Learning Enhancement Through Neurostimulation in Autism
Phase: NA
Conditions: Autism
Sponsor: Medical University of South Carolina

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PROTOCOL TITLE: 
Learning enhancement through neurostimulation (LENS) 
 
PRINCIPAL INVESTIGATOR: 
Jane E. Joseph, PhD 
 
 
 

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1.0 
Objectives / Specific Aims 
 
One of the hallmark symptoms of Autism Spectrum Disorder (ASD) is difficulty with social communication 
and interaction. Although numerous behavioral interventions have been developed to address social 
difficulties in ASD, one evidence-based social skills training program in particular has demonstrated 
promise in improving social skills knowledge and social functioning: the UCLA Program for the Education 
and Enrichment of Relational Skills (PEERS)[1], which is a manualized, evidence-based program for 
high-functioning adolescents with ASD. Despite the success of this program, not all individuals benefit 
from social skills training[2]. Reasons for non-responsiveness are likely complex and varied, ranging from 
differences in neural responsivity, cognitive function, temperament and social support. One 
neurocognitive factor that may impact social learning is the ability to filter out irrelevant information, or 
attend to relevant social information [3]. Therefore, targeting selective attention at the neural level may 
have benefits for social skills learning. Recently, brain stimulation techniques such as transcranial direct 
current stimulation (tDCS) and repetitive transcranial magnetic stimulation (rTMS) have shown promise 
in enhancing learning, attention and other behavioral outcomes in ASD [4-6].  
 
In the present proposal adolescents with ASD who will receive PEERS training with active or sham tDCS 
to determine whether social skills training can be enhanced with neuromodulation. tDCS is a minimally 
invasive neuromodulatory technique that delivers low current through scalp electrodes. tDCS modulates 
ongoing neural activity by affecting neuronal membrane potential. tDCS has shown some promise in 
reducing neuropathic pain [7], alleviating symptoms in some psychiatric disorders [8-9] and enhancing 
motor function following stroke [10].  tDCS was chosen as a neuromodulatory technique in the present 
proposal due to its portability which is well suited to allow for tDCS to be delivered concomitantly with 
social skills training, which requires interaction with a group of individuals. Animal studies also suggest 
that the effects of tDCS stimulation may last beyond the period of stimulation [11].  
 
The aims of this study are to: 
 
• 
Aim 1. Establish the safety and feasibility of administering active and sham tDCS with PEERS 
training in adolescents with ASD. We predict that tDCS administered with 1.5mA current will be safe 
for participants and tolerable for the majority of participants. 
 
• 
Aim 2. Examine the impact of tDCS in improving social skills and attention to faces. We predict that 
active tDCS in conjunction with PEERS training will improve social function and attention to faces to 
a greater degree than sham tDCS plus PEERS training. 
 
• 
Aim 3. Examine the impact of tDCS on neural correlates of social function and attention to faces 
using functional magnetic resonance imaging (fMRI). We predict that activity in regions that underlie 
social behavior (e.g., medial prefrontal cortex, temporoparietal junction, fusiform gyrus, amygdala) 
will increase more in response to social stimuli following active tDCS with PEERS training compared 
to sham tDCS with PEERS training. 
 
Impact. The present study will address the need to find approaches to enhance social learning in ASD. 
Social communication difficulties may become especially apparent during adolescence, a time period 
marked by greater emphasis on social relationships and peer influence. Therefore, the present strategy 
is to examine the efficacy of a minimally invasive neuromodulatory technique in adolescents in 
combination with an evidence-based behavioral intervention, PEERS, to enhance social information 
processing and social interaction, with fMRI markers of neural plasticity before and after intervention. 
 
2.0 
Background 
 

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PEERS. PEERS is one of the only empirically supported social skills programs for adolescents with ASD. 
PEERS utilizes cognitive-behavioral methods to teach social skills[12]. The program specifically targets 
friendship, relationship development, and decreasing isolation in adolescents[13]. The PEERS 
intervention consists of 14 weekly 90-minute sessions for adolescents and their parents. Four previous 
randomized, controlled studies and one quasi-experimental study cited gains in overt social skills, 
improved quality of friendships, and frequency of peer interactions[1, 13-16], with treatment gains 
maintained at 14-week follow-up[1]. 
 
To date, only one study has investigated neural function in a group of adolescents completing the 
PEERS program[13]. This study demonstrated a shift from right-hemisphere gamma-band EEG 
asymmetry to left-hemisphere EEG asymmetry following completion of PEERS. No such changes were 
noted in typically developing adolescents or in wait-listed ASD participants. In addition, left-dominant 
EEG-asymmetry at post-test was associated with increased social contacts, knowledge about social 
skills, and fewer symptoms of ASD. The present study has promising implications for demonstrating that 
cognitive-behavioral intervention is associated with changes in neural activity in adolescents with ASD. 
 
Only two previous studies have investigated the effect of tDCS on children with ASD. Results indicated 
improved syntax acquisition following a 30-minute treatment period[4] and decreased autism symptoms 
and behavioral problems up to seven days post-treatment[17]. Both studies reported that treatment was 
well-tolerated by participants. Recent reviews have also concluded that tDCS is well tolerated and safe 
for adolescents [18]. 
 
Innovation 
 
This study will be the first of its kind to combine evidence-based social skills treatment (PEERS), with 
neurostimulation using tDCS and to evaluate treatment outcomes using both behavioral data and fMRI. 
Should this project establish tDCS as a safe, tolerable and viable neuroenhancement technique, it may 
be added to other behavioral interventions such as, and extended to younger children, including those 
receiving intensive early behavioral intervention. In addition, tDCS is a technique used in animal models 
to improve cognition [19], so it can also be applied to animal models of autism, an area of intense 
investigation. In summary, the impact of the proposed project is to establish tDCS as a means to 
enhance social learning and selective attention in ASD. This not only could enrich research efforts, but 
could also have a broader impact through future integration of this technology into clinical practice.  
 
Preliminary Studies conducted by the research team 
 
Investigator Gwynette and his team are the only PEERS-certified clinicians in SC. Dr. Gwynette has 
extensive experience with pioneering social skills programs at MUSC as director of Project Rex, a social 
skills program that has provided treatment for 88 adolescents with ASD and their families in the past two 
years. In an unpublished analysis of clinical outcomes for thirty-seven adolescents with ASD, participants 
achieved a mean improvement of 10.42 points on the Social Responsiveness Scale parent total score 
following treatment.  
 
Investigators Carpenter and Borckardt have previously conducted a brief, IRB-approved feasibility study 
using tDCS with a child with ASD. Unpublished data demonstrated that the child habituated to the 
sensation within about 10 minutes, and that he was able to move about and interact freely during a 20-
minute stimulation session. Other than slight redness where the forehead electrode was applied, no 
adverse effects were noted. Co-I Borckardt has conducted numerous studies using tDCS in diverse 
clinical populations. He will serve as the NCNMR4 Collaborator for this proposal. 
 
Consultant Manuel Casanova has conducted several clinical trials in people with ASD using brain 
stimulation techniques (primary rTMS). He will provide intellectual input on the overall design of the study 
and guidance on brain stimulation methodology. He will also be a co-Investigator on any grant 
applications that result from this pilot award. 

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PI Joseph conducted an fMRI study [20] in typical and ASD youth to examine neural response to faces 
and non-faces. They found that the right fusiform gyrus showed a trend toward normal development of 
face specialization in ASD (i.e., increased fMRI response to faces relative to non-faces with age), but the 
left amygdala actually showed decreased face specialization with age in ASD. This finding fits in with the 
EEG finding that it was left hemisphere gamma activity that was associated with improved social skills in 
ASD following PEERS training[13] and with the case report that tDCS applied to the left dorsolateral 
prefrontal cortex decreased ASD symptoms[21]. Hence, left-hemisphere structures may show altered 
response to social information, but PEERS training, tDCS, or the combination, as proposed here, may 
mitigate this altered responsivity. 
 
3.0 
Intervention to be studied (if applicable) 
PEERS training will be paired with active or sham tDCS. As described above, PEERS is one of the only 
empirically supported social skills programs for adolescents with ASD. PEERS utilizes cognitive-
behavioral methods to teach social skills[12]. PEERS is a parent-assisted intervention that teaches 
targeted social skills to high-functioning patients with ASD during fourteen weekly sessions. Parents and 
adolescents attend separate concurrent sessions that instruct them on key elements about making and 
keeping friends. Details of the activities that occur during PEERS sessions are provided in the Section 
10.0. 
 
tDCS is a brain stimulation technique that uses 1-2mA current applied to the scalp to affect neuronal 
membrane potential but does not cause neural firing. It is being explored as a therapeutic for a number of 
neurological and psychiatric disorders, and appears to be promising in terms of enhancing behavioral or 
treatment response when administered concurrently with behavioral treatments [22-23]. tDCS is still in 
the early stages in its application to children, with encouraging initial results across disorders and 
computational models for dosage considerations in a youth population[24]. Previous research has 
demonstrated that tDCS is well-tolerated and safe for children and adolescents in a Psychiatry setting 
[18]. It is also tolerated by children with epilepsy with no adverse side-effects and clinically significant 
decreases in seizure activity for 48 hours post-treatment [25]. 
As described more in Section 10.0, active tDCS will be administered to half of the participants and sham 
tDCS will be administered to the other half 
tDCS is not an FDA-indicated technique for autism-spectrum disorders and there are no FDA-approved 
tDCS devices to date. However the Ionto device used for this study is FDA-approved for iontophoresis 
and is equipped with all relevant current and voltage regulation/safety features. As with most tDCS 
studies conducted at MUSC, this device will be used off-label for tDCS delivery. 
 
4.0 
Study Endpoints (if applicable) 
The primary endpoints are changes in responses on various clinical measures pre- and post-intervention: 
the Social Responsiveness Scale, the Social Skills Improvement System, the Quality of Play 
Questionnaire, the Aberrant Behavior Checklist, and the Test of Adolescent Social Skills Knowledge-
Revised. We predict that participants receiving active tDCS will show greater improvement in these 
measures compared to those receiving sham tDCS. This will be assessed using non-parametric t-tests 
(IBM SPSS Statistics, Chicago, IL) conducted separately for each measure. 
 
Secondary endpoints will be fMRI response and reaction time pre- and post-intervention on a laboratory 
test of attention and social information processing. 
 
The primary safety endpoint will be self-reported adverse effects of tDCS collected after each treatment 
session. 
 

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5.0 
Inclusion and Exclusion Criteria/ Study Population 
 
Inclusion Criteria for Adolescents:  
• 
Participants in this study will be youths aged 14-17 with a documented history of ASD who 
are enrolling in a PEERS program at MUSC.  
• 
Participants will be screened for eligibility using the ADOS-2, the gold standard instrument 
for diagnosing ASD. A score falling with the autism spectrum range on the ADOS-2 is 
required.  
• 
Participants will also be screened for IQ using the K-BIT2, an IQ measure appropriate for 
children and adolescents. Subjects must score higher than 70 on the K-BIT2.  
• 
Participants must be willing to enroll in PEERS training and to receive brain stimulation 
prior to being included in this study 
 
Exclusion Criteria for Adolescents: 
• 
Epilepsy, or a seizure in the last year 
• 
Vagal nerve stimulators 
• 
Participants may continue to take prescribed medications during the course of the 
treatment. However, no dosage or agent changes may be made one month prior to the 
study or during the study. If a medical or behavioral treatment change must be made 
during the course of the study, participation will be discontinued. 
• 
Allergy to benzocaine 
• 
Prior brain stimulation (tDCS, TMS, ECT, DBS) intervention 
• 
Inability or unwillingness of subject or legal guardian/representative to give informed 
consent 
• 
Non-native English speaker 
• 
Metal pins, plates or clips in the body or orthodontics 
• 
Surgical implants such as pacemakers or cochlear implants 
• 
Permanent makeup or tattoos near the face or head 
• 
Metal fragments in the body (from welding, shrapnel, BB guns) or suspect that they have 
fragments 
• 
Claustrophobia 
• 
Past closed head injury or concussion 
• 
Currently under the influence of alcohol or other recreational drugs 
• 
Smoker  
• 
Cannot understand the fMRI task instructions 
• 
Cannot lay still in the mock scanner for a period of 5 minutes 
• 
Prior PEERS training 
 
Inclusion Criteria for Parents:  
• 
Have a child with Autism Spectrum Disorder and willingness and ability to participate in 
the weekly PEERS session 
 
Exclusion Criteria for Parents:  
• 
Enrolled in an academic course in which Drs. Joseph, Gwynette, Carpenter or Borckardt 
are instructors 
 
No individual will be excluded based on race, gender, or ethnicity. The parent can be either male or 
female. 

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Only adolescents from age 12-17 will be included because the study is focused on behavioral and 
neurostimulation interventions that are expected to enhance social skills. Adolescence is a 
developmental time period where social information processing is particularly relevant. 
6.0 
Number of Subjects 
A total of 34 subjects will be recruited for the study (17 adolescents and their parent), but a drop-out rate 
of approximately 40% is expected, leaving 10 adolescent subjects with complete datasets. 
7.0 
Setting 
• 
The initial visit to MUSC will take place at the Center for Biomedical Imaging (CBI) at 30 
Bee Street. Baseline assessments using ADOS-2 and K-BIT2 and tDCS acclimation will 
take place in a quiet testing room in the CBI facility. Parents will fill out questionnaires in an 
adjacent area at CBI. These questionnaires will be entered into RedCap and no identifying 
information will be linked to the survey responses. 
• 
tDCS acclimation, Mock scanner training, and fMRI scanning will also take place at CBI.  
• 
Brain stimulation with active or sham tDCS will take place in the MUSC Institute of 
Psychiatry South, 5th Floor 
 
8.0 
Recruitment Methods 
• 
Recruitment will occur during the first 3 months of the study. Potential subjects 
will be recruited through the Department of Psychiatry at MUSC and from the 
greater Charleston area community. 
• 
Potential subjects will be recruited through a variety of online avenues and local 
autism community groups and organizations, as well as advertising to the general 
public.  
• 
Project Rex is an autism-focused program directed by Dr. Gwynette at MUSC, 
and has a robust social media network, a website with significant traffic, and a 
large patient directory. Information regarding the study and digital copies of fliers 
will be posted on social media forums (Facebook, Twitter, Instagram) under 
existing Project Rex accounts, as well as sent via email to the Project Rex mailing 
directory. Dr. Gwynette may discuss the study with patients they are actively 
treating as well as their family members. The study may also be advertised at any 
other groups, projects, or events that are being run conducted Project Rex. 
• 
In addition to Project Rex, investigators will reach out to other local autism 
organizations and groups such as the Lowcountry Autism Foundation (LAF), the 
Lowcountry Autism Consortium, South Carolina Autism Society to provide 
information regarding the study to their members, as well as digital and/or 
physical copies of fliers to distribute to their members if they are willing to do so. 
Investigators will also offer to come to speak about the study and answer 
questions during group meetings in person for any groups who are interested. 
Emails will be distributed by the investigators to families and stakeholders on the 
Project Rex newsletter distribution list and the MUSC broadcast email system.  
• 
Flyers will also be posted around the MUSC campus and hospital once approved.  
 
• 
Investigators will reach out to local psychiatry offices and provide them with 
information regarding the study and digital and/or physical copies of fliers for them 
to share with their patients at their discretion.   
 
 
 

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• 
Flyers will be given to the parents of children who are enrolled in PEERS. Flyers 
and posters will contain information including a basic explanation of the study 
(investigating the use of non-invasive brain stimulation for enhancement of 
learning social skills in autism), eligibility (age range, diagnosis of ASD), 
information about financial compensation and ability to receive behavioral 
intervention at no cost to patient. They will also include study site and contact 
information for study coordinator(s).  
 
9.0 
Consent Process 
 
Consent will take place at the Center for Biomedical Imaging at 30 Bee St on the campus of MUSC. The 
research coordinator will explain study procedures to the parent (or authorized legal guardian) and 
adolescent with ASD. Pictorial descriptions will be provided along with verbal descriptions, which is a 
well-accepted practice when describing research study procedures to individuals with ASD. During the 
consent process, the investigator will make clear that different activities will be completed by the parent 
and the child. To assess level of interest from youth with ASD, the coordinator will ask the parent or child 
volunteer if he or she has any questions about the study procedures. Following this, the coordinator will 
directly ask the child if he or she wants to participate. A verbal indication of “yes” or nodding of the head 
will be taken as assent. The child will be asked to provide their signature on an assent form. Parents will 
provide written consent. If either the child or parent fails to provide assent or consent,  the child will not 
participate and will not be enrolled in the study. The parent will provide written consent for their 
participation. There will be no waiting period between informing the prospective subject and obtaining the 
consent.  
The oldest adolescent participants will be 17 years of age upon enrollment. If a volunteer turns 18 during 
the course of the study, they will be reconsented as an adult at the next visit following their 18th birthday. 
Decision capacity will not need to be determined at this point because all participants will have scored in 
the normal range for IQ as part of the inclusion criteria. 
During the study, continued assent/consent from the ASD volunteers will be indicated by willingness to 
participate in the PEERS group intervention , willingness to wear the tDCS electrodes, and willingness to 
enter the MRI scanner. Verbal or non-verbal protests for any of these procedures will indicate 
unwillingness to participate. However, additional attempts will be made to encourage participation within 
the same session. If the child continues to protest or becomes agitated, uncomfortable or non-responsive 
to experimenter instructions, the procedures will not be continued for that session. The child is 
encouraged to return for additional sessions, but will not be forced to do so. 
 
10.0 Study Design / Methods 
We will conduct brain stimulation with 17 randomized adolescent participants at initial enrollment. Drop-
outs are expected, with the goal of having 10 youths with ASD complete the study, with the same 
number of parents actively participating by the end of the experiment. 
The following table summarizes the schedule of activities for a subject: 
 
Schedule of events 
Activities 
Time commitment 
for volunteer 
Compensation 
Initial visit with 
research coordinator, 
Drs. Gwynette and 
Carpenter 
Consent (parent and child) 
15 min 
$25 (child) 
$15 (parent) 
Medical & MRI screening (parent 
and child) 
5 min 
ADOS-2 & KBIT-2 (with child), 
clinical measures (with parent) 
90 min 

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Mock scanner training with child 
10-15 min 
fMRI scanning with child 
30 min 
tDCS acclimation with child 
10 min 
PEERS weekly sessions 
PEERS training plus active / sham 
tDCS 
1 hr / week x 14 weeks 
$15 per session 
(child) 
$0 (parent) 
Post-intervention visit 
clinical measures (with parent), 
fMRI scanning (with child) 
45 minutes 
$25 (child) 
$25 (parent) 
14-week follow-up visit 
clinical measures completed 
online (by parent) 
30 minutes 
$10 (child) 
$50 (parent) 
 
Parents will make initial phone or email contact with the study coordinator. The study coordinator will 
conduct a brief telephone screening to determine preliminary eligibility for the study. If eligible, the study 
coordinator will schedule the initial visit. 
 
The initial visit will last approximately 3 hours. Following informed consent (see Section 9.0), an in-depth 
MRI screening form will be filled out by the parent and the medical history information obtained during 
the initial telephone interview will be reconfirmed. Any female participants will complete a pregnancy test. 
Dr. Carpenter will then conduct the ADOS and K-BIT with the child while the parent completes the 
following clinical outcome measures on a computer (using RedCap) in a separate room: Social 
Responsiveness Scale-2 [26], the Social Skills Improvement System, the Quality of Play Questionnaire, 
the Aberrant Behavior Checklist, and the Test of Adolescent Social Skills Knowledge-Revised [27]. The 
child and parent are given a 10-minute break and a healthy snack, if desired.  
 
Following the break, the child is introduced to the tDCS electrodes placed on the scalp with no 
stimulation as an initial step in the acclimation process. Because some individuals with ASD can be 
excessively sensitive to certain sensory stimuli, this initial introduction to the electrodes is important. 
While the subject is being acclimated to the electrodes, the research coordinator explains the fMRI task 
to the child and demonstrates the task on a computer. The electrodes are removed, then the child is 
placed in the mock scanner. The mock scanner introduces the participants to the scanning environment 
by laying in the bore of a simulated scanner, listening to MRI sounds, practicing button presses and 
playing a game that awards points for keeping head movement to a minimum (via a head tracker in the 
mock scanner controlling the cursor – the longer the subject keeps their head in the same location, the 
longer the cursor stays on a bullseye and the more points they accumulate). Participants will play the 
bullseye game for 5 minutes. Dr. Joseph’s prior experience in scanning youths with ASD indicates that 
they can keep their heads still for this period of time. The subject will then practice the fMRI task in the 
mock scanner for about 3 minutes. 
 
After mock scanner training, subjects are taken to the MRI scanner and placed on the scanner bed in a 
comfortable position, with blankets and head cushioning. The child is told that the parent is always 
nearby and that the research team will be able to talk to them through the headphones. Additional ear 
protection is provided in the form of foam ear plugs. When subjects are in the scanner but not performing 
any particular task, a movie will be played for them. The child is given a button box to hold in their 
dominant hand in order to make responses during the fMRI task. In the other hand is a squeeze ball that 
should only be used to alert the research team if they feel panicked and need to come out of the 
scanner. During scanning, the research coordinator and MRI technician are in frequent verbal contact 
with the subject and will always tell the subject what to expect in terms of noises and duration of a scan. 
Total scanning time is approximately 20 minutes. 
 

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Pre- and post-treatment fMRI sessions will use a task in which two visual stimuli are presented 
simultaneously then removed, with the location of one image replaced by a probe[28]. Participants 
respond with the index or middle finger of the preferred hand to indicate the probe location. In this type of 
probe task, brain activation is expected to be higher for probes that are in the same location as the 
stimulus that is attended more. Reaction time is also expected to be faster if the probe appears in a 
location that was just recently attended compared to the location that was not attended. In one condition, 
the stimuli are a face and house to assess attentional bias to faces versus non-faces (related to social 
awareness). Another condition presents a face with direct gaze and one with averted gaze (related to 
social motivation, social anxiety). These conditions are implemented in functional runs lasting 5 minutes 
each and each run is repeated twice. The runs are presented in counterbalanced order across subjects.  
Following fMRI scanning, an additional tDCS acclimation session is completed. Electrodes are placed on 
the scalp again, and current is gradually increased to the desired level over a 5-minute period. The child 
will watch a movie or play a video game during this acclimation period.  
 
Following the baseline visit, subjects will return on a different day for the PEERS training. PEERS is a 
parent-assisted intervention that teaches targeted social skills to high-functioning patients with ASD 
during fourteen weekly sessions. Parents and adolescents attend separate concurrent sessions that 
instruct them on key elements about making and keeping friends.  
 
Each adolescent PEERS session begins with a didactic section, approximately 30 minutes in duration. 
Then the group conducts role plays modeling the correct and incorrect ways to utilize the weekly skill set. 
Next, the group reviews homework from last week and then discusses homework for next week. During 
the last 10-15 minutes of the session, the adolescents and parents are reunified to discuss the 
homework assigned for next week.  
 
Each parent session begins with a detailed review of each adolescent’s progress on the previous week’s 
homework. Then the parents are given didactic information about the weekly skills set. Finally, the 
parents are reunified with the adolescents in order to discuss the plan for completion of assigned 
homework for next week.  
 
Topics covered during the PEERS program include the following:  
 
1. Conversational skills, including verbal and nonverbal forms of communication;  
2. Electronic forms of communication, including phone calls, text messaging, instant messaging, 
emailing, and online safety;  
3. Developing friendship networks, including identifying relevant peer 
4. Groups and extra-curricular activities in which to find sources of potential friends;  
5. Appropriate use of humor, including learning to pay attention to humor feedback from 
others;  
6. Peer entry strategies, including how to join conversations with other adolescents;  
7. Peer exiting strategies, including how to assess receptiveness during peer entry and what to do 
when these attempts fail;  
8. How to have successful get-togethers, including how to organize and execute a gathering with 
friends;  
9. Good sportsmanship, including how to appropriately behave during games and sports;  
10. Handling teasing, including distinguishing teasing from embarrassing feedback and handling 
verbal teasing through the use of appropriate behavioral 
responses;  
11. Handling bullying, including identifying strategies for handling cyber bullying and physical threats 
from others;  
12. Changing reputations, including long-term strategies for altering a bad reputation;  
13. Resolving arguments with friends, including specific steps for problem solving disagreements; 
and handling rumors and gossip, including behavioral strategies for minimizing the damage 
caused by gossip. 

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Subjects will receive tDCS weekly in conjunction withtheir PEERS session. Half of the adolescent 
participants will be randomly assigned to receive active tDCS of the left dorsolateral prefrontal cortex 
(DLPFC), and half will receive sham tDCS to the same location. Active / sham assignment does not 
change over the course of the experiment. However, within each condition, half of the participants will 
receive tDCS during the first 30 minutes and half will receive tDCS during the second 30 minutes. This 
schedule will then be reversed at each session. This will counterbalance the time of tDCS delivery and 
will increase the feasibility of setting up tDCS in a reasonable time window. Sham tDCS is achieved by 
wiring all group participants to separate computer-controlled tDCS programs. All participants receive an 
initial brief dose; those receiving sham treatment are then automatically decreased to zero by the 
computer, allowing all clinical personnel to remain blind to the participant’s condition. Participants 
themselves are also blind to condition as most people report that the tingling sensation associated with 
tDCS decreases within the first few minutes of treatment.  
 
For participants randomized to receive active treatment, tDCS will be delivered in 30-minute sessions 
with the Chattanooga Ionto system using 1.5mA current. This constant current device ramps up to the 
desired amplitude to minimize discomfort for participants and ramps the amplitude back to 0mA at the 
end of the session. Electrodes will be standard small (4x4 cm) sponge electrodes soaked in a sterile 
solution of 0.9% sodium chloride insulated by a latex casing. The current density and total charge 
delivered by the above parameters is consistent with those used safely in the current research literature. 
In all tDCS conditions, the anode will be placed on the scalp over the area corresponding to the left 
DLPFC (position F3 from the EEG 10-20 system located via a commercial EEG electrode placement 
cap), a brain region postulated to have deficient neural inhibition in ASD [29-30] and demonstrated to be 
a potential tDCS site for the reduction of symptoms associated with ASD[21]. The cathode will be on the 
scalp over the area corresponding to the right DLPFC (position F4 from the EEG 10-20 system located 
via a commercial EEG electrode placement cap). Specially designed software (authored by investigator 
Borckardt) interfaces with an ONTRAK ADU218 Solid State Relay I/O interface connected to the tDCS 
device permitting normal and reverse current flow between the electrodes in a manner that is completely 
masked. The software reads the assigned condition directly from an encrypted participant-randomization-
file and delivers anodal or sham stimulation in a blinded fashion. 
 
A brief questionnaire about adverse effects will be completed with participants and their parents 
immediately following the second and last treatment sessions. Tolerance for tDCS will be monitored 
during tDCS delivery by noting the frequency with which a subject reported irritation, discomfort, burning 
or pain, whether a subject attempted to remove the tDCS leads, whether a subject wished to discontinue 
the procedures due to the tDCS (rather than the PEERS training). After the second and last PEERS 
sessions, the experimenters will administer a brief questionnaire with the subject about whether they felt 
uncomfortable itching, tingling, burning during the session or whether they have had headaches, neck 
pain, sleepiness, moodiness in the past week. Any of these effects will be recorded. We will conclude 
that tDCS can be tolerated if these effects are experienced less than 25% of the time for a given 
individual. We will also report on how many subjects tolerated the procedures. 
 
The child and parent receive compensation in the form of gift cards following each visit to MUSC (see 
Table above).  
 
After 14-weeks of PEERS training, subjects will return for a post-treatment session in which the clinical 
outcome measures will be completed by parents and fMRI session will be completed by the participants 
(same procedures as before excluding tDCS acclimation). 
 
Finally, 14 weeks after the post-treatment session, the parent will be sent a reminder via RedCap to 
complete the clinical outcome measures. In addition, both parent and child will be asked to guess which 
condition the child was assigned to (active or sham tDCS). Once the final follow-up surveys are 
completed in RedCap, the final gift card of $75 is mailed to the family.  

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Information about which condition a subject was assigned to is not typically provided, but if a subject 
asks, we can tell them after all study procedures are completed and the blind is lifted. Study personnel 
will also be asked to guess the condition before the study blind is lifted.  
 
Source records: the data collected from subjects include: parental and subject responses on clinical tests 
and questionnaires, anatomical and functional MRI scans, reaction time and accuracy responses on the 
fMRI task. 
 
11.0 Specimen Collection and Banking (if applicable) 
N/A 
12.0 Data Management  
 
Statistical Power. Schneider and Hopp [4] reported an effect size of 2.87 (Cohen’s d) for improvement in 
syntax acquisition in minimally verbal children with autism following 30 minutes of tDCS. This large effect 
size requires a minimum sample size of 10 subjects, which is comparable to the proposed sample size. 
However, that studied tested a different domain (syntax acquisition) from the present study (social 
cognition and communication) and sample of children with higher autism severity. Nevertheless, those 
initial findings are promising indicators of the efficacy of the use of tDCS in ASD. 
 
Data Analysis plan. 
 
• 
AIM 1: We predict that adverse effects and ratings of discomfort, pain, and side 
effects will be minimal. Only descriptive statistics will be used – frequency of 
reports of different types of discomfort or pain. 
 
• 
AIM 2: We predict that participants receiving active tDCS will show greater 
improvement on the Social Responsiveness Scale, the Social Skills Improvement 
System, the Quality of Play Questionnaire, the Aberrant Behavior Checklist, and 
the Test of Adolescent Social Skills Knowledge-Revised compared to those 
receiving sham tDCS. This will be assessed by examining descriptive statistics for 
each measure.. 
 
• 
AIM 3: We predict that after intervention, all participants will show increased 
social brain network response to faces (v. objects) and to direct (v. averted gaze), 
with a greater response in those receiving active tDCS. The analysis of fMRI data 
will include preprocessing (geometric distortion correction, head motion and slice 
timing correction, spatial (7-mm FWHM) and temporal high-pass (100 sec cutoff) 
filtering and spatial normalization to MNI space via each subject’s high-resolution 
T1 MPRAGE image. Eight regions of interest (ROIs) will be defined as 10-mm 
diameter spheres located in left and right medial prefrontal cortex, left and right 
temporoparietal junction, left and right fusiform gyrus, left and right amygdala, 
based on prior studies of face processing. In each ROI, percent signal change for 
faces v. objects or for direct v. averted gaze will be extracted for each subject and 
for each time point. The effect of tDCS on fMRI signal will be assessed with 
descriptive statistics.  
 
13.0 Provisions to Monitor the Data to Ensure the Safety of Subjects (if 
applicable) 

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This project involves both a medical device intervention (tDCS) and a behavioral intervention (PEERS 
training). fMRI scanning, while not an intervention, will be conducted prior to and following 14-weeks of 
weekly tDCS sessions. 
For tDCS, safety of the participants will be monitored during and immediately after delivery of tDCS to 
the scalp. During tDCS stimulation, subjects have the option of wearing a ski cap which may reduce 
discomfort. They will be introduced to the ski cap during the tDCS acclimation session on the initial visit. 
Some subjects may opt not to wear the ski cap, but it will not affect tDCS delivery. At the end of the 
sessions that involved tDCS delivery, subjects will be asked if they felt or feel any sensations on the 
scalp where the electrode was and responses are recorded by the experimenter. In Dr. Borckardt’s 
experience and other reports in the literature, any sensations of pain, tingling, itching, stinging or irritation 
follow the onset of stimulation for about 30-60 seconds and do not persist longer than that. If subjects 
report feelings of sensation or pain that are unmanageable, a local analgesic cream (benzocaine) can be 
used or the level of current can be reduced to help them complete the session. Dr. Gwynette will be 
present during all experimental sessions when tDCS is delivered and will be able to monitor for any 
adverse medical effects.  
Adverse effects will be defined by painful sensations that are unmanageable and cannot be alleviated 
using the procedures outlined above or by persistent reports of high levels of pain by a participant. 
Although we do not expect this to occur, such events will be reported to the IRB.  
 
For PEERS training, which is a behavioral intervention, the risks are minimal, but include potential 
discomfort in interacting with other individuals. Should this intervention prove to be too distressful for an 
individual, the individual will have the option to discontinue the study. Distress would be indicated by 
persistent withdrawal from or refusal to engage in PEERS activity, persistent protesting, crying or 
agitation during PEERS sessions. Dr. Gwynette and the research assistant will make the decision as to 
whether an individual is experiencing distress. When these behaviors lead to removal from the study, 
these will be reported as adverse events to the IRB.  
 
To protect against risks associated with fMRI scanning, the following procedures are followed. To 
minimize discomfort in the MRI scanner, every attempt will be made to maximize the comfort of the 
participant by using pillows or other supportive materials for neck and back support and by keeping the 
time in the scanner to a minimum, without sacrificing quality of experimental design. To prevent eye 
strain and dry eyes, we will suggest that volunteers use eye drops before the experiment, if necessary.  
To protect against the loud noise of the MRI scanner, all participants are required to wear ear protection 
provided by the experimenter. Some participants could experience claustrophobia. To prevent this, one 
of the screening questions on the telephone questionnaire asks about a history of claustrophobia. 
However, some individuals may not know they are claustrophobic. One measure to screen for this is the 
use of mock scanner prior to the real scanning session. This allows some individuals to figure out 
whether they would not tolerate the enclosed space before entering the real MRI scanner. However, if an 
individual experiences panic or anxiety at any point while in the MRI scanner, he or she is removed 
immediately from the scanner. While in the MRI scanner, the volunteer holds a squeeze ball that 
produces a loud noise in the control room that can be heard over the noise of the scanner and stops the 
scanner. The experimenters will query the volunteer immediately upon hearing the squeeze ball to 
determine whether the subject is experiening any kind of panic or anxiety. If so, the subject is removed 
from the scanner immediately and allowed to rest comfortably in a chair outside of the scanner area until 
he or she feels calmer. The participant is invited to re-enter the scanner at another time, if they wish.  To 
prevent dizziness from moving too quickly within the magnetic field, individuals are instructed to move 
slowly when laying down and sitting up from the MRI scanner bed. The scanner bed moves very slowly 
to avoid this reaction. To minimize the chance for injury due to the presence of metal in the body 
(excluding dental fillings and permanent retainers) and surgical implants, several measures are taken. 
First, the telephone interview asks about the presence of metal or devices in the body as well as any 
conditions that might have put the individual at risk for having metal in the body (e.g. welding and 

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combat). Second, upon arrival for the study, the individual signs a checklist ensuring that no metal is in 
the body. Third, a small metal detector is also used at this time to make sure that the subject has 
removed all metal (jewelry, coins, belts, hair accessories) from the body. If there is any chance that metal 
exists in the subject’s body (e.g., a history or welding without eye protection or piercings) that cannot be 
removed for purposes of the experiment, the individual is not allowed to enter the MRI scanner. There is 
no risk for injury to the subject or risk for damage to the equipment if all metal has been removed from 
the body and no metal exists in the body. The screening procedures make every attempt to isolate all 
conditions that could potentially lead to injury. However, if the individual does not respond truthfully to 
these inquiries (or may have forgotten some condition), we will have no way to know that metal is 
present in the body. Consequently, there is a potential risk for injury in this case.  
 
High-resolution anatomical scans collected for research purposes as part of the study could reveal some 
type of brain abnormality or pathology. The consent form states that the scanning sequences are not 
optimized to detect clinical conditions and that the MRI scans will not undergo routine reading by a 
qualified neuroradiologist.  However, if the research investigators notice something unusual in the MRI 
images, Dr. Leo Bonilha will be consulted to detemine whether the incidental finding requires an urgent 
response. If Dr. Bonilha deems that the finding is urgent or if the parent and volunteer should be notified, 
the PI will contact the volunteer and parent. If the volunteer/parent would like the brain images collected 
as part of this study to share with their physician, we will provide a copy of the images directly to the 
volunteer. 
 
Response to adverse events for fMRI: Although the risks of MRI scanning are fairly minimal if all safety 
precautions and subject screenings are followed, very rarely adverse events could occur. For example, in 
the presence of a strong magnetic field metal objects can be sucked into the scanner and become 
projectiles causing injury to the subject or personnel. Other potential adverse events (which are very 
rare) might include injuries at the scanner (due to undetected or unreported metal in the body heating up 
or moving in the magnetic field) or intense panic reactions that might need medical attention. The CBI 
requires that two study personnel (or an MRI-technologist and an individual from the research team) 
must be present while scanning a subject. In the rare case that a subject requires medical attention at 
the scanner during an experiment, one of the experimenters or technologist will immediately dial 911 (the 
research MRI scanner at 30 Bee St is not part of the hospital system so we need to dial 911 for 
emergencies). The other experimenter will attend to the subject by safely removing him / her from the 
scanner and placing him or her on the MRI-compatible patient bed (with the help of the second 
experimenter once a call for help is made). 
 
Confidentiality is achieved by (1) assigning a random code to each subject to de-identify data collected 
from the subject and storing that data with the code rather than with any personal identifiers, (2) storing 
any personal identifying information in locked files cabinets in Clinical Sciences Building Room 325F, (3) 
only allowing study personnel to be present at the MRI scanner at 30 Bee Street during the experiment, 
(4) training study personnel to never refer to individual participants by name (or to their parents by 
name), and (5) never identifying an individual participant in scientific papers that summarize the results of 
the studies. 
 
The de-identified electronic data associated with individual subjects will be stored on MUSC secure hard 
drives accessible only to study personnel.  A master file that links a subject’s identity to the random code 
will also be saved on MUSC secure hard drives in a password protected file. 
 
14.0 Withdrawal of Subjects (if applicable) 
Subjects can withdraw from the study voluntarily. Although financial incentives will be provided for 
continued participation, subjects are not forced or otherwise coerced to participate.  
The investigators may withdraw an individual from the study for the following reasons: (a) participant 
does not understand or follow instructions, (b) participant is not cooperative or is disruptive during 
PEERS/ tDCS delivery or fMRI scanning sessions, (c) the safety of the individual is at risk due to tDCS 

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delivery, as described above (persistent or intense experience of pain), (d) the subject exhibits severe 
psychological distress or anxiety during tDCS delivery, PEERS activities or fMRI scanning. If any of 
these reasons leads to withdrawal from the study, Drs. Gwynette / Joseph would discuss the reason(s) 
with the child and parent as soon as possible following the incident. This could be immediate if only the 
volunteer would be affected (e.g., during fMRI scanning), but if there are disruptions or a failure to follow 
instructions during a PEERS session (which takes place in a group format), Dr. Gwynette will discuss the 
issue with the parents following the session. 
15.0 Risks to Subjects 
 
The risks to the adolescent subjects are as follows: 
 
Participants may feel restless or uncomfortable when lying in the MRI scanner. This may occur and is 
generally not serious.  
 
Eye strain and dry eyes may occur. This occurs occasionally but is not serious  
 
The MRI scanner produces loud noise. With adequate ear protection provided by the experimenters, this 
is not a significant risk.  
 
Some participants could experience claustrophobia. This occurs infrequently. 
 
Moving too quickly within the magnetic field can cause dizziness. This occurs occasionally but is not 
serious. 
 
The presence of metal in the body (excluding dental fillings or some types of permanent retainers) and 
surgical implants can potentially cause injury when the individual is placed in a strong magnetic field. 
This occurs very rarely if subjects are well-screened. It is serious. 
 
High-resolution anatomical scans collected for research purposes as part of the study could reveal some 
type of brain abnormality or pathology. This occurs very rarely and may be serious. 
 
tDCS has been linked to onset of seizures in people with epilepsy, but the likelihood of inducing seizures 
in people without epilepsy is extremely low. 
 
tDCS may cause itching, tingling, burning and discomfort at the site of delivery on the scalp. Headaches 
have also been reported. 
 
Some of the activities during PEERS training (e.g., role-playing) may cause mild self-consciousness or 
embarrassment for some individuals. There is potential loss of privacy due to participating in group 
discussions. 
 
 
There is potential loss of confidentiality of research records. 
 
The risks to the parents are as follows: 
 
There is potential loss of confidentiality of research records. 
 
16.0 Potential Benefits to Subjects or Others 
The potential benefit of this study is that tDCS and/or PEERS training will improve social interaction and 
communication skills in individuals with ASD.  
This could also have secondary benefits for family members and friends of the research participants. 

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This study involves procedures for which the risks are known to be minimal; therefore, the potential 
benefit of improved social communication and interaction outweighs these risks. 
17.0 Sharing of Results with Subjects 
Parents will be provided with a brief written summary of ADOS and Cognitive results upon request. As 
discussed above in Section 13.0, incidental findings will be shared with the parent. Disclosure of the 
random assignment of active versus sham tDCS will be provided upon request. 
 
18.0 Drugs or Devices (if applicable)  
 
The tDCS devices, accessories and laptops used in this study will be stored in the Institute of Psychiatry 
South, 5th floor in a locked cabinet. Only authorized personnel have access to the devices. The research 
coordinator will be trained in the use and proper storage of the devices.  
 
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