Feasibility of Deep Brain Stimulation as a Novel Treatment for Refractory
Phase: NA
Conditions: Opioid-Related Disorders
Sponsor: West Virginia University

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CONTENTS 
PAGE 
1 
 
2 
PROTOCOL TEAM ......................................................................................................................4 
3 
Principal Investigator: ..........................................................................................................4 
4 
Co-Investigators: ..................................................................................................................4 
5 
GLOSSARY....................................................................................................................................5 
6 
SCHEMA ........................................................................................................................................6 
7 
1.0 
STUDY OBJECTIVE ........................................................................................................8 
8 
2.0 
INTRODUCTION..............................................................................................................8 
9 
2.1 
Background ..............................................................................................................8 
10 
2.2       Preliminary Data ....................................................................................................10 
11 
3.0 
STUDY DESIGN ..............................................................................................................13 
12 
4.0 
STUDY POPULATION ..................................................................................................13 
13 
4.1 
Inclusion Criteria ...................................................................................................13 
14 
4.2 
Exclusion Criteria ..................................................................................................14 
15 
4.3 
Recruitment Process...............................................................................................16 
16 
4.4       Informed Consent...................................................................................................17 
17 
4.5  
Concomitant Therapy.............................................................................................17 
18 
5.0      STUDY PROCEDURES ..................................................................................................18 
19 
Table 1. Table of Events ....................................................................................................18 
20 
Phase I and II: Screening and Baseline ..............................................................................19 
21 
Phase III: DBS Surgery ......................................................................................................32 
22 
Phase IV: DBS Titration and Stimulation ..........................................................................33 
23 
Phase V:  Follow-up and Monitoring.................................................................................34 
24 
Long-Term Follow up Period ............................................................................................35 
25 
5.1 
Duration .................................................................................................................36 
26 
5.2  
Potential Benefits ...................................................................................................37 
27 
5.3 
Potential Risks .......................................................................................................37 
28 
5.4  
Other Risks.............................................................................................................41 
29 
6.0 
 SAFETY ENDPOINTS ..................................................................................................44 
30 
7.0  
PLAN FOR REPORTING ANTICIPATED AND UNANTICIPATED PROBLEMS 
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AND ADVERSE EVENTS ..............................................................................................44 
1 
8.0  
DATA SAFETY AND MONITORING .........................................................................48 
2 
9.0  
MONITORING PLAN ....................................................................................................52 
3 
10.0  PROCEDURES FOR MINIMIZING RISKS ...............................................................52 
4 
11.0 
DATA AND STATISTICAL CONSIDERATIONS .....................................................56 
5 
12.0  REGULATIONS AND ETHICAL CONDUCT OF THE STUDY .............................59 
6 
13.0  DEVICE DESCRIPTION ...............................................................................................59 
7 
14.0 
REFERENCES .................................................................................................................60 
8 
Appendix A ....................................................................................................................................68 
9 
10 
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PROTOCOL TEAM
1 
2 
Principal Investigator: 
3 
  
4 
Ali Rezai, MD 
5 
West Virginia University 
6 
PO Box 9301 
7 
33 Medical Center Drive 
8 
Rockefeller Neuroscience Institute 
9 
Morgantown, WV  26506 
10 
Phone: 304-293-4816 
11 
FAX: 304-293-7577 
12 
E-Mail: ali.rezai@hsc.wvu.edu 
13 
 
14 
Co-Investigators: 
15 
 
16 
Sally Hodder, MD 
17 
James Berry, DO 
18 
Nicholas Brandmeir, MD, MS 
19 
Marc Haut, PhD 
20 
Laura Lander, MSW, LCISW 
21 
James J. Mahoney, III, PhD 
22 
Patrick Marshalek, MD 
23 
Manish Ranjan, MD 
24 
Wanhong Zheng, MD 
25 
Daniel Farmer, MD 
26 
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GLOSSARY 
1 
 
2 
AIOP  
Adult Intensive Outpatient Program 
3 
ASPD  
Anti Social Personality Disorder 
4 
COAT  
Comprehensive Opioid Addiction Treatment 
5 
CRC  
Chestnut Ridge Center 
6 
CSSRS 
Columbia Suicide Severity Rating Scale 
7 
DA 
 
Dopamine Levels 
8 
DBS  
Deep Brian Stimulation 
9 
DDU  
Dual Diagnosis Unit 
10 
DSMB  
Data Safety and Monitoring Board 
11 
EEG 
 
Electroencephalogram 
12 
FDG  
Fluoro-Deoxy-Glucose 
13 
fMRI  
Functional Magnetic Resonance Imaging 
14 
GSR  
Galvanic Skin Response 
15 
HDE  
Humanitarian Device Exemption 
16 
HPLC  
High pressure liquid chromatography 
17 
IDE 
 
Investigational Device Exemption 
18 
IPG  
 
Implanted Pulse Generator  
19 
IRB 
 
Institutional Review Board 
20 
LFP 
 
Local Field Potential 
21 
MAT  
Medication Assisted Treatment 
22 
MRI 
 
Magnet Resonance Imaging 
23 
NAc 
 
Nucleus Accumbens 
24 
NIH 
 
National Institutes of Health 
25 
NIDA  
National Institute on Drug Abuse 
26 
OUD  
Opioid Use Disorder 
27 
OCD  
Obsessive Compulsive Disorder 
28 
PET 
 
Positron Emission Tomography 
29 
PHI 
 
Personal Health Information 
30 
RMH  
Ruby Memorial Hospital 
31 
SUD   
Substance Use Disorder 
32 
TENS  
Transcutaneous Electrical Nerve Stimulation 
33 
TBI 
 
Traumatic Brain Injury 
34 
THC  
Tetrahydrocannabinol 
35 
US 
 
United States 
36 
VC 
 
Ventral Capsule 
37 
VS 
 
Ventral Striatum 
38 
WV 
 
West Virginia 
39 
WVU   
West Virginia University 
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SCHEMA 
1 
 
2 
PURPOSE 
The purpose of this clinical study is to investigate the 
3 
safety, tolerability, and feasibility of DBS of the NAc/VC 
4 
for participants with treatment refractory opioid use 
5 
disorder (OUD) who have cognitive, behavioral, and 
6 
functional disability. This study is part of a NIDA U01 
7 
cooperative agreement award with WVU that will provide 
8 
critical information for planning subsequent clinical trials.  
9 
 
 
 
10 
DESIGN 
This is an open-label, safety study for participants who 
11 
have severe, treatment refractory OUD that are eligible to 
12 
have DBS targeting the ventral internal capsule (VC) and 
13 
nucleus accumbens (NAc).     
14 
 
15 
DURATION 
Participants will be followed in an inpatient service for 
16 
approximately 2 weeks to gather screening and baseline 
17 
data followed by DBS placement and up to 6 weeks 
18 
inpatient for clinical stabilization and DBS titration. All 
19 
participants will then be followed 2x week for 12 weeks in 
20 
the outpatient setting and then 1x week through 52 weeks 
21 
post titration. At the end of the study, participants may 
22 
enter a long-term safety follow up for up to five years.  
23 
 
24 
SAMPLE SIZE  
 
 
Four participants will be enrolled in this study 
25 
 
26 
POPULATION 
 
 
Persons ages 21- 50 years who meet eligibility criteria. 
27 
 
28 
OBJECTIVE               
The overall objective of this study is to assess the safety 
29 
and feasibility of using DBS to treat opioid use disorder. 
30 
 
31 
PRIMARY ENDPOINTS 
 
32 
• Safety and tolerability, as measured by all adverse events related to DBS will be 
33 
measured for a minimum of 24 weeks. 
34 
• Opioid use as measured by quantitative urine toxicology via high pressure liquid 
35 
chromatography (HPLC) 
36 
 
37 
SECONDARY ENDPOINTS 
 
38 
• Cognitive Function evaluation at 12 and 24 weeks following titration 
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• Drug overdoses defined according to the National Library of Medicine 
1 
(www.nlm.nih.gov)  
2 
• Incidence of serious infectious disease complications (e.g., endocarditis, osteomyelitis, 
3 
septic arthritis, etc.) 
4 
• Retention in traditional medication assisted treatment (MAT) 
5 
• Patient survival 
6 
• Safety and adverse events monitoring for 52 weeks post DBS titration 
7 
• Mood, craving and executive function at 12 and 24 weeks  
8 
• Other substance use as measured by quantitative urine toxicology via high pressure liquid 
9 
chromatography (HPLC) 
10 
• Qualitative urine toxicology for opioids and other substance through 12 and 24 weeks 
11 
• Self-reported opioid and other substance use through 12 and 24 weeks 
12 
• Fluoro-Deoxy-Glucose (FDG) PET/CT (to examine for increased frontal metabolism 
13 
following DBS of the NAc/VC) measured at pre-titration and Week 12 and 52 week 
14 
follow up. 
15 
• If performed, 11C Raclopride PET/CT (to examine for changes in dopamine following 
16 
DBS of the NAc/VC) measured at pre-titration and Week 12 and 52 week follow up. 
17 
• Local field potentials (to examine for changes in the neural response in the NAc 
18 
following DBS of the NAc/VC) measured pre-titration and Week 12 follow up.
19 
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1.0 
STUDY OBJECTIVE 
1 
 
2 
The overall objective of this study is to assess the initial safety, tolerability, and 
3 
feasibility of using DBS to treatment refractory opioid use disorder (OUD). This overall 
4 
objective will be attained through completion of the following specific aims:  
5 
o Evaluate initial safety and tolerability of DBS study in four participants with 
6 
treatment refractory OUD. 
7 
o Demonstrate the physiological changes associated with NAc/VC DBS through 
8 
PET imaging.   
9 
 
10 
2.0 
INTRODUCTION 
11 
 
12 
2.1 
Background 
13 
 
14 
Opioid use disorder (OUD) is a troublesome pattern of opioid use that causes significant 
15 
impairment or distress. It is estimated that almost 16 million worldwide have a current or 
16 
past opioid-use disorder (Soyka, 2015). As per 2016 estimate, in the Unites State of 
17 
America itself there were 11.8 million people who misused opioids (Substance Abuse 
18 
and Mental Health Services Administration ) The global burden of disease from opioid-
19 
related conditions approaches 11 million life-years lost from health problems, disabilities, 
20 
and early death (Degenhardt, Whiteford, & Hall, 2014).  Given the prevalence of opioid 
21 
medical and nonmedical uses, it is considered to be one of the new epidemics and is the 
22 
leading cause of the non-accidental death (Benumof, 2016). As per CDC (Centers for 
23 
Disease Control and Prevention, Understanding the Epidemic) from 1999 to 2016, more 
24 
than 630,000 people have died from a drug overdose, which is 5 times higher than in 
25 
1999 and opioid overdose itself was involved in around 66% of these deaths. As per the 
26 
latest estimate by the CDC, about 115 Americans die every day from an opioid overdose 
27 
(National Center for Health Statistics 2017, Wide-ranging online data for epidemiologic 
28 
research (WONDER). OUD not only results in non-accidental deaths but also has a huge 
29 
social and economic implications. The total economic burden was estimated to be $78.5 
30 
billion for opioid overuse and dependence, of which $28.9 billion was only related to 
31 
increased health care cost (Florence, Zhou, Luo, & Xu, 2016). The OUD is specifically 
32 
concerning for the West Virginia (WV), as the recent data show that West Virginia (WV) 
33 
continues to have the highest drug overdose mortality in the nation with 52 deaths per 
34 
100,000 population (Hedegaard, Warner, & Miniño, 2017) well ahead of all other states.  
35 
 
36 
Current treatment of OUD is far from ideal. State-of-the-art treatment, which includes 
37 
medically assisted treatment (MAT) combined with psychosocial interventions result in a 
38 
50% response rate, at best. Individuals failing standard OUD treatment have a substantial 
39 
risk of death. Given the enormously increasing socio-economical burden and the death 
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risk with the OUD, newer and innovative treatment modalities are urgently needed.  In 
1 
addition to the need for newer and innovative treatments as individuals with addiction are 
2 
literally dying in the streets, we also need to better understand the mechanisms of action 
3 
for addiction for a specifically focused treatment in future.   
4 
 
5 
Deep Brain Stimulation (DBS), where a tiny electrode is precisely placed deep inside the 
6 
brain at a specific target with a computer assisted stereotactic technique and connected to 
7 
a subcutaneous implanted pulse generator (IPG) giving an electrical stimulation to the 
8 
area targeted/implanted, has demonstrated safety and efficacy in treatment refractory 
9 
movement disorders and obsessive-compulsive disorder and is being investigated in a 
10 
number of other neurobehavioral conditions, including but not limited to, obsessive 
11 
compulsive disorders (OCD), depression, tourette’s disease, eating disorders, traumatic 
12 
brain injury, Alzheimer’s disease and addiction (Alonso et al., 2015; de Haan, Rietveld, 
13 
Stokhof, & Denys, 2015; Denys et al., 2010; Dougherty et al., 2015; Greenberg et al., 
14 
2010; Greenberg et al., 2006; Grover et al., 2009; Hamani et al., 2009; Houeto et al., 
15 
2005; Kalivas & Volkow, 2005; Laxton et al., 2010; Lipsman et al., 2017; Lipsman et al., 
16 
2013; Lozano et al., 2016; Mayberg et al., 2005; Muller et al., 2009; Rezai et al., 2018; 
17 
Rezai et al., 2016; Smit et al., 2016; Whiting et al., 2013) With recent developments in 
18 
the understanding of the neural basis of addiction (Kalivas & Volkow, 2005; Koob & 
19 
Volkow, 2010, 2016) the Nucleus Accumbens (NAc) emerged as the key area of the 
20 
nodal neural network with robust neural connections through the ventral internal capsule 
21 
(VC). We hypothesize that in treatment refractory OUD, DBS of the (NAc/VC) will 
22 
modulate the brain reward circuitry by increasing dopamine (DA) levels and thus 
23 
increasing frontal lobe activity.  This will thereby reduce opioid cravings and opioid use 
24 
and additionally improve inhibition and decision making and thus improve outcomes 
25 
(e.g. decreased drug overdoses).  
26 
 
27 
The overarching goal of this study is to evaluate the safety, tolerability, feasibility of 
28 
NAc/VC DBS for treatment refractory OUD. There is a high rate of morbidity and death, 
29 
in addition to a huge health care burden associated with OUD (Benumof, 2016; Centers 
30 
for Disease Control and Prevention, Understanding the Epidemic; Degenhardt et al., 
31 
2014; Florence et al., 2016; National Center for Health Statistics 2017, Wide-ranging 
32 
online data for epidemiologic research (WONDER); National Institute on Drug Abuse. 
33 
Overdose Death Rates, 2017; West Virginia Department of Health and Human Resources 
34 
Bureau for Public Health West Virginia Drug Overdose Deaths Historical Overview 
35 
2001, 2015, 2017). In treatment refractory OUD, given the life threatening nature, 
36 
innovative approaches and more invasive interventions including DBS warrant 
37 
investigation. 
38 
 
39 
 
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The research team led by Dr. Ali Rezai at West Virginia University (WVU) is highly 
1 
experienced in all the elements necessary to conduct this trial: state-of-the-art treatment 
2 
of OUD, NAc/VC DBS surgery, titration and programming, neuroimaging, executive 
3 
function assessment, and clinical trial management.  
4 
 
5 
2.2       Preliminary Data 
6 
 
7 
Current OUD Treatment Outcomes at WVU 
8 
 
9 
The Comprehensive Opioid Addiction Treatment (COAT) program was developed at 
10 
West Virginia University (WVU) in 2004 in response to the emerging opioid epidemic 
11 
(Zheng et al., 2017). The COAT program uses a structured group-based multidisciplinary 
12 
and multimodal approach including: 1) behavioral intervention (both group and 
13 
individual therapy), 2) required participation in community peer recovery support groups, 
14 
and 3) MAT with buprenorphine/naloxone. A key element of the COAT program 
15 
includes continued maintenance on buprenorphine/naloxone rather than mandatory 
16 
tapering.  Clinic visits consists of a shared group-based 30-minute medical appointment 
17 
with the prescribing physician followed by a 90-minute group psychotherapy session 
18 
with a skilled therapist and case manager. In this model of care, participants advance 
19 
through 4 stages of treatment, based on their sustained abstinence and program 
20 
adherence:  Stage 1- treatment initiation with weekly sessions, Stage 2 – those 
21 
successfully sustaining abstinence for 90 days progress to attending clinic bi-weekly, 
22 
Stage 3 – after one year of abstinence, monthly clinic sessions with group therapy, and 
23 
Stage 4 – after two years of abstinence, monthly clinic sessions without group therapy.  
24 
 
25 
The Intensive COAT program, where we will recruit participants for our proposed study, 
26 
is for those patients who are unable to sustain abstinence in the standard COAT program. 
27 
These patients are prone to relapse and fail to sustain recovery in the weekly group and 
28 
are thus seen thrice weekly. While the WVU COAT program has successfully treated 
29 
thousands of OUD patients, the treatment failure rate remains high, with only half of the 
30 
patients continuing to be engaged in COAT at three months. According to a multisite, 
31 
randomized trial, the rate of unsuccessful outcomes following the discontinuation of 12-
32 
weeks of medication assisted treatment (MAT) using buprenorphine-naloxone exceeded 
33 
90%. Moreover, even those who were stabilized on MAT, the rate of successful outcomes 
34 
was less than 50 percent (Weiss et al., 2011), consistent with our own experience. 
35 
 
36 
DBS of NAc/VC Investigations 
37 
 
38 
In the past twenty years, the use of brain pacemakers or deep brain stimulation (DBS), 
39 
has emerged as a promising new therapeutic approach for neuro/psychiatric disorders 
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with over 170,000 DBS implants worldwide. DBS has the advantage of being adjustable 
1 
and reversible since it can be turned off if unwanted effects are reported.    
2 
 
3 
DBS is an FDA approved and Medicare reimbursed therapy for patients with Parkinson’s 
4 
disease, essential tremor, dystonia and OCD (under a Humanitarian Device Exemption 
5 
[HDE]), and most recently, treatment refractory epilepsy. Patients with OCD undergoing 
6 
DBS have obtained significant improvements in overall functioning, independence, 
7 
quality of life enhancement, return to work or school and resumption of daily activities 
8 
(Greenberg et al., 2010; Greenberg et al., 2006) and the same is true for the other medical 
9 
conditions mentioned above, although they will not be reviewed in detail here (Malone et 
10 
al., 2009; Rezai et al., 2018; Rezai et al., 2016). Several clinical investigations have 
11 
explored the utility of DBS to treat a range of neurobehavioral disorders including OCD, 
12 
depression, Tourette’s disease, eating disorders, , traumatic brain injury, Alzheimer’s, and 
13 
addiction (Alonso et al., 2015; de Haan et al., 2015; Denys et al., 2010; Dougherty et al., 
14 
2015; Greenberg et al., 2010; Greenberg et al., 2006; Grover et al., 2009; Hamani et al., 
15 
2009; Houeto et al., 2005; Kalivas & Volkow, 2005; Laxton et al., 2010; Lipsman et al., 
16 
2017; Lipsman et al., 2013; Lozano et al., 2016; Mayberg et al., 2005; Muller et al., 2009; 
17 
Rezai et al., 2018; Rezai et al., 2016; Smit et al., 2016; Whiting et al., 2013)  
18 
 
19 
Although the exact mechanism of action of DBS is still unknown, it is clear that the 
20 
effects of DBS are not achieved by a highly localized effect on neurons adjacent to the 
21 
electrode but by modulating effects on neural networks associated with the target region 
22 
(Benazzouz & Hallett, 2000; Chiken & Nambu, 2016; McIntyre, Savasta, Kerkerian-Le 
23 
Goff, & Vitek, 2004; Montgomery & Gale, 2008; Udupa & Chen, 2015). A distributed 
24 
mechanism of action is supported by the findings of a recent study using DBS of NAc to 
25 
treat OCD (Figee et al., 2013). Using functional magnetic resonance imaging (fMRI) and 
26 
electroencephalography (EEG), the authors showed that NAc-frontal network modulation 
27 
of DBS was able to restore normal NAc function and cortico-striatal circuitry 
28 
connectivity. Dysfunction in cortico-striatal circuitry is postulated to be a core feature of 
29 
OUD, and therefore these findings provide a rationale for the use of DBS in the treatment 
30 
of OUD. 
31 
 
32 
The PI has extensive experience with DBS surgery in various brain targets with more 
33 
than 2000 patients from 1997-2018 with a surgical complication rate of 1% hemorrhage 
34 
(symptomatic 0.1%), 2% infection, and 2% device related complications (personal 
35 
communication-AR), consistent with standards in the field.  Dr. Rezai has further 
36 
participated as a key investigator or PI in several NAc/VC DBS clinical trials for 
37 
neurobehavioral disorders. These studies demonstrated: 1) safety and efficacy for 
38 
intractable OCD (Greenberg et al., 2010; Greenberg et al., 2006), 2) safety but not 
39 
efficacy in a randomized controlled trial for major depression (Dougherty et al., 2015), 3) 
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safety and improved functional outcomes in pilot trials in Alzheimer’s disease (Scharre et 
1 
al., 2018) and traumatic brain injury (Rezai et al., 2016), and 4) lack of feasibility in a 
2 
pilot trial of morbid obesity (Rezai et al., 2018).  Furthermore, Dr. Rezai has experience 
3 
in neuroimaging with DBS, demonstrating impact on brain circuitry (Rauch et al., 2006; 
4 
Rezai et al., 2016; Scharre et al., 2018).  Specifically, FDG PET studies of NAc/VC DBS 
5 
in patients with OCD, and Alzheimer’s disease have shown moderation of pathological 
6 
brain glucose metabolism in the frontal cortex (Rauch et al., 2006; Scharre et al., 2018). 
7 
 
8 
Research Studies in Support of the NAc as a DBS Target for Treatment of OUD 
9 
 
10 
Animal Studies.  DBS to the shell of the NAc in drug-seeking rats selectively blocked 
11 
reinstatement of cocaine seeking induced by a priming dose of psychomotor stimulants 
12 
(Vassoler et al., 2008) and conditioned place preference for morphine in rats is attenuated 
13 
by DBS (Liu et al., 2008). Rats trained to self-administer cocaine in the presence of light 
14 
showed decreased cue-induced reinstatement of cocaine when they were pretreated with 
15 
deep brain stimulation of the NAc (Guercio, Schmidt, & Pierce, 2015). 
16 
 
17 
Lesioning the NAc decreased food hoarding and gave rise to sustained weight reduction 
18 
in obese mice (Halpern et al., 2011; Kelley & Stinus, 1985). Similarly, DBS stimulation 
19 
of the NAc decreased caloric intake and also resulted in a sustained weight loss in obese 
20 
mice (Halpern et al., 2013; Ho et al., 2015). Following high frequency DBS of the NAc 
21 
in animals, there is a decrease in the firing rate of the orbitofrontal cortex pyramidal cells 
22 
and enhanced synchronicity of the thalamo-cortical circuit (McCracken & Grace, 2007, 
23 
2009)  
24 
 
25 
Human Studies.  Review of the DBS literature reveals that stimulation of the NAc and 
26 
VC has been performed since 1998 in patients with various neurobehavioral disorders 
27 
including depression, OCD, other anxiety disorders, addiction, TBI, Alzheimer’s disease 
28 
and eating disorders. DBS of the the NAc/VC has been proven safe and beneficial for the 
29 
treatment of OCD, leading to the FDA HDE approval in 2009 (Greenberg et al., 2010; 
30 
Greenberg et al., 2006; B. Nuttin, Cosyns, Demeulemeester, Gybels, & Meyerson, 1999) 
31 
A double-blind study involving stimulation of the NAc/VC showed a significant 
32 
reduction of OCD symptoms (B. J. Nuttin et al., 2003). In addition, DBS has been shown 
33 
to be safe and effective in open-label pilot study for major depression (Malone et al., 
34 
2009). In a recent double blind, phase III sham-controlled trial for depression, stimulation 
35 
of the NAc/VC was found safe, but failed to show a significant difference in outcome 
36 
between sham and real stimulation (Dougherty et al., 2015). Case reports also show that 
37 
stimulation of the NAc/VC can contribute to smoking cessation (Mantione, van de Brink, 
38 
Schuurman, & Denys, 2010) and to a reduction in heroin seeking behaviors (Zhou, Xu, & 
39 
Jiang, 2011)  
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Recently, Figee et al., examined network changes induced by NAc/VC DBS with fMRI 
1 
and EEG in fully implanted patients with OCD (Figee et al., 2013).  Their findings 
2 
suggest that modulation of NAc/VC activity changes frontostriatal connectivity. These 
3 
changes correlated with symptoms improvement. Moreover, such a study highlights the 
4 
fact that DBS effects may not just be confined locally, to the relatively small target area, 
5 
but may be due to a broader modulation of several neural circuits and networks. Figee et 
6 
al. also measured dopamine D2/3 receptor availability in the straitum with 
7 
iodobenzamide single photon emission computed tomography in OCD patients. 
8 
Following NAc/VC DBS there was a decrease in the binding potential in the NAc 
9 
suggesting that DBS induced striatal dopamine release (Figee et al., 2014). In one of the 
10 
recent study of NAc/VC DBS for heroin addiction done outside USA was very 
11 
encouraging and 5 out of the 8 patients achieved abstinence from heroin for more than 3 
12 
years (Chen et al., 2018).  
13 
 
14 
In summary, the reasons to consider DBS of the NAc/VC as an intervention for patients 
15 
with treatment refractory OUD are threefold: 1) The NAc is heavily implicated in both 
16 
normal and drug-induced reward processes and plays a key role in cue-induced craving. 
17 
Moreover, the NAc acts as a ‘motivation gateway’ between the limbic system involved in 
18 
emotion and systems involved in motor control, and is uniquely located to modulate 
19 
activity in other regions of the brain. 2) OUD, characterized by dysfunction in several 
20 
integrated neural pathways, creates the need for a treatment that directly targets and 
21 
normalizes the affected brain circuits. 3) Preclinical studies and human case studies 
22 
report encouraging results for DBS as a treatment for OUD and have shown that NAc/VC 
23 
appears to be a promising and safe target. 
24 
 
25 
3.0 
STUDY DESIGN 
26 
This is an open-label, safety, tolerability, and feasibility study for participants who have 
27 
treatment refractory OUD that are eligible to have deep brain stimulation (DBS) targeting 
28 
the NAc/VC. The major objective of this study is to test safety, tolerability, and 
29 
feasibility of DBS in this population.  
30 
4.0 
STUDY POPULATION 
31 
 
32 
4.1 
Inclusion Criteria 
33 
 
34 
A candidate will be eligible if he/she meets all the following criteria: 
35 
• Age 21-50 years at time of enrollment. 
36 
• Fulfills current DSM-5 (American Psychiatric Association Diagnostic and statistical 
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manual of mental disorders, 5th ed, 2013) diagnostic criteria for OUD (severe) and at 
1 
least a 5-year history. 
2 
• Participants may have comorbid Substance Use Disorder diagnoses at mild, moderate 
3 
or severe levels, however OUD must be the primary disorder the individual is seeking 
4 
treatment and the other use disorders must occur in the context of relapse. 
5 
• Failed at least two levels of treatment (outpatient/COAT, intensive 
6 
outpatient/intensive COAT, residential, inpatient, AIOP, DDU), which included 
7 
buprenorphine/naloxone. Treatment failure is defined as the initiation and 
8 
discontinuation/completion of treatment with subsequent substance relapse. 
9 
•  At least one lifetime overdose survival. Drug overdose criteria and symptoms 
10 
defined according to the National Library of Medicine. 
11 
•  
12 
• Demonstrated greater than 5 years of refractory symptoms of OUD. 
13 
• Family/Social Support/Involvement (as assessed via the Multidimensional Scale of 
14 
Perceived Social Support) 
15 
• Is able to comprehend the consent form and provide informed consent. 
16 
• Women of reproductive potential must have negative pregnancy test and agree to use 
17 
acceptable forms of contraception. 
18 
 
19 
4.2 
Exclusion Criteria 
20 
 
21 
A candidate will be excluded if he/she meets any of the following criteria: 
22 
• Medical problems requiring intensive medical or diagnostic management. 
23 
• Diagnosis of acute myocardial infarction or cardiac arrest within the previous 6 
24 
months. 
25 
• History of a neurosurgical ablation procedure. 
26 
• Any medical contraindications to undergoing DBS surgery. 
27 
• History of hemorrhagic stroke. 
28 
• Life expectancy of < 3 years 
29 
• Past or present diagnosis of schizophrenia, psychotic disorder, bipolar disorder, or 
30 
untreated depression other than one determined to be substance induced (assessed via 
31 
SCID-5). Any treated depression considered to be non-substance induced has to have 
32 
been in remission for one year. 
33 
• Baseline assessment on the Hamilton Depression Rating Scale (HAM-D) > 17  
34 
• Increased risk of suicide based upon any positive response regarding passive or active 
35 
suicidal ideation with or without intent over the past 3 months or history of active 
36 
suicidal ideation with intent within the past 3 years on the Columbia Suicide Severity 
37 
Rating Scale (CSSRS). 
38 
• Meet the criteria for Cluster A or B Personality Disorders (assessed via SCID-5-PD).  
39 
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• Diagnosis of dementia or any other disorder which has led to a clinically significant 
1 
cognitive impairment (assessed via DRS-2).  
2 
• Personal history of any clinically defined neurological disorder, including organic 
3 
brain disease, epilepsy, stroke, brain lesions, or multiple sclerosis.  
4 
• Personal history of previous neurosurgery (brain) or head trauma that resulted in loss 
5 
of consciousness 
6 
• History of suicide attempt within the past 3 years . 
7 
• Parental history of completed suicide. 
8 
• Abnormal coagulation lab studies, defined as INR >1.4, abnormal PT/PTT. 
9 
• Platelet count < 75×109/L 
10 
• Uncontrolled hypertension (systolic > 185 mmHg and/or diastolic > 110 mmHg), 
11 
demonstrated on each of three repeated measurements taken within one hour 
12 
regardless of whether or not the patient is taking antihypertensive medications. 
13 
• Implanted neurostimulators (e.g., vagus nerve stimulator, spinal cord stimulator, 
14 
DBS) 
15 
• Any current CNS infection or infection with the Human Immunodeficiency Virus 
16 
(HIV) (due to potential for confounding the analysis of study outcomes).  
17 
• Unable to undergo MR-imaging because of implanted pacemakers, medication 
18 
pumps, aneurysm clips, metallic prostheses (including metal pins and rods, heart 
19 
valves or cochlear implants), shrapnel fragments, permanent eye liner or small metal 
20 
fragments in the eye that welders and other metal workers may have, or if candidates 
21 
are uncomfortable in small closed spaces (have claustrophobia) or cannot lie 
22 
comfortably on their back for up to one hour. 
23 
• Documentation of MRI abnormality indicative of a neurological condition that may 
24 
jeopardize the participant’s safety, study conduct, or confound the participant’s 
25 
diagnostic assessments. 
26 
• Substance abuse treatment mandated by court of law. 
27 
• Known destruction and/or damage to the NAc, ventral striatum, or ventral capsule 
28 
region as determined by MRI. 
29 
• Pregnant or planning to become pregnant. 
30 
• History of seizure disorder and/or epilepsy. Participants with documented febrile 
31 
seizures will not be excluded. Seizures which are secondary to substance use and/or 
32 
withdrawal will not be exclusionary as long as they occurred more than one year ago. 
33 
• Conditions requiring repeated MRI scans. 
34 
• Conditions requiring diathermy 
35 
• Uncorrectable coagulopathy and patients on anticoagulant/antiplatelet medications 
36 
who cannot be off anticoagulants/antiplatelet medications during the standard 
37 
perioperative care period..  
38 
• Primary language other than English. 
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• Any evidence of cutaneous bacterial infection (e.g., impetigo, cellulitis, etc.)  
1 
• Any evidence of systemic infection, including fever, malaise, or leukocytosis.   
2 
 
3 
In the event that there is a discrepancy between medical records and other sources of 
4 
information, specifically related to psychiatric diagnoses (e.g. suicidal ideation and/or attempts), 
5 
members of the clinical study team will conduct a thorough investigation to reconcile these 
6 
differences. Other sources of information include self-reported information provided by the 
7 
subject, collateral information provided by others (e.g. members of the subject’s support system), 
8 
and clinical impressions of the treatment team. Similar reconciliation will be performed if 
9 
conflicting documentation related to psychiatric history is present within medical records (e.g. 
10 
inconsistent historical information documented in separate notes). Findings from this 
11 
reconciliation will be presented to the study team and will be reviewed by collaborators at NIDA 
12 
(study sponsor), designated project consultants, the DSMB (which includes external, non-WVU 
13 
faculty), and the designated external independent eligibility reviewer. Eligibility will be 
14 
determined after review of their recommendations. 
15 
 
16 
4.3 
Recruitment Process 
17 
 
18 
Participants will be recruited from the WVU COAT program, a comprehensive treatment 
19 
program that combines medication assisted treatment with psychosocial treatment for 
20 
OUD.  The program has been recognized by Substance Abuse and Mental Health 
21 
Services Administration (SAMHSA) as “The West Virginia Model”. There are currently 
22 
multiple training sites throughout the state and practitioners across the nation come to 
23 
learn about program to implement this treatment in their own region.  COAT utilizes a 
24 
multidisciplinary and multimodal approach including medication assisted treatment 
25 
(buprenorphine/naloxone), behavioral intervention (both group and individual therapy) 
26 
and case management services. There is ongoing enrollment in the COAT program with 
27 
up to 700 active participants at any given time.  As 50% of participants admitted into the 
28 
COAT program are retained, there is a sufficient recruitment pool and experience 
29 
suggests that study recruitment will not be a barrier to the conduct of this clinical trial. 
30 
  
31 
For this protocol, we will recruit participants from the Intensive COAT program for those 
32 
treatment refractory participants who are unable to sustain abstinence with standard 
33 
COAT treatment and repeatedly relapsed and have thus been referred to intensive COAT. 
34 
The standard treatment protocol for Intensive COAT includes thrice-weekly behavioral 
35 
intervention and buprenorphine/naloxone maintenance. If a participant is deemed eligible 
36 
and is enrolled, continued active participation and engagement in the Intensive COAT or 
37 
standard COAT program, as clinically indicated, will be required throughout the duration 
38 
of the proposed study.  
39 
 
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4.4       Informed Consent 
1 
 
2 
Informed consent will be obtained by the PI or their designee with documented specific 
3 
knowledge of the study. The informed consent form will be reviewed with the participant 
4 
and all questions will be addressed before the participant signs the consent form. 
5 
Participants will be given an explanation of the study, including the screening process 
6 
and required testing; educated on the possible risks and benefits to participating 
7 
Participants will have the option to consent to videotaping throughout the study. The 
8 
videotapes will be used for educational purposes. It will be explained that the results of 
9 
the screen will determine if they will be invited to participate in the next phases of the 
10 
study. It will also be explained that even after passing the initial screen and entering the 
11 
study phase, subsequent assessments may determine that he/she is not a suitable 
12 
candidate and be discontinued from the study. The specific procedures will be outlined 
13 
and the risks and benefits clearly described. The participant will be given a copy of the 
14 
signed consent, and a copy of the consent will be placed in the patient’s medical record as 
15 
well as the research file.  
16 
 
17 
The screening process will consist of routine physical, neurological, and psychiatric 
18 
examinations, laboratory tests, cognitive examinations and neuroimaging.  
19 
 
20 
4.5  
Concomitant Therapy 
21 
 
22 
For this study, a prescription medication is defined as one that can be prescribed only by 
23 
a properly authorized/licensed clinician. All supportive care is allowed, there are no 
24 
restrictions on the medications allowed concomitantly during participation on the trial. 
25 
Medications to be reported in the Case Report Form for the duration of the study, from 
26 
the time of informed consent to the end of follow-up, are concomitant prescription 
27 
medications related to buprenorphine/naloxone maintenance. All other concomitant 
28 
medication may be abstracted from medical records as needed during data analysis or 
29 
adverse event reporting. All supportive care is allowed, there are no restrictions on the 
30 
medications allowed concomitantly during participation on the trial. Likewise, 
31 
medications may be added, tapered, or withdrawn as determined by the clinical treatment 
32 
team and/or study investigators.  
33 
 
34 
During the conduct of the trial, shortwave/ultrasound/microwave therapy and 
35 
implantation of metallic items (eg. prostheses) or other neurostimulators are not allowed 
36 
as concomitant therapy, however there are no other restrictions on procedures during 
37 
participation on the trial.  Procedures to be reported in the Case Report Form for the 
38 
duration of the study, from the time of informed consent to the end of follow-up, include 
39 
all medical and surgical procedures including elective ones.  
40 
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1 
5.0      STUDY PROCEDURES 
2 
 
3 
The study design will consist of the following five study phases with the corresponding schedule 
4 
of events related to testing and procedures:  
5 
Table 1. Table of Events 
Method 
Phase I             Phase II 
 
(Upto 5 weeks) 
Phase III 
 
(Up to  
3 weeks) 
Phase IV 
 
(Up to  
3 Weeks) 
Phase V 
(12 week 
timepoint) 
Phase V 
(24 week 
timepoint) 
Phase V 
(52 week 
timepoint) 
Screening         Baseline 
DBS Surgery 
DBS 
Titration and 
Stimulation 
Follow Up 
Follow Up 
Follow Up 
Structural 
/Functional MRI1 
 
 
 
 
 
 
X-Ray, chest2 
 
 
 
 
 
 
 
Electrocardiogram 
(ECG) 
 
 
 
 
 
 
 
History and Physical 
Examination 
 
 
 
 
 
 
 
Vital signs3 
 
 
 
 
 
 
 
 
Blood and urinalysis 
test4 
 
 
 
 
 
 
 
 
MRSA screening 
nasal swab 
 
 
 
 
 
 
 
Urine toxicology5 
 
 
 
 
 
 
 
 
Pregnancy test6 
 
 
 
 
 
 
 
 
Neurological 
Examination 
 
 
 
 
 
 
 
NIH Stroke Scale7 
 
 
 
 
 
 
 
 
 
 
Psychiatric 
Examination 
 
 
 
 
 
 
 
 
Cognitive and 
Behavioral Testing8 
 
 
 
 
 
 
 
 
 
Affective/Emotional 
Assessments8 
 
 
 
 
 
 
 
 
 
 
 
 
 
Opioid and other 
substance use 
assessments8 
 
 
 
 
 
 
 
 
 
 
 
 
 
Executive Function 
Measures8 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physiological 
Monitoring8 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse Effects 
 
 
 
 
 
 
 
 
 
 
 
 
 
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1 Structural MRI scan to be obtained approximately one week prior to surgery (but no more than 2 weeks prior to the surgery 
1 
date) and may be completed at the end of the three-week surgical recovery period prior to the DBS titration and programming, 
2 
and at the 12 and 52 week follow-up visits. Structural MRI may also be performed at PI’s discretion if clinically indicated prior 
3 
to or after DBS surgery. Functional MRI (resting state and task-based using a cue reactivity paradigm) may be performed prior to 
4 
DBS surgery, at the end of the three-week surgical recovery period, and at the 12 and 52 week follow-up visits. and in 
5 
conjunction with LFP acquisition/cue reactivity at long term follow up visits. 
6 
2 Chest x-ray obtained during screening/baseline evaluation. 
7 
3 Vital signs will be measured daily throughout the inpatient stay, twice weekly during follow up through week 12, and then once 
8 
weekly through the week 52 follow up visit. 
9 
4 Labs tests at screening include pregnancy test, CBC with Diff, BMP (Na, K, Cl, HCO3, BUN, Creat, Glucose), PT/INR, PTT, 
10 
Type and Screen, HIV1/HIV2, Hepatitis C, Urinalysis, liver function panel. Labs at 12 week follow up visit include CBC with 
11 
Diff, BMP (Na, K, Cl, CO2, BUN, Creatinine, Glucose), and liver function panel. 
12 
5 Qualitative urine toxicology will be obtained twice weekly through the 12 week follow up, and then once weekly through post-
13 
titration Week 52. Quantitative urine toxicology (HPLC) for Cocaine, Amphetamine, Delta-9-tetrahydrocannabinol, 
14 
benzodiazepines, morphine, heroin, Suboxone, fentanyl, and opioids/opioid analogs will be performed at screening and at  4, 8, 
15 
and 12 weeks following discharge.  
16 
6 Pregnancy testing: Serum hCG will be performed on all women of childbearing potential at screening and at the 12 week and 24 
17 
week follow up visits. Urine pregnancy will be performed twice weekly through the 12 week follow up, and then once weekly 
18 
through post-titration Week 52. When being performed prior to MRI, pregnancy test must be within 24 hours of the MR imaging. 
19 
7 NIHSS will be performed at screening/baseline, then immediately post-operatively, after each titration/stimulation adjustment, 
20 
and then monthly through post-titration Week 52. 
21 
8 Refer to Appendix A 
22 
9 PET scans with and without Methylphenidate, may be performed 
23 
10 Local Field Potentials (LFPs) to be measured during specific tasks and as clinically indicated 
24 
11 EEG may be measured during screening/baseline and post-surgical phases while the subject is at rest and/or during specific 
25 
tasks (e.g. delayed discounting) 
26 
12 Up to 3 weeks outpatient and approximately 2 weeks inpatient 
27 
 
28 
Phase I and II: Screening and Baseline 
29 
 
30 
Screening of participants from the COAT clinic to determine if they meet the inclusion/exclusion 
31 
criteria. Critical to assuring recruitment of appropriate patients meeting the eligibility criteria, 
32 
Dr. Daryl Shorter, a board-certified addiction psychiatrist, but not a member of the study team, 
33 
will review each candidate’s de-identified records prior to enrollment and may unilaterally veto 
34 
enrollment of any patient he deems inappropriate for this protocol.  This independent evaluation 
35 
is to reduce bias from the investigators enrolling their own patients.   
36 
 
37 
Study participants will complete an inpatient stay for approximately 2 weeks at Chestnut Ridge 
38 
Center (CRC; the inpatient psychiatric hospital of WVU) on the addiction service where they 
39 
will undergo screening (Phase I) and then baseline assessment (Phase II) prior to DBS 
40 
placement. After providing informed consent, screening assessments may be initiated prior to 
41 
their admission to the CRC as inpatients. If performed prior to inpatient admission, screening 
42 
C11-Raclopride 
PET/CT9 
 
 
 
  
  
 
 
FDG PET/CT Scan 
 
 
 
 
 
 
 
 
 
Local Field 
Potentials10 
 
 
 
 
 
 
 
 
 
EEG11 
 
 
 
 
 
 
 
 
 
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assessments will be conducted within 3 weeks of the admission date.  
1 
 
2 
After completion of the screening period, if the participant is assessed as being appropriate for 
3 
the surgery, the participant will undergo the baseline assessment and then will undergo the DBS 
4 
placement (Phase III) at Ruby Memorial Hospital (RMH), which includes a total time of up to a 
5 
3-week recovery period at RMH and CRC. Following the surgical recovery period, the 
6 
participants will undergo titration sessions (Phase IV) for up to 3 weeks at CRC. Once titration is 
7 
complete the participants will be discharged from inpatient care to continue outpatient 
8 
monitoring 2 times a week for 12 weeks while continuing with the COAT program. This may be 
9 
at the intensive COAT program or the standard COAT program based on the clinical stability of 
10 
the participant. After the primary outcome assessments 24 weeks after titration, they will be 
11 
followed for up to 52 weeks following DBS titration (Phase V) or until study participation ends. 
12 
 
13 
Participant Replacement Guidelines 
14 
Participants who have signed the informed consent document and have been enrolled in 
15 
the trial may withdraw that consent at any time during the trial.  Data collected up to the time of 
16 
consent withdrawal will remain in the database as part of the study.  Participants withdrawing 
17 
consent before deep brain stimulator (DBS) implantation will not have any collected data 
18 
relevant to the safety or tolerability of the device or other study endpoints.  For that reason, one 
19 
additional participant may be recruited to the study for each participant withdrawing consent 
20 
prior to DBS placement, thereby assuring the required number of participants from whom study 
21 
endpoints are collected.  Participants withdrawing consent after DBS placement will not trigger 
22 
additional participant recruitment. 
23 
 
24 
Screening/Baseline assessments will include: 
25 
• Blood and urine will be collected for the following lab tests: 
26 
o CBC with Differential 
27 
o BMP (Na, K, Cl, CO2, BUN, Creatinine, Glucose) 
28 
o PT/INR 
29 
o PTT 
 
30 
o Type and Screen  
31 
o HIV1/HIV2 
32 
o Hepatitis C 
33 
o Liver function panel 
34 
o Pregnancy test as applicable 
35 
o Urinalysis  
36 
o Qualitative urine toxicology 
37 
o Quantitative Urine Toxicology (HPLC)  
38 
 Cocaine 
39 
 Amphetamine 
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 Delta-9 tetrahydrocannabinol 
1 
 Benzodiazepines 
2 
 Morphine 
3 
 Heroin 
4 
 Suboxone 
5 
 Fentanyl  
6 
 Opioids and any detectable opioid analogs 
7 
• MRSA screening by nasal swab 
8 
• History and physical examination, neurological examination, psychiatric examination 
9 
• ECG 
10 
• Imaging tests (MRI/Chest x-ray) 
11 
• Vital signs 
12 
 
13 
Demographic and Drug and Alcohol Use Inventory: Demographic information including 
14 
age, sex, education, ethnicity and characterizes years, recent (days in the past 30) 
15 
(Mahoney, Kalechstein, Newton, & De La Garza, 2017), and daily drug use for opioids 
16 
and other illicit substances. (Paper- or computer-based assessment will be completed at 
17 
Screening) 
18 
Behavioral Assessments (Approximate time to administer-2 hours) 
19 
The study will utilize various established neuroimaging tests as well as 
20 
neuropsychological, behavioral, mood, cognitive, and addiction measures to evaluate the 
21 
status of the participant. These measures are employed to support the primary and 
22 
secondary objectives of the study.  
23 
Structured Clinical Interview for DSM-5 Axis I Disorders (SCID-5) (First et al., 2016a): 
24 
The SCID-5 is a semi-structured interview guide for making DSM-5 diagnoses. It is 
25 
administered by a clinician or trained mental health professional that is familiar with the 
26 
DSM-5 classification and diagnostic criteria. Guide covers the DSM-5 diagnoses most 
27 
commonly seen in clinical settings including depressive and bipolar disorders, 
28 
schizophrenia spectrum and other psychotic disorders, substance use disorders, anxiety 
29 
disorders, obsessive-compulsive disorder, posttraumatic stress disorder, attention-
30 
deficit/hyperactivity disorder, and adjustment disorder. This paper-based measure uses an 
31 
algorithmic approach to scoring, assessing, and diagnosing DSM-5 disorders and takes 
32 
approximately 45 minutes to administer. (Paper-based assessment will be completed at 
33 
screening.) 
34 
Structured Clinical Interview for DSM-5 Axis II Personality Disorders (SCID-5-PD) 
35 
(First et al., 2016b): SCID-5-PD is a semi-structured interview guide for making DSM-5 
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diagnoses. The SCID-5-PD is the updated version of the former Structured Clinical 
1 
Interview for DSM-IV Axis II Personality Disorders (SCID-II) to assess the 10 DSM-5 
2 
Personality Disorders across Clusters A, B, and C as well as Other Specified Personality 
3 
Disorder. This measure is designed to build rapport, the SCID-5-PD can be used to make 
4 
personality disorder diagnoses, either categorically (present or absent) or dimensionally. 
5 
Assessment will be completed at screening.) 
6 
Multidimensional Scale of Perceived Social Support (MSPSS) (Zimet, Dahlem, Zimet, & 
7 
Farley, 1988): Brief research tool designed to measure perceptions of support from 3 
8 
sources: Family, Friends, and a significant Other.  The scale is comprised of a total of 12 
9 
items, with 4 items for each subscale. (Assessment will be completed at screening). 
10 
Brief Psychiatric Rating Scale (BPRS) (Overall, Gorham, 1988) is a clinician 
11 
administered instrument which assesses the level of 18 symptom constructs such as 
12 
hostility, suspiciousness, hallucination, and grandiosity. The rater enters a number for 
13 
each symptom construct that ranges from 1 (not present) to 7 (extremely severe). 
14 
(Assessment will be completed at baseline, pre/post DBS surgery, and post each titration 
15 
session at Investigator discretion) 
16 
 
17 
 
Depression and suicidal ideation assessment and monitoring 
18 
(To be administered at screening, three times weekly during the inpatient period, post 
19 
each titration session, twice weekly during the outpatient period through the 12 week 
20 
follow up, and then once weekly through Week 52 post-titration. To be administered in 
21 
the long-term follow up period quarterly (approximately every three months) or more 
22 
frequently at investigators discretion based on clinical assessment (e.g. subjective 
23 
changes in craving, mood, etc.) and after any stimulation adjustments. During the 
24 
inpatient titration phase, these required post-titration assessments will count toward the 
25 
three-time weekly inpatient assessment requirement as long as they remain within normal 
26 
limits following the titration session. If a titration session is performed during the 
27 
outpatient phase or long-term follow up period, these required post-titration assessments 
28 
will count towards the outpatient assessment requirement as long as they remain within 
29 
normal limits following the titration session.  
30 
Hamilton Depression Rating Scale (HAM-D) (Hamilton, 1960) is an multiple item 
31 
questionnaire used to assess depression and has been clinically validated. Depression is 
32 
rated based on the responses and takes about 10 minutes to complete. 
33 
Columbia–Suicide Severity Rating Scale (C-SSRS) (Posner et al., 2011) is a suicidal 
34 
ideation and behavior rating scale and has been clinically validated. It is assessed through 
35 
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a series of questions for suicidal risk and takes about 5-10 minutes to complete. 
1 
Cognitive Assessments (Clinical Neuropsychological Measures)  
2 
(These standard clinical measures of cognitive/neuropsychological function will be 
3 
administered at screening/baseline, and 12, 24 and 52 weeks following titration with 
4 
approximate time to administer-2 hours) 
5 
 
6 
Dementia Rating Scale – 2nd Edition (DRS-2) (Jurica, 2001): Measures cognitive 
7 
function at lower ability levels where some other evaluation instruments are limited by 
8 
floor effects. The DRS-2 also can be used to track changes in cognitive status over time. 
9 
By design, the DRS-2 measures deficits in a large range of higher cortical functions and 
10 
differentiates deficits of varying severity levels. Utilizes frequently as a screener for DBS 
11 
eligibility.  Estimated administration time is 30 minutes. 
12 
 
13 
Wide Range Achievement Test-Fourth Edition, Reading Subtest (Wilkinson, 2006): The 
14 
WRAT-4 is an individually administered test of word reading. The participants read the 
15 
words and the examiner determines whether the word is pronounced correctly. The 
16 
participants are not corrected if they do not say the word correctly. The total number of 
17 
correctly pronounced words is transformed into a Standard Score with a mean of 100 +/- 
18 
15. Age norms are used. The test is used to roughly approximate the participant's general 
19 
ability (IQ). It takes about 5 minutes to administer. Estimated administration time is 5 
20 
minutes. 
21 
Wechsler Abbreviated Scale of Intelligence – Second Edition (WASI-II) (Wechsler, 
22 
2011) Provides an index of estimated intellectual functioning via the Vocabulary, 
23 
Similarities, Block Design, and Matrix Reasoning subtests. Estimated administration time 
24 
is 30 minutes.  
25 
Wechsler Adult Intelligence Scale-Fourth Edition (WAIS-IV) – Digit Span Subtest 
26 
(Wechsler, 2008): The Digit Span subtest will assess focused auditory attention and 
27 
concentration. Estimated administration time is 5 minutes. 
28 
California Verbal Learning Test-Second Edition, Short Form (CVLT-II-Short) (Delis 
29 
D.C., 2000): The CVLT-II-Short measures verbal learning and memory.  It includes 9 
30 
words across a series of 4 trials, free recall following a short delay, free and cued recall 
31 
following a delay, recognition, and forced choice. This test will provide information on 
32 
the effects of DBS on verbal learning and memory. Estimated administration time is 15 
33 
minutes. 
34 
Brief Visuospatial Memory Test-Revised  (BVMT-R) (Benedict, Schretlen, Groninger, 
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Dobraski, & Shpritz, 1996):  Assess visual learning and memory (outcome variables: the 
1 
number of figure details recalled across the three learning trials, number recalled 
2 
following a 25 minute delay, and number correct when presented in recognition format). 
3 
Estimated administration time is 10 minutes. 
4 
Trails Making Test Parts A and B (TMT-A, TMT-B) (Reitan, 1958)): The TMT provides 
5 
a measure of visual scanning and mental flexibility. It involves drawing lines between 
6 
letters and numbers, in sequential order. Estimated administration time is 10 minutes. 
7 
Controlled Oral Word Association Test (COWAT) and Animal Fluency (Lezak, 1995): 
8 
The COWAT provides a measure of verbal fluency. The timed task measures include 
9 
phonemic fluency, which requires the participant to name as many words as possible that 
10 
begin with a specified letter in one minute. Also includes semantic fluency which 
11 
requires the participant to name as many animals as the can in one minute. Estimated 
12 
administration time is 5 minutes. 
13 
Stroop Color-Word Interference Task (SCWT) (Stroop, 1935): Assess information 
14 
processing and inhibition (outcome variables: total number of words read and colors 
15 
named in 45 seconds). Estimated administration time is 5 minutes. 
16 
Wisconsin Card Sorting Test (WCST) (Berg, 1948): Assess the ability to display 
17 
flexibility in the face of changing schedules of reinforcement. A number of stimulus 
18 
cards are presented to the participant. The participant is told to match the cards, but not 
19 
how to match; however, he or she is told whether a particular match is right or wrong. 
20 
Estimated administration time is 10 minutes.  
21 
Embedded Performance Validity Tests – Obtained via the WAIS-IV Digit Span subtest 
22 
(Wechsler, 2008) and CVLT-II-SF Forced Choice Recognition (Delis D.C., 2000).  
23 
Assesses the participant’s engagement during testing.  
24 
Affective/Emotional Measures (Approximate time to administer is 30 minutes)  
25 
 
26 
Comprehensive Psychopathological Rating Scale (CPRS) (Asberg, Montgomery, Perris, 
27 
Schalling, & Sedvall, 1978): The CPRS rates anxiety and depression and is completed by 
28 
the participants using paper and pen.  This paper- or computer-based measure takes less 
29 
than 5 minutes to complete. (To be administered at screening/baseline, three times 
30 
weekly during the inpatient period, twice weekly during the outpatient period through the 
31 
12 week follow up, and then once monthly through Week 52 post-titration.) 
32 
Young Mania Rating Scale (YMRS) (Young, Biggs, Ziegler, & Meyer, 1978): The 
33 
YMRS scale consists of 11 items to monitor the development of hypomanic/manic 
34 
symptoms during the study.  Items 5, 6, 8, and 9 are rated on a scale from 0 (symptom not 
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present) to 8 (symptom extremely severe). The remaining items are rated on a scale from 
1 
0 (symptom not present) to 4 (symptom extremely severe). Items 5, 6, 8, and 9 
2 
(irritability, speech, content and disruptive-aggressive behavior) are given twice the 
3 
weight of the remaining 7 in order to compensate for the poor condition of severely ill 
4 
participants. The YMRS total score ranges from 0 to 60.This paper- or computer-based  
5 
scale is done with a clinician or other trained rater with expertise with manic participants 
6 
and takes 5-10 minutes to complete. (To be administered at screening/baseline, three 
7 
times weekly during the inpatient period, post each titration session, twice weekly during 
8 
the outpatient period through the 12 week follow up, and then once monthly through 
9 
Week 52 post-titration. During the inpatient titration phase, this required post-titration 
10 
assessment will count toward the three-time weekly inpatient assessment requirement as 
11 
long as it remains within normal limits following the titration session. If a titration 
12 
session is performed during the outpatient phase, this required post-titration assessment 
13 
will count towards the once or twice weekly outpatient assessment requirement as long as 
14 
it remain within normal limits following the titration session). YMRS will also be 
15 
performed after any titration in the long-term follow up period. 
16 
Profile of Mood States-Short Form (POMS-SF) (Curran, Andrykowski, & Studts, 1995): 
17 
The POMS-SF is a commonly used measure of psychological distress. It provides a rapid, 
18 
accurate assessment of fluctuating mood states. The POMS will provide another 
19 
assessment of the potential changes in mood following DBS. This paper- or computer-
20 
based assessment takes 3-5 minutes to complete. (To be administered at 
21 
screening/baseline, three times weekly during the inpatient period, twice weekly during 
22 
the outpatient period through the 12 week follow up, and once monthly through Week 52 
23 
post-titration.) 
24 
Positive Affect Negative Affect Schedule-Short Form (PANAS-SF) (Watson, Clark, & 
25 
Tellegen, 1988) as measure of negative and positive affect. The PANAS consists of 10 
26 
items: five positive items and five negative items. Participants will indicated whether 
27 
they agree with a statement (e.g. I feel upset right now) on a 5-point scale (1 = not at all 
28 
to 5 = extremely). This paper- or computer-based assessment takes approximately 3 
29 
minutes to complete. (To be administered at screening/baseline, three times weekly 
30 
during the inpatient period, twice weekly during the outpatient period through the 12 
31 
week follow up, and once monthly through Week 52 post-titration.) 
32 
Barratt Impulsiveness Scale (BIS) (Patton, Stanford, & Barratt, 1995): 30-item self-report 
33 
questionnaire assessing impulsive personality traits. Each item is rated on a 4-point scale 
34 
ranging from 1 (never) to 4 (always) with a range from 30–120. This paper- or computer-
35 
based assessment takes 5 minutes to complete. (To be administered at screening/baseline, 
36 
three times weekly during the inpatient period, twice weekly during the outpatient period 
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through the 12 week follow up, and once monthly through Week 52 post-titration.) 
1 
Snaith-Hamilton Pleasure Scale (SHAPS) (Snaith et al., 1995): The SHAPS is a brief 
2 
(14-item) self-report instrument that measures anhedonia. It has been validated in both 
3 
healthy volunteers and psychiatric participants including those with depressive, psychotic 
4 
spectrum and substance use disorders. This paper- or computer-based measure takes 2-5 
5 
minutes to complete. (To be administered at screening/baseline, three times weekly 
6 
during the inpatient period, twice weekly during the outpatient period through the 12 
7 
week follow up, and once monthly through Week 52 post-titration.) 
8 
Opioid and Other Substance Consumption and Craving Measures (Approximate time to 
9 
administer these paper- or computer-based assessments is 30 minutes).   
10 
Brief Substance Craving Scale (BSCS) (Dyrenforth, Goldsmith, Mezinskis, Cohen, 1995) 
11 
The BSCS is a 16 item, self-report instrument which assesses craving for substances of 
12 
abuse over a 24 hour period. Intensity and frequency of craving are recorded on a five-
13 
point Likert scale. (To be assessed up to twice daily, based on subject’s availability, from 
14 
screening through Week 52 post-titration.) 
15 
Timeline Follow-back (TLFB): The TLFB is an assessment method that obtains estimates 
16 
of daily opioid and other substance use.  Using a calendar, the participants provide a 
17 
retrospective estimate of daily substance use since their previous self-report. This paper-
18 
and-pencil or smartphone/tablet measure takes 5 minutes to complete. (To be 
19 
administered at screening/baseline, three times weekly during the inpatient period, twice 
20 
weekly during the outpatient period through Week 52 post-titration.) 
21 
Sensitivity to Reinforcement of Addictive and other Primary Rewards (STRAP-R) 
22 
(Goldstein et al., 2010). This 3-item test assesses participant’s response to substances and 
23 
natural reward. This smartphone/tablet measure takes 5 minutes to complete. (To be 
24 
administered at screening/baseline, three times weekly during the inpatient period, twice 
25 
weekly during the outpatient period through the 12 week follow up, and then once 
26 
monthly through Week 52 post-titration.) 
27 
Cue Presentation and Craving Measurements: A set of 20 images of opioid and other 
28 
substance related pictures from our laboratory library will be presented. Prior to and 
29 
immediately after viewing the cues, participants will complete paper- or computer-based 
30 
assessment visual analog scale (VAS) designed to assess craving and mood. This 
31 
assessment takes 5 minutes to complete. (Craving VAS (without cues) will be 
32 
administered on a smartphone/tablet up to twice daily, based on subject’s availability, 
33 
from screening through Week 52 post-titration. Cue presentation/Cue Induced Craving 
34 
VAS Measurements will be performed up to three times weekly from screening 
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throughout the inpatient period, once weekly through Week 24 post-titration, and once 
1 
monthly through Week 52 post-titration. Cue presentation/Cue Induced Craving VAS 
2 
Measurements may be conducted more frequently at the investigator’s discretion. In the 
3 
long-term follow up period, cue reactivity will be performed quarterly (approximately 
4 
every 3 months) or more frequently at investigators discretion based on clinical 
5 
assessment (e.g. subjective changes in craving, mood, etc.) and may be performed in 
6 
conjunction with data collection from the Percept device. 
7 
Experimental Measures of Executive Function 
8 
 
9 
The proposed study will employ a series of experimental cognitive tests focused on 
10 
elements of executive function that supplement the clinical neuropsychological measures. 
11 
The following tasks will be administered to participants via a smartphone/tablet to 
12 
capture day-to-day variability in measures of response inhibition, working memory, 
13 
cognitive flexibility, and attention. In addition to the analysis of performance scores that 
14 
data will be integral for the development of a machine learning model to predict recovery 
15 
and relapse. The battery of tests will take approximately 15 minutes.     
16 
The Eriksen Flanker Task (Eriksen, 1974) is a response inhibition test to assess the 
17 
participant’s ability to suppress a response that is inappropriate based on the task rules. 
18 
Participants are to respond, left or right, to the direction of the middle arrow (target 
19 
arrow) of five aligned items. The task consists of congruent stimulus (the direction of the 
20 
target arrow and flanker arrows are the same), incongruent stimulus (the direction of the 
21 
target arrow is opposite of the flanker arrows), and neutral stimulus (flanker items are 
22 
different then the target arrow). The dependent variable is the measurement of reaction 
23 
time to select the direction of the target arrow. The standard findings are that the 
24 
incongruent stimulus has greater reaction times as compared to congruent and neutral 
25 
stimulus. (To be assessed up to twice daily, based on participant’s availability, from 
26 
screening through Week 52 post-titration.) 
27 
N-Back Task (Kirchner, 1958) is a measure of working memory where participants 
28 
monitor a series of stimuli and respond whenever a stimulus is presented that is the same 
29 
as the one presented in a predefined previous trial. Test are defined as items that are 1, 2, 
30 
or 3 items back from the current stimulus whereas 1-back is less difficult then then 3-
31 
back since less information is needed in working memory to correctly respond. The 
32 
dependent variable is the percentage of correctly identified items. (To be assessed up to 
33 
twice daily, based on subject’s availability, from screening through Week 52 post-
34 
titration.) 
35 
The Psychomotor Vigilance Task (PVT; Dinges, Powell, & Computers, 1985) is a 
36 
reaction time test that measures a person’s sustained attention to a cue presented on a 
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screen at random inter-stimulus intervals. In addition to the measures of reaction time to 
1 
correct responses the errors of commission (responding when there is not response cue) 
2 
and omission (failing to respond to a response cue). A variation of the PVT will also be 
3 
utilized to examine cognitive flexibility. A rule set, which changes between trials, will be 
4 
given to the participant where they will have to respond to specific colors and withhold 
5 
respond from others (i.e. respond to red dots and not green). (To be assessed up to twice 
6 
daily, based on subject’s availability, from screening through Week 52 post-titration.) 
7 
 
8 
Balloon Analogue Risk Task (BART) (Lejuez, Read, Kahler, Richards, Ramsey, Stuart, 
9 
Strong, Brown, 2002) The Balloon Analogue Risk Task is a computerized measure of 
10 
risk taking behavior. The BART models real-world risk behavior through the conceptual 
11 
frame of balancing the potential for reward versus loss. In the task, the participant is 
12 
presented with a balloon and offered the chance to earn money by pumping the balloon 
13 
up by clicking a button. Each click causes the balloon to incrementally inflate and money 
14 
to be added to a counter up until some threshold, at which point the balloon is over 
15 
inflated and explodes. Thus, each pump confers greater risk, but also greater potential 
16 
reward. If the participant chooses to cash-out prior to the balloon exploding then they 
17 
collect the money earned for that trail, but if balloon explodes earnings for that trial are 
18 
lost. Participants are not informed about the balloons breakpoints; the absence of this 
19 
information allows for testing both participants' initial responses to the task and changes 
20 
in responding as they gain experience with the task contingencies. Risk taking is a 
21 
related, but phenomenologically distinct process from impulsivity. (To be administered 
22 
up to twice weekly, based on subject’s availability, from screening through the inpatient 
23 
period, and may be performed once weekly during outpatient phase through Week 24, 
24 
and approximately once monthly through Week 52 post-titration). To be administered in 
25 
the long-term follow up period quarterly (approximately every three months) or more 
26 
frequently at investigators discretion based on clinical assessment (e.g. subjective 
27 
changes in craving, mood, etc.) 
28 
 
29 
Delayed Discounting Task (Richards, Zhang, Mitchell, de Wit, 1999) assesses cognitive 
30 
functions which are often impaired in substance users including: decision-making, 
31 
impulsivity, and inhibitory control. This task presents subjects with hypothetical choices 
32 
between $10 available after a specified delay (i.e., 1, 2, 30, 180 or 365 days) and a 
33 
smaller amount available immediately (e.g., “Would you rather have $10 in 30 days or $2 
34 
now?”; Richards et al., 1999). An adjusting amount procedure is used to derive 
35 
indifference values (i.e., the primary outcome on this measure) between the delayed 
36 
standard and immediate adjusting options for each of the five delays assessed. An 
37 
indifference value reflects the smallest amount of money an individual chooses to receive 
38 
immediately instead of the delayed standard amount ($10) at the specified delay. (To be 
39 
administered (May be performed in combination with EEG; To be administered up to 
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twice weekly, based on subject’s availability, from screening through the inpatient 
1 
period, and may be performed once weekly during outpatient phase through Week 24, 
2 
and approximately once monthly through Week 52 post-titration). To be administered in 
3 
the long-term follow up period quarterly (approximately every three months) or more 
4 
frequently at investigators discretion based on clinical assessment (e.g. subjective 
5 
changes in craving, mood, etc.). 
6 
 
7 
Dot-Probe Task (Halkiopoulos, 1981) Assesses selective attention. Two stimuli, one of 
8 
which is neutral and one of which is threatening, appear randomly on either side of the 
9 
screen. The stimuli are presented for a predetermined length of time (most commonly 
10 
500ms), before a dot is presented in the location of one former stimulus. Participants are 
11 
instructed to indicate the location of this dot as quickly as possible, either via keyboard or 
12 
response box. (To be administered up to twice weekly, based on subject’s availability, 
13 
from screening through the inpatient period, and may be performed once weekly during 
14 
outpatient phase through Week 24, and approximately once monthly through Week 52 
15 
post-titration) 
16 
 
17 
Physiological Monitoring via wearable devices such as a wrist device and/or finger ring:  
18 
The participant will wear a Garmin watch and/or Oura ring as much as possible for the 
19 
duration of the study (inpatient and outpatient). Measures of continuous heart rate and 
20 
activity are collected as well as spot measurements of heart rate variability, body 
21 
temperature, and rate of respiration. Sleep durations (onset and offset) will also be 
22 
measured from the two devices. Data from the Garmin watch and Oura ring will be 
23 
uploaded automatically into the RNI cloud infrastructure (FusionSports’s Smartabase). 
24 
ECG (heart rate data) and GSR (Galvanic Skin Response) may be collected from 
25 
Shimmer3 (https://imotions.com/shimmer3-gsr/) units. Eye tracking (measures of 
26 
fixation, saccade, scan patterns, pupil dilation) may be collected from Tobii pro x3-120 
27 
(https://www.tobiipro.com/product-listing/tobii-pro-x3-120/) during cue presentation 
28 
sessions. 
29 
 
30 
Interoceptive processing (Park, 2016) will be used to assess how the nucleus accumbens 
31 
processes and predicts interoceptive signals. Tactile and/or auditory stimuli will be 
32 
presented at different intensities, and the participant will have to reply whether he/she 
33 
perceived the stimulus or not. May be performed in combination with EEG. (To be 
34 
administered up to two times during each inpatient study phase and up to once monthly 
35 
during the outpatient follow-up phase).   
36 
 
37 
NIH Stroke Scale (NIHSS): NIHSS will be performed at screening/baseline, then post-
38 
operatively, after each titration/stimulation adjustment, and then monthly through Week 
39 
52 post-titration. In the long-term follow up period, the NIHSS will be performed after 
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any stimulation adjustments. 
1 
 
2 
The National Institutes of Health Stroke Scale (NIHSS) is a systematic assessment tool 
3 
that provides a quantitative measure of stroke-related neurologic deficit.  The NIHSS is a 
4 
15-item neurologic examination stroke scale used to evaluate the effect of acute cerebral 
5 
infarction on the levels of consciousness, language, neglect, visual-field loss, extraocular 
6 
movement, motor strength, ataxia, dysarthria, and sensory loss.  A trained observer rates 
7 
the patient’s ability to answer questions and perform activities.  Ratings for each item are 
8 
scored with 3 to 5 grades with 0 as normal, and there is an allowance for untestable items.  
9 
The paper- or computer-based assessment requires less than 10 minutes to complete.  
10 
 
11 
PET/CT Scans 
12 
 
13 
The study will utilize PET imaging to demonstrate the physiological changes associated 
14 
with NAc/VC DBS. FDG PET/CT will be used to assess changes in prefrontal brain 
15 
metabolism with DBS. FDG PET/CT will be collected at WVU. 11C Raclopride PET/CT 
16 
may be conducted to measure changes in dopamine brain metabolism, through the 
17 
measurement of dopamine binding, associated with NAc/VC DBS. If conducted, this will 
18 
be in collaboration with the National Institute of Drug Abuse (NIDA), who have 
19 
developed expertise in PET dopamine imaging, 11C Raclopride PET/CT will be 
20 
conducted at NIH Clinical Center in Bethesda, Maryland, and images will be analyzed by 
21 
investigators at WVU and NIDA. Participants, accompanied by an RN experienced in 
22 
behavioral health and addiction, will be transported by medical transport to and from the 
23 
NIH Clinical Center for PET/CT scans.  Before travelling to NIH the PI or delegated 
24 
physician will determine if they continue to have decision making capacity. This will 
25 
involve an overnight stay the evening before the PET/CT scans at the Clinical Center 
26 
under the care/supervision of Dr. David “Ted” George of NIH. 
27 
 
28 
If conducted, there will be a total of nine PET/CT scans performed for each participant 
29 
during this study 1) Session one with three scans at the end of the three week surgical 
30 
recovery period and prior to the DBS titration and programming 2) Session two with 
31 
three scans at 12 weeks after completion of the titration period. 3) Session three with 
32 
three scans at 52 weeks after completion of the 52-week enrollment. Each session will 
33 
consist of three PET scans: 1) FDG PET/CT to assess prefrontal brain glucose 
34 
metabolism, 2) 11C -Raclopride PET/CT placebo (no methylphenidate) and 3) 11C-
35 
Raclopride PET/CT (with methylphenidate) challenge to determine binding potential of 
36 
dopaminergic D2/D3 receptors and dopamine release. Methylphenidate will be 
37 
administered orally at a dose of 60 mg prior to the scan per the standard protocol 
38 
developed at NIDA. 
39 
 
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CT Scans 
1 
 
2 
Two high resolution CTs of the head will be obtained, one prior to surgery and one post-
3 
operatively to verify placement of electrodes. The patient will require a CT scan of the 
4 
head after application of the Leksell stereotactic frame on the morning of surgery, co-
5 
registered to pre-operative MRI scans, for intra-operative anatomic localization per 
6 
standard care. The patient will also require a CT scan, co-registered to pre-operative 
7 
images, immediately after implantation of intracranial leads to confirm placement of the 
8 
electrodes and to evaluate for intracranial hemorrhage and air. The participant may 
9 
require an additional CT scan post-operatively for clinical reasons, for example to 
10 
identify intracranial bleeding. 
11 
 
12 
MRI Scans 
13 
 
14 
High resolution MRI of the brain will be obtained approximately one week prior to 
15 
surgery (but no more than 2 weeks prior to the surgery date) and may be completed at the 
16 
end of the three week surgical recovery period prior to the DBS titration and 
17 
programming, and at the 12 and 52 weeks follow-up visits. Additional Structural MRI 
18 
may be completed at investigator’s discretion, if clinically indicated, prior to or after 
19 
DBS surgery. Functional MRI (resting state and task-based using a cue reactivity 
20 
paradigm) may be performed prior to DBS surgery, at the end of the three week surgical 
21 
recovery period, at the 12 and 52 weeks follow-up visits and in conjunction with LFP 
22 
acquisition/cue reactivity at long term follow up visits. 
23 
  MR-imaging uses a strong magnetic field and radio waves to take pictures of the brain. 
24 
The MR-scanner is a metal cylinder surrounded by a strong magnetic field.  During the 
25 
MR-imaging, the patient will lie on a table that can slide in and out of the cylinder.  The 
26 
patient will be in the scanner about 40 minutes. The patient may be asked to lie still for 
27 
up to 15 minutes at a time.  During the task-based fMRI, opioid and other substance 
28 
related pictures may be presented for approximately 10 minutes while the subject is in the 
29 
MRI. Prior to and immediately after viewing the cues, participants will rate their craving 
30 
levels. While in the scanner the patient will hear loud knocking noises and will be fitted 
31 
with earplugs or earmuffs to muffle the sound. The patient will be able to communicate 
32 
with the MR-staff at all times during the scan and may ask to be moved out of the 
33 
machine at any time.  
34 
During part of the MR-imaging a contrast agent (Gadolinium) will be given through an 
35 
IV catheter. A needle will be used to guide the catheter into an arm vein. The needle will 
36 
be removed, leaving only the catheter in the vein. The catheter will be taped to the skin to 
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hold it in place. 
1 
Electroencephalogram 
2 
Electroencephalogram (EEG) will be used to evaluate the electrical activity in the brain 
3 
during pre- and post-surgical phases of the study. EEG may be performed while the 
4 
subject is at rest or while completing specific tasks (e.g. delayed discounting, 
5 
interoceptive processing). 
6 
Phase III: DBS Surgery  
7 
 
8 
DBS surgery will be performed using standard stereotactic implantation of FDA 
9 
approved leads (Medtronic Neurological) bilaterally in the NAc/VC in each participant 
10 
using standard stereotactic techniques used for this DBS target since 1999. The specific 
11 
target can be directly visualized on axial, coronal, and sagittal T1, T2, and inversion-
12 
recovery MRI scans that are obtained approximately one week prior to the surgery (but 
13 
no more than 2 weeks prior to the surgery date). 
14 
 
15 
On the day of surgery, standard clinical care requires a head CT with the stereotactic head 
16 
frame and merging of the CT and MRI images for targeting the NAc/VC. The DBS 
17 
electrodes implanted into the NAc/VC will be connected to pulse generators (Medtronic 
18 
Percept PC, Activa RC or PC systems, as considered appropriate clinically) in the chest 
19 
wall in the usual standard fashion as for all DBS procedures. After DBS placement, 
20 
patients will undergo a post-operative CT scan on the same day as surgery to rule out 
21 
hemorrhage. After DBS surgery, the participants will be followed on the neurosurgical 
22 
step-down unit and patient ward until deemed clinically stable, at which point they will 
23 
be transferred to our inpatient addiction psychiatry service for a up to a total time of 3 
24 
weeks post DBS surgery. DBS surgery involves FDA approved standard stereotactic 
25 
implantation of DBS electrodes (Medtronic Neurological Model 3387S) bilaterally in the 
26 
NAc/VC in each participant using anatomical and physiological guidance and single cell 
27 
microelectrode recording. The specific target can be directly visualized on axial, coronal, 
28 
and sagittal T1, T2, and inversion-recovery MRI scans, similar to what has been 
29 
described previously for this target in the literature. The trajectory planning will be based 
30 
on avoidance of vasculature while maximizing the approach through the internal capsule 
31 
to the ventral striatum and the NAc. The anatomical target will correspond to the 
32 
stereotactic targets coordinates of approximately 5 to 10mm lateral to the midline, 1 to 5 
33 
mm anterior to the anterior commissure, and 2 to 5mm ventral to the anterior 
34 
commissure. Single-cell micro-electrode recording will be performed to verify the 
35 
anatomical target traversing the internal capsule white matter with white matter 
36 
recordings and cells in the NAc. The DBS electrodes implanted to the target will be 
37 
connected to pulse generators (Medtronic Percept PC, Activa RC or Activa PC in the 
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chest wall in the usual fashion as for all DBS procedures.)  
1 
 
2 
To investigate the role of the NAc/VC in addictive behaviors we will assess the extent to 
3 
which its local field potentials and single unit activity track the computation of value for 
4 
choices that relate to addiction (i.e., items representing drugs) vs. control items (e.g., food 
5 
items). In an intraoperative experiment, we will collect trial-by-trial estimates of decision 
6 
confidence while patients chose between pairs of items. We expect neural activity in the 
7 
NAc/VC to differ between addiction-related vs. control items. Together with 
8 
computational models of decision making, these data will help determine optimal lead 
9 
placement and refine future therapies for addiction.  
10 
 
11 
Phase IV: DBS Titration and Stimulation  
12 
 
13 
Up to a three-week time period will be allocated for initial programming, titration, and 
14 
safety check/follow-up, while inpatient for safety.  Titration will be based on stimulation 
15 
parameters used in previous studies examining the role of DBS of the NAc in the 
16 
treatment of OCD and depression, Since it is difficult to titrate stimulation parameters for 
17 
efficacy in OUD while in a sheltered hospital setting, the titration stimulation will be 
18 
based, first, on the absence of adverse effects, and, second, on whether the stimulation 
19 
parameters help to maximize performance on a range of cognitive tasks selected to index 
20 
decision making and cognitive control (e.g. Flanker, N-Back, and Psychomotor Vigilance 
21 
tasks) and the discretion of the research team with regards to behavioral addiction 
22 
features.  The optimum setting and as well the effect of DBS will be determined based 
23 
upon reported craving, mood, and/or physiological response. 
24 
 
25 
The DBS system is turned on with a standard monopolar or bipolar setting, as deemed 
26 
necessary per the medical team, after reviewing each contact setting while the 
27 
participants are being monitored for adverse effects. Stimulation will be delivered 
28 
initially at 90-185 Hz, in pulse widths ranging from 90 - 210 µsec. The polarity, 
29 
frequency, pulse width and intensity will be adjusted using the standard range used for 
30 
OCD and depression based on previous experience with NAc/VC DBS. Stimulation will 
31 
be used on the electrode contact mapped to the stereotactic target used during surgery, 
32 
unless side effects at that contact preclude any stimulation. During this phase, the Percept 
33 
PC neurostimulator may be accessed to obtain local field potentials recorded from the 
34 
patient’s brain during initial adjustments and programming. 
35 
 
36 
Amplitude of stimulation will be increased in small increments, slowly, while the patient 
37 
is monitored for immediate side effects. Immediate side effects can include sensory 
38 
changes, motor symptoms, immediate mood changes, non-specific drowsiness, 
39 
discomfort, or eye deviation. The stimulation will not exceed the 30 µcoulomb/cm² 
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charge density safety limit. After the programming session and safety follow-up of up to 
1 
three weeks, participants will be discharged to home and monitored via standard visits 
2 
with the COAT program as per the protocol.  
3 
 
4 
During the DBS Titration and Stimulation Phase, in the event that no adjustments are 
5 
needed, there may be sessions conducted similar to a typical titration session with the 
6 
exception that no changes will actually be made to the stimulation parameters. This will 
7 
be performed in an attempt to decrease any anticipatory bias on behalf of the subject (e.g. 
8 
knowing that an adjustment will be made and subsequently anticipating that there will be 
9 
an effect).  After completion of the titration and stimulation phases, participants may 
10 
have their stimulation parameters adjusted to maintain or improve efficacy at the 
11 
discretion of the treatment team during the follow up phase of the study. There may also 
12 
be sessions conducted where no changes are made to the parameters to decrease the 
13 
potential of anticipatory bias as mentioned above.  
14 
 
15 
Each participant will be given a copy of the Medtronic Patient Therapy Guide, which 
16 
describes the DBS unit and its care, before the DBS unit is implanted, as well as 
17 
individual teaching regarding the contents of the Guide from the study team.  Participants 
18 
will also receive a smaller pocket-size Quick Guide reference.  At discharge, the 
19 
participants will be given the Medtronic patient controller for safety. The access will be 
20 
set to “limited: view battery status only”. In this setting, the participants can confirm that 
21 
the stimulator is on and working correctly, but they cannot see the voltage at which they 
22 
are programmed. If severe side effects are experienced and the stimulator needs to be 
23 
turned off, they will be able to do so with their patient controller.  
24 
 
25 
Participants and their caregivers will be instructed on care of the DBS, including avoiding 
26 
magnetic fields They will be instructed to carry their DBS controller with them when 
27 
attending medical appointments and emergency visits (for the rare event that the DBS 
28 
unit must be turned off). Participants will be given a wallet ID card describing the DBS 
29 
unit. 
30 
 
31 
Phase V:  Follow-up and Monitoring  
32 
 
33 
After discharge from the hospital they will return to the clinic twice weekly for 12 weeks 
34 
and then once weekly for the remainder of the study. See Table 1 and Appendix A for 
35 
detailed lab testing to be performed at Week 12 follow up. 
36 
 
37 
After discharge from the hospital, any further requirements for inpatient treatment related 
38 
to OUD will follow the COAT program standard of care.  
39 
 
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The impedance of each DBS electrode will be assessed at each outpatient visit to ensure 
1 
the device is properly functioning and connected. DBS settings will be maintained at 
2 
previously-set levels unless adverse effects are noted, in which case the settings will be 
3 
adjusted back to the previous level at which the participant had no adverse effect. After 
4 
completion of the titration and stimulation phases, participants may have their stimulation 
5 
parameters adjusted to maintain or improve efficacy at the discretion of the treatment 
6 
team during the follow up phase of the study. There may also be sessions conducted 
7 
where no changes are made to the parameters to decrease the potential of anticipatory 
8 
bias as mentioned previously. The Percept PC device allows recording of local field 
9 
potentials non-invasively from the implanted DBS system. Patients with an implanted 
10 
Percept PC will be able to have events marked either in clinic or in the community (by 
11 
themselves or the care/investigative team). These events could include increased cravings 
12 
or feelings of wellness for example. The Percept PC device will also record averaged 
13 
local field potentials continuously against time and these will be obtained from the 
14 
Percept PC device at programming sessions to be evaluated later. The Percept can also 
15 
record and stream local field potential data in realtime. This feature may be used during 
16 
the planned behavioral (e.g. cue induced craving) and cognitive (e.g. delayed discounting, 
17 
balloon analog risk task) assessments. 
18 
 
19 
The primary outcome of safety will be formally assessed at 24 weeks post titration phase 
20 
as an outpatient. 
21 
 
22 
Final safety assessment will occur at 52 weeks post DBS titration. We will monitor 
23 
depression and suicidality for the duration of the 52 weeks post titration follow-up, at 
24 
minimum, on a weekly basis using the HAM-D and C-SSRS. 
25 
 
26 
Participants are followed for 52 weeks and we will post the results on ClinicalTrials.Gov 
27 
no later than 24 weeks after the last participant has completed follow up or hastened to 
28 
within 12 weeks if at any point the trial is stopped for safety by WVU IRB or the FDA. 
29 
 
30 
The results of this study will be specifically generalizable to those individuals with OUD 
31 
who are disabled from their life threatening condition and/or are Medicare beneficiaries. 
32 
 
33 
Long-Term Follow up Period 
34 
 
35 
Participants who consent to the long-term follow up will have assessments quarterly 
36 
(approximately every 3 months), or more frequently at investigators discretion based on 
37 
clinical assessment (e.g. subjective changes in craving, mood, etc.), for up to 5 years 
38 
including LFP recordings, cue reactivity (with/without fMRI), HAM-D, CSSRS, BART 
39 
and Delayed Discounting 
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1 
5.1 
Duration  
2 
 
3 
It is anticipated that the study will take approximately 52 weeks to complete following 
4 
completion of inpatient DBS titration. After the completion of the 52 week protocol, 
5 
patients who remain in treatment with the COAT program (or comparable WVU 
6 
Behavioral Medicine program) and consent to the long-term follow up will be followed 
7 
approximately every 3 months, or more frequently at investigators discretion based on 
8 
clinical assessment (e.g. subjective changes in craving, mood, etc.), for a period of up to 
9 
5 years. If the patient is no longer in a WVU Behavioral Medicine program, we will 
10 
attempt to contact them via available methods (e.g. phone, email) and they may still 
11 
participate in the long-term follow up. 
12 
 
13 
When evaluated during these long-term follow-up visits, DBS impedances will be 
14 
checked similar to as described above during the Phase V: Follow-Up and Monitoring 
15 
Phase to ensure that the device is working properly. Changes in LFPs may be measured 
16 
in association with cue-induced craving (cue reactivity) and experimental measures of 
17 
executive function (BART, Delayed Discounting), safety measures (HAM-D, CSSRS), 
18 
and other assessments (e.g. interoceptive processing) if the Percept PC device is used. 
19 
When LFPs are obtained in conjunction with behavioral/executive tasks, it is necessary to 
20 
produce an identifiable signal that can be aligned to both the events in the behavioral task 
21 
and the LFP signal to ensure that the responses and signal are synchronized. This will be 
22 
achieved via a commercially available transcutaneous electrical nerve stimulation 
23 
(TENS) device which can produce artifacts within the LFP recordings and serve this 
24 
synchronizing function without undesirable side effects (Thenaisie et al. 2021). An 
25 
adhesive electrode pad connected to the TENS unit will be placed on the patient’s upper 
26 
body in proximity to the DBS device. TENS stimulation will consist of one or more short 
27 
(< 1 second) pulses of no greater than 5 mA, 80-100 Hz, charge-balanced current. A 
28 
current of 5 mA is below the reported thresholds for a patient to detect (Dailey et al. 
29 
2013) and have no known risks. 
30 
  
31 
a) Battery Replacement – Participants may receive either the Activa or Percept PC 
32 
neurostimulator at the discretion of the Principal Investigator as described in 
33 
section 5.3 and 7.0. Replacement with the Percept PC neurostimulator will be 
34 
possible for those participants who received the Activa neurostimulator during 
35 
initial placement. Given that this will provide us with the ability to measure LFPs 
36 
in participants who did not previously have the Percept device, data may be 
37 
collected in similar fashion as described above and in Table 1 and Appendix A 
38 
which includes LFP acquisition as clinically indicated, at rest, and during specific 
39 
tasks such as cue reactivity with/without fMRI). Also, given that the Percept 
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device passively collects LFP data, when checking the impedances of the device 
1 
during follow-up visits to ensure proper functionality, this LFP data will be 
2 
automatically downloaded for all patients who receive this device. Participants 
3 
who initially received the Activa device and already had a replacement with the 
4 
Percept device will have the DBS stimulator turned off for up to 3 days in an 
5 
inpatient setting for a washout period to record LFPs in a DBS off-state (non-
6 
stimulation). 
7 
b) DBS Stimulation Adjustments – Over time, the participant may develop tolerance 
8 
to the stimulation and/or the final DBS settings established in the trial may no 
9 
longer be optimal (e.g. evidenced by the participant’s increased cravings, 
10 
reductions in mood, etc.).  In these cases, an adjustment of DBS parameters may 
11 
be warranted at the discretion of the study investigators. If changes are made to 
12 
the settings, pre-/post-stimulation behavioral changes will be measured and safety 
13 
profile assessments will be performed (e.g. HAM-D, YMRS. CSSRS, NIHSS, 
14 
BPRS (if necessary)). Any side effects will be assessed in similar fashion as when 
15 
these adjustments were made during the 52 week protocol enrollment period. 
16 
c) Participants who do not consent to be in the long-term follow up phase will have 
17 
the device explanted as there is no mechanism to ensure the safety of these 
18 
participants when not under regular observation.  
19 
 
20 
UADEs and SAEs that are attributable to the device and/or stimulation will be reported 
21 
according to FDA and IRB reporting criteria 
22 
5.2  
Potential Benefits 
23 
 
24 
Patients may not receive any health benefit from participating in this study. NAc/VC 
25 
DBS may suggest a novel therapeutic approach for individuals with treatment refractory 
26 
OUD and to learn about the effects of DBS in the modulation of brain networks in 
27 
patients with OUD. This knowledge may lead to new clinical insights that will improve 
28 
treatment for OUD. 
29 
5.3 
Potential Risks 
30 
 
31 
General Risks Associated with DBS 
32 
The general risks associated with DBS for OUD are similar as with DBS applications 
33 
involving Parkinson’s disease, dystonia, essential tremor, chronic pain, Tourette’s, 
34 
epilepsy, OCD, major depression, and TBI. The potential risks for any DBS procedure 
35 
are divided into three categories. These include risks associated with the actual surgical 
36 
implantation of the DBS lead and pulse generator, risks associated with the implantable 
37 
device, and risks associated with the programming of the device. 
38 
 
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The surgical risks for DBS implantation are the same as for any intracranial stereotactic 
1 
procedure. This includes hemorrhages (intraparenchymal, subdural or epidural 
2 
hematoma), paralysis, coma and/ or death, stroke, leaking of cerebrospinal fluid, seizures, 
3 
infection, allergic reaction, temporary or permanent neurological complications, 
4 
confusion or attention problems, pain at the surgery sites and headaches.  
5 
 
6 
The risk of a seizure due to deep brain stimulation (DBS) is less than 1%. The risk of a 
7 
seizure associated with DBS in this study may be no different than when DBS is used for 
8 
other medical conditions. 
9 
 If a seizure occurs while participant is an inpatient at WVU, immediate actions will be 
10 
taken by qualified medical personnel to reduce the risk of injury and prolonged seizure 
11 
activity. These actions will be in accordance with WVU Medicine approved patient care 
12 
protocols and latest American Epilepsy Society guidelines for treatment of seizures that 
13 
occurs in a hospital or inpatient setting. All outpatient medical emergencies including 
14 
seizures will follow standard 911 protocol.  The risks associated with the devices include 
15 
mechanical, electrical, software, and others device related system failures. Additional 
16 
risks include battery failure, electric shock and reactions to the components of the device. 
17 
The lead or lead extension connector may move, which would require surgical 
18 
intervention to readjust. 
19 
 
20 
Stimulation related side effects are most commonly reversible by adjusting the 
21 
stimulation parameters and re-programming. In addition to re-programming, the system 
22 
can be turned OFF and the intensity placed at 0 V. A recent summary of the risks profile 
23 
for DBS in movement disorders is reviewed in Rezai et al. (Rezai et al., 2008). These 
24 
include suicidal ideation, depression, gastrointestinal disturbances, nausea, muscle 
25 
weakness or partial paralysis, jolting or shocking sensation, numbness, paresthesias, 
26 
facial flushing and motor contraction, dizziness, headaches pain, changes in vital signs, 
27 
hyperactivity or euphoria, pain or discomfort, dry mouth, itching at the surgical site, 
28 
insomnia, increased fatigue, cognitive disturbance, restlessness, weight gain or loss, 
29 
speech and visual difficulties, blurred or double vision, unusual smell and taste 
30 
sensations, cognitive and/or behavioral changes, mood changes, and energy level 
31 
changes.  
32 
 
33 
A list of potential titration and programming related side effects include: 
34 
 
35 
• Depression (feeling sad, down, or blue, and/or a loss of interest in things usually 
36 
enjoyed) 
37 
• Changes in mood (positive and negative) 
38 
• Anger, aggression 
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• Gastrointestinal disturbances (changes in digestion) or nausea 
1 
• Tingling sensation (paresthesia) 
2 
• Dizziness or lightheadedness (disequilibrium) 
3 
• Facial and limb muscle weakness or partial paralysis (inability to move arms or legs) 
4 
(paresis) 
5 
• Facial flushing (red or rosy facial color) or facial muscle contractions 
6 
• Jolting or shocking sensation (sudden movements) 
7 
• Hypomania 
8 
• Numbness (hypoesthesia) 
9 
• Increased heart rate 
10 
• Increased respiratory rate 
11 
• Increased blood pressure 
12 
• Hyperactivity or euphoria (hypomania) 
13 
• Pain or discomfort 
14 
• Headaches 
15 
• Dry mouth 
16 
• Itching at the surgical site(s) 
17 
• Irritability 
18 
• Insomnia 
19 
• Increased fatigue (feeling exhausted or moving slower than usual) 
20 
• Cognitive disturbance (“cloudy” thinking) 
21 
• Restlessness 
22 
• Weight gain or weight loss 
23 
• Sleep disturbance 
24 
• Speech and visual difficulties 
25 
• Blurred vision 
26 
• Double vision 
27 
• Unusual smell and taste sensations 
28 
• Changes in mood, memory, thinking and energy level 
29 
 
30 
There are potential adverse events that could be related to the non-surgical procedures.  
31 
 
32 
Risks associated with the implantable DBS device. The risks associated with the device 
33 
include mechanical, electrical, software, and others device related system failures. 
34 
Additional risks include battery failure, electric shock and reactions to the components of 
35 
the device. The lead or lead extension connector may move, which would require surgical 
36 
intervention to readjust. 
37 
 
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The brain stimulation system may affect the operation of other surgically placed devices, 
1 
such as cardiac pacemakers, and implantable defibrillators, which may interfere with the 
2 
device function. Electrocautery, external defibrillators, radiation therapy, ultrasonic 
3 
devices may interfere with the function of the neurostimulator and may even cause some 
4 
damage to it. In addition, the electrical signal from the neurostimulator may interfere with 
5 
the function of an external defibrillator. The safety of external defibrillators on patients 
6 
with this surgically placed system has not been established. 
7 
Electromagnetic interference (EMI) is a field of energy (electrical, magnetic or a 
8 
combination of both) that is generated by various equipment found in medical, work, and 
9 
home environments.  
10 
This equipment can create enough interference to do the following: 
11 
• Turn the neurostimulator off or on 
12 
• Cause stimulation that can result in an uncomfortable sensation 
13 
• Reset the neurostimulator to factory settings, which will require reprogramming 
14 
 
15 
The neurostimulator is designed to protect against most EMI. However, strong 
16 
electromagnetic fields and permanent magnets can interfere with the system. Even when 
17 
the DBS is turned off, interference can affect the lead(s). Subjects will be instructed on 
18 
the risks and potential sources of EMI, and what to do if EMI is suspected. 
19 
 
20 
They will be instructed to move away from the source of the EMI or if possible, turn off 
21 
the suspected source of EMI. They will be instructed to use the control magnet to turn the 
22 
DBS unit on or off. 
23 
 
24 
Additional Concerns.  There may be pain, lack of healing, or infection where the brain 
25 
stimulation system parts are surgically placed. 
26 
• 
The brain’s stimulation system parts may wear through the participant’s skin, 
27 
which can cause an infection or scarring. 
28 
• 
The lead or lead/extension connector may move. Participants may need surgery to 
29 
re-adjust the location. 
30 
• 
Components or parts of the brain stimulation system may break or fail to work 
31 
properly. Participants may need surgery to replace the system parts. 
32 
• 
The brain stimulation system could stop because of mechanical or electrical 
33 
problems. Either of these would require surgery. DBS service life depends on 
34 
individual use. 
35 
• 
The participant’s body may have an allergic reaction to the brain stimulation 
36 
system. The system materials coming in contact with tissue include titanium, 
37 
polyurethane, silicone, and nylon. The body could also reject the system (as a 
38 
foreign body). 
39 
• 
There is the possibility of tissue damage resulting from the programming 
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parameters or a malfunction of one of the parts of the brain stimulation system. 
1 
 
2 
DBS systems have a battery life of approximately 2-9 years, depending upon the uses and 
3 
the model; WVU Medicine will provide follow up care (at no cost to the participant) 
4 
related to battery replacement, as well as any other related follow-up DBS care. 
5 
 
6 
Using the different configurations of the Percept PC device may lower battery life. The 
7 
minimum expected battery life, even with maximal use, is well within the 2-9 years of 
8 
current DBS systems and use of the Percept PC device is, on average, not expected to 
9 
significantly alter battery life of the system. We estimate an average time of live 
10 
streaming LFP data to be 180 hours or on average 3 hours per week (as clinically 
11 
indicated). This use will result in an estimated average loss of battery life of less than six 
12 
months (1 hour of live streaming = loss of 20 hours of battery life). We estimate the 
13 
typical battery life lost from live streaming to be approximately 165 days over the course 
14 
of a 52 week follow up (which equates to a 5-6% loss of the 2-9 year battery life). As an 
15 
example, we will obtain live streaming LFP during tasks involving experimental 
16 
measures of executive function (e.g., BART and Delayed Discounting) and cue reactivity 
17 
(assesses cue induced craving). The extent of live streaming will be variable, subject 
18 
dependent and may be far less than estimated.  
19 
 
20 
Risks of DBS System Revision.  There is a possibility that the DBS system may need to 
21 
be revised (removed, replaced, or repositioned) before the end of the research study. 
22 
Possible reasons for revision might be infection, malfunction, or other reasons. If revision 
23 
is necessary, the participant will need to have surgery similar to when the system was put 
24 
in. There might be a “buildup” of scar tissue (related to the original surgery) that may 
25 
make replacement of the leads unsafe. In some cases, it may not be possible to remove 
26 
the leads. If the electrodes or stimulator need to be removed, then the operation to remove 
27 
them may be associated with additional risks of bleeding, infection, pain, and surgical or 
28 
anesthesia complications. Replacement with the Percept PC neurostimulator will be 
29 
possible for those participants who received the Activa neurostimulator during initial 
30 
placement. 
31 
 
32 
 5.4  
Other Risks 
33 
 
34 
Blood Sample Risks.   The risks of drawing blood include temporary pain from the 
35 
needle stick, bruising, bleeding, and rarely, infection. 
36 
 
37 
X-ray Risks. X-ray technology uses radiation. The average amount of radiation that the 
38 
average person would receive from the x-rays for the research study is less than that 
39 
received from natural sources of radiation in a year. At this level, no harmful effects of 
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radiation have been demonstrated and the risk, if any, is minimal. 
1 
 
2 
Medication-Related Risks.  During the study, participants will be asked to continue the 
3 
same medications they were taking before the surgery. As a result, they may experience 
4 
the side effects associated with these medications. Some neurologic medications cause 
5 
withdrawal reactions if they are stopped suddenly. Withdrawal reactions can include 
6 
anxiety, feeling dizzy, headaches, and possibly seizures. For this reason participants 
7 
should not stop taking any medications suddenly without specifically discussing it with 
8 
the study doctors. 
9 
 
10 
Risks of MRI.  People are at risk for injury from the MRI magnet if they have 
11 
pacemakers or other implanted electrical devices, some types of dental implants, 
12 
aneurysm clips (metal clips on the wall of a large artery), metallic prostheses (including 
13 
metal pins and rods, heart valves, and cochlear implants), permanent eyeliner, implanted 
14 
delivery pump, or shrapnel fragments.  Welders and metal workers are also at risk for 
15 
injury because of possible small metal fragments in the eye of which they may be 
16 
unaware.  Participants will be screened for these conditions before having any scan, and 
17 
if they have any, they will not receive an MRI scan.  If participants have a question about 
18 
any metal objects being present in their body, they should inform the staff.  In addition, 
19 
all magnetic objects (for example, watches, coins, jewelry, and credit cards) must be 
20 
removed before entering the MRI scan room. 
21 
 
22 
It is not known if MR-imaging is completely safe for a developing fetus.  Therefore, all 
23 
women of childbearing potential will have a pregnancy test performed no more than 24 
24 
hours before each MRI scan.  The scan will not be done if the pregnancy test is positive.  
25 
People with fear of confined spaces may become anxious during an MR-imaging.  Those 
26 
with back problems may have back pain or discomfort from lying in the scanner.  The 
27 
noise from the scanner is loud enough to damage hearing, especially in people who 
28 
already have hearing loss. Everyone having a research MRI scan will be fitted with 
29 
hearing protection.  If the hearing protection comes loose during the scan, the participants 
30 
will let MR-imaging staff know right away. Participants will notify staff of any hearing 
31 
or ear problems.  Participants will be asked to complete an MR-screening form for each 
32 
MRI scan.  There are no known long-term risks of MRI scans. 
33 
 
34 
The risks of an IV catheter include bleeding, infection, or inflammation of the skin and 
35 
veins with pain and swelling.  Symptoms from the contrast infusion are usually mild and 
36 
may include coldness in the arm during the injection, a metallic taste, headache, and 
37 
nausea.  In an extremely small number of patients, more severe symptoms have been 
38 
reported including shortness of breath, wheezing, hives, and lowering of blood pressure.  
39 
People with kidney disease are at risk for a serious reaction to gadolinium contrast called 
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“nephrogenic systemic fibrosis” which has resulted in a very small number of deaths.  If 
1 
participants have diabetes, kidney disease or liver disease, a blood test of kidney function 
2 
will be done within 4 weeks before any MR-scan with gadolinium contrast.  Participants 
3 
will not receive gadolinium for a research MR-scan if their kidney function is not normal.   
4 
 
5 
Medtronic DBS systems are MRI Conditional and safe in the MRI environment as long 
6 
as certain conditions are met. If the conditions are not met, a significant risk is tissue 
7 
lesions from component heating, especially at the lead electrodes, resulting in serious and 
8 
permanent injury including coma, paralysis, or death. DBS of the Nucleus accumbens is 
9 
off label and therefore there are unknown risks in general. 
10 
 
11 
Risks of Radiation Exposure from Positron Emission Tomography (PET), Computer-
12 
assisted Tomography (CT), chest radiograph, and intra-operative fluoroscopy.   
13 
 
14 
This research study involves exposure to radiation from six C11 Raclopride PET/CT scans 
15 
(if conducted), three FDG PET/CT scans, two CT scans, one chest x-ray, and intra-
16 
operative fluoroscopy.  The participant may require another CT to evaluate for the 
17 
development of a blood clot while the electrodes are in place (for clinical care reasons).  
18 
The amount of radiation participants will receive in this study is estimated at 4.2 rem, 
19 
which is below the guideline of 5 rem per year allowed for research participants by the 
20 
NIH Radiation Safety Committee.  The average person in the United States receives a 
21 
radiation exposure of 0.3 rem per year from natural sources, such as the sun, outer space, 
22 
and the Earth's air and soil.   
23 
 
24 
The MRI, CT, PET, fluoroscopy, and chest radiograph used in this study can be harmful 
25 
to a developing fetus.  Therefore, sexually active women who are able to get pregnant 
26 
must use effective methods of contraception (birth control) from the time of screening 
27 
until the end of the study in order to avoid exposure to the radiation required in by 
28 
procedures this study.  Everyone receives a small amount of unavoidable radiation each 
29 
year. Some of this radiation comes from space and some from naturally occurring 
30 
radioactive forms of water and minerals. This research gives the participant’s body the 
31 
equivalent of about 11.8 extra years' worth of this natural radiation. 
32 
 
33 
A possible health problem seen with radiation exposure is the development of a second 
34 
cancer later in life. This extra cancer risk is higher at younger ages and for girls and 
35 
women. The extra lifetime risk of dying of a fatal cancer due to the radiation exposure 
36 
from this research may range from about one in 2,000 to about one in 700.  At such low 
37 
radiation exposures, scientists disagree about the amount of risk. These estimates are very 
38 
uncertain, and there may be no extra risk at all. 
39 
  
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6.0 
 SAFETY ENDPOINTS 
1 
 
2 
The study safety endpoints will include a characterization of all adverse events (AE) for 
3 
all participants, including those related to the implant surgical procedure, the implantable 
4 
device, and stimulation of the NAc/VC in patients with OUD.  In addition, these safety 
5 
profile elements will be compared across the various phases of the study. Patients with 
6 
clinically significant complications related to surgery (hemorrhage, stroke, infection) will 
7 
not undergo DBS implantation or further participation in the study.  
8 
 
9 
7.0  
PLAN FOR REPORTING ANTICIPATED AND UNANTICIPATED PROBLEMS 
10 
AND ADVERSE EVENTS 
11 
 
12 
All serious unanticipated problems, major protocol deviations, serious adverse events 
13 
(SAEs) and unanticipated device effects will be reported to the IRB as soon as possible, 
14 
but not more than 5 days after the PI first learns of the event. As is required for device 
15 
research, the PI will report to the IRB any deviation from the investigational plan to 
16 
protect the life or physical well-being of a subject in an emergency as soon as possible, 
17 
but no later than 5 working days after the emergency occurred.  
18 
All SAEs will be reported to NIDA within 72 hours of the PI being aware of the event. 
19 
At the time of continuing review, the PI will provide the WVU IRB with an aggregated 
20 
summary of all unanticipated problems and all protocol deviations. The PI is responsible 
21 
for detecting, documenting, and reporting unanticipated problems, adverse events (AEs), 
22 
including serious adverse events (SAEs), and deviations in accordance with IRB 
23 
requirements, and federal regulations. Relatedness to the research of all adverse events 
24 
will be determined by the PI or designated co-investigator. 
25 
 
26 
Serious Adverse Events 
27 
 
28 
An adverse event or suspected adverse reaction is considered serious if, in the view of the 
29 
investigator or the sponsor, it results in any of the following: 
30 
• Death 
31 
• A life-threatening adverse experience 
32 
• Prolongation of existing hospitalization or new hospitalization 
33 
• Persistent or significant incapacity or substantial disruption of the ability to 
34 
conduct normal life functions 
35 
• A congenital anomaly/birth defect 
36 
• Required intervention to prevent permanent impairment or damage 
37 
 
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Important medical events that may not result in death, be life-threatening, or require 
1 
hospitalization may be considered a serious adverse device experience when, based upon 
2 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
3 
medical or surgical intervention to prevent one of the outcomes listed in this definition 
4 
Unanticipated Adverse Device Effects 
5 
An unanticipated adverse device effect (UADE) is any serious adverse effect on the 
6 
health and/or safety or any life threatening problem or death caused by or associated with 
7 
the device and/or stimulation if that effect, problem, or death was not previously 
8 
identified in nature, severity, or degree of incidence in the investigational plan; or any 
9 
other unanticipated serious problem associated with a device that relates to the rights, 
10 
safety, or welfare of participant.   
11 
Unanticipated adverse device effects will be categorized as they related to: 
12 
• The implanted components (lead, extension, neurostimulator) 
13 
• The lead/extension tract or neurostimulator pocket 
14 
• The burr hole site. 
15 
An event will not be considered related to the device when it is the result of: 
16 
• A preexisting medical condition 
17 
• A medication. 
18 
 
19 
Device Malfunction  
20 
 
21 
A device malfunction is the failure of a device to meet its performance specifications or 
22 
other performance as intended.  Performance specifications include all claims made in the 
23 
labeling for the device.  The intended performance of a device refers to the intended use 
24 
for which the device is labeled or marketed (21 CFR 803.3).  
25 
The PI will report UADEs as soon as possible, but no more than 10 working days after 
26 
the PI first learns of the event.  For IDE research, the PI will report deviations from the 
27 
investigational plan that were intended to protect life or physical well-being of a subject  
28 
in an emergency to the IRB within 5 days.  Unanticipated adverse device effects will be 
29 
reported to the IRB and not more than 5 days after the PI first learns of the event. 
30 
Documentation of Adverse Events 
31 
The study PI and co-investigators will be responsible for the evaluation, monitoring, and 
32 
documentation of events meeting the criteria and definition of an adverse event (AE) or 
33 
serious adverse event (SAE) as provided in this clinical investigation.  The study 
34 
participants will be evaluated for any possible AEs from the time written study informed 
35 
consent is obtained until study closure or the subject exits the study. Please note that the 
36 
following will not be considered an AE: 
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• Reprogramming of the DBS system due to lack of efficacy. 
1 
• Transient undesirable stimulation-produced effects that occur during 
2 
programming sessions that resolve with or without programming changes prior to 
3 
the subject leaving a study follow-up visit and do not require follow-up medical 
4 
care.  
5 
• Any normal expected postoperative complaints or symptoms, unless the event 
6 
involves a clinically significant change in a patient’s severity or duration of 
7 
symptoms, or that requires clinical intervention other than the ordinary 
8 
postoperative care. The following are some expected postoperative outcomes that 
9 
may occur: headache, incision pain, nausea, vomiting, low grade fever, dizziness, 
10 
sleepiness, nervousness, insomnia, constipation, urinary retention, confusion, etc.  
11 
• Any pre-existing condition, unless a worsening of that condition in terms of 
12 
nature, severity, or frequency develops.  
13 
• Medical or surgical procedure unrelated to the clinical protocol (i.e., dental or 
14 
elective cosmetic procedure) 
15 
• Routine neurostimulator replacement for battery depletion (will be documented as 
16 
a system modification) Replacement with the Percept PC neurostimulator will be 
17 
possible for those participants who received the Activa neurostimulator during 
18 
initial placement.  
19 
• Technical observation or a device event that does not result in a medically 
20 
undesirable situation for the participant. 
21 
All AEs from the time the study informed consent is signed through the final study visit 
22 
will be recorded as AEs on the study event log, each event being documented separately.  
23 
All AEs and SAEs will be followed until: 
24 
• AE is resolved, has returned to normal/baseline, or has stabilized. 
25 
• Participant has withdrawn from the study. 
26 
• AE is judged by the investigator to be no longer clinically significant 
27 
• Study closure. 
28 
 
29 
In the long-term follow up period, only UADEs and SAEs that are attributable to the 
30 
device and/or stimulation will be reported according to FDA and IRB reporting criteria.  
31 
 
32 
All non-serious adverse events will be reported to the FDA and IRB during the 
33 
continuing review.  All adverse events, which include serious adverse events, will be 
34 
categorized unrelated, unlikely, possibly, probably, or definitely related as follows: 
35 
Not related: Temporal relationship of the onset of the event, relative to administration of 
36 
the product, is not reasonable or another cause can by itself explain the occurrence of the 
37 
event. 
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Unlikely related: Temporal relationship of the onset of the event, relative to 
1 
administration of the product, is likely to have another cause, which can by itself explain 
2 
the occurrence of the event. 
3 
Possibly related: Temporal relationship of the onset of the event, relative to 
4 
administration of the product, is reasonable but the event could have been due to another, 
5 
equally likely cause. 
6 
Probably related: Temporal relationship of the onset of the event, relative to 
7 
administration of the product, is reasonable and the event is more likely explained by the 
8 
product than any other cause. 
9 
Definitely related: Temporal relationship of the onset of the event, relative to 
10 
administration of the product, is reasonable and there is no other cause to explain the 
11 
event. 
12 
As applicable, relationship may also be categorized as related to: 
13 
• Surgical/Procedure-Related: associated with surgical implantation of the DBS 
14 
system; 
15 
• Device-Related*: caused by the implanted system; 
16 
• Stimulation-Related*: caused by the electrical stimulation of the nervous system 
17 
while treating the participant’s symptoms; 
18 
• Disorder-Related: an event that might reasonably be attributed to the patients 
19 
underlying disease state. 
20 
• NA = Not related. 
21 
 
22 
If considered at least possibly related, multiple relationship(s) could also be associated 
23 
with each adverse event. 
24 
 
25 
*For those events that are determined to be at least possibly related to stimulation or the 
26 
DBS device, the sponsor/investigator will report the strength of the relatedness using the 
27 
following definitions: 
28 
Definite: The event is resolved with reprogramming of the stimulation parameters and is 
29 
confirmed by the reappearance of the event when the device settings are returned to the 
30 
settings programmed at the time the event was observed; 
31 
Probable: The event resolves upon reprogramming of the stimulation parameters and 
32 
cannot be reasonably explained by the participant’s current clinical state; 
33 
Possible: The event may have been produced by the study participant’s clinical state; 
34 
however, the effect of stimulation cannot be ruled out. 
35 
In addition, the relationship between the device/procedure and the occurrence of each 
36 
adverse event may be assessed and categorized using the criteria above in addition to 
37 
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clinical judgement. Alternative causes, such as natural history of the underlying diseases, 
1 
concomitant therapy, and other risk factors may also be considered.  
2 
 
3 
Reporting of Serious Adverse Events 
4 
Adverse events (AE) will be monitored by direct questioning and examination at each 
5 
study visit and by patient self-report.  NCI Common Toxicity Criteria (NCI-CTCAE 
6 
v.5.0) grade 3 or higher in the neurology domain will be considered as severe AE 
7 
prompting evaluation of the cause. Any grade 4 or higher in any other NCI-CTCAE 
8 
domain will also be considered a severe AE, prompting evaluation of cause. Any subject 
9 
withdrawal due to a severe or serious AE will be submitted orally immediately and in 
10 
writing within 15 working days to the Data and Safety Monitoring Board (DSMB) and 
11 
the IRB for evaluation, and an assessment of the safety of continuing the entire study 
12 
protocol will be made.  Care will be provided to attempt stabilization of the patient's 
13 
condition and an investigation will be initiated for possible concurrent conditions causing 
14 
the deterioration, including imaging, urine and blood tests.  The DBS leads and unit can 
15 
be removed at the patient's request, or with the patient's consent if judged necessary by 
16 
the investigators.  Similarly, new persistent neurologic deficit(s) or worsening of previous 
17 
deficit(s) causing intolerable patient distress will prompt changing the DBS paradigm and 
18 
if needed termination of DBS and subject withdrawal.  The same measures described 
19 
above will be employed. 
20 
The PI will make a preliminary determination of whether the SAE is related to the DBS 
21 
system or therapy.  The DSMB will make the final determination of relatedness. 
22 
The sponsor /investigator will report the available information on all SAEs to the FDA 
23 
within 10 working days of learning of the event.  Any SAE which occurs during the 
24 
study, whether related to the DBS-system or not, will be reported to the DSMB.  Any 
25 
SAE related to the DBS system will be reported to the device manufacturer. 
26 
The inpatient screening/baseline, DBS surgery, and DBS titration phases, and 
27 
hospitalization for DBS battery replacement and period of DBS-off state for washout to 
28 
collect LFPs, will not be considered an SAE. Likewise, if the participant is admitted to 
29 
the hospital during follow up Phase 4 or 5 through the COAT clinic standard of care, the 
30 
hospitalization will not be considered an SAE if it was related to pre-existing conditions 
31 
(e.g. inpatient hospitalization for substance use treatment and/or deemed not related to the 
32 
study intervention by the PI, co-investigators and/or study team (consultation will be 
33 
made with consultants, DSMB, and NIDA as appropriate in making this determination. 
34 
 
35 
 8.0  
DATA SAFETY AND MONITORING 
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1 
This study will be monitored by an independent DSMB. The DSMB will be composed of 
2 
5 individuals, 2 with collective expertise in addiction and behavioral medicine, 1 with 
3 
neurosurgical expertise, 1 with expertise of neurologic critical care, and 1 with statistical 
4 
expertise.  
5 
 
6 
Prior to the review of the protocol, each member of the DSMB discloses in writing to the 
7 
sponsor any potential conflicts of interest, actual or implied by appearance. Should an 
8 
unanticipated situation arise that the Board member feels represents a conflict of interest, 
9 
the Board member should recuse themselves. 
10 
 
11 
Ongoing Study Meetings: During study conduct the DSMB will meet prior to the start of 
12 
enrollment and every six months or more frequently as needed (details regarding meeting 
13 
time frames following key events can be found below). The DSMB may meet in person 
14 
or via teleconference. During these meetings the DSMB will be assigned to review study 
15 
data, including all adverse events, patient withdrawals, and baseline and any re-
16 
evaluation data. 
17 
 
18 
• 
Interim data review: The DSMB will review interim data to detect evidence of or 
19 
trending of adverse effects and determines if the trial should continue as originally 
20 
designed, or whether it should be changed or stopped.  
21 
• 
Progress evaluation: The DSMB may also evaluate the progress of the trial, 
22 
including assessments of data quality/completeness, achievement of recruitment 
23 
goals, protocol adherence, accrual and retention of participants, and other factors 
24 
that may affect the study outcome. 
25 
• 
Protection of confidentiality: Study participant confidentiality will be maintained 
26 
by providing only de identified data to the DSMB. All source data will be stripped 
27 
of identifiers and given a study assigned number before providing to the board. 
28 
The DSMB will protect the confidentiality of study participants, trial data and the 
29 
results of the monitoring. 
30 
• 
For each participant, the DSMB will meet within 2 weeks following the 
31 
completion of the titration phrase, review AEs, and provide a go/no-go vote 
32 
before enrolling the next participant. 
33 
• 
DSMB will meet within 2 weeks of every SAE. 
34 
• 
DSMB will meet biannually after all 4 patients titrated. 
35 
 
36 
The DSMB will evaluate the safety of the subjects as pre-specified in the protocol, and 
37 
the DSMB will make recommendations to researchers to continue, to amend, or to 
38 
terminate a clinical trial. The DSMB will be assigned to review study data, including all 
39 
adverse events, patient withdrawals, and baseline and any re-evaluation data. Each SAE 
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and significant medical event will prompt a review by the DSMB, and the study will be 
1 
suspended until it is determined whether the SAE is study-related or unrelated.  DSMB 
2 
analysis of safety data will be performed after the first participant has completed 12 
3 
weeks of ON stimulation.  
4 
 
5 
During the long-term follow-up, the DSMB will review any UADEs and SAEs that are 
6 
attributable to the device and/or stimulation within 2 weeks. 
7 
 
8 
TRIAL STOPPING RULES 
9 
If repeated (more than 2) SAE or 2 patients develop SAE that are probably or definitely 
10 
related to the DBS implantation or stimulation, this will trigger a review by the DSMB 
11 
and the FDA. DSMB will meet within two weeks of every SAE. At the time of the 
12 
review by the DSMB and the FDA, enrollment, and/or treatment if indicted, will be 
13 
paused until a determination is made.  The DSMB and the FDA will recommend to the PI 
14 
to resume or stop the protocol.  The following specific conditions will result in a pause 
15 
and review by the DSMB and the FDA for final determination of stopping the study: 
16 
• 
Any participant with a symptomatic intraparenchymal hemorrhage or acute subdural 
17 
hematoma. (The expected incidence of symptomatic intracranial hemorrhage with DBS 
18 
surgery is 1-3%). 
19 
• 
Confusion lasting more than 2 weeks after surgery in 2 patients. 
20 
• 
Postoperative edema or symptoms that do not resolve with a month of onset in 2 patients.  
21 
• 
Infection requiring hospitalization or extend the post-operative period for more than a 
22 
week in 2 patients.   
23 
• 
2 patients that develop post-operative seizures without a preoperative diagnosis of seizure 
24 
disorder. 
25 
• 
Worsening neurological status due to study related procedures according to a change on 
26 
the NIH Stroke Scale of a least 5 for greater than one week in 2 patients. 
27 
• 
A single death. 
28 
Additional Stopping Criteria 
29 
The assessments described below will be administered to establish baseline 
30 
measurements of psychosis, mania, depression, and/or suicidality prior to DBS surgery 
31 
and following DBS surgery before the first titration session. The symptoms noted above 
32 
may emerge following surgery and/or titration. If the clinician or study staff observe any 
33 
of these symptoms clinically/behaviorally, these assessments will be re-administered.  In 
34 
addition, following the titration sessions, these measures will be administered and 
35 
compared to the baseline assessments to monitor changes. 
36 
 
37 
While the primary objective of the titration sessions is to determine the optimal DBS 
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settings in achieving the desired outcome (e.g. reduced craving), these potential side 
1 
effects will be monitored during the process of optimizing the DBS settings. Assessing 
2 
the resolution of these potential side effects, if present and necessary, will be performed 
3 
as described below. If any of these symptoms arise and do not remediate, this will trigger 
4 
DSMB consultation.  
5 
  
6 
• 
Symptom: Psychosis 
7 
• 
Assessment: Brief Psychiatric Rating Scale (BPRS) 
8 
• 
Stopping Criteria: If patient endorses moderate scores or higher (raw score ≥4) on 
9 
items related to psychosis post-surgery or post-titration sessions for >24 hours and 
10 
if symptoms do not resolve with further titration. 
11 
 
12 
• 
Symptom: Mania 
13 
• 
Assessment: Young Mania Rating Scale (YMRS) 
14 
• 
Stopping Criteria: If patient endorses moderate scores or higher (raw score of 
15 
>25) persistently for one week post-surgery or during titration and if symptoms 
16 
do not resolve with further titration. 
17 
 
18 
• 
Symptom: Depression 
19 
• 
Assessment: Hamilton Rating Scale for Depression (HAM-D) 
20 
• 
Stopping Criteria: If patient endorses severe scores or higher (raw score of >17) 
21 
persistently for one-week post-surgery or during titration and if symptoms do not 
22 
resolve with further titration. 
23 
 
24 
• 
Symptom: Suicidality 
25 
• 
Assessment: Columbia Suicide Severity Rating Scale (C-SSRS) 
26 
• 
Stopping Criteria: If patient endorses active thoughts of self-harm post-surgery or 
27 
post-titration sessions for >24 hours and if symptoms do not resolve with further 
28 
titration. 
29 
 
30 
In addition, if an annual review indicates that the study is not likely to be completed 
31 
within a reasonable timeframe the protocol will be stopped.  Finally, other SAE and 
32 
unanticipated problems will be reported to and discussed with the DSMB prior to 
33 
continuing protocol enrollment. 
34 
  
35 
If the adverse events are not of a higher incidence than expected, enrollment may 
36 
continue. If adverse events are of a higher incidence than expected, then additional 
37 
analysis of causal effects will be performed.  All DSMB reports will be sent to the PI who 
38 
will forward copies to the IRB and FDA and may request discussion with the IRB and 
39 
FDA regarding the need for an amendment.  
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1 
9.0  
MONITORING PLAN  
2 
 
3 
The data management for this study will maintain a level of data integrity and 
4 
confidentiality that will provide optimum adherence to all 21 CFR regulations, while 
5 
providing a standardized method of data collection and recording to enable the 
6 
investigators, sponsors and regulatory agencies to accurately reconstruct the events of a 
7 
study, confirm protocol compliance, and produce data that is accurate and appropriate in 
8 
demonstrating study results.  
9 
• 
Study coordinators at the RNI will perform primary data collection based on source 
10 
documents following good documentation practices (GDP) at all times. Source data 
11 
for the study may be paper based surveys and questionnaires, EMR or a copy of the 
12 
CRF labeled clearly as SOURCE may also be used as source to collect data not 
13 
captured in the EMR. 
14 
• 
Paper or electronic case report forms (CRFs) that have been validated by a Quality 
15 
control check will be used to collect study data.  
16 
• 
Compliance of regulatory documents and study data accuracy and completeness will 
17 
be maintained through an internal quality control and quality assurance process. 
18 
• 
Internal Quality Control:  All data collected (CRF Pages) will be 100% source 
19 
verified on an ongoing basis (as data becomes available) by a qualified clinical 
20 
research team member.  
21 
• 
Review of the regulatory documents will be performed by a qualified clinical research 
22 
team member prior to study initiation and prior to each participant enrollment. 
23 
• 
 QA review will be performed periodically during each subjects study participation 
24 
and at least once every quarter. This will include verification of data completeness 
25 
and accuracy for records that reflect safety and study endpoints, protocol adherence 
26 
and regulatory documents. Written reports will be provided to the PI that will include 
27 
scope of the review and observations. 
28 
• 
All electronic records and computer systems used for recording, transmitting or 
29 
storing data will be 21 CFR 11 compliant. 
30 
• All evaluation forms, assessment results, and other records that leave the site will be 
31 
identified by coded number only to maintain participants’ confidentiality. All study 
32 
records will be kept locked at the RNI or CRC. All computer entry and networking 
33 
programs will be done with coded numbers only. Clinical information will not be 
34 
released without written permission of the participants, except as necessary for 
35 
monitoring or auditing purposes. 
36 
 
37 
10.0  PROCEDURES FOR MINIMIZING RISKS 
38 
 
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Participants, after screening for eligibility, will be recruited for participation in the study. 
1 
Consent will be conducted by members of the study team, and all risks and benefits will 
2 
be described to the participants in written and oral presentation. Participants will be made 
3 
to understand that their participation is voluntary, and that they will be provided with any 
4 
new information that develops during the study that might affect their decision to 
5 
continue with the study. A sixth-grade reading level will be considered when developing 
6 
the consent materials, and the informed consent will be on file with the WVU IRB. 
7 
 
8 
Participants will be pre-screened for decision-making capacity prior to the consenting 
9 
process. A clinical determination will be made at the time of the consent by a WVU 
10 
Medicine Behavioral Medicine Clinician to determine if participants are competent for 
11 
consenting. 
12 
 
13 
All evaluation forms, assessment results, and other records that leave the site will be 
14 
identified by coded number only to maintain participants’ confidentiality. All study 
15 
records will be kept locked at the WVU Rockefeller Neuroscience Institute. All computer 
16 
entry and networking programs will be done with coded numbers only. Clinical 
17 
information will not be released without written permission of the participants, except as 
18 
necessary for monitoring by the IRB. 
19 
 
20 
If serious adverse events become evident, the study will be terminated after review and 
21 
recommendation by the DSMB. All participants previously enrolled will be immediately 
22 
contacted regarding findings. 
23 
 
24 
Vulnerable subjects: We consider participants in this study to be vulnerable due to the 
25 
presence of OUD and the resultant stigma engendered by this diagnosis. Special 
26 
protections for participants include a full-time patient navigator on call to address 
27 
emergent issues as well as a Certificate of Confidentiality that is extended to participants 
28 
in all NIH-supported trials. 
29 
 
30 
Women of reproductive potential must use acceptable forms of contraception from the 
31 
time of enrollment through the completion of study participation. 
32 
Acceptable effective methods of contraception for this study include: 
33 
• Hormonal contraception (birth control pills, injected hormones, hormonal 
34 
implants, or vaginal ring). 
35 
• Intrauterine device. 
36 
• Barrier methods (condom or diaphragm) combined with spermicide. 
37 
• Surgical sterilization (hysterectomy, tubal ligation, or vasectomy) 
38 
It is important for the participant to know that no method of birth control is totally 
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effective in preventing pregnancy except for surgical sterilization (hysterectomy or tubal 
1 
ligation) and total abstinence from sexual relations. 
2 
 
3 
The long-term effects of DBS on pregnancy and a fetus are not known. The MR-imaging, 
4 
CT scans, PET scans, and surgery used in this study can be harmful to a developing fetus. 
5 
At a minimum, pregnancy testing will be performed on all women of childbearing 
6 
potential at screening, monthly, and before MR-imaging, CT scan, PET scans, and 
7 
surgery. Presence of confirmed pregnancy will result in study discontinuation if DBS 
8 
surgery has not yet been done. If pregnancy occurs after DBS placement, imaging studies 
9 
will not be performed, however, the participant will be followed through the duration of 
10 
the study, and pregnancy outcome will be assessed. 
11 
 
12 
The investigators involved with this study have a great deal of expertise with the 
13 
conduction of DBS surgeries. The surgical team has over 20 years of experience with 
14 
DBS with over 2000 DBS implants for various indications. The study inclusion/exclusion 
15 
criteria have been developed to select those who would most likely benefit from this 
16 
study as well as excluding those with higher risks. Study participants will be monitored 
17 
after DBS implantation in neurosurgical and physiological monitoring units with 
18 
personnel experienced in the care of complex neurosurgical participants and monitoring 
19 
neurological status. After surgical stabilization, participants will be monitored on an 
20 
inpatient addiction service, which is staffed by personnel experienced in monitoring 
21 
psychiatric and addiction care. 
22 
 
23 
We plan a number of measures to mitigate occurrence of adverse events.  Patients will be 
24 
carefully examined for presence of infection prior to DBS placement.  Specifically, 
25 
patients with any evidence of cutaneous bacterial infection (e.g., impetigo, cellulitis, etc.) 
26 
will be excluded as will patients with any evidence of systemic infection, including fever, 
27 
malaise, or leukocytosis.  As surgical -site infections occur with increased frequency 
28 
among nasal carriers of Staphylococcus aureus, we screen all potential DBS candidates 
29 
for staph nasal carriage and, if present, treat with mupirocin to eliminate the carrier state 
30 
prior to DBS implantation.  We also instruct all patients to use chlorhexidine wash prior 
31 
to the surgery.   
32 
 
33 
Our standard of care for all DBS surgeries includes 24 hours of peri-operative 
34 
prophylactic IV antibiotics after implantation of the DBS lead 5-7 days of prophylactic 
35 
oral antibiotics after the pacemaker battery implantation. 
36 
 
37 
Patients will additionally be carefully followed for evidence of implant/hardware 
38 
infection, not only in the post-operative period but throughout the subsequent year.  Any 
39 
evidence of possible hardware infection will be pursued for definitive diagnosis and 
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treatment for which infectious diseases consultation will be sought. 
1 
 
2 
The risk of infection will be further mitigated chiefly by careful and meticulous surgical 
3 
technique.  Should the patient present with signs or symptoms consistent with wound 
4 
breakdown or infection, contrast enhanced imaging will be obtained to ensure there is no 
5 
intracranial involvement.  The most conservative reports give a risk of infection around 
6 
1/20 over the lifetime of the device, with about 1/40 requiring lead explantation over the 
7 
life of the device.  Treatment will then consist of a combination of antibiotics, wound 
8 
cultures, surgical exploration and wound revision, and if the implanted system is deemed 
9 
to be unsalvageable, explantation.  Multiple reports have shown that up to 50% of 
10 
infections/wound breakdowns associated with deep brain stimulation can be successfully 
11 
treated without lead explantation. Should explantation become necessary after an 
12 
infection, it will almost always lead to a rapid resolution of both wound healing and 
13 
infection issues.  The risk of explantation will be mitigated by using meticulous surgical 
14 
technique and a very experienced implanting surgeon.  Also, the risk will be mitigated by 
15 
utilizing conservative strategies if appropriate to avoid DBS explantation.  
16 
 
17 
The risk of intracranial hemorrhage will be mitigated by meticulous surgical planning and 
18 
stereotactic techniques.  Hemorrhage will also be evaluated with post-operative CT scans 
19 
obtained on every patient to ensure that if a hemorrhage occurs, it is diagnosed early and 
20 
treated early as well.  Prevention of hardware damage is chiefly done with good surgical 
21 
technique in applying strain relief loops of the wire at the cranial and pectoral sites of the 
22 
implant as well as keeping wires away from pressure points, where skin wearing can 
23 
cause breakdown.   Other risks associated with the surgery are much rarer than 
24 
hemorrhage, infection/wound breakdown, and hardware damage.  These will be managed 
25 
according to the best evidence and experience of the implanting surgeon.  
26 
 
27 
The risk of explantation after a DBS surgery is about 1 in 40 over the lifetime of the 
28 
device when implanted for movement disorders.  Reasons for explantation are usually 
29 
wound breakdown/infection or damage to cranial DBS lead wire or other portion of the 
30 
system.  This risk can be minimized by using meticulous surgical technique and ensuring 
31 
adequate healthy scalp/skin coverage over the implanted device.  Should explantation 
32 
become necessary, it carries a similar risk profile to the implantation surgery, although 
33 
these risks, especially brain hemorrhage, are less likely to occur. 
34 
 
35 
Risks are minimized in all of the non-surgical procedures including phlebotomy as well 
36 
as the neuroimaging procedures by having trained and highly experienced personnel 
37 
performing all those tasks/procedures.  
38 
 
39 
After the surgery, the DBS system will be interrogated and monitored by individuals who 
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have expertise in programming of neurostimulators.  In the event that after titration is 
1 
complete, symptoms develop that affect the safety or quality of life of the patient, 
2 
stimulation parameters first will be adjusted.  If these symptoms persist, stimulation will 
3 
be discontinued. Symptoms that would necessitate divergence from the protocol would 
4 
include any condition or occurrence that would be deemed serious and significantly 
5 
divergent from typical clinical symptoms seen with OUD patients. Examples might 
6 
include any unexplained sudden or severe cognitive and functional loss or severe 
7 
behavioral disturbances out of the ordinary for this population that is profoundly affecting 
8 
quality of life of the participants.  
9 
 
10 
Participants may also terminate from the study if they wish at any time. Study 
11 
participants may also wish to discontinue stimulation for any reason. DBS systems will 
12 
also be removed if the participant/representative asks for removal. Subjects who 
13 
prematurely withdraw from the study due to an adverse event will be followed (e.g. 
14 
telephone contact, and/or follow-up visits, etc.) until resolution of the event. In addition, a 
15 
designated investigator/programmer will have access to treatment status at all times and 
16 
provide that information to appropriate medical personnel in the event of medical 
17 
emergencies. The DBS device may be explanted for participants who are discontinued 
18 
from the study for any reason. 
19 
 
20 
Risks to confidentiality are negligible in this protocol, since participants will not be 
21 
identified by name, or by any personal data, in any summary reports or publications. Case 
22 
Report Forms (CRFs) will be maintained in locked files and password-protected 
23 
databases. Subject identification codes will be used in place of names, with the key 
24 
linking data to names kept separate from the data. Data and safety monitoring activities 
25 
for this study will continue until all subjects have completed their participation in the 
26 
study.  
27 
 
28 
11.0 
DATA AND STATISTICAL CONSIDERATIONS 
29 
 
30 
The study seeks to assess the safety and feasibility of enrolling 4 participants with 
31 
treatment refractory opioid use disorder. The primary endpoint is safety, which will be 
32 
assessed through meticulous collection and grading of all adverse events as well as 
33 
attribution as to whether or not the adverse events are related to study procedures or to 
34 
DBS (See safety plan for details). Descriptive statistics will be used given the small 
35 
sample size (n=4). 
36 
 
37 
Secondary endpoints include the following and will be assessed using descriptive 
38 
statistics: 
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Opioid and other substance exposure as determined by quantitative urine toxicology via 
1 
high pressure liquid chromatography (HPLC) will be measured at screening/baseline and 
2 
4, 8, and 12 weeks of outpatient follow-up. Comparisons will be made between baseline 
3 
(pre- DBS implantation) and post-surgery follow-up, measured at 4, 8, and 12 weeks 
4 
following discharge. Qualitative urine toxicology obtained twice weekly through 12 
5 
weeks and once weekly from weeks 13-52; in conjunction with self-reported substance 
6 
use throughout the study. Comparisons will be made between baseline (pre- DBS 
7 
implantation) and post-surgery follow-up, measured at 12 weeks and 24 weeks following 
8 
discharge. Exploratory analyses will include the data collected through the 52-week study 
9 
completion. 
10 
Mood (depression and anxiety), via the Comprehensive Psychopathological Rating Scale 
11 
(CPRS), will be assessed three times weekly during the inpatient phases, two times 
12 
weekly through Week 12 follow up, then once monthly through Week 52. Comparisons 
13 
will be made between baseline (pre-DBS implantation), measured at 12 weeks and 24 
14 
weeks after titration. Exploratory analyses will include the data collected through the 52-
15 
week study completion. 
16 
Craving will be assessed up to twice-daily using a 100mm Visual Analog Scale (where 0 
17 
= no craving, and 100 = maximum craving) which will ask “How much do you crave 
18 
opioids right now?” Daily ratings will be averaged for one week prior and one week after 
19 
selected time points (baseline (pre-DBS implantation), measured at 12 weeks and 24 
20 
weeks after titration). Cue-induced craving will be assessed up to three times weekly 
21 
during screening/baseline, DBS surgery and titration periods; up to once weekly through 
22 
Week 24, then once a month through Week 52. Daily ratings will be averaged for one 
23 
week prior and one week after selected time points (baseline (pre-DBS implantation) and 
24 
compared to week 12 and week 24 after titration. Executive function will be assessed per 
25 
Appendix A and analyzed using descriptive statistics. Measures will be averaged for one 
26 
week prior and one week after selected time points (baseline (pre-DBS), 12 and 24 weeks 
27 
after titration.  Exploratory analyses will include the data collected through the 52-week 
28 
study completion as well as data collected during the long-term follow-up. 
29 
Change in FDG PET/CT from baseline (defined as pre-titration/programming) compared 
30 
with 12 and 52 weeks post-titration. 
31 
The metabolic images (normalized to whole-brain metabolism) will be analyzed using the 
32 
Statistical Parametric Mapping (SPM) (Friston et al., 1995) package SPM12 (Wellcome 
33 
Trust Centre for Neuroimaging) or other appropriate image processing tool as 
34 
appropriate. Specifically, the PET images will be spatially normalized to the stereotactic 
35 
space of the MNI using a 12-parameter affine transformation. The SPM2 FDG template 
36 
(PET.mnc) was used to normalize the metabolic images, which were then normalized to 
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their mean signal intensity. These normalized and transformed images will be used for 
1 
comparisons between baseline (pre-titration) and 12 weeks following titration to examine 
2 
increases in the prefrontal cortex metabolism.  
3 
 In addition, if performed, the following will be used: 
4 
• 
Change in 11C Raclopride PET/CT from baseline (defined as pre-
5 
titration/programming) compared with 12 and 52 weeks post-titration. 
6 
• 
Change in 11C Raclopride PET/CT using methylphenidate challenge to determine 
7 
binding potential of dopaminergic D2/D3 receptors from baseline (defined as pre-
8 
titration/programming) compared with 12 and 52 weeks post-titration. 
9 
• 
If collected, the 11C Raclopride images will be analyzed according to procedures 
10 
described by Volkow et al.(Volkow et al., 2013). We will estimate the distribution 
11 
volume (DV) for each voxel, and a custom MNI template, which was previously 
12 
developed using DVimages from 34 healthy subjects that were acquired with 11C 
13 
Raclopride and the same PET scanning sequence (Wang et al., 2012), will be used for 
14 
the spatial normalization of the DV images. Data will be analyzed via SPM 12, 
15 
confined to ROIs in the basal ganglia and NAc, to evaluate changes at baseline (pre-
16 
titration) and 12 and 52 weeks following titration. 
17 
In addition, if performed, comparisons in resting state and task based functional 
18 
connectivity (assessed via fMRI) from baseline (defined as pre-titration/programming) 
19 
compared with 12 and 52 weeks post-titration. 
20 
Evaluations of neuropsychological functioning will be assessed using descriptive 
21 
statistics between baseline (pre-DBS), 12 and 24 weeks following titration for the 
22 
neuropsychological battery which includes, but is not limited to:  1) Wide Range 
23 
Achievement Test-Fourth Edition, Reading Subtest, 2) Wechsler Abbreviated Scale of 
24 
Intelligence, 3) Wechsler Adult Intelligence Scale-Fourth Edition – Digit Span Subtest, 
25 
4) Trail Making Test, 5) Stroop Color Word Test, 6) Controlled Oral Word Association 
26 
Test and Animal Naming Test, 7) California Verbal Learning Test 8) Brief Visuospatial 
27 
Memory Test-Revised, 9) Dementia Rating Scale – 2nd Edition, and the Wisconsin Card 
28 
Sorting Test (WCST). Similar analyses will be conducted for the experimental measures 
29 
of executive functioning comparing baseline, 12 and 24 weeks following titration. 
30 
Exploratory analyses will include the data collected during the final assessment at the 52-
31 
week study completion as well as the experimental measures of executive functioning 
32 
data collected during the long-term follow-up. 
33 
 
34 
 
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12.0  REGULATIONS AND ETHICAL CONDUCT OF THE STUDY 
1 
 
2 
The trial will be carried out in accordance with International Conference on 
3 
Harmonisation Good Clinical Practice (ICH GCP) and the following:  
4 
 
5 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 
6 
CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR 21 CFR Part 812) 
7 
 
8 
This protocol will be reviewed and approved by the WVU IRB responsible for oversight 
9 
of the study. 
10 
 
11 
13.0  DEVICE DESCRIPTION 
12 
 
13 
The devices to be used in this study are the standard Medtronic devices which are FDA 
14 
approved for movement disorders such as Parkinson’s’ disease, essential tremor, 
15 
dystonia, OCD and recently epilepsy. 
16 
  
17 
The device consists of a lead, a neurostimulator, and an extension that connects the lead 
18 
to the neurostimulator.  Medtronic Model 3387S, DBS leads will be used for this study, 
19 
besides the DBS implanted pulse generator (IPG) or battery Activa RC neuostimulator 
20 
37612 or Activa PC Neurostimulator 37601, and Model 37086 Extension, and related 
21 
DBS therapy accessories.   
22 
 
23 
Model 3387S, DBS Lead. The DBS lead consists of a polyurethane protective sheath 
24 
with four platinum/iridium electrodes near the tip of each lead that deliver stimulation to 
25 
the target site.  The leads are stereotactically introduced into the target and fixed at the 
26 
skull with a burr hole cap and ring.  
27 
 
28 
Model 37612 Activa RC or 37601 Activa PC or Model B35200 Percept PC  
29 
Neurostimulators. The neurostimulator is implanted subcutaneously in the subclavicular 
30 
or upper abdominal region.  It is comprised of a battery and integrated circuits that are 
31 
hermetically sealed within an oval-shaped titanium enclosure. The neurostimulator 
32 
delivers electrical stimulation pulses with a variety of parameters, modes, and polarities.  
33 
The electrical pulses are carried from the neurostimulator to an implanted deep brain 
34 
stimulation lead by means of a lead extension. The Percept PC Neurostimulator also has 
35 
the ability to record and export local field potentials from the implanted brain electrodes. 
36 
 
37 
Model 37086 Extension. The extension is a set of wires within silicone tubing that 
38 
connects the lead to the neurostimulator, providing an electrical path that allows 
39 
stimulation to be delivered to the target site.  The extension is subcutaneously passed 
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from the scalp area, where it connects to the lead, through to the subclavicular area or 
1 
upper abdominal region, where it connects to the neurostimulator.   
2 
 
3 
Recharger Model 37651. The Activa RC is a rechargeable neurostimulator and is 
4 
charged externally for the internally implanted IPG in subclavicular or upper abdominal 
5 
region with the Medtronic charger for Activa DBS Therapy - Medtronic, Inc. Model 
6 
37651. It has 3 components; the AC power supply and its cord, the charger and an 
7 
antenna. The antenna establishes communication with the subcutaneously implanted 
8 
Activa RC IPG, which can be used over a belt or the strap. The Therapy screen of the 
9 
patient therapy controller (Model 37642 RC therapy controller), supplied with the patient 
10 
or caregiver, shows the neurostimulator battery status and charging requirements can be 
11 
tailored for the individual patients. While charging, the charging status is displayed on 
12 
the neurostimulator charging screen and when the neurostimulator battery is fully 
13 
charged, the Neurostimulator Charge Complete screen appears and the charger stops. 
14 
 
15 
Model CT900A. The clinical programmer Model No CT900A is an FDA approved 
16 
device, which is a tablet based programming device and works wirelessly. It has an 
17 
encrypted Bluetooth connection from the programmer to the communicator and has a 
18 
proprietary, proximal telemetry from the communicator to the implanted device. The 
19 
Medtronic Clinical Programmer Model CT900A contains the necessary software and 
20 
options to program neurostimulator. 
21 
 
22 
Model 8880T2. The Model 8880T2 communicator is a telemetry head and connects 
23 
wirelessly through an encrypted Bluetooth connection to the clinician programmer model 
24 
no. CT900A. The device is kept close to the IPG and once establishes the connection 
25 
with the clinical programmer, DBS setting is programmed as per the requirement. 
26 
 
27 
Model 37642 RC Therapy Controller or Model A620 Percept PC patient programmer. 
28 
The therapy controller is designed for use by a patient or caregiver.  Using the therapy 
29 
controller, the patient or caregiver can turn therapy on or off, check whether the therapy 
30 
is on or off, and check the condition of the neurostimulators battery. The Percept PC 
31 
patient programmer also has the ability to mark events based on patient perceptions. 
32 
  
33 
The Medtronic Deep Brain Stimulation components have been commercially approved as 
34 
components of the Medtronic Activa Tremor Control System (PMA P960009, and all 
35 
associated amendments) Medtronic Activa Parkinson’s Control Therapy (P960009) and 
36 
Medtronic HDE H050003 (S001)  
37 
 
38 
 
39 
14.0 
REFERENCES 
40 
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1. Alonso, P., Cuadras, D., Gabriels, L., Denys, D., Goodman, W., Greenberg, B. D., 
1 
Menchon, J. M. (2015). Deep Brain Stimulation for Obsessive-Compulsive Disorder: A 
2 
Meta-Analysis of Treatment Outcome and Predictors of Response. PLoS One, 10(7), 
3 
e0133591. doi:10.1371/journal.pone.0133591 
4 
2. American Psychiatric Association Diagnostic and statistical manual of mental disorders, 
5 
5th ed. (2013). Arlington, VA: American Psychiatric Publishing. 
6 
3. Asberg, M., Montgomery, S. A., Perris, C., Schalling, D., & Sedvall, G. (1978). A 
7 
comprehensive psychopathological rating scale. Acta Psychiatr Scand Suppl(271), 5-27.  
8 
4. Benazzouz, A., & Hallett, M. (2000). Mechanism of action of deep brain stimulation. 
9 
Neurology, 55(12 Suppl 6), S13-16.  
10 
5. Benedict, R. H. B., Schretlen, D., Groninger, L., Dobraski, M., & Shpritz, B. (1996). 
11 
Revision of the Brief Visuospatial Memory Test: Studies of normal performance, 
12 
reliability, and validity. Psychological Assessment, 8(2), 145-153. doi:10.1037/1040-
13 
3590.8.2.145 
14 
6. Benumof, J. L. (2016). Treatment of Opioid-Use Disorders. N Engl J Med, 375(16), 
15 
1596. doi:10.1056/NEJMc1610830 
16 
7. Beric, A., Kelly, P. J., Rezai, A., Sterio, D., Mogilner, A., Zonenshayn, M., & Kopell, B. 
17 
(2001). Complications of deep brain stimulation surgery. Stereotact Funct Neurosurg, 
18 
77(1-4), 73-78. doi:10.1159/000064600 
19 
8. Centers for Disease Control and Prevention, Understanding the Epidemic. (2017). 
20 
Retrieved from https://www.cdc.gov/drugoverdose/epidemic/index.html 
21 
9. Chen, L., Li, N., Ge, S., Lozano, A. M., Lee, D. J., Yang, C., Gao, G. (2018). Long-term 
22 
results after deep brain stimulation of nucleus accumbens and the anterior limb of the 
23 
internal capsule for preventing heroin relapse: An open-label pilot study. Brain Stimul. 
24 
doi:10.1016/j.brs.2018.09.006 
25 
10. Chiken, S., & Nambu, A. (2016). Mechanism of Deep Brain Stimulation: Inhibition, 
26 
Excitation, or Disruption? Neuroscientist, 22(3), 313-322. 
27 
doi:10.1177/1073858415581986 
28 
11. Curran, S. L., Andrykowski, M. A., & Studts, J. L. (1995). Short Form of the Profile of 
29 
Mood States (POMS-SF): Psychometric information. Psychological Assessment, 7(1), 
30 
80-83. doi:10.1037/1040-3590.7.1.80 
31 
12. Dahlem, N. W., Zimet, G. D., & Walker, R. R. (1991). The Multidimensional Scale of 
32 
Perceived Social Support: a confirmation study. J Clin Psychol, 47(6), 756-761.  
33 
13. de Haan, S., Rietveld, E., Stokhof, M., & Denys, D. (2015). Effects of Deep Brain 
34 
Stimulation on the Lived Experience of Obsessive-Compulsive Disorder Patients: In-
35 
Depth Interviews with 18 Patients. PLoS One, 10(8), e0135524. 
36 
doi:10.1371/journal.pone.0135524 
37 
14. De Martino, B., Fleming, S. M., Garrett, N., & Dolan, R. J. (2013). Confidence in value-
38 
based choice. Nat Neurosci, 16(1), 105-110. doi:10.1038/nn.3279 
39 
15. Degenhardt, L., Whiteford, H., & Hall, W. D. (2014). The Global Burden of Disease 
40 
projects: what have we learned about illicit drug use and dependence and their 
41 
contribution to the global burden of disease? Drug Alcohol Rev, 33(1), 4-12. 
42 
doi:10.1111/dar.12088 
43 
16. Delis D.C., K. J. H., Kaplan E., Ober B.A. (2000). California Verbal Learning Test – 
44 
second edition. Adult version. Manual. San Antonio, TX Psychological Corporation. 
45 
17. Denys, D., Mantione, M., Figee, M., van den Munckhof, P., Koerselman, F., Westenberg, 
46 
Approved:6-Feb-2024Expires:5-Feb-2025Number:1903499841

 
DBS_OUD_Version 10 25 Jan 2023 
 Page 62 of 73 
H.,  Schuurman, R. (2010). Deep brain stimulation of the nucleus accumbens for 
1 
treatment-refractory obsessive-compulsive disorder. Arch Gen Psychiatry, 67(10), 1061-
2 
1068. doi:10.1001/archgenpsychiatry.2010.122 
3 
18. Deuschl, G., Schade-Brittinger, C., Krack, P., Volkmann, J., Schafer, H., Botzel, 
4 
K.German Parkinson Study Group, N. S. (2006). A randomized trial of deep-brain 
5 
stimulation for Parkinson's disease. N Engl J Med, 355(9), 896-908. 
6 
doi:10.1056/NEJMoa060281 
7 
19. Dinges, D. F., Powell, J. W. J. B. R. M., Instruments,, & Computers. (1985). 
8 
Microcomputer analyses of performance on a portable, simple visual RT task during 
9 
sustained operations. 17(6), 652-655. doi:10.3758/bf03200977 
10 
20. Dougherty, D. D., Rezai, A. R., Carpenter, L. L., Howland, R. H., Bhati, M. T., 
11 
O'Reardon, J. P., Malone, D. A., Jr. (2015). A Randomized Sham-Controlled Trial of 
12 
Deep Brain Stimulation of the Ventral Capsule/Ventral Striatum for Chronic Treatment-
13 
Resistant Depression. Biol Psychiatry, 78(4), 240-248. 
14 
doi:10.1016/j.biopsych.2014.11.023 
15 
21. Eriksen, B., Eriksen, CW. (1974). Effects of noise letters upon the identification of a 
16 
target letter in a nonsearch task. Perception & Psychophysics, 16(1), 7. 
17 
doi:https://doi.org/10.3758/BF03203267 
18 
22. Figee, M., de Koning, P., Klaassen, S., Vulink, N., Mantione, M., van den Munckhof, P., 
19 
Denys, D. (2014). Deep brain stimulation induces striatal dopamine release in obsessive-
20 
compulsive disorder. Biol Psychiatry, 75(8), 647-652. 
21 
doi:10.1016/j.biopsych.2013.06.021 
22 
23. Figee, M., Luigjes, J., Smolders, R., Valencia-Alfonso, C. E., van Wingen, G., de 
23 
Kwaasteniet, B., . . . Denys, D. (2013). Deep brain stimulation restores frontostriatal 
24 
network activity in obsessive-compulsive disorder. Nat Neurosci, 16(4), 386-387. 
25 
doi:10.1038/nn.3344 
26 
24. First, M. B., Williams, J. B. W., Karg, R. S., & Spitzer, R. L. (2016a). Structured Clinical 
27 
Interview for DSM-5® Disorders—Clinician Version (SCID-5-CV). Arlington, VA: 
28 
American Psychiatric Association Publishing. 
29 
25. First, M. B., Williams, J. B. W., Karg, R. S., & Spitzer, R. L. (2016b). Structured Clinical 
30 
Interview for DSM-5® Personality Disorders (SCID-5-PD). Arlington, VA: American 
31 
Psychiatric Association Publishing. 
32 
26. Florence, C. S., Zhou, C., Luo, F., & Xu, L. (2016). The Economic Burden of 
33 
Prescription Opioid Overdose, Abuse, and Dependence in the United States, 2013. Med 
34 
Care, 54(10), 901-906. doi:10.1097/MLR.0000000000000625 
35 
27. Franken, I. H., Hendriksa, V. M., & van den Brink, W. (2002). Initial validation of two 
36 
opiate craving questionnaires the obsessive compulsive drug use scale and the desires for 
37 
drug questionnaire. Addict Behav, 27(5), 675-685.  
38 
28. Friston, K. J., Holmes, A. P., Poline, J. B., Grasby, P. J., Williams, S. C., Frackowiak, R. 
39 
S., & Turner, R. (1995). Analysis of fMRI time-series revisited. Neuroimage, 2(1), 45-53. 
40 
doi:10.1006/nimg.1995.1007 
41 
29. Goldstein, R. Z., Woicik, P. A., Moeller, S. J., Telang, F., Jayne, M., Wong, C.,  Volkow, 
42 
N. D. (2010). Liking and wanting of drug and non-drug rewards in active cocaine users: 
43 
the STRAP-R questionnaire. J Psychopharmacol, 24(2), 257-266. 
44 
doi:10.1177/0269881108096982 
45 
30. Greenberg, B. D., Gabriels, L. A., Malone, D. A., Jr., Rezai, A. R., Friehs, G. M., Okun, 
46 
Approved:6-Feb-2024Expires:5-Feb-2025Number:1903499841

 
DBS_OUD_Version 10 25 Jan 2023 
 Page 63 of 73 
M. S., . . . Nuttin, B. J. (2010). Deep brain stimulation of the ventral internal 
1 
capsule/ventral striatum for obsessive-compulsive disorder: worldwide experience. Mol 
2 
Psychiatry, 15(1), 64-79. doi:10.1038/mp.2008.55 
3 
31. Greenberg, B. D., Malone, D. A., Friehs, G. M., Rezai, A. R., Kubu, C. S., Malloy, P. F., 
4 
. . . Rasmussen, S. A. (2006). Three-year outcomes in deep brain stimulation for highly 
5 
resistant obsessive-compulsive disorder. Neuropsychopharmacology, 31(11), 2384-2393. 
6 
doi:10.1038/sj.npp.1301165 
7 
32. Grover, P. J., Pereira, E. A., Green, A. L., Brittain, J. S., Owen, S. L., Schweder, P., . . . 
8 
Aziz, T. Z. (2009). Deep brain stimulation for cluster headache. J Clin Neurosci, 16(7), 
9 
861-866. doi:10.1016/j.jocn.2008.10.012 
10 
33. Guercio, L. A., Schmidt, H. D., & Pierce, R. C. (2015). Deep brain stimulation of the 
11 
nucleus accumbens shell attenuates cue-induced reinstatement of both cocaine and 
12 
sucrose seeking in rats. Behav Brain Res, 281, 125-130. doi:10.1016/j.bbr.2014.12.025 
13 
34. Halpern, C. H., Tekriwal, A., Santollo, J., Keating, J. G., Wolf, J. A., Daniels, D., & Bale, 
14 
T. L. (2013). Amelioration of binge eating by nucleus accumbens shell deep brain 
15 
stimulation in mice involves D2 receptor modulation. J Neurosci, 33(17), 7122-7129. 
16 
doi:10.1523/JNEUROSCI.3237-12.2013 
17 
35. Halpern, C. H., Torres, N., Hurtig, H. I., Wolf, J. A., Stephen, J., Oh, M. Y.,  Baltuch, G. 
18 
H. (2011). Expanding applications of deep brain stimulation: a potential therapeutic role 
19 
in obesity and addiction management. Acta Neurochir (Wien), 153(12), 2293-2306. 
20 
doi:10.1007/s00701-011-1166-3 
21 
36. Hamani, C., Mayberg, H., Snyder, B., Giacobbe, P., Kennedy, S., & Lozano, A. M. 
22 
(2009). Deep brain stimulation of the subcallosal cingulate gyrus for depression: 
23 
anatomical location of active contacts in clinical responders and a suggested guideline for 
24 
targeting. J Neurosurg, 111(6), 1209-1215. doi:10.3171/2008.10.JNS08763 
25 
37. Hedegaard, H., Miniño, A. M., & Warner, M. (2018). Overdose Deaths in the United 
26 
States, 1999–2017. Retrieved from National Center for Health Statistics. NCHS Data 
27 
Brief No. 329, November 2018, Hyattsville, MD: 
28 
https://www.cdc.gov/nchs/data/databriefs/db329-h.pdf. 
29 
38. Hedegaard, H., Warner, M., & Miniño, A. M. (2017). Drug overdose deaths in the United 
30 
States, 1999–2016. Retrieved from National Center for Health Statistics. NCHS Data 
31 
Brief, no 294, Hyattsville, MD: https://www.cdc.gov/nchs/data/databriefs/db294.pdf 
32 
39. Ho, A. L., Sussman, E. S., Pendharkar, A. V., Azagury, D. E., Bohon, C., & Halpern, C. 
33 
H. (2015). Deep brain stimulation for obesity: rationale and approach to trial design. 
34 
Neurosurg Focus, 38(6), E8. doi:10.3171/2015.3.FOCUS1538 
35 
40. Houeto, J. L., Karachi, C., Mallet, L., Pillon, B., Yelnik, J., Mesnage, V., Agid, Y. 
36 
(2005). Tourette's syndrome and deep brain stimulation. J Neurol Neurosurg Psychiatry, 
37 
76(7), 992-995. doi:10.1136/jnnp.2004.043273 
38 
41. Jurica, P. J., Leitten, C. L., & Mattis, S.  (2001). Dementia Rating Scale-2. Professional 
39 
Manual. . Lutz, FL: Psychological Assessment Resources. 
40 
42. Kalivas, P. W., & Volkow, N. D. (2005). The neural basis of addiction: a pathology of 
41 
motivation and choice. Am J Psychiatry, 162(8), 1403-1413. 
42 
doi:10.1176/appi.ajp.162.8.1403 
43 
43. Kelley, A. E., & Stinus, L. (1985). Disappearance of hoarding behavior after 6-
44 
hydroxydopamine lesions of the mesolimbic dopamine neurons and its reinstatement with 
45 
L-dopa. Behav Neurosci, 99(3), 531-545.  
46 
Approved:6-Feb-2024Expires:5-Feb-2025Number:1903499841

 
DBS_OUD_Version 10 25 Jan 2023 
 Page 64 of 73 
44. Kirchner, W. K. (1958). Age differences in short-term retention of rapidly changing 
1 
information. J Exp Psychol, 55(4), 352-358.  
2 
45. Koob, G. F., & Volkow, N. D. (2010). Neurocircuitry of addiction. 
3 
Neuropsychopharmacology, 35(1), 217-238. doi:10.1038/npp.2009.110 
4 
46. Koob, G. F., & Volkow, N. D. (2016). Neurobiology of addiction: a neurocircuitry 
5 
analysis. Lancet Psychiatry, 3(8), 760-773. doi:10.1016/S2215-0366(16)00104-8 
6 
47. Kuhn, J., Moller, M., Treppmann, J. F., Bartsch, C., Lenartz, D., Gruendler, T. O., Sturm, 
7 
V. (2014). Deep brain stimulation of the nucleus accumbens and its usefulness in severe 
8 
opioid addiction. Mol Psychiatry, 19(2), 145-146. doi:10.1038/mp.2012.196 
9 
48. Laxton, A. W., Tang-Wai, D. F., McAndrews, M. P., Zumsteg, D., Wennberg, R., Keren, 
10 
R., Lozano, A. M. (2010). A phase I trial of deep brain stimulation of memory circuits in 
11 
Alzheimer's disease. Ann Neurol, 68(4), 521-534. doi:10.1002/ana.22089 
12 
49. Lezak, M. D. (1995). Neuropsychological assessment, 3rd ed. New York, NY, US: 
13 
Oxford University Press. 
14 
50. Lipsman, N., Lam, E., Volpini, M., Sutandar, K., Twose, R., Giacobbe, P., Lozano, A. M. 
15 
(2017). Deep brain stimulation of the subcallosal cingulate for treatment-refractory 
16 
anorexia nervosa: 1 year follow-up of an open-label trial. Lancet Psychiatry, 4(4), 285-
17 
294. doi:10.1016/S2215-0366(17)30076-7 
18 
51. Lipsman, N., Woodside, D. B., Giacobbe, P., Hamani, C., Carter, J. C., Norwood, S. J., 
19 
Lozano, A. M. (2013). Subcallosal cingulate deep brain stimulation for treatment-
20 
refractory anorexia nervosa: a phase 1 pilot trial. Lancet, 381(9875), 1361-1370. 
21 
doi:10.1016/S0140-6736(12)62188-6 
22 
52. Liu, H. Y., Jin, J., Tang, J. S., Sun, W. X., Jia, H., Yang, X. P., . . . Wang, C. G. (2008). 
23 
Chronic deep brain stimulation in the rat nucleus accumbens and its effect on morphine 
24 
reinforcement. Addict Biol, 13(1), 40-46. doi:10.1111/j.1369-1600.2007.00088.x 
25 
53. Lozano, A. M., Fosdick, L., Chakravarty, M. M., Leoutsakos, J. M., Munro, C., Oh, 
26 
E.,Smith, G. S. (2016). A Phase II Study of Fornix Deep Brain Stimulation in Mild 
27 
Alzheimer's Disease. J Alzheimers Dis, 54(2), 777-787. doi:10.3233/JAD-160017 
28 
54. Mahoney, J. J., 3rd, Kalechstein, A. D., Newton, T. F., & De La Garza, R., 2nd. (2017). 
29 
The limited impact that cocaine use patterns have on neurocognitive functioning in 
30 
individuals with cocaine use disorder. J Psychopharmacol, 31(8), 989-995. 
31 
doi:10.1177/0269881117715606 
32 
55. Malone, D. A., Jr., Dougherty, D. D., Rezai, A. R., Carpenter, L. L., Friehs, G. M., 
33 
Eskandar, E. N., . . . Greenberg, B. D. (2009). Deep brain stimulation of the ventral 
34 
capsule/ventral striatum for treatment-resistant depression. Biol Psychiatry, 65(4), 267-
35 
275. doi:10.1016/j.biopsych.2008.08.029 
36 
56. Mantione, M., van de Brink, W., Schuurman, P. R., & Denys, D. (2010). Smoking 
37 
cessation and weight loss after chronic deep brain stimulation of the nucleus accumbens: 
38 
therapeutic and research implications: case report. Neurosurgery, 66(1), E218; discussion 
39 
E218. doi:10.1227/01.NEU.0000360570.40339.64 
40 
57. Mayberg, H. S., Lozano, A. M., Voon, V., McNeely, H. E., Seminowicz, D., Hamani, C., 
41 
. . . Kennedy, S. H. (2005). Deep brain stimulation for treatment-resistant depression. 
42 
Neuron, 45(5), 651-660. doi:10.1016/j.neuron.2005.02.014 
43 
58. McCracken, C. B., & Grace, A. A. (2007). High-frequency deep brain stimulation of the 
44 
nucleus accumbens region suppresses neuronal activity and selectively modulates 
45 
afferent drive in rat orbitofrontal cortex in vivo. J Neurosci, 27(46), 12601-12610. 
46 
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DBS_OUD_Version 10 25 Jan 2023 
 Page 65 of 73 
doi:10.1523/JNEUROSCI.3750-07.2007 
1 
59. McCracken, C. B., & Grace, A. A. (2009). Nucleus accumbens deep brain stimulation 
2 
produces region-specific alterations in local field potential oscillations and evoked 
3 
responses in vivo. J Neurosci, 29(16), 5354-5363. doi:10.1523/JNEUROSCI.0131-
4 
09.2009 
5 
60. McIntyre, C. C., Savasta, M., Kerkerian-Le Goff, L., & Vitek, J. L. (2004). Uncovering 
6 
the mechanism(s) of action of deep brain stimulation: activation, inhibition, or both. Clin 
7 
Neurophysiol, 115(6), 1239-1248. doi:10.1016/j.clinph.2003.12.024 
8 
61. Montgomery, E. B., Jr., & Gale, J. T. (2008). Mechanisms of action of deep brain 
9 
stimulation (DBS). Neurosci Biobehav Rev, 32(3), 388-407. 
10 
doi:10.1016/j.neubiorev.2007.06.003 
11 
62. Muller, U. J., Sturm, V., Voges, J., Heinze, H. J., Galazky, I., Heldmann, M.,  Bogerts, B. 
12 
(2009). Successful treatment of chronic resistant alcoholism by deep brain stimulation of 
13 
nucleus accumbens: first experience with three cases. Pharmacopsychiatry, 42(6), 288-
14 
291. doi:10.1055/s-0029-1233489 
15 
63. National Center for Health Statistics 2017, Wide-ranging online data for epidemiologic 
16 
research (WONDER) Retrieved from http://wonder.cdc.gov. 
17 
64. National Institute on Drug Abuse. Overdose Death Rates. (2017). Retrieved from 
18 
https://www.drugabuse.gov/related‐topics/trends‐statistics/overdose‐death‐rates 
19 
65. Nuttin, B., Cosyns, P., Demeulemeester, H., Gybels, J., & Meyerson, B. (1999). 
20 
Electrical stimulation in anterior limbs of internal capsules in patients with obsessive-
21 
compulsive disorder. Lancet, 354(9189), 1526. doi:10.1016/S0140-6736(99)02376-4 
22 
66. Nuttin, B. J., Gabriels, L. A., Cosyns, P. R., Meyerson, B. A., Andreewitch, S., Sunaert, 
23 
S. G., . . Demeulemeester, H. G. (2003). Long-term electrical capsular stimulation in 
24 
patients with obsessive-compulsive disorder. Neurosurgery, 52(6), 1263-1272; discussion 
25 
1272-1264.  
26 
67. Patton, J. H., Stanford, M. S., & Barratt, E. S. (1995). Factor structure of the Barratt 
27 
impulsiveness scale. J Clin Psychol, 51(6), 768-774.  
28 
68. Powell, D. D. a. J. (1985). Microcomputer analyses of performance on a portable, simple 
29 
visual RT task during sustained operations. . Behavior Research Methods, Instruments, & 
30 
Computers, 17, 4.  
31 
69. Rauch, S. L., Dougherty, D. D., Malone, D., Rezai, A., Friehs, G., Fischman, A. J.,  
32 
Greenberg, B. D. (2006). A functional neuroimaging investigation of deep brain 
33 
stimulation in patients with obsessive-compulsive disorder. J Neurosurg, 104(4), 558-
34 
565. doi:10.3171/jns.2006.104.4.558 
35 
70. Reitan, R. M. (1958). Validity of the trail making test as an indicator of organic brain 
36 
damage. Perceptual and Motor Skills, 8, 271-276.  
37 
71. Rezai, A. R., Krishna, V., Bogner, J., Kramer, D., Needleman, B., Emerson, A. M., . 
38 
.Corrigan, J. D. (2018). Letter: Feasibility of Nucleus Accumbens Deep Brain 
39 
Stimulation for Morbid, Treatment-Refractory Obesity. Neurosurgery, 82(5), E136-E137. 
40 
doi:10.1093/neuros/nyx630 
41 
72. Rezai, A. R., Machado, A. G., Deogaonkar, M., Azmi, H., Kubu, C., & Boulis, N. M. 
42 
(2008). Surgery for movement disorders. Neurosurgery, 62 Suppl 2, 809-838; discussion 
43 
838-809. doi:10.1227/01.neu.0000316285.52865.53 
44 
73. Rezai, A. R., Sederberg, P. B., Bogner, J., Nielson, D. M., Zhang, J., Mysiw, W. J., 
45 
Corrigan, J. D. (2016). Improved Function After Deep Brain Stimulation for Chronic, 
46 
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DBS_OUD_Version 10 25 Jan 2023 
 Page 66 of 73 
Severe Traumatic Brain Injury. Neurosurgery, 79(2), 204-211. 
1 
doi:10.1227/NEU.0000000000001190 
2 
74. Rodriguez-Oroz, M. C., Obeso, J. A., Lang, A. E., Houeto, J. L., Pollak, P., Rehncrona, 
3 
S.,Van Blercom, N. (2005). Bilateral deep brain stimulation in Parkinson's disease: a 
4 
multicentre study with 4 years follow-up. Brain, 128(Pt 10), 2240-2249. 
5 
doi:10.1093/brain/awh571 
6 
75. Scharre, D. W., Weichart, E., Nielson, D., Zhang, J., Agrawal, P., Sederberg, P. B.,  
7 
Alzheimer's Disease Neuroimaging, I. (2018). Deep Brain Stimulation of Frontal Lobe 
8 
Networks to Treat Alzheimer's Disease. J Alzheimers Dis, 62(2), 621-633. 
9 
doi:10.3233/JAD-170082 
10 
76. Schuepbach, W. M., Rau, J., Knudsen, K., Volkmann, J., Krack, P., Timmermann, L., 
11 
Group, E. S. (2013). Neurostimulation for Parkinson's disease with early motor 
12 
complications. N Engl J Med, 368(7), 610-622. doi:10.1056/NEJMoa1205158 
13 
77. Serre, F., Fatseas, M., Debrabant, R., Alexandre, J. M., Auriacombe, M., & Swendsen, J. 
14 
(2012). Ecological momentary assessment in alcohol, tobacco, cannabis and opiate 
15 
dependence: a comparison of feasibility and validity. Drug Alcohol Depend, 126(1-2), 
16 
118-123. doi:10.1016/j.drugalcdep.2012.04.025 
17 
78. Shiffman, S., Stone, A. A., & Hufford, M. R. (2008). Ecological momentary assessment. 
18 
Annu Rev Clin Psychol, 4, 1-32.  
19 
79. Smit, J. V., Janssen, M. L., Engelhard, M., de Bie, R. M., Schuurman, P. R., Contarino, 
20 
M. F.,Stokroos, R. J. (2016). The impact of deep brain stimulation on tinnitus. Surg 
21 
Neurol Int, 7(Suppl 35), S848-S854. doi:10.4103/2152-7806.194156 
22 
80. Snaith, R. P., Hamilton, M., Morley, S., Humayan, A., Hargreaves, D., & Trigwell, P. 
23 
(1995). A scale for the assessment of hedonic tone the Snaith-Hamilton Pleasure Scale. 
24 
Br J Psychiatry, 167(1), 99-103.  
25 
81. Soyka, M. (2015). New developments in the management of opioid dependence: focus on 
26 
sublingual buprenorphine-naloxone. Subst Abuse Rehabil, 6, 1-14. 
27 
doi:10.2147/SAR.S45585 
28 
82. Stroop, J. R. (1935). Studies of interference in serial verbal reactions. Journal of 
29 
Experimental Psychology, 18(6), 643-662. doi:10.1037/h0054651 
30 
83. Substance Abuse and Mental Health Services Administration, 2018. (U.S. Department of 
31 
Health and Human Services, AATOD March 14, 2018). Retrieved from 
32 
https://www.samhsa.gov/sites/default/files/aatod_2018_final.pdf 
33 
84. Udupa, K., & Chen, R. (2015). The mechanisms of action of deep brain stimulation and 
34 
ideas for the future development. Prog Neurobiol, 133, 27-49. 
35 
doi:10.1016/j.pneurobio.2015.08.001 
36 
85. Vassoler, F. M., Schmidt, H. D., Gerard, M. E., Famous, K. R., Ciraulo, D. A., 
37 
Kornetsky, C.,Pierce, R. C. (2008). Deep brain stimulation of the nucleus accumbens 
38 
shell attenuates cocaine priming-induced reinstatement of drug seeking in rats. J 
39 
Neurosci, 28(35), 8735-8739. doi:10.1523/JNEUROSCI.5277-07.2008 
40 
86. Volkow, N. D., Tomasi, D., Wang, G. J., Telang, F., Fowler, J. S., Logan, J., Wong, C. T. 
41 
(2013). Predominance of D2 receptors in mediating dopamine's effects in brain 
42 
metabolism: effects of alcoholism. J Neurosci, 33(10), 4527-4535. 
43 
doi:10.1523/JNEUROSCI.5261-12.2013 
44 
87. Watson, D., Clark, L. A., & Tellegen, A. (1988). Development and validation of brief 
45 
measures of positive and negative affect: the PANAS scales. J Pers Soc Psychol, 54(6), 
46 
Approved:6-Feb-2024Expires:5-Feb-2025Number:1903499841

 
DBS_OUD_Version 10 25 Jan 2023 
 Page 67 of 73 
1063-1070.  
1 
88. Wechsler, D. (2008). Wechsler Adult Intelligence Scale-Fourth Edition (WAIS-IV): 
2 
Pearson Inc. 
3 
89. Wechsler, D. (2011). Wechsler Abbreviated Scale of Intelligence - Second Edition 
4 
(WASI-II): Pearson Inc. 
5 
90. Weiss, R. D., Potter, J. S., Fiellin, D. A., Byrne, M., Connery, H. S., Dickinson, W., . 
6 
Ling, W. (2011). Adjunctive counseling during brief and extended buprenorphine-
7 
naloxone treatment for prescription opioid dependence: a 2-phase randomized controlled 
8 
trial. Arch Gen Psychiatry, 68(12), 1238-1246. doi:10.1001/archgenpsychiatry.2011.121 
9 
91. West Virginia Department of Health and Human Resources Bureau for Public Health.  
10 
West Virginia Drug Overdose Deaths Historical Overview 2001‐2015. (2017). Retrieved 
11 
from http://dhhr.wv.gov/oeps/disease/ob/documents/opioid/wv‐drug‐overdoses‐
12 
2001_2015.pdf 
13 
92. Whiting, D. M., Tomycz, N. D., Bailes, J., de Jonge, L., Lecoultre, V., Wilent, B., Oh, M. 
14 
Y. (2013). Lateral hypothalamic area deep brain stimulation for refractory obesity: a pilot 
15 
study with preliminary data on safety, body weight, and energy metabolism. J Neurosurg, 
16 
119(1), 56-63. doi:10.3171/2013.2.JNS12903 
17 
93. Wilkinson, G. S., & Robertson, G. J. . (2006). Wide Range Achievement Test (Fourth 
18 
Edition ed.). Lutz, FL: Psychological Assessment Resources. 
19 
94. Young, R. C., Biggs, J. T., Ziegler, V. E., & Meyer, D. A. (1978). A rating scale for 
20 
mania: reliability, validity and sensitivity. Br J Psychiatry, 133, 429-435.  
21 
95. Zhang, C., Huang, Y., Zheng, F., Zeljic, K., Pan, J., & Sun, B. (2018). Death From 
22 
Opioid Overdose After Deep Brain Stimulation: A Case Report. Biol Psychiatry, 83(1), 
23 
e9-e10. doi:10.1016/j.biopsych.2017.07.018 
24 
96. Zheng, W., Nickasch, M., Lander, L., Wen, S., Xiao, M., Marshalek, P., Sullivan, C. 
25 
(2017). Treatment Outcome Comparison between Telepsychiatry and Face-to-face 
26 
Buprenorphine Medication-assisted Treatment for Opioid Use Disorder: A 2-Year 
27 
Retrospective Data Analysis. J Addict Med, 11(2), 138-144. 
28 
doi:10.1097/ADM.0000000000000287 
29 
97. Zhou, H., Xu, J., & Jiang, J. (2011). Deep brain stimulation of nucleus accumbens on 
30 
heroin-seeking behaviors: a case report. Biol Psychiatry, 69(11), e41-42. 
31 
doi:10.1016/j.biopsych.2011.02.012 
32 
98. Zimet, G. D., Dahlem, N. W., Zimet, S. G., & Farley, G. K. (1988). The 
33 
Multidimensional Scale of Perceived Social Support. Journal of Personality Assessment, 
34 
52(1), 30-41. doi:10.1207/s15327752jpa5201_2 
35 
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Appendix A 
1 
  
  
  
Phase 
Phase I 
Phase II 
Phase  III  
Phase IV 
  
  
  
Phase V 
  
  
  
  
  
Procedure 
Screening 
Baseline 
DBS 
Surgery 
DBS 
Titration 
Follow-Up 
12 Week 
Follow-up 
Visit 1 
Follow-Up 
24 Week 
Follow-up 
Visit 2 
Follow-Up 
52 Week 
Follow-up 
Visit 3 
  
  
  
Inpatient / 
Outpatient 
  
Inpatient 
Outpatient 
  
  
  
Duration 
Up to 5 weeks1  
Up to 3 weeks 
Up to 3 
weeks 
52 weeks 
  
  
  
Time Point 
(Week) 
  
 -7 and -6  
  
-5 – -3 
-2 – 0 
 1 – 11 
12 
13 – 23 
 24 
25 – 51 
52 
  
Inclusion 
Requirement 
  
Procedure / 
Assessment 
  
  
  
  
  
  
  
  
  
  
Medical 
History and  
Medical 
Assessments 
  
  
Yes 
1 
Medical 
History / 
Physical 
Examination 
x 
  
  
  
  
  
  
  
  
  
Yes 
2 
Neurological 
Examination 
x 
  
  
  
  
  
  
  
  
  
Yes 
3 
Psychiatric 
Examination 
x 
  
  
x 
  
  
  
  
  
  
Yes 
4 
NIH Stroke 
Scale 
x 
  
x (post-
operatively) 
x (post-each 
titration) 
x (1x monthly)  
Yes 
5 
Lab Tests 
x 
  
  
  
  
x 
  
  
  
  
Yes 
6 
X-Ray 
x 
  
  
  
  
  
  
  
  
  
Yes 
7 
MRSA Nasal 
Swab 
x 
  
  
  
  
  
  
  
  
  
Yes 
8 
Urine 
Toxicology 
(Qualitative) 
 x (2x weekly)  
 x (2x weekly)  
x (1x weekly) 
No 
8.1 
Urine 
Toxicology 
(Quantitative) 
x 
  
  
  
X 
(Weeks 
4 and 8)  
x 
  
  
  
  
Yes 
9 
Pregnancy 
(Qualitative) 
x (2x weekly)  
x (2x weekly) 
x (1x weekly) 
Medical 
History and 
Yes 
9.1 
Pregnancy 
(Serum) 
x 
  
  
  
  
x 
  
x 
  
  
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Phase 
Phase I 
Phase II 
Phase  III  
Phase IV 
  
  
  
Phase V 
  
  
  
  
  
Procedure 
Screening 
Baseline 
DBS 
Surgery 
DBS 
Titration 
Follow-Up 
12 Week 
Follow-up 
Visit 1 
Follow-Up 
24 Week 
Follow-up 
Visit 2 
Follow-Up 
52 Week 
Follow-up 
Visit 3 
  
  
  
Inpatient / 
Outpatient 
  
Inpatient 
Outpatient 
  
  
  
Duration 
Up to 5 weeks1  
Up to 3 weeks 
Up to 3 
weeks 
52 weeks 
  
  
  
Time Point 
(Week) 
  
 -7 and -6  
  
-5 – -3 
-2 – 0 
 1 – 11 
12 
13 – 23 
 24 
25 – 51 
52 
Medical 
Assessments 
Yes 
10 
Vital Signs 
 x (1x daily)  
x (2x weekly) 
x (1x weekly) 
Yes 
11 
ECG 
x 
  
  
  
  
  
  
  
  
  
Yes 
12 
Demographic 
& Drug / 
Alcohol Use 
Inventory 
x 
  
  
  
  
  
  
  
  
  
Yes 
13 
Adverse 
Events 
 x  
 x  
x 
x 
x 
x 
x 
x 
x 
x 
Yes 
14 
Concomitant 
Medications 
 x  
 x  
x 
x 
x 
x 
x 
x 
x 
x 
Yes 
15 
MR Checklist 
x 
  
  
  
  
  
  
  
  
  
 
Behavioral 
Assessments 
Yes 
16 
SCID-5 
x 
  
  
  
  
  
  
  
  
  
Yes 
17 
SCID-5-PD 
x 
  
  
  
  
  
  
  
  
  
Yes 
18 
MSPSS 
x 
  
  
  
  
  
  
  
  
  
No 
19 
BPRS 
  
x 
x (pre / post-
surgery) 
x (post-
titration prn) 
  
  
  
  
  
  
Yes 
20 
HAM-D6 
x 
x (3x weekly) 
x (2x weekly) 
x (1x weekly) 
Yes 
21 
C-SSRS6 
x 
 x (3x weekly)   
x (2x weekly) 
x (1x weekly) 
 
Cognitive 
Assessments 
 
Yes 
22 
DRS-2 
x 
  
  
  
  
x 
  
x 
  
x 
No 
23 
WRAT-IV 
  
x 
  
  
  
x 
  
x 
  
x 
No 
24 
WASI-II 
  
x 
  
  
  
x 
  
x 
  
x 
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Phase 
Phase I 
Phase II 
Phase  III  
Phase IV 
  
  
  
Phase V 
  
  
  
  
  
Procedure 
Screening 
Baseline 
DBS 
Surgery 
DBS 
Titration 
Follow-Up 
12 Week 
Follow-up 
Visit 1 
Follow-Up 
24 Week 
Follow-up 
Visit 2 
Follow-Up 
52 Week 
Follow-up 
Visit 3 
  
  
  
Inpatient / 
Outpatient 
  
Inpatient 
Outpatient 
  
  
  
Duration 
Up to 5 weeks1  
Up to 3 weeks 
Up to 3 
weeks 
52 weeks 
  
  
  
Time Point 
(Week) 
  
 -7 and -6  
  
-5 – -3 
-2 – 0 
 1 – 11 
12 
13 – 23 
 24 
25 – 51 
52 
No 
25 
WAIS-IV 
(DS) 
  
x 
  
  
  
x 
  
x 
  
x 
No 
26 
CVLT-II 
(Short) 
  
x 
  
  
  
x 
  
x 
  
x 
No 
27 
BVMT-R 
  
x 
  
  
  
x 
  
x 
  
x 
No 
28 
TMT A&B 
  
x 
  
  
  
x 
  
x 
  
x 
No 
29 
COWAT 
  
x 
  
  
  
x 
  
x 
  
x 
No 
30 
SCWT 
  
x 
  
  
  
x 
  
x 
  
x 
No 
31 
WCST 
  
x 
  
  
  
x 
  
x 
  
x 
No 
32 
Performance 
Validity Tests 
  
x 
  
  
  
x 
  
x 
  
x 
 
Affective / 
Emotional 
Assessments 
No 
33 
CPRS 
x 
 x (3x weekly)  
x (2x weekly) 
x (1x monthly) 
No 
34 
YMRS6 
x 
 x (3x weekly)  
x (2x weekly) 
x (1x monthly) 
No 
35 
POMS-SF 
x 
 x (3x weekly)  
x (2x weekly) 
x (1x monthly) 
No 
36 
PANAS-SF 
x 
 x (3x weekly)  
x (2x weekly) 
x (1x monthly) 
No 
37 
BIS 
x 
 x (3x weekly)  
x (2x weekly) 
x (1x monthly) 
No 
38 
SHAPS 
x 
 x (3x weekly)  
x (2x weekly) 
x (1x monthly) 
 
Opioid and 
Other 
Substance Use 
No 
39 
BSCS2 
 x (Up to 2x daily)  
No 
40 
Craving 
VAS2  
  x (Up to 2x daily) 
Approved:6-Feb-2024Expires:5-Feb-2025Number:1903499841

 
DBS_OUD_Version 10 25 Jan 2023 
 Page 71 of 73 
  
  
  
Phase 
Phase I 
Phase II 
Phase  III  
Phase IV 
  
  
  
Phase V 
  
  
  
  
  
Procedure 
Screening 
Baseline 
DBS 
Surgery 
DBS 
Titration 
Follow-Up 
12 Week 
Follow-up 
Visit 1 
Follow-Up 
24 Week 
Follow-up 
Visit 2 
Follow-Up 
52 Week 
Follow-up 
Visit 3 
  
  
  
Inpatient / 
Outpatient 
  
Inpatient 
Outpatient 
  
  
  
Duration 
Up to 5 weeks1  
Up to 3 weeks 
Up to 3 
weeks 
52 weeks 
  
  
  
Time Point 
(Week) 
  
 -7 and -6  
  
-5 – -3 
-2 – 0 
 1 – 11 
12 
13 – 23 
 24 
25 – 51 
52 
(Craving and 
Use)  
No 
41 
Cue 
Presentation / 
VAS2 
x (Up to 3x weekly) 
x (1x weekly) 
x (1x monthly) 
No 
42 
TLFB 
x 
 x (3x weekly) 
x (2x weekly) 
No 
43 
STRAP-R2 
x 
 x (3x weekly) 
x (2x weekly) 
x (1x monthly) 
 
Experimental 
Measures  
of Executive 
Function  
No 
45 
Eriksen 
Flanker2  
x (Up to 2x daily) 
No 
46 
N-Back2 
x (Up to 2x daily) 
No 
47 
Psychomotor 
Vigilance2 
 x (Up to 2x daily)  
No 
48 
Balloon 
Analogue 
Risk Task2 
  
x (Up to 2x weekly) 
  
x (1x weekly) 
x (1x monthly) 
No 
49 
Delay 
Discounting2 
 x (Up to 2x weekly)  
x (1x weekly) 
x (1x monthly) 
No 
50 
Dot-probe 
Task2 
x (Up to 2x weekly) 
x (1x weekly) 
x (1x monthly) 
 
No 
50.1 
Interoceptive 
processing 
x (Up to 2x during each inpatient study phase) 
Up to once monthly 
 
Continuous 
Physiological 
Monitoring 
  
  
No 
51 
Heart Rate3 
x (continuously) 
No 
52 
Heart Rate 
Variability3 
x (continuously) 
No 
53 
Sleep 
Duration3 
x (1x daily) 
Approved:6-Feb-2024Expires:5-Feb-2025Number:1903499841

 
DBS_OUD_Version 10 25 Jan 2023 
 Page 72 of 73 
  
  
  
Phase 
Phase I 
Phase II 
Phase  III  
Phase IV 
  
  
  
Phase V 
  
  
  
  
  
Procedure 
Screening 
Baseline 
DBS 
Surgery 
DBS 
Titration 
Follow-Up 
12 Week 
Follow-up 
Visit 1 
Follow-Up 
24 Week 
Follow-up 
Visit 2 
Follow-Up 
52 Week 
Follow-up 
Visit 3 
  
  
  
Inpatient / 
Outpatient 
  
Inpatient 
Outpatient 
  
  
  
Duration 
Up to 5 weeks1  
Up to 3 weeks 
Up to 3 
weeks 
52 weeks 
  
  
  
Time Point 
(Week) 
  
 -7 and -6  
  
-5 – -3 
-2 – 0 
 1 – 11 
12 
13 – 23 
 24 
25 – 51 
52 
No 
54 
Sleep 
onset/offset3 
x (1x daily) 
  
  
  
  
No 
55 
Body 
Temperature3 
 x (continuously) 
No 
56 
ECG3,4,5 
x (Up to 2x weekly) 
No 
57 
Eye 
Tracking3,4,5 
x (Up to 3x weekly) 
x (Approximately 1x weekly) 
x (Approximately 1x 
monthly) 
No 
58 
GSR3,4,5 
x (continuously) 
No 
58.1 
Respiration3 
Rate 
x (continuously) 
 
 
  
  
  
  
  
  
  
  
  
  
Neuroimaging
  
No 
59 
Structural and 
Functional 
MRI7 
x 
x  
 
 
x 
 
 
 
x 
No 
60 
CT Scan   
  
 
x (pre/post 
DBS surgery  
  
  
  
  
  
  
  
No 
61 
FDG PET/CT 
  
  
x (pre-
titration) 
  
  
x 
  
  
  
 x 
No 
62 
C11-
Raclopride 
PET/CT 
(Placebo) 
  
  
x (pre-
titration) 
  
  
x 
  
  
  
 x 
No 
63 
C11-
Raclopride 
PET/CT 
(Methylpheni
date) 
  
  
x (pre-
titration) 
  
  
x 
  
  
  
 x 
Approved:6-Feb-2024Expires:5-Feb-2025Number:1903499841

 
DBS_OUD_Version 10 25 Jan 2023 
 Page 73 of 73 
  
  
  
Phase 
Phase I 
Phase II 
Phase  III  
Phase IV 
  
  
  
Phase V 
  
  
  
  
  
Procedure 
Screening 
Baseline 
DBS 
Surgery 
DBS 
Titration 
Follow-Up 
12 Week 
Follow-up 
Visit 1 
Follow-Up 
24 Week 
Follow-up 
Visit 2 
Follow-Up 
52 Week 
Follow-up 
Visit 3 
  
  
  
Inpatient / 
Outpatient 
  
Inpatient 
Outpatient 
  
  
  
Duration 
Up to 5 weeks1  
Up to 3 weeks 
Up to 3 
weeks 
52 weeks 
  
  
  
Time Point 
(Week) 
  
 -7 and -6  
  
-5 – -3 
-2 – 0 
 1 – 11 
12 
13 – 23 
 24 
25 – 51 
52 
 
No 
64 
Local field 
potentials8 
 
 
 
x 
x 
x 
x 
x 
x 
x 
 
No 
65 
EEG9 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
1 Baseline and Screening procedures will occur over a two week inpatient phase.  Screening assessments may be initiated prior to their admission to the CRC as 
1 
inpatients. If performed prior to inpatient admission, screening assessments will be conducted within 3 weeks of the admission date.  
2 
2 Administered on Electronic Device (Smartphone/Tablet/Computer) 
3 
3 Assessed via Wearable Technology 
4 
4 Assessed during Cue Presentation 
5 
5  These are exploratory endpoints and may be collected as specified in the text. 
6 
6  Assessments are also completed post each titration 
7 
7  Structural MRI scan to be obtained may be completed at the end of the three-week surgical recovery period prior to the DBS titration and programming and a 
8 
the 12 and 52-week follow up visits. Structural MRI may also be performed at PI’s discretion if clinically indicated prior to or after DBS surgery. Functional 
9 
MRI (resting state and task-based using a cue reactivity paradigm) may be performed prior to DBS surgery, at the end of the three-week surgical recovery period, 
10 
and at the 12 and 52 week follow-up visits and in conjunction with LFP acquisition/cue reactivity at long term follow up visits. 
11 
8Local field potentials (LFPs) to be measured during specific tasks and as clinically indicated 
12 
9EEG may be measured during screening/baseline and post-surgical phases while the subject is at rest and/or during specific tasks (e.g. delayed discounting) 
13 
Approved:6-Feb-2024Expires:5-Feb-2025Number:1903499841