TMS for Improving Response Inhibition in Adolescents With OCD
Phase: NA
Conditions: Obsessive-Compulsive Disorder
Sponsor: Bradley Hospital

Kristen Benito, PhD 
 
Protocol 
Bradley Hospital, Rhode Island Hospital 
 
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TMS for Improving Response Inhibition in Adolescents With OCD 
NCT05104697 
November 19, 2024 
 
 
 
 

Kristen Benito, PhD 
 
Protocol 
Bradley Hospital, Rhode Island Hospital 
 
Page 2 of 15  
Title of the Protocol: 
TMS for improving Response Inhibition in Adolescents with OCD 
 
Type of Investigation: 
Double-blinded Randomized Crossover Trial 
 
Objectives of the Investigation: 
 The study will examine whether inhibition of the pre-supplementary motor area (pSMA) using transcranial 
magnetic stimulation (TMS) normalizes activity in pSMA-connected circuits, improves response inhibition, and 
reduces compulsions in adolescents with OCD.   
 
Participants:  
The participants for this study will consist of 14 youth ages 13-18 years with OCD. 
 
Duration of the Investigation:  
Length of the study is one year. Duration of the study for individual participants will be 3-4 weeks.  
 
Study Design:  
We will use a within-subject, counterbalanced design comparing TMS vs Sham in a brief 2-visit protocol enrolling 
14 youth (age 13-18) with OCD. At each visit, youth will complete the Stop Signal Task (SST) with concurrent 
electroencephalogram (EEG) pre- and post- TMS or Sham. TMS will be delivered over pSMA using continuous 
TBS (cTBS). After each visit, youth will rate symptoms using ecological momentary assessment (EMA). 
 
Study Procedures:  
Overall, study procedures include (a) pre-screening for initial eligibility determination; (b) clinical interview for 
final eligibility determination, (c) two study visits at which youth will receive TMS or Sham and complete EEG and 
SST procedures. Assessment procedures include structured diagnostic interviews, and safety screening for TMS. 
Interested participants will complete a brief phone screen and provide medical records for review before scheduling 
a clinical interview. Clinical Interview: Participants will complete informed consent (signature required from one 
parent/guardian), child assent, and assessment of inclusion/exclusion criteria (Mini Kid, CYBOCS, TMS screen; see 
Measures). Interviews will be administered by the RA, who is already employed at PARC and trained to a reliable 
standard on all measures. At each of visits 1 and 2, participants will complete a TMS safety screen and medication 
tracking form; they will then complete the SST with concurrent EEG pre- and post- TMS or Sham. The AEQ will be 
completed at the end of each visit. Between visits, youth will rate symptoms using EMA (see Measures). Visits 1 
and 2 will occur at least one week apart to ensure that any acute TMS effects are no longer active by visit 2. Single 
session rTMS aftereffects on EEG suggests aftereffect durations <70 min63. 
 
Inclusion Criteria: 
● 
Age 13-18 years 
● 
Presence of OCD, as indicated by score on the Children’s Yale-Brown Obsessive-Compulsive Scale  
● 
Patient and one parent speak English fluently (to ensure comprehension of study measures and instructions 
● 
Right-handed 
● 
If taking psychotropic medications, these have been stable for > 6 weeks and are expected to remain stable 
for the approximately 3-week study protocol  
● 
If currently in psychotherapy, symptom improvement has plateaued (no improvement in the past 6 weeks 
and symptoms expected to remain stable for the approximately 3-week study protocol) 
 
Exclusion Criteria: 

Kristen Benito, PhD 
 
Protocol 
Bradley Hospital, Rhode Island Hospital 
 
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• 
Medical conditions contraindicated for TMS or EEG, including history of intracranial pathology, increased 
intracranial pressure, epilepsy or seizures, traumatic brain injury, brain tumor, stroke, implanted medical 
devices, possible pregnancy (female of childbearing age not using effective contraception), or any other 
serious medical condition (note that medical history will be reviewed by a study physician prior to TMS 
administration) 
• 
Metal in the head, except mouth (e.g., cochlear implant,  implanted brain stimulators, aneurysm clips)  
• 
Active suicidality or psychosis 
• 
Existing diagnosis of Autism Spectrum Disorder, mental retardation, or cognitive disability 
• 
Substance abuse or dependence 
• 
Taking a stimulant medication (and unwilling to forgo on study visit days) 
• 
Taking medication with the potential to lower seizure threshold (e.g., neuroleptics, antipsychotics) 
• 
Patient is a ward of the state 
 
To increase external validity of findings, we will include participants taking psychotropic medications that have 
been stable for 6 weeks and expect to remain stable for the approximately 3-week study protocol (with the exception 
of those taking medications that reduce seizure threshold).  
 
Study Design Flow Chart:  
 
Study Assessment Measures: 
1) Mini-Kid64; the Mini-Kid 7.0 is a brief, structured interview measuring psychiatric diagnoses in children 
according to DSM-V and ICD-10 criteria.  
2) CY-BOCS65, is the “gold standard” clinical interview for assessment of OCD symptoms.  
3) Screening Questionnaire for TMS Candidates66-67; screens for TMS contraindications and will be administered in 
an interview format with both the child and parent present.  
4) TMS Adverse Effects Questionnaire (AEQ68) is a 13-item questionnaire completed by patient (items 1-10) and 
clinician (items 11-13).  
5) The SST is a well-validated computerized task measuring RI69-70. The SST is a visual choice reaction time task in 
which participants watch arrows (left or right) on the screen and respond by pressing the appropriate button. In a 
randomly assigned proportion of trials, an audible signal is heard after presentation of the arrow, and subjects are 
instructed to inhibit the motor response (button press). The inter-stimulus interval and stop-signal delay are varied 
according to individual performance so that each person can successfully inhibit responses to 50% of stop trials. 
SSRT (time required to inhibit a prepotent motor response) is calculated from these data. Successful stop trials (i.e., 
those in which a motor response is successfully inhibited) are most relevant for understanding functional neural 
correlates of RI, and will be of primary interest in EEG analyses (see below).  
6). EMA will be used to obtain youth ratings on three items (modified from NIMH rating scales) assessing 
obsessions, compulsions, and mood on a 7-point scale (1 = not at all to 7 = very much). These items have shown 
differential change with frequent assessment post-TMS for adults with OCD71 and have been used in EMA studies 
of OCD72. Youth will receive a text message prompt every two hours (between 9am and 9pm) over the two days 
following the clinical interview and each study visit (6 days total). The text prompt will include a redcap link for 
completing EMA items. Similar EMA items and procedures have been used successfully with adolescents of diverse 
backgrounds in a large number of studies to date73.  

Kristen Benito, PhD 
 
Protocol 
Bradley Hospital, Rhode Island Hospital 
 
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7). HARM Form. At visits 1 and 2, we will administer the HARM form to assess for new or worsening suicidal or 
homicidal ideation (SI or HI). The Harm Form was developed for SI/HI monitoring by the Child and Adolescent 
Multimodal treatment Study (CAMS) team105 and NIMH program staff and was also used in the POTS II and POTS 
Jr trials for youth with OCD61-62. The form is designed to ascertain the presence of any thoughts, wishes, or 
behaviors related to self-harm or harm to others since the last study contact. This brief measure consists of two 
broad initial probes—one asking about self-harm and the other about harm to others—and 5-8 contingent follow-up 
questions assessing acute risk status.  
 
EEG procedures: 
EEG Acquisition. EEG will be recorded continuously (band pass 0.1 - 100 Hz; sampling rate 10000 Hz) from the 
scalp using Brainvision system with the actiCAP slim 64 channel cap with a nose reference, along with additional 
electrodes to record the vertical and horizontal electrooculogram (EOG). All electrode impedances will be 
maintained below 10 kΩ.  
 
EEG Data processing. EEG pre-processing: EEG recordings will be band-pass filtered between 1 and 55 Hz and 
visually inspected to remove segments with extreme motion artifacts. Noisy channels and dead channels will be 
removed, and the missing channels interpolated. To correct for eye-related artifacts (saccades and blinks), temporal 
independent component analysis will be performed74-75. The components that have a correlation higher than 0.8 with 
the EOG electrodes will be removed, and the remaining components will be added together to restore the EEG 
signal without the artifacts. The cleaned EEG will be segmented into epochs consisting of the time period during 
auditory stimulus presentation, along with a 100 ms baseline and a 500 ms offset period. Epochs with a voltage 
greater than ± 100 µV will be considered an artifact, and if the artifact cannot be corrected, will be excluded from 
the analysis. All EEG data preprocessing will be performed using the software package MNE-python76. Variable 
calculation. P3 is a well-established correlate of RI performance on the SST (including SSRT55) and of activation in 
inhibitory networks. We will calculate P3 amplitude on successful stop trials by averaging the epochs of successful 
stop trials time-locked to the stop signal from the midline electrode (Cz)55.  
 
Randomization: 
The order in which participants receive TMS and Sham (visit 1 or 2) will be randomly assigned (blocking on 
medication status, biological sex, and baseline CYBOCS severity) and masked for all study staff except for the 
statistician. 
 
TMS Protocol: 
During TMS, a pulsed magnetic field is produced by a small coil positioned over a targeted area on the scalp, 
inducing an electric current in the brain that temporarily modulates cortical activity. Repetitive TMS (rTMS) 
paradigms use trains of pulses to induce cortical effects that outlast the duration of stimulation.63 The direction of the 
rTMS effect, either facilitation or suppression of cortical activity, depends on pulse frequency and sequence (i.e., 
intertrain interval). Research using neuroimaging and electrophysiological recordings has demonstrated that single 
low frequency (1Hz) and continuous bursting frequency (continuous theta burst stimulation; cTBS) induce 
inhibitory effects.63,78-80 rTMS augmentation of cortical targets can impact local activity, connectivity, and network 
properties.81 TBS and conventional rTMS have comparable effects on cortical excitability82-83 and similar safety 
profiles in pediatric samples.47,103 TBS has particular advantages for a pediatric population, specifically much shorter 
stimulation duration (i.e., 2-3 min for TBS vs. 20-30 min for rTMS) and lower stimulation intensity.47 
 
TMS Device. We will use a Magstim SuperRapid2 Plus 1 TMS system with matching active and sham air-cooled 
coils (Magstim, Carmarthenshire, UK) (http://www.magstim.com, UK) to stimulate over pSMA target. 
 
TMS Targeting. Targeting will be carried out using the 10-20 EEG system. Scalp vertex (Cz) will be defined based 
on the midpoint of the inion and the nasion on the sagittal midline. Prior research77 has defined the SMA as 15% of 

Kristen Benito, PhD 
 
Protocol 
Bradley Hospital, Rhode Island Hospital 
 
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the distance between inion and nasion (I-N distance) anterior to Cz. Our research using neuronavigation to locate 
left pSMA indicated that average distance from Cz is 15.9% of the I-N distance anterior to Cz. Based on this 
information, we will target 16% of the I-N distance anterior to Cz (placement illustrated in the figures below, 1.5 cm 
from midline).  
 
 
 
 
 
 

Kristen Benito, PhD 
 
Protocol 
Bradley Hospital, Rhode Island Hospital 
 
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TMS Parameters. TMS will be delivered over pSMA using cTBS. Research using neuroimaging and 
electrophysiological recordings has demonstrated that single low frequency (1Hz) and cTBS typically induce 
inhibitory effects63,78-80. rTMS augmentation of cortical targets can impact local activity, connectivity, and network 
properties81. TBS and conventional rTMS have comparable effects on cortical excitability82-83 and similar safety 
profiles in pediatric samples47,84. TBS has particular advantages for a pediatric population, specifically much shorter 
stimulation duration (i.e., 2-3 min for TBS vs. 20-30 min for rTMS) and lower stimulation intensity47. cTBS will 
consist of bursts of 3 pulses at 30 Hz repeated every 200ms (5 Hz burst frequency), single uninterrupted 40 sec train, 
600 total pulses; 90% RMT. This sequence has been used in prior pediatric compulsivity samples85. 30 Hz is 
advantageous over conventional 50 Hz TBS in developmental samples as it can be delivered at higher stimulation 
intensity86 and children have higher motor thresholds87. Single session aftereffects are approximately 60 min for 
cTBS88-89. 
 
Motor threshold (MT) determination. Resting MT will be defined as the minimum magnetic flux needed to elicit 
observed twitch of the thumb (resting target muscle: abductor pollicis brevis) in 5/10 trials using single-pulse TMS 
administered to the contralateral hand area of primary motor cortex (as described by Badran and colleagues106). The 
MT procedure will occur during the first visit and this MT will be used to calculate stimulation intensity for all TMS 
sessions. Patients will be in the same position (upright) during both motor threshold and stimulation procedures. The 
figure below demonstrates placement for eliciting twitch in resting target muscle (abductor pollicis brevis): 
 
Category 
Parameter 
Coil type 
Shape 
Figure 8 
Size 
70mm 
Coil Placement 
Orientation 
45° 
Stimulation site 
Left pSMA 
Method for locating stimulation site 
Scalp measurement based on 10-
20 system 
Stimulation parameters 
Pulse intensity 
90% RMT 
Pulse frequency 
30 Hz 
Train length 
40 sec 
Number of trains 
1 
Intertrain interval 
0 
Session parameters 
Pulses per session 
3 
Number of sessions 
1 

Kristen Benito, PhD 
 
Protocol 
Bradley Hospital, Rhode Island Hospital 
 
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Sham procedures. Sham stimulation will use the Magstim sham air-cooled coil, which produces auditory signals 
identical to an active coil but contains a mu-metal shield that diverts the majority of the magnetic flux such that a 
minimal (<3%) magnetic field is delivered to the cortex. Forms assessing blinding adequacy will be given to 
participants, parents, and blinded staff who study visits. 
 
Masking procedures will be implemented to control for expectancy effects related to TMS stimulation. Persons who 
will be masked to TMS status are: participants; parents (if applicable), study staff administering clinical 
assessments, SST, and EEG, study staff administering TMS, and all study investigators except for the study 
statistician responsible for randomization. Forms assessing masking adequacy will be given to participants, parents, 
and staff administering TMS. Study staff administering TMS will remain masked using the following procedures. 
The Sham and Active Coils are identical in appearance. The motor threshold coil which will be used for all 
procedures is different in appearance than the active and sham treatment coils. Each coil will each be labeled with a 
unique random number (e.g. 1639 vs 2740) but the technician will not know which is active and which is sham. The 
Neuromodulation Facility Manager will hold the masking log in a secure location. A masked TMS coil assignment 
log (included in CRF) will be used for the study with consecutively consented subjects assigned to consecutive ID#s 
that appear in the form. For each ID# there will be a coil number (e.g., 1639 or 2730) assigned in random order prior 
to start of the study. At the time of each treatment, the technician will confirm the participant's name and consult this 
form to select the correct coil to attach for the treatment session that day. The date of each session must be 
documented, along with the maximum intensity (relative to MT) applied in the session that day,etc. 
 
Description of the Statistical Methods:  
 
Statistical methods align with the Aims of the study, which are as follows: 
 
Aim 1. Safety and Tolerability. TMS will be safe and tolerable, as indicated by a comparable rate of side effects 
associated with TMS vs. Sham (hypothesis 1) and no serious adverse events associated with TMS (hypothesis 2). 
 

Kristen Benito, PhD 
 
Protocol 
Bradley Hospital, Rhode Island Hospital 
 
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Aim 2. Neural Target Engagement: TMS-induced changes in the RI Network. Compared with sham, 
participants will demonstrate significant post-TMS neural changes during SST stop trials, as indicated by increase in 
frontocentral P3 amplitude 
 
Aim 3. Behavioral Target Engagement: TMS-induced changes in RI behavior. Compared with sham, 
participants will demonstrate a significant post-TMS decrease in SSRT (Hypothesis 1) and EMA-rated compulsions 
(Hypothesis 2).  
 
Data Analysis. We will test Aim 1 (Safety and Tolerability) using descriptive data as follows. Hypothesis 1. TMS 
will be safe and tolerable as shown by total AEQ ratings that are no more than 1 SD higher for TMS vs. Sham 
(hypothesis 1) and no serious adverse events associated with TMS reported on the AEQ (hypothesis 2). Remaining 
analyses will use Generalized Linear Mixed Models (GLMM), a variant of Generalized Linear Models (GLM; of 
which ANOVA, t-test, and regression are special cases) that permit outcome variables with distributions other than 
Gaussian and additionally permit modeling both fixed and random hierarchical (nested) effects. For each model, the 
distribution will be selected based on theory (e.g., Poisson for count) and model residuals. Aim 2 (Neural Target 
Engagement). We will examine the significance of TMS-induced neural changes during SST stop trials by testing 
an interaction between visit type (TMS vs. Sham) and timing of assessment (pre vs. post TMS/Sham) for the the 
outcome of frontocentral P3 (hypothesis 1). Aim 3. Behavioral Target Engagement: We will test an interaction 
between visit type (TMS vs. Sham) and timing of assessment (pre vs. post TMS/Sham) on RI efficiency as measured 
by the SSRT (hypothesis 1) and EMA-rated compulsions (hypothesis 2).  
 
Sample size and power. We anticipate some minimal EEG/SST data loss and participant attrition, very 
conservatively resulting in a final sample size of N = 10 participants (each with four EEG/SST observations; pre- 
and post- TMS and Sham). Given this sample size and assuming .80 correlation among repeated measures, power 
calculations indicate that Aim 2 and 3 analyses would reach 0.8 power with a medium effect size (Cohen’s d = 
0.51) and alpha = .05. Assuming .60 correlation among repeated measures, analyses would reach .8 power with a 
medium-large effect size (d = .70). Using a TMS protocol similar to that proposed in this application, Obseso (2017) 
found large effect sizes for cTBS of pSMA on SSRT in healthy adults (d = .95). Available data for proposed 
outcome variables suggest that repeated measures correlations will fall between .60 and .80, with SSRT showing 
correlations between .65-.73101 and P3 showing correlations of .68-.71102.  
 
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