Evaluation of NeoSync EEG Synchronized TMS For the Treatment of Major Depressive Episode in Bipolar Disorder and Associated Neural Response: An Open Label Trial
Phase: PHASE2
Conditions: Major Depressive Episode, Bipolar Depression, Bipolar Disorder, Mood Disorders
Sponsor: Butler Hospital

Uploaded to ClinicalTrials.gov 14 Feb 2020 
Clinicaltrials.gov Record Summary Documents Cover Page (IRB Approved 12/13/2017) 
 
NeoSync TMS Treatment for Bipolar I Depression (NCT02839798)   
 
Attached document is protocol with statistical analysis plan as approved by Butler IRB. 
 
The study had no external funding (investigational devices provided by the company Neosync, 
which no longer exists). This pilot trial was stopped early due to lack of funding. 
 
 

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IRB # 1601-004 
BUTLER HOSPITAL 
INSTITUTIONAL REVIEW BOARD 
PROTOCOL 
ATTENTION: 
 Before completing this protocol, go to the Butler IRB Forms library on IRBNet and 
 Download the most recent version.  Consult the IRB Guidelines for updated directions. 
 
TITLE OF PROJECT: Evaluation of NeoSync EEG Synchronized TMS For the Treatment of Major 
Depressive Episode in Bipolar Disorder and Associated Neural Response: An Open Label Trial 
 
Principal Investigator (PI): Linda Carpenter, MD 
 
 
 
 
 
 
Other Investigator(s):  Noah S. Philip MD, 
 
 
 
  
                              
 Description of Study 
A.  Specific Aims   
The objective of this study is to establish the safety and preliminary efficacy of Synchronized 
Transcranial Magnetic Stimulation (sTMS) treatment, for subjects with Bipolar Disorder type I (BD-
I) in a major depressive episode (BDD – bipolar depression, hereafter). 
 
B.  Background  
Bipolar disorder is one of the top ten most debilitating of all illnesses. Two reports from the NIMH 
Collaborative Depression Study demonstrated that individuals with bipolar disorder experience 
depression much more frequently than hypomania or mania (Judd et al. 2002; Judd et al. 2003; Judd 
et al. 2012). Specifically, in these studies the hallmark symptoms of bipolar disorder (i.e. hypomanic 
or manic symptoms) occurred only during 9% of the time in individuals with BD-I, and in only 1% 
of the time in individuals with BD-II. During the depressed phase of bipolar disorder illness, 
affected individuals present with depressed mood, loss of interest or pleasure, feelings of guilt, low 
self-worth, disturbed sleep or appetite, low energy, and poor concentration.   
 
Despite the high prevalence and cost of bipolar depression, there is a paucity of treatment options 
available to offer individuals struggling with this severe illness. Mood stabilizers are the 
mainstream option to treat bipolar depression, yet only a few choices are available. Quetiapine, 
olanzapine/fluoxetine combo and more recently lurasidone are few of the drugs that are FDA 
approved to treat bipolar depression. In comparison, depression in Major Depressive Disorder 
(MDD) is mainly treated with antidepressants, with several classes and options. Unfortunately, 
antidepressant treatment may adversely affect the overall course of bipolar illness, increasing the 
rates of mood destabilization and rapid cycling (Perlis et al. 2010; Valentí et al. 2012). 
 
In addition to the psychopharmacologic treatments for depression, other therapies such as 
electroconvulsive therapy (ECT) and repetitive transcranial magnetic stimulation (rTMS, or simply 
“TMS”) have been shown to have a potential therapeutic effect in MDD (for review: Noda et al. 
2015). TMS uses magnetic pulses to induce excitation/inhibition of specific areas in the brain.   
Treatment with repetitive stimulation is intended to stimulate groups of cells in areas of the brain 
linked to depression.  The exact mechanism by which the therapy works is still unknown (Pascual-
Leone et al. 2000; Fecteau et al. 2006; Rossi et al. 2009; Noda et al. 2015). It is recognized that high-
frequency rTMS can enhance cortical excitability consistently, whereas low-frequency seems to 
exert inhibitory effects on excitability (Fitzgerald et al. 2006). While the therapy is non-invasive, it 
is expensive and requires subjects to be treated daily at a treatment center because of the 
complexity of locating the point of stimulation as well as the potential for seizures.   

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On the other hand, the efficacy of rTMS for bipolar depression has not been widely investigated. 
From this perspective, a number of open label studies showed positive effect for rTMS (with a 
mixed range of parameters) in depressed patients with BDD (Dell'Osso et al. 2009; Cohen et al. 
2010; Harel et al. 2011), and such result has been confirmed in few double- blind, sham-controlled 
studies with limited samples (Dolberg et al. 2002; Nahas et al. 2003; Tamas et al. 2007). Two of 
these studies were limited by small samples. Dolberg investigated a sample on 20 individuals with 
bipolar depression, ten in each arm (TMS parameters were not reported). In comparison, Tamas 
studied 5 individuals with bipolar depression (one in the sham arm and 4 in the active arm – 1Hz 
right frontal cortex). Nahas treated a mixed sample of 23 individual with bipolar 1 and 2, while in 
depressed ⁄ mixed episode (12 in the sham arm and 11 in the active arm – 5Hz left frontal cortex). 
However, there are case reports indicating mood destabilization leading to a manic episode after 
TMS treatment (Dolberg et al. 2001). It is still up to debate if rTMS using standard protocols are 
safe to be used in bipolar disorder. 
 
Despite the ongoing debate regarding TMS’ excitatory/inhibitory properties, it has been well 
established that TMS alters the oscillation of underlying brain tissue as measured with 
electroencephalography (EEG) (Paus et al. 2001; Klimesch et al. 2003; Fuggetta et al. 2005; Brignani 
et al. 2008; Fuggetta et al. 2008; Hamidi et al. 2009; Johnson et al. 2010). In particular, alpha band 
activity appears to exert “top down” control over broadly distributed functions in the brain, 
allowing selective activation of brain areas for optimal brain function (Klimesch et al. 2007). 
Klimesch and colleagues (2003) have proposed that one key factor determining whether TMS 
pulses are inhibitory or excitatory of task performance is the relationship of the frequency of TMS 
stimulation to the participants’ intrinsic alpha frequency (IAF).   Moreover, the alpha frequency 
range appears to be particularly involved in modulating connections among the dorsal anterior 
cingulate cortex, anterior insula, anterior prefrontal cortex and thalamus (Sadaghiani et al. 2010).  
Several of these brain areas are involved both in cognition and in regulation of mood. Furthermore, 
alpha frequency plays a central coordinating role in regulating brain activity.  Higher mean IAF is 
associated with greater regional cerebral blood flow (Jann et al. 2010).  In contrast, higher power 
and broadly synchronized alpha is associated with lower blood flow (Feige et al. 2005).  Taken as a 
whole, these findings suggest that intrinsic alpha activity can lead to activation or inhibition of a 
brain region depending upon the intensity, frequency, and synchronization of the activity.   
 
NeoSync, Inc. has developed an EEG synchronized TMS (sTMS) system for the treatment of MDD 
(Leuchter et al. 2015).  The sTMS device uses low energy alternating magnetic fields at a subject’s 
intrinsic alpha frequency.  The NeoSync sTMS device that is to be used in the proposed trial 
provides therapy by generating an alternating magnetic field in close proximity to the head of the 
subject using diametrically magnetized cylindrical neodymium magnets. These magnets rotate to 
generate a sinusoidal magnetic field set at the average individualized alpha frequency calculated 
from the subject’s EEG. The magnetic field generated is less than 2% of that required for active 
depolarization of neurons and approximately only 10% of conventional TMS output. In comparison, 
the total amount of magnetic field exposure for a full course of sTMS therapy is approximately only 
a minimal fraction of the exposure from a single scan with an MRI, which is widely used to study 
brain function in the psychiatric population, including children and infants. NeoSync’s sTMS device 
is not an implantable device, is not used in supporting or sustaining human life, and does not 
present a potential for serious risk to the health, safety, or welfare of a subject. Based upon the 
profile of the product, the FDA considers the low energy emitting NeoSync sTMS device to be a 
“non-significant risk” (NSR) device.  However, sTMS has not been studied in bipolar disorder; sTMS 
might be particularly safe due its low magnetization protocol, with potentially low risk for mood 
destabilization and manic episode induction. 
 

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Furthermore, bipolar depression is associated with a range of emotional and affective disturbances, 
coupled with deficiencies in cognitive and reward function (Almeida and Phillips 2013; Phillips and 
Kupfer 2013; Nusslock et al. 2014). Moreover, bipolar disorder is associated with hypersensitivity 
to reward cues that may lead to increased approach or goal-directed motivation to stimuli or life 
events involving reward pursuit; which, in the extreme, might be reflected in manic symptoms. By 
contrast, MDD is characterized by reduced sensitivity to reward cues, which has been related to 
anhedonic symptoms. Current neuroimaging findings suggest that bipolar depression can be 
modeled as dysfunction in two neural systems: 1) increased attention bias to emotional rather than 
neutral stimuli associated with abnormally increased activity in an amygdala-centered system 
associated with anterior cingulate dysregulation underlying emotion processing; and 
2)hypersensitivity to reward stimuli associated with abnormally increased activity in ventral 
striatum and ventro-lateral pre-frontal cortex within the fronto-striatal neural circuit implicated in 
reward system. The former (1) may underlie the emotional lability, the latter (2) the 
hypersensitivity to positive stimuli, and the combination of both abnormalities are core clinical 
features of bipolar depression. Furthermore, resting state connectivity studies in adults with 
bipolar disorder suggests a decoupling between frontal, temporal and subcortical regions. 
 
The proposed research will evaluate (1) the safety and preliminary efficacy of sTMS as adjunct 
treatment in bipolar depression; and (2) the extent to which task performance impairments and 
associated functional abnormalities within these two main neural systems may predict and 
moderate treatment response in bipolar depression using sTMS. 
 
C.  Experimental Method 
 
C1.  Brief Description of Subjects 
Approximately 20 male and female subjects aged 18 to 80 years who present with a primary 
diagnosis of bipolar disorder type 1 currently in a major depressive episode (i.e. bipolar 
depression) and taking at least one mood stabilizer will receive open label treatment with sTMS. 
Furthermore, subjects will also complete weekly EEGs and some of the subjects will complete 
baseline and follow-up brain fMRI. Eligible subjects must provide written informed consent, be 
capable of comprehending the nature of the study, and be considered by the Investigator as likely to 
comply with the visit schedule. Subjects will be recruited from self-referral, clinician referral, and 
through contacts with the Mood Disorders Research Program. Additional inclusion/exclusion 
criteria are listed below. 
 
C2.  Study Design 
This clinical trial is a prospective, open label, single center study (Butler Hospital). This study is 
designed to evaluate the safety and effectiveness of sTMS for symptoms of major depressive 
episode in subjects with bipolar disorder type I. A total of 20 subjects will receive 5 daily 
treatments per treatment week for 6 treatment weeks (total of 30 treatments) or when remission is 
achieved.  
 
After providing written informed consent, subjects will start the assessment phase. Subjects must 
be on a stable dose of at least one mood stabilizer for at least 4 half-lives. Subjects will be assessed 
using clinician based interviews and self-rating scales (to determine baseline clinical 
characteristics). Subjects will also complete a baseline EEG. 
 
Treatment will be initiated on Day 1 of the study and will be delivered daily for 6 weeks or when 
remission is achieved. Remission will be defined by Inventory of Depressive Symptomatology, Self-

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Report Version (IDS-SR) score <14 for at least 14 calendar days. Subjects will be evaluated at the 
end of each treatment week during the treatment period.  
 
At the end of each treatment week, subjects will repeat self-rating scales (see study flow chart, 
below).  
 
A subset of the subjects will also complete a baseline and follow-up fMRI to investigate brain 
functioning (pending additional funding to support the scans); participation in the brain imaging at 
baseline and at endpoint will be optional. fMRI procedures will consist of a one hour session in the 
scanner during which subjects will complete protocols for assessing resting state, emotional 
processing, and reward processing, which are considered core components of bipolar disorder 
psychopathology.  fMRI procedures will occur within one week of baseline assessments and study 
endpoint.  
 
The end point assessments will be completed within 5 days of the final treatment day. In final 
evaluation, subjects will be assessed using clinician-based interviews and self-rating scales to 
evaluate efficacy of the treatment. Side effects will be recorded as described by study participants at 
any visit or during any contact with the subjects. 
 
Two weeks after the last sTMS treatment, subjects will be contacted by telephone for a brief follow-
up safety assessment  
 
C3.  Specific Procedures or Treatments 
 
C3a.  Open Label Trial:  
This study is an open label pilot study, to determine effect size for sample estimation, and 
determine safety and preliminary efficacy. Subjects will start treatment after baseline assessments 
are completed; treatment will continue for 6 treatment weeks (or until subject remits per IDSSR 
criterion score sustained for 14 days). A treatment week will consist of 5 treatment days within 8 
calendar days. Furthermore, all subjects must have at least 5 treatments within 10 calendar days; 
and 30 treatments within 6 treatment weeks (plus 3 days grace period), which will lead to 45 
calendar days.  
 
 

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Study Occasion – Open Label, not sham controlled 
  
Assessment Phase 
Treatment Phase 
(week) 
Termination Phase 
Rating or procedure 
Screening 
MRI 
Baseline 1 2 3 4 5 6 MRI 
End 
Point 
Phone 
Check-in 
CONSENT/ELIGIBILITY 
X 
  
  
  
  
  
  
  
  
  
  
  
SCID-5-RV 
X 
  
  
  
  
  
  
  
  
  
  
  
Consent/MRI 
X 
  
  
  
  
  
  
  
  
  
  
  
EEG: IAF 
x 
  
  
  
  
  
  
  
  
  
  
  
CTQ 
x 
  
  
  
  
  
  
  
  
  
  
  
HRSD/MADRS 
X 
  
X 
  
  
  
  
  
  
  
X 
  
YRMS 
X 
  
X 
  
  
  
  
  
  
  
X 
X 
BAS/BIS 
  
  
X 
  
  
  
  
  
  
  
X 
  
PCGI-I 
  
  
  
  
  
  
  
  
  
  
X 
  
CGI-Bipolar 
  
  
X 
X X X X X X 
  
X 
X 
IDS-SR 
  
X 
x* 
X X X X X X 
x* 
X 
  
ASRM 
  
X 
x* 
X X X X X X 
x* 
X 
  
PHQ9 
  
X 
x* 
X X X X X X 
x* 
X 
  
EEG: Resting 
  
  
x 
  
  
  
  
  
  
  
X 
  
MRI – resting state, cerebral 
blood flow, reward processing, 
emotion processing, cognitive 
processing 
  
X 
  
  
  
  
  
  
  
X 
  
  
 
 
x* Baseline measures repeated, if needed 
only if >3 days from MRI or first treatment 
 
 

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Altman Self-Rating Mania Scale (ASRM) 
Behavioral Activation System / Behavioral Inhibition System (BAS/BIS) 
Childhood Trauma Questionnaire (CTQ)  
Clinical Global Impressions  - Bipolar Version (CGI-Bipolar) 
Hamilton Rating Scale for Depression (HRSD) 
Electroencephalogram (EEG) Recording: Individual Alpha Frequency (IAF)  
Inventory of Depressive Symptomatology, Self-Report Version (IDS-SR)  
Montgomery–Asberg Depression Rating Scale (MADRS) 
Magnetic Resonance Imaging (MRI) 
Patient Clinical Global Impression – Improvement (PCGI-I) 
Patient Health Questionnaire-9 (PHQ-9) 
Structured Clinical Interview for DSM-5 Research Version (SCID-5-RV) 
Electroencephalogram  (EEG) Recording: Resting State 
Young Rating Mania Scale (YRMS) 
 
C3b: Clinical Assessments:  
(1) Structured Clinical Interview for DSM-5 Research Version (SCID-5-RV) diagnoses at 
Screening (First et al. 2015); (2) Hamilton Rating Scale for Depression (HRSD) 17 items, standard 
depression severity rating scales by clinician interview at Baseline and End Point (Hamilton 1960); (3) 
Young Mania Rating scale (YMRS), standard mania severity rating scales by clinician interview at 
Baseline and End Point (Young et al. 1978); (4) Childhood Trauma Questionnaire (CTQ), self-
report measure of child abuse and neglect at Baseline (Bernstein et al. 2003); (5) Patient Clinical 
Global Impression for Improvement, standard self-rating scale at End Point; (6) Clinical Global 
Impressions for Severity (CGI-S) scores by clinical rater at Baseline, Week 1-6  and End Point and 
Improvement (CGI-I) Bipolar Disorder version  at End Point only (Spearing MK et al 1997); (7) 
Inventory of Depressive Symptomatology (IDS-SR), standard self-rating scale for depressive 
symptoms at Baseline, Week 1-6 and End Point (Rush et al. 1996; Trivedi et al. 2004); (8) Altman 
Self-Rating Mania Scale (ASRM), standard self-rating scale for manic symptoms at Baseline, Week 1-
6 and End Point (Altman et al. 1997); (9) Patient Health Questionnaire-9 (PHQ-9), standard self-
rating scale for depressive symptoms at Baseline, Week 1-6 and End Point (Kroenke et al. 2001); (10) 
Release of Health Information, subject will sign releases of information for their last appointment 
with their PCP for medical comorbidities/ general health and for psychiatric care 
inpatient/outpatient for chart review for documented manic episodes;(11) Behavioral Activation 
System / Behavioral Inhibition System (BAS/BIS),  self rating scale for measures of the sensitivity 
of incentive and aversive motivational systems at Baseline and End Point (Carver, C. S., & White, T. L. 
1994), (12) Montgomery–Asberg Depression Rating Scale (MADRS), standard depression severity 
rating scales by clinician interview at Baseline and End Point (Montgomery and Asberg 1979) 
 
C3c: Electroencephalogram (EEG):  
EEG data will be acquired using a research grade wireless EEG headset designed for rapid 
application of multiple sensors at locations corresponding to the 10-20 International System. The 
EEG recording system uses dry electrodes and is comfortable, portable, and easy to set up for 
recording EEG in under 5 minutes. In this study, brain waves will be recorded during 20 minutes 
while the patient has eyes closed and relaxes. After the recording session, the headset will be 
removed and cleaned.  
 
C3d: Magnetic Resonance Imaging (MRI), optional measure pending extra funding: 
Neuroimaging data will be collected in some of the subjects at the Brown University MRI Research 
Facility (MRF).  The MRF includes a research dedicated Siemens 3 Tesla PRISMA scanner with a 32 
channel head coil that improves signal to noise ratio. Participants will complete the MRI safety 

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form, and a 60-minute multi-modal MRI session. The session will include a 1) 3 plane localizer scan 
for slice positioning; (2) high-resolution T1-weighted MPRAGE anatomical scan with whole-brain 
coverage for structural MRI analysis and fMRI spatial normalization; (3) BOLD EPI scans for event-
related fMRI and task-dependent activity/connectivity; (4) 1 EPI scan while the participant is at 
rest for task-independent (default mode network) analyses; and (5) ASL scan while the participant 
is at rest for cerebral blood flow analyses. MRI scan parameters will be per facility protocol. All 
participants will be studied awake and without sedation. Procedures will be stopped immediately 
at the participant’s request or for any signs of significant distress. All standard procedures for 
ensuring safety during scanning will be followed (e.g., exclusions due to pregnancy, metal 
fragments in the body). Before the scan session, subjects will receive brief training in each task to 
ensure adequate performance. After scanning, participants will be debriefed about task content. 
Emotion Processing Task (EPT): The EPT is an emotional Stroop task to probe implicit emotion 
regulation processes during the presentation of conflicting emotional information. Stimuli consists 
of 148 pictures of emotional faces (happy or fearful), and participants will be asked to label the 
expression while ignoring an emotion word (“happy” or “fear”) that overlays the image. The 
emotion words either matchs (congruent trials) or conflicts (incongruent trials) with the emotional 
face. Stimuli will be presented for 1000ms, with a variable inter-stimulus interval (3000-5000ms, 
M=4000ms), in a pseudo-random order, counterbalanced as a function of expression, word, gender, 
and response button; Monetary Incentive Delay (MID) Task: The MID task assesses both 
anticipation and feedback phases of reward and loss processing unbiased by performance or 
success rate. The task consists of 24 reward trials, 24 loss trials, and 24 neutral trials in random 
order. During each trial, participants are shown a geometric shape cue to signal trial type (circles 
for reward, squares for loss, and triangles for neutral trials; 2000 msec), followed by a fixation-
crosshair (variable interval: 2000–2500 msec) and then a white square target to which participants 
are supposed to respond by pressing a button during its presentation. The target duration time is 
adapted throughout the task based on the success rate, such that participants would succeed on 
approximately 66% of the trials. After a jittered delay (700–2100 msec), participants receive 
feedback (1920 msec) notifying them about their present trial and total score, followed by an 
intertrial interval of 4000 milliseconds. On reward trials, participants can win $0.50 when pressing 
in time but will never lose money when failing to do so. Conversely, loss cues signas that 
participants could prevent losing money by successful button press or lose $0.50 upon failure. 
Finally, neutral trials result in $.00, irrespective of performance. The money won during the 
particiapation is not actual money but rather imaginary money, only used as an incentive for 
the participant. Default Mode Network (BOLD and ASL): eight-minute scan sessions in which 
subjects will be instructed to keep their eyes open looking at a fixation cross. 
 
Total scan time will be approximately 60 minutes, and total subject involvement will be 
approximately 2 hours.   
 
C3e. NeoSync Investigational Device: The NeoSync sTMS 
device provides therapy via an alternating magnetic field in 
close proximity to the head of the subject, generated by 
diametrically magnetized cylindrical neodymium magnets 
(each 1 inch diameter and length, with a surface field of 
6,430 Gauss or 0.64 Tesla).  These magnets rotate to 
generate a sinusoidal magnetic field set at precisely the 
average individualized alpha frequency (IAF, see below) 
calculated from the subject’s EEG. The device contains three 
magnets in the saggital line above the subject’s scalp, which 

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rotate along a transverse axis.  sTMS is delivered broadly over the prefrontal and frontal regions of 
the brain. 
 
The NeoSync sTMS device is powered by a medical-grade power supply that plugs into any 110-
220VAC wall socket. A housing structure encloses the 3 rotating magnets of the device and keeps 
them in close proximity to the subject’s scalp.  The housing (“treatment arm”) can be raised and 
lowered so that it rests on the subject’s head while the subject lies in the device.  The Figure (right 
side) shows a schematic of the device positioned on a subject’s head, with the approximate area of 
stimulation indicated for each magnet.  
 
The treatment arm can be latched in the fully raised position to allow the subject to position his/her 
head in the device.  The base of the device extends under the treatment arm and an ergonomic 
pillow rests on the base to provide the subject with a comfortable, stable platform that keeps 
his/her head in the correct position during therapy.  To administer therapy, the subject lays with 
his/her head under the treatment arm, face up.  The treatment arm is gently lowered so that 
Magnet #1 rests on the subject’s forehead and the other magnets are in the correct position against 
the scalp.  The magnet housing can be tilted up to 10 degrees to provide the most comfort to the 
subject.  Also, if the subject indicates that the pressure on his/her forehead is uncomfortable, the 
Head Size Adjustment Knob may be used to reduce the pressure. 
 
C3f: Individualized Alpha Frequency:  
 
(1) Electroencephalogram (EEG) (by NeoSync device) to measure Individualized Alpha Frequency 
(IAF) at Screening. To determine each subject’s baseline IAF, the NeoSync sTMS device includes an 
EEG recording module.  A single channel (sensing lead, reference lead, and a ground reference) pre-
treatment EEG will be recorded to determine each subject’s Alpha Frequency in a Patient Passport 
Module (PPM). To record EEG, 2 disposable patch Ag-AgCl snap-type electrodes are affixed to the 
subject’s head, one high on the right forehead and the other above the mastoid bone behind the left 
ear.  A finger-clip electrode is used as a ground reference.  EEG recording is done automatically at 
the push of the START button. This recording takes approximately 5-10 minutes while the subject 
lies still, relaxed, awake, with eyes closed. The NeoSync sTMS device uses a proprietary algorithm 
to determine the IAF and records the value to the PPM, then indicates to the user that EEG 
recording has completed. EEG recording at the screening visit is done to verify that the subject’s IAF 
can be determined, as a very small percentage of the population (<5%) do not have a strong enough 
alpha strength to capture using EEG.   After this, the PPM is considered valid and may be used 
whenever the subject undergoes therapy. The IAF obtained at baseline is used to determine 
parameters for sTMS delivered throughout the study.   
 
C3g. The sTMS Treatment Procedure:  
Each patient’s IAF is stored on their PPM, which is inserted into the USB port on the NeoSync sTMS 
device to program the sTMS parameters. During therapy, the subject lies still, relaxed, awake with 
eyes closed. Each therapy session lasts 30 minutes.  If the treatment arm is raised to the latched 
position or drops to the bottom, the session will pause, and will resume only when the treatment 
arm is moved back into position.  The therapy is intended to target “whole brain” rather than 
discrete anatomical regions, so minor shifting of the subject’s head or body will not affect the 
efficacy of the therapy. A backlit LCD screen displays the current Patient ID and the status of the 
system. In order to prevent a subject from undergoing therapy more than once per day, a 12-hour 
lockout of the device occurs after a therapy session has ended or is cancelled. 
 
 

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C4.  Data Analysis:  
A total of 20 subjects will be enrolled and treated.  The sample size for this open-label study is 
based on estimations regarding the appropriate amount of information required to inform next 
steps in trial design rather than on statistical significance calculations for any primary safety or 
efficacy endpoint. For the primary efficacy endpoint, we will analyze change in total scores on the 
IDS-SR, HRSD, and MADRS scores from baseline to End Point. Categorical response (50% decrease 
from pre-treatment baseline on IDS-SR) and Remission (IDS-SR score <14) will be calculated to 
determine treatment efficacy.  
 
Neuroimaging data will be pre- processed and analyzed using statistical parametric mapping 
software SPM5 (http://www.fil.ion.ucl.ac.uk/spm).  For both experiments, a first-level effect model 
will be constructed with conditions entered separately in the design matrix.  
 
D.  Material Inducements 
Subjects will not compensated for the sTMS treatment but rather receive it free of charge. Subjects 
that participate in each neuroimaging session will receive a gift card with value of $25 for each MRI 
scan they complete. 
 
E.   Training of Research Personnel 
Clinical data will be collected, entered and analyzed by Dr. Almeida in the Mood Disorders Research 
Program and research assistants trained under his supervision. Neuroimaging data will be 
processed and analyzed by Dr. Almeida and research assistants trained under his supervision.  Dr. 
Linda Carpenter will provide overall supervision and oversight for the study. 
 
3)  Human Subjects 
A.  Subject Population (include number; gender; age; diagnosis; inpatient vs. outpatient; 
 
physical health; inclusion/exclusion criteria; rationale for use of special groups)  
 
A total of 20 male and female subjects, age 18 to 80 years, who are suffering from bipolar disorder 
type 1, currently depressed, will be enrolled into the study and treated.  All subjects will receive 
open label sTMS treatment. Subjects will be recruited from outpatient setting and in stable physical 
health. 
 
Inclusion Criteria: Subjects must meet all of the following inclusion criteria to qualify for 
enrollment into the study:  
(1) 18 – 80 years of age;  
(2) DSM-5 primary diagnosis of Bipolar Disorder type 1 (with a documented diagnosis of the 
disorder on medical record), currently in a Major Depressive Episode by diagnostic criteria elicited 
by structured clinical interview (SCID-5-RV);  
(3) MADRS score > 20;  
(4) Duration of current episode >4 weeks  
(5) YMRS score ≤ 12;  
(6) baseline EEG of sufficient quality for quantitative analysis processing;  
(7) willing and able to adhere to the intensive treatment schedule and all required study visits;  
(8) currently on adequate dose of mood stabilizer with significant evidence base or FDA approval 
for maintenance therapy of bipolar disorder (valproic acid/divalproex, carbamazepine, lamotrigine, 
lithium, aripiprazole, ziprasidone, risperidone, quetiapine, olanzapine, asenapine, haloperidol, 
chlorpromazine, paliperidone, cariprazine).   
 

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Exclusion Criteria: Subjects will be excluded from study participation if one of the following 
exclusion criteria applies:  
(1) unable or unwilling to give informed consent;  
(2) diagnosed with current primary psychotic disorder (rather than BD); 
(3) diagnosed with current mania or hypomanic mood episode;  
(4) history of moderate to severe substance use disorder within the past 6 months (except nicotine 
and caffeine); 
(5) currently being treated with a stimulant;  
(6) clinically defined major neurological disorder; including, but not limited to, seizure disorder and 
history of loss of consciousness due to head injury for greater than 10 minutes, or with documented 
evidence of brain injury; 
(7) increased risk of seizure for any reason, including diagnosis of increased intracranial pressure, 
comorbid neurological disorder, use of certain medications, highly unstable use of alcohol or 
benzodiazepines; 
(8) Initiation of new antidepressant treatments (new medication, new device-based stimulation, or 
new psychotherapy) within 6 weeks prior to baseline;  
(9) active suicidal intent or plan as detected on screening assessments, or in the Investigator’s 
opinion, is likely to attempt suicide within the next six months;  
(10) presence of implanted cardiac pacemakers, implanted medication pumps, or intracardiac lines;  
(11) intracranial implant (e.g., aneurysm clips, shunts, stimulators, cochlear implants, stents, or 
electrodes) or any other metal object within or near the head (excluding the mouth), which cannot 
be safely removed;  
(12) clinically significant unstable medical condition;  
(13) if female: pregnant, not using medically acceptable means of birth control, or currently 
breastfeeding;  
(14) other condition, which in the judgment of the Investigator could prevent the subject from 
completion of the study. 
 
(15) for participants in the MRI study: ferromagnetic metal implant or other contraindication to 
imaging in a 3 Tesla MRI (see Brown MRF consent for MRI included with this protocol); 
 
B.  Recruitment and Consent Procedures  
Community psychiatrists and other physicians will be made aware of this study to facilitate referral 
of potentially appropriate candidates. Postings describing the study and basic eligibility criteria 
may be advertised through local print, internet, radio, or other media. Subjects interested in 
participating will be grossly assessed for eligibility through basic phone screen queries. If a 
potential participant is found to be eligible for enrollment, the study consent form will be reviewed 
with the subject and the study methods and requirements will be explained. Written informed 
consent will then be obtained.  A pre-screening log will be maintained to record data about subjects 
who are screened for enrollment, but either do not qualify or decide not to participate in the study. 
A copy of the signed consent form will be provided to the study participant and the original signed 
consent form will be maintained in the subject’s files.  
 
Once a subject has been consented, the screening process will include review of past treatments.  
This process may include a detailed interview with the patient to obtain history of illness and 
treatments; a phone consultation with the subject’s attending physician/psychiatrist or prescribers, 
and/or a full review of the subject’s relevant past medical records, including pharmacy records, if 
available. Participants may be asked to provide written permission for the researchers to request 
medical record documentation supporting past history of manic episode. This process will 
specifically ensure eligible subjects have the correct diagnosis and are currently taking a mood 
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C.  Potential Risks   
 
Risk of Mood Destabilization: Risks associated with participation in this trial include possible lack 
of positive response to the treatment, and/or worsening of depressive symptoms and/or mood 
destabilization. In addition, occasionally some emotional discomfort may occur while filling out 
questionnaires or being interviewed about matters pertaining to emotions, mental health, 
functioning and other relevant experiences. 
 
Risk of Side Effects from sTMS: Risk related to treatment with the NeoSync device is minimal. In a 
recently completed sham controlled trial with the same device and similar treatment schedule, both 
active and sham treatments were well tolerated, with no significant difference between the active 
and sham arms in the incidence, severity, or clinical significance of adverse events (or relationship 
to treatment of adverse events) reported with an incidence rate of >2%. Headache was most 
common, occurring in 21% of active and 19% of sham subjects, followed by back pain (8.7% active 
v. 4.0% sham), insomnia (6.8% active v. 5.1% sham), respiratory infection (7.8% active v. 5.1% 
sham), paresthesia (3.9% active v. 0% sham), nonspecific GI discomfort (3.9% active v. 3.0% sham). 
The Severity of these events was considered mild, and none of them resulted in a subject dropping 
out of the research trial. There was no significant difference in treatment discontinuation due to 
reported adverse events in the active versus sham groups (2 and 5 subjects, respectively). The only 
suicide attempt reported during the blinded trial occurred in a sham-treated subject. No SAEs were 
attributable to either active or sham treatment. Upon review of the available preliminary data, the 
FDA classified the NeoSync sTMS device as a “nonsignificant risk” device and as such there are 
abbreviated IDE requirements and no FDA requirement for IDE filing for the current investigator-
initiated study in bipolar depression. 
 
Risk of discomfort during EEG:  Subjects may feel areas of pressure on their scalp at the location 
of the recording electrodes during collection of EEG data.  
 
Risk during MRI procedures: MRI imaging is generally considered to be safe if participant does 
not have metallic objects in the body.  Some people experience anxiety, panic or a sensation of 
claustrophobia when lying in the MRI machine.  A separate consent form associated with use of the 
Brown MRI Facility will be reviewed with the subject and signed prior to participating in the scan. 
Subjects will also be informed that the scan provided does not constitute a clinical scan and that 
researchers are not board-certified neuroradiologists. The scanner also makes loud noises during 
imaging.   
 
The alternatives to participation in this study: (1) not receiving treatment for bipolar 
depression, or (2) receiving standard treatment administered by a clinician and/or prescribed by a 
physician or nurse outside of this research study. The primary risk of untreated BDD is prolonged 
disability and suffering, or if the condition becomes severe/worsens, possibly attempting or 
completing suicide.  Risks related to obtaining treatment for depression outside of this study are 
the ones typically associated with available antidepressant and mood stabilizer pharmacotherapies, 
somatic therapies, or psychotherapy (side effects unique to each), and the risk of non-response to 
treatment interventions.   
 
D.  Protection of the Subject (include: D.1. measures to minimize potential risks; D.2 measures to 
ensure confidentiality; D.3. data safety monitoring plan) 
D1. Measures to minimize potential risks: 
 

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Risk of Mood Destabilization: As part of inclusion criteria, subjects are required to receive stable 
and therapeutic doses of mood stabilizers, which should minimize TMS related mood 
destabilization. Furthermore, sTMS is potentially well suited to be used in bipolar disorder due to 
the relatively low intensity of stimulation, compared to standard rTMS.  The magnetic field 
generated by sTMS is approximately only 10% of conventional TMS output. Moreover, in 
comparison, the total amount of magnetic field exposure for a full course of sTMS therapy is 
approximately only a minimal fraction of the exposure from a single scan with an MRI, which is 
widely used to study brain function in the psychiatric population, including children and infants.  
Furthermore, mood stability will be assessed weekly with Altman Self-Rating Mania Scale as a 
screening tool, and values above 6 on that screening scale will prompt further clinical evaluation 
that will include assessment with YRMS. Subjects will also be assessed weekly with self-rating 
scales for depression. 
 
Risk of Side Effects from sTMS: A trained member of the research staff will administer each 
treatment and be present throughout treatment sessions to observe the participants. Moreover, all 
procedures will occur as part of the Butler Hospital’s neuromodulation clinic, and a physician will 
be available at all times during treatments. Serial assessments side effects and contacts with 
research staff and study physicians will be used to identify and address any treatment-emergent 
side effects. 
 
Risk of discomfort during EEG:  The EEG headset allows adjustments to reduce scalp pressure if it 
is uncomfortable. EEG recording will be aborted if it cannot be done comfortably for any subject. 
 
Risk during MRI procedures: Subjects will fill out standard questionnaires and informed consent 
provided by the Brown MRI research facility (MRF). Subjects will be screened for metallic objects or 
exposure that would preclude them from participation in the study.  Investigators and research 
technicians associated with the MRF will screen for claustrophobia.  If there is concern for a 
physical abnormality on structural scan, the principal investigator will provide an appropriate 
clinical referral.  Ear protection will be provided to reduce the noise level.  Participant may stop 
during the procedure for any reason by telling the technician through the intercom or by squeezing 
a ball that we will place in the participant’s left hand.   
 
Subjects will be told the following, which is reiterated in the ICF: “during the scan itself, you will lie 
on a table that slides into a horizontal cylinder slightly wider than your body.  You will be asked to 
lie still, but you will be able to hear and speak to the MRI personnel.   If you feel uncomfortable for 
any reason before or during the procedure, please tell the researcher.  If for any reason during the 
procedure you want to stop, you may do so at any time by telling the technician through the 
intercom or by squeezing a ball that we will place in your left hand.  This ball is connected to a 
buzzer that tells us you want to stop.” 
 
D2. Measures to ensure confidentiality: 
Subjects will be told that their participation in this study is strictly voluntary and that they can 
change their minds at any time without impacting their present or future research participation. 
They will be assured of confidentiality in the handling of data generated by their participation in 
this study.  
 
Subjects will also be informed that their participation in this study and the clinical information 
relevant to safe treatment with sTMS will be documented in the Butler Hospital medical record. 
Other research-related information will be stored in locked research files in the Mood Disorders 
Research Clinic and subject names will not appear on any research forms (only identification 

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numbers). Data will be stored on secure hospital servers and in secure, password-protected 
REDCAP databases. 
 
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).  
Those regulations require a signed subject authorization informing the subject of the following: 
What protected health information (PHI) will be collected from subjects in this study; Who will 
have access to that information and why; Who will use or disclose that information; The rights of a 
research subject to revoke their authorization for use of their PHI.  
 
In the event that a subject revokes authorization to collect or use PHI, the Investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization. For subjects that have revoked authorization to collect or use PHI, attempts will be 
made to obtain permission to collect at least vital status (i.e. that the subject is alive) at the end of 
their scheduled study period.  
 
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 Institutional Review Board (IRB), in agreement with local legal prescriptions, for 
formal approval of the study conduct. 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.  
 
D.3. data safety monitoring plan: 
 
Study Monitoring Plan: This study will be monitored with regard to progress, adverse events, and 
other unexpected events at weekly research staff meetings with the investigators. The Butler IRB 
will provide review and oversight of progress through continuing review and through review of 
Serious/Unexpected Adverse Events. A data safety monitoring board will be convened annually to 
review the progress. Together these measures will act to ensure its scientific integrity, the quality of 
data, the safety of human subjects, and compliance with the ethical principles that have their origin 
in the Declaration of Helsinki, the ICH guideline for Good Clinical Practice (GCP), applicable local 
regulatory requirements, and Sponsor regulations, guidelines, and policies. 
 
E.  Potential Benefits  
For Subjects: Benefits to subject’s participation in this trial include a thorough evaluation of 
depressive symptoms at no cost, and possible relief from BDD symptoms from an investigational 
treatment with a favorable side effect profile. 
 
For Society: The potential benefits of this project to society may include enhanced knowledge about 
treatment options for BDD. 
 
F.  Risk-Benefit Ratio  
The risk-benefit ratio of this study is favorable.  Risks of adverse events associated with the use of 
this device (rated as nonsignificant risk by FDA) are minimal.  Risk of potential non-response 
associated with lack of efficacy is managed through oversight by a trained physician.  Patients will 
be under the care and supervision of experienced research psychiatrists and will be seen in by 
research clinic staff five (5) days per treatment week for treatment and assessment of worsening of 
symptoms/adverse events.   

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2015 
14. Fuggetta, G., A. Fiaschi and P. Manganotti (2005). "Modulation of cortical oscillatory activities induced by 
varying single-pulse transcranial magnetic stimulation intensity over the left primary motor area: a 
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activities during short trains of high-frequency repetitive transcranial magnetic stimulation of the 
human motor cortex: a combined EEG and TMS study." Hum Brain Mapp 29(1): 1-13. 
16. Hamidi, M., H. A. Slagter, G. Tononi and B. R. Postle (2009). "Repetitive Transcranial Magnetic Stimulation 
Affects behavior by Biasing Endogenous Cortical Oscillations." Front Integr Neurosci 3: 14. 
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18. Harel, E. V., A. Zangen, Y. Roth, I. Reti, Y. Braw and Y. Levkovitz (2011). "H-coil repetitive transcranial 
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behavior." Brain Topogr 22(4): 281-293. 
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Keller (2003). "A prospective investigation of the natural history of the long-term weekly 
symptomatic status of bipolar II disorder." Arch Gen Psychiatry 60(3): 261-269. 

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22. Judd, L. L., H. S. Akiskal, P. J. Schettler, J. Endicott, J. Maser, D. A. Solomon, A. C. Leon, J. A. Rice and M. B. 
Keller (2002). "The long-term natural history of the weekly symptomatic status of bipolar I disorder." 
Arch Gen Psychiatry 59(6): 530-537. 
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(2012). "Prevalence and clinical significance of subsyndromal manic symptoms, including irritability 
and psychomotor agitation, during bipolar major depressive episodes." J Affect Disord 138(3): 440-
448. 
24. Klimesch, W., P. Sauseng and C. Gerloff (2003). "Enhancing cognitive performance with repetitive 
transcranial magnetic stimulation at human individual alpha frequency." Eur J Neurosci 17(5): 1129-
1133. 
25. Klimesch, W., P. Sauseng and S. Hanslmayr (2007). "EEG alpha oscillations: the inhibition-timing 
hypothesis." Brain Res Rev 53(1): 63-88. 
26. Kroenke, K., R. L. Spitzer and J. B. Williams (2001). "The PHQ-9: validity of a brief depression severity 
measure." J Gen Intern Med 16(9): 606-613. 
27. Leuchter, A. F., I. A. Cook, D. Feifel, J. W. Goethe, M. Husain, L. L. Carpenter, M. E. Thase, A. D. Krystal, N. S. 
Philip, M. T. Bhati, W. J. Burke, R. H. Howland, Y. I. Sheline, S. T. Aaronson, D. V. Iosifescu, J. P. 
O'Reardon, W. S. Gilmer, R. Jain, K. S. Burgoyne, B. Phillips, P. J. Manberg, J. Massaro, A. M. Hunter, S. H. 
Lisanby and M. S. George (2015). "Efficacy and Safety of Low-field Synchronized Transcranial 
Magnetic Stimulation (sTMS) for Treatment of Major Depression." Brain Stimul 8(4): 787-794. 
28. Nahas, Z., F. A. Kozel, X. Li, B. Anderson and M. S. George (2003). "Left prefrontal transcranial magnetic 
stimulation (TMS) treatment of depression in bipolar affective disorder: a pilot study of acute safety 
and efficacy." Bipolar Disord 5(1): 40-47. 
29. Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry. 
1979 Apr;134:382-9.  
31. Noda, Y., W. K. Silverstein, M. S. Barr, F. Vila-Rodriguez, J. Downar, T. K. Rajji, P. B. Fitzgerald, B. H. Mulsant, 
S. N. Vigod, Z. J. Daskalakis and D. M. Blumberger (2015). "Neurobiological mechanisms of repetitive 
transcranial magnetic stimulation of the dorsolateral prefrontal cortex in depression: a systematic 
review." Psychol Med 45(16): 3411-3432. 
31. Nusslock, R., C. B. Young and K. S. Damme (2014). "Elevated reward-related neural activation as a unique 
biological marker of bipolar disorder: assessment and treatment implications." Behav Res Ther 62: 
74-87. 
32. Pascual-Leone, A., V. Walsh and J. Rothwell (2000). "Transcranial magnetic stimulation in cognitive 
neuroscience--virtual lesion, chronometry, and functional connectivity." Curr Opin Neurobiol 10(2): 
232-237. 
33. Paus, T., P. K. Sipila and A. P. Strafella (2001). "Synchronization of neuronal activity in the human primary 
motor cortex by transcranial magnetic stimulation: an EEG study." J Neurophysiol 86(4): 1983-1990. 
34. Perlis, R. H., M. J. Ostacher, J. F. Goldberg, D. J. Miklowitz, E. Friedman, J. Calabrese, M. E. Thase and G. S. 
Sachs (2010). "Transition to mania during treatment of bipolar depression." 
Neuropsychopharmacology 35(13): 2545-2552. 
35. Phillips, M. L. and D. J. Kupfer (2013). "Bipolar disorder diagnosis: challenges and future directions." 
Lancet 381(9878): 1663-1671. 
36. Rossi, S., M. Hallett, P. M. Rossini, A. Pascual-Leone and S. o. T. C. Group (2009). "Safety, ethical 
considerations, and application guidelines for the use of transcranial magnetic stimulation in clinical 
practice and research." Clin Neurophysiol 120(12): 2008-2039. 
37. Rush, A. J., C. M. Gullion, M. R. Basco, R. B. Jarrett and M. H. Trivedi (1996). "The Inventory of Depressive 
Symptomatology (IDS): psychometric properties." Psychol Med 26(3): 477-486. 
38. Sadaghiani, S., R. Scheeringa, K. Lehongre, B. Morillon, A. L. Giraud and A. Kleinschmidt (2010). "Intrinsic 
connectivity networks, alpha oscillations, and tonic alertness: a simultaneous 
electroencephalography/functional magnetic resonance imaging study." J Neurosci 30(30): 10243-
10250. 
39. Spearing MK, Post RM, Leverich GS, Brandt D, Nolen W. Modification of the Clinical Global Impressions 
(CGI) Scale for use in bipolar illness (BP): the CGI-BP. Psychiatry Res. 1997 Dec 5;73(3):159-71. 
40. Tamas, R. L., D. Menkes and R. S. El-Mallakh (2007). "Stimulating research: a prospective, randomized, 
double-blind, sham-controlled study of slow transcranial magnetic stimulation in depressed bipolar 
patients." J Neuropsychiatry Clin Neurosci 19(2): 198-199. 

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41. Trivedi, M. H., A. J. Rush, H. M. Ibrahim, T. J. Carmody, M. M. Biggs, T. Suppes, M. L. Crismon, K. Shores-
Wilson, M. G. Toprac, E. B. Dennehy, B. Witte and T. M. Kashner (2004). "The Inventory of Depressive 
Symptomatology, Clinician Rating (IDS-C) and Self-Report (IDS-SR), and the Quick Inventory of 
Depressive Symptomatology, Clinician Rating (QIDS-C) and Self-Report (QIDS-SR) in public sector 
patients with mood disorders: a psychometric evaluation." Psychol Med 34(1): 73-82. 
42. Valentí, M., I. Pacchiarotti, C. M. Bonnín, A. R. Rosa, D. Popovic, A. M. Nivoli, J. M. Goikolea, A. Murru, J. 
Undurraga, F. Colom and E. Vieta (2012). "Risk factors for antidepressant-related switch to mania." J 
Clin Psychiatry 73(2): e271-276. 
43. Young, R. C., J. T. Biggs, V. E. Ziegler and D. A. Meyer (1978). "A rating scale for mania: reliability, validity 
and sensitivity." Br J Psychiatry 133: 429-435. 
 
5) CRITERIA FOR WAIVER OF AUTHORIZATION FOR USE OF PROTECTED HEALTH 
INFORMATION (PHI) 
 
5A. Does the requested use of PHI involve more than minimal risk to privacy? 
 YES [if " YES," project is not eligible for PHI Waiver]    
  NO [if "NO," address 1-3 below] 
 
Plan to Protect Patient Identifiers from Improper Use and Disclosure: 
Data obtained from screening phone calls, faxed referral documents, and chart reviews will be 
treated confidentially and at the earliest possible point, be given anonymous numerical 
designations to protect PHI and stored on spreadsheets in secured locations.  All research 
personnel have completed appropriate research ethics training. 
 
Plan to Destroy Identifiers or Justification for Retaining Identifiers: 
All unique subject identifiers will be removed from the final data set. 
 
Assurances that the PHI will not be Re-used or Disclosed: 
Protected health information will not be re-used or disclosed to any other person or entity, except 
as required by law, for authorized oversight of the research study.  Co-investigators will review the 
data for accuracy. 
 
5B. Could the research be practicably conducted without a waiver? 
 YES    
  NO 
5C. Could the research be practicably conducted without access to and use of the PHI? 
 YES   
  NO 
5D. PHI is only needed for activities preparatory to research 
 YES    
  NO 
 
DESCRIPTION OF PHI TO BE COLLECTED UNDER WAIVER  
We will collect screening information from potential participants (who are referred or screened 
prior to signing informed consent for participation) from their verbal report, their medical records, 
or from their referring clinicians, including: 1) Name, 2) Date of Birth, 3) Phone Number, 4) 
Treatment History 5) Diagnosis. The PHI information will be kept in a separate file from the 
participant’s research data, and only selected and authorized staff will have access to PHI on an as 
needed basis.  
 
 
ADVERTISEMENTS 
See attached. 

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8) INFORMED CONSENT FORM (ICF) 
See attached 

 
Date most recently revised  (11/15/17) 
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_______________________________________________________________________________________________________________ 
BUTLER HOSPITAL CONSENT FOR PARTICIPATION IN A RESEARCH PROJECT  
_______________________________________________________________________________________________________________ 
  
Evaluation of NeoSync EEG Synchronized TMS For the Treatment of Major Depressive 
Episode in Bipolar Disorder and Associated Neural Response: An Open Label Trial 
 
Sponsorship 
This study is supported by internal funds at Butler Hospital/The company that makes the 
investigational treatment device (NeoSync) has loaned equipment to Butler Hospital for this 
study. 
 
 
Research Project Summary  
You are invited to participate in a study designed to assess efficacy, tolerability and safety of 
synchronized transcranial magnetic stimulation (abbreviated “sTMS”) for the treatment of 
depression and associated brain functioning changes.  You have been invited to participate 
because you have a diagnosis of Bipolar I Disorder and symptoms of a major depressive episode 
that are not relieved by medication. 
 
If you decide to participate, your participation in the study will last for approximately 30 
treatment days plus clinical evaluations before and after the treatment procedures. You may be 
asked to participate in a magnetic resonance imaging (abbreviated “MRI”) scan before starting 
and after finishing the series of sTMS treatments.  
 
A series of treatment will require approximately 30minutes per day, five days a week, for 6 
weeks. Additionally, once a week, you will participate in self-rating. There will be a clinical 
assessment and recording of brainwaves before starting the first treatment (approximately 4 
hours). When you complete the study there will be a final 1 hour assessment and another brain 
wave recording session. The main risks related to participation are lack of efficacy (the device 
doesn’t work to relieve your symptom), and risks related to MRI scans. These are described in 
more detail below. 
 
Description of Procedures 
If you decide to participate, you will participate in clinical assessments, brainwave recordings 
(called electroencephalograms, abbreviated “EEG”), a procedure to take pictures of your brain 
(called MRI scan) and investigational brain stimulation treatments. 
 
Clinical Assessments: you will participate in clinical interviews during which you will be asked 
about your depression symptoms and health history.  You will also be asked to complete 
questionnaires or self-rating scales to measure the severity of your depression. Assessments may 
be done with paper and pencil, or through a computer screen. You will repeat the clinical 
assessments at multiple visits in this study. Finally, you will also perform a safety follow-up 
assessment or phone call two weeks after your final treatment. 
 
EEG: your brain waves will be recorded using an EEG system with a cap and/or sticky patches. 
Several disposable, adhesive, snap-type electrode “patches” will be temporarily stuck on your 
head so your “brainwaves” can be recorded for about 5-10 minutes. You will not feel anything 
happening during the EEG recording procedure, other than the electrode patches stuck or 

 
Date most recently revised  (11/15/17) 
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Page 2 of 6 
clipped to your body. You will be asked to be still and remain quiet while the EEG recording is 
taking place. 
 
MRI scan: you may participate up to two (at the beginning and at the end of the study) brain 
scans in a MRI scanner located at Brown University campus. 
 
sTMS: is a noninvasive method used to stimulate the brain by a series of magnetics that move in 
a device close to your head. The device can be raised and 
lowered so that it rests gently on your head while you lay 
flat on a table. Adjustments can be made to the device if you 
find the pressure on your forehead uncomfortable.  You will 
remain quiet and awake during each 30-minute session. All 
participants will receive “active” or “real” stimulation from 
the sTMS device. There are no “sham” or “fake” treatments 
in this study. A pillow rests on the base of the device to 
provide you with a comfortable, stable platform that keeps 
your head in the correct position during sTMS treatment 
sessions.  You will hear some subtle sounds and feel some subtle mechanical vibration as the 1-
inch cylinder-shaped magnets rotate in the device over your forehead. 
 
Risks and Inconveniences  In order to decide whether or not you wish to be a part of this 
research study, you should know enough about its risks and benefits to make an informed 
judgment.  This consent form gives you detailed information about the research study which a 
member of the research team will discuss with you.  This discussion should go over all aspects of 
this research:  its purpose, the procedures that will be performed, risks associated with the 
procedures, possible benefits of participation, and possible alternatives.  Once you understand 
the study, you will be asked if you wish to participate; if so, you will be asked to sign this form.  In 
preparation of this consent form, it was necessary to use several technical words.  Please ask for 
an explanation of any that you do not understand. 
 
Risk of Mood Destabilization: Risks associated with participation in this trial include possible 
lack of positive response to the treatment, and/or worsening of depressive symptoms and/or 
mood destabilization. Furthermore, there is a theoretical risk of mood swing from depression to 
hypo/mania episode with the treatment. In addition, occasionally some emotional discomfort 
may occur while filling out questionnaires or being interviewed about matters pertaining to 
emotions, mental health, functioning and other relevant experiences. 
 
Risk of Side Effects from sTMS: Risks related to treatment with the NeoSync device is minimal. 
In a previous study, common side effects included back pain (8.7%) and paresthesia, or 
numbness/tingling (3.9%). 
 
Upon review of the available preliminary data, the US Food and Drug Administration, who 
regulates these devices, classified the NeoSync sTMS device as a “nonsignificant risk” device, 
which means that the device does not present a potential for serious risk to health.  
 
Risk of discomfort during EEG:  Subjects may feel areas of pressure on their scalp at the 
location of the recording electrodes during collection of EEG data.  
 

 
Date most recently revised  (11/15/17) 
Version (5.2) 
 
Page 3 of 6 
Risk during MRI procedures: MRI imaging is generally considered to be safe if the participant 
does not have metallic objects in the body.  Some people experience anxiety, panic or a sensation 
of claustrophobia when lying in the MRI machine.  A separate consent form associated with use 
of the Brown MRI Facility will be reviewed with you prior to participating in the scan. The MRI in 
this study does not constitute a clinical scan, which means the MRI cannot be used for diagnostic 
purposes. The scanner also makes loud noises during imaging.   
 
Any intervention may have unforeseen side effects.  You should know that the prediction of 
treatment effects in any individual cannot be done with certainty, and unexpected potentially 
harmful effects occasionally occur with the administration of any type of intervention.  If you 
have questions about magnetic stimulation, or if you experience any disturbing side effects 
during the study, inform study personnel.   In the event of any unexpected, potentially harmful 
effects of any treatment administered in this study, we will monitor your condition closely and 
institute appropriate treatment. 
 
Women Please Note:   
sTMS is not recommended for use during pregnancy.  sTMS may be harmful to a developing 
fetus.  Therefore, you may be tested for pregnancy at the time of your admission to the study.  
Prior to your beginning the study we will discuss with you in more detail the importance of 
avoiding pregnancy.  We will specifically ask you to let us know if you change your mind and 
decide to become pregnant during the study. 
 
Benefits 
If you decide to participate in the study, you will receive a thorough evaluation of your 
depressive symptoms at no cost to you, and possible relief from bipolar depression symptoms 
from an investigational treatment with a favorable side effect profile. Furthermore, it will also 
help to advance the understanding of treatment options for bipolar depression in general. 
 
Economic Considerations   
You will not receive payment for your participation in the study. However, you will receive 
investigational sTMS treatments and clinical assessments at no cost to you. If you participate in 
the MRI scans, you will receive a gift card in the value of $25.00 for each of the MRI scans. 
 
NeoSync is providing the devices to Butler Hospital so the researchers can offer the study 
intervention at no cost to you.  sTMS treatments and all of the tests and procedures that will be 
done only for this research will be paid for by the study funds.   
 
In Case of Injury   
We will offer you services in Care New England facilities as needed to treat any injury that 
results directly from taking part in this research study.  We reserve the right to bill your 
insurance company or other third parties, if appropriate, for the care you get for the injury.  We 
will try to have these costs paid for, but you may be responsible for some of them.  For example, 
if the care is billed to your insurer, you will be responsible for payment of any deductibles and 
co-payments required by your insurer.   
 
Injuries sometimes happen in research even when no one is at fault.  There are no plans to pay 
you or give you other compensation for any injury, should one occur.  However, you are not 
giving up any of your legal rights by signing this form.   

 
Date most recently revised  (11/15/17) 
Version (5.2) 
 
Page 4 of 6 
If you think you have been injured or have experienced a medical problem as a result of taking 
part in this research study, tell the person in charge of this study as soon as possible.  The 
researcher’s name and phone number are listed on the last page of this consent form.    
 
Alternative Treatments  
sTMS is an investigational treatment and it is not known if it will help relieve symptoms of 
depression in patients with bipolar disorder. If you choose not to participate in this study, there 
are standard treatments for bipolar depression such as medication and psychotherapy, which 
can be administered by a clinician and/or prescribed by a physician or nurse outside of this 
research study. The primary risk of untreated BD is prolonged disability and suffering, or if the 
condition becomes severe or worsens, possibly attempting or completing suicide.  
 
Alternative to Participation 
As an alternative to participating, you may choose not to participate in these research 
procedures and have usual care for bipolar depression as directed by community healthcare 
providers.  Your current or future care at Butler Hospital will not be affected in any way if you 
decide not to participate in this research study. 
 
Financial Disclosure   
Butler Hospital has received research funding from NeoSync, Inc. to conduct research trials with 
the device used in this study.  The study physicians and research staff are employees of Butler 
Hospital and have no direct personal financial relationships with the company that makes the 
sTMS device (NeoSync, Inc.).  
 
Voluntary Participation 
You are free to decide whether or not to participate in this study, and you are free to withdraw 
from the study at any time.  A decision not to participate or to withdraw from the study will not 
adversely affect your current or future interactions with Butler Hospital or Care New England. 
Your participation in the study may be terminated by the researchers without regard to your 
consent; in that case, you are entitled to an explanation of the circumstances leading to that 
decision. 
 
Confidentiality 
Personal identifiers will be removed from any identifiable private information about you in the 
final research dataset created by this study. The de-identified information may be used for future 
research studies or distributed to another investigator for future research studies without 
additional informed consent from you. You will not be personally identified in any reports or 
publications that may result from this study.  The confidentiality of the information you provide 
to us will be maintained in accordance with state and federal laws.  If you tell us something that 
makes us believe that you or others have been or may be physically harmed, we may report that 
information to the appropriate agencies. 
 
To keep your information safe,  research data will be captured in a de-identified way (without 
your name or other information that identifies you personally) and a list linking your identity 
with a coded ID number for this study will be kept in a restricted-access file on a password-
protected server maintained by CNE. Any paper documents that contain personal health 
information about you will be stored in locked cabinets or secure spaces dedicated for research 
records.  General information about this study has been or will be submitted to the federal 

 
Date most recently revised  (11/15/17) 
Version (5.2) 
 
Page 5 of 6 
clinical trial registry databank, which can be accessed on the Internet at www.ClinicalTrials.gov 
 
Authorization for use/disclosure of Health Information that Identifies you for a Research Study 
If you sign this document, you give permission to researchers at Butler Hospital to use and share your 
health information that identifies you, for the purpose of conducting the research study described above. 
Your health information related to this study may also be shared with and used by individuals outside of 
Butler Hospital, including your psychiatric clinicians or other healthcare providers involved in your 
medical care, the Butler Hospital Institutional Review Board, the Brown MRI facility staff. 
 
The health information that we may use or share with others for research purposes includes your 
diagnosis and medications, current and past medical and treatment history.  
  
Your health information may also be shared with a public health authority that is authorized by law to 
collect or receive such information for the purpose of preventing or controlling disease, injury, or 
disability, and conducting public health surveillance, investigations, or interventions. The U.S. Food and 
Drug Administration (FDA) may inspect all study records to ensure that the study is being conducted in 
accordance with FDA regulations.  
 
Butler Hospital is required by law to protect your health information. Individuals outside of Butler that 
receive your health information may not be required by Federal privacy laws (such as the HIPAA Privacy 
Rule) to protect it, so we cannot guarantee that they will not share it without your permission. 
 
Please note that:  
 
You do not have to sign this consent form, but if you do not, you may not participate in or receive 
research-related treatment in this study.   
 
Butler Hospital may not withhold treatment or refuse to treat you, based on whether you sign this 
consent form.  
 
You may change your mind and revoke (take back) this consent and authorization at any time. If 
you no longer want to give us permission to use your health information for this research study, 
you must contact the Principal Investigator, Dr. Linda Carpenter, and you will be instructed to 
provide a written statement.  
 
Even if you revoke (take back) this consent and authorization, Butler researchers may still use or 
share health information about you that they already have obtained, when doing so is necessary 
to maintain the integrity or reliability of the current research.  
 
You generally will not have access to your personal health information related to this research 
until the study is completed. At the conclusion of the research and at your request, you will have 
access to your health information that Butler Hospital maintains in a designated record set, 
according to the Notice of Privacy Practices provided to you by Butler Hospital. The designated 
record set includes medical information or billing records used by doctors or other health care 
providers at Butler Hospital to make decisions about individuals.  
 
Your health information will be provided to you or to your physician if it is necessary for your 
care. 
 
This Authorization does not have an expiration date. 
 
Questions 
In preparation of this consent form it was necessary to use several technical words.  Please ask for an 
explanation of any that you do not understand. 
 

 
Date most recently revised  (11/15/17) 
Version (5.2) 
 
Page 6 of 6 
Authorization:   
I have read this form and decided that _________________________________________________________________ 
 
 
 
 
 
 
 
 (name of participant) 
will participate in the project described above.  Its general purposes, the nature of my 
involvement, and possible hazards and inconveniences have been explained to my satisfaction. I 
have received a copy of this consent form. 
 
__________________________________________________________  
_____________________________________ 
Signature  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date 
Relationship: (self, parent, guardian)_____________________________________________________________________ 
 
 
 
 
 
 
 
__________________________________________________________  
_____________________________________ 
Signature of Principal Investigator  
 
 
 
 
 
Date  
 
 
 
 
 
 
 
~or~ 
__________________________________________________________  
_____________________________________ 
Signature of Person Obtaining Consent  
 
 
 
 
Date 
Telephone Number of Principal Investigator or Person Obtaining Consent_________________________ 
 
If you have further questions about this project or about research-related injuries, please contact 
Linda Carpenter at 401-455-6537.  If you have questions about your rights as a research subject, 
please contact Paul F. Malloy, Ph.D., Associate Chair, Butler Hospital Institutional Review Board, 
at 401-455-6355. 
THIS FORM IS NOT VALID UNLESS THE FOLLOWING 
BOX HAS BEEN COMPLETED BY THE IRB OFFICE 
 
 
THIS FORM IS VALID UNTIL: 
 
 
    DATE: December 31, 2018 
 
 
    IRBNET ID# 839938 
    BUTLER IRB REFERENCE# 1601-004 
 
 
    BY (ADMINISTRATOR):