implantation of each of the target sites [85], (i.e. two electrodes and 1 Activa PC+S 
pulse generator). However, patients with bilateral neuropathic pain symptoms may require 
bilateral implantation of both target sites (i.e. a total of 4 electrodes and 2 Activa PC+S pulse 
generator devices). Bilateral implantation of the anterior cingulate has been shown to alleviate 
pain with open-loop stimulation [93, 94]. Additionally, for the past 10 years, effective results of 
bilateral open-loop stimulation of the cingulate cortex have been reported for the treatment of 
depression utilizing Medtronic devices [142]. Lastly, preliminary safety and feasibility of two 
Activa PC+S device implants with two bilateral electrode implants is suggested by another 
clinical trial which currently uses a similar surgical design (two Activa PC+S devices implanted 
in the chest in the same patient, connected to bilateral thalamic and bilateral 
electrocorticography strips) [141]. 
 
The UCSF Institutional Review Board (IRB) has approved our investigational plan and protocol, 
in which we propose to conduct the testing in three phases for each subject, (see Figure: Overall 
study visit timeline). 
 

 
 
V10.01.2019 
9 
Figure 3: Overall study visit timeline 
 
 
 
Phase 1 – At-home recordings 
In phase 1, patients will be implanted and undergo long-term ambulatory monitoring of their 
self-reported pain states along with recordings of LFPs from electrodes implanted in the 
cingulate and orbitofrontal paired regions (~6 months in duration, time period based on 
previous pain studies [2, 85], visits 6-10, approximately 1 visit per month, up to 10 visits, if 
needed). Neural activity from implanted electrodes will be simultaneously recorded, one lead 
per recording channel. During this time period, neural data in combination with pain state 
reports will be analyzed in order to identify biomarkers of the pain experience and develop a 
predictive model of increased pain.   Importantly, although recruitment will only include 
patients who are treatment-resistant to pain medication, patients will likely be on medication 
regimens for pain relief.  These will continue to be managed by the patient’s regular pain 
management team (i.e. will be independent of this study).  We will closely monitor the 
medication regimen and any changes to the regimen. Patients will be asked to record activities 
at least 3 days a week at the following times: 
 
a. Immediately after waking up in the morning  
b. 30 mins post medication use 
c. afternoon between 1200 - 1400 pm 
d. immediately before bedtime  
Also, twice a week, patients will be asked to record during pre-identified activities that 
exacerbate pain (e.g. bending, climbing stairs, etc.). Patients will also be asked to wear a FitBit 
or similar activity monitor and upload their anonymized data (i.e. no personal health 
information shared). 
 
Phase 1 – In-clinic sessions 
In clinic sessions will also occur in Phase 1, occurring approximately every 3 weeks, taking the 
measures of VAS pain, VAS unpleasantness, C-SSRS, BDI/BAI, Neuropathic Pain Questionnaire, 
NIH PROMIS Global health and physical function scales and SF-36. Baseline LFP recordings will 
also be taken from ~2 minutes. At the study visits from week 3 onwards, we will also include 

 
 
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Quantitative sensory testing (QST) with the Medoc device.  Using cold and heat, we will test 
sensory perception and pain thresholds 3 times each in the aspect of both hands (contra and 
ipsi lateral to pain). The device will slowly increase/ decrease temperature until the patient 
reports sensation (1st endpoint) and then pain (2nd endpoint) which will be recorded. Heat and 
cold perception and pain thresholds will be tested, with the patient record VAS for pain 
threshold on each trial. Three consecutive trials will be conducted in each session to establish 
reliability. LFP recordings will be recorded during the QST sessions with clinician-initiated 
recording. A computerized cognitive-attention task will be performed. We will test patient 
reaction time and short-term memory recall using a computerized task, requiring patients to 
respond to tasks by pressing a keyboard key and verbally recalling words during the memory 
task. Three consecutive trials will be conducted within a single session with the task order 
shuffled to establish test reliability. LFP recordings will be recorded during the cognitive-
attention task sessions with clinician-initiated recordings. We will also conduct an anticipatory 
anxiety task where participants will be provided with a non-painful, random buzzing 
stimulation on the finger paired with a continuous auditory cue indicating which period of time 
will contain random irritating stimulation. Finger stimulation using a BIOPAC stimulation will 
be titrated up to a non-painful, highly irritating voltage before each task session. We will be 
collecting LFP recordings throughout this task to record pain anticipation signals. LFP 
recordings will also be recorded during pre-identified painful activities or movement and after 
painful activity with VAS scores recorded during these times as well. Patients will be asked to 
avoid pain medication two hours prior to their appointments. Post-testing, patients will then 
take medications and 2-minutes of recording will be obtained 15-minutes after pain medication 
is given. We may also use electroencephalography (EEG) to record brain data during some 
clinic visits to support biomarker identification.  
 
A predictive biomarker of pain will be discovered in phase 1 from data collected with at-home 
and in-clinic recording sessions. This biomarker discovery will be implemented in Phase 2. In 
phase 1, if data of sufficiently high quality is collected before the 6-month phase period ends, 
and a predictive biomarker is found before the 6-month phase period ends, the patient can 
accelerate to the next phases of the study to help ensure a rapid positive clinical outcome.  
 
Phase 2 
In the first two weeks of Phase 2, patients will be seen daily for up to two weeks to optimize 
DBS parameters (visits 11-24), based on biomarker discovery from Phase 1. EEG may be used 
during this phase for safety, to ensure that subclinical seizure activity is not present during 
stimulation. If data-collection during the initial two-week period is curtailed for any reason, 
additional DBS optimization visits may be scheduled so as to sufficiently optimize the 
biomarker and stimulation settings to enable closed-loop stimulation. 
 
Patients will then have closed-loop stimulation enabled for at-home stimulation, with follow-
up clinic visits scheduled every 3 weeks. Stimulation will be enabled or disabled in an 
ON/OFF state with patient blinded to stimulation status to test for potential placebo / sham 
effects. In addition to at-home reporting (similar to Phase 1), efficacy of stimulation will be 
tested every three weeks in-clinic. Additional in-clinic testing of stimulation-related 
analgesia efficacy and mechanism of action will be done using acute administration of 
intranasal (4mg/0.1ml, up to two doses), intramuscular (0.4mg/1ml) or IV naloxone 
(0.4mg/1ml), or saline as control. Study team will assist in administering naloxone before 
and during analgesic stimulation ON/OFF. Patients and study team will be blinded to what 
is being provided. Patients who are participating in pain management using opioids will be 
excluded from performing this study procedure. Phase 2 will last approximately 6 months in 
duration, time period based on previous unpublished observations in human Parkinson’s 

 
 
V10.01.2019 
11 
patients from our group [143] and published non-human primate observations [58]. Phase 2 
in-clinic visits occurring every 3 weeks will test the following: 
 
1) VAS pain, VAS unpleasantness, C-SSRS, BDI/BAI, Neuropathic Pain Scale, NIH PROMIS 
Global health and physical function scales, and SF-36 
2) Baseline LFP 
3) Stimulation off  + QST (no pain medication) 
4) Stimulation on + QST (no pain medication) 
5) Stimulation off + anticipatory anxiety task 
6) Stimulation off + anticipatory anxiety task 
7) Stimulation off + cognitive-attention task 
8) Stimulation off + cognitive-attention task 
9) Stimulation off + naloxone 
10) Stimulation on + naloxone 
11) Wash-out, stimulation off period 
12) LFP recording after painful activity 
13) Recording after pain medication 
 
Phase 2 will test the effectiveness of closed-loop stimulation in comparison to no-stimulation. 
In phase 3, the effectiveness of closed-loop stimulation will be tested in comparison to open-
loop stimulation settings. If data of sufficiently high quality are collected before the 6-month 
phase period ends in Phase 2, depending on pain relief symptoms, the research team may 
accelerate phase 2 to phase 3 before the 6-month period ends to ensure rapid positive clinical 
outcomes. 
 
 
Phase 3 
In phase 3, patients will continue with at-home stimulation with either personalized closed-
loop or traditional open-loop stimulation strategies enacted via their implanted system. 
Patients will be blinded to the stimulation strategy in which they are assigned. Assignment of 
open-loop or closed-loop will be randomized and occur in 6-week time periods, with each 
patient serving as his or her control as to which stimulation treatment is more effective. EEG 
may be used during this phase for safety, to ensure that subclinical seizure activity is not 
present during stimulation. 
 
During this phase, patients will be monitored closely, with daily at-home phone calls and 
frequent in-clinic appointments. This phase of the study will last approximately 1 year (time 
line based on previous published reports [2, 85, 94], with in-clinic appointments occurring 
approximately every 6 weeks.  
 
In-clinic appointments will consist of the following: 
1) VAS pain, VAS unpleasantness, C-SSRS, BDI/BAI, Neuropathic Pain Scale, NIH PROMIS Global 
health and physical function scales,  and SF-36 
2) Baseline LFP 
3) Stimulation off  + QST (no pain medication) 
4) Stimulation on + QST 
5) Stimulation off + anticipatory anxiety task 
6) Stimulation on + anticipatory anxiety task 
7) Stimulation off + cognitive-attention task 
8) Stimulation off + cognitive-attention task 
9) Stimulation off + naloxone 
10) Stimulation on + naloxone 

 
 
V10.01.2019 
12 
11) Wash-out, stimulation off period 
12) LFP recording after painful activity 
13) Recording after pain medication 
14) Closed-loop DBS being turned to open-loop stimulation setting, previous open-loop 
stimulation being turned to closed-loop DBS setting, randomized, or turning stimulation off for 
a wash-out period of up to 2-months. 
 
Phase 3 will inform the research team as to whether open-loop or closed-loop stimulation is 
most effective on a patient-by-patient basis. 
 
At the end of the study, patients will have the option for 1) continued active closed-loop or 
open-loop stimulation with the current implanted device, with in-clinic appointments, 2) 
discontinuing stimulation with the device turned off or 3) having the device removed. 

 
 
V10.01.2019 
13 
2.0 
Patient Eligibility 
 
Inclusion Criteria. 
• 
Age ≥ 21 years 
• 
Clinical diagnosis of post-stroke pain (thalamic-pain), spinal cord injury or phantom limb 
pain with allodynia or dysesthesia with pinprick anesthesia or hypoesthesia on the 
affected hemibody or limb (anesthesia dolorosa). 
• 
For Post-Stroke Pain: Stroke of ischemic etiology only. MRI done within one year of the 
first visit showing a lesion that involves the contralateral brainstem, thalamus or cortex. 
The lesion will involve cortical-subcortical areas in topography consistent with sensory 
thalamocortical connections. This will include patients with infarcts in the territory of the 
middle cerebral artery or those with cavernous malformations. A more recent MRI may be 
required if the patient's condition changed within the previous year. 
• 
For Phantom limb pain: MRI done within one year not showing any contraindication to 
surgery such as mass, lesion, hemorrhage or other abnormality near target 
• 
For Spinal Cord Injury pain: MRI done within one year not showing contraindication to 
surgery such as mass, lesion, hemorrhage or other abnormality near target 
• 
One year or more of medically refractory severe pain (see below) 
• 
Average daily pain for the past 30 days reported as >5 on a 0-10 numeric rating scale 
(NRS) 
• 
Failure to respond adequately to at least one antidepressant, one anti-seizure medication 
and one oral narcotic with current stable doses of medications. 
• 
Ability to speak / read English 
• 
Capable of understanding and providing informed consent 
• 
Stable doses of pain medications (e.g. anticonvulsant drug, anti-depressants, and opioids 
etc.) 
• 
Women of childbearing age must be on regular use of an accepted contraceptive 
method(s). 
 
Exclusion Criteria. 
• 
Pregnancy or breast feeding 
• 
Inability to speak and / or read English 
• 
Inability to give consent 
• 
Significant cognitive impairment or Dementia (MoCA < 25) 
• 
Aphasia severe enough to limit the consent process or communication between the 
investigators and the patient. Patients with mild or recovering aphasia may be considered 
candidates at the discretion of the PI. 
• 
Active depression (BDI > 20) or other untreated or uncontrolled psychiatric illness (active 
general anxiety disorder, schizophrenia, bipolar disorder, obsessive-compulsive disorder 
(OCD), or personality disorders (e.g. multiple personality disorder, borderline personality 
disorder, etc.) or other neuropsychiatric conditions that evaluating psychiatrist would 
recommend exclusion of patient after neuropsychiatric evaluation.  
• 
Suicide attempt </= 12 months or imminent suicide risk 
• 
History of substance abuse in past 3 years 
• 
Major medical co-morbidities increasing the risk of surgery including uncontrolled 
hypertension, severe diabetes, major organ system failure, history of hemorrhagic stroke, 
need for chronic anticoagulation other than aspirin, active infection, 
immunocompromised state or malignancy with < 5 years life expectancy 
• 
Inability to stop Coumadin or platelet anti-aggregation therapy for surgery and after 
surgery. Patients taking these medications will need to discuss the need/risk of 
continuing these medications with their physicians and the PI or study personnel may 

 
 
V10.01.2019 
14 
contact the treating physician(s) as well to discuss the risks of anticoagulation / 
antiaggregation therapy discontinuation. 
• 
Coagulopathy. Patients will be excluded unless assessed and cleared by hematology. 
• 
Implantable hardware not compatible with MRI or with the study. 
• 
MRI (done within one year of the first visit) with abnormalities other than those 
associated with the neurological disorder causing chronic pain. 
• 
Inability to comply with study follow-up visits 
• 
Previous ablative intracranial surgery for the management of the thalamic pain syndrome. 
• 
Previously implanted with deep brain stimulation system or any previously implanted 
device treatment involving brain stimulation. 
• 
Major neurological disorder other than the one that led to the chronic pain including 
epilepsy, neurodegenerative condition, or any history of seizure 
• 
Requires diathermy, electroconvulsive therapy (ECT) or transcranial magnetic 
stimulation (TMS) to treat a chronic condition 
• 
Has an implanted electronic device such as a neurostimulator, cardiac pacemaker or 
medication pump  
• 
Allergies or known hypersensitivity to materials in the Activa PC+S system (i.e. titanium, 
polyurethane, silicone, polyetherimide, stainless steel) 
• 
Pregnancy or lack of regular use of contraceptives. Patients who become pregnant after 
enrollment may be excluded from the study. Patients who become pregnant prior to the 
surgical implantation of the DBS systems will be excluded from the study. 
• 
Patients may be excluded from enrollment due to a condition that, in the judgment of the 
PI, significantly increases risk or reduces significantly the likelihood of benefit from DBS. 
 
 
5.0 
Study Device(s) 
 
Investigational 
• 
Activa PC+S implantable pulse generator, Model 37604 
• 
Sensing Programmer Model 8181 for Activa PC+S 
• 
Sensing Programmer Software Model 8180 for Activa PC+S 
• 
Intercept Patient Programmer, model 37441 
• 
Activa PC+S lead extension model 37087 
• 
Nexus-D (vD3) / E Systems 
• 
Nexus-D Application Programming Interface [1] (v1.5) 
• 
Nexus-E Activator Model 4NR005 
 
Approved for other indications 
• 
Medtronic Resume II paddle electrode model 3587A 
• 
Medtronic Resume II paddle electrode model 031930 
• 
N'Vision Clinical Programmer Model 8840 
• 
Clinician Programmer Software Model 8870 
• 
Patient Programmer Model 37642  
• 
Patient Programmer Antenna Model 37092  
• 
Lead Models 3389S / 3387S / 3391S 
• 
External Neurostimulator 37022 
• 
Lead extension model 37086 

 
 
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16 
3.0 
Study Procedure  
 
Study Duration: The duration of this pilot study will be five years.  We expect that all 10 patients 
will be recruited in the first 2.5 years, and data collection, stimulation and analysis will be 
completed at 5 years.  
 
Patient recruitment and clinical characterization:  Patients with refractory chronic neuropathic 
pain specific to spinal cord injury, post-stroke or phantom limb pain will be recruited from 
clinics specializing in chronic pain at UCSF and the San Francisco VA Medical Center. To the 
extent possible within our patient population, we will seek to minimize the diversity of 
neuropathic pain diagnoses represented across the two pain etiologies thereby optimizing 
opportunity for cross-patient comparative analysis.  
 
The overall study design is summarized in Figure 3: Overall study visit timeline. Also see 
Table: Protocol chart. 
 
The schedule of events is as follows: 
PHASE 1: 
Prior to surgery 
1. Prior to the start of the study, an informal phone interview to schedule in-clinic evaluation 
will take place, (noted as visit 1.1). An in-person visit at the clinic will then be scheduled. 
 
2. The research study PI(s) will obtain informed consent at the in-person visit at the clinic. 
During this visit, (noted as visit 1.2) the study team will begin establishing eligibility based on 
the following inclusion and exclusion criteria, with method for establishing eligibility in 
parenthesis.  
 
i. During this visit, PI will obtain consent for medical record review by HIPAA authorization 
form signed by patient. Medical record review will be also done after the in-person visit. 
 
ii. Pregnancy test and other paper-pen testing as noted below will also be conducted. 
 
This visit will primarily serve to obtain consent for the study and HIPAA authorization, as well 
as discuss the study in detail and answer any questions and begin confirmation of 
inclusion/exclusion criteria of the patient.  
 
iii. During visit 1.2, Inclusion / Exclusion criteria will be investigated as follows:  
 
Inclusion: 
• 
Patient is age ≥ 21 years (medical record review and asking patient); 
• 
Clinical diagnosis of post-stroke pain (thalamic pain), Spinal Cord Injury or phantom limb 
pain with allodynia or dysesthesia with pinprick anesthesia or hypoesthesia on the 
affected hemibody or limb (anesthesia dolorosa), (medical record review); 
• 
For Post-Stroke Pain: Stroke of ischemic etiology only. MRI done within one year of the 
first visit showing a lesion that involves the contralateral brainstem, thalamus or cortex. 
The lesion will involve cortical-subcortical areas in topography consistent with sensory 
thalamocortical connections. This will include patients with infarcts in the territory of the 
middle cerebral artery or those with cavernous malformations. A more recent MRI may be 
required if the patient's condition changed within the previous year. (medical record 
review); 

 
 
V10.01.2019 
17 
• 
For Phantom limb pain: MRI done within one year not showing any contraindication to 
surgery such as mass, lesion, hemorrhage or other abnormality near target, (medical 
record review); 
• 
For Spinal Cord Injury pain: MRI done within one year not showing contraindication to 
surgery such as mass, lesion, hemorrhage or other abnormality near target (medical 
record review) 
• 
One year or more of medically refractory severe pain (asking patient and medical 
record review); 
• 
Average daily pain for the past 30 days reported as >5 on a 0-10 numeric rating scale 
(NRS), (asking patient and medical record review); 
• 
Failure to respond adequately to at least one antidepressant, one anti-seizure medication 
and one oral narcotic with current stable doses of medications. (asking patient and 
medical record review); 
• 
Ability to speak / read English; (based on conversation during informed consent and 
asking patient); 
• 
Capable of understanding and providing informed consent (based on conversation 
during informed consent and asking patient); 
• 
Stable doses of pain medications (e.g. anticonvulsant drug, anti-depressants, and opioids 
etc.) (medical record review and asking patient) 
• 
Women of childbearing age must be on regular use of an accepted contraceptive 
method(s), (urine pregnancy test and asking patient). 
 
Exclusion Criteria. 
• 
Pregnancy or breast feeding (urine pregnancy test and asking patient). 
• 
Inability to speak and / or read English, (based on conversation during informed 
consent and asking patient); 
• 
Inability to give informed consent, (based on conversation during informed consent 
and asking patient); 
• 
Significant cognitive impairment of Dementia (MoCA<25) (based on Montreal 
Cognitive Assessment paper/pen test given by research team and medical record 
review). 
• 
Aphasia severe enough to limit the consent process or communication between the 
investigators and the patient. Patients with mild or recovering aphasia may be considered 
candidates at the discretion of the PI, (based on medical record review and 
conversation during informed consent). 
• 
Active depression (BDI > 20) or other untreated or uncontrolled psychiatric illness (active 
general anxiety disorder, schizophrenia, bipolar disorder, obsessive-compulsive disorder 
(OCD), or personality disorders (e.g. multiple personality disorder, borderline personality 
disorder, etc.) or other neuropsychiatric conditions that evaluating psychiatrist would 
recommend exclusion of patient after neuropsychiatric evaluation (based on paper/pen 
tests of Beck Depression Inventory and Beck Anxiety Inventory scores, along with 
psychiatric evaluation-visit 1.3).  
• 
Suicide attempt </= 12 months or imminent suicide risk (Paper/pen test of C-
SSRS=Columbia Suicide Severity Rating Scale, medical record review and 
psychiatric evaluation, visit 1.3). 
• 
History of substance abuse in past 3 years, (medical record review and psychiatric 
evaluation). 
• 
Major medical co-morbidities increasing the risk of surgery including uncontrolled 
hypertension, severe diabetes, major organ system failure, history of hemorrhagic stroke, 
need for chronic anticoagulation other than aspirin, active infection, 

 
 
V10.01.2019 
18 
immunocompromised state or malignancy with < 5 years  life expectancy, (medical 
record review). 
• 
Inability to stop Coumadin or platelet anti-aggregation therapy for surgery and after 
surgery. Patients taking these medications will need to discuss the need/risk of 
continuing these medications with their physicians and the PI or study personnel may 
contact the treating physician(s) as well to discuss the risks of anticoagulation / 
antiaggregation therapy discontinuation, (medical record review). 
• 
Coagulopathy. Patients will be excluded unless assessed and cleared by hematology 
(medical record review). 
• 
Implantable hardware not compatible with MRI or with the study (medical record 
review and asking patient).  
• 
MRI (done within one year of the first visit) with significant abnormalities other than 
those associated with the neurological disorder causing chronic pain, (medical record 
review). 
• 
Inability to comply with study follow-up visits 
• 
Previous ablative intracranial surgery for the management of the thalamic pain syndrome 
(medical record review).. 
• 
Previously implanted with deep brain stimulation system or any previously implanted 
device treatment involving brain stimulation (medical record review). 
• 
Major neurological disorder other than the one that led to the chronic pain including 
epilepsy, or neurodegenerative condition, or any history of seizure (medical record 
review). 
• 
Requires diathermy, electroconvulsive therapy (ECT) or transcranial magnetic 
stimulation (TMS) to treat a chronic condition, (medical record review). 
• 
Has an implanted electronic device such as a neurostimulator, cardiac pacemaker or 
medication pump, (medical record review). 
• 
Allergies or known hypersensitivity to materials in the Activa PC+S system (i.e. titanium, 
polyurethane, silicone, polyetherimide, stainless steel), (medical record review). 
• 
Pregnancy or lack of regular use of contraceptives. Patients who become pregnant after 
enrollment may be excluded from the study. Patients who become pregnant prior to the 
surgical implantation of the DBS systems will be excluded from the study. (urine 
pregnancy test and asking patient). 
• 
Patients may be excluded from enrollment due to a condition that, in the judgment of the 
PI, significantly increases risk or reduces significantly the likelihood of benefit from DBS 
(medical record review). 
 
3. A Separate visit for psychiatric evaluation (visit 1.3) will evaluate patient’s eligibility further 
for the study. 
 
4. MRI scans (visit 1.4) will be obtained to establish eligibility will be done if patient does not 
have recent evaluation and / or scans.  
 
After eligibility is established through the phone screen (visit 1.1), pre-study visit (1.2) and 
psychiatric evaluation (visit 1.3), the patient will then have a separate visit, (visit 1.4) (after 
additional medical record review) to obtain the following: 
 
 
5. Visit 1.4 (baseline visit): 
 
Physical examination including the following: 
• 
Obtain patient demographics; 

 
 
V10.01.2019 
19 
• 
Obtain major pain symptoms and site of pain; 
• 
Obtain vital signs; 
• 
Obtain medical history systems review; 
• 
Obtain list of current medications taking; 
• 
Obtain general health status;  
• 
Obtain current physical characteristics of pain, as measured pain intensity from pain 
visual analog scales []; 
• 
In the case that the visit can be coordinated with pain medication status, a pain relief 
VAS can also be taken after medication. 
• 
Pen / paper forms / computerized versions for  
o clinical global impression,  
o SF-36 health survey,  
o the NIH PROMIS, tests,  
o Columbia Suicide Severity Rating Scale (C-SSRS);  
o Beck Depression Inventory (BDI);  
o Beck Anxiety Inventory (BAI); 
o Neuropathic pain questionnaire (NPQ).  
• 
Pre-operative MRI scan will also be obtained, after the baseline visit, but prior to 
surgery. If needed, this can be done during the hospitalization.   
 
 
6. On the day of surgery, patient will under go the following (visit 2): 
 
• 
Preoperative blood work: On the day of surgery, pre-operative blood work will be 
obtained for for lab tests including  
o CBC,  
o BMP,  
o PT/ PTT,  
o ESR,  
o Urinalysis.   
• 
Antibiotic medications will be given prior to surgery.  
• 
Pre-operative MRI scan may also be obtained for surgical planning, if a recent one of 
adequate quality has not been obtained.   
• 
Surgery / implant of Activa PC+S device (see below for more details) with intra-
operative CT. 
• 
Activa data collection during surgery 
 
Surgery:  DBS electrodes (Medtronic Model 3587A, 3389, 3387 or 3391 electrodes) will be 
inserted bilaterally or unilaterally, dependent on pain characterization (see above section 3.0), 
into dorsal regions of the cingulate cortex and orbital frontal cortex, specific to each patient 
pain characteristics and as determined at the pain neurosurgery case conference.  
 

 
 
V10.01.2019 
20 
 
 
Figure 4: Schematic of unilateral implanted hardware 
 
The leads will be advanced through two to four frontal burr holes or frontal craniotomy, 
dependent on implantation site and number of implantations, with correct placement 
confirmed by intraoperative CT [48].  Lead placements will be re-confirmed by CT at the 2-
month visit, as post-operative standard of care.  Stim-loc devices will be used for DBS 
anchoring, with a strain relief loop anterior to the site of anchoring to prevent movement or 
torque on the lead over time, Figure 4: Schematic of unilateral implanted hardware).  
 
The free ends of the DBS leads are then placed in a subgaleal pocket, created by blunt dissection 
in the parietal area.  After induction of general anaesthesia, the head, neck and chest are 
prepped and draped, and the free ends of the leads are accessed via a new 2 cm incision in the 
parietal area. This lead extender is tunnelled subcutaneously between the parietal incision and 
a 5 cm incision over the pectoralis muscle, where a pocket is bluntly dissected for the Activa 
system (either on one side of the chest, with one pulse generator, or both sides of the chest, 
with two pulse generators, dependent on patient’s clinical pain presentation (see Section 3.0).  
 
Activa Data collection sessions: During data collection we will sample two time series channels 
at 422 Hz or 800 Hz and also collect power spectral data at high gamma (120-150 Hz) 
through two separate channels allowed by PC+S. Data download is then performed non-
invasively using the Medtronic model 8181 sensing programmer provided by Medtronic Inc., 
via a wand resting on the skin over the Activa device. At home downloads will be conducted 
between week 3 and month 6, with up to five data downloads per week, self-reporting on pain 
VAS via a web interface or text-messaging system that does not record or store any 
identifying patient information. At-home data collection will be optional and determined by 
the patient. If the patient is not able to participate in home data collection, data will only be 
collected in the clinic for that particular patient. It should be noted that it is NOT possible to 
activate stimulation with the at-home data downloads. Only recordings of the data can be 
sensed by the at-home sensing programmer. 
 
7. Visit 3+: Post-operatively, prior to hospital discharge and during hospitalization: 
• 
Clinical: follow-up physical prior to hospital discharge 
• 
Research:  Activa Data collection daily while in hospital, pain assessment for clinical 
characterization daily while in hospital, and C-SSRS/BDI/BAI/ NIH PROMIS /NPQ prior 
to hospital discharge 
 
8. Visit 4: 10 days post implantation (+/- 3 days):  
• 
Clinical:  follow up physical and staple removal and wound check  

 
 
V10.01.2019 
21 
• 
Research:  Teach at-home patient activation of the brain recording function (see 
below**), Activa Data collection and C-SSRS/BDI/BAI/ NIH PROMIS /NPQ/SF-36, 
(including QST and baseline LFP recording), recording with painful activity, pain 
medication 
 
**.Behavioral and neural states for Activa brain data collection: For each at-home recording 
session, data will be collected during various conditions, four times daily, three days a week at 
the following times: 
 
a. Immediately after waking up in the morning  
b. 30 mins post medication use 
c. afternoon between 1200 - 1400 pm 
d. immediately before bedtime  
 
Also, twice a week, patients will be asked to record during pre-identified activities that 
exacerbate pain (e.g. bending, climbing stairs, etc.). Patients will be asked to keep an online 
recording diary, in which their individual VAS scores can be updated and tabulated by the 
research team when recordings are made by the patient. No Identifying information will be 
stored or recorded through the online recording diary. Patients may also be asked to text the 
research team VAS scores via a cellphone when patients are recording at home. 
 
A predictive biomarker of pain will be discovered in phase 1 from data collected with at-home 
and in-clinic recording sessions. This biomarker discovery will be implemented in Phase 2. 
 
9. Visit 5: Three weeks post implantation (+/- 7 days) (research visit only): 
 
o Activa Data collection, (including QST), recording with painful activity, pain medication:  
o Baseline LFP recordings will also be taken from ~2 minutes.  
o Quantitative sensory testing (QST) with the Medoc device.  Using cold and heat, 
we will test sensory perception and pain thresholds 3 times each in the aspect 
of both hands (contra and ipsi lateral to pain). The device will slowly increase/ 
decrease temperature until the patient reports sensation (1st endpoint) and 
then pain (2nd endpoint) which will be recorded. Heat and cold perception and 
pain thresholds will be tested, with the measures of VAS for pain threshold on 
each trial. Three consecutive trials will be conducted in each session to establish 
reliability. LFP recordings will be recorded during the QST sessions with 
clinician initiated recording. LFP recordings will also be recorded during pre-
identified painful activities or movement and after painful activity with VAS 
scores recorded during these times as well.  
o Patients will be asked to avoid pain medication two hours prior to their 
appointments. Post-testing, patients will then take medications and 2-
minutes of recording will be obtained 15-minutes after pain medication 
is given. 
o C-SSRS, BDI/BAI, Neuropathic Pain Questionnaire, NIH PROMIS Global health and 
physical function scales and SF-36 
 
10. Visit 6: Two Months (+/- 10 days) 
o Clinical:  HEAD CT for stability 
o Activa Data collection, (including QST), recording with painful activity, pain medication:  
 

 
 
V10.01.2019 
22 
o Baseline LFP recordings will also be taken from ~2 minutes.  
o C-SSRS/BDI/BAI/ NIH PROMIS /NPQ/physical function scales and SF-36 
 
12. Visit 8-10: months 4-6, every 4 weeks: 
Clinical:  visits 8 and 10: History and Physical at 4 month and 6 mo. 
Research: visits 8, 9, 10:  
o Activa Data collection, (including QST), recording with painful activity, pain medication:  
o Baseline LFP recordings will also be taken from ~2 minutes.  
o Quantitative sensory testing (QST) with the Medoc device.  Using cold and heat, 
we will test sensory perception and pain thresholds 3 times each in the aspect 
of both hands (contra and ipsi lateral to pain). The device will slowly increase/ 
decrease temperature until the patient reports sensation (1st endpoint) and 
then pain (2nd endpoint) which will be recorded. Heat and cold perception and 
pain thresholds will be tested, with the patient record VAS for pain threshold 
on each trial. Three consecutive trials will be conducted in each session to 
establish reliability. LFP recordings will be recorded during the QST sessions 
with clinician initiated recording. LFP recordings will also be recorded during 
pre-identified painful activities or movement and after painful activity with 
VAS scores recorded during these times as well.  
o Patients will be asked to avoid pain medication two hours prior to their 
appointments. Post-testing, patients will then take medications and 2-
minutes of recording will be obtained 15-minutes after pain medication 
is given. 
o C-SSRS/BDI/BAI/ NIH PROMIS /NPQ/physical function scales and SF-36 
o We may use EEG (electroencephalography) data from a multichannel scalp electrode 
system to noninvasively collect brain signals that can aid in biomarker detection, using 
the EEGi or similar clinical system.  
 
PHASE 2:  
 
In the first two weeks of Phase 2, patients will be seen daily for up to two weeks to optimize 
DBS parameters (visits 11-24), based on biomarker discovery from Phase 1. Patients will then 
have closed-loop stimulation enabled for at-home stimulation, with follow-up clinic visits 
scheduled every 3 weeks. During this phase, patients will be monitored closely, with daily at-
home phone calls and frequent in-clinic appointments. Stimulation will be enabled or disabled 
in an ON/OFF state with patient blinded to stimulation status to test for potential placebo / 
sham effects. In addition to at-home reporting (similar to Phase 1), efficacy of stimulation will 
be tested every three weeks in-clinic. Phase 2 will last approximately 6 months in duration, 
time period based on previous unpublished observations in human Parkinson’s patients from 
our group [55] and published non-human primate observations [49], visits 11-31, if needed). 
 
Nexus System Study: Patients who have had the Activa PC+S device implanted for approximately 
4 months (Phase 1 of the clinical study) will start Phase 2 of the study, which implements the 
Nexus external interface.  The Nexus System is capable of open-loop and closed-loop 
stimulation, allowing potential therapeutic applications of Activa PC+S.  Patients will 
participate in phase 2 of the trial between 7 and 12 months post implantation, involving up to 
ten additional study visits, in addition to daily visits for up to the first 2 weeks of phase 2.  
 
Stimulation will test a strategy of disruption of pain states, with optimal stimulation 
parameters to the orbital frontal and cingulate as determined by phase 1. Furthermore, closed-

 
 
V10.01.2019 
23 
loop stimulation will test a strategy for automated control of DBS settings with aberrant 
signaling in pain states triggering stimulation. To test stimulation strategies, at the start of a 
session in phase 2, LFP data will be collected in elevated pain states. These data will be 
streamed using the Nexus System in conjunction with software from the Nexus programming 
interface. The Nexus System provides a conduit between Activa PC+S and a computer and can 
transfer stimulation update commands to Activa PC+S. During the streaming procedure 
stimulation settings may be automatically, iteratively, adjusted based on markers of oscillatory 
activity such as cortical phase-amplitude coupling (PAC) or beta band power. These 
adjustments will always remain within allowable settings pre-programmed by a clinician using 
standard procedures (i.e. using the Medtronic 8840 programmer).  
Phase 2 will test the effectiveness of closed-loop stimulation in comparison to no-stimulation. 
Daily visits will take place for the first 2 weeks of phase 2, and regular clinic visits occurring 
every three weeks during Phase 2 (~ 6 months in duration).  
 
Stimulation states for Activa PC+S brain data collection: In phase 1, the optimal times of day that 
patients are most likely in a pain state will be assessed and used to schedule appointments in 
the outpatient clinic for phase 2 (i.e., we will schedule phase 2 recording and stimulation 
sessions for each patient to coincide with optimal time of pain states, as determined by patterns 
of maximum and predictable pain states from phase 1). In Phase 2, for the first recording 
session that includes a DBS-on condition, (after the initial up to 2 week period of optimizing 
stimulation parameters), the following data will be recorded: 
 
1) VAS pain, VAS unpleasantness, C-SSRS, BDI/BAI, Neuropathic Pain Questionnaire, NIH 
PROMIS Global health and physical function scales and SF-36  
2) Baseline LFP 
3) Stimulation off  + QST (no pain medication) 
4) Stimulation on + QST 
5) Wash-out, stimulation off period  
6) LFP recording after painful activity 
7) Recording after pain medication 
8) EEG activity 
 
Visits are as follows: 
 
13. Visit 11-24: Every day for 2 weeks, stimulation optimizing:  
o Clinical only: Daily visits 11-24 DBS programming initial and revisits if needed. Full 
history and physical exams to document changes that occur during closed loop 
stimulation.  
o Research: C-SSRS, BDI/BAI visits 11, 18 and 24. 
 
14. Visits 25-31: every 3 weeks for closed loop / placebo randomization: 
o Clinical: visit 28 only; History and Physical for stability 
o Research:  visits 25-31: Activa Data collection + QST: 
o Quantitative sensory testing (QST) with the Medoc device.  Using cold and heat, we 
will test sensory perception and pain thresholds 3 times each in the aspect of both 
hands (contra and ipsi lateral to pain). The device will slowly increase/ decrease 
temperature until the patient reports sensation (1st endpoint) and then pain (2nd 
endpoint) which will be recorded. Heat and cold perception and pain thresholds will 
be tested, with the patient record VAS for pain threshold on each trial. Three 
consecutive trials will be conducted in each session to establish reliability. LFP 
recordings will be recorded during the QST sessions with clinician initiated recording. 
LFP recordings will also be recorded during pre-identified painful activities or 

 
 
V10.01.2019 
24 
movement and after painful activity with VAS scores recorded during these times as 
well.  
o Patients will be asked to avoid pain medication two hours prior to their appointments. 
Post-testing, patients will then take medications and 2-minutes of recording will be 
obtained 15-minutes after pain medication is given. 
o  Baseline LFP recordings will also be taken from ~2 minutes.  
o Stimulation off  + QST (no pain medication) 
o Stimulation on + QST 
o Wash-out, stimulation off period  
o LFP recording after painful activity 
o Recording after pain medication 
o C-SSRS/BDI/BAI/ NIH PROMIS /NPQ/physical function scales and SF-36 
 
Phase 2 will last approximately 6 months in duration, time period based on previous 
unpublished observations in human Parkinson’s patients from our group [143] and published 
non-human primate observations [58], visits 11-34, if needed) 
 
Phase 2 will test the effectiveness of closed-loop stimulation in comparison to no-stimulation.  
 
In phase 3, the effectiveness of closed-loop stimulation will be tested in comparison to open-
loop stimulation settings. 
 
Phase 3 
In phase 3, patients will continue with at-home stimulation with either personalized closed-
loop or traditional open-loop stimulation strategies their implanted system. Patients will be 
blinded to the stimulation strategy in which they are assigned. Assignment of open-loop or 
closed-loop will be randomized and occur in 6-week time periods, with each patient serving 
as his or her control as to which stimulation treatment is more effective.  
 
During this phase, patients will be monitored closely, with daily at-home phone calls and 
frequent in-clinic appointments. This phase of the study will last approximately 1 year (time 
line based on previous published reports [3, 11, 202, 85, 94], with in-clinic appointments 
occurring approximately every 6 weeks. Patients may also participate in at-home reporting 
(similar to Phase 1 and Phase 2). 
 
In-clinic appointments will consist of the following:  
1) VAS pain, VAS unpleasantness, C-SSRS, BDI/BAI, Neuropathic Pain Questionnaire, NIH 
PROMIS Global health and physical function scales, and SF-36  
2) Baseline LFP 
3) Stimulation off  + QST (no pain medication) 
4) Stimulation on + QST 
5) Wash-out, stimulation off period  
6) LFP recording after painful activity 
7) Recording after pain medication 
8) Closed-loop DBS being turned to open-loop stimulation setting, or previous open-loop 
stimulation being turned to closed-loop DBS setting, randomized 
9) EEG activity 
 
15. Visit 32-41 ++: Months 13-24: Every 6 weeks, +/- 10 days); Assignment to open-loop 
or closed loop, blinded randomization every 6 weeks. 
 
Clinical: visit 32, 36, 39 and final visit of study: Health status and physical by physician; 

 
 
V10.01.2019 
25 
Research: visits 32-41++:  Activa Data collection and VAS scores before and during 
stimulation, (including QST), recording with painful activity, pain medication. 
o Research:  visits 32-41++: Activa Data collection + QST: 
o Quantitative sensory testing (QST) with the Medoc device.  Using cold and heat, we 
will test sensory perception and pain thresholds 3 times each in the aspect of both 
hands (contra and ipsi lateral to pain). The device will slowly increase/ decrease 
temperature until the patient reports sensation (1st endpoint) and then pain (2nd 
endpoint) which will be recorded. Heat and cold perception and pain thresholds will 
be tested, with the patient record VAS for pain threshold on each trial. Three 
consecutive trials will be conducted in each session to establish reliability. LFP 
recordings will be recorded during the QST sessions with clinician initiated recording. 
LFP recordings will also be recorded during pre-identified painful activities or 
movement and after painful activity with VAS scores recorded during these times as 
well.  
o Patients will be asked to avoid pain medication two hours prior to their appointments. 
Post-testing, patients will then take medications and 2-minutes of recording will be 
obtained 15-minutes after pain medication is given. 
o  Baseline LFP recordings will also be taken from ~2 minutes.  
o Stimulation off  + QST (no pain medication) 
o Stimulation on + QST 
o Wash-out, stimulation off period  
o LFP recording after painful activity 
o Recording after pain medication 
o C-SSRS/BDI/BAI/ NIH PROMIS /NPQ/physical function scales and SF-36 
 
++Patients may have the option to continue at-home stimulation, in which additional visits, 
every 6 weeks, would be required for follow-up.  
 
16. Final Research visit: Post-intervention Neuropsychological / Behavioral testing.  
Various pen/paper and computerized neuropsychological tests will be given. Evaluation by 
study researchers will also taken place.  
 
Phase 3 will inform the research team as to whether open-loop or closed-loop stimulation is 
most effective on a patient-by-patient basis.  

 
 
V10.01.2019 
26 
Table:'Protocol'Chart
Study&visit
Time
Activities
Phases
Clinical:'None
Research:&Phone&screen
1.2
Pre'study-visit
Research:&Informed-Consent;-HIPPA-Authorization-for-medical-record-
review;-Establish-eligibility-through-inclusion-/-exclusion-criteria
Inclusion)Criteria:)patient)interview)(including)numeric)rating)scale)of)pain)for)
past)30)days),)medical)record)review,)urine)pregnancy)test
Exclusion)Criteria:)Montreal)Cognitive)Assessment)(MoCa),)Beck)Depression)
Inventory)and)Beck)Anxiety)Inventory),)
Clinical:'Psych'evaluation'(also'part'of'Eligibility);
Research:&Columbia&Suicide&Severity&Rating&Scale
1.4
Baseline
Clinical:-History-and-Physical'include)current)meds,)vitals,)general)health,)
physical)characteristics)of)pain,)as)measured)by)VAS;)pain)relief)from)meds)as)
measured)by)VAS,)PreJoperative)MRI)will)also)be)obtained,)after)the)baseline)
visit,)but)prior)to)surgery.)If)needed,)this)can)be)done)during)the)hospitalization.))
Research:-clinical-global-impression,--SFJ36,)C'SSRS/BAI/-NIH-PROMIS-/NPQ-
Clinical:''
possibly)preJop)MRI)for)surgical)planning)if)one)of)adqeuate)quality)has)
not)been)obtained
preoperative)labs)(CBC,)BMP,)PT/PTT,)ESR)and)urinalysis)
antibiotics)(prior)to)surgery)
Implant)surgery,)
CT)Head
Research:&&Activa-Data-collection-(intraoperatively-and-daily-while-in-
hospital)
Clinical:&follow=up&physical&prior&to&discharge
Research:&&
Activa-Data-collection-daily,-
pain-assessment-daily-for-clinical-characterization,-and-
C'SSRS/BDI/BAI/-NIH-PROMIS-/NPQ-prior-to-discharge
Clinical:''
follow'up'physical)and)
staple)removal)and)wound)check
Research:&&
Teach&at=home&monitoring,&
Activa-Data-collection-and-C'SSRS/BDI/BAI/-NIH-PROMIS-/NPQ,-
(including-QST+-baseline-LFP-recording),-recording-with-painful-activity,-
pain-medication
Three-weeks-post-implantation
(+/'-7-days)
Clinical:&none
Visit-for-research-only
Research&visit&only:&visit&5&&
Activa-Data-collection-and-C'SSRS/BDI/BAI/-NIH-PROMIS-/NPQ/SF'36,
(including-QST),-recording-with-painful-activity,-pain-medication
Research:&&Activa-Data-collection-and-C'SSRS/BDI/BAI/-NIH-PROMIS-
/NPQ/SF'36,-(including-QST+baseline-LFP-recording),-recording-with-
painful-activity,-pain-medication
-Three-Months-(+/'-10-days);
Clinical:&none
Research&visit&only:&&
Activa-Data-collection-and-C'SSRS/BDI/BAI/-NIH-PROMIS-/NPQ/SF'36,-
(including-QST+baseline-LFP-recording),-recording-with-painful-activity,-pain-
medication
Every-4-weeks
Clinical:''visits'8'and'10:'History)and)Physical)at)4)month)and)6)mo.
Research:&visits&8,&9,&10:&
Activa-Data-collection-and-C'SSRS/BDI/BAI/-NIH-PROMIS-/NPQ,-SF'36
(including-QST+baseline-LFP-recording),-recording-with-painful-activity,-pain-
medication
11'24
Every-day-for-2-weeks,-stimulation-
optimizing-(START-PHASE-2)
Clinical'only:'visits'11B24''DBS)programming)initial)and)revisits)if)needed.;)
Research:)11)and)24)visit:)CJSSRS/BDI/BAI
Clinical:'visit'28'only;'History)and)Physical)for)stability
Research:&&visits&25=31;&
Activa-Data-collection-and-VAS-scores-before-and-during-stimulation,-
including-QST+baseline-LFP-recording,-recording-with-painful-activity,-pain-
medication.-C'SSRS/BDI/BAI/-NIH-PROMIS-/NPQ,-SF'36.-DBS-on/-off-
Clinical:'visit'32'and'36'and'final'visit'of'study:'H&P)for)stability
Research:&visits&32=41:&&Activa-Data-collection-and-VAS-scores-before-and-
during-stimulation,-(including-QST+baseline-LFP-recording),-recording-with-
painful-activity,-pain-medication;-(including-QST),-recording-with-painful-
activity,-pain-medication.-C'SSRS/BDI/BAI/-NIH-PROMIS-/NPQ,-SF'36.-DBS-
open-vs-closed
Final&Research&visit:-Post'intervention-Neuropsychological-/-Behavioral-
testing
1.3
-
*Abbreviation:-C'SSRS=Columbia-Suicide-Severity-Rating-Scale;-BDI=Beck-Depression-Inventory;-BAI=Beck-Anxiety-Inventory.-
Phase'2:'
Months)7J12;)
Daily)visits)for)2)weeks)
followed)by)7)study)visits
Phase'3:'
Months)13J24;))
visit)every)6)weeks,)
8J10)visits
Phase'1:
0)to)6)months;)8J10)visits
every-3-weeks-for-closed-loop-
randomization
25'31
7
8'10
Clinical:''HEAD)CT)for)stability
Within-90-days-prior-to-surgery
1.1
10-days-post-implantation-
(+/'-3-days)
4
Post'operatively,-
prior-to-hospital-discharge,-and-
during-hospitalization
3
Day-of-surgery
2
(Every-6-weeks,-+/'-10-days),-
Months-13'24---(PHASE-3)
32'41-++
Two-Months-(+/'-10-days)
6
5

 
 
V10.01.2019 
27 
  
Progression of phases: We anticipate approximately 6 months for phase 1, a time period based 
on previous studies [2, 85]. As phase 2 may provide a potential for therapeutic relief of pain 
symptoms, if patients’ pain signatures are reliably detected in a shorter time period in phase 1, 
the patient may opt to proceed to phase 2 at an earlier time point (i.e. fewer sessions for phase 
1). If data of sufficiently high quality is collected before the 6 month phase period ends in Phase 
2, depending on pain relief symptoms, the research team may accelerate phase 2 to phase 3 
before the 6-month period ends to ensure rapid positive clinical outcomes (in which longer 
pain relief may occur). 
  
 In certain patients who do not experience a sufficiently wide range of pain fluctuation 
scores (ie. Pain ranges always from 8-9 /10) , it may be difficult to create a predictive model of 
pain from neural data during phase 1. In these cases, we may opt to proceed to phase 2 at an 
earlier time point, as soon as 6 weeks post-implantation. Using potentially therapeutic 
stimulation of ACC or OFC to decrease pain scores at the start of phase 2, we can then aim to 
calculate biomarkers of pain relief and elevated pain states at the start of phase 2 during 
stimulation optimization. Additionally, if in phase 1 we anticipate difficulty in successfully 
collecting biomarker information for any reason, we may opt to progress to phase 2 at an 
earlier time point to support a positive clinical outcome for the patient.  
 
  
Conclusion of study: Formal data collection will be completed at 24 months post implantation.  
However, it is expected that patients will be followed for life in our clinic, as is the case for most 
patients implanted with DBS devices. At the end of the clinical trial, in consultation with 
patients’ regular pain management teams, patients may be offered a potential therapeutic 
stimulation strategy (either open-loop or closed-loop), dependent on his or her pain alleviation 
from the clinical trial period. Patients will have the option to 1) continue active stimulation at 
the current setting with current device implantation, 2) continue stimulation but searching for 
a new setting, 3) discontinue stimulation (turning the device off) or 4) have the device removed. 
If patients opt to continue at-home active DBS after formal data collection has been completed, 
follow-up appointments will occur every 6 weeks.  
 
Patient activation of the brain recording function:  All data collection in the formal study visits 
described above will be initiated by the study staff. In addition to these data collections, the 
patient will be given the Intercept Patient Programmer, model 37441, allowing triggered brain 
data recording in their own home at specified times (see above). Patient will be instructed how 
to collect and download data at home. If the patient is not comfortable downloading the data at 
home, a family member or friend can also be taught how to use the device for download, or 
with the patient’s permission, arrangements can be made for the study staff to visit the patient’s 
home for data downloads. Study staff may also arrange with patients to visit their homes to 
help with initiating data collection.  Such visits will ensure that data collection is initiated 
correctly, and by completing downloading at home, will reduce time spent during formal study 
visits to the clinic. The intercept patient programmer does not enable stimulation of the 
electrodes; it only enables recordings of the data and is thus safe for patients to use at-home 
after initial training with research staff. 
 
Nexus System Study: Patients who have had the Activa PC+S device implanted for approximately 
4 months (Phase 1 of the clinical study) will start Phase 2 of the study, which implements the 
Nexus external interface.  The Nexus System is capable of open-loop and closed-loop 
stimulation, allowing potential therapeutic applications of Activa PC+S.  Patients will 
participate in phase 2 of the trial between 7 and 12 months post implantation, involving up to 
ten additional study visits.  

 
 
V10.01.2019 
28 
Stimulation will test a strategy of disruption of pain states, with optimal stimulation 
parameters to the orbital frontal and cingulate as determined by phase 1. Furthermore, closed-
loop stimulation will test a strategy for automated control of DBS settings with aberrant 
signaling in pain states triggering stimulation. To test stimulation strategies, at the start of a 
session in phase 2, LFP data will be collected in elevated pain states. These data will be 
streamed using the Nexus System in conjunction with software from the Nexus programming 
interface. The Nexus System provides a conduit between Activa PC+S and a computer and can 
transfer stimulation update commands to Activa PC+S. During the streaming procedure 
stimulation settings may be automatically, iteratively, adjusted based on markers of oscillatory 
activity such as cortical phase-amplitude coupling (PAC) or beta band power. These 
adjustments will always remain within allowable settings pre-programmed by a clinician using 
standard procedures (i.e. using the Medtronic 8840 programmer).  
Phase 2 will test the effectiveness of closed-loop stimulation in comparison to no-stimulation. 
Daily visits will take place for the first 2 weeks of phase 2, and regular clinic visits occurring 
every three weeks during Phase 2 (~ 6 months in duration).  
 
In phase 3 (year 2 of the study), the effectiveness of closed-loop stimulation will be tested in 
comparison to open-loop stimulation settings. Patients will be blinded to the stimulation 
strategy in which they are assigned. Assignment of open-loop or closed-loop will be 
randomized and occur in 6-week time periods, with each patient serving as his or her control 
as to which stimulation treatment is more effective.  
 
During this phase, patients will be monitored closely, with frequent at-home phone calls and 
in-clinic appointments. This phase of the study will last approximately 1 year (time line based 
on previous published reports [2, 85, 94], with in-clinic appointments occurring 
approximately every 6 weeks.  
 
For the first two weeks of Phase 3, medical staff or researchers will contact patients on a daily 
basis to examine any changes in mood or pain symptoms. Clinic visits will also be scheduled 
every 6 weeks for 1 year, to examine pain and mood symptoms and routine follow-up care.  
Conclusion of study: Formal data collection will be completed at 24 months post implantation.  
However, it is expected that patients will be followed for life in our clinic, as is the case for most 
patients implanted with DBS devices. At the end of the clinical trial, in consultation with 
patients’ regular pain management teams, patients may be offered a potential therapeutic 
stimulation strategy (either open-loop or closed-loop), dependent on his or her pain alleviation 
from the clinical trial period. Patients will have the option to 1) continue active stimulation at 
the current setting with current device implantation, 2) continue stimulation but searching for 
a new setting, 3) discontinue stimulation (turning the device off) or 4) have the device removed. 
If patients opt to continue at-home active DBS after formal data collection has been completed, 
follow-up appointments will occur every 6 weeks.  
  
The end of battery life for Activa PC+S is expected to occur 2-4 years after placement, depending 
on the chronic therapeutic stimulation parameters (similar to the sister device Activa PC that 
does not have a sensing function). The lead extender connecting the DBS leads to the pulse 
generator should not require replacement. When battery end of life occurs, it is expected that 
the Activa PC+S system will be removed, via the original chest incision, or replaced, dependent 
on further obtained approval based on the data collected in the present study and consultation 
with the regular pain management team.  
 
 
 

 
 
V10.01.2019 
29 
4.0 
Clinical Measurements 
 
Primary 
 
Clinical ratings of pain will be measured by visual analog scales for pain as well as 
unpleasantness of pain sensation (i.e. “how much pain are you in right now?” and “how much 
is the pain bothering you right now?”). Patient reports of sensory and pain detection using the 
Quantitative sensory testing (QST) with the Medoc device will also be used, with and without 
stimulation.  
 
Physiological measurements related to neural oscillatory activity during various triggered 
neural recordings with various pain states, activity states, medication states, etc. (~14 
recordings per week at home, ~6-8 recordings per in-clinic visit, ) will include: wide spectrum 
power-spectral analysis as well as using specific frequency domain for mean log power (i.e. in 
the delta, theta, alpha, beta, gamma bands), pain-related changes in broad spectrum power 
density, and coupling between the phase of low frequency rhythms and broadband gamma 
amplitude (phase-amplitude coupling, abbreviated PAC) [145-147].  
 
 
Clinical measures and physiological measurements will be collected and recorded by members 
of the research and clinical team, as well as from at-home data collection sessions. 
 
Secondary 
 
Measures from Neuropathic Pain Questionnaire, Beck Depression and Anxiety, NIH PROMIS 
Global health and physical function scales and SF-36 will also be compared from pre-
intervention to post Phase 1, phase 2 and phase 3 time points.  
 

 
 
V10.01.2019 
30 
5.0 
Data Management 
 
All physiological data will be stored in password-protected computers in the PI’s laboratory 
that is always locked with a touchpad keyless entry system. Data will be backed up on UCSF’s 
HIPPA-compliant server. In publications or presentations of the data, data will be grouped by 
case number in chronological order with no name identification.  All DBS patients at our center 
routinely undergo videotaping and sign a separate consent to be videotaped. When presenting 
videotape data at scientific conferences, we will utilize only videos from patients who have 
consented to have their videos shown.  De-identified electrophysiological data may be shared 
with other researchers at other institutions. 
 
Clinical data (baseline and follow up rating scales) will be entered into a customized, password-
protected encrypted web-based database (LAVA). This resides on a server at UCSF and is 
managed by the Department of Neurology, with backup support by the information technology 
service at UCSF. The database can be accessed by a licensed user from a secure Internet server 
at UCSF but is protected by firewalls from networks outside of our institution.  
 
Any on-line or text messaging data collected will not include personal identifiers. 

 
 
V10.01.2019 
31 
6.0 
Statistical Methods and Data Analysis 
 
Ratings of pain will be measured by visual analog scales for pain as well as unpleasantness of 
pain sensation (i.e. “how much pain are you in right now?” and “how much is the pain bothering 
you right now?”). Patient reports of sensory and pain detection using the Quantitative sensory 
testing (QST) with the Medoc device will also be used, with and without stimulation.  
 
In Phase 2, patients will serve as their own controls in a single-blinded phase (6-months in 
duration) in which placebo versus active open-loop stimulation is used. During this 6-month 
period, four sham and four active stimulation periods will occur in a random, blinded 
assignment. During the 8 in-clinic visits, the threshold for sensory and pain detection with the 
Medoc device will be used and scores will be compared for each patient during sham versus 
active stimulation periods in one-sample, two-tailed t-test. The 10 patients’ sham versus 
stimulation scores will also be used in group analysis to test the effects of open-loop and closed-
loop stimulation. 
 
In Phase 2, the visual analog scale scores recorded during the at-home recording sessions for 
various activities will be compared for each patient [(see Figure 3; 168 scores for sham sessions 
and 168 scores for active stimulation sessions, per patient); (i.e. 3 times per week for 4 
activities and 2 times per week for at least 1 painful activity, for at least 14 VAS scores per week; 
24 weeks total with 3 weeks per session-sham or stimulation, 8 sessions total, 4 sham sessions 
and 4 stimulation sessions)].  
 
Multiple regression analysis of all patients will also be used to test for effects of stimulation on 
various activities, time of day, stimulation effects over time in trial and potential differences in 
stimulation effects on pain etiologies (i.e. spinal cord injury versus phantom limb versus post-
stroke). 
 
Phase 1 (no-intervention) VAS scores will be compared to Phase 2 (sham controlled and active 
stimulation) VAS scores.  
 
In Phase 3, patients will serve as their own controls in a single-blinded phase (12-months in 
duration) in which closed-loop versus active open-loop stimulation is used. During this 12-
month period, ~four sham and ~four active stimulation periods will occur in a random, blinded 
assignment. During the ~8-9 in-clinic visits, the threshold for sensory and pain detection with 
the Medoc device will be used and scores will be compared for each patient during sham versus 
active stimulation periods in one-sample, two-tailed t-test. The 10 patients’ sham versus 
stimulation scores will also be used in group analysis to test the effects of open-loop and closed-
loop stimulation. 
 
In Phase 3, the visual analog scale scores recorded during the at-home recording sessions for 
various activities will be compared for each patient [(see Figure 3; ~364 scores for sham 
sessions and ~364 scores for active stimulation sessions, per patient); (i.e. ~3 times per week 
for 4 activities and 2 times per week for at least 1 painful activity, for at least ~14 VAS scores 
per week; ~52 weeks total with 6 weeks per session-sham or stimulation, ~8 sessions total, 4 
sham sessions and 4 stimulation sessions)].  
 
Multiple regression analysis of all patients will also be used to test for effects of stimulation on 
various activities, time of day, stimulation effects over time in trial and potential differences in 
stimulation effects on pain etiologies (i.e. spinal cord injury versus phantom limb versus post-
stroke). 
 

 
 
V10.01.2019 
32 
Phase 1 (no-intervention) and Phase 2 (sham controlled and open-loop stimulation) VAS scores 
will be compared to Phase 3 (open-loop stimulation and closed-loop) VAS scores. 
 
LFP data will be analyzed using wide spectrum power-spectral analysis as well as using specific 
frequency domain for mean log power (i.e. in the delta, theta, alpha, beta, gamma bands).  We 
will also examine coherence and cross-frequency coupling between the channels [145-147]. 
Using a repeated measures ANOVA statistical analysis, summary statistics for power in relevant 
frequency bands, pain-related power changes, and indices of phase-amplitude coupling will be 
compared at different time points, different DBS conditions (on and off), possible medication 
states (on and off) and different pain states.  Although the sample size is small, we will assess 
the correlation between pain and non-pain states with brain physiology measures, and clinical 
instruments used to measure pain relief produced by DBS. Additionally, bootstrapping 
statistical applications (i.e. a Monte Carlo algorithm) and general linear mixed models can be 
utilized to investigate potential statistical effects, given the small sample size. 
 
Neural activity will be compared during pain states, activity states, medication states, etc. for 
Phase 1 (no-intervention), as well as Phase 2 (sham controlled and open-loop stimulation) and 
Phase 3 (open-loop stimulation and closed-loop stimulation). 
 
Sample size calculation:  This is a pilot study consisting of existing chronic brain recording 
technology. The goals are to provide pain relief strategies using the Activa PC+S neural 
interface, as well as assess feasibility and to collect data that will be used to inform treatment 
plans using DBS mechanisms. Thus, there is no formal sample size calculation.  However, the 
study is designed such that patients will serve as their own controls in a blinded, placebo versus 
active open-loop stimulation design, with multiple periods of placebo versus active stimulation. 
Patients will also serve as their own controls in open-loop versus closed-loop stimulation, in a 
randomly assigned, blinded, multiple 6-week time periods of open-loop versus closed-loop 
stimulation. At-home recording sessions will also be utilized to increase the number of testing 
samples per patient over the trial. In this manner, the statistical power is increased to show 
treatment efficacy in either of these phases. 
 
 
Criteria for study success that would justify a larger subsequent trial: This study will be 
considered to justify a larger subsequent trial if we can demonstrate that: 
1) Chronic LFP recordings are of adequate quality to assess the LFP signatures of elevated 
pain. 
2) No permanent serious adverse events occur (such as trauma with long-term motor 
deficit). 
3) Using the Nexus System, therapeutic benefit from stimulation can be demonstrated (i.e. 
cessation of a pain episode or decreased pain symptoms). 
 
 
 
 
 
 

 
 
V10.01.2019 
33 
7.0 
Regulatory Requirements 
 
Prior to the start of the study, the following documents will be collected and filed: 
• Signed protocol signature page 
• Curriculum vitae of the PIs and Sub-investigators, updated within 2 years 
• Current medical licenses for the PIs and all Sub-investigators 
• Financial disclosure form signed by the PIs and all Sub-investigators listed on the 
• Copy of the IRB approval letter for the study and the IRB Membership List 
• Investigator Agreement 
 
Investigators Obligations 
 
Drs. Chang and Shirvalkar will be responsible for ensuring that all study site personnel, adhere 
to all FDA regulations and guidelines regarding clinical trials, including guidelines for GCP 
(including the archiving of essential documents), both during and after study completion. 
Additionally, they will be responsible for the subject’s compliance to the study protocol. 
 
All information obtained during the conduct of the study with respect to the patients’ state of 
health will be regarded as confidential. This is detailed in the written information provided to 
the patient. An agreement for disclosure of any such information will be obtained in writing 
and will be signed by the patient. 
 
Informed Consent 
 
The investigators will obtain and document informed consent for each patient screened for this 
study. All patients will be informed in writing of the nature of the protocol and investigational 
therapy, its possible hazards, and their right to withdraw at any time, and will sign a form 
indicating their consent to participate prior to the initiation of study procedures.  
 
Institutional Review Board 
 
This protocol and relevant supporting data were submitted and approved by the UCSF IRB 
(UCSF, Human Research Protection Program, 3333 California Street, Suite 315, San Francisco, 
CA, 94118, FWA#00000068; IRB Registration 00000229, Lisa Denney, HRRP Director, please 
see Appendix G). Amendments to the protocol will also be submitted to the IRB prior to 
implementation of the change. The PI is responsible for informing the IRB of the progress of 
the study and for obtaining annual IRB renewal. The IRB must be informed at the time of 
completion of the study and should be provided with a summary of the results of the study by 
the PI. The PI must notify the IRB in writing of any SAE or any unexpected AE according to ICH 
guidelines. 
 
 
Data safety monitory board (DSMB) and safety monitoring plan 
 
Treatment emergent adverse events that are assessed by the principal investigators as 
possibly, probably, or definitely related to surgical implantation or chronic cortical recording 
AND are unexpected or meet seriousness criteria (death, immediately life threatening, 
hospitalization >24 hours, persistent or significant disability, or significant intervention 
required to prevent one of the previously-stated outcomes) will be recorded and reported to 
the IRB, device manufacturer and the FDA via the MedWatch online voluntary reporting form 
within 10 working days of the study team’s knowledge of the event. 
 

 
 
V10.01.2019 
34 
All such events will also be reported to the data safety monitor board (DSMB), led by Dr. Line 
Jacques, a neurosurgeon at our home institution, who does not have direct involvement in this 
study but who has expertise in implantable devices, pain management and neurosurgery. The 
DSMB will meet regularly to review data related to the clinical trial, provide guidance and 
feedback, and review any adverse event reports. Treatment-related adverse events assessed as 
definitely, probably, or possibly related to study procedures and either serious or unexpected, 
noted by any study personnel will be reported within 10 working days of their knowledge of 
the event to the DSMB.  The DSMB will then advise the PI on potential changes in procedures 
to improve safety. The safety endpoint will consist of all adverse events. 
 
Throughout the clinical trial, should a serious adverse event occur that is assessed to be surgery 
or stimulation-related, or related to the presence of the DBS leads, such as focal seizure or 
motor weakness congruent with device localization or infection, in discussion with the patient 
and DSMB, a decision will be made regarding the possibility of lead removal and the study being 
halted for the patient. Removal will be accomplished by re-opening the original incisions and 
grasping the lead at or just posterior to the burr hole originally used for placement.   
 
Furthermore, if there is a serious surgery or stimulation-related adverse event, or if the patient 
reports greater than 25% increased pain (post-surgery recovery period compared to pre-
surgery) or onset of suicidality, the study will be halted for the patient.  
 
If two patients meet one or more of these criteria (i. serious surgery or stimulation-related 
adverse event, ii. greater than 25% increase pain, or iii. onset of suicidality), the study will be 
halted until information is reviewed by the DSMB and FDA. 
 
Release of results on pre-specified outcomes 
 
All outcomes that are negative or positive arising in the first 10 months of the study will be 
reported in peer-reviewed published journals within 1 year of surgical implantation. 
Continued published reports will occur as additional patients undergo surgery and treatment, 
with outcomes being reported within 1 year of their appearance. Release of negative 
outcomes will be within less than 1 year if the study is terminated early. 
 
 
 
 

 
 
V10.01.2019 
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