Long Term Efficacy of rTMS in Managing MTBI-related Headache
Phase: NA
Conditions: Traumatic Brain Injury (TBI)
Sponsor: VA Office of Research and Development

Long Term efficacy of rTMS in Managing 
MTBI-related Headache
NCT03314584
December 6, 2023

Human Protocol (Version 1.32)
General Information
*Please enter the full title of your study::
Long Term Efficacy of rTMS in Managing MTBI-Related Headache
 
 
*Please enter the Study Number you would like to use to reference the study:
Long Term Efficacy TBI
* This field allows you to enter an abbreviated version of the Study Title to quickly identify this 
study.
 
 
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Primary? Department Name
VASDHS - VASDHS
 
Assign key study personnel(KSP) access to the study
*Please add a Principal Investigator for the study:
 
Leung, Albert Y., MD
 
3.1 If applicable, please select the Research Staff personnel
 
A) Additional Investigators
Krug, Paul B., DNP, RN 
 Co-Investigator
Le, Lu D., DO 
 Co-Investigator
Lee, Roland R., MD 
 Co-Investigator
Lin, Lisa L., MD 
 Co-Investigator
Polston, Gregory R., MD 
 Co-Investigator
Pyo, Jay, D.O. 
 Co-Investigator
Rimmele, Carl T., PhD 
 Co-Investigator
Rutledge, Thomas R., PhD 
 Co-Investigator
G

Vaninetti, Michael A., MD 
 Co-Investigator
B) Research Support Staff
Golshan, Shahrokh, PhD 
 Biostatistician
Ho, Michael Paul, BS 
 Study Coordinator
Hughes, Talyn, BS 
 Study Coordinator
Kennedy, Michelle, BA 
 Lab Manager
Le, Valerie G. 
 Research Associate
Le, Valerie G. 
 Study Coordinator
Lopez, Caleb, BS 
 Clinical Research Associate
Lopez, Caleb, BS 
 Study Coordinator
Mallina, Seshagiri 
 Research Associate
*Please add a Study Contact
 
Kennedy, Michelle, BA 
Leung, Albert Y., MD 
Lopez, Caleb, BS 
The Study Contact(s) will receive all important system notifications along with the Principal 
Investigator. (e.g. The project contact(s) are typically either the Study Coordinator or the Principal 
Investigator themselves).
 
VASDHS IRB
Human Subjects Protocol
v20190121
Section 1 - Preliminaries
Principal Investigator:
Albert Y. Leung, MD
Protocol Title:
Long Term Efficacy of rTMS in Managing MTBI-Related Headache
IRB Protocol Number:
H170053
Protocol Nickname:
Long Term Efficacy TBI
Form Template Version:
v20150115
Date Prepared:

12/06/2023
Please be advised that this protocol application form has changed as a result of the 2018 Common 
Rule.  There are new questions and sections, and you may be required to provide additional information to 
previous sections.
1a) Is this study considered human research?
Yes 
No 
I don't know 
1b) Please select:
This is an application for a NEW human subject research protocol 
This is a revision of an existing protocol 
Was this study initially approved prior to January 21, 2019?
 Yes  
 No
Were you instructed to convert to the 2018 Common Rule Requirements?
 Yes  
 No
 Section 2 - Research Subjects
 
2a) What is the total planned number of VA-consented subjects?
Include the total number of subjects who will prospectively agree to participate in the study (e.g., documented 
consent, oral consent, or other).
200
 
2b) What is the total number of VA subjects who WILL NOT be consented?
Include the total number of subjects that will be included without consent (e.g., chart review).  Note: Data about 
people are still considered “human subjects” by the IRB, so even if you do not intend to contact the patients 
whose charts you will review, you still should enter the number of charts as your “planned subjects."
0
 Section 2.1 Consented Subject Groups
2.1) For each of the subject categories listed below, indicate whether or not these subject groups will 
participate in the study: 
2.1a) Children under the age of 18
Note:   If neonates or children will be involved in this study, certification by the Medical Center Director will be 
required. Only minimal risk research may be performed with children.  Only non-invasive monitoring and/or 
prospective observational and retrospective record review studies that are minimal risk can be conducted in VA 
involving neonates.
  Yes  
  No
2.1b) Pregnant women
  Yes  
  No
2.1c) Individuals with cognitive/decisional impairment

  Yes  
  No
2.1d) Non-English-speaking individuals
  Yes  
  No
2.1e) Prisoners of War (explicitly targeting this group)
  Yes  
  No
2.1f) Non-Veterans (Note: Justification for inclusion of non-Veterans will be required)
 Yes  
 No
2.1g) Incarcerated individuals (Note: VA CRADO approval will be required)
  Yes  
  No
2.1h) VA employees - including VA paid, IPA, or WOC (Note: Union review and authorization may be 
required)
  Yes  
  No
2.1i) Students of the institution (e.g., resident trainees) or of the investigator
  Yes  
  No
2.1j) Patients with cancer (or high cancer risk) [explicitly targeting this group]
  Yes  
  No
 Section 3 - Study Features   (these items default to "No" for convenience)
  
3) This section consists of several Yes/No questions addressing protocol characteristics.     Click on Save and 
.
Continue
 Section 3.1 Protocol Basics
Select all that apply
3.1a) The research 
 the participant.
intends to change
 Yes  
 No
3.1b) 
 with living participants to collect data or specimens with no intent to change them.
Interactions
  Yes  
  No
3.1c) This is a study that 
 has any 
 
never
subject contact and does not collect subject identifiers
  Yes  
  No
3.1d) This is a 
study involving retrospective or prospective medical records.
chart review 
  Yes  
  No
3.1e) This is a 
study occurring in-part or in-full at other locations.
multi-site 
  Yes  
  No
3.1f) There is an 
 component to this research. 
international
International research includes sending or receiving 
human derived data or specimens (identifiable, limited data set, coded, or deidentified) to or from an 
international source.  International research does not include studies in which VA is only one of multiple 
participating sites where the overall study-wide PI is not a VA investigator.
  Yes  
  No

3.1g) This study includes 
 (not including VA-leased space or CBOC clinics) conducted 
off-station activity
under VASDHS IRB approval.  Note: this does not include research conducted by a collaborator at their home 
institution under their institutional approval.
 Yes  
 No
3.1h) VA subjects will 
 in part or in full 
 (not including VA-leased space or 
participate
at other locations
clinics) under VASDHS IRB approval. Note: if this study involves remote participation of subjects, please 
indicate "no" and describe their remote participation in section 9 of the application.  This question is intended 
to understand whether participants must physically go to a non-VA location to participate in this VA research 
study. 
 Yes  
 No
 Section 3.2 Specimen Use and Data Repository
Indicate whether or not each of the following applies to this protocol
3.2a) Involves specimens that are left over from pathological or diagnostic testing (
)
non-research specimens
  Yes  
  No
3.2b) Involves 
 purposes 
specimens collected for research
only
  Yes  
  No
3.2c) This study includes 
 (specimens are retained for use outside of the purposes of this 
specimen banking
protocol)
  Yes  
  No
3.2d) The study involves 
genotyping or other 
DNA 
genetic analysis
  Yes  
  No
3.2e) Biological
will be sent outside of the VA.
 specimens/material 
  Yes  
  No
3.2f) A 
 is maintained (data are retained after completion of the protocol for other uses, 
data repository
 see  before checking "yes")
IMPORTANT:
?
  Yes  
  No
3.2g)  
of the VA (identifiable, coded, limited data set, or deidentified)
Data will be shared outside 
  Yes  
  No
 Section 3.3 Treatment and Clinical Trials
Indicate whether or not each of the following applies to this protocol
3.3a) Includes a 
 component (a research treatment)
treatment
 Yes  
 No
3.3b) Study is a 
  
clinical trial. Note:  A clinical trial is a research study in which one or more human subjects 
are 
 (which may include placebo or other control) to 
prospectively assigned to one or more interventions
evaluate the effects of the interventions on biomedical or behavioral health-related outcomes.
 Yes  
 No
3.3c) Has a data safety monitoring board (
or data safety monitoring committee.
DSMB) 
 Yes  
 No

3.3d) Has a 
 (but not a DSMB) (this is not the data security plan, it is a safety plan).
data safety monitoring plan
  Yes  
  No
 Section 3.4 Drugs and Devices
Indicate whether or not each of the following applies to this protocol
3.4a) 
 that require 
 action such as an Investigational New Drug (IND) approval or exemption or 510
Drugs
FDA
(k) approval.
  Yes  
  No
3.4b) Other drugs, supplement, etc. that
action for inclusion in the study.
 do not require FDA 
  Yes  
  No
3.4c) Medical 
 IDE approval or waiver
devices requiring FDA
 Yes  
 No
3.4d)
 medical 
 Other
devices
  Yes  
  No
 Section 3.5 Risk and Hazards
Indicate whether or not each of the following applies to this protocol
3.5a) Study places subjects at 
(do not include risks that are due to standard care)
greater than minimal risk 
 Yes  
 No
3.5b) Human subjects are exposed to 
 (do not include standard care).
radioisotopes
  Yes  
  No
3.5c) Subjects have other 
 (e.g., x-rays) (do not include standard clinical use).
radiation exposure
  Yes  
  No
3.5d) Target population has psychiatric diagnosis, behavioral complaint, or chronic pain.
  Yes  
  No
 Section 3.6 Clinical Facilities and Standard Care
Indicate whether or not each of the following applies to this protocol
3.6a) Study 
 (e.g., adds required tests run in the VA lab for study purposes; research 
uses VA clinical services
procedures concurrent with clinical care)
  Yes  
  No
3.6b) Includes procedures or drugs that will be considered part of standard care.
  Yes  
  No
3.6c) Involves 
purposes.
lab tests done for research 
  Yes  
  No

 Section 3.7 Subject Expenses and Compensation
Indicate whether or not each of the following applies to this protocol
3.7a) There may be expense or added 
or the subject's insurance.
costs to the subject 
  Yes  
  No
3.7b) This is a 
 and subjects may be billed for study drugs or procedures.
qualifying cancer treatment trial
  Yes  
  No
3.7c) This is a cancer treatment trial but 
 for study drugs or procedures.
subjects will not be billed
  Yes  
  No
3.7d) Subjects will be
(either in cash or other means such as a gift certificate).
 compensated 
 Yes  
 No
 Section 3.8 Subject Activities
Indicate whether or not each of the following applies to this protocol
3.8a) Involves 
 completed by subjects
surveys or questionnaires
 Yes  
 No
3.8b) Includes the use of 
 such as flyers, advertisements, or letters
recruitment materials
 Yes  
 No
3.8c) Involves facial 
 or audio or video 
of 
photographs
recordings 
patients
  Yes  
  No
 Section 3.9 Sponsors and Collaboration
Indicate whether or not each of the following applies to this protocol
3.9a) This research is a funded research project (commercial (industry) sponsor, NIH, VA, other).
 Yes  
 No
3.9b) Other 
is provided (e.g., drugs or supplies).
commercial (industry) non-financial support 
  Yes  
  No
3.9d) The protocol has 
 involvement (e.g., subjects or funding).
Department of Defense
  Yes  
  No
3.9c) The PI or other study staff member has a financial interest or other
related to 
 real or potential conflict 
this study.
  Yes  
  No
3.9e) This study involves 
research activities (research conducted at other institutions under the 
c llaborative 
o
authorities or approvals of the other institution/s). Note: this may include other VA and/or non-VA institutions, 
but does not include off-site VA research.
 Yes  
 No

 Section 4 - Estimated Duration
4) What is the estimated duration of the entire study?  (From IRB approval to IRB closure)
6 years
 Section 5 - Lay Language Summary
5) Provide a summary or synopsis of the proposed study using non-technical language (not more than 1 
paragraph)
Persistent headache is one of the most common debilitating symptoms in military personnel 
suffering from mild traumatic brain injury (MTBI). This study aims to assess the long-term effect 
of repetitive transcranial magnetic stimulation (rTMS) in managing MTBI related headaches for 
up to 2-3 months by comparing the treatment effect of active-rTMS to sham-rTMS.
 Section 6 - Specific Aims
6) Provide a statement of specific aims and 
 that serve as the basis for this protocol.  Emphasize 
hypotheses
those aspects that justify the use of human subjects.
1) Compare the long term treatment effect of active rTMS (Group A) to sham LMC rTMS (Group 
B) in reducing the intensity, frequency and duration of MTBI-HA and the overall analgesic usage; 
Hypothesis #1: Active rTMS at LMC provides significantly more reduction in headache intensity, 
duration and frequency of exacerbation than sham rTMS; 
2) Compare the long term treatment effects of Group A to Groups B in improving quality of life, 
mood and functions in patients with MTBI-HA;
Hypothesis #2: Active rTMS at LMC provides significantly more improvement in quality of life, 
mood and functions than sham LMC stimulations;
Coinciding with the specific aims, the proposal also consists of the following exploratory aims: 
1) Explore the treatment effect on resting state supraspinal functional connectivity in the pain 
related network; 
2) Explore moderators’ effect of injury mechanisms (blast and non-blast) and the headache 
severity on the treatment .
 Section 7 - Background and Significance
7) Provide a succinct discussion of relevant background information to justify performing the proposed study.
Background
            Headache is one of the most common debilitating chronic pain conditions in 
either active or retired military personnel with MTBI. This high prevalence of 
persistent chronic headache is often associated with neuropsychological 
dysfunction in mood, attention, and memory, which casts a profound negative 
impact on patients' quality of life and increases stress in their caregivers. 
Unfortunately, as witnessed by the investigators in their clinical practices, 
conventional pharmacological treatments for MTB related headache (MTBI-HA) has 
not been shown to be effective and drugs such as narcotics contain many long-term 
untoward psychosomatic and abusive side effects [13; 50; 60].  This calls for an 
urgent need in developing alternate and innovative long-term headache 
management strategies for this rapidly increasing patient population. 

Our group was the first in the VA system to adopt brain magnetic 
resonance imaging (MRI) neuronavigation guided repetitive transcranial 
magnetic stimulation (rTMS) as a non-invasive treatment option for chronic 
pain including MTBI-HA in 2010. Our prospective follow-up survey indicated 
over 150 patients with MTBI-HA treated with rTMS demonstrated over 50% 
reduction in headache intensity with correlated reduction (>50%) in the 
frequency and duration of debilitating headache exacerbation. Close to 90% 
of these initial treatment responsive patients are currently on a maintenance 
treatment protocol, which continues to demonstrate sustainable headache 
prevention and relief benefit. This ongoing clinical observation supports the 
feasibility of using rTMS for long-term headache management in patients 
with MTBI-HA. Further support for adopting this innovative therapy for 
MTBI-HA comes from our recently completed randomized sham 
controlled study indicating an initial week long course (3 sessions) of 
rTMS at the left motor cortex (LMC) can alleviate MTB related headache 
symptoms and reduce the exacerbation pattern for up to one month 
without significant side effects. 80% of the patients received the real 
treatment demonstrated at least 50% headache reduction in 
comparison to only 20% of the patients in the sham group [43]. For long-
term management, published case series show subsequent maintenance treatment sessions can be 
feasibly applied at a much lesser frequency than the initial sessions of rTMS with sustainable headache 
relief benefit [41; 81]. Coinciding with other published treatment protocols related to traumatic brain 
injury and pain [32; 55], this initial clinical evidence provides compelling support for the current 
proposal aiming to assess the effect of a longer duration of rTMS protocol in managing MTBI-HA for up 
to 10 weeks after the initiation of the treatment. Given existing treatment options for MTBI-HA are limited, 
validating such a non-pharmacological and non-invasive treatment option will significantly enhance the capability 
of the VA healthcare system in caring for this rapidly increasing patient population.
 
Pathophysiology of MTBI
In assessing the underlying pathophysiology of MTBI related 
morbidities, although gross structural lesions are usually not detected by 
conventional anatomical brain neuroimaging techniques such as MRI or 
computer tomography, studies with diffusion tensor imaging (DTI) suggest 
that MTBI patients suffer from diffuse axonal injury in the major cortical white 
matter tracts including corpus callosum, anterior corona radiata, corticospinal 
tract, and internal capsules, which are crucial for intracortical connectivity.  Th
ese abnormal findings as reflected by the diminished fractional anisotropy 
index found in the frontal cortices and often directly correlated with deficit in 
fine motor skill, attention, mood and memory identified with 
neuropsychological and motor functional assessments [5; 59].  In the area of 
neurophysiological assessments, MTBI patients appear to suffer from long 
lasting elevation of resting motor threshold, suggesting a deficiency in 
cortical excitability and conductivity in brain areas associated with pain 
modulation/adaptation in this patient population [71].  In addition, these 
structural and electrophysiological abnormalities found in MTBI population 
also correlated with findings in a blood perfusion study, which demonstrated 
MTBI patients presented with hypoperfusion in the basal ganglion, a key 
relay center between the cortical areas (particularly the prefrontal cortical 
area and parietal cortices) and the limbic system, suggesting a dissociative 
state between the affective (hyperactive) and modulatory (hypoactive) 
aspects of suprapsinal activities [46]. Our studies with functional magnetic resonance 
imaging (fMRI) further confirmed a diminished state of supraspinal prefrontal cortical modulatory 

functional connectivity to other pain related supraspinal regions in patients with persistent MTBI-HA in 
comparison to age and gender matched healthy controls in both resting and evoked pain states [44]. 
Therefore rectifying this dissociative state and enhancing supraspinal modulatory functional 
connectivity by means of non-invasive brain stimulation can be the key for addressing MTBI related 
symptoms.
Central Pain Processing and Modulation
            Based on previous studies, the supraspinal pain processing network is 
known to involve thalamus (TH) and pons, which relate sensory afferent 
signs to other supraspinal regions including: 1) sensory discriminatory 
regions such as the primary and secondary somatosensory cortices (SSC1 
and SSC2), and the inferior parietal lobe (IPL); 2) affective regions such as 
the anterior cingulate cortex (ACC) and the insula (IN); and 3) modulatory 
regions involving various regions of the prefrontal cortices (PFCs) [54]. 
Decreases of medial prefrontal cortical activities and other motor cortical functions are known to be associated 
with central hyperalgesia [68]. As pain perception and relief relies heavily on the balance between the affective 
and modulatory/adaptive functions of the pain network, a disruption in the intra-dynamic of the network such as 
diminished modulatory/adaptive function can often lead to the development of central pain states with 
associated neurological symptoms (chronic headache), and neuropsychological dysfunction (attention deficit 
and depression) [8; 72]. Consequentially, one of the feasible ways to correct the imbalance is to actively 
stimulate the modulatory supraspinal regions that are known to exhibit endogenous analgesic and mood 
enhancing benefits. 
 
Transcranial Magnetic Stimulation (TMS) for Pain and Behavioral 
Functions
Recognizing these structural, electrophysiological and neuropsychological abnormalities 
associated with MTBI provides an opportunity to formulate potential treatment strategies for this 
patient population. TMS  non-invasively stimulates the brain by utilizing 
electromagnetic principles to produce small focal electrical currents in the 
 
cortex [74; 75]. The device usually consists of an insulated electric coil, which 
with the passing of electrical current generates a dynamic magnetic field 
through the scalp and skull, and into the first few millimeters of the cortex 
without attenuation. A figure-of-eight coil is commonly used because it gives 
a precise localization.  Depolarization of corticospinal tracts with TMS occurs 
at about the junction of the grey and white matter [14]. Studies in animal demonstrate 
that TMS can alter neural plasticity by affecting the amount of beta-adrenergic receptor in rat cortex consistent 
with the response to all clinically effective antidepressants and electroconvulsive shock [3; 18].  Other 
studies concur that TMS has the ability to influence neuron-transmitters, 
receptors and associated second messengers systems, which are important 
in pain regulation [29; 33]. TMS also has the ability to increase gene activity in neural and supportive 
elements which are important for nerve repair/regeneration in neurofunctional degenerative conditions such as 
MTBI [21]. 
            While both dorsolateral prefrontal cortex (DLPFC) and motor cortex 
(MC) high frequency (> 1Hz) rTMS can result in an analgesic benefit, their 
  
relative mechanisms appear to be different. With stimulations at the motor 
cortex, a strong focal activation was observed in thalamus, insula, cingulate-
orbitofrontal junction and periaqueduct grey (PAG) area in the brainstem, 
suggesting that a direct top-down activation of descending pain control 
system mediating via a motor-thalamus and/or motor-brainstem functional 
linkage [22; 63].  On the other hand, rTMS at the DLPFC exerts a “top-down” 
inhibitory effect along the descending midbrain-thalamic-cingulate pathway 
through the descending fibers from the prefrontal cortex [48; 49].  In addition, 
while administering naloxone will block the analgesic effect of high frequency 
(10hz) motor cortex rTMS, it has no effect on the analgesic effect of left 
DLPFC stimulation suggesting that the analgesic effect mediated via the 
DLPFC stimulation may not be directly related to endogenous opioid release [
9].  However, these two regions appear to be highly interactive with the left 

DLPFC stimulation found to potentiate the excitability of the MC [61]. Given 
that tonic pain reduces motor intracortical excitability, stimulating the motor 
cortex provides the most direct means in restoring motor cortical excitability 
and its pain modulatory functions. (See figure below: different arrow colors 
represent different interconnected pathways) [7]. In the area of clinical evidence, although 
evidence supporting rTMS at the DLPFC for mood enhancement in depression is strong (level A 
evidence), its support for treating central neuropathic pain states or headache is not as robust as rTMS 
at the MC as one recent study has found DLPFC stimulation ineffective for poststroke central pain [10]. 
On the other hand, a consortium of European experts has found level A evidence of “definite efficacy” 
of high frequency (> 1Hz) rTMS of the primary MC for neuropathic pain states [37].
                                 
Aside from enhancing inter-cortical connectivity, rTMS can also 
correct brain pre-existing structural abnormalities and improve functional 
deficit.  rTMS is also known to increase white matter FA in cortical and 
subcortical regions in patients suffering from stroke and depression 
respectively with correlated functional and behavioral improvement [56; 62].  A
previous meta-analysis study conducted by the investigators demonstrated the analgesic benefit of 
rTMS at the MC appeared to have a neuroanatomical hierarchy suggesting pain originating from the 
more centrally located neuroanatomical structure responds more favorably than peripherally originated 
neuropathic pain states [42]. Increasing evidence suggests that MTBI result in central neurological 
injury as in post-stroke central pain, and thus supporting the notion that persistent MTBI-HA represents 
a central neuropathic pain state [19; 39; 44]. Thus, the use of rTMS at the MC as a 
useful and safe way of neuromodulation in managing the associated 
headache (neuropathic pain) and neuropsychological deficits.  In 
regards to treatment protocols, although various treatment protocols 
have been reported for pain and headaches, a recently published 
guideline for neuropathic pain and other published studies related to 
traumatic brain injury suggests a 10 consecutive weekday treatment 
regimen at 10/20 Hz as the initial treatment protocol. In addition, 
outcomes of the intervention should be observed several weeks after 
the treatments [32]. With the MTBI-HA relief benefit observed one month after a short course (3 
sessions) of rTMS at the left MC [43], the proposed study adopting this longer duration of treatment 
sessions will likely result in more robust long term benefits in headache management. 
Safety of rTMS 
            rTMS is currently FDA approved for treating major depression and 
  
single pulse TMS is approved for treating migraine headaches.
This 
treatment technology has an excellent safety track record when used under 
the safety guideline established in 1998 [74].  A recent study demonstrated that 
unilateral rTMS as well as bilateral combined rTMS revealed no detrimental effects on cognition in 
comparison to the sham group 3 months after the treatment [2].  On the other hand, rTMS is 
found to have mild beneficial cognitive effects [24]. In lack of any major breakthrough in 
establishing other effective long-term treatment regimen for MTBI-HA and co-morbidities, this safety track record 
and potential benefits associated with rTMS supports the feasibility of the proposed study in a rapidly growing 
patient population with debilitating symptoms. 

PTSD and MTBI
            Headache, MTBI and Post-traumatic Stress Disorder (PTSD) can 
be co-morbid conditions [51; 78]. Therefore, the potential benefits of 
rTMS in relieving PTSD related symptoms have been assessed in the 
investigators’ previous studies related to rTMS and MTBI-HA.  While in 
both studies (one published, one in preparation)[43], the investigators found 
patients with MTBI-HA on average consists of a slightly elevated score in the Clinician Administered 
PTSD Scale (CAPS), the majority of the individual scores and their overall average score did not meet 
the clinical diagnostic criteria of PTSD. In addition rTMS did not appear to have a significant impact in 
either improving or worsening their overall CAPS scores. Therefore, while patients will be screened for 
PTSD, the current proposed study will primarily focus on the stated specific aims. However, screening 
the study cohort’s baseline (pre-treatment) PTSD severity will allow the investigators to conduct 
analyses if necessary with built-in covariates should the baseline CAPS scores are significantly 
different (although not expected) between the two proposed study groups.
Preliminary Data
Our group has conducted several prior studies to support the 
feasibility of the current proposal. The results of these studies are discussed 
as follows:
1) rTMS for neuropathic pain and MTBI-HA
            In a collaborative meta-analysis study [39] from six major 
multinational TMS research centers with pooled individual data (n=149) from 
5 published clinical trials, we were able to reveal the overall treatment effect 
of rTMS in neuropathic pain states.  The result of the analysis strongly 
suggests that the analgesic efficacy of multiple sessions of rTMS is more 
superior to a single session of rTMS as the overall treatment effect for the 
multiple session study is 20.4 % significantly (P=0.003) better than the 
  
overall effect of the single treatment session studies. The analysis also 
demonstrates the effect of rTMS on neuropathic pain consists of a differential 
“top-down” pattern based on the neuroanatomical origins of the neuropathic 
pain pathophysiology with centrally originated pain states such as post-
stroke central pain syndrome as the top responders (see below for 
  
excerpted study result figures) to motor cortex rTMS.
Like the post-
stroke central pain patients, MTBI patients are known to demonstrate central 
diffuse neuronal injury, which makes them the ideal candidates for the 
treatment. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
2) rTMS at the LMC in reducing MTBI-HA
            In our recently published study, MTBI-HA subjects were randomized to 
receive three sessions of either real (N=12) or sham (N=12) rTMS at the left 
motor cortex with brain MRI neuronavigation guidance. Subjects received the 
real rTMS demonstrated a significantly higher degree of headache relief up 
to one month in the comparison to the sham group (see below for excerpted 
figures 3a and 3b from Appendix #6a) [44]. This observed headache relief efficacy with a 
relatively short duration of treatment sessions warrants further studies assessing the long–term benefit of rTMS 
in MTBI-HA management with a more robust and longer duration of treatment sessions.
 
3) Prospective Case Series demonstrating the feasibility of rTMS in 
long-term management of MTBI-HA
            Our internal prospective follow-up survey in over 150 patients and 
recently published case series supports the feasibility of using rTMS as a 
long-term therapeutic tool for MTBI-HA and migraine headache  management
 [41; 81]. A well powered sample size and controlled study with a longer duration of treatment is warranted.
4) Supraspinal Functional deficit in patients with MTI-HA
            Our published studies with functional magnetic resonance imaging 
(fMRI) suggest that patients with persistent MTBI-HA have significant 

compromised medial prefrontal modulatory response to heat pain stimuli and 
their resting state medial prefrontal cortical connectivities to other pain 
related regions are diminished in comparison to age and gender matched 
healthy controls (See excerpted study figures 3&4 from appendix #6b) [44
]. Although a previous study suggested blast-related traumatic brain injury (TBI) appeared to have a unique 
effect on brain function associated with cognitive inhibitory tasks that could be distinguished from TBI resulting 
from non-blast (blunt or motor vehicle injury) related TBI [17], our preliminary assessment with experimental 
heat pain stimulation found no significant difference in supraspinal modulatory response to experiment heat pain 
between blast (n=7) and non-blast Veterans (N=7) (Leung et al., unpublished data). When turning our attention 
to assess the headache severity related supraspinal pain modulatory functions, we found Veterans with Mild (£I 
4 on a 0-10 NRS, numerical pain rating scale) intensity of headache appeared to have higher level of left medial 
prefrontal cortical function in comparison to their counterparts with Moderate-to-Severe (≥5 on 0-10 NRS) head
ache intensity in their response to heat pain stimulation under functional magnetic resonance imaging (fMRI). 
Therefore further mechanistic exploration is required to understand the potential impact of injury mechanisms 
and headache severities on the treatment outcome.
 

 
 Section 9 - Design and Methods
9) Describe the research design and the procedures to be used to accomplish the specific aims of the 
project.  Provide a precise description of the planned data collection (include what systems or databases will 
be used/accessed to gather data), analysis and interpretation.  For chart review studies, include the timeframe 
of collection.  Address sample size, inclusion of women and minorities.  Define in clear terms exactly what will 
 
be done to the human subjects.
Research Design:
 
A total of 200 will  be consented and 128 (64 per group, accounted for 36% 
dropout rate) patients will be randomized to be stratified based on their injury 
mechanisms (blast, non-blast) and headache severities (mild, moderate, 
severe) and enrolled over 6 years from VASDHS, and Naval Medical Center 
San Diego (MNCSD).  Patients meeting study enrollment criteria will be 
randomized into one of the two study groups (A&B) based on their 
mechanisms of injury, gender, severity of headache, and past failed 
therapies for their headache. The overall study duration for each subject is 
about 14 weeks developed into three phases according to the following 
schedule:
1) PRE-TREATMENT PHASE (weeks 1-2) consists of Visit 1 (Screening 
Visit) and Visit 2 (Pre-treatment Assessments); 
2) TREAMENT PHASE (week 3-4) consists of Visits 3-12 (Neuronagvigation 
guided rTMS consisting of 10 weekday treatments at >24 and < 72 hours 
apart, weekends excluded, maximum 5 weeks for treatment completion) 
rTMS will take place in Building 23 Room 105 at the VASDHS; and 

3) POST-TREATMENT PHASE (week 5-14) consists of two initial weekly 
visits (Visits 13&14) and two additional biweekly visits (Visits 15&16) and one 
monthly visit (Visit 17). 
 
Brain anatomical and functional MRI will be performed within 72 hours after 
Visits 2 and 13. Subjects will be required to fill out headache diary between 
assessment visits.  Headache assessments along with quality of life, mood 
and functions assessments will be carried out at Visits 1,2, and 13--17.  This 
frequency of treatment and duration of follow-up is in line with recently 
published rTMS articles related to TBI, headache and pain, and also in 
accordance with the 3-month post treatment initiation follow-up guideline
/recommendation [32; 55; 80]. 
 
A) Headache assessment (specific aim #1, see Appendix 6b for 
assessment samples)
            Due to the persistent and debilitating nature of MTBI-HA, two areas 
of headache characteristics: 
; and 2) 
1) Persistent Daily Headache
Debilitati
 will be especially assessed during the study in 
ng Headache Exacerbation
addition to more conventional headache assessments. Patients will be 
provided with a daily headache diary, which they will fill out every evening 
during the study between-visit periods (B1-B6). In the diary, they will report if 
they have a persistent (non-stop, 24/7) headache over the last 24 hours and 
rate the average intensity of the headache on a 0-10 Numerical Rating Scale 
(NRS). In addition, they will be asked to report the duration and intensity of 
any debilitating headache exacerbations, which 
 incapacitate their 
completely
daily functions. 
            For persistent headache, the intensity of the headache from the diary 
will be averaged (sum of headache NRS scores/number of days) as between-
visit persistent headache severity assessment.  Should the headache 
becomes sporadic after the study rTMS interventions, the subjects will then 
record the total number hours of headaches over the previous 24 hours and 
the average intensity of the headache, they will still record the duration and 
intensity of any debilitating headaches. The occurrence of lingering 
persistent daily headaches and average intensity of daily headaches will be 
recorded [38; 43].  
            For debilitating headache exacerbation, a composite score will be 
generated by multiplying the average duration (hours/episode) of the 
headache exacerbation by the average frequency (episodes per day) and 
the average intensity (NRS) of the headache exacerbation [38; 45] . 
            Aside from assessing the daily intensity and exacerbation pattern of 
MTBI-HA, additional assessments for the impact of headaches on the 
patients’ quality of life will include: 
1) the 
which will assess the impact of 
Headache Impact Test (HIT-6) 
headaches on the subjects' ability to function on the job, at school, at home 
and in social situations [66; 79]; 

2) 
 will 
Neurobehavioral Symptom Inventory (NSI) assessment which
assess the pattern of headaches and other co-morbid neurological 
symptoms in Visits 2, 13, 14, 15, 16 & 17 [31; 60]. As a fail-safe assessment 
for any missing data, subjects will also be asked to rate the average intensity 
of headache in Visits 2, 13, 14, 15, 16 and 17 for the prior between-visit 
durations on a 0-100 Mechanical Visual Analogue Scale (M-VAS) [64].
B) Neuropsychological Assessments (Specific Aim #2, see Appendix 6c 
for assessment samples)
Attention, memory, executive functioning and depression are 
commonly disrupted following TBI and for some, these impairments persist 
as part of a post concussive syndrome [52].  There is evidence to suggest 
that rTMS has resulted in benefits in these same cognitive domains 
[11].  The tests in the assessment battery were selected with several factors 
in mind: (a) validity and reliability; (b) relevance to the literature and prior 
experience with these tests in previous studies of rTMS; (c) limiting the 
length of the battery to reduce fatigue and facilitate compliance; (d) targeting 
measurement of neurocognitive functions commonly found to be impaired in 
patients with TBI.  Details regarding the following measures are provided in 
Appendix 6c.  
I). Cognition: (a) Attention: Conner’s Continuous Performance Test (CPT II) 
[4; 58] and added Eye-Tracker assessment. (b) Memory: Hopkins Verbal 
Learning Test[16; 36; 73]; (c) Executive Functioning: Trail Making Test A and 
B; Stroop Test  ; 
II). Mood: Hamilton Rating Scale for Depression (HRSD) [1; 6; 65]; 
III). Quality of Life: SF-36;
IV). PTSD (only at Visit 2): Clinician-Administered PTSD Scale (CAPS); and
 
Brief Pain Inventory (BPI)
IV). Global Pain: 
The duration of all neuropsychological/behavioral tests is estimated to 
be less than 2 hours 45 minutes. The duration of the assessment appears to 
be reasonable and non-excessive for the patients based on the investigators' 
previous experience. However, if the subjects are unable to complete all the 
assessments in one setting, they will be asked to return in the following day 
to complete the assessment.
C) Other study associated assessments consist of: 
1) Weekly Phone Assessment: After the post-treatment one-week 
assessment, the study coordinator will conduct weekly phone contacts with 
the subjects for pain and side effect assessments until the completion of the 
study. The study coordinator will also trouble shoot any potential issues that 
may lead to unnecessary subject dropout with the assistance of the PI; 
2) 
During each study related visit (after Visit 2) 
Side Effect Assessment: 
and weekly phone assessment, side effect assessment will be conducted to 
monitor any study related complication. Patient will be asked to report any 

potential neurological side effect such as soreness at the side of the 
treatment, dizziness, or increase of pain related to the treatment. 
Investigators will determine whether these side effects are study or non-
study related and report to the Institutional Human Subject Protection 
Committee, VA Research and Development Committee  and the study Data 
Safety Monitoring Board according to the protocol; and 
3) 
 
Concomitant Medication: Any medication that a subject uses during the 
study is considered concomitant medication. This includes prescription and 
non-prescription treatment such as contraceptives, vitamins, topical 
preparations, herbal preparations, and non-pharmacological therapies. 
Concomitant medication information (please see Human Subject for 
will be 
allowable and prohibited concomitant medications during the study) 
collected for all subjects during the screening, treatment, between visits 
(recorded in the Daily Headache Log) and subsequent post treatment visits. 
Information regarding subjects’ previous failed treatments will also be 
collected at the screening visit. Subjects will be instructed not to alter 
medication regimens during the study without consultation with the 
investigators.
D) Functional imaging
Resting state functional imaging of the brain will be obtained after (within 72 
hours) Visits 2 and 13.  To minimize medication related interference, patients 
will be asked not to take any headache related rescue medications 24 hours 
prior to the scanning. Head movement during scanning will be minimized by 
instructing the subjects to hold their head still during the scanning, applying 
padding between the subjects’ head and the head coil, and having subjects 
wear a cervical collar to minimize both lateral and axial head movements [40; 
69]. 5-minute resting fMRI data will be collected via a 1.5T GE scanner with 
T2*- weighted EPI-sequence (TE=30 ms, TR=2.0s, a=90°, TH=4mm, 32 
slices, FOV=220x220 mm , MA=64x64.
2
Evoked Heat pain state fMRI will be conducted according to a well 
established protocol[79-81] (See Appendices 3B&3C). During the scan, an 
intermittent thermal heat pain stimulation will be delivered via a thermode 
controlled by a computer at the left calf area in 15 second pulse rates for 
about 10 minutes. The equipment used is called a quantitative sensory 
threshold (QST) and has been used in several pervious studies. 
 
To be consistent with the stimulation site in the study, the location for the 
evoked heat pain measurement was marked at the medial aspect of the left 
calf between the 6  and 7  marking of an elastic band which consisted of a 
th
th
total of 13 increments, extending from the medial malleolus to the medial 
tibial plateau.  This method of peripheral sensory testing has been well 
established in literature and has been used extensively in pain-related 
studies [74-78]. The subjects are then asked to rate the intensity of HP on a 
M-VAS. 

E) Study intervention
            Prior to study intervention (within 72 hours of Visit 2), brain anatomical 
scans will be obtained with rapid gradient-echo (MP RAGE) sampling (176 
slices T1, 256x256 and 1cm slice thickness) in GE 3.0 MRI scanner. The 
images will then be processed by ANT Visor2-XT software for the 
neuronavigation guided rTMS treatments according to the following protocol:
I). Preparation:  The patients will be asked to sit in a comfortable chair and relax as 
much as possible.  Electromyography (EMG) recordings from the contralateral abductor 
digit minimi (ADM) muscle will be acquired with silver-silver chloride surface electrodes, 
using a muscle belly-tendon set-up, with a 3cm diameter ground electrode placed at the 
wrist.  Manufacturer pre-installed software will be used to collect signal with a recording 
time window of 200ms. TMS will be performed with a figure-of-eight coil connected to 
MagPro B65 (Alpine BioMed, Fountain Valley, CA). Before beginning a rTMS session, 
subjects will be asked to sit in the study intervention chair with the rTMS coil positioned 
on their head, keeping their head as still as possible for 3.5 minutes. This is to acclimate 
the patients to the study intervention set-up prior to initiating the intervention.
 
II). TMS Neuronavigation System 
All patients' brain anatomical MRI will be obtained and examed by Dr. 
Roland Lee, Chief of Neuroradiology. The acquired scans will then be 
processed by the ANT Visor 2-XT Software.  During TMS Neuronavigation, 
stereotaxic data for the localization of the TMS stimulation site are recorded 
and will allow the investigators to visualize the TMS coli and focus the 
magnetic flux onto the target region.  The three fiducial points (nasion, left 
, treatment location will be marked onto the patients' 
and right perauricular)
cortical image so that the location of each treatment and distance between 
the center for the coil and target region will remain the same for each 
treatment session.  This approach will account for the variability of location 
between subjects and treatments, which may arise without the 
neuronavigation guidance.
III). Determination of resting motor threshold
This assessment will be conducted at the first (Visit 3) and the last (Visit 12) 
treatment session.  A constant suprathreshold stimulus intensity will be 
applied via a figure-of-eight coil, which will be moved under the guidance of 
TMS Neuronavigation over the left motor cortex (Brodmann Area 4).  Once 
the optimal location is visually identified, a single pulse TMS will be delivered 
to that location starting at the suprathreshold intensity and decreasing in 
steps of 2 % of the stimulator output. The resting motor threshold (RMT) will 
be defined as the minimal intensity required to elicit motor evoked potentials 
of 50 V peak to peak amplitude in five out of 10 consecutive trials [30].  The 
location of the cortex used for the establishment of the RMT will be marked 
on the neuronavigational software and used for subsequent treatments. The 
distance between the center of the probe and  the target site will be recorded 
as well.
IV).  Active/Sham-rTMS at left MC 

Active or sham rTMS will be delivered via the MagVenture Cool-B65 Active
/Placebo coil which performs as a coil with both active (A) and placebo (P) 
functions. This is an ideal coil for double-blinded clinical studies requiring a 
very high number of stimuli. It consists of a built-in orientation software 
controlled by the randomization code , which determines which side of the 
coil should be placed towards the subject. The coil symmetrical design with 
no indication of active vs. placebo sides makes it ideal for double-blinded 
studies. This coil with the projection of live neuronavigation guidance images 
and noise generator addresses several pertinent blinding parameters related 
to rTMS clinical trials by providing: 1) the auditory click of coil discharge; 2) 
the visual stimulation including the coil location and orientation; 3) the tactile 
sensation of coil tapping or scalp muscle activation; and 4) no direct brain 
stimulation when the placebo coil is faced towards the targeted brain region. 
The treatment site for the left MC will be the same as the site where the RMT 
is determined. The stimulation target will be marked on cortical surface using 
the ANT Neuronavigation System, which is compatible with the Cool B65 A/P 
coil. The marked location will be used for all subsequent treatments. Active-
rTMS consists of 20 trains with each train containing 100 pulses delivered at 
10 Hz and 80% RMT stimulation intensity over the area as determined 
above.  A total of 2,000 pulses will be delivered at each area over 3 to 4 
minutes.  This treatment protocol is within the treatment safety guideline 
recommended by the FDA and the PI has been using this protocol for over 
six years with good clinical outcome and minimal side effects [74].
VI).  Process of randomization and treatment double blinding
The un-blinded study biostatistician, Dr. Golshan, will create a list of 
patient identification numbers with randomized treatment assignments (A = 
Active/Real, B = Sham) using the SPSS software prior to the start of the 
study subject recruitment. Blocked randomization will be used with random 
block size of 3 or 6.  Separate lists (up to 12) of replacement patient 
identification numbers will also be created so that replacement patients are 
assigned the same treatment as patients they are replacing. Patients will be 
randomized to study treatment groups in a 1:1 ratio.  Dr. Golshan will be 
contacted by the study coordinator with subjects’ unique master ID number 
(sequential number, independent from any protected health information or 
any other identification source) and their descriptive information. After a 
subject signs the study consent, the study coordinator will be provided with 
that subject’s randomization code. A minimization random assignment 
procedure will be used to match subjects on four variables: 1) mechanisms 
of injury; 2) gender; 3) severity of headache, and 4) past failed therapies for 
their headache. The minimization random assignment procedure aims to 
obtain equal numbers of subjects at the different levels of each matching 
variable. In contrast to stratified randomization, which aims for equal 
numbers of subjects in each treatment for every possible combination of the 
interested variables, the minimization method restricts its aim to equalizing 
treatment numbers at the different levels of each variable taken separately 
[20; 77]. Essential for this study, the procedure allows sequential assignment 
of subjects. This method has been shown to be superior to both simple and 

stratified randomization in producing a balance for separate prognostic 
variables, particularly when the number of strata is large in comparison with 
the number of subjects. In addition to violations of inclusion and exclusion 
criteria, reasons for randomization failure include major protocol deviation, 
lost to follow-up, voluntary withdrawal, and study termination will be 
communicated with Dr. Golshan. The randomization code will be input into 
the TMS software in guiding the orientation of the Cool B65 A/P coil for each 
subject based on a built-in gravity sensor mechanism. This method of double 
blinding with the use of Cool B65 A/P coil as recommended in a recent 
guideline for rTMS in pain/headache related studies [32] will blind both the 
subjects and the investigators to the study treatments.
 
E) Blinding Strategy and Assessment
          In addition to the double blinding A/P coil, several blinding strategies 
will be applied to minimize biases in the study: 1) All subjects are allowed to 
visualize the TMS coil over the cortical treatment sites on a projected screen 
and hear the clicking noise during either active or sham rTMS; 2) Standard 
instruction before and after each rTMS treatment will be given to each 
subject to minimize instructional related study biases; 3) The procedure for 
determining the RMT will be identical for each subject. To ensure adequate 
blinding throughout the study, all subjects will be surveyed whether they 
receive active-rTMS (Groups A) vs. sham-rTMS (Group B) at Visits 5, 8 and 
14; and 4) To minimize investigators' bias, the study coordinator responsible 
for assessment will go through extensive training by the study PI prior to 
enrollment of any subjects on both the protocol and administration of 
assessments.  The inter-rater reliability (an intra-class correlation coefficient 
of  0.90) between the study coordinator and the gold standard will be 
>
established by the PI.  This reliability will be monitored every six months by 
study statistician, Dr. Golshan.  Both the study coordinator and the 
investigators will be blinded to the treatment given to the subject. The 
randomization list will be provided by the study biostatistician. In addition, all 
data collected will be organized and sent directly to the biostatistician for 
analysis without going through the PI or any other investigators. 
F) Weekly Phone Assessment
             After the TREATMENT PHASE, the study coordinator will conduct 
weekly phone contacts with the subjects to ensure their compliance with 
filling out the headache diary and to assess any side effect until the 
completion of the study. The study coordinator will also trouble shoot any 
unnecessary subject dropout with the 
potential issues that may lead to 
assistance of the PI.
G) Side Effect Assessment
            During each study related visit and weekly phone assessments, side effect assessments 
will be conducted to monitor any study related complication. Patient will be asked to report any 
potential neurological side effect related to the study treatment. Investigators will determine 
whether these side effects are study or non-study related and report the findings to the 
Institutional Human Subject Protection Committee, VA Research and Development Committee 

and the study Data Safety Monitoring Board according to the protocol. If necessary, severe 
adverse events such as death , suicide, or other life-threatening events or issues will be reported 
immediately to the HRPP for expedited reporting.
Data Management, Analysis and Power Calculations:
            Missing data values will be minimized by intensive training of the staff 
involved in the study. Missing data will be examined to assess randomness 
and the pattern of missing data according to the procedure recommended by 
Little and Rubin [47]. The investigators will test whether the dropouts are 
random or systematic by comparing the dropouts with the study completers 
on the baseline data. An absence of significant differences would support the 
random nature of dropouts.  
Initially, descriptive statistics and exploratory graphing such as 
frequencies, means, standard deviations, box and whisker plots, stem and 
leaf diagrams, and scatter plots will be used to assess the normality of the 
data in terms of the presence of skew and/or outliers. The continuous 
outcome data will be transformed if necessary by using an appropriate 
transformation such as the log transform for skewed long tailed data. 
Similarly, potential covariates will also be summarized with descriptive 
statistics and graphs to determine the most appropriate way to treat these 
variables and to decide if a continuous, categorical, or an interval 
representation is the most appropriate approach. 
Data acquired in this project will be managed and analyzed by the 
study statistician, Dr. Golshan. Customized database system will be 
developed for this project to ensure the highest possible data reliability by 
the study biostatistician.  The system will include but is not restricted to: (i) 
patient demographic input and query; (ii) patient recruitment, scheduling and 
protocol tracking; (iii) data storage, compilation, selection, and summary 
transfer to various statistical and graphical sub-systems; (iv) administrative 
document and report management and, (v) data backup and archival 
control.  Data entry programs will include item prompts, skip patterns, range 
checks, and logical validity routines.  Standard data security protocol will be 
used for this project.  These include, but are not limited to: assigning a 
unique ID number for each subject, storing confidential information in an 
encrypted form, using VA secure server, limiting accessibility of data to 
authorized Center personnel.  An electronic archive of all data is kept offsite 
to insure against loss by fire, theft, etc. All statistical transfer routines are 
inherently secure via their operating platform and they contain no patient 
names or personal data.  
For hypotheses 1 and 2, where multiple analyses are conducted, 
correction for family-wise Type I error rates will be made using the Westfall-
Young randomization maxTprocedure, which adjusts p-values for 
significance while taking into account the correlation of the outcomes [76]. In 
this way, the study can control for an overall family-wise error rate of .05 
while achieving more power than Bonferroni adjustments. Using this method 
of power analysis, the investigators estimated a sample size of 128 (64 per 
group, accounted for a 20% dropout rate) provides the study with 85% power 

to detect a medium effect size (RMASS program provided by Hedeker) [25; 
26]. Medium effect sizes were used based on the results included in the 
above sections.  Medium effect size is defined as a between-group 
difference increasing linearly from 0 at baseline to .5 SD units at the last time 
point. The minimum power estimation is based on sample size calculation for 
10% and 20% attrition, correlations of 0.2, 0.5, and 0.8 between the repeated 
measures, and for medium and large effect sizes. Data will be analyzed 
using SPSS version 23, all analyses will be two-tailed, where applicable with 
= .05.
 
Hypothesis #1: Active rTMS at LMC provides significantly more reduction 
in headache intensity, duration and frequency of exacerbation than sham 
rTMS.
Independent Variables: Treatment Groups with two levels (Groups A & B), 
Visits up to 8 (See below).  Dependent Variables: Primary outcome: Average 
daily headache assessments (B1, B2, B3, B4, B5, B6); Secondary outcome: 
Debilitating Headache Composite Score (B1, B2, B3, B4, B5, B6); M-VAS 
Scores of headache (Visits 2, 7, 12, 13, 14, 15, 16 17); HTL-6 and NSI 
(Visits 2,13,14,15, 16, 17); headache rescue medication usage (Visits 2,13, 
14, 15,16, 17). Note, not all variables are collected at all visits.
Statistical Analysis:  
Data will be analyzed using mixed effects model [12; 27; 35].  This approach 
provides more information and therefore, more power compared to cross-
sectional analyses, which focus on the analysis of one summary index, or 
more traditional analytic approaches such as a change score, end-point or 
repeated measures analysis of variance.  In this approach, the repeated 
measures over time for each individual subject form a trajectory that can be 
described by a relatively simple model with a few parameters, such as 
intercept (baseline value) and slope (rate of change). With repeated 
measures, repeated observations within subjects are potentially correlated 
for any impact on the resulting tests of significance [34]. When this within 
subject correlation is properly incorporated, the repeated measures analysis 
takes full advantage of all information obtained from each subject, thereby 
greatly increasing the statistical power over methods that compare 
treatments cross-sectionally [23]. This approach can model for the 
differential patterns over the repeated assessments, instead of the totals at 
one point. As a result, this analytical approach increases the reliability of the 
measurement of response (since the slope combines repeated measures, 
which cancel much of the error of measurement), and will increase the 
protection against the major effects of missing data. In addition, the influence 
of missing data is reduced since it maximizes the number of subjects by 
allowing the inclusion of subjects with missing data, dropouts or those who 
are terminated early in the study without relying on data imputation 
procedures. The investigators will use pattern-mixture models to assess if 
there is any bias due to drop out or missing data. These will result in 

increased power to detect effects and precision for the estimation of the 
effect sizes without requiring increased sample size, and provide the study 
with a uniform method of data analysis for all hypotheses that include 
multiple measurements from the same subjects.  The mixed effects model 
method provides an estimate of the individual variability around the 
population trend, the variability of the individual intercepts (baseline values) 
and slopes (changes across time), and the correlation between them. A fully 
saturated treatment by time model will be utilized for inference. Co-variance 
structure will be chosen based on Akaikes Information Criterion (AIC). This 
allows for any group level effects to be incorporated into the model. 
Denominator degrees of freedom will be calculated using the Kenward-
Roger small sample correction. Analyses will be conducted within and across 
nested levels of the study design; this will involve within-subject analyses 
(comparison of occasions of measurement nested within an individual), as 
well as between-subject analyses (comparison of two groups). In addition, 
any treatment group comparison can be adjusted for subject-specific 
characteristics and adjustments for changes in these characteristics over the 
course of the study, and incorporated into the single-subject analyses. Based 
on investigators’ experience with previously completed studies, we expect a 
dropout rate of 10 to 20% throughout the study.   All analyses will be two-
tailed, where applicable, with = .05.  Correction for family-wise Type I error 
rates will be made using the Westfall-Young randomization maxTprocedure, 
which adjusts p-values for significance while taking into account the 
correlation of the outcomes [70]. In this way we can control for an overall 
family-wise error rate of .05 while achieving more power than Bonferroni 
adjustments. 
Hypothesis #2:  Active rTMS at LMC provides significantly more 
improvement in quality of life, mood and functions than sham LMC 
stimulations.
Independent Variables: Treatment Groups with two levels (Groups A & B), 
Visits with 8 levels: pre-treatment (Visit 2), treatment (Visits 7 &12), and Post-
treatment (Visits 13,14, 15, 16, 17).
Dependent Variables: Attention (CPT II), Memory (Hopkins Verbal Learning 
Test) Execute function (Trail Making Test A and B, and Stroop Test), 
Hamilton Depression Scale, SF-36 and BPI.
Statistical Analysis: Data will be analyzed similar to hypothesis 1 and we 
estimated to have a minimum power of 85% for these analyses using similar 
method described above.
Exploratory aims:
1) Explore the treatment effect on resting state supraspinal 
functional connectivity; 
2) Explore moderators’ effect of injury mechanisms (blast and non-
blast) and the headache severity on the treatment outcomes. 

Effect of treatment on the resting state supraspinal functional 
connectivity will be explored by using Self-organizing Group Level 
Independent Component Analysis (SogICA)[15; 28]. Primary focus will be 
placed on the medioprefrontal cortices (MPFCs) and the anterior cingulate 
cortex (ACC) regions, which were found to have altered functional 
connectivity in the MTBI patients in comparison to healthy controls in a 
recently published study conducted by the investigators [44]. These regions 
will serve as the primary seeded regions for subsequent pre- and post- 
treatment between-group ANCOVA resting state functional connectivity 
analyses.  Additional levels of exploratory analyses will also include baseline 
between-group assessments with and without factoring in the mechanisms of 
injury and headache severities. For exploratory aim #2, the Injury 
mechanism (blast vs. non-blast) will be explored by adding it as independent 
variables to the mixed model.  The effect of initial headache severity (Visit 2) 
will be explored by adding this baseline outcome to the mixed model as a 
fixed covariate. 
 
Children and Women
No children will be recruited for this study. VA requires a waiver for a 
research on children and currently VASDHS does not offer a pediatric 
service. Female subjects who meet the study inclusion and exclusion criteria 
will be recruited. Female Subjects at childbearing age will be required to 
have a urine pregnancy test prior to the enrollment.
 
Follow Up Appointments in response to COVID-19: 
In response to COVID-19, we are requesting that follow up visits 
be conducted via telephone, Doximity, and/or email. 
Questionnaires (Headache Impact Test, Neurobehavioral Symptom 
Inventory, Brief Pain Inventory, SF-36, and Modified Fatigue 
Impact Scale) will be emailed to subjects to view and a phone or 
Doximity call will be conducted where subjects can verbally 
respond to the questionnaires emailed and the Hamilton Rating 
Scale for Depression and Hopkins Verbal Learning Test will be 
administered. This will be applicable for subjects currently in the 
follow up phase and for use only during the COVID-19 response. 
 
Protocol Changes in Response to COVID-19
In response to the COVID-19 pandemic, we are proposing changes 
in study design with increased safety measures based on the 12-
step model listed in “Guidelines for TMS/tES Clinical Services and 
Research through the COVID-19 Pandemic” by Ehktiari et al. to 
reestablish research and open enrollment while mitigating potential 
risks associated with the virus. The changes to the protocol will 

consist of conducting baseline and follow up assessment visits over 
phone or video call. Some assessments will be removed due to the 
inability to conduct them over phone/video call. Consenting and 
screening will also be conducted over the phone/video call. In 
addition, stringent safety and sanitization measures will be 
implemented to reduce risk that include limiting staff presence, 
PPE for subjects and staff, COVID-19 screening, and increased and 
frequent sanitization of equipment.
STUDY DESIGN - COVID-19
The original study design was conducted according to the following 
schedule where all visits were conducted On-site:
Visit 1: Consent and Screening Visit;
Visit 2: Pre-treatment Assessments and MRI Scan;
Visits 3-12: Study Treatments;
Visit 13: Post-treatment 1-week assessment and MRI Scan;
Visit 14: Post-treatment 2-week assessment;
Visit 15: Post-treatment 4-week assessment;
Visit 16: Post-treatment 8-week assessment;
Visit 17: Post-treatment 12 -week assessment
To reduce physical interaction and exposure risk, a new study 
timeline will convert all visits that do not necessitate an on-site 
visit (i.e. consenting, screening, and assessments) to remote 
telehealth visit. In addition, visits 2 and 13 will be broken up to 2 
visits in which assessments will conducted remotely and the MRI 
conducted on site. These on-site visits will not be implemented 
until written approval from the ACOS/R&D that on-site visits may 
be resumed. The visits will be revised as the following with visits 
either conducted through telehealth (TH) or onsite (OS):
1: Consent/Screen - TH;
2a: Pre-treatment (TX) Assessments - TH;
2b: Pre-TX MRI - OS;
3-12: Induction Treatments - OS;
13a: Post-TX 1-week assessment - TH;
13b: Post-TX MRI - OS;
14: Post-TX 2-week assessment - TH;
15: Post-TX 4-week assessment - TH;

16: Post-TX 8-week assessment - TH;
17: Post-TX 12-week assessment - TH;
The following table summarizes the visits, location of each visit, 
timeline, and procedures to be conducted at each visit:
Visit
 
Visit Name
Location Timeline
Procedures
1
Consent
/Screen
Telehealt
h
Day 0
Consent/HIPAA 
Form
Screen for eligibility
2a
Pre-TX 
Assessments
Telehealt
h
Within 7 days 
of consent
Assessments and 
Questionnaires
2b
Pre-TX MRI
On-Site
Within 1-2 
days of V2a
Anatomical, DTI, 
Resting and HP fMRI
Physical exam for 
screening
3-12 Induction 
Treatments
On-Site
First 
treatment to 
begin 7-10 
days of V2b
TMS Treatments 
(>24 and <72 
hours apart)
13a
Post-TX 1 
Week 
Assessments
Telehealt
h
Within 6-8 
days of V11
Assessments and 
Questionnaires
13b
Post-TX MRI
On-Site
Within 6-8 
days of V11
Anatomical, DTI, 
Resting and HP fMRI
14
Post-TX 2 
Week 
Assessments
Telehealt
h
Within 28-31 
days of V11
Assessments and 
Questionnaires
15
Post-TX 4 
Week 
Assessments
Telehealt
h
Within 28-31 
days of V11
Assessments and 
Questionnaires

16
Post-TX 8 
Week 
Assessments
Telehealt
h
Within 56-62 
days of V11
Assessments and 
Questionnaires
17
Post-TX 12 
Week 
Assessments
Telehealt
h
Within 84-93 
days of V11
Assessments and 
Questionnaires
Table 1: Summary of Study Design in Response to COVID-19
TELEHEALTH VISITS
All telehealth visits will be conducted through video call through 
Doximity or VA Video Connect. However, phone calls will be 
available as back up if there are issues with connectivity or other 
technical issues preventing video. Video calls will allow the study 
team to better monitor subjects and create a more personal visit.
Consent/Screening – Visit 1
Consent and screening will take place remotely in which a member 
of the study team will go over the study details, eligibility, and 
answer any questions or concerns. Subjects will be given a copy of 
the consent/HIPAA forms prior to the scheduled visit through 
MyHealtheVet or mail. Once the consent form/HIPAA has been 
reviewed and the subject agrees to participate, the subject will be 
asked to sign the forms (either handwritten or electronically) and 
return the forms to the study team through either MyHealtheVet or 
FAX. Subjects will also be screened for the study and COVID-19 
over the video call and a physical exam will be conducted by the PI 
during the first on-site visit (2b). If a subject indicates they have 
had symptoms of COVID-19, they will be advised to come into the 
hospital for testing. A negative test (or confirmation that they are 
no longer positive) will be required before enrollment.
Once a subject is enrolled, an additional phone call will be 
conducted prior to their baseline assessments to go over the 
various platforms (Doximity, MyHealtheVet, and VA Video 
Connect) that will be used for the telehealth visits.
Assessment Based Visits – Pre-treatment assessments 
(V2a), Post-TX 1-week (V13a), Post-TX 2-week (V14), Post-
TX 4-week (V15), Post-TX 8-week (V16) and Post-TX 12 
week (V17)
Pre and post-treatment assessments will be conducted over video 
call, and questionnaires to be completed by subjects will be 
provided prior to each visit through MyHealtheVet or mailed to the 
subjects. Subjects will be given the choice to either: 1) complete 
questionnaires within 24hours of their video appointment and 

1.  
1.  
2.  
3.  
4.  
return them through MyHealtheVet or FAX; or 2) complete them 
during the video call where subjects will provide their verbal 
responses and the study coordinator will document the response. 
The following assessment will have changes on administration:
Mechanical Visual Analogue Scale (MVAS) of Headaches, 
Muscle, and Joint Pain: subjects will rate their pain on the 0-
100 MVAS scale at all On-site visits
The following assessments will not be conducted as they require in-
person administration:
Stroop Test
Eye Tracking Assessment
Conner’s Performance Test II
Trail Making Test
These assessments are part of the secondary hypothesis, 
measuring attention and executive functioning. Though these 
functions will not be measured, the primary aim of this study is to 
assess headache and quality of life and assessments related to the 
primary aim will still be administered.
All other assessments listed in the protocol will be administered 
with no changes, other than being conducted remotely. Subjects 
will continue to keep a daily log of their headaches and medication 
usage throughout the course of the study which will be collected 
by either sending it through MyHealtheVet or through FAX.
The following table summarizes the assessments/questionnaires 
administered:
Visit
 
2
a
2
b
3-
12
1
3
a
1
3
b
1
4
1
5
1
6
1
7
Location
 
T
H
O
S
OS T
H
O
S
T
H
T
H
T
H
T
H
Brief Pain Inventory-Short 
Form (BPI)
Self-
administere
d
x
 
 
x
 
x
 
x
 
Neurobehavioral Symptoms 
Inventory (NSI)
Self-
administere
d
x
 
 
x
 
x
 
x
 
x
 
 
x
 
x
 
x
 

Headache Impact Test (HIT-
6)
Self-
administere
d
Short Form Health Survey-36 Self-
administere
d
x
 
 
x
 
x
 
x
 
Hopkins Verbal Learning Test 
(HVLT)
Study 
Coordinator
x
 
 
x
 
x
 
x
 
Hamilton Rating Scale for 
Depression (HRSD)
Study 
Coordinator
x
 
 
x
 
x
 
x
 
Clinician-Administered PTSD 
Scale (CAPS-5)
Study 
Coordinator
x
 
 
x
 
x
 
x
 
Modified Fatigue Impact Scale Self-
administere
d
x
 
 
x
 
x
 
x
 
MVAS – Sliding Scale
Study 
Coordinator
 
x x
 
x
 
x
 
x
TH: Telehealth; OS: On-site
Table 2: Summary of Assessments in Response to COVID-19
 
ONSITE VISITS (ONCE WRITTEN APPROVAL FROM ACOS
/R&D FOR RESUMING ON-SITE VISITS IS PROVIDED)
MRI scans (2b and 13b) and treatment-based visits (3-12) will be 
conducted onsite at the UCSD fMRI Center and at VA San Diego 
Building 23, respectively, with increased safety measures.
 
 Section 9.4 Devices
9.4) For each research device, state the status of the device, the PI’s determination as to whether the device is 
a significant or non-significant risk device, and provide justification for this determination. A copy of 
  
determinations from the FDA should be attached. - Also, for investigational devices describe how and by 
whom the device will be received, stored, secured and dispensed.
Device: TMS Magpro Magventure, previously approved through engineering department for 
research studies H130281, H160047 

rTMS is currently FDA approved for treating major depression and single pulse TMS is approved 
for treating migraine headaches. This treatment technology has an excellent safety track record 
when used under the safety guideline established in 1998 [74]. A recent study demonstrated 
that unilateral rTMS as well as bilateral combined rTMS revealed no detrimental effects on 
cognition in comparison to the sham group 3 months after the treatment [2]. On the other hand, 
rTMS is found to have mild beneficial cognitive effects [24]. In lack of any major breakthrough in 
establishing other effective long-term treatment regimen for MTBI-HA and co-morbidities, this 
safety track record and potential benefits associated with rTMS supports the feasibility of the 
proposed study in a rapidly growing patient population with debilitating symptoms. 
The PI believes that this device does not meet the definition for a significant risk device (SR) and 
therefore falls into the non-significant risk (NSR) device classification under the current FDA 
guidelines:
According to the FDA, under 21 CFR 812.3(m), an SR device means an investigational device 
that:
• Is intended as an implant and presents a potential for serious risk to the health, safety, or 
welfare of a subject;
• Is purported or represented to be for use supporting or sustaining human life and presents a 
potential for serious
risk to the health, safety, or welfare of a subject;
• Is for a use of substantial importance in diagnosing, curing, mitigating, or treating disease, or 
otherwise
preventing impairment of human health and presents a potential for serious risk to the health, 
safety, or welfare of
a subject; or
• Otherwise presents a potential for serious risk to the health, safety, or welfare of a subject.
Therefore, the PI has determined an abbreviated IDE designation is applicable due to the fact 
that this device is a NSR that has been approved by the FDA, however for the study it will be 
used in an off-label manner. (http://www.fda.gov/oc/ohrt/irbs/devrisk.pdf)
Similar devices have also been studied and the results concerning device safety have been 
published:
1. Anand S, Hotson J. Transcranial magnetic stimulation: Neurophysiological applications and 
safety. Brain and Cognition. 2002;50:366-386.
2. Rossini PM, Rossi S. Transcranial magnetic stimulation: diagnostic, therapeutic, and research 
potential. Neurology. 2007;68:484-488.
3. Wassermann EM, Lisanby S. Therapeutic application of repetitive transcranial magnetic 
stimulation: a review. Clin Neurophysiol. 2001;112:1367-1377.
Further information on Transcranial magnetic stimulation:
The principle of inductive brain stimulation with eddy currents has been noted since the 20th 
century. The first successful TMS study was performed in 1985 by Anthony Barker and his 
colleagues in Sheffield, England.[4] Its earliest application demonstrated conduction of nerve 
impulses from the motor cortex to the spinal cord, stimulating muscle contractions in the hand. 
As compared to the previous method of transcranial stimulation proposed by Merton and Morton 
in 1980[5] in which direct electrical current was applied to the scalp, the use of magnets greatly 
reduced the discomfort of the procedure, and allowed mapping of the cerebral cortex and its 
connections.
4. Barker, AT; Jalinous, R; Freeston, IL (1985). "Non-Invasive Magnetic Stimulation of Human 
Motor Cortex". The Lancet 325 (8437): 1106–1107. doi:10.1016/S0140-6736(85)92413-4. PMID 
2860322.
5. Merton, P. A.; Morton, H. B. (1980). "Stimulation of the cerebral cortex in the intact human 
subject". Nature 285
(5762): 227. doi:10.1038/285227a0. PMID 7374773.
FDA DOCUMENTS
MagPro rTMS: K091940 & K061645
MEDOC TSA II NeuroSensory Analyzer: k010981 & TSA-II_Brochure (FDA Approval)
Request for NSR justification & abbreviated IDE designation
MagPro rTMS: This device study is one that does not meet the definition for an SR device study 
and therefore falls into the NSR classification under the current FDA
The device has been used by the PI in 5-6 approved studies, the latest one being protocol 
#H160047.

 Section 9.8 Questionnaires & Surveys
9.8) Provide the name and a reference for questionnaires/surveys that are standard or identify them here and 
attach a copy of the questionnaire/survey.  Questionnaires or surveys that are not clinical standard references 
must be uploaded.  Reference the help link for additional information related to surveys administered to VA 
 
personnel and approved platforms for web-based surveys.
Questionnaires & Surveys (copies attached): 
1.Numerical Pain Rating Scale (NPRS): scale that ranges from no pain to worst possible pain. 
2.Headache Log: Daily log to report if they have a persistent (non-stop, 24/7) headache over the 
last 24 hours and rate the average intensity of the headache on a 0-10 Numerical Rating Scale 
(NRS). In addition, they will be asked to report the duration and intensity of any debilitating 
headache exacerbations, which completely incapacitate their daily functions. 
3.Neurobehavioral Symptoms Inventory (NSI): A self-report on the severity of each symptom is 
measured using a 5-item scale. It asks the subjects to indicate the extent to which each 
symptom has disturbed them.
4.Headache Impact Test (HIT-6): Measures how impact headaches affect the individual’s ability 
to function in different domains.
5.Short Form Health Survey-36: A patient-reported survey of patient health. It is a measure of 
health status and quality of life in regards to eight main areas: vitality, physical functioning, 
bodily pain, health perceptions, physical, emotional, and social role functioning and mental 
health.
6.Clinician-Administered PTSD Scale (CAPS-5): A 30-item structured interview that can be used 
to diagnose PTSD and associated symptoms. 
7.Conner’s Continuous Performance Test (CPT II): A widely used test of sustained attention using 
a computer program. It provides a detailed picture of response time, impulsivity, and 
attentiveness.
8.Hopkins Verbal Learning Test: Hopkins Verbal Learning Test: This is a verbal list learning 
measure with multiple equivalent forms to minimize practice effects in repeat testing. It provides 
information about learning acquisition as well as short and long delayed recall. It has been used 
successfully in previous trials of rTMS. 
9.Trail Making Test A and B: This is a widely used test of executive functioning. It consists of an 
attention/processing speed condition (connecting numbers in order quickly) followed by a more 
complex sequencing task (alternating between numbers and letters).
10.Stroop Test: Participants must inhibit a pre-potent response to provide the required response 
on this test of inhibition.
11. Hamilton Rating Scale for Depression (HRSD: This scale is a well-established questionnaire 
which consists of 21 questions and rates the severity of symptoms observed in depression such 
as low mood, insomnia, agitation, anxiety and weight loss. The scale is frequently used in TBI 
related studies for assessing the severity of depression.
12. Brief Pain Inventory: Assesses the intensity of physical pain and the levels of interference 
using a numerical rating scale (1 to 10). 
13. Eye-Tracker Assessment: assesses eye movement during a test to learn more about 
attention in this population.
 Section 9.9 Data Safety Monitoring Board or Plan
9.9) Provide a Data Safety Monitoring Plan (DSMP) or the details of a Data Safety Monitoring Board; if a 

written plan is available, attach a copy of the plan to the submission form.
The DSMB will review all unanticipated problems involving risk to study subjects, serious adverse 
events, and all subject deaths associated with the protocol, and provide an unbiased written 
report of the event within 10 calendar days. The DSMB will provide an independent evaluation of 
adverse events and unanticipated problems involving risk to subjects to the Human Subject 
Protection Committee. The DSMB will comment on the outcomes, adverse events, and 
relationship of the events to the protocol. The DSMB will
indicate whether they concur with the details of the report provided by the PI. The DSMB 
promptly reports discrepancies or problems to the Committee. They have the authority to stop a 
research study in progress,remove individual volunteers from a study, and take whatever steps 
will be necessary to protect the safety and well being of research subjects until the IRB can 
assess the report. The members of the DSMB for this proposal will comprise of a pain specialist, 
a clinical psychologist and a biostatistician who will be independent of the investigative team and 
possess sufficient educational and professional experience to serve as the subjects' advocate. 
The members of DSMB also have no apparent conflicts of interest.
The DSMB members include:
Carter Jones, M.D., Ph.D. (pain specialist)
Dr. Jones is an Assistant Professor of Anesthesiology at UC San Diego, School of Medicine, with 
sub-specialty training in pain management.
William Perry, Ph.D. (psychologist)
Dr. Perry is a Professor of Psychiatry at UC San Diego, School of Medicine. He is the Associate 
Director of the Neuropsychiatry and Behavioral Medicine Service at the UCSD-Medical Center. He 
also serves as the Chief Supervising psychologist at UCSD-Medical Center and is a member of 
Neuropsychological Associates.
Robert Chen, MA, MBBChir, MSc, FRCPC (Neurologist, rTMS expert)
Dr. Chen is a Professor of Neurology at the University of Toronto. He is an expert of rTMS in both 
clinical application and basic science research.
Ronghui Xu, Ph.D. (Biostatistician)
Dr. Xu is the current Director of Biostatistics at the UC San Diego, Clinical and Translational 
Research Institute. She is experienced in analyzing data from large-scale clinical trials.
The members of the DSMB will meet on an as needed basis. Given the geographical location 
difference and lack of other local experts in rTMS, Dr. Chen will join the board meeting via 
teleconference. If a serious AE or UPR occur, then the members of the DSMB will be contacted by 
the PI and a meeting will be set up to address the situation as soon as possible. 
The members of the DSMB will not have access to the subject identifying information when 
reviewing adverse events, and will only be presented with the unique study number. 
SAFETY MEASURES IN RESPONSE TO COVID-19
The following safety measures will be used to reduce risk and compliance is to be documented at 
each On-site visit: screening for COVID-19, PPE, hand washing, reduced staff and scheduling, 
and sanitization of equipment. A checklist will be used to document that all safety measures are 
followed and has been attached to the protocol revision. 
COVID-19 Screening: 
During consent/screening call, subjects will be screened for COVID-19 with the questions 
provided by the research office to be enrolled in the study: 
1. Do you have:
a. A Fever
b. New or worsening cough or shortness of breath
c. Flu-like symptoms
2. Have you or a close contact travelled to an area with community transmission of COVID-19 
within the past 21 days? For example, including but not limited to Europe, the middle east, Asia, 
and/or areas of the United States with significant spread of COVID 19, such as Washington 
State, New York, Massachusetts and Northern California
3. Have you been in close contact with someone, including health care workers, confirmed to 
have the coronavirus disease?
Subjects who answer “no” to all questions will be enrolled in the study. Should a subject answer 

that they have had symptoms of COVID-19, they will be advised to come into the hospital for 
testing and a negative test (or confirmation that they are no longer positive) will be required 
before enrollment. 
1-2 days before an on-site visit, subject will be contacted via phone call to screen for COVID 
symptoms. On arrival at site, screening will be conducted at the entrance of the hospital and 
when entering the lab for their appointment. Subjects will also be required to have their 
temperatures check with an IR thermometer. If all symptomology is negative, subjects will be 
enrolled/allowed to continue with their visit. 
If a subject indicates moderate to severe symptoms, subjects will be required to report to the 
COVID-19 triage for testing. If a subject indicates mid symptoms, such as low fever or only one 
symptom, and the VA is unable to provide testing, subjects will be asked to stay/return home 
and will be provided with a COVID-19 home testing kit. If positive results, subjects will be asked 
to stay home for at least 14 days and seek medical attention through their primary care 
provider. Subjects may continue with the study after 2 weeks of quarantine or with note from 
their care provider that they are no longer positive for COVID-19 and under the discretion of the 
PI. If the subject is unable to meet the study timelines due to COVID-19 the subject may be 
withdrawn from the study under the discretion of the PI. 
Any staff in contact with the subjects will be asked to return home, monitor for COVID-19 
symptomology, and tested for COVID-19 with home kit. If test is positive and staff shows 
symptoms, medical care should be sought and staff are to stay home until they are healthy. If 
test is positive but employee is asymptomatic, staff should stay quarantined for 2 weeks. If the 
test is negative, staff should stay at home for 2-5 days to ensure before returning to work as a 
safety precaution. Staff will also be screened by the hospital when reporting to duty each day. 
PPE/Handwashing 
Subjects will be required to wear a face mask, wash or use hand sanitizer (before and after 
visit), and wear gloves (provided by the lab) during the visit. Staff will be required to wear a face 
mask, eye protection, gloves, disposable gown, and ensure hands are washed before and after 
each appointment.
Reduced Staff and Scheduling 
On-site staff will be limited to 2 study coordinator and the PI and in-person interactions with 
subjects will be limited to one study coordinator and the PI. Only one subject will be enrolled per 
week, at least a 30-minute window between each appointment, and only 2 subjects will be in the 
treatment phase at a given time with alternating treatment schedules. 
Sanitization 
Equipment must be wiped down with antiseptic cloth before and after each visit which includes 
the treatment machine, coil, chair, the neuronavigation equipment (pointer, headband, and 
clicker), laptop, mouse, EMG wires, MVAS sliding scale, door handles, desk, and any other 
surfaces that may come into contact with patients and staff. In addition, pillowcases and any 
sheets used will be changed after each subject. 
UCSD Keck MRI Center 
The UCSD MRI Center has also implemented increased safety measures that include: screening 
for COVID-19, wearing face masks, washing hands, limiting study team to 1 operator and 1 
assistant, mandatory 30 minute gap between appointments, disposable gloves to be work by 
staff and subject once inside MRI center, sanitization of all equipment before and after scanning, 
and documenting all safety measures. The regulations implemented by the MRI center has been 
attached to the protocol revision. 
 Section 9.12 Off Station Activities
9.12) Describe each off-station activity including where it occurs, subject involvement, and any additional 
required protections.  Note:  if the off-station activity is being conducted under the approval authority of another 
institution, this is not VA offsite research and should be described as collaborative research effort.  Please contact 
the HRPP office if you have any questions
Brain anatomical and functional MRI will be performed within 72 hours after Visits 2 and 13. 
These scans will be conducted at the Center for Functional MRI (CFMRI)at the UC San Diego 
School of Medicine. The Study Coordinator will be MRI Operator certified through the center and 
will conduct the scans. This is the only off-station activity.

 Section 10 - Human Subjects
10) Describe the characteristics of the proposed subject population. Include age, gender, ethnicity, and health 
status as appropriate.  Note: Data about people are still considered “human subjects” by the IRB, so even if you 
do not intend to contact the patients whose charts you will review, you still describe the characteristics related to 
   
the subjects whose charts you will review.
Provide inclusion and exclusion criteria as appropriate.  Provide a statement how non pregnancy is 
confirmed if pregnancy is an exclusion criteria.
For multisite studies, provide the total number of subjects from all sites and include description of the 
local site's role as a coordinating center if applicable.
Indicate the number of VA participants to be studied.
Indicate the estimated number of 
 subjects that will fail the screening process, if any.
consented
Number of Participants: 200
Inclusion:
The following diagnostic criteria for MTBI based on the 1993 American Congress of Rehabilitation 
Medicine and recent recommendation from the DOD, and the current diagnostic criteria adopted 
by the VASDHS TBI Clinic will be used for the study [67]:
A traumatically induced physiological disruption of brain function, as manifested by at least one 
of the following: 1) any loss of consciousness; 2) any loss of memory for events immediately 
before or after the accident; 3) any alteration in mental state at the time of the accident (e.g., 
feeling dazed, disoriented, or confused) and focal neurologic deficit (s) that may or may not be 
transient but where the severity of the injury does not exceed the following: 1) loss of 
consciousness of approximately 30 min or less; 2) after 30 min, an initial Glasgow Coma Scale 
score of 13–15; and 3) post-traumatic amnesia not greater than 24 hrs.
In addition, the following established diagnostic criteria for “ Persistent headache attributed to 
mild traumatic injury headache” based on the International Classification of Headache Disorder 
(ICHD-3)[57] will be applied to the study subjects:
A. Any headache fulfilling criteria C and D
B. Traumatic injury to the head has occurred
C. Headache is reported to have developed within 7 d after one of the following:
1. injury to the head
2. regaining of consciousness following the injury
3. discontinuation of medication(s) that impairs the ability to sense or report headache following 
the injury
D. Headache persists for >3 mo after injury to the head
E. Not better accounted for by another ICHD-3 diagnosis
Additional Inclusion Criteria: 
1. male or female age between 18 to 65; 
2. no prior experience of TMS treatment; 
3. average persistent headache intensity more than 30 on the 0-100 mechanical visual analog 
scale(M-VAS) at the screening visit (visit 1)[64] and average persistent headache intensity score 
greater than 3/10 on a numerical rating scale (NRS) reported in the headache diary (between 
visits 1&2); 
4. no history of daily persistent headache prior to the MTBI incidence: 
Exclusion 
1. pregnancy; To be eligible for the study and to ensure no pregnancy risk, you will need to 
utilize contraception or practice abstinence until your study participation is completed 
2. history of pacemaker implant; any ferromagnetic material (e.g. bullet fragment, shrapnel, 
device implant) in the brain or body that would prohibit the patients from having a brain MRI; 
3. history of dementia, major psychiatric or life threatening diseases; 
4. presence of any other chronic neuropathic pain states; 
5. history of seizure; 
6. pending litigation; 
7. lack of ability to understand the experimental protocol and to adequately communicate in 
English; 
8. history of chronic headache diagnoses such migraine, tension or cluster headaches prior to the 
incidence of MTBI. 

9. history of chronic headache prior to the MTBI incidence at a frequency more than once a 
month lasting more than one hour.
10. evidence in the chart of recent exacerbation of depressive or anxiety symptoms, active 
substance dependence, suicidal intent or attempt within
the previous month, and/or current psychotic symptoms
Medications:
Medications allowed during the study will include stable (been used at least 30 days prior to the 
screening visit) regimens of:
1) Non-narcotic analgesics such as non-steroidal anti-inflammatory, acetaminophen, tramadol, 
Aspirin. 
2) Antidepressants such as Serotonin Specific Reuptake Inhibitors and Tricyclic Antidepressants 
used mainly for sleep only;
3) Anxiolytics/benzodiazepine hypnotics such as Alprazolam, lorazepam, triazolam used at 
bedtime only;
4) GABA-A partial agonists/non benzodiazepine hypnotics such as Zolpidem, eszopiclone used for 
sleep only.
Subjects who receive any narcotic based analgesic, steroid and local anesthetic injection in the 
peri-scalp region, triptans, anticonvulsants, and antipsychotic medications less than 7 days prior 
to the pre-treatment assessment will not be enrolled for the study. Non-pharmacologic 
treatments, including but not limited to, transcutaneous electrical nerve stimulation unit (TENS), 
acupuncture, acupressure and therapeutic massage above the neck will be prohibited during the 
entire study. Subjects should not have elective surgery or elective interventional medical 
procedures for the duration of the study. Subjects are allowed to use additional acetaminophen 
(up to a maximum total of 3g per day) as the only rescue medication during the study. The use 
of the rescue and other concomitant medications will be documented in the daily pain log. 
 Section 10.1 Non-Veteran Subjects
10.1a)  Recruitment of non-Veterans cannot be for the sake of convenience for this study.  Provide the 
objective and justification for the inclusion of non-Veteran subjects.  Identify how the research results will be 
generalizable to the Veteran population.  NEW:  ORD now requires completion of a Request to Enroll Non-
Veterans form (available in the help section of OnRAMP) for any VA studies requesting to enroll non-
Veterans.  This form will be reviewed by the local RDC before the application may be considered by the 
 
IRB.  Complete the form and upload with this submission.  
The only non-veteran subjects that would be included would be those that are considered still 
active military personnel.
10.1b) Non-Veterans must be given a copy of the VA Notice of Privacy Practices (NOPP) and sign the 
acknowledgement form when their health information is used/collected for research purposes.  In addition, 
the Privacy Officer must be notified of the non-Veteran enrollment and be provided with a copy of the signed 
NOPP, when applicable.  If CPRS notes are entered, and the acknowledgement must also be scanned into 
CPRS.  The NOPP, Acknowledgement form, and instructions to provide the completed form to the PO are 
available under the ? at the top right corner of this page.
 Agree
 Disagree
 Section 11 - Recruitment
11) Describe, step-by-step, the plans for recruitment of subjects (or selection of subjects as in record review). 
This description must include how, when, and where potential subjects are approached as well as procedures 
for identifying potential participants (through medical records, physician referral, third-party 
sources, etc.).  Include how selection is equitable.  Indicate if vulnerability to coercion may be present and if so 
plans to ensure voluntary participation.

Patients are identified for the study via four ways:
1: Subjects will be recruited from the TBI, Anesthesia Pain Clinic and Neurology TBI Headache 
Clinic at the VA San Diego Healthcare System (VASDHS)
Patients are referred and evaluated for the rTMS treatment, they are offered the opportunity of 
study participation with the understanding that they have the option of not participating in the 
study and still receive clinical treatment protocol.
Veterans referred for possible rTMS treatment are being evaluated during regular clinic visits. 
The PI and other qualified providers (co-investigators) will evaluate the patient for the treatment 
based on their medical conditions. If they are determined to be good candidates for the 
treatment, the nature of the clinical (non-research) treatment protocol, and the risk and benefits 
of the treatment will be explained and discussed to the patient. In addition, patients will be 
offered the opportunity of participating in the IRB approved research protocol. The providers will 
emphasize to the patients that their decisions of study participation will not interfere with their 
regular care. If they decide not to participate in the study protocol, they can still receive the 
rTMS treatment via the clinical treatment protocol during regular Anesthesia TMS procedure clinic 
hours. If a patient expresses interest in the study and agrees to meet the study coordinator, the 
PI or other qualified providers will contact the study coordinator to come meet the potential 
patient subject for study informed consent.
2:Patients respond to study flyers
For subjects responding to advertisements who are not patients of the PI or other qualified 
providers, the appointment will be scheduled by the study coordinator receiving the telephone 
calls from the potential subjects. The study coordinator will obtain the consent from the patient 
before screening data are collected. The subjects will also medically be evaluated by the PI or 
other qualified providers to determine whether their medical conditions meet the study inclusion 
and exclusion criteria. Before subjects are entered into this study, the purpose and nature of the 
study as well as possible adverse effects will be explained to them in the presence of a witness. 
The subject must sign a statement, which complies with the requirements of the US Code of 
Federal Regulations. A signed original should be given to the subject. With study informed 
consent signed, the PI will review all the screening information with the study coordinator to 
determine whether the patient meets the study inclusion or exclusion criteria for enrollment. 
3. Naval Medical Center San Diego (NMCSD) flyer recruitment from the C5 and Pain Clinic. Same 
process as recruitment from the VASDHS flyer/brochure method, the Study coordinator will be 
contacted by the interested subjects on the designated research phone. A separate IRB approval 
will be obtained from the NMCSD for the sole purpose of posting recruitment flyers and handing 
out study brochures to the clinics. There will not be any patient screening needed at NMCSD, no 
research activities will take place there either. The research study is independent of an IRB 
recruitment flyer approval through the NMCSD. Brochures will be given to those that might be 
interested to see if they are eligible and flyers posted in designated areas. The NMCSD is 
considered a non-VA research collaborator for allowing brochures / flyer distribution if approved 
through their IRB for that recruitment method. 
4. In order to boost recruitment, we plan to contact veterans who have enrolled in the VA IRB 
approved registry, VASDHS TBI/PTSD Registry - H170023, allowing themselves to be contacted 
by future VA IRB studies. In section 12.10, we ask for a waiver of partial HIPAA so we can 
contact the Veteran via their preferred method of contact. If, at any time, the Veteran enrolled in 
the VASDHS TBI/PTSD Registry lets this study know that they want to withdraw from the registry 
and no longer want to be contacted, we will contact H170023's study coordinator as soon as 
possible.
5. A letter will be mailed to potential veterans from the TBI, Anesthesia Pain Clinic, Neurology 
TBI Headache Clinic, and the VASDHS TBI/PTSD Registry for recruitment which describes the 
study and asks for a response indicating whether they are interested or not. 
6.We will also receive referrals from other VA studies. These studies will provide referrals of 
veterans who have consented to be contacted for additional studies. Studies we will recruit from 
include protocol numbers H190062, H160089, and H190078. Subjects from these studies who 
appear to be eligible for participation in this study and who have consented to be contacted 
about future research opportunities will be sent a recruitment letter via mail prior to contact by 
phone unless they have specifically consented to phone contact.
Children and Women
No children will be recruited for this study. The VA requires a waiver for a research on children 
and currently VASDHS does not offer a pediatric service. Female veterans who meet the study 

inclusion and exclusion criteria will be recruited. Female Veterans at child bearing age will be 
required to have a urine pregnancy test (ordered by the PI) prior to the enrollment.
 Section 11.1 Recruitment Materials
11.1) Identify all recruitment materials (flyers, advertisements, letters, etc.) that will be used; include the web 
address for any web-based advertisements. The text of all communications with prospective participants must 
be reviewed and approved by the IRB before it can be used.  You will be reminded to attach copies of 
recruitment materials to the initial submission packet.  Note:  Posting of flyers with pull tabs is not permitted 
within VASDHS (including the VMRF building).  However, you may request to advertise on the e-boards (located 
 
at the elevators and throughout the facility) or on the VASDHS Research Opportunities web-page.
A recruitment flyer will be utilized for posting in approved VASDHS areas. A letter will be mailed 
to potential subjects describing the study.
 Section 12 - Informed Consent
12) Indicate whether or not each category of consent is involved in this study:
12a) Will the study team obtain information or biospecimens for the purpose of screening, recruiting, or 
determining the eligibility of prospective subjects without (or prior to) obtaining informed consent of the 
prospective subject or the prospective subject’s LAR?
 Yes  
 No
Check one or both of the below boxes if they apply to this study:
Information will be obtained through oral or written communication with the prospective subject or the subject’s 
Legally Authorized Representative (LAR) and this is not a FDA regulated study.
  Yes  
  No
Identifiable information or biospecimens will be obtained by accessing records or stored identifiable 
biospecimens and this is not an FDA regulated study.
  Yes  
  No
Since both boxes were checked "no", a request for an informed consent waiver is needed.
12b) 
 informed consent
Signed
 Yes  
 No
12c) Waiver of documented consent (e.g., 
consent) for all or part of the study.
oral 
  Yes  
  No
12d) Request for a 
 of consent for all or some study activities.
waiver
 Yes  
 No
12e) Alteration of 
 of consent.
other required elements
  Yes  
  No
12f) 
assent to participate (Director approval will be required)
Child 
  Yes  
  No
12g) Will any language 
 be used by those obtaining consent and understood by the 
other than English
prospective participant or the legally authorized representative?
  Yes  
  No
12h) 
 to determine if participants have the capacity to consent for themselves.
Decisional Capacity Assessment

  Yes  
  No
12i) 
 consent (legally authorized representative)
Surrogate
  Yes  
  No
 Section 12.1 Informed Consent Process
12.1a) Will consent be obtained before any study procedures are performed (including screening procedures 
 
except screening procedures with Consent and/or HIPAA waiver when required)?
 Yes  
 No
12.1b) Will the information being communicated to the participant or legally authorized representative 
during the consent process include exculpatory language through which the participant or legally authorized 
representative is made to waive or appear to waive any of the participant’s legal rights or release or appear to 
release the Researcher, Sponsor, the VA or its agents from liability for negligence.
  Yes  
  No
12.1c) A master list of all VA subjects consented (written or not) under this protocol will be maintained.
 Agree
 Disagree
12.1d) Identify the circumstances under which consent will be obtained including where the process will take 
place; any waiting period between describing the research and obtaining consent including sufficient time for 
the prospective participant to consider participation, and any steps taken to minimize the possibility of 
coercion or undue influence.
Consenting will take place at the VASDHS in Building 23 Room 105 and 108. This is designated 
research space under the PI. The waiting period between describing the research and obtaining 
consent is dependent on the potential subject and when they are able to schedule a time with 
the Study Coordinator to be consented.
 Section 12.4 Waiver of Informed Consent
12.4a) Is it practicable to conduct the research without the waiver or alteration of consent?
  Yes  
  No
12.4b) Does the research examine public benefit or service programs and is subject to state or local 
government approval?
  Yes  
  No
12.4c) Will the research involve greater than minimal risk?
  Yes  
  No
12.4d) Will waiving or altering informed consent adversely affect the subjects’ rights and welfare?
  Yes  
  No

12.4e) Is it appropriate to provide pertinent information to subjects later BUT this information will NOT be 
provided?
  Yes  
  No
12.4f) Identify to what aspects of the study you are requesting a waiver of consent (i.e., full study or specific 
aspects). Describe the waiver or alteration needed and why it can be granted (include why the research is not 
practical without the waiver or alteration and how the waiver enables conducting the study).
Waiver of informed consent or alteration of consent elements may be allowed if the IRB documents these 
findings and approves waiver or alteration.
The waiver of informed consent is requested for recruitment purposes pertaining to pre-
screening over the phone. Pre-screening the potential subject by reviewing inclusion/exclusion 
criteria over the phone ensures that the individual meets the basic requirements before obtaining 
the individuals name and number to schedule the consenting visit. The ability to pre-screen 
potential subjects enables the research to be conducted efficiently and without wasting the 
potential subjects or research staffs time by consenting someone who does not meet the basic 
inclusion criteria of the study.
12.4g) Explain why the research could not practicably conducted without using identifiable information.
The research could not practically be conducted without pre-screening over the phone for 
inclusion/exclusion criteria and obtaining the name and number of subjects eligible for the 
consenting visit. If prescreening
was unable to be done then there would be a lot more consented subjects failing the screen, 
wasting the time of the research staff involved as well as the veterans coming in for the study.
 Section 12.9 HIPAA Authorization
For each category below, indicate whether or not this study involves the indicated process:
12.9a) 
 HIPAA Authorization.  
Signed
**New Template is available in the ?  Help section**
 Yes  
 No
12.9b) HIPAA waiver to cover the entire study
  Yes  
  No
12.9c) HIPAA waiver for recruitment, screening, and/or for a portion of the study.
 Yes  
 No
12.9d) HIPAA Authorization or waiver is 
 for some or all of the study subjects (e.g. no health data).
not required
  Yes  
  No
 Section 12.10 HIPAA Waivers and Alterations
12.10a) Describe the purpose/nature of the HIPAA waiver or alteration and list specifically, what identifiers 
and health information are being requested under the waiver/alteration and identify whether the waiver is 
for access, use, and/or collection of this information.
Referrals from study H170023, the VA IRB approved VASDHS TBI/PTSD Registry, have given 
their documented oral consent to be contacted by future studies. We request a HIPAA waiver so 
that we can contact the Veteran via his or her preferred method of contact. In addition, if 
veterans in our study are interested in being added to the VASDHS TBI/PTSD Registry, their 

information can be available. The specific identifiers being collected are the name, preferred 
contact (phone number or e-mail), age, gender, and whether the Veteran has TBI and/or PTSD. 
No other demographic information will be collected.
12.10b) The proposed access, use, and/or disclosure of PHI involves no more than a minimal risk to the 
privacy of individuals.
 Agree
 Disagree
12.10c) The plan to protect the identifiers from improper use and disclosure is adequate.
 Agree
 Disagree
Describe the plan
The identifiers will be kept on an electronic call log behind the VA firewall so that it can be 
referenced if needed for call backs or reminder texts. The information will be deleted if no longer 
needed, and only kept if the potential subject gets consented. The only PHI collected at pre-
screen phone call is name and phone number and inclusion/exclusion criteria for reference when 
coming in for the consenting and full screening visit.
12.10d) An adequate plan to destroy the identifiers at the earliest opportunity consistent with conduct of the 
research, unless there is a health or research justification for retaining the identifiers or such retention is 
otherwise required by law.
 Agree
 Disagree
12.10d2) Describe the plan:
Identifiers that are not needed for research will be deleted immediately. There will be no 
hardcopy versions.
12.10e) By signing this protocol for submission, the PI is providing written assurance that the PHI will not be 
reused or disclosed to any other person or entity, except as required by law, for authorized oversight of the 
research project, or for other research for which the use or disclosure of protected health information would 
 
be permitted by the Privacy Rule.
:  If the waiver of HIPAA authorization is for 
38 U.S.C. 7332 Information
the use of 38 USC 7332 information (applicable to drug abuse, alcohol abuse, HIV infection, and sickle cell 
anemia records), by signing this protocol for submission the PI is providing written assurance that the 
purpose of the data is to conduct scientific research and that no personnel involved may identify, directly or 
indirectly, any individual patient or subject in any report of such research or otherwise disclose patient or 
subject identities in any manner. (Ref:  38 U.S.C. 7332(b)(2)(B))
 Agree
 Disagree
12.10f) The research could not practicably be conducted without the waiver or alteration.
 Agree
 Disagree
12.10f2) Describe how the waiver/alteration enables the research to be conducted
The waiver/alteration enables the research to conduct more efficiently so that the researchers 
can do a pre-screen on the phone to see if the potential subject sounds eligible. The only PHI 
collected are their name and phone number and inclusion/exclusion criteria. It allows the 
researchers to follow up with them if they want to schedule at a later date, have a call back or 
need a reminder text for a consenting visit.
12.10g) The research could not practicably be conducted without access to and use of the PHI.
 Agree
 Disagree

12.10g2) Describe why it would be impracticable to conduct this research without the PHI described 12.10a. (v3
/8/18)
Research could not be conducted without the phone number and documented name of the 
individual prior to consenting as no confirmation text or contact could be given, thus making it 
difficult to coordinate meeting the potential subject in person when they do come in. In addition, 
if inclusion /exclusion criteria are unable to be asked during the pre-screening, then a lot of 
individuals will have wasted their time if they come in for consenting to find out during the full 
screen that they were not eligible on criteria that could have been asked before coming in. 
Asking questions over the phone regarding inclusion/exclusion ensures that the research is done 
efficiently, and time is being respected.
 Section 13 - Alternatives to Participation
13) Describe the alternatives to participation in this research study (see  for guidance)
?
If the potential subjects are not interested in participating in the research study, they can discuss 
alternatives with their primary care physician. If they are patients of the co-investigators or PI 
they can be referred to receive rTMS treatment via the clinical treatment protocol during regular 
Anesthesia TMS procedure clinic hours.
 Section 14 - Potential Risks
14) Describe any potential or known risks or discomforts and assess their likelihood and seriousness (see  for 
?
guidance)
Risks associated with Repetitive Transcranial Magnetic Stimulation (rTMS) are minimal. A 
potential side effect of rTMS is a mild headache or headache increase, resulting from muscle 
stimulation on the scalp. Typically, the headache will resolve spontaneously a few hours after the 
treatment or with a dose of acetaminophen. Occasionally, skin irritation can occur. This 
occurrence will be dealt with conservatively. Noise during treatment may also be a concern. 
However, all subjects will be required to wear earplugs during the treatment session. Some 
patients may experience sleep disturbance during the course of rTMS or a feeling of increase
/decrease of energy level. Although seizure occurrence was reported in the past, to the best 
knowledge of the investigators, no seizure occurrence has been reported with treatment setting 
similar to the proposed treatment protocol since the introduction of standard treatment guideline 
in 1998. These and other risks of the intervention will be fully discussed with the subjects prior 
to the study and side effect will be assessed during the study as well. Since the MRI scan room 
consists of strong magnetic field, instruction will be given to each subject prior to entering the 
scan room so that no subjects with any metal denture, implanted metal device such as aneurysm 
clips, cardiac pacer or spinal fusion rods will be allowed to enter the scan room. A screening 
survey will be conducted as required by the MRI center. The magnet of scanner may cause 
dizziness, which can be avoided
with slow movement when the subjects are near the scanner. These and other risks of the 
intervention will be fully discussed with the subjects prior to the study and side effects will be 
assessed during the study as well.
 Section 15 - Risk Management
15) Describe the procedures for protecting against or minimizing any potential risks/discomforts, and the 
adequacy of resources for conducting the study and resources participants may need as a consequence of the 
research.  When applicable, include detail of the following safety measures:   
(a) The type of safety 
information to be collected, including AEs; 
(b) Frequency of safety data collection; 
(c) 
Frequency or periodicity of review of cumulative safety data; 
(d) Statistical tests for analyzing the 
safety data to determine if harm is occurring; and 
(e) Conditions that trigger an immediate suspension 
of the research.  See  for further requirements.
?
Protection from Risk
1)All procedures will be performed directly or under the direct supervision of the PI or one of the 
clinical co-investigators in a controlled hospital setting. 

2)Subjects with a history of a cardiac arrhythmia that has led to the placement of a cardiac pacer 
or defibrillator will be excluded from the study. 
3)The PI will review the patients' MRIs or consult with Dr. Roland Lee, a neuroradiologist co-
investigator to rule out any lesions or ferromagnetic fragments. If any notable findings are 
discovered through Dr. Lee, the PI will relay that information to the subject. 
4)The rTMS stimulation setting used in the study is within the current safety guidelines. 
However, if the subject feels that the discomfort is excessive, the study will be stopped 
immediately. 
5)Only the PI and the investigators will have access to the research records. Research records 
will be kept confidential to the extent provided by law. During the study, the patient’s name and 
identity will not be publicly disclosed without their written permission. The results of this study 
will likely be published in medical journals or presented at medical meetings. However, the 
authors can only use the assigned patient number in the article or presentation. All research 
records and data will be kept in a locked cabinet in the PI's research at a VMRF/VA assigned 
research facility.
6)Minor complications such as local skin irritation or headache will be managed conservatively 
with rest and /or oral non-narcotic analgesics. Transient seizure activity will be managed with 
close neurological monitoring. The PI and the co-investigators are either board certified 
anesthesiologist or ACLS certified.
 Section 17 - Potential Benefits
17) Discuss benefits that may be gained by the subject as well as potential benefits to society in general  (see  ?
for guidance)
Patients with TBI related headache would benefit from the study with potential headache 
intensity reduction and cognitive function improvement. In addition, the information obtained 
can potentially explain the cause(s) of their symptoms and guide the development of treatments 
that can potentially correct the aberrant supraspinal functions leading to their debilitating 
symptoms.
The outcome of the study can help validate the treatment effect of a novel, non-invasive, low-
risk and low cost treatment modality to the general VA patient population.
 Section 18 - Risk/Benefit Analysis
18) Discuss why the risks to subjects are reasonable in relation to the anticipated benefits to subjects and in 
relation to the importance of the knowledge that may reasonably be expected to result.
Given that headache can significantly impair a patient’s daily function and quality of life and 
conventional therapy with multiple pharmacological agents usually consist of many side effects, 
the minimal risk associated with TMS treatment, the risk /benefit ratio in the current study is 
very low. Therefore, the proposed study can potentially gain crucial knowledge about the 
utilization of a novel non-invasive therapy for Veterans with MTBI and impairing chronic 
headache problem.
 Section 20 - Compensation for Participation
20) Provide all details and justifications of the compensation plan.  See  for detailed requirements.
?
To compensate the study subjects for their travel expense and time spent with the study 
activities, and to maximize subject retention, each subject will be reimbursed $30 for the 
screening visit (Visit 1) and each of the 10 treatment visits (Visits 3-12). For all the other visits, 
each subject will receive $50 for each of the 6 assessment visits and 2 MRI visits. For all the 
visits, we budget a total $730 compensation fee for each subject. The payments will be made 
directly to their bank account using electronic funds transfer.

 Section 21 - Responsibilities and Qualifications
Here are the identified study staff members
Albert Y. Leung, MD
Carl T. Rimmele, PhD, Gregory R. Polston, MD, Jay Pyo, D.O., Lisa L. Lin, MD, Lu D. Le, DO, 
Michael A. Vaninetti, MD, Paul B. Krug, DNP, RN, Roland R. Lee, MD, Thomas R. Rutledge, PhD, 
Caleb Lopez, BS, Caleb Lopez, BS, Michael Paul Ho, BS, Talyn Hughes, BS, Valerie G. Le, 
Shahrokh Golshan, PhD, Michelle Kennedy, BA, Seshagiri Mallina, Valerie G. Le
21) For each staff member listed above, describe their role and qualifications.  Also indicate which of the 
study staff are authorized to obtain consent, when applicable to the study. 
Albert Leung, M.D. (AL): Principal Investigator
Dr. Leung is a Clinical Professor of Anesthesiology at the University of California, San Diego 
(UCSD), a Staff Physician at Veteran Affairs San Diego Healthcare System (VASDHS), and 
Research Scientist at Veterans Medical Research Foundation (VMRF). He holds joint 
appointments with UCSD, VASDHS and VMRF. Dr. Leung has served the VASDHS as a staff 
physician since 1999 and was the Director of the Anesthesia Pain Service from 2001 to 2006. He 
founded the first Transcranial Magnetic Stimulation (TMS) treatment clinic for treating intractable 
central pain in the VA system in 2010. The clinic now provides repetitive TMS (rTMS) therapy as 
an non-invasive therapeutic option for veterans with intractable chronic pain conditions such as 
MTBI. He has extensive experience in human experimental pain, functional imaging data 
acquisition and analysis from prior studies. Dr. Leung will assume full responsibility for all 
activities related to the conduct of the study. He will coordinate the activities of the research 
team with assistance from the study coordinator. He will assist in data analysis, and outcomes 
interpretation. He will also take primary responsibility for manuscript preparation for publication. 
He will present findings at scientific meetings. Dr. Leung will train study personnel on protocol 
implementation and to standardize evaluation and treatment procedures.
Thomas Rutledge, Ph.D. (TR): Co-Investigator
Dr. Rutledge is a clinical psychologist at the VASDHS. He has extensive clinical and research 
experience in pain management, depression and PTSD. He will also provide support for the PI 
and other co-investigators for managing any psychiatric emergency. He will provide training or 
guidance for the study coordinator to conduct all neuropsychological assessments proposed in 
the study. 
Roland Lee, M.D. (RL): Co-Investigator
Dr. Lee is a neuroradiologist, currently on staff at VASDHS and UCSD. He is the current Director, 
UC San Diego Magnetoencephalography (MEG) Lab and Chief of Neuroradiology. He and the PI 
have collaborated in previous studies involving fMRI to assess the central functional response 
related to TMS treatment. Dr. Lee will provide the PI with clinical and research support for any 
clinical issues related to MRI interpretation which will be used for neuronavigation guided TMS 
and neurofunctional imaging data obtained from the study. 
Michael Vaninetti, M.D., Co-investigator 
Dr. Vaninetti is an Assistant Clinical Professor of Anesthesiology at UCSD. He will assist the PI 
with the recruitment of study patients, answering of patient questions, delivering treatment to 
the study subjects, supervising the study coordinator, and making final conclusions about this 
study.
Lisa Lin, M.D., Co-Investigator 
Dr. Lisa Lin is staff physician for Physical and Rehab Medicine at the VASDHS. She has 
collaborated with the PI before in previous studies. She will be assisting in referrals for 
recruitment.
John D'Andrea, M.D., Co-Investigator 
Dr. D'Andrea is staff physician for Physical and Rehab Medicine at the VASDHS. He will be 
assisting in referrals for recruitment.
Jay Pyo, D.O., Co-Investigator 
Dr. Pyo is the Chief of the Physical Medicine Rehabilitation Service at the VASDHS. He has 
collaborated with the PI before in previous studies. He will be assisting in referrals for 
recruitment.
Paul Krug, NP/RN: Co-Investigator
Mr. Krug is the nurse practitioner for the TMS Clinic at the VASDHS. He will be assisting in 

referrals for recruitment.
Shahrokh Golshan, Ph.D. (SG): Study Biostatistician 
Dr. Golshan is a Project Scientist in the UCSD Department of Psychiatry and the PI and Director 
of the Methodology, Biostatistics and Data Management Unit for the Advanced Center for 
Innovation in Services and Intervention Research since 2000. Dr. Golshan will be available to 
provide statistical and data management consultation during the design, implementation of this 
study and will be responsible for randomization and will conduct all of the statistical analyses.
Lu D Le, DO: Co-Investigator
Dr. Le is the Medical Director at the Aspire Center for the VASDHS. He will provide support for 
the PI and other co-investigators for mental health related questions pertaining to the study. He 
will provide training or guidance for the study coordinator with the neuropsychological 
assessments proposed in the study. 
Carl Rimmele, PHD: Co-Investigator
Dr. Rimmele is the VA ASPIRE Center Director. He will provide support for the PI and other co-
investigators for mental health related questions pertaining to the study. In addition, he will 
provide information regarding the study to veterans who may be interested in participating, 
giving them the study coordinator contact information for follow up. 
Michelle Kennedy, B.A.: Lab Manager 
Ms. Kennedy is well versed in the research environment, has been trained by the PI in the 
various assessments related to the current proposal. She will be responsible for assisting in the 
daily operations of the study. She will be able to obtain consent. 
Talyn Hughes, B.S.: Study Coordinator / Research Assistant 
Ms. Hughes is well versed in the research environment, has been trained by the PI in the various 
assessments related to the current proposal. She will be responsible for assisting in the daily 
operations of the study. She will be able to obtain consent. 
Valerie Le, BS; Study Coordinator 
Ms. Le will be responsible for assisting the study coordinator with research activities, including 
recruiting, consenting, administering neuropsychological assessments, assisting with study 
treatments, and follow up visits. She was previously a volunteer at the lab for 2 years and is 
familiar with human subject research. She has been trained by the PI and current study staff.
Michael Ho, BS; Study Coordinator 
Mr. Ho will be responsible for assisting the study coordinator with research activities, including 
recruiting, consenting, administering neuropsychological assessments, assisting with study 
treatments, and follow up visits. He has been trained by the PI and current study staff.
Caleb Lopez, BS; Clinical Research Associate
Mr. Lopez is well versed in the research environment, has been trained by the PI in the various 
assessments related to the current proposal. He will be responsible for assisting in the daily 
operations of the study. He will be able to obtain consent.
Seshagiri Mallina; Research Associate
Mr. Mallina is well versed in the research environment, has been trained by the PI in MRI 
analysis related to the current proposal. He will primarily assist with MRI-related tasks for this 
study including processing, analysis and running of scans.
 Section 22 - Bibliography
22) List relevant articles that the IRB can use to provide necessary background for the protocol. Do not 
include an extensive NIH-grant-style bibliography.  (Up to 5 recommended, but use more if needed to support 
the protocol or citations above.)
Lefaucheur JP, Andre-Obadia N, Antal A, Ayache SS, Baeken C, Benninger DH, Cantello RM, 
Cincotta M, de Carvalho M, De Ridder D, Devanne H, Di Lazzaro V, Filipovic SR, Hummel FC, 
Jaaskelainen SK, Kimiskidis VK, Koch G, Langguth B, Nyffeler T, Oliviero A, Padberg F, Poulet E, 
Rossi S, Rossini PM, Rothwell JC, Schonfeldt-Lecuona C, Siebner HR, Slotema CW, Stagg CJ, 
Valls-Sole J, Ziemann U, Paulus W, Garcia-Larrea L. Evidence-based guidelines on the 
therapeutic use of repetitive transcranial magnetic stimulation (rTMS). Clin Neurophysiol 2014;
125(11):2150-2206.
Leung A, Shukla S, Fallah A, Song D, Lin L, Golshan S, Tsai A, Jak A, Polston G, Lee R. Repetitive 

Transcranial Magnetic Stimulation in Managing Mild Traumatic Brain Injury-Related Headaches. 
Neuromodulation 2015.
Neville IS, Hayashi CY, El Hajj SA, Zaninotto AL, Sabino JP, Sousa LM, Jr., Nagumo MM, Brunoni 
AR, Shieh BD, Amorim RL, Teixeira MJ, Paiva WS. Repetitive Transcranial Magnetic Stimulation 
(rTMS) for the cognitive rehabilitation of traumatic brain injury (TBI) victims: study protocol for a 
randomized controlled trial. Trials 2015;16:440.
Patil VK, St Andre JR, Crisan E, Smith BM, Evans CT, Steiner ML, Pape TL. Prevalence and 
treatment of headaches in veterans with mild traumatic brain injury. Headache 2011;51(7):1112-
1121.
Tallus J, Lioumis P, Hamalainen H, Kahkonen S, Tenovuo O. Long-lasting TMS motor threshold 
elevation in mild traumatic brain injury. Acta Neurol Scand 2011.
 Section 23 - Sponsors and Collaborators
23) Clarify any industry financial or other support (e.g., NIH funds the study or Company X provides the 
    
assay kits).
Identify non-VA Research collaborators and their role in this protocol, including whether or not 
 
they have access to subjects or identified data.
Dr. Alireza Salami is an assistant professor through the Department of Neurobiology at the 
Karolinska Institute, Stockholm, Sweden. He has a PhD in Computational Neuroscience and will 
assist the study staff in understanding functional magnetic resonance imaging data analysis. He 
will not have access to subjects or identified data. 
In the submission form, upload a copy of the grant, subaward, CRADA, etc. as appliable to the study.
 Section 27 - Privacy, Confidentiality, and Information Security
27a) Provide a brief description of how participant privacy and confidentiality will be protected in this study. 
Describe the circumstance under which it may be possible for a research team member to identify subjects 
and any related protections or assurances to prohibit or avoid identification. Describe how the number of 
people with access to identifiers for research purposes is limited in order to protect a participant’s privacy.
Participant information will be kept behind the password protected VA network firewall. In 
addition, any hardcopies will be locked in both a cabinet and in a locked room in Room 112, 110, 
107 of Building 23. There are limited people with access to identifiers in order to protect the 
participants' privacy.
27.b) Entry of a CPRS 
is required when subjects will be 
 
Research Informed Consent Note
admitted as 
for research 
the study 
inpatients or treated as an outpatients 
 
and
involves research medical care or may affect 
medical care.
If a Research consent Note is required, then a 
 should also be entered for each 
Research Progress Note
procedure or intervention.
Scanning the Consent and HIPAA Authorization into CPRS is 
.  Linking the Consent to the 
not required
Research Informed Consent Note may be permitted and can be useful for trials involving the Research 
Pharmacy or when research will be performed in conjunction with clinical procedures.
For Non-Veterans, if Research Informed Consent Notes are entered, then the 
 
NOPP Acknowledgment
must be scanned into the record.  Otherwise a copy of the signed NOPP must be retained with the 
Investigator's research records and a copy sent to the Privacy Officer; see the   Help for more information.
 ?
27.b1) Is entry of CPRS notes required based on the above criteria?
CPRS notes are needed for ALL subjects 
CPRS notes are needed for SOME subjects 
CPRS notes are NOT needed for any subjects 

27c) Select the VA Sensitive Information (VASI) use category
This study does not collect or use any VASI 
This study uses but does not save, collect, copy, or record VASI 
This study does collect or record VASI 
 Section 27.1  VA Sensitive Information (VASI)
27.1a) For each type of VASI, indicate all that apply:
Indicate which of the following will be collected/recorded:
Protected Health Information (PHI)
Names
Device identifiers and serial numbers
E-mail addresses
Medical record numbers
URLs (Universal Resource Locator)
All elements of dates (except year) or any age over 89
Health plan beneficiary numbers
IP Addresses (Internet Protocol)
Telephone numbers
Account numbers
Biometric Identifiers including finger and voice print
Fax numbers
Certificate or license numbers
Full face photographic images and comparable images
All geographic subdivisions smaller than a state
Vehicle ID and serial numbers including license plate numbers
Social security numbers or scrambled SSNs (describe below)
Other unique identifying number, characteristic, or code (describe below)
27.1a1)  Describe why SSN are needed for this study
Their SSN will be collected for use with HIPAA compliance and authorization. The last four of 
their SSN will be stored securely behind the VA firewall with their demographic information on 
the secured electronic master list of consented subjects.
27.1b) Consent Forms and/or HIPAA Authorization
 Yes  
 No
27.1c) Images with personal identifiers are used for this study (x-rays, MRI images with patient names, record 
numbers, dates, etc.)?
 Yes  
 No
27.1c1) Identify where images will be stored (e.g., in the medical record, with study hardcopy records, with 
study electronic VASI records).

The MRI images collected will be named with the coded subject ID and the date of the MRI. It is 
stored on secured VMRF server under the PI: Dr. Albert Leung's private data folder.
27.1d) Photos with faces or audio video recordings are used for this study.
  Yes  
  No
27.1e) Biological specimens with identifiers are used for this study.
  Yes  
  No
 Section 27.2  Data Collection, Tools, and Resources
27.2a)  Will any specially obtained software be used?
 Yes  
 No
27.2a1) Describe the software, and identify license requirements and the ownership of the software or 
license.  Identify on what computer/network the software will be used (e.g., VA, VA Research/VMRF, local 
hard drive) and any data that will be stored in temporary files on the computer’s hard drive
The ANT Neuro Visor2 neuronavigation system will be used during treatment sessions and is 
specialized software owned by the PI. It is on a stand alone laptop not connected to any network 
and any data stored in temporary files are anonymized and do not contain any identifiers.
27.2b) Will any mobile devices (laptop, tablet, portable hard-drive, etc.) be used in support of this study?
 Yes  
 No
27.2b1) Provide details of the device/s.  Indicate whether the device is FIPS 140-2 encryption validated and 
confirm that the device is listed in the VA EIL.  Provide details regarding the nature of the data that will be 
stored or transmitted on the device and confirm whether a copy of all data will be stored on the VA network. 
A laptop will be used to conduct treatment sessions for the study. The laptop is not connected to 
any network and data is not stored on it. It is merely for visualizing the treatment location during 
treatment sessions per subject using the Visor2 software. It works with the Visor2 equipment 
needed for treatment,
the equipment is tagged as EE110005.
27.2c) Does the study require use of an electronic data capture system? 
  Yes  
  No
27.2d) Will any other web-based applications be used (e.g., for recruitment, completing online questionnaires, 
or processing data)?

  Yes  
  No
27.2e)  Will coded data that excludes personal identifiers be used?   Coded data excludes 
HIPAA identifiers 
all 
(per VHA Handbook 1605.1 Appendix B), including dates
 Yes  
 No
27.2e1) Identify where the code key is stored and in what format (electronic, paper).
The electronic master list of consented subjects holds the date of consent, demographic 
information, names and subject ID.
 Section 27.3  Data Sharing and Transportation
27.3a) Does this study involve collecting, sharing or transporting any type of data outside of the local VA?
 Yes  
 No
27.3b) This study collects VASI outside of VA (i.e., at a non-VA location).
 Yes  
 No
27.3b1) Describe what is collected outside the VA and how it is secured in transit back to the VA. Note: An 
approved Authorization to Transport will be required.
The MRI images are collected at the UCSD Keck Imaging center where the date of the scan is the 
only identifier. It is directly transferred to the UCSD server for download on the VA premises. 
There is no physical transportation of data. This process has been approved in previous studies, 
see H160047 for
reference.
27.3c) VASI is transported outside of VA for any purpose other than sharing.
  Yes  
  No
27.3d) PHI may be disclosed to monitoring/auditing agencies by HIPAA Authorization.  Note:  The Research 
Office must be notified when monitors come to audit
 Yes  
 No
27.3e) Data may be shared with collaborators or others in the conduct of this protocol.

  Yes  
  No
 
Section 27.4  Research Record Storage and Retention
For each type of record, indicate whether it is collected for this study
27.4a) Hardcopy records/data (includes paper, pictures, film, etc.)
 Yes  
 No
27.4a1) Identify precisely where hardcopy data will be stored to include physical site, building, and room 
number, etc.  For each location identify whether VASI or non-sensitive information is stored at that 
location.  For VASI, identify how the data is secured. 
Hardcopy data will be stored in Building 23, Room 112, 110, 107, 108. VASI to include hardcopy 
consent documents will be stored separate from hardcopy data folders, in a locked cabinet in 
Room 112, 110, 107, 108.
27.4a2) Are all of the above locations at VA?
 Yes  
 No
27.4b) Electronic study records (includes computer files, removable disk files, digital files, etc.).
 Yes  
 No
27.4b1) Identify precisely where 
electronic records/data will be stored to include the full map 
 
non-sensitive
drive, network location/server name, etc., and a brief description of what data/information is stored at each 
location.
R:\Leung\NEW MASTER STUDY FOLDER\1. Master Research Folders\H170053 ---This is where 
blank assessments will be stored, IRB stamped documents and other anonymized documents.
R:\Leung\Access Database ---This is where anonymized data will be stored electronically. It is a 
microsoft database behind the VA firewall.
27.4b2) Identify precisely where 
electronic records/data will be stored to include the full map drive, 
 
VASI
network location/server name, etc., and a brief description of what data/information is stored at each location.
If no VASI is collected or recorded for this study, simply indicate that the “Study does not collect or record 
VASI”.
R:\Leung\NEW MASTER STUDY FOLDER\1. Master Research Folders\H170053 ---This is where 
blank assessments will be stored, IRB stamped documents and other anonymized documents.
R:\Leung\Access Database ---This is where anonymized data will be stored electronically. It is a 
microsoft database behind the VA firewall.
Server: smb://132.239.102.236/Leung ---This is the VMRF dedicated server where the MRI 
images are stored for backup. The only identifier on these images are the date.

27.4b3) Are any of the locations described in 27.4b outside of the VA Secure Network? Note: this includes 
storage on a computer local hard drive.
  Yes  
  No
27.4c)  Record Retention - VHA requires compliance with Records Control Schedule (RCS-10) for retention 
of electronic and hard copy records.  Following study closure, these temporary records must be retained 
for six years and then destroyed.  Longer retention may be permitted if required by other Federal regulations 
or requirements.  Will RCS-10 requirements be followed (i.e., 6-year retention)?
I will adhere to VHA Records Control Schedule-10 requirements 
I request an exception to RCS-10 requirements 
 Section 27.5  Additional Privacy or Information Security Details
Provide any other privacy or information security details here.
 Section 27.6  Attestations
In the event of real or suspected breach of security, the Information Security Officer, Privacy Officer, VA 
Police (if appropriate), and the individual’s supervisor will be notified within one hour of learning of the event.
 Agree
 Disagree
Study staff will be up to date on any required VHA Privacy Policy and Information Security training or they 
will not be allowed access to VA Sensitive Information.
 Agree
 Disagree
Access to research sensitive information, if any, will be removed when study personnel are no longer part of 
the research team.
 Agree
 Disagree
At least one copy of all study records (whether sensitive or non-sensitive) will be retained under VA control 
and only destroyed in compliance with the approved Records Control Schedule
 Agree
 Disagree
The VA retains ownership of the research data.  Should the investigator leave the VA, custody of the research 
records will be assigned to another investigator and the Research Service notified in writing, or custody of the 
research records will be transferred to the Research Service.
 Agree
 Disagree
 Section 28 - Protocol Association to New or Existing Project
  
28) Is this a new R&D Project?  Before you go on to complete the 
 (which is 
Initial Review Submission Form
used for attachments), please address the association of this Protocol to an R&D Committee Project.  This 
Protocol may represent a new R&D Project, or it may be an additional Protocol under an existing R&D 
  
Project (such as when a single grant supports multiple Protocols).  Will this Protocol be submitted to the 
R&D Committee as a new Project?

  Yes  
  No
 Section 29 - Existing Project Association
  
29) The associated R&D Project should already exist in the database.  Identify the R&D Project(s) that 
correspond to this protocol.
Project Status
Proposal Number
Project Title
Principal 
Investigator
No Projects are Linked to this Study
 The Protocol Application is now complete for a Protocol attached to an existing Project.
 
Next you will go on to the Initial Review Submission Form.  This form is used to collect the Application 
and any other needed attachments for submission to the IRB for review.
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