Non-Invasive Brain Stimulation and Substance Use
Phase: NA
Conditions: Substance Use Disorders
Sponsor: University of North Carolina, Chapel Hill

 
Non-Invasive Brain Stimulation and Substance Use 
 
 
NCT03122587 
 
December 16, 2016 
 
 

1 Non-Invasive Brain Stimulation and Substance Use 
 
PROTOCOL SUMMARY  
 
 
 
 
 
 
 
1 
Title Non-Invasive Brain Stimulation and Substance Use 
Purpose This pilot study will investigate the feasibility and effect of non-invasive transcranial 
alternating current stimulation (tACS) on distress tolerance and inhibitory control in individuals 
with substance use disorder. 
Method Following screening, eligible participants will engage in two sessions. The primary 
outcomes, inhibitory control and distress tolerance, will be administered at each assessment 
session. During the first session, participants will complete both tasks while receiving the active 
sham tACS. During the second session, participants will complete both tasks and receive one of 
three tACS conditions based on a randomization procedure: (1) 10 Hz, (2) 40 Hz, or (3) active 
sham. Participants will also provide sociodemographic and mood information via self-report 
forms and interviews with research staff. Participants will be compensated at the end of the 
second session and debriefed at the end of all study data collection. 
Population Participants will be patients with current substance use disorder, aged 18-55, and 
currently receiving outpatient substance use treatment. Participants will be recruited at the 
Garner location of the SouthLight Treatment Center located in Raleigh, NC. 
Number of Sites This is a single site study Garner location of the SouthLight Treatment Center 
located in Raleigh, NC. 
Study Duration We estimate 1 year to complete study enrollment and data collection.   
Participation Duration Eligible participants will have a total of 4 contacts: (1) screening and the 
first session (approximately 1.5 hours), (2) a reminder call between the first and second session 
(approximately 5 minutes), (3) the second session (approximately 1.5 hours), and the debriefing 
at the completion of all data collection (approximately 15 minutes).  We estimate that total 
participation to be approximately 3 hours and 20 minutes. 
Description Transcranial alternating current stimulation (tACS) may be a particularly promising 
approach as it is a safe and non-invasive method of electric stimulation that has the potential to 
effectively modulate neural network and circuit dynamics, closely aligning with a network-based 
conceptualization of affective and cognitive processes, such as distress tolerance and inhibitory 
control. Furthermore, tACS allows for targeted stimulation with the potential to modulate specific 
frequencies of endogenous cortical oscillations at the administered frequency of stimulation 
(Hermann et al., 2013). More specifically, this more targeted approach allows for direct 
enhancement of selective cognitive functions. We will be using an active sham, 10 Hz tACS, 
and 40 Hz tACS. Utilizing an active sham stimulation condition will allow for higher confidence 
that changes in task performance, associated arousal, and affective symptoms are due to 
experimental manipulation rather than the placebo effect.   
Schematic of Study Design 
Table 1. Participants will be randomized into one of three of the following groups: 

2 Non-Invasive Brain Stimulation and Substance Use 
 
Group 1 
Active Sham 
Group 2 
10 Hz tACS 
Group 3 
40 Hz tACS 
Research Staff 
 
 
 
 
 
 
 
 
 
 
 
Principal Investigator 
Stacey Daughters, Ph.D. 
UNC - Chapel Hill, Department of Psychology & 
Neuroscience 
Email: daughter@unc.edu 
Office: 247 Davie Hall 
Phone: (919) 962-9924 
Co – Investigators 
Regina Carelli, Ph.D.  
UNC - Chapel Hill Department of Psychology & 
Neuroscience 
Email: rcarelli@unc.edu 
Office: 115 Davie Hall 
Phone: (919) 962-8775 
 
Flavio Frolich, Ph.D. 
UNC – Chapel Hill, UNC School of Medicine, Department 
of Psychiatry 
Email: flavio_frohlich@med.unc.edu 
Office: 4109F Neuroscience Research Building 
Phone: (919) 966-4584 
Project Manager &  
Study Coordinator 
Jennifer Yi 
Post-Doctoral Fellows Ryan Bell, Ph.D. 
Deepika Anand, Ph.D. 
Travis Moschak, Ph.D. 
Research Assistants 
Rachel Haake 
Elizabeth Reese 
Yun Chen 
Kimberley Johnson 
Sydney Baker 
Rachel Phillips 
John Thorp 
Katie McKay 
Savita Madan 
 
 
 

3 Non-Invasive Brain Stimulation and Substance Use 
 
STUDY DESIGN 
 
 
 
 
  
 
 
 
 
  2 
 
The design of this pilot study is a randomized, sham-controlled, single-site study, which will be 
used to ideally demonstrate the feasibility administering tACS and to investigate the effects of 
tACS on distress tolerance and inhibitory control (Primary Outcomes) among treatment-seeking 
individuals with substance use disorder. Participants will be assigned to a block based on their 
age: (1) 18-25 years old, (2) 25-35 years old, (3) 35-45 years old, and (4) 45-55 years old. 
Within each block, participants will be randomized to one of three groups: (1) tACS at 10 Hz, (2) 
tACS at 40 Hz, or (3) active sham stimulation. This randomization will be done by an individual 
that is not part of the research staff. We hypothesize that individuals who receive 10 Hz tACS 
will demonstrate a significantly greater increase in distress tolerance compared to individuals 
who receive the active sham condition and the 40 Hz tACS condition. 
Research staff will recruit individuals at the Garner location of the SouthLight Treatment Center 
in Raleigh, NC by making weekly announcements at the end of the substance abuse intensive 
outpatient program (SAIOP) groups. Eligible participants will be screened using the Word 
Reading Subtest of the Wide Range Achievement Test (WRAT), Fagerstrom Test for Nicotine 
Dependence, and the Alcohol Use Disorder, Substance Use Disorder, and Psychotic Disorder 
Modules of the Mini International Neuropsychiatric Interview (MINI) 7.0, which will both be 
administered in an interview format. Eligibility based on the study's inclusion and exclusion will 
be recorded on the Screening Form. Potential participants who do not meet criteria for the study 
will be informed of this decision and thanked for their time. Eligible patients who are willing to 
participate, provide informed consent, and sign the HIPAA Authorization Form and the UNC 
Release of Information Form will continue to the procedure of the first session.  
Participants will receive compensation upon the completion of their second session. If the 
individual withdraws from the study before completing the second session, they will not be 
compensated. This information will be clearly delineated verbally during the informed consent 
procedure and in written form in the consent form. Participants will be compensated with $30 in 
cash upon completion of their second session.  
 
 

4 Non-Invasive Brain Stimulation and Substance Use 
 
STUDY ENROLLMENT AND WITHDRAWAL 
 
 
 
 
 
  3 
Participant Inclusion Criteria  
 
 
 
 
 
 
 
3.1 
In order to be eligible to participate in this study, a participant must meet all of the following 
criteria: 
o Ages 18-55  
o Current DSM-V Substance Use Disorder, diagnosed by the Mini International 
Neuropsychiatric Interview (MINI) 7.0  
o Current smoker, as assessed by the Fagerstrom Test for Nicotine Dependence (FTND) 
o Abstinent from all substances (except nicotine) for at least the past 2 weeks  
o Verbal & written informed consent (signed & dated) 
Participant Exclusion Criteria  
 
 
 
 
 
 
 
3.2 
A potential participant who meets any of the following criteria will be excluded from participation 
in this study: 
o < 6 months since an electroconvulsive therapy (ECT) session  
o Current DSM-V Psychotic Disorder, diagnosed by the Mini International Neuropsychiatric 
Interview (MINI) 7.0  
o Inability to read at a minimum of a 5th grade reading level, as assessed by the Wide 
Range Achievement Test (WRAT) Word Reading Subtest  
o Non-English speaker  
o Pregnancy and/or nursing  
o Prior brain surgery  
o Ongoing or history of traumatic brain injury (TBI), reoccurring seizures, stroke, or brain 
tumors  
o Medical or neurological illness (e.g., cardiac disease, AIDS, liver or renal impairment), or 
treatment for such an illness that could interfere with study participation  
o Any brain devices or implants (e.g., cochlear implants, aneurysm clips)  
o Current use of antiepileptic drugs  
o Current use of benzodiazepines 
Reporting of Pregnancy 
 
 
 
 
 
 
 
 
3.3 
Female participants who are enrolled in the study with undergo safety screening. At the first 
assessment during the screening procedure, female participants will be asked to take a 
pregnancy test by providing a urine sample. Although the theoretical risk to the mother or fetus 
is exceedingly small, no safety data for pregnancy is known to exist for transcranial direct 
current stimulation (tDCS) or transcranial alternating current stimulation (tACS) studies. Thus, if 
at any time a female participant is found to be pregnant (by verbal confirmation or a positive 
pregnancy test). she will be excluded from the study.  
Reasons for Withdrawal 
 
 
 
 
 
 
 
 
3.4 

5 Non-Invasive Brain Stimulation and Substance Use 
 
We will not withdraw participants from the study unless they fulfill one of the following criteria:  
o Voluntarily refuse continued participation in the study  
o Demonstrate an inability to comply with study procedures where collected data is found 
to be unreliable, misconstrued, or fabricated  
o Reveal information that they did not reveal during the screening procedure that prevents 
them from participating (e.g., personal or family history of a neurological condition, 
current use of an antiepileptic drug, pregnancy).  
o Experience serious adverse side effects (e.g., seizure)  
o Fail to attend the second session  
o Are asked to leave SouthLight by SouthLight staff before their expected treatment 
completion date due to disruptive behavior or poor attendance to their treatment 
program. In these cases, participants may no longer be eligible for participation in the 
study, even if they have already been screened and consented. 
Referral Procedure 
 
 
 
 
 
 
 
 
 
3.5 
In the event that participants are found to be in need of medical attention or psychological 
counseling, senior research staff will determine necessary routes of treatment and care and 
refer participants to appropriate medical and psychological services. In addition, research staff 
will inform SouthLight health care professionals (e.g., medical doctors, nurses, psychologists, 
counselors) in the case that immediate medical attention or psychological counseling is deemed 
necessary. 
Termination of Study   
 
 
 
 
 
 
 
 
3.6 
This study may be prematurely terminated if, in the opinion of the investigator, there is sufficient 
reasonable cause.  Circumstances that may warrant termination include, but are not limited to: 
o Experience of a recruitment rate of < 20% of approached patients at SouthLight (who 
would otherwise qualify for our study); we will cease recruitment due to limitations 
surrounding generalizability.  
o An event during which a participant experiences a seizure during an assessment, a 
temporary hold will be placed over the study and further investigation will be pursued. 
Based on investigational findings, the study may be stopped prematurely or may be 
continued with further safety measures in place. If more than one participant 
experiences a seizure during his/her assessment, the study will be stopped prematurely. 
These individuals will be referred for further medical attention. 
The IRB will be informed promptly and provided the reason(s) for the termination or suspension 
by the sponsor or by the investigator/institution, as specified by the applicable regulatory 
requirement(s). 
 
 

6 Non-Invasive Brain Stimulation and Substance Use 
 
STUDY SCHEDULE 
 
 
 
 
 
 
 
 
4 
Recruitment 
 
 
 
 
 
 
 
 
 
 
4.1 
Research staff will recruit individuals at the Garner location of the SouthLight Treatment Center 
in Raleigh, NC by making weekly announcements at the end of the substance abuse intensive 
outpatient program (SAIOP) groups. Research staff will introduce themselves as members of 
the UNC research team and provide brief information about the research that they are 
conducting in order to learn more about addiction. This brief information will include an overview 
of the study procedures including two research sessions and the potential to review non-
invasive, safe brain stimulation while playing computer games, in addition to answering 
interview questions and filling out self-report questionnaires. Any interested individuals will be 
asked to stay after their group to discuss the date of the next screening session. 
Screening 
 
 
 
 
 
 
 
 
 
 
4.2 
Research staff will meet with interested individuals one-by-one in a private room where they will 
be screened to determine eligibility based on the study inclusion and exclusion criteria. Potential 
participants will be screened using the Word Reading Subtest of the Wide Range Achievement 
Test (WRAT) and the Alcohol Use Disorder and Substance Use Disorder Modules of the Mini 
International Neuropsychiatric Interview (MINI) 7.0, which will both be administered in an 
interview format. During the screening procedure, research staff will also ask potential 
participants about their age, most recent substance use, pregnancy/nursing status (females 
only), current medical conditions and medical history, current medications, and most recent 
electroconvulsive therapy (ECT) session. Eligibility based on the study's inclusion and exclusion 
will be recorded on the Screening Form. Potential participants who do not meet criteria for the 
study will be informed of this decision and thanked for their time. Eligible patients who are willing 
to participate, provide informed consent, and sign the HIPAA Authorization Form and the UNC 
Release of Information Form will continue to the procedure of the first session. Administration of 
the screening procedure should take no longer than 45 minutes. 
Stimulation Sessions  
 
 
 
 
 
 
 
 
4.3 
First Session Participants will be escorted to a private room. Female participants will undergo a 
pregnancy test that must be negative in order for further participation in the study. Female 
participants will be asked escorted to the bathroom and asked to provide a urine sample. Upon 
collection, the research staff will run the pregnancy test and inform the participant of the results 
in a private room. Female participants that have a positive pregnancy test will be provided a 
written referral to a SouthLight on-site physician that is a member of the participant's treatment 
team in order to obtain information on follow-up services, as well as a list of OBGYN referrals 
that will be prepared with SouthLight staff before initiation of study recruitment and enrollment 
procedures. Female participants that have a positive pregnancy test will also be informed of 
their withdrawal from study participation and thanked for their time and efforts. Participants who 
remain eligible for the study will complete a battery of self-report and interview measures with 
research staff, including the Contact Form, Demographics Form, Use of Medications Form, 
Beck Anxiety Inventory (BAI), Beck Depression Inventory-II (BDI-II), Psychiatric Research 

7 Non-Invasive Brain Stimulation and Substance Use 
 
Interview for Substance and Mental Disorders (PRISM) Timeline, Timeline Followback (TLFB), 
and the Timeline Followback (TLFB) Supplementary Form. After the participant completes these 
measures, the research staff will have the participant sit in front of the computer and fill out the 
pre-tasks Positive and Negative Affect Schedule (PANAS) and Brief Substance Craving Scale 
(BSCS). Next, the research staff will attach the physiological recording equipment and begin 
recording. Then, the research staff will prepare the stimulator and the participant, including 
measuring the participant’s head for proper coordinate determination and applying the 
stimulation electrodes. Then the research staff will initiate the active sham stimulation. The 
participant will then engage in the Go/No-Go task, rate his/her level of distress on the Subjective 
Units of Distress Scale (SUDS.), and complete the distress tolerance (DT) task, the 
Computerized Paced Auditory Serial Addition Task (PASAT-C). After the participant completes 
the DT task, the research staff will stop the stimulation and remove the physiological recording 
equipment, and the participant will complete the post-tasks PANAS, BSCS, PASAT-C 
Questionnaire, and the Post-Stimulation Questionnaire. Twenty minutes after the completion of 
the DT task, the research staff will assess the participant's level of distress by asking the 
participant to rate how distress s/he is feeling again using the SUDS. If the participant provides 
a SUDS rating 2 or more points higher than their pre DT task SUDS rating, the research staff 
will guide the participant through a planned relaxation exercise using a pre-recorded audio file 
until their SUDS has returned to baseline. After, the participant will be given a reminder card 
with the date, time, and location of the second session. After the completion of the first session, 
participants will be randomized by a non-research team member to one of the three stimulation 
conditions using a stratified randomization procedure.  
Second Session Upon their arrival, participants will be escorted to a private room. The 
participant will complete a battery of self-report and interview measures with research staff, 
including updates on the Demographics Form, Use of Medications Form, TLFB, and the Contact 
Form. The research staff will have the participant sit in front of the computer and fill out the pre-
tasks PANAS and BSCS. Next, the research staff will attach the physiological recording 
equipment and begin recording. Then, the research staff will prepare the stimulator and the 
participant, including measuring the participant’s head for proper coordinate determination and 
applying the stimulation electrodes. Then the research staff will initiate the stimulation, based on 
the participant's randomization condition. The participant will then engage in the Go/No-Go task. 
After the participant completes the Go/No-Go task, the participant will rate his/her level of 
distress on the SUDS, and then completed the DT task. After the participant completes the DT-
task, the research staff will stop the stimulation and remove the physiological recording and 
tACS equipment, and the participant will complete the post-tasks PANAS, BSCS, PASAT 
Questionnaire, and the Post-Stimulation Questionnaire. Twenty minutes after the completion of 
the PASAT, the research staff will assess the participant's level of distress by asking the 
participant to rate how distress s/he is feeling again using the SUDS. If the participant provides 
a SUDS rating 2 or more points higher than their first SUDS rating, the research staff will guide 
the participant through a planned relaxation exercise using a pre-recorded audio file. 
Participants will be compensated and thanked for their time and efforts. 
Debriefing At the completion of all study data collection, participants will be contacted via 
telephone in order to complete the debriefing procedure. Participants will have the opportunity to 

8 Non-Invasive Brain Stimulation and Substance Use 
 
ask questions and voice concerns, as well as withdraw their data, if they choose. After the 
debriefing procedure, participants will not be re-contacted. 
 
 

9 Non-Invasive Brain Stimulation and Substance Use 
 
STUDY PROCEDURES & EVALUATIONS 
 
 
 
 
 
5 
Clinical Evaluations 
 
 
 
 
 
 
 
 
 
5.1 
Several clinical evaluations will be used throughout this study. These assessments are listed 
below. 
Beck Anxiety Inventory (BAI; Beck et al., 1988) – The BAI is a 21-item self-report questionnaire 
that assesses the severity of anxiety. It has demonstrated high internal consistency (α=.92), 
strong convergent validity with other clinical measures of anxiety (r=.25-.51). The questionnaire 
will be administered at the first session and is estimated to take about 5 minutes to complete.  
Beck Depression Inventory - II (BDI-II; Beck et al., 1996) – The BDI-II is a 21-item self-report 
questionnaire that assesses symptoms of depression currently and in within the past 7 days. It 
has demonstrated strong convergent validity with other measures of depression (r=.71) 
compared to measures of anxiety (r=.47). It has also demonstrated no association with 
demographic variables including gender, ethnicity, and age. The questionnaire will be 
administered at the first session and is estimated to take about 5 minutes to complete.  
Brief Substance Craving Scale (BSCS; Somoza et al., 1995) - The BSCS is a 16-item self-report 
questionnaire that assess craving for substances during the past 24 hours. For the purposes of 
this study, the first item ("The intensity of my craving, that is, how much I desired this substance 
in the past 24 hours was...") will be administered before and after completion of the PASAT. 
This item is assessed is a 5-point Likert scale (0=none at all, 1=slight, 2=moderate, 
3=considerable, 4=extreme). This item is estimated to take less than 1 minute to complete.  
Demographics Form – This form will include basic demographic questions including age, sex, 
date of first day of last menstrual cycle (for females only), ethnicity/race, education level, 
employment status, occupation, and income. The questionnaire is estimated to take about 5 
minutes to complete.  
Fagerstrom Test for Nicotine Dependence (FTND; Heatherton et al., 1991) - The FTND 
is a 6-item self-report questionnaire that assesses the severity of nicotine dependence. 
The questionnaire will be administered during the screening procedure and is estimated 
to take 2-3 minutes to complete. 
Go/No-Go Task (as used in Bell et al., 2014) – This version of the Go/No-Go consists of a 
series of neutral scenes from the International Affective Picture System (IAPS) (Lang et al., 
1999). Participants view a serial stream of pictures and are instructed to continuously press a 
button on the computer keyboard, but inhibit responses when pictures are presented 
consecutively. Accuracy (% correct non-occurrences/omissions) and mean response time will 
be recorded. This task will be used to assess inhibitory control. The task will take approximately 
12 minutes to complete.  
MINI International Neuropsychiatric Interview (MINI; Sheehan et al., 1998) - The MINI is 
a short, structured diagnostic interview. It will be administered during the screening 

10 Non-Invasive Brain Stimulation and Substance Use 
 
procedure in order to assess for a current substance use disorder (Modules I and J) and 
psychotic disorder (Module K). The interview will take approximately 20 minutes to 
complete. 
Computerized Paced Auditory Serial Addition Task (PASAT-C; Lejuez et al., 2003) – The 
computerized PASAT is a psychological distress-inducing task. Numbers are presented 
sequentially on a computer screen and participants are asked to add the currently presented 
number to the previously presented number before the next number is presented. Participants 
select the answer using a computer mouse on a number pad displayed on the computer screen 
below the presented numbers. Presented numbers range from 0 to 20 with no sums greater 
than 20 in order to limit the role of mathematical skill. During the easy/titration phase (5 
minutes), an algorithm will automatically titrate the speed of the number presentations in order 
to account for some individual differences in cognitive capacity, but not to secure equal 
performance among individuals. During the hard phase (5 minutes), the individually titrated task 
speed will be maintained throughout. During the distress tolerance (DT) phase (up to 15 
minutes), the individually titrated task speed will be maintained throughout, but individuals will 
be told that they have the option to quit the task at any point. Incorrect or delayed responses are 
met with an aversive explosion sound. Participants will be told that their score, presented in the 
corner of the computer screen will increase by 1 point with each correct answer. In addition, 
participants will be told that compensation for the task will be determined by their performance 
on the task. Accuracy (% correct and % omitted), mean inter-stimulus interval (ISI = ISImean - 
ISIbaseline), and latency to task termination (i.e., quit time) will be recorded. Participants will 
engage in this task at both sessions, always after the Go/No-Go task. The task will take 
between 10 and 25 minutes, depending on if and when a participant decides to quit the task 
during the distress tolerance phase.  
PASAT Questionnaire – This will be administered following administration of the DT task. The 
questionnaire is composed of 4 questions asking about the participant’s experience playing the 
computer game. The questionnaire is estimated to take about 2-3 minutes to complete.  
Positive and Negative Affect Scale (PANAS; Crawford & Henry, 2004) – This is a 20-item self-
report measure that assesses changes in positive (PA) and negative (NA) affect. PA assesses 
the extent to which an individual feels enthusiastic, alert, and active. NA assesses the extent to 
which an individual feels subjective distress and additional components of negative mood such 
as anger, contempt, disgust, and guilt. Individuals are asked to rate to what extent a they have 
felt a feeling/emotion (represented by single words, e.g., hostile, guilty, interested) over a 
specified time interval (e.g., at the present moment, today, past few days, week, past few 
weeks, year, in general). In this study, participants will be asked to rate based on how they feel 
at the present moment. The PANAS has demonstrated good internal consistency for both the 
PA (α=.89) and NA (α=.85) scales (Watson et al., 1988). This will be administered before and 
after each time a participant completes the PASAT. The questionnaire is estimated to take 
about 2-3 minutes to complete.  
Psychiatric Research Interview for Substance and Mental Disorders (PRISM) Timeline (Hasin et 
al., 1996; 1998; 2001; 2006) - This is a structured clinical interview that assesses a wide range 

11 Non-Invasive Brain Stimulation and Substance Use 
 
of psychiatric disorders. For the purposes of our study, we will be using the Substance 
Screening Subscale timeline to assess previous periods of chronic intoxication and binge use of 
various substances. This is estimated to take about 5-20 minutes, depending on the 
participant's substance use history.  
Subjective Units of Distress Scale (SUDS; Wolpe, 1969) - The SUDS is a scale to measure an 
individual's self-reported distress from 0 to 100, with higher ratings indicating higher levels of 
distress. It will be used administered to assess participants' residual level of distress at the 
completion of the testing session. It is estimated to take less than 1 minute to complete.  
Timeline Followback (TLFB; Sobell et al., 1979) – The TLFB is a clinician administered measure 
of substance use. It has demonstrated high test-retest reliability (ICC=.70-.94, p<.001), 
convergent and discriminant validity with other measures, agreement with collateral informants’ 
reports of patients’ substance use, and agreement with the results form patients’ urine analysis 
(Fals-Sterwart et al., 2000). The measure is estimated to take about 10 minutes to complete. 
Timeline Followback (TLFB) Supplementary Form – This form provides a summary of an 
individual's most recent substance use, as well as the amount, duration, and frequency. This 
form is estimated to take about 5-10 minutes to complete.  
Use of Medications Form - This form asks individuals about their current use of mood- and non-
mood-related medications. This will be administered in an interview format and will be 
administered at both sessions. It is estimated to take approximately 3-5 minutes to complete.  
Wide Range Achievement Test Revised (WRAT-R) Word Reading Subtest (Jastak & Wilkinson, 
1984) – This assesses an individual’s ability to read and comprehend words. In particular for 
this study, this will be used during the screening procedure to assess an individual’s reading 
level prior to providing consent in order to determine if an individual can read at a fifth grade 
level. This is necessary for an individual to be able to comprehend and participate in the written 
proportions of the study. The assessment is estimated to take about 10 minutes to complete. 
Equipment & Forms  
 
 
 
 
 
 
 
 
5.2 
BIOPAC Data Acquisition System (BIOPAC Systems, Inc., Goleta, CA) – Autonomic arousal will 
be measured throughout both assessments from measures of galvanic skin response (GSR), 
heart rate (HR), and pulse using two wireless devices of the BIOPAC MP150 system (BIOPAC, 
2011). GSR will be recorded using the GSR wireless module, which will be wrapped comfortably 
around the participant's wrist and Ag/AgCl electrodes attached to the first and third fingers of the 
participant's non-dominant hand. HR and pulse will be recorded using the ECG wireless 
module, which will be wrapped around the participant's waist and secured to the chest using an 
adhesive, and recorded from electrodes attached to the participant’s upper chest and lower rib. 
GSR and HR will be recorded throughout the entire duration of both tasks (Go/No-Go and 
PASAT) at both sessions. 
Contact Form – This form including the participant’s best phone numbers, addresses, and 
alternate contacts, will be used to improve study retention by maintaining contact with 

12 Non-Invasive Brain Stimulation and Substance Use 
 
participants throughout the duration of the study. It will be administered in an interview format 
and is estimated to take about 10 minutes.  
Debriefing Information Sheet – Participants will be provided with appropriate and correct 
information about their study participation and of particular note, of the minor deception involved 
in the study. Participants will also be given a chance to ask any questions about the study. 
Participants and experimenters will sign and date the information sheet to document the 
completion of the debriefing procedure.  
Drop Out Questionnaire – This questionnaire will document the reason for a participant’s (self-
initiated) withdrawal from the study. This questionnaire is estimated to take 2-3 minutes to 
complete.  
Planned Relaxation Exercise – Participants will be led through a planned relaxation exercise if 
they report residual distress as indicated on the SUDS, using a pre-recorded audio file. The 
audio for the exercise is approximately 3 minutes long.  
Post-Stimulation Questionnaire - This questionnaire will be administered after the stimulation 
procedures at both sessions in order to assess (1) safety of the tACS, (2) participant 
experiences with the tACS, and (3) physical and psychological symptoms that participants may 
believe are associated with tACS. This data will be used to assess whether participants were 
successfully blinded during the course of the study. This questionnaire is estimated to take 
about 5 minutes to complete.  
Pregmate One Step Urine Human Chorionic Gonadotropin (hCG) Pregnancy Test – Female 
participants will provide a urine sample for a pregnancy test at the beginning of the first session 
to confirm that they are not pregnant before undergoing the stimulation procedures. The urine 
pregnancy test will provide results after 5 minutes.  
Screening Form – This form will be used to record a participant's eligibility status according to 
the study's inclusion and exclusion criteria. 
Transcranial Current Stimulator (Pulvinar Neuro LLC, 2016) - We will be using a transcranial 
current stimulator developed, XCSITE 100, by Pulvinar Neuro LLC for investigational research 
purposes. The device is not implanted and has not been designed for or being used to support 
or sustain human life. This device does not have a potential for serious risk to the health, safety, 
or welfare of the participant. There has never been an instance of serious side-effect reported 
due to use of transcranial brain stimulation. This device has been used in previous studies by 
the Frohlich Lab and which have always been classified as “non-significant risk” by the UNC 
IRB. This device is functionally equivalent to the CE-certified Neuroconn Plus stimulator. The 
use of this device in this study has previously received a NSR designation on initial review by 
the full UNC IRB. Both devices are electrically equivalent and provide the same stimulation. In 
addition, the stimulator has built in safety features. The device is equipped with 5 different 
stages of safety protection, all of which protect the stimulant from high currents. (See Additional 
Device Information for more details.) 
Additional Device Information 

13 Non-Invasive Brain Stimulation and Substance Use 
 
The device consists of the following main components/subsystems: 
1. Tablet with user interface application (App) 
2. Microprocessor 
3.  Function generator chip 
4. Voltage controlled current source 
5. Safety circuitry 
First, the stimulation parameters are specified by the user through the app.  The parameters 
are: 
1. Number of channels 
2. Alternating (AC) or Direct Current (DC) 
3. Verum or Active Sham Stimulation 
4. Amplitude in miliamperes 
a. 2 mA peak-to-eak sine wave stimulation 
5. Stimulation frequency (ignored for direct current) in Hertz 
a. 10 or 40 Hz 
6. Stimulation duration in seconds 
7. Ramp Up duration in seconds 
8. Ramp Down duration in seconds 
9. Active Sham duration (ignored for verum stimulation) in seconds 
 
Next, the parameters are sent via Bluetooth™ to the microprocessor.  The microprocessor 
interprets these parameters if the parameters fall within the acceptable ranges the 
microprocessor returns them to the app for verification and programs the function generator chip 
accordingly.  Once started by pressing the physical button on the device, the function generator 
then creates the programmed waveform, which is ultimately a voltage signal.  The voltage signal 
is applied to a voltage controlled current source, which generates the specified amount of 
current through an arbitrary load resistance. 
Operation 
A. The desired current value is scaled to a register value and stored in the function 
generator. 
B. The value in the register determines the percent of full scale output current, generated 
by the function generator. 
C. The generated current waveform from the function generator is driven through a 
specified resistance.  The resulting voltage drop is amplified by an instrumentation 
amplifier.  
D. The voltage waveform from the output of the instrumentation amplifier is applied to a 
voltage controlled current source. 
Current Sensor Circuit - A 33.2 Ω sense resistor is placed in series with the stimulation 
electrodes on the high side.  Since high-side current sensing is used, any short circuit of the 

14 Non-Invasive Brain Stimulation and Substance Use 
 
electrode terminals to ground will be detected.  The stimulation current flows through this 
resistor and generates a voltage.  The voltage across this resistor is sensed and amplified by 
the AD628 difference amplifier.  The gain of the difference amplifier is set to 9.9039.  The 
current sensor voltage is then shifted before it is read by the microprocessor and the hardware 
overcurrent safety feature.   
Voltage Sensor Circuit - The differential voltage across the electrodes is measured so that the 
impedance can be calculated.  The voltage is measured by buffering the positive electrode and 
negative electrode each with a unity gain op-amp circuit.  The voltage sensor output is then 
shifted before it is read by the microprocessor using the same level shifting circuit described in 
the current sensor section.   
Safety Precautions 
The device is equipped with 5 different stages of safety protection, all of which protect the 
stimulant from high currents.  The stages are as follows: 
1. Software parameter validation. All stimulation parameters are checked to be within the 
allowable ranges for those parameters. If values outside of this range are entered the 
app will not allow stimulation to start. 
2. Automatic software current cutoff.  The output of the current sensor described above is 
read by a microprocessor, which compares the reading to a value of +/- 2.3 mA peak.  If 
the current exceeds these limits, stimulation is stopped, a relay in series with the 
electrode is opened, and the power supply used for stimulation is turned off.  The user is 
then given the option to investigate the issue, and cancel or resume the test.  Since 
high-side current sensing is used (described above), any short circuit of the electrode 
terminals to ground will be detected.  
3. Automatic hardware current cutoff.  The output of the current sensor is fed into a pair of 
comparators which detect if the current exceeds +/- 4.5 mA.  If so, the fault is latched 
such that the relay in series with the electrodes is opened.  Additionally, the 
microprocessor is notified of this instance through an interrupt.  Upon this interrupt, the 
microprocessor immediately stops stimulation and the power supply used for stimulation 
is turned off. 

15 Non-Invasive Brain Stimulation and Substance Use 
 
 
Figure 1: Example hardware cutoff function. At – 54 μs, the current sensor is raised 
artificially (blue). With a latency of 54 μs, the high voltage rails are turned off (purple). 
The stimulation output (green) is zeroed 190 μs after the high current was detected. 
4. Permanent hardware current cutoff.  A 5 mA fast-acting fuse is in series with the 
electrode connector.  If the above over-current detection methods fail, the fuse will blow, 
and the participant will no longer be electrically connected to the current generator. 
5. Power supply fuse.  Finally, if for any other reason the entire device draws too much 
current, the main power supply fuse is blown.  This fuse is rated for 400 mA which is 
approximately 200% of nominal operating current. 
 
Risk Monitoring 
 
 
 
 
 
 
 
 
 
 5.3 
Risk of discomfort or injury caused by tACS administration is rare. tACS has been successfully 
utilized without any reports of serious side effects, deeming tACS an extremely safe and non-
invasive approach to modulate neural oscillations. tACS passes weak electric current through 
the scalp, which is routinely done using other methodologies such as electroencephalography 
(EEG). It is important to note that tACS does not use the same procedures/methods as 
electroconvulsive therapy, that applies many orders of magnitude higher of stimulation current. 
tACS uses a weak electric current, such as it does not produce super-threshold activation of 
neurons (Frohlich & McCormick, 2010).  
There is a rare, theoretical likelihood that neural stimulation can lead to epileptic discharges. 
Previous studies using tDCS in patients with depression and schizophrenia have reported no 
seizures (Berlim et al., 2013; Brunelin et al., 2012). In order to minimize this occurrence, we will 
exclude individuals with personal and family history of neurological conditions and individuals 
who are currently taking benzodiazepines from the study during the screening procedure. For 
the same reason, we will also exclude individuals that have not been abstinent for more than 2 
weeks from the study during the screening procedure. 

16 Non-Invasive Brain Stimulation and Substance Use 
 
In previous tACS research, some individuals have reported transient tingling underneath the 
electrodes on the scalp, including itching, headache, burning sensations, and minor discomfort. 
However, a recent meta-review has failed to find any significant differences in occurrence rates 
of these symptoms between tDCS and a sham control condition (Brunoni et al., 2011). In 
addition, rTMS has also proven to be well tolerated by individuals with substance use disorders 
(Gorelick et al., 2014). More specifically, in studies utilizing rTMS on individuals with substance 
use disorders, active and shame rTMS groups had comparable drop-out rates and no reports of 
serious or unexpected adverse events.  
Safety Monitoring 
 
 
 
 
 
 
 
 
 
5.4 
After each stimulation session (active sham and tACS), the Stimulation Adverse Effects 
Questionnaire will be administered. This will be used to document any side effects experienced 
during stimulation. In addition, throughout the stimulation sessions, the researcher will check 
with the participant to make certain that no discomfort or injury is felt or has occurred. In the 
case that a participant reports unmanageable discomfort or pain, the stimulation session will be 
terminated immediately. 
 
 

17 Non-Invasive Brain Stimulation and Substance Use 
 
DATA ANALYSIS 
 
 
 
 
 
 
 
 
 
  6 
 
Sample Size Considerations  
 
 
 
 
 
 
 
6.1 
Due to the fact that this is a pilot study, and the first study (to our knowledge) to administer tACS 
in a sample of substance users, we utilized effect size estimates from tACS studies with mainly 
healthy controls. Using G*Power 3.1, we conducted a power analysis with a conservative effect 
size of 0.3 and a desired power of 0.80, which calculated a total sample size needed of 39 
participants. The results of this pilot study will provide effect size estimates to conduct a power 
analysis in future studies specifically with a sample of substance users. We plan to report effect 
sizes between 0.3 and 0.5 (Chi et al, 2010; Kar & Kerkelberg, 2014) 
Data Management 
 
 
 
 
 
 
 
 
 
6.2 
Interview and hardcopy questionnaires that cannot be computerized will be entered into Excel 
(password protected) and SPSS databases on a secure UNC server, only accessible to the 
research staff. Data will be coded with study ID numbers that can only be matched to a 
participant's name via a database stored in a separate, secure location on the server, only 
accessible to the researcher staff using a password. Data entry of these questionnaires will 
utilize a double-entry approach, such that data will be entered twice by two separate 
researchers. A third researcher will clean the data using SPSS Data Entry Builder to identify and 
correct discrepancies between the primary and secondary entries. The project coordinator will 
be responsible for ensuring data quality and control, and data management oversight. 
Confidentiality  
 
 
 
 
 
 
 
 
 
6.3 
All of the information obtained from participants will be entirely for research purposes and de-
identified using study IDs. Data will be kept in locked confidential filing cabinets in a secure 
office space at UNC, only accessible to the research staff. The consent forms and the Contact 
Forms will be kept separately from the data in a locked filing cabinet, also only accessible to the 
principal investigator and the study coordinator. All computerized data collection methods will 
use a secure, encrypted web survey, using the Qualtrics online survey platform. Only study IDs 
will be used in the collection of this data. This data will be stored on a secure network at UNC, 
only accessible to research staff. All data will be stored in password protected files on password 
protected computers located in a secure office space at UNC. Only research staff will have 
access to these files, computers, and office space. Data will only be transmitted via HIPAA 
compliant storage devices or encrypted email services 
Final Analysis Plan 
 
 
 
 
 
 
 
 
 
6.4 
Aim 1 To investigate the real-time effect of transcranial alternating currently stimulation (tACS) 
on inhibitory control and distress tolerance. 
Descriptive statistics (e.g., mean, standard deviation, variance, range) will be generated for all 
continuous study variables. Continuous study variables will also be examined for normality and 
homogeneity of variances using visual inspection methods (e.g., histograms, box plots, 
residuals, Normal Q-Q plots) and quantitative methods (Shapiro-Wilk test). If these assumptions 

18 Non-Invasive Brain Stimulation and Substance Use 
 
are violated, the continuous study variables will be transformed, as necessary (e.g., log 
transformation). We will use hierarchical linear regression to test whether there is a statistically 
significant effect of condition (tACS at 10 Hz, tACS at 40 Hz, or active sham stimulation) on 
session 2 DT and IC (controlling for session 1).  
The latency to quit on the PASAT during the distress tolerance phase and d-prime on the Go/No 
Go primary outcomes of this pilot study.  
Aim 2 To demonstrate the feasibility of administering transcranial alternating currently 
stimulation (tACS) among a sample of adults with SUD recruited from a substance use 
outpatient treatment center. Descriptive statistics and frequencies will be generated for all study 
variables related to assessing the feasibility of administering tACS (e.g., drop-outs, occurrence 
of unexpected and/or adverse events and side effects). 
Given that this is a pilot study, we hope to use the results of this study to act as a foundation for 
a larger, future study with the aim of examining the effect of tACS on substance use treatment 
outcomes and engagement among treatment-seeking adults with SUD, with a focus on distress 
tolerance and inhibitory control as mechanisms of change. This larger, future study will be in line 
with our long-term goal of developing and implementing a novel non-invasive brain stimulation 
paradigm, using tACS, for the treatment of substance use disorders.