Synchronized TMS for Posttraumatic Stress Disorder and Comorbid Depressive Symptoms
Phase: NA
Conditions: PTSD, Depression
Sponsor: Providence VA Medical Center

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Investigator Initiated Proposal: “Synchronized TMS for Posttraumatic Stress Disorder and 
Comorbid Depressive Symptoms”
Noah S. Philip, MD; Providence VA Medical Center
830 Chalkstone Ave Providence RI
Email: Noah_Philip@Brown.edu
Tel: 401-273-7100 x2369
Paul Holtzheimer MD; White River Junction VA Medical Center
215 N Main St, White River Junction, VT 05009
Email: Paul.E.Holtzheimer@hitcock.org
Tel: 802-295-9363 x6994
Dartmouth-Hitchcock Medical Center
One Medical Center Drive, Lebanon, NH 03756
Tel: 603-650-4914
I.
Specific Aims
i.
To evaluate the safety and efficacy of synchronized transcranial magnetic stimulation 
(sTMS) using the NeoSync device for adults with posttraumatic stress disorder (PTSD) 
and comorbid depressive symptoms in a pilot sham-controlled study. 
ii.
To explore the relationship between frontal alpha and treatment outcomes.
iii.
To generate pilot data for future trials using the device in the home setting 
II.
Background
The impact of Post-Traumatic Stress Disorder (PTSD) cannot be overstated in the 
Veteran population. PTSD is highly prevalent, affecting up to 12.5% of returning Veterans from 
Operation Iraqi Freedom and Operation Enduring Freedom (Hoge et al., 2008) as well as 
among Veterans from Operation Desert Storm and the Vietnam War (Magruder et al., 2005).  
Furthermore, PTSD is associated with high degrees of psychiatric and medical comorbidity 
(Magruder et al., 2005) and significant utilization of healthcare resources (Spiro et al., 2006). 
Most importantly, PTSD prevents Veterans from reintegrating into society and is associated 
with poor quality of life and significant occupational and social dysfunction (Thomas et al., 
2010). Despite its prevalence and impact, available treatments for PTSD have limited efficacy.  
Evidence-based pharmacotherapy and psychotherapy approaches have had only modest success 
in improving symptoms and function in Veterans with PTSD (Watts et al., 2013). Therefore, 
there is a pressing need to identify effective adjunctive treatments for PTSD. 
Despite a vastly growing body of research on the use of non-invasive neuromodulation 
for mental disorders, the application of these techniques to PTSD remains much less explored. 
Repetitive Transcranial Magnetic Stimulation (rTMS) is a non-invasive, outpatient procedure 
that uses an electromagnetic field to stimulate or inhibit cortical neurons (George et al., 2002). 
Our group, together with others, has previously reported on rTMS efficacy for depression 
(Carpenter et al., 2012). Devices for rTMS are currently FDA-cleared to improve symptoms of 
treatment-resistant depression, are in use in over 650 outpatient locations in the U.S., and an 
increasing number are within the VA system. Yet in comparison to depression, there is only a 
small emerging literature supporting the use of rTMS for PTSD, as participants with PTSD were 
excluded from the original studies of rTMS for MDD (i.e., O’Reardon et al., 2007 and George et 
al., 2010).
After several case reports and uncontrolled studies (McCann et al., 1998; Grisaru et al., 
1998; Rosenberg et al., 2002), Cohen et al. (2004) performed the first formal evaluation of 
rTMS for PTSD.  Following this original study subsequent controlled studies have investigated 

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its use, including studies from Boggio et al. (2010) and Watts et al. (2012).  Moreover, we 
recently evaluated the efficacy of rTMS in individuals suffering from comorbid depression and 
anxiety, which found modest outcomes (Philip et al., 2015).  Karsen et al. (2014) performed a 
meta-analysis of rTMS for PTSD which supports that targeting the right dorsolateral prefrontal 
cortex (DLPFC) with either inhibitory or excitatory rTMS is safe and has a significant effect size 
on symptom reduction (pooled Hedges g 2.67; CI 1.11-4.23).  Moreover, in patients with 
comorbid major depressive disorder rTMS also had significant effects on a reduction in 
depressive symptoms (pooled Hedges g 2.82; CI 1.99-3.65). However, this meta-analysis was 
based on only 3 out of the 8 trials, reflecting a relatively high proportion of uncontrolled reports, 
indicating that further studies are needed.
Of particular relevance to this application are the burdens associated with standard 
rTMS therapy. Current rTMS protocols for depression require daily sessions, each taking 45 
minutes – for up to 6-8 weeks (O’Reardon et al., 2007).  In our clinic this has imposed a 
significant burden on Veterans, as they attempt to balance treatment requirements with re-
integration into society, family needs and cope with other stressors.  Moreover, the trend in 
PTSD rTMS protocol development is to increase the number of pulses and treatment sessions to 
improve outcomes, supported by evidence showing a positive relationship between symptom 
improvement and number of pulses delivered (Karsen et al., 2014). From this perspective, 
future “conventional” rTMS protocols for PTSD will be longer and carry an increased treatment 
burden for Veterans. 
Taken together, research on non-invasive brain stimulation for PTSD remains in its early 
stages, and it is critical to develop novel interventions that a) use an individual biomarker to 
select the treatment frequency, b) reduce the burden of care on Veterans, and c) addresses the 
common comorbidity of PTSD and depressive symptoms.  This poises the synchronized TMS 
(sTMS, NeoSync Inc.) device to potentially revolutionize the treatment of PTSD with non-
invasive stimulation.  This is additionally informed by our own preliminary work in patients 
with PTSD and comorbid depressive symptoms, where we have found their IAF approximates 
those found in the general population (mean IAF of 9.58 ± 1.1, n = 18, unpublished data), 
suggesting that sTMS synchronized to the alpha range will also be feasible in the population 
under study.
With these considerations in mind, we propose a small, two-site, sham-controlled pilot 
study of sTMS in patients with comorbid PTSD and depressive symptoms.  We hypothesize that 
sTMS will be effective for PTSD and mood symptoms in this sample. 
III.
Experimental Methods
1.  Brief Description of Subjects
Subjects will be outpatients who meet the DSM-V criteria for PTSD (acute or chronic, 
confirmed by the Clinician Administered PTSD Scale [CAPS] and at least moderate severity, 
defined as score > 33 on the PTSD checklist [PCL-5]) and have at least moderate symptoms of 
depression (defined by moderate symptoms, or score ≥ 11 on the Quick Inventory for Depressive 
Symptomatology – Subject Rated [QIDS-SR]) and are 18 to 70 years of age (inclusive). Up to 35 
participants will complete the study at the two sites, the Providence VAMC (Providence, RI) and 
the White River Junction VAMC (White River Junction, VT).  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. Additional 
inclusion/exclusion criteria are listed below.
2.  Study Design  
This study is a prospective, sham-controlled, trial of sTMS delivered to patients who are 
symptomatic despite ongoing pharmacotherapy for PTSD and mood symptoms.  Serial self-
report symptom assessments will take place at screening/baseline and weekly during the 4 

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weeks of the study. The treatment course will comprise a total of 20 double-blind treatment 
sessions.  Treatments windows will be 10 calendar days to complete 5 treatments, with a 40-day 
window in total to complete 20 treatments.  Post-treatment assessment sessions will take place 
on the last day of treatment, and again 1 month after the final treatment.  
All veterans who complete the sham-controlled series will be offered open-label 
continuation treatment following the same administration structure (i.e., 20 open-label 
treatment sessions, with 10 calendar days to complete 5 treatments, within a 40-day window for 
all 20 treatments), with a 1-month, post-treatment visit).  Of note, for patients who continue in 
open-label participation, the 1 final study visit (PT2, below) will occur 1 month after the final 
open label treatment. 
3.  Specific Procedures or Treatments
A.  Screening:  Patients who call in response to advertisements for the study or are 
referred by clinicians and meet preliminary demographic eligibility criteria upon phone screen 
will be invited to the clinic for a screening visit. Participants will also be drawn from clinical and 
research clinics at participating sites. After providing written informed consent, psychiatric 
interview and self-report measures will be used to confirm eligibility with regard to diagnosis, 
past psychotropic treatment history, current health history, and current symptom severity. The 
requirement for maintenance on a stable regimen of psychotropic medications for 6 weeks prior 
to baseline and during participation in the course of sTMS will be discussed. 
B. Baseline/First Treatment Day:  Patients meeting eligibility criteria will return within 2 
weeks to begin the treatment protocol. Consent will be reviewed and confirmed with standard-
of-practice forms for each institution. If indicated, women will be given a pregnancy test to make 
sure they are not pregnant. Clinical assessments will be updated (if more than 2 weeks have 
passed since screening visit), and data regarding functioning and quality of life will be collected 
with standardized measures. sTMS delivery will be calibrated using standard NeoSync 
procedures found in the device’s user manual. 
C. Serial Assessments: In the table below, PT1 refers to the assessment after the final 
sTMS treatment (i.e., after week 4 of the sham-controlled phase and, if relevant, after week 8 of 
the open-label phase). PT2 refers to the assessment completed 1 month after the final treatment 
(sham-controlled or open-label).  PT1 and PT2 will include a psychiatric interview with the study 
PI or their designee.  SC= screening visit, BL=Baseline/first treatment day, OL = open-label, 
with brackets indicating procedures done only in patients participating in the OL continuation 
phase. End-of-treatment week assessments are listed according to number of weeks of sTMS 
therapy completed by the time of assessment. * Indicates repeat evaluation at baseline if more 
than two weeks has passed since screening.   Note that psychiatric assessments will occur at 
SC/BL, PT1, [OL PT1,] and PT2.  

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Table 1: Serial Assessments 
Abbrev:
Assessment Title:
Administered at:
CAPS
Clinician Administered PTSD Scale
SC, BL*, PT1, [OL PT1,] PT2
CTQ
Childhood Trauma Questionnaire
SC, BL*
CGI-S
Clinical Global Impression - Severity
SC, BL*, PT1, [OL PT1,] PT2
QIDS-SR
Quick Inventory of Depressive Symptoms – 
Self Report
SC, BL*, Weeks 1-3,PT1, [OL 
Weeks 5-7, OL PT1,] PT2
PCL-5
PTSD Checklist 
SC, BL*, Weeks 1-3,PT1, [OL 
Weeks 5-7, OL PT1,] PT2
GAD7
7 Item Generalized Anxiety Disorder Scale
SC, BL*, PT1, [OL PT1] PT2
Q-LES-
Q-SF
Quality of Life Enjoyment and Satisfaction 
Questionnaire
SC, BL*, PT1, [OL PT1] PT2
CGI-I
Clinical Global Impression – Improvement
PT1, [OL PT1,] PT2
PGI-I
Patient Global Impression - Improvement
PT1, [OL PT1,] PT2
D.  sTMS Treatment Administration: sTMS will be delivered following NeoSync 
administration guidelines using the device user manual.  Acting under the direct supervision of 
a TMS-credentialed physician, trained sTMS operators will supervise all treatments.  
Treatment emergent side effects associated with stimulation (during treatments) and 
emerging between treatment sessions will be queried on each treatment day and recorded.
E. Serial Imaging: Participants (at Providence VAMC site) found eligible at SC may 
undergo three MRI scanning sessions during the course of this study. Scans may occur prior to 
BL/first treatment day and after completing each study phase (i.e., after PT1 and PT1 OL). Scans 
will be completed at Brown University MRI Facility (MRF) or Providence VAMC; with scanner 
location remaining consistent for each participant (i.e., a participant BL screened at Brown will 
undergo PT1 scan at Brown, not PVAMC). Eligible participants will be scheduled to arrive at 
either facility 1 hour prior to MRI start time. At that time research staff will review MRI safety 
and study procedures, and discuss any changes in mood, sleep, and/or medication since their 
last visit. Additionally, participants will be asked to complete the Perceived Stress Scale prior to 
entering the scanner. Once in the magnet, research staff will ensure that the participant is 
comfortable, able to view the task screen, and has been provided the necessary instructions 
regarding communication with research staff during the scan (e.g., using emergency squeeze 
ball). After each scan, the participant will be queried about their experience in the scanner to 
assess for anxiety and/or discomfort.     
Images will be acquired using either a Siemens (Erlangen, Germany) TIM TRIO or 
VERIO 3.0 Tesla scanner located at Brown MRF and PVAMC (Building 1), respectively. Imaging 
acquisition and procedures are well established at both scanner locations. The scan session will 
start with a T1 anatomic scan for reference, followed by blocks of n-back tasks (working 
memory) during BOLD imaging in between BOLD and multi-band EPI resting blocks (resting 
state image acquisition), and finish with a DTI sequence. We have experience using this 
sequence order (see Table 2) in similar research projects, and have found that is effective in 
minimizing in-scanner fatigue. Total in-scanner time will be approximately 42 minutes.   
Table 2. MRI Sequence
Run
Duration (sec)
Sequence
Task
Volumes (TRs)
1
250
MPRAGE
N/A
N/A
2
480
EPI
Rest-Fixation Cross
192
3
300
EPI
2-Back
116
4
300
EPI
2-Back
116
5
480
MB-EPI
Rest-Fixation Cross
480

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6
720
DTI
N/A
N/A
Total time: 2530 sec (42.2 min)
Imaging Sequences. High-resolution (1 mm3) whole brain T1 images will be acquired for 
anatomic reference using MPRAGE sequence, and pulse oximetry and respiratory bellows will 
be measured for use as potential covariates during processing and analyses. Functional 
connectivity during tasks will be evaluated with multi-band and BOLD echoplannar imaging 
(EPI) sequences. Diffusion tensor imaging (DTI) parameters will utilize double spin echo echo-
planar DWI, with diffusion gradients applied in 64 non-collinear directions (b = 1000), one 
DWI for each gradient direction and 10 non-weighted (b = 0) normalization images, using 
Siemens MDDW protocol with partial echos and interpolation on. All parameters are outlined in 
the table below.
Table 3. Imaging Parameters
Parameter/Sequence
Sagittal MPRAGE
Axial BOLD (EPI)
MB-EPI
DTI (DWI)
Slice (mm)
1
3
2
1.8
TE (ms)
2.98
28
30.2
10060
TR (ms)
1900
2500
1050
103
FOV (mm)
2562
1922
1922
226
Tasks. During resting state image acquisition, participants will be instructed to keep 
their eyes open and view a grey fixation cross against a black background. Working memory will 
be tested using a standard n-back task as used in previous studies. During the DTI sequence 
participants will be instructed to remain awake, but given the option as to whether they prefer 
keeping their eyes opened or closed. 
4. Power Calculations and Data Analysis 
We aim to maximize power through collaborative analyses including data collected from 
the two sites of the study.  De-identified data will be shared for final analyses. At least 20 
subjects will be completed in total.  The sample size for this pilot controlled 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. Previous studies of different TMS parameters for PTSD (without comorbid MDD) 
have utilized sample sizes of ~ N = 20.  By employing a comparable sample size we anticipate 
having sufficient power to detect significant differences between baseline and endpoint. This 
sample size will be adequate to determine the appropriate sample size for a subsequent trial. 
For the primary efficacy endpoint, we will analyze change in total scores on both PCL-5 
scores from baseline to end point PT1. Categorical response (empirically defined as 50% 
decrease from pre-treatment baseline) and remission (below threshold score, per published 
standards for each scale) will be calculated for each scale, and these will be reported in a 
descriptive manner for the sample. Secondary efficacy endpoints will utilize pre- and post-
treatment scores on the self-report scales and CAPS.  Open-label results, potentially informing 
issues related to duration of treatment, will be reported descriptively.
IV.  Material Inducements
Participants will be offered payments in the form of gift cards, for completion of three 
milestones in the study: $25 giftcard for completion of all baseline procedures, $25 giftcard for 
completion of all PT1 procedures, and $50 giftcard for completion of PT2 procedures. There is a 
maximum total payment of $100 to offset time and travel expenses incurred as a result of 
participation in the research assessments that are not standard of care for non-research patients 
who undergo sTMS therapy.  Participants who undergo open-label treatment will receive an 
additional $25 for completing OL PT1 procedures, bringing the maximum total of $125 

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(inclusive of acute phase and open-label inducements). Additionally, participants who undergo 
serial MRI imaging will receive an additional $50 at each scanning session. There is a maximum 
total payment of $150 for completing 3 serial MRI sessions. Thus, participants that complete all 
primary study procedures and serial imaging procedures may receive a maximum of $275. 
Payments may occur via gift cards or EFT. 
V.   Training of Research Personnel
All research staff will receive study specific training from their site PI prior to their 
involvement in the study, and all staff will receive device-specific training from NeoSync. 
Research staff meetings will be scheduled as needed for further training, especially if the 
protocol is amended. Study PIs will be available to research staff by phone and email to answer 
any study related questions. Study PIs or their designees will train and supervise research 
assistants to process and analyze the research data. Study PIs will be responsible for 
documentation of all training that will be placed in the study’s regulatory files.  Study PIs or 
providers with experience in neuromodulation will supervise delivery of sTMS during the study. 
VI. Human Participants  
1.  Participant Population 
Up to 35 male and female subjects , age 18 to 70 years, who are suffering from PTSD and 
comorbid depressive symptoms, will complete the study. 
Inclusion Criteria: 
(1) To ensure subjects can safely receive sTMS, eligible subjects must meet all established 
screening criteria for safety during MRI (magnetic resonance imaging).  These are conservative 
measures require a patient not having the following (unless MRI-safe): Cardiac pacemaker, 
implanted device (deep brain stimulation) or metal in the brain, cervical spinal cord, or upper 
thoracic spinal cord;
(2) Outpatients 18-70 years of age (inclusive);
(3) Meet DSM-V criteria for PTSD (acute or chronic) at the time of the screening and/or 
baseline visit; AND report at least moderate symptom severity of depressive symptoms.  
Participants with bipolar II or otherwise unspecified, who are currently in a depressed episode, 
will be eligible to participate;
(4) Have a baseline score of “Moderately Ill” or worse on the CGI-S;
(5) Be on a stable psychotropic regimen for at least 6 weeks prior to baseline, or no psychotropic 
medication at all (for at least 6 weeks prior to baseline), and be willing to maintain the current 
regimen and dosing for the duration of the study (unless medically necessary to make changes 
with notification of research staff);
 (7) If female and of child bearing potential, agree to use an acceptable method of birth control 
for the duration of the study treatment period; 
(8) Be willing and able to comply with all study related procedures and visits;
(9) Be capable of independently reading and understanding patient information materials and 
giving written informed consent.
Exclusion Criteria: 
Subjects will be excluded from participation if they meet any of the following:
(1) Are pregnant or lactating or planning to become pregnant within the next three months;
(2) Have a lifetime history of loss of consciousness due to head injury for greater than 10 
minutes, or any lifetime history of loss of consciousness due to a head injury with documented 
evidence of brain injury (including brain atrophy);
(3) Current (or past if appropriate) significant neurological disorder, or lifetime history of a) 
seizure disorder b) primary or secondary CNS tumors c) stroke or d) cerebral aneurysm; 

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(4) Unstable medical illness, or, in the opinion of the investigator, significant absence of 
appropriate medical care;
(5) Current Axis 1 primary psychotic disorder, or bipolar I disorder, active moderate/severe 
substance use disorders (within the last month, excluding nicotine/caffeine).  Veterans on stable 
(>3 months), monitored opiate agonist therapy may be included at the investigator’s discretion;
(6) Past failed treatment with rTMS or ECT; any past treatment with deep brain stimulation or 
vagus nerve stimulation;
(7) Have 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;
(8) Demonstrate the presence of any other condition or circumstance that, in the opinion of the 
investigator, has the potential to prevent study completion and/or to have a confounding effect 
on outcome assessments.
(9) Inability to obtain EEG of sufficient quality and duration that can be processed for use to 
calibrate the study device. 
2.  Recruitment and Consent Procedures 
Potential participants will be recruited through advertisements in the community. 
Announcements to hospital and community clinicians will be made to facilitate referrals. 
Research assistants will provide preliminary screening with callers who express interest. Written 
informed consent will take place as described above, during the screening visit.
3.  Potential Risks to Participants 
A. Risk of side effects from sTMS treatments: The U.S. Food and Drug Administration 
has designated this device as a “non-significant risk device” in MDD patients, and in the largest 
sTMS trial to date for MDD, there were no statistically significant differences in side effects 
between active and sham sTMS (Leuchter et al., 2015).  The most commonly side effect reported 
was headache (21.4% in active sTMS, 19.2% in sham sTMS). Over-the-counter pain medications 
such as acetaminophen or ibuprofen may be helpful for reducing discomfort associated with 
sTMS.  Because sTMS remains investigational, study staff will assess subjects’ well being and 
functioning before and after each treatment to minimize the risk of experiencing these or any 
other side effects.
B. Risk of Worsening PTSD/Depression Symptoms or Lack of Improvement: Risks 
associated with participation in this trial include possible lack of positive response to sTMS 
treatment. Worsening of PTSD/Depressive symptoms is also a risk. There is no guarantee that 
the treatment will lead to improvement of symptoms. During the course of sTMS treatments or 
after finishing the final session in an sTMS treatment series, symptoms may worsen. The 
research staff will evaluate subjects at every sTMS treatment session, and the study physician 
will be available at all times to ensure that participation in this research continues to be safe and 
reasonable for them. 
C. Risk of Inconvenience and Burden of Required Time/Travel: Subjects may engage in 
screening procedures and learn they are not eligible for participation in the research treatment 
trial.  Emotional discomfort may be associated with completing the assessments and 
questionnaires. Frequent visits to the research clinic for the sTMS treatments (5 days per week) 
for up to 10 weeks may represent a considerable inconvenience, especially if a subject travels a 
great distance or has other constraints on their time or transportation. A small payment will be 
offered to cover part of the subject’s expenses related to participation in this research study, but 
subjects will not be offered reimbursement for all of the expenses they may incur.
D. Confidentiality: There is some risk to patient confidentiality associated with 
participation in research clinical trials, as more data are collected than would happen in usual 
medical practice. Steps will be taken to protect privacy of patient health information. 
Participants’ records/assessments will not become a part of their permanent medical record.  All 

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study forms and data will be identified only by code numbers, and will be stored in locked file 
cabinets or on secure research servers. Identifying information (contact information, name, 
consent documents) will be separated from the research data and be stored separately in a 
different locked file cabinet. All computerized data will be de-identified and stored on secure, 
password-protected files. No personal participant information will be presented in any 
publication or presentations resulting from this research. Only the PI and study team will have 
access to materials gathered during the study.  Patients will be told that information about their 
sTMS therapy will be shared with their prescribing psychiatrist and primary care provider, per 
best-practice standards.  De-identified EEG data may be acquired, downloaded to and stored via 
NeoSync-provided utilities and recording equipment. De-Identified data may be shared with 
NeoSync, Inc., the device manufacturer. De-identified data from study sites will be entered into 
a shared database for analysis at the completion of the study.
E. There may be other risks that are currently unknown. Although sTMS is a designated 
a non-significant risk device in an MDD population, the long-term effects of sTMS on 
individuals are not completely known. The research team will notify subjects if anything new is 
learned about the safety of sTMS that might make them change their mind about participating 
in this study. 
3.  Further Detail of Protection Against Risks 
A. sTMS: A licensed study physician with experience and training in neuromodulation 
will be available throughout all sTMS sessions.  Study technician (defined as a non-LIP) will be 
within the sTMS treatment area during all sTMS sessions. Spontaneous report of side effects of 
sTMS will be used to identify and address any sTMS-emergent adverse effects. Risk of other 
serious adverse events related to stimulation will be mitigated by careful screening of past health 
history, identification of underlying risk factors, and application of the study 
inclusion/exclusion criteria. 
B. Confidentiality, privacy and security: 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. whether the 
subject is alive) at the end of their scheduled study period.  
If a potential participant is found ineligible on phone pre-screen or elects not to 
participate prior to signing a consent form, all their identifying information will be maintained 
only with age and gender. To protect participant’s confidentiality all study data collected at each 
site will be labeled with a unique code and have none of the eighteen personal identifiers on 
them. The link to this code will be stored on a VA secure server with access only by research staff 
designated by the PI. Consent forms and participant demographic data will be stored separate 
from the study data. All research data and study documents collected at the VA site will be 
stored in locked files in an office at that location.  
4.  Potential Benefits and Importance of Knowledge to Be Gained
For Subjects: Benefits to subject participating in this trial include a thorough evaluation 
of mood and anxiety symptoms at no cost, and possible relief from PTSD and depressive 
symptoms from sTMS, a treatment with a very favorable safety profile. 

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For Society: The potential benefits of this project to society may include enhanced 
knowledge about treatment options for PTSD, about EEG-synchronized brain stimulation, and 
outcomes among the type of patients often encountered in clinical practice but excluded from 
participation in most large clinical trials – those with comorbid PTSD and depressive syndromes 
with chronic and often disabling symptoms 
5.  Risk-Benefit Ratio 
The risk-benefit ratio of this study is favorable, particularly since the US FDA designated 
this device as non-significant risk.  As such, it is considerably safer than a current study of 
standard rTMS therapy.  Risks of adverse events associated with the use of the sTMS device are 
minimal and minimized by study design.  Risk of potential nonresponse is managed through 
oversight by trained physicians.  Patients will be under the care and supervision of experienced 
research psychiatrists and will be seen in by research clinic staff five days per treatment week for 
treatment and assessment of worsening of symptoms/adverse events.
6. Data Safety and Monitoring Plan
The site principal investigators will review all data collected and will report any adverse 
events to the IRB, as appropriate.  To ensure the integrity of the data the site PI will review all 
the data for errors or inaccuracy within one week after it is obtained.  All data will be entered 
into a research database as it is collected using RedCap, and study personnel will meet weekly or 
as appropriate to review ongoing subject data. All research staff members are trained in basic 
first aid and CPR.  Following standard practice, serious and unexpected adverse events will be 
reported to the relevant IRBs within the designated IRB guidelines.   For example, a serious 
adverse event will be reported by fax or e-mail within 1 business day, followed by a written 
report within 7 days.  NeoSync will be notified immediately after IRB notification.  If a pattern 
or potential pattern of unexpected adverse events emerges during the course of the study, the 
site PI will discuss this pattern with the other study PI and other physicians with expertise in 
brain stimulation in this population, and review whether the creation of a formal data safety and 
monitoring board would be indicated. 
IV.  REFERENCES 
Kessler, R. C., et al. (2005). "Lifetime prevalence and age-of-onset distributions of DSM-IV 
disorders in the National Comorbidity Survey Replication." Arch Gen Psychiatry 62(6): 
593-602. 
Hoge, C. W., et al. (2004). "Combat duty in Iraq and Afghanistan, mental health problems, and 
barriers to care." N Engl J Med 351(1): 13-22. 
Thomas, J. L., et al. (2010). "Prevalence of mental health problems and functional impairment 
among active component and National Guard soldiers 3 and 12 months following combat 
in Iraq." Arch Gen Psychiatry 67(6): 614-623.
Karsen, E. F., et al. (2014). "Review of the Effectiveness of Transcranial Magnetic Stimulation 
for Post-traumatic Stress Disorder." Brain Stimul 7(2): 151-157.
McCann, U. D., et al. (1998). "Repetitive transcranial magnetic stimulation for posttraumatic 
stress disorder." Arch Gen Psychiatry 55(3): 276-279.
Rosenberg, P. B., et al. (2002). "Repetitive transcranial magnetic stimulation treatment of 
comorbid posttraumatic stress disorder and major depression." J Neuropsychiatry Clin 
Neurosci 14(3): 270-276.

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Boggio, P. S., et al. (2010). "Noninvasive brain stimulation with high-frequency and low-
intensity repetitive transcranial magnetic stimulation treatment for posttraumatic stress 
disorder." J Clin Psychiatry 71(8): 992-999.
Grisaru, N., et al. (1998). "Effect of transcranial magnetic stimulation in posttraumatic stress 
disorder: a preliminary study." Biol Psychiatry 44(1): 52-55.
Cohen, H., et al. (2004). "Repetitive transcranial magnetic stimulation of the right dorsolateral 
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