Combining Neuro-Imaging and Non-Invasive Brain Stimulation for Clinical Intervention in Opioid Use Disorder
Phase: NA
Conditions: Opioid-Related Disorders, Heroin Dependence, Morphine Dependence
Sponsor: University of Minnesota

PROTOCOL TITLE: Combining Neuro-Imaging and Non-Invasive Brain Stimulation for 
Clinical Intervention in Opioid Use Disorder 
VERSION DATE: 2022-02-11 
 
Page 1 of 32 
TEMPLATE Last Revised On: 3/26/2018 
 
Protocol Title 
Combining Neuro-Imaging and Non-Invasive Brain Stimulation 
for Clinical Intervention in Opioid Use Disorder 
Principal 
Investigator/Faculty 
Advisor 
Name: Kelvin O. Lim, MD 
Department: Department of Psychiatry 
Telephone Number: (612) 626-6772 
Email Address: kolim@umn.edu 
Co-Investigators 
Y. Jazmin Camchong, PhD 
Department of Psychiatry 
(612) 624-0134 
camch002@umn.edu 
 
Name:  Gavin Bart, MD PhD FACP DFASAM  
Director, Division of Addiction Medicine 
Hennepin Healthcare 
Associate Professor of Medicine 
University of Minnesota 
bartx005@umn.edu 
612-873-9095 
 
Student 
Investigator 
Name: 
Current Academic Status (Student, Fellow, Resident): 
  
Department: 
Telephone Number: 
Institutional Email Address: 
Scientific 
Assessment 
HRPP facilitated scientific assessment 
IND/IDE # (if 
applicable) 
N/A. 
IND/IDE Holder 
N/A. 
Investigational Drug 
Services # (if 
applicable) 
N/A. 
Version 
Number/Date: 
V6           February 11, 2022 
 
PROTOCOL COVER PAGE 
 
 

PROTOCOL TITLE: Combining Neuro-Imaging and Non-Invasive Brain Stimulation for 
Clinical Intervention in Opioid Use Disorder 
VERSION DATE: 2022-02-11 
 
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TEMPLATE Last Revised On: 3/26/2018 
REVISION HISTORY 
 
Revision 
# 
Version 
Date 
Summary of Changes 
Consent 
Change? 
6 
220211 
● Added recruitment of buprenorphine 
subjects. 
● Added mail ads as a source of 
recruitment 
● Proposed adding review of medical 
records as a source of recruitment. 
Yes 
5 
210830 
● 3.1: Corrected a typo. 
● 11: Added recruitment sites and methods 
● Expanded recruitment methods 
○ Expanded sites to methadone 
clinics in Twin Cities area 
○ Allowed for referral via clinical 
staff colleague 
○ Expanded recruitment to 
community advertisements 
○ Added recruitment tablet 
No 
4 
210615 
● 3.2, 5.2: Removed references to Rey 
subtests from cognitive battery as they are 
not needed for grant milestones. 
● 4.0 Study Intervention(s)/Investigational 
Agent(s): Removed description of unused 
Starstim device system, updated 
description of Taskflow device system. 
● Raised cap on recruitment in order to meet 
goal of 30 completed participants 
○ 5.1, 10.0: FROM  “up to 40” TO 
“up to 250” 
● Lengthened treatment window to allow 
protocol to be more compatible with 
participants’ busy schedules 
○ 5.2: Separate Days 2, 8, and 14 into 
2 visits each 
○ 5.2: Change sentences to lengthen 
window of initial 14 visits from 30 
days to two months 
○ 5.2: Change sentences to lengthen 
treatment window 2 weeks for each 
of the 5 tDCS sessions 
○ 5.3: Change anticipated study 
duration  
FROM 2.5 months  
TO 2.5-4 months. 
Yes 

PROTOCOL TITLE: Combining Neuro-Imaging and Non-Invasive Brain Stimulation for 
Clinical Intervention in Opioid Use Disorder 
VERSION DATE: 2022-02-11 
 
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TEMPLATE Last Revised On: 3/26/2018 
● Changed exclusion in order to more 
accurately represent the MAT population 
○ 8.2: FROM “any stimulant use in 
the past 30 days)” 
○ TO “stimulant use greater than 10 
days in the 30 days prior to 
enrollment” 
● Changed compensation distribution (but 
keep total amount the same): 
○ 11.4: Increased tDCS visit 
compensation for each of the 10 
tDCS visits 
FROM $10 TO $15 
○ 11.4: Decreased Follow-up 2 visit 
compensation  
FROM $100 TO $50 
3 
200217 
●  Replaced all references of “WAIS-WISC” 
with “WAIS” for simplicity 
● Abbreviations”: Replaced reference to 
MINI Version 6 with MINI Version 7. 
● 5.0: Specified that WAIS and D-KEFS will 
be administered on the digital platform Q-
Interactive. 
● 5.2: Replaced “reversal learning task” with 
“executive functioning tasks” 
● Added locations for study visits 
● Section 22: Clarified Multi-Site section 
● Secton 9.1: Checked “None of the above” 
● Added language to accommodate a flexible 
schedule of events 
● Removed Rey Visual Memory Test 
● Corrected minor errors and formatting 
errors 
No 
2 
190806 
● Added second tDCS device 
● Modified task delivery platform 
description  
● Changed length of time for tDCS delivery 
● Changed cognitive training software 
● Change total recruitment from “30” to “up 
to 40” 
● Added notice of video and audio recording 
to consent form 
● Added second tDCS device 
● Changed cognitive training software 
Yes 

PROTOCOL TITLE: Combining Neuro-Imaging and Non-Invasive Brain Stimulation for 
Clinical Intervention in Opioid Use Disorder 
VERSION DATE: 2022-02-11 
 
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TEMPLATE Last Revised On: 3/26/2018 
● Added language to address tDCS voltage 
adjustments for subjects in the event of 
discomfort 
● Added language detailing protection of 
vulnerable populations 
● Remove reference to probation or parole 
● Change total recruitment from “30” to “up 
to 40” 
1 
190301 
Change procedures in protocol, including: 
Addition of 5 sessions for a total of 10 tDCS 
sessions, addition of a midpoint assessment and 
MRI after 5 tDCS sessions to assess interim safety 
and progress; change in compensation proportional 
to the additional study visits; addition of the 
Timeline Follow Back instruments to study 
assessments; addition of drug screens 
(urine/saliva) as often as weekly to ensure data 
quality and continued sobriety during study 
participation. 
Yes 
 
 
 

PROTOCOL TITLE: Combining Neuro-Imaging and Non-Invasive Brain Stimulation for 
Clinical Intervention in Opioid Use Disorder 
VERSION DATE: 2022-02-11 
 
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TEMPLATE Last Revised On: 3/26/2018 
Table of Contents 
 
1.0 
Objectives ................................................................................................................ 7 
2.0 
Background .............................................................................................................. 7 
3.0 
Study Endpoints/Events/Outcomes .......................................................................... 8 
4.0 
Study Intervention(s)/Investigational Agent(s) ...................................................... 10 
5.0 
Procedures Involved ............................................................................................... 11 
6.0 
Data and Specimen Banking .................................................................................. 15 
7.0 
Sharing of Results with Participants ...................................................................... 16 
No results are shared with participants. ............................................................................ 16 
8.0 
Study Population .................................................................................................... 16 
9.0 
Vulnerable Populations .......................................................................................... 17 
10.0 Local Number of Participants ................................................................................ 19 
11.0 Local Recruitment Methods ................................................................................... 19 
12.0 Withdrawal of Participants .................................................................................... 22 
13.0 Risks to Participants ............................................................................................... 22 
14.0 Potential Benefits to Participants ........................................................................... 24 
15.0 Statistical Considerations ....................................................................................... 24 
16.0 Confidentiality ....................................................................................................... 25 
17.0 Provisions to Monitor the Data to Ensure the Safety of Participants .................... 25 
18.0 Provisions to Protect the Privacy Interests of Participants .................................... 25 
19.0 Compensation for Research-Related Injury ........................................................... 26 
20.0 Consent Process ..................................................................................................... 26 
21.0 Setting .................................................................................................................... 28 
22.0 Multi-Site Research: N/A ...................................................................................... 28 
23.0 Resources Available ............................................................................................... 28 
24.0 References .............................................................................................................. 30 
 

PROTOCOL TITLE: Combining Neuro-Imaging and Non-Invasive Brain Stimulation for 
Clinical Intervention in Opioid Use Disorder 
VERSION DATE: 2022-02-11 
 
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ABBREVIATIONS/DEFINITIONS 
 
● DLPFC - Dorsolateral Prefrontal Cortex 
● NAcc - Nucleus accumbens 
● FC - Functional connectivity 
● OUD - Opioid use disorder 
● fMRI - Functional magnetic resonance imaging 
● tDCS - Transcranial direct current stimulation 
● CMRR - Center for magnetic resonance research 
● HCP - Human Connectome Project 
● MOUD - Medications for opioid use disorder 
● MINI - Mini International Neuropsychiatric Interview, Version 6 
● TLFB - Timeline Follow Back 
 
 

PROTOCOL TITLE: Combining Neuro-Imaging and Non-Invasive Brain Stimulation for 
Clinical Intervention in Opioid Use Disorder 
VERSION DATE: 2022-02-11 
 
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TEMPLATE Last Revised On: 3/26/2018 
1.0 
Objectives 
1.1 
Purpose: The overarching goal of this project is to expand the traditional 
expertise in non-invasive neuromodulation at the University of Minnesota 
towards developing novel paired-neuromodulation approaches using tDCS for 
new addiction treatments that support long-term abstinence.  This study will allow 
us to investigate whether the pairing of DLPFC stimulation and cognitive training 
can enhance FC between DLPFC and NAcc.  We have identified higher FC 
between DLPFC and NAcc in alcoholics that have successfully maintained 
abstinence for extended periods of time (7 years). This paired-neuromodulation 
approach can potentially be used as a therapeutic intervention to decrease 
substance use probability in addiction (e.g. opioid use disorder). The long term 
goal is to develop new addiction treatments that support long-term abstinence in 
opioid use disorder.  The overall objective of this proposal is to enhance FC 
between DLPFC and NAcc as a therapeutic intervention to enhance cognition and 
reduce substance use rates in opioid use disorder. 
 
2.0 
Background 
2.1 
Significance of Research Question/Purpose: More effective interventions 
for opioid use disorder (OUD) are needed.  With more than 115 individuals in the 
US dying daily from opioid overdose (HHS 2018), the opioid epidemic is a public 
health emergency. Despite effective medications for opioid use disorder, 
treatment discontinuation and substance use approaches 50% at one year. The fact 
that OUD is so difficult to treat may be reflective of extensive neuroplastic 
changes that induce and maintain the pathological addiction state.  Existing 
treatment programs using medication and/or behavioral modification tools (e.g. 
12-step) may not be sufficiently powerful to overcome the mechanisms 
maintaining this pathological state. We propose a neuroplasticity based 
intervention approach utilizing transcranial direct current stimulation (tDCS) and 
cognitive training with tasks selected to functionally target cognition and brain 
circuits that are impaired in opioid use disorder with the goal of reducing 
substance use.  
 
2.2 
Preliminary Data: Combination of active tDCS and cognitive training 
increases frontal-striatal resting state functional connectivity (RSFC) and reduces 
time to relapse in alcohol use disorder. Our neuroimaging studies have identified 
a key frontal-striatal network associated with treatment outcome: low frontal-
striatal RSFC predicts relapse (Camchong, Stenger, and Fein 2013b; Camchong, 
Endres, and Fein 2014) and high frontal-striatal RSFC supports long-term 
abstinence (Camchong, Stenger, and Fein 2013a, [c] 2013). These neuroimaging 
findings highlight the key role of frontal-striatal RSFC in supporting long-term 
abstinence. In our pilot randomized controlled study of participants with alcohol 
use disorder (n=11; Camchong PI) designed to enhance frontal-striatal RSFC and 
cognition, 6 subjects who received active tDCS (2mA anode over left DLPFC, 
cathode over right DLPFC) were compared to 5 subjects who received sham 

PROTOCOL TITLE: Combining Neuro-Imaging and Non-Invasive Brain Stimulation for 
Clinical Intervention in Opioid Use Disorder 
VERSION DATE: 2022-02-11 
 
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tDCS. Intervention sessions were 46 minutes (13 min tDCS - 20 min off - 13 min 
tDCS), for five consecutive days (Trojak et al. 2016; Klauss et al. 2014). All 
participants underwent concurrent cognitive training (Reversal Learning task and 
BART) during the 46 minute session. Rest fMRI data was collected pre- and post-
intervention. We found: significant Group (active vs sham tDCS) x Time 
interaction in prefrontal-nucleus accumbens (NAcc) RSFC (F=7.105, p=0.026; 
eta-square η2=0.441), with prefrontal-NAcc RSFC increase in the active tDCS 
group but not the sham group (Figure 2). Findings suggest active tDCS during 
cognitive training can increase frontal-striatal RSFC in addiction. Eight-month 
follow-up showed that those receiving sham+cognitive training had a significantly 
shorter time to relapse (M=19 days, SD=5.66; 50% relapse rate) than those who 
received active tDCS + cognitive training (M=110 days, SD=27.05; 60% relapse 
rate) (p=0.021). While these are promising findings for alcohol use disorder, the 
safety, feasibility, and effect of this combined intervention (tDCS+cognitive 
training) has not been investigated in individuals with OUD.   
 
2.3 
Existing Literature: Opioid misuse is an epidemic in the United States. 
While medications for opioid use disorder (MOUD) are highly effective, 
approximately 40% of patients receiving them return to opioid use within the first 
year of treatment. Available treatments are not very effective with very high 
relapse rates. Chronic opioid use is associated with cognitive impairments that 
interfere with adaptive behavior needed for successful recovery (Terrett et al. 
2017; Mercuri et al. 2016; Verdejo-García and Pérez-García 2007; Baldacchino, 
Balfour, and Matthews 2015). These cognitive impairments and their underlying 
neural substrates are promising targets for intervention that can augment MOUD 
and reduce substance use rates. Evidence suggests that cognitive training can 
improve cognition in individuals with opioid addiction, strengthen neural 
networks mediating cognition (Ramsay, Nienow, and MacDonald 2017; Haut, 
Lim, and MacDonald 2010; Zhang et al. 2015), and improve treatment outcome 
(Rezapour et al. 2017). However, cognitive training is effort intensive, has small 
effect sizes and may have limited durability. The primary objective of this study is 
to test whether transcranial direct current stimulation (tDCS) can be used to boost 
the effectiveness of cognitive training in enhancing NAcc-frontal functional 
connectivity and cognition in opioid addiction to improve MOUD treatment 
outcome. Transcranial direct current stimulation (tDCS) is a non-invasive brain 
stimulation technique that can modulate brain connectivity. DLPFC stimulation 
may increase input to NAcc to facilitate proper selection of goal-directed behavior 
and may also decrease craving in individuals with substance use disorder (Boggio 
et al. 2008). 
 
3.0 
Study Endpoints/Events/Outcomes 
3.1 
Primary Endpoint/Event/Outcome: In a double-blind randomized design, 
up to      250 individuals with a current opioid use disorder (OUD) diagnosis, age 
18-60 years, enrolled in a methadone or buprenorphine treatment program and 

PROTOCOL TITLE: Combining Neuro-Imaging and Non-Invasive Brain Stimulation for 
Clinical Intervention in Opioid Use Disorder 
VERSION DATE: 2022-02-11 
 
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clinically stable will be recruited. We will recruit individuals who have been 
treatment with methadone or buprenorphine for at least 2 months. Patients will 
receive 10 sessions (2 5-day blocks of 46-minute daily tDCS intervention) of 
either (i) transcranial direct current stimulation (tDCS) to PFC or (ii) sham-tDCS. 
All subjects will perform cognitive training during tDCS intervention (active or 
sham) to prime the engagement of the NAcc-PFC brain circuit. Rest fMRI will be 
collected pre-intervention, after 5 sessions, and post-intervention. Follow-up 
interviews will be conducted 1- and 2-months after intervention completion to 
assess cognition, assess behavior, and query substance use. Dependent variables 
will be (i) change in NAcc-PFC FC across intervention imaging sessions, (ii) 
change in cognitive performance across intervention sessions, and (iii) substance 
use status 2 months after study participation. The Specific Aims are to determine 
if the intervention: (A1) is feasible and safe in individuals with OUD, (A2) 
induces circuit-based target engagement (an NIH funding requirement), (A3) 
induces cognitive performance changes, and (A4) is related to substance use 
status 2 months after study.   
 
To evaluate feasibility (A1), withdrawal and retention policies are described in Section 
12.0. To evaluate safety (A1), we will use the Treatment Side Effects 
Questionnaire to record intervention side effects. Based on our alcohol tDCS 
study and studies from other research groups, we hypothesize that the intervention 
will be feasible and safe.  
 
To evaluate circuit-based target engagement (A2) we will compare brain activation 
change (from pre-intervention to post-intervention) between active tDCS and 
sham groups. We hypothesize that the active tDCS group will have a larger 
increase in brain circuit engagement than the sham group.  
 
To evaluate cognitive performance changes (A3), we will compare cognitive 
performance change from pre-intervention to post-intervention) between active 
tDCS and sham groups. We hypothesize that the active tDCS group will have a 
larger improvement in cognitive performance than the sham group.  
 
To evaluate substance use status during participation and 1- and 2-months later (A4), we 
will administer the Timeline Follow Back(Sobell and Sobell 1996) questionnaire, 
assess the number of days of opioid use, and amount at peak use at follow-up (1- 
and 2-months later). We will also collect saliva/urine samples as often as every 
week. Based on our alcohol pilot study and literature on the effect of tDCS in 
other addictions (Lupi et al. 2017; Batista et al. 2015), we hypothesize that the 
active tDCS group will have lower followup substance use rates and longer 
abstinence periods than the sham group. 
 
3.2 
Secondary Endpoint(s)/Event(s)/Outcome(s): To determine generalization 
and durability of cognitive training, patients will be asked to complete the 
following tasks at pre-intervention, post-intervention, 1-month follow-up and 2-

PROTOCOL TITLE: Combining Neuro-Imaging and Non-Invasive Brain Stimulation for 
Clinical Intervention in Opioid Use Disorder 
VERSION DATE: 2022-02-11 
 
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TEMPLATE Last Revised On: 3/26/2018 
month follow-up to examine generalization and durability effects of training: D-
KEFS Trail Making Test, D-KEFS Verbal Fluency, D-KEFS Color Word, Digit-
Span (WAIS-WISC), Digit Symbol (WAIS-WISC). 
 
4.0 
Study Intervention(s)/Investigational Agent(s) 
Description: Transcranial Direct Current Stimulation (tDCS) - The tDCS will be 
performed with the TaskFlow Transcranial Electrical Stimulation device 
(TaskFlow-TES), IRB approved under different studies (STUDY00009059, 
STUDY00003506, STUDY00010333). The TaskFlow Transcranial Electrical 
Stimulation device (TaskFlow-TES) is a custom brain stimulation device 
developed in-house at the University of Minnesota. The performance of the 
Taskflow-TES device underwent laboratory bench testing to determine whether a 
programmed range of current levels (0.0 to 2.0 milliamps in 0.1 increments) was 
delivered by the device. The laboratory bench testing was conducted by a 
Biomedical Engineer, Dr. Mo Chen, Manager of the MnDRIVE Brain Conditions 
Noninvasive Neuromodulation Laboratory. For the tested range of 0.0 to 2.0 
milliamperes, the deviation in delivered current was no more than 1%.  
The FDA has deemed this device as a nonsignificant risk (NSR), however an NSR 
study is still subject to abbreviated investigational device exemption (IDE) 
requirements laid out in section 812.2(b) of the IED regulations (see FDA 
minimal risk letter). TaskFlow-TES is battery powered, communicates with the 
control computer via Bluetooth and monitors impedance and delivered current.  
To assess subject perceptions of the intervention, we will ask what treatment they 
believe they received each session. 
 
Stimulation will consist of three periods: RampUp (30 sec), Constant (20 min), 
RampDown (30 sec). During the Ramp periods, 2 mA current will be delivered to 
both AF3 and AF4 with an ascending (RampUp) and descending ramp 
(RampDown) over 30 sec via two saline soaked electrode sponges (~ 25cm²; 
current density = 0.08 mA/cm²). Active tDCS: A 2-mA current will be 
administered via two circular carbon rubber core electrodes in saline-soaked 
surface sponges (25 cm2), placed in a neoprene headband with marked locations 
based on the 10-20 EEG system. The anodal stimulating electrode will be at 
location AF3, over left dorsolateral prefrontal cortex (DLPFC) and cathodal 
electrode at location AF4, over right DLPFC. Sham tDCS: For sham stimulation, 
the electrodes will be placed at the same positions as for active stimulation (F3 
and F4), but current will be ramped down immediately after the initial 30 s ramp 
up period. Thus, participants will feel the initial itching sensation associated with 
tDCS but will receive no active current for the rest of the stimulation period. This 
method of sham stimulation has been shown to be reliable (Gandiga, Hummel, 
and Cohen 2006). To assess subject perceptions of the intervention, we will ask 
what treatment they believe they received each session. Executive Function 
Focused Cognitive Training Protocol. WM focused training occurs on a computer 
and consists of a variety of exercises selected to i) place demands on the executive 
and storage functions of working memory ii) adapt to challenge the participant’s 

PROTOCOL TITLE: Combining Neuro-Imaging and Non-Invasive Brain Stimulation for 
Clinical Intervention in Opioid Use Disorder 
VERSION DATE: 2022-02-11 
 
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TEMPLATE Last Revised On: 3/26/2018 
current ability level, iii) provide ongoing feedback, and iv) present novel stimuli 
across verbal, visual and spatial modalities. Training tasks are developed in-
house. Tasks for each subject are delivered from our AHC-IS server 
(cnc2.med.umn.edu).  Responses of subjects and session audio and video are 
saved on our AHC-IS server for analysis of training performance and 
engagement. The aim of using multiple tasks that require WM functions is to 
engage thalamocortical connectivity in a number of different ways to promote 
generalization. In this scheme, experimenters will monitor each participant's 
training and customize the intervention to balance challenge and engagement. In 
addition, each week participants will perform 4-minute versions of a word and a 
spatial 3-back task that will remain the same across all weeks (but differ from the 
assessment versions) to allow us to track training improvements using a constant 
difficulty level. 
 
Participant effort will be rated by experimenters at each session using the Work 
Behavior Inventory (Bryson, Bell, Lysaker, & Zito, 1997). Just before the end of 
each training session, subjects will complete a brief questionnaire that also asks 
about their perceived engagement in the training that day, as well as their mood, 
previous night’s sleep, discomfort, and their perceived experimental condition. 
Finally, at the end of each session, the participant will select the final task from an 
array of fun games, which we have found promotes agency and improves 
attendance. 
 
4.1 
Drug/Device Handling: We will use transcranial direct current stimulation 
(tDCS) to stimulate dorsolateral prefrontal cortex (DLPFC).  TDCS is a non-
invasive brain stimulation technique that can modulate brain connectivity. TDCS 
involves applying a weak electrical current (2mA or less) to the scalp via anodal 
and cathodal electrode sponges, causing either increases or decreases in cortical 
excitability, respectively. Research has shown in both healthy subjects and 
patients (e.g. Alzheimer’s disease, Parkinson’s disease, stroke, and depression) 
that tDCS has the potential to modulate synaptic strengthening and 
neurotransmitter-dependent plasticity underlying changes in behavior and 
learning (Lang et al. 2005). 
 
4.2 Biosafety: N/A 
 
4.3 Stem Cells: N/A 
 
5.0 
Procedures Involved 
5.1 
Study Design:  
This study is double-blind, within subject, within study staff, and sham-
controlled. The scientific integrity of the trial and the credibility of the data from 
the trial depend substantially on the trial design.  A description of the trial design 
includes: In a double-blind randomized design, up to 250 individuals with a 

PROTOCOL TITLE: Combining Neuro-Imaging and Non-Invasive Brain Stimulation for 
Clinical Intervention in Opioid Use Disorder 
VERSION DATE: 2022-02-11 
 
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TEMPLATE Last Revised On: 3/26/2018 
current opioid use disorder (OUD) diagnosis, age 18-60 years, enrolled in a 
methadone or buprenorphine treatment program and clinically stable will be 
recruited. Patients will receive 10 days (1 20-minute administration per day) of 
either (i) transcranial direct current stimulation (tDCS) to PFC or (ii) sham-tDCS. 
All subjects will perform cognitive training during tDCS intervention (active or 
sham) to prime the engagement of the NAcc-PFC brain circuit. Rest fMRI will be 
collected pre-intervention, at the midpoint of intervention, and post-intervention. 
The purpose for adding the midpoint MRI is to increase the statistical power of 
showing the trend of the experimental treatment’s effectiveness over time. 
Follow-up interviews will be conducted 1- and 2-months after intervention 
completion to query substance use.  
 To examine generalization and durability effects of training, patients will be 
asked to complete the following tasks at pre-intervention, post-intervention, 1-
month follow-up and 2-month follow-up: D-KEFS Trail Making Test, D-KEFS 
Verbal Fluency, D-KEFS Color Word, Digit-Span (WAIS-WISC), Intra-Extra 
Dimensional Set-Shift Task. Saliva/Urine tests checking for substance use will be 
administered at each follow-up timepoint. 
 
5.2 
Study Procedures:  
Randomization: Random permuted blocks (subgroups of 4) will be used to ensure 
equal group assignment (active or sham tDCS) at predefined equally spaced 
points in the sequence of patient assignment. Blinding: Participants will not be 
informed on their assigned protocol. During consent, they will be informed that 
there is a 50% chance of receiving active tDCS or sham tDCS every visit for five 
study visits. 
 
Participants who consent to the study and meet study criteria as per the screening 
evaluation will be asked to participate in up to 17 study visits over a period of up 
to two months. This time period includes 10 tDCS sessions over a period of up to 
5 weeks. 
Participants will also be asked to be available for in-person 1- and 2-month 
follow-up visits after intervention completion to query substance use and 
complete cognitive tasks. All sessions will be coordinated with participants’ visits 
to the clinic to minimize burden. 
 
VISIT ONE/Screening Visit:  After the participant has agreed to be in the study and 
signed the consent, the participant will be interviewed by a research staff member 
from the University of Minnesota and asked questions about the participant's 
health history and clinical symptoms. Females who could potentially be pregnant 
will be tested for pregnancy and, if positive, will not be allowed to participate.  If 
testing is refused, participation will not be allowed. If eligible, the participant will 
complete the Timeline Follow Back (TLFB) and other paper questionnaires 
reporting opioid use and craving levels.  Participants will complete baseline 
measures for: D-KEFS Trail Making Test, D-KEFS Verbal Fluency, D-KEFS 

PROTOCOL TITLE: Combining Neuro-Imaging and Non-Invasive Brain Stimulation for 
Clinical Intervention in Opioid Use Disorder 
VERSION DATE: 2022-02-11 
 
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TEMPLATE Last Revised On: 3/26/2018 
Color Word, Digit-Span (WAIS-WISC).  The participant will then be asked to 
complete a series of questionnaires that assess behavior, personality and substance 
use.  Day 1 assessments will take about 2 hours total. After consent and after the 
participant acknowledges full understanding of the intervention, the participant 
will be randomly assigned (with 50% chance) to receive either active tDCS or 
sham tDCS while the participant performs the reversal learning task (see 
description of intervention under day 3).  
 
VISIT 2-3/PRE-INTERVENTION: The participant will undergo a pre-intervention 
assessment, lasting about 2 hours. During the assessment, participants will 
complete a series of questionnaires that assess opioid use and craving levels, 
behavior, personality and substance use.  
 
The participant will also undergo a pre-intervention MRI, lasting about 2 hours. 
The MRI involves taking pictures of the participant's brain, from which the 
properties of certain brain tissues can be measured.  While sometimes MRI scans 
are done for clinical purposes, the scans the participant will receive are being 
done for research purposes.  Since these scans are not designed for clinical or 
medical reading, the participant's scans will not receive a clinical or medical 
interpretation. For the scan, the participant will be asked to lie down quietly on a 
bed, and the bed will slide into the scanner. Once the participant is inside the 
scanner, it will start to take the pictures. During the scan, the participant will 
simply lie quietly in the scanner with eyes closed while the scanner takes images 
of the participant's brain. The MRI scan will be performed at the University of 
Minnesota’s Center for Magnetic Resonance Research.  
 
The assessment visit may be performed before, same-day, or after the MRI visit 
for ease of accommodating the schedule of the scanner or participant. 
 
VISITS 4-8:  Will involve cognitive training tasks concurrently with tDCS, with tDCS 
for the first 20 minutes (46 minutes total per day). We will first explain to the 
participant what the training tasks entail and detail tDCS procedures.  TDCS side-
effects questionnaire will be administered daily before and after intervention. 
 
During tDCS intervention (active) the participant will be seated in a reclining chair while 
the participant perform the reversal learning task. Total participation time for 
visits 4-8 will be about 1 hour each day, or about 5 hours over a period of 2 
weeks. 
 
VISITS 9-10/MIDPOINT:  At the midpoint assessments and MRI, the participant will be 
administered the same cognitive assessments, and substance use questionnaires as 
Visit Two. Craving will be re-assessed and follow-up MRI scan with same 
procedures as Visit Three will be collected.  Total participation time for Visits 9-
10 will be about 4 hours. 
 

PROTOCOL TITLE: Combining Neuro-Imaging and Non-Invasive Brain Stimulation for 
Clinical Intervention in Opioid Use Disorder 
VERSION DATE: 2022-02-11 
 
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The assessment visit may be performed before, same-day, or after the MRI visit 
for ease of accommodating the schedule of the scanner or participant. 
 
 
VISITS 11-15:  Will involve cognitive training tasks concurrently with tDCS, with tDCS 
for the first 20 minutes (46 minutes total per day). We will first remind the 
participant what the tasks entail and detail tDCS procedures. TDCS side-effects 
questionnaire will be administered daily before and after intervention. 
 
During tDCS intervention (active or sham) the participant will be seated in a 
reclining chair while the participant perform the reversal learning task. Total 
participation time for days 3-7 will be about 1 hour each day, or about 5 hours 
over a period of 2 weeks. 
 
VISITS 16-17/POST-INTERVENTION:  At the post-intervention assessments and MRI, 
the participant will be administered the same clinical assessments, cognitive 
assessments, and substance use questionnaires as Visits 9-10. Craving will be re-
assessed and follow-up MRI scan with same procedures as baseline will be 
collected.  Total participation time for Visits 16-17 will be about 4 hours. 
 
The assessment visit may be performed before, same-day, or after the MRI visit 
for ease of accommodating the schedule of the scanner or participant. 
 
IN PERSON FOLLOW-UP:  The participant will be asked to return 1-  and 2-months 
after intervention to fill out the same clinical, cognitive and substance use 
questionnaires that were administered on Visits 2, 9, and 16.  Follow-up visits will 
be about 1.5 hours each. Subjects will undergo saliva/urine tests evaluating recent 
drug/alcohol use. 
At follow-up timepoints, we will contact subjects two weeks prior to the next 
follow-up to coordinate scheduling with sufficient time so that data is collected as 
close to the target as possible. 
Retention: To maximize participant retention we will have all consented 
participants fill out a “contact” document in which they will provide at least two 
telephone numbers to be reached and one home address. We will ask participants 
to provide the phone number of a good friend or relative who will know their 
whereabouts to help us re-contacting the participant if needed. Before follow-up 
appointments, we will call participants over the phone to confirm their attendance 
and we will send reminder cards through regular mail. If participants give their 
consent, we will also send a text to their contact phone number.  
 
5.3 
Study Duration:  
● The anticipated duration an individual participant’s participation in 
the study is 2.5-4 months since recruitment. 

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● The duration anticipated to enroll all study participants: 
Anticipated end date Summer 2022. 
● The duration anticipated to complete all study procedures and data 
analysis: Anticipated end date Fall 2023. 
 
5.4 
Individually Identifiable Health Information: We have submitted the 
University’s Privacy Office online application for data privacy and security 
review. We will print and upload the application with this protocol. 
 
5.5 Use of radiation: N/A 
 
5.6 
Use of Center for Magnetic Resonance Research: This study will be 
approved by the CMRR (PARS) Project Application Review System.  
 
6.0 
Data and Specimen Banking 
6.1 
Storage and Access: Only research staff will have access to subject 
information. Data contained on paper records and computer files will not include 
names or other identifying information of subjects. Records containing identifying 
information will be stored in a private research office in a locked file cabinet and 
be accessible only by the principal investigator and the study coordinator. The 
study coordinator or the principal investigator will review and remind research 
staff of this guideline on a regular basis. Paper and electronic records will be kept 
for 3 years or longer. Paper records not under use will be stored in locked file 
cabinets in a private research space. Any identifying information on magnetic or 
optical media will be stored in a similar manner or be password protected. The 
password for accessing this information will be available to only select staff that 
need access to the information to conduct their research duties. All other data will 
not contain identifying information. All other data will be stored on encrypted 
magnetic or optical media that is secured or on computer systems accessible only 
by research staff and computer system administrators via password. There is a 
slight possibility that data (without identifiers) will be requested by reviewers and 
other scientists when study data is presented to the scientific community 
 
6.2 
Data: All diagnostic and other sensitive data will be kept in a locked file 
and be available only to authorized investigators involved in this study.  
Identifiers will include name, birthdate, address, and telephone numbers.  The PI 
will keep the data file containing the link between subject number and identity.  
This will be kept in a password-protected computer file and also in printed form 
in a locked file cabinet. Research staff will have access to the identifiers only after 
a subject has agreed to participate in the study. They will use this information 
only for making contact to schedule visits, etc. 

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6.3 
Release/Sharing: The data collected may represent a unique resource for 
some investigators. Following HHS/CDC (Department of Health and Human 
Services/Centers for Disease Control and Prevention) policy, we will make the 
de-identified data available to interested investigators who contact us for access to 
the data. As the proposed work is a clinical trial, the most appropriate database for 
our collected data appears to be clinicaltrials.gov.  The investigator, co-
investigator, and research staff will permit trial-related monitoring, audits, 
IRB/IEC(s) review and regulatory inspection(s) by providing direct access to 
source data/documentation. 
 
7.0 
Sharing of Results with Participants 
No results are shared with participants. 
 
8.0 
Study Population 
8.1 
Inclusion Criteria: Participants will have a current diagnosis of OUD, be 
age 18-60 years, be enrolled in a methadone or buprenorphine treatment program 
in Hennepin Healthcare and be clinically stable. We will recruit individuals who 
have been in treatment with methadone or buprenorphine for at least 2 months. 
Inclusion criteria: (i) ability to provide written consent and comply with study 
procedures; (ii) meet the Diagnostic and Statistical Manual of Mental Disorders 
(DSM-V) diagnostic criteria for OUD. Subjects may have current comorbid drug 
use, but their primary substance use disorder diagnosis needs to be based on 
opioid use. Subjects must have the intention to remain in the methadone or 
buprenorphine treatment program until the end of the intervention portion of the 
study. Vulnerable populations will not be included. 
 
8.2 
Exclusion Criteria: Any medical condition or treatment with neurological 
sequelae (i.e. stroke, tumor, loss of consciousness>30 min, HIV); (ii) a head 
injury resulting in a skull fracture or a loss of consciousness exceeding 30 minutes 
(i.e., moderate or severe TBI); (iii) any contraindications for tDCS or MRI 
scanning (tDCS contraindication: actively receiving treatment for  seizures or 
epilepsy; MRI contraindications; metal implants, pacemakers or any other 
implanted electrical device, injury with metal, braces, dental implants, non-
removable body piercings, pregnancy, breathing or moving disorder); (iv) current 
active psychosis or mania; (v) presence of a condition that would render study 
measures difficult or impossible to administer or interpret (e.g. current mania, 
active psychosis); (vi) age outside the range of 18 to 60; (vii) primary current 
substance use disorder diagnosis on a substance other than opioid except for 
caffeine or nicotine; (viii) have current significant stimulant use  (stimulant use 
greater than 10 days in the 30 days prior to enrollment) (ix) history of ECT or 
cortical energy exposure within the past 12 months, including participation in any 
other neuromodulation studies, (x) prisoners. Nicotine use will be recorded.  

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The study staff person will thoroughly describe the study and read the consent 
form. Then the patient will be given time to read the consent form and ask 
questions of study staff. If the patient agrees they will sign the consent with the 
study staff person looking on. Part of the consent involves asking questions of the 
patient via the UBACC form and having him or her record their responses to 
ensure they understand the study and that they can terminate participation at any 
point. To protect vulnerable populations, if the patient does not seem to fully 
understand the nature of the study (including procedures, risks, confidentiality, 
voluntary nature), they will not be included in the study. They are also informed 
that study staff may terminate study participation at any point if they are 
concerned about the patient’s welfare or behavior.  
 
8.3 
Screening:  Individuals will be screened using an IRB approved screening 
questionnaire that asks about demographics, type of substance use, clinical and 
psychiatric history, and MRI compatibility.  If they do qualify for the study, they 
are asked if they are still interested in participating, and informed consent process 
starts. After informed consent, individuals will complete a screening 
questionnaire for contraindications of MRI scanning. Any affirmative responses 
on the questionnaire will result in an interview regarding the possible 
contraindication. CMRR staff will need to approve any affirmative response 
before a participant can undergo MRI scanning. Female subjects in child-bearing 
years will be informed that their consent to participate indicates that they are 
willing to complete a urine pregnancy test to demonstrate that they are not 
pregnant. 
 
9.0 
Vulnerable Populations 
9.1 Vulnerable Populations:  
☐ Children 
☐ Pregnant women/Fetuses/Neonates 
☐ Prisoners 
☐ Adults lacking capacity to consent and/or adults with diminished capacity 
to consent, including, but not limited to, those with acute medical 
conditions, psychiatric disorders, neurologic disorders, developmental 
disorders, and behavioral disorders 
☐ Approached for participation in research during a stressful situation such 
as an emergency room setting, childbirth (labor), etc. 
☐ Disadvantaged in the distribution of social goods and services such as 
income, housing, or healthcare 
☐ Serious health condition for which there are no satisfactory standard 
treatments 
☐ Fear of negative consequences for not participating in the research (e.g. 
institutionalization, deportation, disclosure of stigmatizing behavior) 

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☐ Any other circumstance/dynamic that could increase vulnerability to 
coercion or exploitation that might influence consent to research or 
decision to continue in research 
☐ Undervalued or disenfranchised social group 
☐ Members of the military 
☐ Non-English speakers 
☐ Those unable to read (illiterate) 
☐ Employees of the researcher 
☐ Students of the researcher 
☐ None of the above 
9.2 Additional Safeguards:  
● 
Study will recruit individuals (18-60 years old) who have been in treatment 
with methadone or buprenorphine for at least 2 months. Recruited 
individuals will meet DSM-V criteria for opioid use disorder (OUD; a 
psychiatric disorder). Potential participants will self-identify based on 
response to a flyer posted on IRB approved boards within the treatment 
program. 
● 
Opioid use disorder is considered a psychiatric disorder, capacity to consent 
will be evaluated thoroughly by research staff as detailed below. Potential 
participants may have a lifetime psychiatric diagnosis (e.g. Anxiety or 
depression, not psychosis) that is under stable treatment or medication.  
● 
Part of the consent involves asking questions of the subject and having him 
or her record their responses to ensure they understand the study and that 
they can terminate participation at any point. Participants are explained the 
study in detail before giving informed consent and evaluated on their 
capacity to consent with a form that contains the following items:  
-Participant was given time to review the consent form 
-The Consent document was explained, discussed, and reviewed 
-Study explanation and discussion was completed (check all that apply) 
-The participant’s comprehension was assessed to ensure that he/she understands 
the research and the risks and benefits involved in the study 
-Participant’s questions were answered satisfactorily and concerns were addressed 
-Upon completion of conversation, participant did not have any additional questions 
or concerns 
-The participant has agreed to participate in the study, and has signed and dated the 
most current, 
-IRB-approved consent form prior to the start of any study procedures. 
-Written consent was obtained with most recent IRB approved consent form 
-Participant was given a copy of the consent form 
-The original signed and dated consent form was placed in the research record or 
participant study binder 
● 
To protect vulnerable populations, if the patient does not seem to fully 
understand the nature of the study (including procedures, risks, 
confidentiality, voluntary nature), they will not be included in the study. 

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They are also informed that study staff may terminate study participation at 
any point if they are concerned about the patient’s welfare or behavior. 
● 
Importance of knowledge to be gained: There are increasing data supporting 
specific cognitive and brain functional connectivity abnormalities in opioid 
use disorder.  An understanding of whether these specific abnormalities can 
be modulated with cognitive training and non-invasive brain stimulation 
interventions will hold significant promise in designing new targeted 
interventions that can reduce vulnerability to relapse and improve treatment 
outcome.  
● 
Protection Against Risk. Trained research staff will be instructed to keep the 
content of the records confidential. During the initial consent process 
subjects will be told that they have the right to refuse to answer questions; 
however, this may affect whether they continue in the study. At all points in 
the study subjects will be warned at the beginning of procedures which 
involve the disclosure of personal and sensitive information. These warnings 
will occur in the introductory comments of interviews or in the instructions 
of questionnaires and surveys. 
● 
Importance of Knowledge Gained. The knowledge derived from this 
research will allow us to gather crucial evidence supporting the therapeutic 
use of interventions targeting both cognitive and underlying neural 
mechanisms that support abstinence. The knowledge gained from this study 
may eventually help guide further research in the area and future studies to 
improve addiction treatment programs. 
● 
Recruitment will conform to HIPAA requirements regarding protection of 
private health information. 
● 
To protect vulnerable populations, if the patient does not seem to fully 
understand the nature of the study (including procedures, risks, 
confidentiality, voluntary nature), they will not be included in the study. 
They are also informed that study staff may terminate study participation at 
any point if they are concerned about the patient’s welfare or behavior. 
● 
After detailed informed consent, participants’ capacity is further evaluated 
with the UCSD Brief Assessment of Capacity to Consent (UBACC).  
● 
No neonates, prisoners, individuals who have not attained legal age for 
consent. 
10.0 Local Number of Participants 
10.1 Local Number of Participants to be Consented: Up to 250 
 
11.0 Local Recruitment Methods 
11.1 
Recruitment Process:  
(1) Patients enrolled in a      methadone or buprenorphine treatment program in 
the Twin Cities Area      (such as Hennepin Healthcare and VA Medical 
Center) will learn about the study through an IRB-approved brochure or flyer 
posted on a board     . Participants will also learn about the study via word of 

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mouth at their treatment program. Participants will self-identify and call 
research staff to learn more. 
(2) Clinical staff colleagues will inform patients about the study via a recruitment 
card or brochure if he or she believes it would be beneficial to the patient.  
These participants will call research staff to learn more if interested. 
(3) Study staff will post advertisements online and paper flyers in community 
publications. Participants will self-identify and call research staff to learn 
more. 
(4) Patients enrolled in a methadone or buprenorphine treatment site who agree to 
do study recruitment (such as Hennepin Healthcare) will learn about the study via 
a displayed tablet paired with the words “Research Opportunity”. If a patient is 
interested in learning more about participation in the study, they are directed to 
complete the opt-in REDCap form on the tablet. Research staff will review the 
survey and call the participant back with an eligibility decision or more 
information. 
(5) Patients enrolled in a methadone or buprenorphine treatment site will be sent 
mail ads for the study. 
 
If a patient is interested in participating in the study, they are instructed to call 
research staff. During this first contact call, patients are given general information 
about the study and if patients want to learn more about the study and to find out 
if they qualify to be in it, a phone appointment or in-person appointment is set up 
to meet research staff at a specific date and time. At this appointment, research 
staff will give the patient detailed information about the study. If participants are 
still interested in participating in the study after learning all details of the study, 
research staff will ask them if they would like to answer confidential questions to 
determine if they qualify to be in the study. 
 
If participants do not qualify to be in the study, research staff will thank them for their 
time and tell them the general reasons why they do not qualify to be in the study. 
If participants do qualify to be in the study, research staff will let them know that 
they do qualify to be in the study and ask them if they are still interested to be in 
the study. If so, research staff will proceed with enrollment (e.g. consent, HIPAA, 
etc.). 
 
A trained and IRB-approved study staff person will carry out the consent process. The 
subject will be given time to read the consent form and to ask questions. If the 
subject agrees they will sign the consent form with the study staff person looking 
on. Part of the consent involves asking questions of the subject and having him or 
her record their responses to ensure they understand the study and that they can 
terminate participation at any point. They are also informed that study staff may 
terminate study participation at any point if they are concerned about the subject’s 
welfare or behavior. 
 

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11.2 
Identification of Potential Participants: Individuals with opioid use 
disorder (OUD) will be recruited      via the methods described in 11.1. We will 
monitor recruitment progress and expand outreach goals to other clinics if we are 
not meeting project targets.      Clinic staff will not be involved in the 
intervention.  
Participants will not be recruited based on information contained in 
private/protected records. 
● No private/protected records will be used. 
● Potential participants will self-identify and express their interest after 
learning about the study on IRB approved      materials in the treatment 
program, word of mouth, community referral, or referral via clinical staff 
colleague.      
● MEDICAL records will be used to send recruitment letters, in a manner as 
approved by the partner treatment site (e.g. MHealth Fairview)  
● HIPAA form states that the participant does agree to have research staff 
communicate with treatment program staff that they are participating in 
research. 
11.3 
Recruitment Materials: Participants will see a flyer posted (uploaded to 
Ethos) in poster boards within the treatment program. If interested, participants 
call phone number in flyer to set up an in-person informational/screening 
appointment.  
 
11.4 
Payment: Participant compensation will be provided according to the 
schedule below: 
 
● Screening/Visit 1: $10 for screening evaluation; $25 for 
completing baseline questionnaires 
● Visits 2-3: $25 for completion of pre-intervention assessments; $25 
for completion of MRI scan 
● Visits 4-8: $15 for tDCS interventions (up to $75) 
● Visit 9-10: $25 for completion of midpoint assessments; $25 for 
completion of MRI scan 
● Visits 11-15: $15 for tDCS interventions (up to $75) 
● Visits 16-17: $25 for completion of post-intervention assessments; 
$25 for completion of MRI scan 
● Follow-up visit 1: $50 
● Follow-up visit 2: $50 
 
The total amount a participant could receive if he/she completes all study visits 
and activities is $435. 
 

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12.0 Withdrawal of Participants 
12.1 
Withdrawal Circumstances: Participants will be able to discontinue study 
participation at any time. The participants may choose to discontinue stimulation 
at any time during the session if experiencing excessive discomfort or side effects. 
Criteria for discontinuation related to intervention: i) sores at the tDCS 
administration site; ii) headaches that impair global functioning.  If subjects 
choose to stop their participation, they will be released from the study. To protect 
vulnerable populations, if a patient that was deemed capable of providing consent 
goes through unforeseeable situations that may affect their capacity to consent, 
their capacity will be reassessed, and if not deemed capable, they will be 
withdrawn from the study. Participants are also informed that study staff may 
terminate study participation at any point if they are concerned about the patient’s 
welfare or behavior.  
 
12.2 
Withdrawal Procedures: Participants will be withdrawn from the study if 
they report any side effects of greater than moderate severity or that raise any 
safety concerns. Subjects may also be withdrawn from the study if they fail to 
follow study procedures (e.g., show up to scheduled study visits). Additionally, 
subjects will be told that participation is voluntary and that they may discontinue 
participation at any time for any reasons. 
 
If participants withdraw from procedures, all their data collected until the withdrawal 
data will be retained.  No new data will be collected from any private/protected 
record.  
 
Participants who withdraw from the study after having received tDCS will be asked if 
they can be contacted by telephone to ascertain substance use status. We will 
attempt to contact participants by telephone who do not show up to scheduled 
visit to ascertain if they wish to continue to participate in the study (and if not, 
why not) and to determine substance use status.   
 
12.3 
Termination Procedures: If at any point research staff is concerned about 
participant’s welfare or behavior, they will notify the participant that their 
participation in the study needs to terminate because of safety reasons.  The 
participant will be paid for their time as per 11.4 until their last active 
participation day. Data collected until the termination date will be used and 
considered incomplete.  
 
 
13.0 Risks to Participants 
13.1 
Foreseeable Risks:  
TDCS is considered to be a safe brain stimulation technique that rarely results in adverse 
events. There is currently no evidence of serious side-effects. Mild side-effects 

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that typically resolve upon discontinuing tDCS include light itching under the 
electrode at the beginning of administration, headache, fatigue, and nausea. The 
subject may choose to discontinue stimulation at any time during the session if 
experiencing excessive discomfort or side effects. Although seizures are not a 
known risk of tDCS intervention (Fregni et al. 2006), anyone with a history or a 
risk for seizures will be excluded from the study.  No other risks related to tDCS 
are anticipated. To minimize risks regarding tDCS, study staff will be using 
standards of administration that have been shown as safe in numerous other 
studies using transcranial direct current stimulation.  The length of administration 
of the current, size of electrode sponges used, and method of applying stimulation 
are the same as methods of administration that have been demonstrated as safe.  
 
The other potential risks pertain to the maintenance of confidentiality. Participants will be 
probed for personal information during the interviewing process. As noted in the 
consent form, participants will be told that all diagnostic and other sensitive raw 
data will be kept in a locked file and available only to authorized investigators 
involved in this study. To minimize confidentiality risks, as noted in the consent 
form, all diagnostic and other sensitive raw data will be kept in a locked file and 
be available only to authorized investigators involved in this study. 
 
MRI risks. Individuals will complete a screening questionnaire for contraindications of 
MRI scanning. Any affirmative responses on the questionnaire will result in an 
interview regarding the possible contraindication. An attempt will be made to 
secure any records of the nature of the possible contraindication and this 
information will be reviewed by the PI and CMRR staff at the University of 
Minnesota. A determination will be made regarding the level of risk to the subject 
and whether they are approved for scanning. If approved for scanning by 
professionals, all risks to the subject will be conveyed to him or her so they can 
deliberate as to whether or not they want to complete the procedure. Any concerns 
from the review committee will be conveyed to the participant at that time. If the 
subject has certain problematic iron or steel implants in their body that cannot be 
removed, the subject may not have the scan and will be excluded from the study. 
 
There are no known risks to humans due to the static magnetic field. Subjects, operators, 
and guests are carefully screened prior to entering the magnetic environment, and 
frequently reminded of the potential danger of introducing magnetic objects to the 
controlled area.  Subjects are carefully screened and excluded from the study if 
they have any implanted devices.  Subjects are always accompanied when near 
the magnet, and reminded to move slowly and carefully as they enter and leave 
the magnet. 
 
The risk of tissue damage by energy emitted by the MRI device is controlled by 
compliance with FDA guidelines for commercial MRI devices.  Safety devices 
are in place so that the magnet will cease to operate should any parameters begin 
to exceed their preset safety limits. The risk of peripheral nerve stimulation by 
dB/dt is limited by safety devices. The noise levels generated by each scan are 

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monitored to ensure adherence to guidelines. In addition, subjects are provided 
with earplugs and secondary protection (foam covering or headphones) to 
increase comfort during the scan. 
 
13.2 
Reproduction Risks: Since the MRI risks to fetuses are unknown, pregnant 
women are excluded from the study.  Female subjects in child-bearing years will 
be informed that their consent to participate indicates that they are willing to 
complete a urine pregnancy test to demonstrate that they are not pregnant. 
 
13.3 Risks to Others: N/A 
 
14.0 Potential Benefits to Participants 
14.1 
Potential Benefits: No benefit is guaranteed for the subject from being in 
this study, yet some individuals may feel rewarded by contributing to science. 
 
15.0 Statistical Considerations 
15.1 
Data Analysis Plan: Compare brain FC between groups: Sham vs Active 
tDCS. Compare FC within groups to examine time effects: before and after 
intervention. Look for interaction effects (group x time).  
 
15.2 
Power Analysis: The study in reference is a pilot study for which a power 
analysis is not applicable. 
 
15.3 Statistical Analysis: A mixed model analysis of variance will be conducted 
with between-group measures (sham vs active tDCS) and within-group 
measures (FC and craving reports before and after cognitive training and 
tDCS intervention).  This mixed model analysis will examine main- and 
interaction-effects. To examine the long-term effects of cognitive training 
and tDCS, we will conduct a repeated measures analysis using longitudinal 
data collected at 1- and 2-month follow-up timepoints after intervention 
completion.  A Log-rank (Mantel-Cox) Test (used in (Klauss et al. 2014) 
will be conducted to establish the efficacy of cognitive training and active 
tDCS vs. cognitive training and sham tDCS in the time domain. 
  
15.4 
Data Integrity: The principal investigator and co-investigator will monitor 
data quality for this study.  They will ensure that data are generated, documented 
(recorded), and reported - in compliance with this protocol, with Good Clinical 
Practice, and any other applicable regulatory requirements. 
 

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16.0 Confidentiality 
16.1 
Data Security: Trained research staff will be instructed to keep the content 
of the records confidential. During the initial consent process subjects will be told 
that they have the right to refuse to answer questions; however, this may affect 
whether they continue in the study. At all points in the study subjects will be 
warned at the beginning of procedures which involve the disclosure of personal 
and sensitive information. These warnings will occur in the introductory 
comments of interviews or in the instructions of questionnaires and surveys. 
 
Only research staff will have access to subject information. Data contained on paper 
records and computer files will not include names or other identifying information 
of subjects. Records containing identifying information will be stored in a private 
research office in a locked file cabinet and be accessible only by the principal 
investigator and the study coordinator. The study coordinator or the principal 
investigator will review and remind research staff of this guideline on a regular 
basis. Paper and electronic records will be kept for 3 years or longer. Paper 
records not under use will be stored in locked file cabinets in a private research 
space. Any identifying information on magnetic or optical media will be stored in 
a similar manner or be password protected. The password for accessing this 
information will be available to only select staff that need access to the 
information to conduct their research duties. All other data will not contain 
identifying information. All other data will be stored on encrypted magnetic or 
optical media that is secured or on computer systems accessible only by research 
staff and computer system administrators via password.  
 
No copy of the consent form or other research study information will be placed in the 
participants’ medical, employment, or educational records. 
 
17.0 Provisions to Monitor the Data to Ensure the Safety of 
Participants 
17.1 
Data Integrity Monitoring. The study will be monitored by CTSI in 
accordance with its institutionally approved monitoring plan. 
 
17.2 
Data Safety Monitoring: It is the responsibility of the Principal 
Investigator to oversee the safety of the study at his/her site.  This safety 
monitoring will include careful assessment and appropriate reporting of adverse 
events.  Medical monitoring will include a regular assessment of the number and 
type of serious adverse events. 
 
18.0 Provisions to Protect the Privacy Interests of Participants 

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18.1 
Protecting Privacy: The study consent form will describe in detail any 
intrusive, uncomfortable, or unfamiliar questions, procedures, or interactions with 
researchers or study personnel that the participant will be asked to complete. 
Furthermore, the study consent form will communicate that it is the participant’s 
right to opt-out of any study procedures or the study as a whole or withdraw from 
the study at any time and this information will be reiterated and revisited 
periodically throughout the study in advance of intrusive, uncomfortable, or 
unfamiliar questions procedures or interactions. Participants will not be compelled 
or pressured to provide information or specimens or study data that they do not 
wish to provide. 
Access to Participants: Participants will be fully informed of the ways in which 
their data will/may be used during the informed consent process. The 
research team has been trained in conducting these conversations and the 
participants are also assessed for their understanding of consent prior to 
signing the consent form or initiating any study procedures. 
19.0 Compensation for Research-Related Injury 
19.1 
Compensation for Research-Related Injury: There is no compensation in 
the event of research-related injury.  The consent form states: “In the event that 
this research activity results in an injury, treatment will be available, including 
first aid, emergency treatment and follow-up care as needed.  Care for such 
injuries will be billed in the ordinary manner, to you or the participant's insurance 
company.  If you think that you have suffered a research-related injury, please let 
us know right away.”  
 
19.2 Contract Language: N/A 
 
20.0 Consent Process 
20.1 
Consent Process (when consent will be obtained): Screening and 
consent will take place in a private room in Hennepin Healthcare. 
The study research staff will thoroughly describe the study and read the consent 
form. Then the patient will be given time to read the consent form and ask 
questions of study staff. If the patient agrees, they will sign the consent 
with the study staff person looking on. Part of the consent involves asking 
questions of the patient and having him or her record their responses to 
ensure they understand the study and that they can terminate participation 
at any point. To protect vulnerable populations, if the patient does not 
seem to fully understand the nature of the study (including procedures, 
risks, confidentiality, voluntary nature), they will not be included in the 
study. They are also informed that study staff may terminate study 
participation at any point if they are concerned about the patient’s welfare 
or behavior.  

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The study staff person will thoroughly describe the study and read the consent 
form. Then the patient will be given time to read the consent form and ask 
questions of study staff. If the patient agrees they will sign the consent with the 
study staff person looking on. Part of the consent involves asking questions of the 
patient and having him or her record their responses to ensure they understand the 
study and that they can terminate participation at any point. To protect vulnerable 
populations, if the patient does not seem to fully understand the nature of the 
study (including procedures, risks, confidentiality, voluntary nature), they will not 
be included in the study. They are also informed that study staff may terminate 
study participation at any point if they are concerned about the patient’s welfare 
or behavior. 
To protect vulnerable populations, if the patient does not seem to fully understand 
the nature of the study (including procedures, risks, confidentiality, voluntary 
nature), they will not be included in the study. They are also informed that study 
staff may terminate study participation at any point if they are concerned about 
the patient’s welfare or behavior.  
To ensure ongoing consent: After consent is provided and at each intervention 
day, participants are monitored for any concerns they have about the 
intervention with the Treatment Side Effect Questionnaire. Participants 
who agree to continue in the study will sign this questionnaire daily. 
 
20.2 Waiver or Alteration of Consent Process (when consent will not be 
obtained):  N/A 
 
20.3 Non-English Speaking Participants: N/A 
 
20.4 Participants Who Are Not Yet Adults (infants, children, teenagers under 18 
years of age): N/A 
 
20.5 
Cognitively Impaired Adults, or adults with fluctuating or diminished 
capacity to consent:  We will record informed consent process in the 
“Documentation of the Informed Consent Process” to ensure full understanding of 
study procedures and voluntary nature.  
 
20.6 Adults Unable to Consent: N/A 
● 
Permission:  
 
● 
Assent: 
 
● 
Dissent:  

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21.0 Setting 
21.1 
Research Sites:  
● Participants will be recruited from a methadone or buprenorphine 
treatment program in Hennepin Healthcare.  
o No Hennepin Healthcare staff will be involved in the 
intervention. 
● Screening, consent, interview, assessments and tDCS intervention 
will take place at Hennepin Healthcare.  
● Brain scans will be conducted at the Center for Magnetic 
Resonance Research (CMRR) at the University of Minnesota. 
o If participants can transport themselves to CMRR, we will 
meet them at CMRR. If participants need assistance with 
transportation, we will provide it, with Uber/Lyft/Taxi. 
 
21.2 International Research: N/A 
 
 
22.0 Multi-Site Research: N/A 
22.1 Study-Wide Number of Participants:  
 
22.2 Study-Wide Recruitment Methods:  
 
22.3 Study-Wide Recruitment Materials:  
 
22.4 Communication Among Sites: 
 
22.5 Communication to Sites:  
 
23.0 Resources Available 
23.1 
Resources Available: To collect complete follow-up data for participants 
with opioid use disorder.   
 
Facilities: 
Laboratory of Neuropsychiatric Imaging (LNPI; led by Dr. Lim). Drs. Lim and 
Camchong are part of the LNPI, a multidisciplinary research group that studies 
the biological underpinnings of neuropsychiatric disorders by combining imaging 
techniques with neurocognitive assessments and genetics. Dr. Lim and Dr. 

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Camchong’s offices and research team are located in Suite 516 within the 717 
Delaware Research Building (717 Delaware St. SE, Minneapolis, MN). The 
facility is a fully equipped and secure research laboratory supported by the UMN 
Medical with private offices and conference rooms, full computer and 
telecommunication systems and support, secure entrance and file storage, private 
research testing rooms, a reception desk and waiting area for research subjects, 
and physical space to house multiple research staff and support graduate student 
research efforts. All of these resources are currently and will continue to be 
available to the investigators. 
 
Center for Magnetic Resonance Research (CMRR). The CMRR is located on the UMN 
campus. This imaging center was established in 1991 as a result of the rapidly 
growing and successful in vivo magnetic resonance imaging (MRI). CMRR is an 
interdepartmental and interdisciplinary research laboratory that provides state-of-
the-art instrumentation, expertise, and infrastructure to carry out biomedical 
research utilizing the unique capabilities provided by high field MRI and MRS 
methodology. The central aim of the research conducted in CMRR is to non-
invasively obtain functional, physiological, and biochemical information in intact 
biological systems, and use this capability to probe biological processes in health 
and disease. The CMRR is currently equipped with nine high field magnets for 
humans with magnetic field strength of 3 Tesla and greater, with the most notable 
being a 10.5 Tesla/89cm. MRI data (resting, task-evoked and high-resolution 
structural scans) will be collected using a 32-channel head coil on a Siemens 
Prisma FIT 3T scanner (Siemens Medical Solutions, Erlangen, Germany). The 
Prisma was inspired by the success of the Connectome 3T systems, in particular 
the one-of-a-kind modified Siemens Skyra system that was built specifically for 
the WU-Minn Human Connectome Project (HCP) consortium (Connectome 
Skyra). The HCP is from the 16 NIH Institutes and Centers that support the NIH 
Blueprint for Neuroscience Research. The consortium led by Washington 
University, University of Minnesota, and Oxford University (the WU-Minn HCP 
consortium) is comprehensively mapping human brain circuitry in a target 
number of 1200 healthy adults using cutting-edge methods of non-invasive 
neuroimaging. The unique features of the Prisma system are based on an 
integrated system that combines a high strength gradient system with capability of 
80 mT/m @ 200 T/m/s (FDA approved mode, but capable of 100 mT/m in 
research mode)), an advanced RF receiver system that provide better signal-to-
noise performance, 64 channel receive capability. Accelerated data collection 
provides improved signal in resting state networks (Griffanti et al. 2014). HCP 
has developed and supports multiband acquisition sequences for the Prisma, 
which accelerate data acquisition by a factor of up to 12. These fMRI sequences 
use MB factor of 8, allowing us to collect 32 slices in 1/8 TR, which is 8 
simultaneous slices in one TR. 
 
Kelvin O. Lim, MD will be available in case of unanticipated issues. 
 

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All research staff will undergo protocol training. Only trained research staff will obtain 
consent. 
 
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