Repetitive Transcranial Magnetic Stimulation (rTMS) for Obsessive-Compulsive Disorder (OCD)
Phase: NA
Conditions: Obsessive-Compulsive Disorder
Sponsor: Columbia University

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[TMS for OCD]  
Version: Edited (04-06-17); Initial (11-15-15) 
NCT02904356
REPETITIVE TRANSCRANIAL MAGNETIC STIMULATION 
(RTMS) FOR OBSESSIVE-COMPULSIVE DISORDER (OCD)
Sameer Sheth, MD, PhD  
Yagna Pathak, PhD 
Brainsway™ cingulate coil (HAC coil) 
Regulatory Sponsor (S-I): 
Co-Investigator:   
Study Product:  
Protocol Number:   
AAAQ8771 

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Study Summary 
Title 
Repetitive Transcranial Magnetic Stimulation (TMS) for Obsessive-Compulsive 
Disorder (OCD)  
Short Title 
rTMS for OCD 
Protocol Number 
Initial version 
Methodology 
Open-label study to investigate the feasibility and effectiveness of 
administering rTMS to patients suffering from OCD.  
Study Duration 
Study duration will be 3 weeks 
Study Center(s) 
Single-center 
Objectives 
The goal of the study is to assess whether repetititve transcranial magnetic 
stimulation (rTMS) can be used as a non-invasive option to benefit patients 
suffering from Obsessive Compulsive Disorder (OCD)  
Number of Subjects 
15 
Diagnosis and Main 
Inclusion Criteria  
Obsessive-compulsive disorder  
Study Product and 
Planned Use  
Brainsway™  HAC-coil to target the cingulate cortex 
Reference therapy 
N/A 
Statistical  
Methodology 
Statistics will be computed to observe changes within subjects and between 
subjects to assess the effectiveness of rTMS  
1 Introduction 
1.1 Background 
With a prevalence of nearly 3%, obsessive-compulsive disorder (OCD) is one of the most common 
psychiatric disorders in the US (1). Its clinical manifestation includes persistent, intrusive and irrational 
thoughts, such as obsessions, and repetitive behaviors, i.e., compulsions, that cause distress and 
impairment for the individual (2). From an international perspective, the WHO has reported that OCD 
accounts for approximately 1% of global years lost due to disability (1). Thus, it is a disease with notable 
socioeconomic impact both on a national and global scale.  
The first line of treatment for OCD comprises pharmacotherapy with serotonin reuptake inhibitors (SRIs) 
and cognitive behavioral therapy (CBT). Although adherence to these therapies has been shown to improve 
symptoms in at least half of patients, 30-40% have residual symptoms (3) and 10-15% are refractory to 
standard therapies (4). Options are limited, but do exist for treatment-refractory patients or individuals with 
residual symptoms. Although the mechanisms of action are not fully understood, deep brain stimulation 
(DBS) (5, 6) and stereotactic lesions (7, 8) represent two invasive interventions that have shown promise 
in alleviating residual or refractory OCD symptoms.   
However, transcranial magnetic stimulation (TMS) may offer an alternate, less-invasive therapy. Repetitive 
TMS (rTMS) has been the most studied non-invasive modality in the OCD population, and preliminary data 

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demonstrate varying degrees of success (9). rTMS hyperpolarizes and depolarizes targeted brain regions 
by delivering magnetic current through a coil (10-11).   
The symptoms of OCD are a result of generalized deficits in cognitive control, defined as the processes 
that enable pursuit of a goal while overcoming strong, automatic competing influences (12). Response 
inhibition is an executive cognitive process and one aspect of cognitive control that has been shown to be 
deficient in OCD patients (13-15).   
The dorsal anterior cingulate cortex (dACC) and its associated neurocircuitry play an important role in 
cognitive control. Neuroimaging studies (fMRI and PET) have shown the dACC to be hypermetabolic in 
individuals suffering from OCD (16-25). The inputs to and projections from dACC suggest that it may be a 
cognitive control “hub,” such that it would integrate incoming signals and in effect weigh the costs and 
benefits of exerting control, termed expected value of cognitive control (12). There is evidence to support 
this putative role for dACC at the level of neuroanatomy, neurophysiology, and functional imaging (26-29). 
Deficient fear extinction may also be present in patients with OCD as demonstrated by studies showing 
decreased activation of dACC in fMRI during fear conditioning tasks (30). Finally, it has also been observed 
that OCD individuals are less quick to change behavior after making a mistake on a task, and such cognitive 
inflexibility is associated with altered fMRI activation of dACC and other cortical areas (3132).   
Electroencephalography (EEG) can be used to measure event-related potentials (ERPs) associated with 
cognitive control signals. Specifically, error-related negativity (ERN) signals that have been localized to 
dACC (33), are produced during tasks that involve cognitive control (34), and have been found to have 
increased amplitude in OCD patients, perhaps reflecting overactive error monitoring (35-37). Evidently, 
increase in the “frontal midline theta” power correlates with clinical measures of anxiety and conflict (34).   
To summarize, rTMS can serve as a promising neuromodulatory intervention to manage refractory and 
residual symptoms associated with OCD. It can non-invasively target dACC, the putative “hub” for the 
cognitive processes, i.e., cognitive control, that are deficient in OCD patients. The present proposal is aimed 
at examining the effect of rTMS delivered with an H1 coil at the dACC on neurophysiological activity during 
a cognitive control task, as measured with fMRI and EEG.   
1.2 Investigational Device 
The coil used in the study to apply rTMS is an H1-coil geometry manufactured by Brainsway™ , specifically 
to target the cingulate cortex (HAC, Brainsway™  cingulate coil). The design of the coil is patented and 
aimed to induce stimulation at deeper regions without over-stimulating facial nerves or other superficial 
cortical regions. While not approved for OCD yet, the H-coil has received an IDE for cocaine addiction and 
was IDE exempt for marijuana addiction. The rTMS coil includes a flexible base shaped to fit the human 
head. The base is optimally fitted to the scalp at the desired region. This coil will be used in conjunction 
with a Magstim Rapid Stimulator (Magstim Company Limited, Whitland, UK).   
1.3 Preclinical Data  
The abnormal neural circuitry that exists in OCD involves a relative decrease in glutamatergic signaling 
and grey matter within the dACC compared to healthy controls. rTMS has been explored as a method of 
treatment for cases of OCD that are refractory to medical treatment. Rupp et al used a rodent model to 
discern the pattern of brain activation after subjecting the animals to rTMS.  The researchers used a 
round coil to deliver 25-Hz pulses for 2 seconds, then euthanized and decapitated the animals 45-60 
minutes later to examine their brain tissue. They found that the rats subjected to rTMS had increased cfos 
expression in the cingulate, primary and secondary motor cortices, suggesting that these areas were 
selectively stimulated by rTMS. Expression was greatest in the ACC. This shows promise for targeting the 
dACC in OCD patients (38). Several OCD animal models have demonstrated that applying high 
frequency stimulation to certain areas of the brain, such as the subthalamic nucleus and the nucleus 
accumbens, can decrease compulsive behavior. Kupsch et al subjected quinpirole-induced rats to high 
frequency stimulation (130Hz) to functionally inhibit the subthalamic nucleus and observed significantly 

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decreased compulsive checking behavior (39). Winter et al later applied the same high frequency 
stimulation to the nucleus accumbens via deep brain stimulation and also observed significantly 
decreased compulsive checking (40). It can be inferred that applying similar electrical stimulation to 
modulate dACC circuitry may also yield significant reductions in the severity of OCD symptoms.  
1.4 Clinical Data to Date  
An initial feasibility study was conducted with the Brainsway™  H1-coil at the NIH on 6 healthy volunteers. 
The device was determined to be non-significant risk (NSR) and therefore, the trial was conducted under 
an IRB approval. Another safety study was conducted in 2005 at the Shalvata Mental Health Center, Hod 
Ha Sharon, Israel. The study compared H1-coil, H2-coil, standard figure-8 coil and a sham coil in healthy 
subjects. Additionally, Brainsway™ has also conducted a clinical study for the indication of MDD. This 
study is summarized in their IDE and a recent publication (41).   
  
The aforementioned pilot and feasibility studies confirm the safety profile of the coil. It should be noted, 
that the parameters that will be employed in our OCD study, while different from those of the MDD study, 
comply with the safety guidelines recommended by the manufacturer.   
1.5 Research Risks & Benefits  
1.5.1 Risk of Investigational Device  
The risks of rTMS include seizures, headaches, and hearing problems. Since the rTMS induces an 
electrical field on the brain, the most serious risk is the possibility of having a seizure.   
  
The rTMS coil that is being used in this study is called the “HAC coil”. While rTMS has been approved by 
the FDA for some neuropsychiatric indications such as MDD, this particular coil is experimental and has 
not yet been approved by the FDA for OCD. Seizures from any kind of rTMS treatment are rare and occur 
at a rate of about 2/1000. In people who received rTMS in the past with similar intensity and the same 
Hcoil we will be using in this study, three out of more than 200 people had a seizure. Patients 
experiencing adverse effects were on certain medications that made them more prone to seizures. In 
order to minimize the risk for seizures, patients will not be able to participate in this study if they have a 
medical or psychiatric condition that requires them to take certain medications regularly. Patients will also 
not be allowed to participate if they have a family history of seizures. A physician will be present during 
each rTMS treatment and will provide necessary care in case of adverse events. Additionally,  suicidal 
ideation and emergence of manic symptoms following rTMS treatment are also potential risks.  Should 
any of these occur, patients will not be able to continue with the remainder of the study.  
  
There is also a risk of hearing problems (hearing loss or ringing in the ears) after rTMS. This problem is 
less likely to occur with the proper use of earplugs. The most common risk of rTMS is the possibility of 
having a headache after the sessions. Over the counter pain medicines (like ibuprofen or acetaminophen) 
can be taken if needed. Additional risks include scalp and dental pain, which can be treated with over the 
counter pain medications also. In case of any other adverse events, rTMS will be stopped and patient will 
be monitored closely.  
1.5.2 Other Risks of Study Participation  
While there have been no reports of any harmful long-term effects caused by the MRI scanner, including 
magnets of high strength, the long-term effects of being placed in a magnet of the strength used in this 
study are unknown. Although there are no known risks associated with pregnancy, females cannot 
participate in this study if pregnant. A negative pregnancy test (urine analysis) is required at the time of 
screening as well as the day of the fMRI scans.   
  
Some people have reported sensations during MRI scans, such as "tingling" or "twitching" (or, very rarely, 
a painful sensation), which are caused by changes in the magnetic field that can stimulate nerves in your 

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body. With any MRI scan, on occasion, some people experience nervousness or discomfort due to the 
scanner's small space and the need to lie still. Except for pacemakers, some types of metallic implants, 
and medication patches, we are not aware of any other potentially dangerous interactions or hazards 
associated with the MRI scan. The MRI scanner also produces a loud noise; earplugs will be provided to 
reduce this discomfort. It may be uncomfortable to lie motionless in the scanner, and it may cause the 
patient to feel anxious. A member of the research staff will be available to provide support.   
  
The only risk associated with psychological testing and behavioral assessment is potential 
nervousness/frustration with the tasks. The research team will thoroughly explain the tests and will be 
available to answer questions that may arise during tasks.   
1.5.3 Potential benefits  
Throughout the course of the study, rTMS may decrease symptoms associated with OCD. rTMS may also 
ease the patient’s ability to engage in cognitive behavior therapy (CBT), which may also help control their 
symptoms. However there is a possibility of no therapeutic effect for OCD, and therefore there might be no 
direct benefit to the patient.   
  
As a benefit to the OCD patient cohort, neuroimaging during this study will be used to evaluate rTMS as a 
screening procedure to help determine which patient populations might derive the most benefit from 
currently implemented invasive treatment options such as cingulotomy or DBS.  Likewise, findings from 
neuroimaging and EEG will also add to our knowledge of the circuit involved in OCD by assessing acute 
and longitudinal biomarkers.   
2 Study Objectives  
The purpose of this study is to understand how rTMS might best benefit patients suffering from disorders 
of the dACC. In particular, we will determine how rTMS affects patients with OCD. We also aim to evaluate 
rTMS as a screening procedure to help determine which patient populations might derive the most benefit 
from currently implemented invasive treatment options such as cingulotomy or DBS. Lastly, we will study 
how neuromodulation affects the circuitry of the brain by assessing acute and longitudinal biomarkers from 
neuroimaging.   
 
3 Study Design  
3.1 General Design  
rTMS delivery: High-frequency (10 Hz) deep TMS will be administered at the dACC to patients over 3 weeks 
using the HAC-coil (Brainsway™  cingulate coil) designed specifically to target the cingulate cortex and the 
Magstim Rapid stimulator (Magstim Company Limited, Whitland, UK).  Sessions will be administered five 
times a week with a total of 15 visits. The intensity of stimulation will be relative to resting motor threshold 
(110%). Forty 3-second trains with an inter-train period of 20 seconds will be applied. Total number of 
pulses administered will be 1200. Periodic weekly behavioral assessments will be performed with the Yale-
Brown Obsessive Compulsive Scale (Y-BOCS) to monitor OCD symptoms. We will also test for suicidal 
ideation (C-SSRS) and monitor manic symptoms (YMRS) twice a week in addition to baseline and at the 
end of treatment course (x 8 total) and test cognitive function with Minimental status examination (MMSE). 
Subjects will be compensated for their daily visits in order to offset inconvenience related to time, effort and 
transportation costs. They will receive $100 per fMRI session (x2 total) plus $40 per TMS session (x15 total) 
over the study period.  
  
Neuropsychological scales and tests: Neuropsychological evaluations will be administered at baseline 
and at the end of the study.  
  
1. Scales (expected to take 30-40 minutes total):  
• 
USP-Sensory Phenomena Scale  

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• 
Hamilton Depression Rating Scale  
• 
Hamilton Anxiety Rating Scale  
• 
Beck Anxiety Inventory  
• 
Beck Depression Inventory, 2nd Edition  
• 
Sheehan Disability Scale  
• 
Barratt Impulsiveness Scale (BIS -11)  
• 
Clinical Global Impression (CGI)  
• 
Quality of Life Enjoyment and Satisfaction- short form (Q-LES)  
  
2. Neuropsychological measures (expected to take about 90 minutes and can be performed in separate 
sessions as needed):  
• 
Wechsler Abbreviated Scale of Intelligence (WASI)  
• 
WMS-III Faces, LM, Digit Span, Spatial Span, LNS  
• 
Rey Osterrieth Complex Figure (ROCF)  
• 
California Verbal Learning Test, 2nd Edition (CVLT-II)  
• 
Iowa Gambling Test (IGT)  
• 
Wisconsin Card Sort Task (WCST)  
• 
Judgment of Line Orientation  
• 
Boston Naming Test  
• 
DKEFS Verbal Fluency, Trails, Color Word Interference Test  
• 
Grooved Pegs  
  
Multi-Source Interference Task (MSIT): We will use the multi-source interference task (MSIT) to engage the 
dACC and study cognitive control in OCD. The MSIT combines elements of Simon and Ericksen flanker 
tasks. A 3-number cue is presented to the subject on a screen. Of the three numbers, 2 are the same and 
represent ‘distractors’. The unique different number is the ‘target’. The patient is instructed to press the 
button corresponding to the ‘target’ number (left button if the target is ‘1’, middle if ‘2’, right if ‘3’). Importantly, 
the subject should push the button corresponding to the target regardless of where that target is in the 
sequence. Four levels of conflict are presented:   
1) No conflict: Distractors are absent and target is in correct spatial location (ex: 020)  
2) Flanker Interference: Distractors present and target is in correct spatial location (ex: 121)  
3) Spatial Interference:  Distractors are absent, but target is not in correct spatial location (ex: 200)  
4) Both Interference: Distractors are present and target in not in correct spatial location (ex: 211) 
Behavior will be quantified based on response accuracy and reaction time during the task. These 
results will be correlated with changes in Y-BOCS and changes in neuroimaging to determine the 
effect of rTMS on cognitive control in OCD.   
  
Simultaneous fMRI/EEG scans along with structural and diffusion MRI will be acquired at the beginning 
and end of treatment protocol. Pre and post-TMS EEG will also be collected 2 times a week.  
  
Neuroimaging and Neurophysiology: High resolution (3T) structural MRI will be acquired along with DTI at 
the beginning and completion of treatment. Also, a simultaneous fMRI-EEG (40 channels) scan will be 
acquired at these times while the patient is completing the MSIT. An EEG-based fMRI analysis will help us 
overcome limitations of spatial and temporal resolution that are evident when using either technique alone. 
A data-driven approach will be used to identify temporally specific and task-relevant projections of the EEG 
data, which will then be used to construct fMRI regressors. This approach will allow us to link BOLD 
correlates with task engagement, which is not possible with traditional acquisitions. Further, it will enable 
us to study trial-to-trial variability as we can measure both the amplitude and variance of the ERPs.  
  
Additionally, pre-rTMS and post-rTMS high-density scalp EEG data (128 channels) will be acquired two 
times a week for a total of 12 EEG acquisitions. The patient will be engaged in the MSIT during EEG 
acquisitions. EEG analysis will be used to quantify acute effects of rTMS by exploring within-session data, 

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and longitudinal effects of rTMS by exploring between-session data. The high-density acquisition will also 
allow for a thorough analysis in sensor and source domains.   
  
Data Analysis: fMRI regressors will be constructed at multiple offsets in the epoched EEG data to view the 
temporal progression of the discriminating components (Walz 2013). Linear classifiers will be trained on 
EEG data to estimate a set of spatial weights to maximize discrimination of 2 conditions. Regressors will 
also account for single-trial variability. Lastly, we will compute ICA-based source localization on the fMRI 
data to extract the nodes of the underlying network evoked during this task.  
  
For the EEG analysis, we will first analyze the data in sensor domain and assess the effect of rTMS by 
computing differences in ERPs and midline frontal theta. This initial analysis will then be used to reconstruct 
source signal. Region-specific measures (power) and connectivity measures (frequencydependent 
coherence) will also be computed. Although EEG measures correspond to a fraction of total synaptic action 
in a particular tissue volume, strong correlations have been reported between cognitive processing and 
event-related potentials that occur due to interactions with background synaptic action fields. Therefore, by 
extending our measures from source activity to source connectivity, we can indirectly measure changes in 
synaptic plasticity.  
  
Each patient will serve as their own control and statistical comparisons will be made between measures at 
baseline and at the end of the TMS protocol (3 weeks). Although this study design doesn’t address time-
effects, we believe it is a crucial first step towards a better understanding of the effects of TMS.   
  
Effectiveness Variables:   
  
1) Changes in midline frontal theta and ERPs will be compared pre and post rTMS for OCD  
2) Changes in dACC connectivity with frontal regions (DLPFC and OFC) will be assessed over the 
course of rTMS treatment for OCD  
3) Changes in YBOCS will be assessed over the course of rTMS as a measure of secondary 
effectiveness. Clinical response will be defined as 35% reduction in YBOCS from baseline.  
 
3.2 Primary Safety Endpoints  
According to the safety guidelines recommended by Brainsway™ corresponding to the HAC coil, 3 weeks 
is an acceptable study duration with the investigational HAC-coil. Brainsway™ has performed studies in 
control subjects and in subjects with clinical conditions (MDD, schizophrenia, bipolar disorder, addiction, 
PTSD) (Brainsway, Ltd. Unpublished data). They have currently tested 209 subjects (98 without 
concomitant psychotropic medication; 111 with psychotropic medication) with high-frequency, 
highintensity rTMS. Of the subjects who were still taking psychotropic medications that could lower 
seizure thresholds, 3 suffered a seizure. Should the patient experience adverse effects prior to completion 
of study, their participation will be discontinued in lieu of their safety. Additionally, we will account for the 
incidence, severity and frequency of all Adverse Events (AEs), including seizures and suicidality (i.e., 
suicide attempts and completed suicides).    
 
4 Subject Selection and Withdrawal  
 
CRITERION  
METHOD OF ASCERTAINMENT  
Inclusion:  
  
1) Male or female outpatients, 18 to 65 years of age.  
  
Self report  
2) Primary diagnosis of Obsessive Compulsive Disorder, as 
confirmed by the Structured Clinical Interview for the DSM-V-TR 
(SCID).  
  
SCID, DSM-IV-TR  

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3) Subjects should have at least a moderate level of OCD severity 
as defined by a Yale-Brown Obsessive Compulsive Disorder Scale 
(YBOCS) score of greater than 10 on either obsession section or 
compulsion section (YBOCS-O ≥ 10 or YBOCS-C ≥ 10).   
YBOCS  
3) Patients currently on OCD medication must be at the same stable 
dose(s) and be willing to continue the same dose(s) through the 
duration of the study.   
  
Note: Subjects should be maintained on SSRI medications (with or 
without additional antidepressant or psychotropic augmentation for 
treatment of OCD) at a stable therapeutic dosage for at least 2 
months prior to study entry and for the duration of the trial, and/or 
subjects are maintained on psychotherapeutic behavioral 
intervention therapy (subjects undergoing CBT treatment must be in 
the maintenance stage and not in the assessment or skills 
acquisition or training stages).   
  
Physician Evaluation  
4) Patients must continue to be under the care of their treating 
psychiatrist who will be writing prescriptions for concomitant 
medications through the duration of the study.   
  
Physician Evaluation  
5) Capable and willing to provide informed consent  
  
Physician Evaluation  
6) Signed HIPAA authorization  
  
Physician Evaluation  
Exclusion:  
  
1) Investigators, and their immediate families (defined as spouse, 
parent, child or sibling, whether by birth or legal adoption).   
Self Report  
2) Individuals diagnosed by the investigators with the following 
conditions:   
Bipolar Disorder (lifetime), any Psychotic Disorder (lifetime), history 
of substance abuse or dependence within the past year (expect 
nicotine and caffeine).   
  
Physician Evaluation, SCID, 
DSMIV-TR  
3) An Axis II Personality Disorder, which in the judgment of the 
investigator may hinder the patient in completing the procedures 
required by the study protocol.  
Physician Evaluation, Private 
Psychiatrist Reports  
4) Individuals with a clinically defined neurological disorder including, 
but not limited to: stroke, tics, space occupying brain lesion, any 
history of seizures except those therapeutically induced by ECT, 
history of cerebrovascular accident, transient ischemic attack within 
two years, cerebral aneurysm, dementia, Parkinson’s Disease, 
Huntington Chorea, Multiple Sclerosis.  
  
Physician Evaluation, Medical 
Records  
5) Increased risk of seizure for any reason, including prior diagnosis 
of increased intracranial pressure (such as after large infarctions or 
trauma), or history of significant head trauma with loss of 
consciousness for >5 minutes.  
  
Patient Reports  
6) History of treatment with rTMS therapy for any disorder.  
  
Patient Reports  

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Subjects with positive responses to the  
Transcranial Magnetic Stimulation Adult safety  
screen (TASS, enclosed)  
TASS  
7) History of treatment with Deep Brain Stimulation.  
  
Patient Reports  
8) Use of any investigational drug within 12 weeks of the 
randomization visit.  
  
Patient Reports  
9) Current use of any medications with proconvulsive action, such as 
bupropion, maprotiline, tricyclic antidepressant, clomipramine, 
classical antipsychotics.   
  
Physician Evaluation, Medical 
Records  
10) Inability to obtain a motor threshold in patients due to chronic use 
of 
a 
medication 
(eg. 
anticonvulsants, 
benzodiazepines, 
sedative/hypnotics and atypical antipsychotics)  
  
Physician Evaluation, Medical 
Records  
11) Significant acute suicide risk, based on the current state or 
recent history using Columbia Suicide Severity Rating Scale 
(CSSRS).   
  
C-SSRS  
12) Cardiac pacemakers, implanted medication pumps, intracardiac 
lines, or acute, unstable cardiac disease.  
  
Physician Evaluation  
13) Intracranial implants (e.g. aneurysm clips, shunts, stimulators, 
cochlear implants, or electrodes) or any other metal object within or 
near the head, excluding the mouth, that cannot be safely removed.   
  
Physician Evaluation  
14) If participating in psychotherapy, must have been in stable 
treatment for at least three months prior to entry into the study, with 
no anticipation of change in frequency of therapeutic sessions, or the 
therapeutic focus over the duration of the rTMS trial.  
  
Private Psychiatrist Reports  
15) Current illicit drug use.  
  
Physician Evaluation and urine 
drug screen  
  
16) Current significant laboratory abnormality.  
  
Note: Clinically significant laboratory abnormality refers to patient lab 
results that fall outside the established normal ranges, may be 
indicative of the presence of a medical condition, and are not thought 
to reflect an artifact or routine lab error (e.g. hemolysis). Results of 
laboratory tests are reviewed by the study physician prior to any 
treatment. Abnormal lab results of clinical significance that cannot be 
resolved (e.g. by repeating the test to rule out laboratory error or poor 
quality of the original sample) will lead to exclusion from the study.  
  
Physician Evaluation  
17) Known or suspected pregnancy.  
Urine pregnancy test  
18) Women who are breast-feeding.  
  
Self Report  
19) Women of childbearing potential not using a medically accepted 
form of contraception when engaging in sexual intercourse.   
  
Self Report  

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Patient Discontinuation:  
  
A subject will be discontinued from the study for any of the following reasons:  
• 
Inability to locate and quantify a motor threshold (MT) as defined in the protocol.  
• 
The investigator decides that the patient should be withdrawn for the safety and welfare of the 
patient. For example, the patient experiences a clinically significant adverse event that is 
inconsistent with continuation in the study.  
• 
The patient withdraws consent.  
• 
Subject has significant tremor in any limb.  
• 
Subject experiences a seizure.  
• 
Subject has an elevated risk of suicide, based on results from the Columbia Suicide Severity 
Rating Scale (C-SSRS) and/or psychiatric interview or attempts suicide after receiving rTMS. The  
study investigator should refer the subject to his/her primary psychiatrist or inpatient 
hospitalization in case the patient is discontinued from the study.   
• 
Subject becomes pregnant.    
  
The safety of the patient following their discontinuation will be ensured by their primary physician.  
5 Study Device   
5.1 Description  
The study device is a rTMS HAC-coil manufactured by Brainsway™ to target the dACC. This will be used 
with the Magstim Rapid Stimulator. The coil and the stimulator are the major components of the system. 
Stimulation paradigm can be programmed before the patient arrives to deliver trains at a specific 
frequency. See section 1.2 or the attached manual for details.   
5.2 Treatment Regimen  
Patients will undergo 3 weeks (5x per week) of high-frequency (10-Hz) rTMS at the dACC interspersed 
with EEG and neuroimaging acquisitions. The protocol will be administered at the Psychiatric Institute. 
The intensity of stimulation will be based on resting-motor threshold (RMT). If the patient is unable to 
tolerate the intensity, this parameter may be reduced to make the patient more comfortable.  
5.3 Prior and Concomitant Therapy  
• See section 4.  
5.4 Receiving, Storage, Dispensing and Return  
5.4.1 Receipt of Study Device  
The device is currently on the medical campus.  
5.4.2 Storage  
The stimulation set-up is currently housed at the New York State Psychiatric Institute on the third floor. 
Trained investigators or physicians will have access to the setup and will administer the stimulation. A 
physician will be present during rTMS sessions to ensure patient safety.  
6 Study Procedures  
  
  
  
Sample Schedule  

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Monday  
Tuesday  
Wednesday  
Thursday  
Friday  
Baseline  
Neuroimaging, Neurophysiology and Neuropsychiatry evaluations  
Week 1  
rTMS  
  
rTMS  
preTMS EEG  
postTMS EEG 
MMSE,  
YMRS,CGI,  
CSSRS  
rTMS  
rTMS  
preTMS EEG  
postTMS EEG  
YBOCS, MMSE,  
YMRS, CGI,  
CSSRS  
rTMS  
  
Week 2  
rTMS  
rTMS  
preTMS EEG  
postTMS EEG  
MMSE, YMRS,  
CGI, CSSRS  
rTMS  
rTMS  
preTMS EEG  
postTMS EEG  
YBOCS, MMSE,  
YMRS, CGI,  
CSSRS  
rTMS  
  
Week 3  
rTMS  
rTMS  
preTMS EEG  
postTMS EEG  
MMSE, YMRS, 
CGI, CSSRS  
rTMS  
rTMS  
preTMS EEG  
postTMS EEG  
YBOCS, MMSE,  
YMRS, CGI,  
CSSRS  
rTMS  
  
Follow-up  
Neuroimaging, Neurophysiology and Neuropsychiatry evaluations  
  
7 Statistical Plan  
Statistical analyses with time series data and factor analysis will be carried out both within subject (to 
assess reliability of the observed effects across trials) and across subjects (to assess the generalizability 
across participants). Sample sizes are chosen based on expected effect sizes and the large 
heterogeneity in this subject population.  
 
8 Safety and Adverse Events  
8.1 Definitions  
Unanticipated adverse device effect (UADE): Any serious adverse effect on health or safety or any 
lifethreatening problem or death caused by, or associated with, a device, if that effect, problem, or death 
was not previously identified in nature, severity, or degree of incidence in the investigational plan or IDE 
application (including a supplementary plan or application), or any other unanticipated serious problem 
associated with a device that relates to the rights, safety, or welfare of subjects.  
Associated with the investigational device: There is a reasonable possibility that the adverse effect 
may have been caused by the investigational device.  
Life-threatening adverse effect: Any adverse effect that places the subject, in the view of either the 
investigator or the sponsor, at immediate risk of death from the effect as it occurred.  It does not include a 
reaction that, had it occurred in a more severe form, might have caused death.  
Serious adverse effect: An adverse effect is considered “serious” if, in the view of either the investigator 
or the sponsor, it results in any of the following outcomes:   
• 
death   
• 
a life-threatening AE  

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• 
inpatient hospitalization or prolongation of existing hospitalization •  
a persistent or 
significant disability/incapacity  
• 
a congenital anomaly/birth defect.  
Unanticipated adverse effect: Any adverse effect, the nature, specificity, severity, or frequency of which 
is not consistent with the risk information in the clinical study protocol or elsewhere in the current IDE 
application.  
8.2 Recording of Adverse Device Effects  
All observed or volunteered adverse effects (serious or non-serious) and abnormal test findings, 
regardless of treatment group, if applicable, or suspected causal relationship to the investigational device 
or, if applicable, other study treatment or diagnostic product(s) will be recorded in the subjects’ case 
histories.  For all adverse effects, sufficient information will be pursued and/or obtained so as to permit 1) 
an adequate determination of the outcome of the effect (i.e., whether the effect should be classified as a 
serious adverse effect) and; 2) an assessment of the casual relationship between the adverse effect and 
the investigational device or, if applicable, the other study treatment or diagnostic product(s).    Adverse 
effects or abnormal test findings felt to be associated with the investigational device or, if applicable, 
other study treatment or diagnostic product(s) will be followed until the effect (or its sequelae) or the 
abnormal test finding resolves or stabilizes at a level acceptable to the sponsor-investigator.  
8.3 Reporting of Adverse Device Effects and Unanticipated Problems  
8.3.1 Investigator reporting: Notifying the IRB  
The investigator will report any adverse events to the IRB as outlined in the IRB’s Unanticipated Problems 
(UP) Policy.    
8.3.2 Sponsor reporting: Notifying the FDA  
  
FDA Reporting Process  
  
For any observed or volunteered adverse event that is determined to be a UADE, the sponsorinvestigator 
will submit an expedited safety report to the FDA’s Center for Devices and Radiological Health.  The 
expedited safety report will consist of:  
• 
a completed Form FDA 3500A   
• 
a cover letter analyzing the significance of the event    
A copy of this safety report will be provided to all participating study investigators.    
The completed Form FDA 3500A and cover letter will be submitted to the FDA as soon as possible and, 
no, later than 10 working days after the sponsor-investigator first receives notice of the adverse effect.  
  
If, following receipt and investigation of follow-up information regarding an adverse effect that was 
previously determined not to be a UADE, the sponsor-investigator determines that the event does meet 
the requirements for expedited reporting, the sponsor-investigator will submit a completed Form FDA 
3500A and cover letter as soon as possible, but no later than 10 working days, after the determination is 
made.  
  
Subsequent to the initial submission of a completed FDA Form 3500A, the sponsor-investigator will 
submit additional information concerning the reported adverse effect as requested by the FDA. Medical 
Device Reports, whether for anticipated or unanticipated device-related effects, are to be submitted on 
FDA Form 3500A. The contact information for submitting MDR reports is noted below:  
  
Food and Drug Administration  
Center for Devices and Radiological Health  

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Medical Device Reporting  
PO Box 3002  
Rockville, MD  20847-3003  
8.4 Stopping Rules   
The patient will be allowed to stop participating in the study at any point. Additionally, any safety 
considerations will be taken into account and the study will be stopped in accordance with patient comfort. 
More immediately, rTMS administration will be stopped in the occurrence of any adverse event (See 
section 4). Regarding the study, we will stop the study if serious AEs are observed in more than 3 
subjects.   
8.5 Medical Monitoring  
It is the responsibility of the Principal Investigator to oversee the safety of the study at his/her site.  This 
safety monitoring will include careful assessment and appropriate reporting of adverse events as noted 
above, as well as the construction and implementation of a site data and safety-monitoring plan (see 
section 9 Auditing, Monitoring and Inspecting).  Medical monitoring will include a regular assessment of 
the number and type of adverse device events.  
9 Data Handling and Record Keeping  
9.1 Confidentiality  
Information about study subjects will be kept confidential and managed according to the requirements of 
the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  All study data will be coded with 
a unique alphanumeric identifier. The coded data will be stored on an end user device protected by a 
strong password. The key will be stored in an encrypted spreadsheet on an end-user device belonging to 
the primary investigator. All paper documents, including outcome measurement tools, consent and HIPAA 
forms will be maintained in a locked file cabinet. We will collect the minimum amount of information 
necessary for the purposes this study. Only approved study personnel will have access to this data, and 
all of the information gathered will be used for this study unless data has clinical relevance to the patient’s 
treatment, in which case it will be shared with the patient’s clinical team.   
 
9.2 Source Documents  
Source data is all information, original records of clinical findings, observations, or other activities in a 
clinical trial necessary for the reconstruction and evaluation of the trial.  Source data are contained in 
source documents.  Examples of these original documents, and data records include: hospital records, 
clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions 
certified after verification as being accurate and complete, microfiches, photographic negatives, microfilm 
or magnetic media, x-rays, subject files, and records kept at the pharmacy, at the laboratories, and at 
medico-technical departments involved in the clinical trial.  
9.3 Records Retention  
The sponsor-investigator will maintain records in accordance with 21 CFR 812, Subpart G.  
 
10 Study Monitoring, Auditing, and Inspecting  
10.1 Study Monitoring Plan  
This study will be monitored in accordance to the monitoring plan described in Section 4.  The investigator 
will allocate adequate time for such monitoring activities.  The Investigator will also ensure that the 
monitor or other compliance or quality assurance reviewer is given access to all the above noted study-
related documents and study related facilities (e.g. pharmacy, diagnostic laboratory, etc.), and has 

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adequate space to conduct the monitoring visit. In addition, a monitoring log along with case report forms 
(CRFs) will be kept with research records.  
10.2 Auditing and Inspecting  
The investigator will permit study-related monitoring, audits, and inspections by the EC/IRB, the sponsor, 
government regulatory bodies, and University compliance and quality assurance groups of all study 
related documents (e.g. source documents, regulatory documents, data collection instruments, study data 
etc.).  The investigator will ensure the capability for inspections of applicable study-related facilities (e.g. 
pharmacy, diagnostic laboratory, etc.).  
 
11 Ethical Considerations  
This study is to be conducted according to US and international standards of Good Clinical Practice, 
applicable government regulations and Institutional research policies and procedures.  
  
This protocol and any amendments will be submitted to a properly constituted independent Ethics 
Committee (EC) or Institutional Review Board (IRB), in agreement with local legal prescriptions, for formal 
approval of the study conduct.  The decision of the EC/IRB concerning the conduct of the study will be 
made in writing to the investigator and a copy of this decision will be provided to the sponsor before 
commencement of this study.  The investigator should provide a list of EC/IRB members and their affiliate 
to the sponsor.  
  
All subjects for this study will be provided a consent form describing this study and providing sufficient 
information for subjects to make an informed decision about their participation in this study.  See 
Attachment for a copy of the Subject Informed Consent Form.  This consent form will be submitted with 
the protocol for review and approval by the EC/IRB for the study.  The formal consent of a subject, using 
the EC/IRB-approved consent form, must be obtained before that subject undergoes any study 
procedure.  The subject or legally acceptable surrogate will sign the consent form along with the 
investigator-designated research professional obtaining the consent.   
  
Patients will be recruited directly by the clinician, who will ask potential subjects if they would like to enroll 
in the study. Appropriate candidates will be asked to participate using standard informed consent 
processes. We will emphasize the fact that the decision to participate in the study in no way will affect 
medical care or other services provided at our institution, and that participation in this research is 
completely voluntary.   
  
An approved study investigator will obtain informed consent prior to patient enrollment, using Columbia 
University Medical Center IRB approval consent forms, which will be signed to indicate the participant’s 
consent. The consent will include a description of the study and the data that will be gathered. The patient 
will be allowed to consent to any, all, or none of the parts of the study. Under no circumstances will 
consent be sought on the day of procedure.  
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