Theta Burst Transcranial Magnetic Stimulation of Fronto-parietal Networks: Modulation by Mental State
Phase: NA
Conditions: Healthy
Sponsor: University of Michigan

 
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Full title:  
 
Theta burst transcranial magnetic stimulation of fronto-parietal networks: Modulation 
by mental state 
 
 
 
 
Principal Investigator: 
Stephan F. Taylor, M.D.,  
Professor, Department of Psychiatry, University of Michigan 
Co-investigators: 
Taraz Lee, PhD 
Assistant Professor of Psychiatry, University of Michigan 
Luis Hernandez, PhD 
Research Professor of Biomedical Engineering, University of Michigan 
 
Sponsor: NIMH, R21 MH120633-01 
Other Identifying Numbers: 19-PAF01859  
University of Michigan IRBMED:  HUM00165239 
NCT#: 04010461 
Version Day Month Year:  27Jan2022 
 
 
 
 
 
 

 
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Table of Contents 
 
 
Page 
Protocol Summary ..................................................................................................................... iii 
1.0 Introduction and Background ............................................................................................. 1 
2.0 Specific Aims and Study Outcome Measures ..................................................................... 3 
3.0 Study Design ...................................................................................................................... 3 
4.0    Study Participants………………………………   …………………………………… .......... … 4              
         4.1 
Participant Inclusion/Exclusion Criteria ................................................................... 4 
4.2 
Informed consent .................................................................................................... 4 
4.3 
Strategies for Recruitment and Retention ............................................................... 5 
4.4 
Intervention Assignment Procedures  ..................................................................... 5 
5.0    Study Intervention  ............................................................................................................. 5  
6.0    Study schedule and assessments ...................................................................................... 6  
6.1      Consenting procedures  .......................................................................................... 6 
6.2 
Screening assessment visits................................................................................... 6 
6.3 
Visits 3,4,5, Combined iTBS/MRI sessions  ............................................................ 8 
6.4 
Reimbursment of partcipants  ................................................................................. 9 
6.5 
Participant discontinuation/withdraw ....................................................................... 9 
7.0 Assessment of Safety and Regulatory Reporting  ............................................................ 10 
7.1 
Data Safety and Management Plan  ..................................................................... 10 
7.2 
Event Windows, Missed Assessments, Missed Sessions and Protocol Deviation 
Reporting .............................................................................................................. 11 
8.0 Statistical Analysis ........................................................................................................... 12 
9.0 Ethics and Protectionn of Human Subjects....................................................................... 16 
9.1 
Ethical Standard and IRB Review  ........................................................................ 16 
9.2 
Subject Confidentiality .......................................................................................... 16 
9.3 
Potential Risks and Minimization of Risks ............................................................. 16 
9.4 
Potential Benefits and Justification of Risk ............................................................ 21 
10.0 Data Handling and Record Keeping  ................................................................................ 21 
11.0 References  ...................................................................................................................... 23 
 
 
 

 
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Protocol Summary 
 
This proposal will examine a particular type of TMS, known as theta burst stimulation (TBS), 
which has been shown to induce longer lasting effects than other forms of TMS, making TBS an 
important tool for therapeutic applications.  While TBS provides relatively focal stimulation, effects on 
the brain occur through interconnected networks in ways that are poorly understood. Moreover, 
stimulation is highly state-dependent, and the use of TMS in most therapeutic settings, such as the 
treatment of depression, leaves mental state uncontrolled. Augmenting TMS therapy by inducing 
specific mental states is an attractive idea for improving therapeutic TMS, but the relevant knowledge 
base is sparse. To address this critical gap, this exploratory R21 proposal will examine the effects of 
TBS on specific brain networks and the interaction between TBS and mental state. We will test the 
broad hypothesis that when TBS is applied during a controlled mental state, network changes will be 
facilitated, compared to stimulation when mental state is uncontrolled.  We will focus on the dorsolateral 
prefrontal cortex (dlPFC) and the associated fronto-parietal network (FPN), which subserves cognitive 
control -- the ability to flexibly adapt and regulate behavior, an ability known to be impaired in 
neuropsychiatric conditions such as depression and dementia. We will use an ‘n-back’ task tapping 
cognitive control and the FPN.  We will employ a within-subjects design with 40 healthy subjects in 4 
MRI sessions. Each MRI session will consist of blood oxygenation level-dependent (BOLD) fMRI during 
an n-back task, resting state BOLD fMRI to measure connectivity and resting state arterial spin labeling 
(ASL) MRI to measure cerebral blood flow (rCBF) and examine effects on resting activity level. BOLD 
activation during the n-back will identify the FPN and the target site for dlPFC TBS. After a baseline 
fMRI session, subsequent sessions over different days will entail TBS, immediately followed by an MRI 
session to assess the effects of stimulation. TBS will involve: 1) dlPFC stimulation by active iTBS (600 
pulses) alone or 2) while simultaneously performing an n-back cognitive task or 3) vertex (control) iTBS 
stimulation, alone. The following aims will be pursued: 
 
 
Population: Healthy control subjects with no significant mental health problems. 
Site: University of Michigan 
Study Duration: 2 years  
Subject Participation Duration: 3-4 weeks 
Study Design:  Basic experimental study in humans, single-blinded, cross-over  
Number of subjects:  up to 60 (to achieve 40 analyzable subjects) 
Description of Intervention: Basic Experimental Studies with Humans (BESH) 
Estimated Time to Complete Enrollment: 2 years

 
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1.0 Introduction and Background 
   
1.1 The need to improve our understanding of non-invasive brain stimulation  
 
Devices to deliver energy (magnetic, electrical, ultrasound) to nervous tissue have proliferated 
in the last decade, but there remains a dearth of knowledge about how these devices 
affect brain networks. This proposal will focus on TMS, which uses magnetic energy to induce 
electrical currents in nervous tissue, and even though several decades of work has detailed 
effects of TMS on cortical physiology,(1, 2) many questions remain unanswered about how TMS 
affects the brain, particularly at the meso-scale of brain networks which subserve complex 
behaviors. TMS has frequently been employed to disrupt cortical activity with focal stimulation, 
inducing a ‘virtual lesion’ and enabling inferences about the function of regions interrupted by 
stimulation,(3, 4) and it has also been used to enhance brain function.(5, 6) In the United States, 
it has been cleared for therapeutic use in the treatment of major depressive disorder,(7) 
obsessive-compulsive disorder(8) and migraine headache.(9) Numerous research studies have 
also reported benefits for many other neuropsychiatric conditions,(10-15) and more recent work 
has sought to combine TMS with behavioral interventions.(8, 16-18) While the combination of 
TMS with other interventions has intrinsic appeal, there is little scientific value in showing that 
two therapies, combined, work better than a single therapy, alone. If these efforts are to be 
more than therapeutic mashups, we will need a deeper understanding of the effects of TMS on 
brain networks, as this R21 project proposes.  
 
Our approach will focus on cognitive control and the underlying FPN(s) which carry out 
this cognitive process. Cognitive control, also referred to as executive functioning, is the ability 
to flexibly adapt and regulate behavior in accord with goals and plans.(19) It is impaired in 
multiple neuropsychiatric conditions, such as depression (20), obsessive-compulsive 
disorder,(21) dementia(22) and schizophrenia.(23) Cognitive control is carried out in fronto-
parietal networks,(19, 24, 25) including the dorsolateral prefrontal cortex, which is typically 
targeted by rTMS treatment for depression. As we review below, critical gaps in our knowledge 
exist about how TMS affects FPN and cognitive control, gaps which motivate the proposed 
work. 
 
1.2 What is known about how TMS affects brain activity?   
 
Non-repetitive pulses of TMS stimulate neurons and affect local micro-circuitry in complex ways 
(see(1, 2)), but persisting, so-called ‘plastic,’ effects require repetitive TMS (rTMS). The exact 
mechanism(s) of enduring changes in neural activity remain unknown. Persistent rTMS effects 
are complex, involving direct and indirect effects on excitatory and inhibitory neurons at the 
focus of stimulation, as well as secondary and tertiary effects on connected regions.(26, 27)  
Timing, intensity, direction and frequency of stimulation all have differential effects.(2, 27, 28) In 
general, low frequency rTMS (≤1 Hz) reduces cortico-spinal excitability, measured as increasing 
levels of stimulation necessary to elicit a motor response (‘motor evoked potential,’ or MEP), 
whereas high frequency rTMS (generally ≥ 5 Hz) has an opposite, facilitatory effect on MEP, 
with effects generally lasting as long as the period of stimulation.(2, 28, 29)  Longer lasting 
effects have been demonstrated by high frequency (50 Hz) bursts (‘theta burst stimulation’ or 
TBS), causing MEP facilitation for up to 15 minutes after a 190 sec period of intermittent 
stimulation (iTBS). On the other hand, continuous TBS (cTBS) for 40 sec causes MEP 
inhibition.(30, 31)  The TBS protocols were designed to elicit long term potentiation and long 
term depression, the most widely studied mechanisms of neural plasticity,(32) although data 
suggests that responses measured in the MEP are more complex than LTP or LTD measured at 
the cellular level.(33, 34) A variety of cellular and molecular effects of rTMS/TBS have been 
described (see(34) for recent review), and meso-scale effects have also been studied with 

 
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electroencephalography,(35-37) but in order to best localize network effects, this proposal will 
focus on the persisting effects revealed through neuroimaging, including resting 
perfusion/metabolism, task-related activation and connectivity.  
In general, the most consistent neuroimaging result observed in ‘offline’ (conducted after 
a period of rTMS stimulation) studies is that changes occur in regions beyond that stimulated, 
but anatomically and functionally connected.(38-41) Furthermore, it is not always possible to 
predict effects based on assumptions taken from MEP measurement.  For example, ‘inhibitory’ 
cTBS increased cerebral blood flow in the motor cortex in one study,(42) and another study 
found that MEP measurement after ‘excitatory’ iTBS exhibited an inverse relationship between 
BOLD signal and the MEP increase induced by iTBS.(43) cTBS to the dlPFC increased 
connectivity amongst regions of the FPN,(44) and reduced the tuning of visual cortical activity 
and performance during a working memory task.(45) Overall, the effects of TMS on 
neuroimaging measures are difficult to predict and there are relatively few studies of offline 
effects of excitatory iTBS to the dlPFC. Therefore, Aim 1 will address a question not 
sufficiently answered in the literature:  What is the effect of iTBS to the FPN networks on 
resting perfusion, task-related activation and connectivity?  
 
1.3 State-dependency of TMS stimulation   
 
A critical fact about TMS is that effects are highly state-dependent. The phenomenon known as 
‘metaplasticity’ refers to neural plasticity modulated by prior activity in a neuron,(46) and an 
analogous process may occur with TMS.(47, 48) Extracellular recordings in animals have 
shown that increased visual cortical activity during excitatory TMS leads to greater post-TMS 
activity.(49) From the earliest days of TMS research in humans, it was noted that stimulation of 
motor cortex during active muscle contraction increased the size and number of descending 
volleys compared to stimulation when the hand was at rest.(50, 51) Since then, multiple 
examples of state-dependency have been described. For example, activating the ipsilateral 
hand during stimulation alters the response and coupling in the contralateral cortex during TMS 
to premotor cortex.(52) Directing attention to the contralateral hand during 5 Hz stimulation 
leads to larger MEP increases than when attention is directed to the ipsilateral hand.(53) Global 
changes in brain state, such as sleep, have demonstrated large effects, reducing the 
propagation of a single TMS pulse across the cortex when measured by surface 
electroencephalography.(54) In summary, multiple paradigms have demonstrated state-
dependency of persisting TMS effects. 
In spite of what is known about the state-dependency of TMS, most therapeutic uses of 
rTMS do not systematically control the mental state of subjects during stimulation, although this 
is starting to change. rTMS has been combined with psychotherapy for depression.(16) Cue 
exposure in addiction(55) and exposure therapy for post-traumatic stress disorder(17) and 
OCD(8) have been paired with TMS. A commercial system that combines rTMS with cognitive 
training in dementia patients has been cleared for marketing in the EU, even though differential 
effects in a sham-controlled study were not found (n=26).(18) In spite of this work, there are no 
neuroimaging studies identifying the neural effects of state-dependency in paradigms relevant to 
therapeutic TMS. Examining motor function, Narayana and colleagues showed that, in 4-week 
training paradigm, subjects who received 5 Hz rTMS to the motor cortex while they performed a 
digit sequence task showed improved motor performance and increased cerebral blood flow, 
relative to sham stimulation, in regions linked to skill learning.(56) For cognitive control, many 
studies have examined neural effects of TMS delivered ‘offline’(prior to neuroimaging) to a brain 
at rest,(39, 41, 57, 58) but virtually no work has examined offline, persisting effects of TMS 
delivered while a person is engaged in a task.  These persisting effects of TMS interacting with 
brain state are critical to understand how this interaction could be harnessed for improved 
therapeutic effect. Thus, in Aim 2 we will address the question: How does mental state 
modulate the effect of rTMS on FPN networks? 

 
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The phenomenon of task state interacting with TMS has been used to target specific 
neural populations within a stimulated region, a paradigm known as ‘TMS adaptation.’(59) It has 
been used to augment brain mapping studies of language processing(60) and higher level 
perception.(61) For example, Silvanto and colleagues(62) showed that when subjects viewed 
visual motion while receive inhibitory cTBS to direction sensitive neurons in V1/V2, performance 
after stimulation was impaired for the direction-sensitive neurons that were not activated during 
the passive viewing task. In other words, neurons engaged by the task appeared to be 
‘protected’ from inhibitory cTBS. This motivates our Aim 3, asking whether excitatory iTBS 
stimulation while the FPN is engaged would improve subsequent performance. 
 
 
2.0 Study aims and outcome measures 
 
Specific Aim 1: Localize neural effects of dlPFC TBS  We will show that persisting neural 
changes induced by TBS to the dlPFC will affect the FPN. We predict that TBS alone (subjects 
not performing a cognitive task), compared to vertex stimulation, will increase fMRI activation in 
the FPN during the n-back and increase FPN connectivity during resting state BOLD.  We also 
predict that TBS will increase resting perfusion in the FPN.  Exploratory analyses will search for 
regions outside the FPN that change with stimulation to develop a comprehensive picture of 
how TBS to the dlPFC interacts with brain networks.   
 
Specific Aim 2: Demonstrate modulation of the effect of dlPFC TBS by a cognitive task 
We predict that FPN changes during iTBS administered while subjects perform the n-back task 
will be greater than when they are not performing a task.  We will also test the same hypothesis 
for BOLD resting state connectivity, and ASL-measured perfusion, in addition to exploratory 
hypotheses on brain networks outside the FPN. 
 
Primary outcome measures for Aims 1 & 2: 
1) 2-back minus 1-back BOLD activation, voxelwise in FPN  
2) FPN connectivity to dlPFC TBS stimulation target 
3) rCBF at stimulation target 
 
Secondary outcome measures for Aims 1 & 2: 
1) 2-back minus 1-back BOLD activation, voxelwise in whole brain 
2) rCBF in FPN  
 
 
Specific Aim 3: Demonstrate improvement in cognitive control with TBS, modulated by 
cognitive task during stimulation  We will test predictions that n-back performance will improve 
following TBS to dlPFC, but not vertex, and will improve even more following TBS during n-back 
performance. Exploratory analyses will examine correlations between performance changes 
and network changes, suggesting mechanistic connections between TBS and performance 
changes. 
 
Primary outcome measure for Aim 3:  accuracy to 2-back 
 
Secondary outcome measures for Aim 3:  d-prime, reaction time 
 
 
3.0 Study design 
 
The study is a within-subjects design that will expose subjects to three TMS/TBS sessions, with 
each followed by an MRI session. The first MRI session, without TMS, will obtain baseline 

 
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measurements of FPN activation (providing the target for iTBS stimulation – see below), resting 
state connectivity and resting state cerebral perfusion. The subsequent 3 MRI sessions will 
occur in a counterbalanced order, acquiring the same imaging sequence, and following one of 
three iTBS sessions: 1) To dlPFC, without a concurrent task; 2) to vertex, without any 
concurrent task, and 3) To dlPFC, while subjects perform an n-back task. 
 
 
4.0 Study Participants 
 
4.1 Participants inclusion/exclusion criteria   
 
Participants will be healthy individuals, ages 18-50. The upper limit of 50 will reduce variance 
from older subjects, who exhibit less specific activation patterns.(63, 64) We will recruit ~60 
individuals (50% women) to allow for drop-outs and subjects who cannot tolerate TBS, aiming 
for 40 subjects in the final analysis.     
 Inclusion/exclusion criteria: (1) No history of past or current mental illness (except for 
simple phobias), but prior h/o substance dependence OK if in remission for greater than 5 
years; (2) Not taking any medication, prescription or non-prescription, with psychotropic effects 
(birth control medications allowed); (3) No first-degree family members with a history of 
epilepsy; (4) Age 18 –50; (5) If a woman of child bearing age, not pregnant or trying to become 
pregnant; (6) No history of serious neurological illness (including, but not limited to, 
seizures/epilepsy) or current medical condition that could compromise brain function, such as 
liver failure; (7)  No history of closed head injury, e. g. loss of consciousness > ~5 min, 
hospitalization, neurological sequela; (8) Ability to tolerate small, enclosed spaces without 
anxiety;  (9) No family history of epilepsy in first degree relatives; (10) No metals, implants or 
metallic substances within or on the body that might cause adverse effects to the subject in a 
strong magnetic field, or interfere with image acquisition, e. g. aneurysm clips, retained particles 
(e.g. metal workers with exposures), neurostimulators, foil-backed transdermal patches, carotid 
or cerebral stents, CSF shunts; magnetic dental implants, ferromagnetic ocular implants, 
pacemakers, automatic implantable defibrillators; (11)  Size compatible with scanner gantry, e. 
g. men over 6 feet tall that weigh more than 250 lbs, men under 6 feet tall that weigh over 220 
lbs, women over 5’11” tall that weigh more than 220 lbs, or women under 5’10” tall that weigh 
more than 200 lbs.  Subjects of these weights or greater typically have difficult fitting into the 
fMRI scanner properly; (12) Ability and willingness to give informed consent to participate. 
 
4.2 Informed consent  
 
In most cases, potential subjects will learn basic information about the study during in-person or 
telephone screenings conducted by study personnel, and informed consent/assent forms will be 
given, mailed or emailed to those who are eligible for/interested in the study. A meeting with the 

 
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study coordinator will then be scheduled, at which time subjects will be given detailed 
information about the study and provided with an opportunity to enter our mock scanner to 
better understand how participation in an fMRI study “feels”.  During this meeting, the potential 
subject will be encouraged to ask questions about the study, after which the informed consent 
form will be reviewed and signed.  A copy of the document will be given to the study participant 
and the original informed consent document will be kept in a locked cabinet in the principal 
investigator’s laboratory, separate from all other study materials.   
 
4.3 Strategies for recruitment and retention   
 
These subjects will be recruited by community advertisements (flyers, social media campaigns) 
and word of mouth. A website, maintained by the University of Michigan provides a central 
recruitment portal for all subjects in this study (UMHealthResearch.org), although we expect that 
most of the subjects replying to this site will be healthy controls.  Potential study participants go 
to the website and search for protocols in which they can participate.  The website also features 
an email notification system that will let potential participants know when a new study is 
recruiting subjects. 
 
When subjects contact the study team expressing an interest in participation, a pre-
screening interview will occur.  The interview will consist of a description of the study, and if the 
potential participant expresses interest, then pre-screening questions will be administered to 
determine initial eligibility and safety status. Participants will be asked questions from the fMRI 
Safety Screening form and the Transcranial Magnetic Stimulation Adult Safety Screen (TASS) 
(71) to ensure that there are no contraindications. Female subjects will be asked about 
pregnancy or the possibility becoming pregnant during this study. Part of this process may occur 
over email, with appropriate precautions taken to limit email exchange of sensitive information.  
For sensitive information, such as questions about history of mental illness or substance use, 
secure email messaging will be used.  Subjects who pass pre-screening will be invited for a 
screening session.  A waiver of HIPAA authorization for recruitment purposes will also be 
obtained so that medical records might be accessed in the UMHS system to address questions 
around eligibility. Subjects will be given detailed instructions, as well as reminder 
texts/emails/calls (their preference) about upcoming visits.  
 
4.4 Intervention assignment procedures   
 
All subjects will receive all interventions in a cross-over design.  The three intervention sessions 
(visits 3, 4 & 5) will be given in counter-balanced order, stratified by gender. Subjects will be 
blind to the nature of the questions being asked; however, they will be told that different 
stimulation paradigms will be used, which will be evident to the subjects as they go through the 
procedures.  
 
 
5.0 Description of intervention 
 
This mechanistic intervention consists of rTMS, specifically iTBS, which will be delivered 
through a MagPro X100 with MagOption magnetic stimulator and a 90mm statically cooled 
figure-8 coil (MCF-B70, MagVenture Inc.). The MagVenture MagPro TMS system is a class II 
medical device, regulated by the FDA.  Its intended use is for stimulation of peripheral nerves, 
and it has been cleared under FDA 510(K) regulations (K091940). Use in the submitted 
proposal constitutes off-label use of this device. It is not being used as a diagnostic device, and 
it is subject to Investigational Device Exemption regulations.  In consideration of regulations 21 
CFR § 812.3 (m) and 812.20 (a), the device is not a significant risk device, i. e. it is not intended 
as an implant,  not for use in supporting or sustaining human life, not for substantial importance 
in diagnosing, curing, mitigating or treating disease and it does not present a potential for 
serious risk to health or safety of a subject. Therefore, the device qualifies as a non-significant 

 
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risk device, subject to the approval of the local Institutional Review Board, and the investigator 
will comply with the abbreviated IDE requirements, per 21 CFR § 812.2 (b). 
 
6.0 Study Schedule 
Section 6.0 makes repeated references to remote visits, which will be conducted via an 
encrypted, HIPAA-compliant video conferencing platform (e.g., Blue Jeans, Zoom for Health, 
etc.) It will be standard practice to conduct said procedures remotely to better protect 
participants and staff against the risk of COVID-19. However, in cases where a remote visit is 
not possible, in-clinic visits will be allowed and the study will follow all UM safety guidelines for 
entering and being in UM buildings (e.g., COVID screenings, PPE, social distancing, etc.). 
 
Pre-Screening assessment preparations: Participants who screen-in from the phone screen will 
be scheduled for a remote video conference session. They will be emailed a link, given 
instructions about the visit (e.g., how to open the link on their phone or computer), and sent a 
blank copy of the consent to review prior to their session. 
 
6.1 Consenting procedures 
Informed consent will be obtained at the beginning of the remote visit. Electronic informed 
consent signatures will be collected from adult participants using SignNow. All procedures will 
adhere to the IRBMED Guidance for use of SignNow for Electronic Informed Consent 
Procedures. All woman of childbearing age will be given an option for a urine pregnancy test the 
day of the fMRI scan, or they may decline this option and sign a pregnancy attestation form via 
SignNow indicating that they do not believe they could be pregnant. Woman with a positive 
pregnancy test will not be permitted in the study. 
 
If in-person visit required: The day before their scheduled visit, study staff will contact 
participants to administer the COVID pre-screen questionnaire required for entry into the 
Rachel Upjohn Building. If cleared by the screener, participants will be scheduled to 
come to the Rachel Upjohn Building following current COVID protocols. Staff will escort 
them to a private interview room with a laptop or computer where a remote session will 
be established with the study team (in another room). Study staff will return to their office 
and provide all above-mentioned informed consent procedures remotely. All signatures 
will be collected using SignNow. 
 
6.2 Screening assessment visits 
The screening assessment visits will be separated into two parts: Part 1, which can be done 
remotely or as an in-person visit, and Part 2, which will be done in-clinic at the Rachel Upjohn 
Building. 
 
6.2.1 Part 1: Remote or in-person visit 
Screening assessments: The assessment session will include the following: 
1) Acquisition of basic demographic data and medical history. 
2)  M.I.N.I. or SCID-IV (65) to exclude psychiatric illness and substance use disorders. 
o If suicide assessment in M.I.N.I uncovers suicidal plans, intentions, or recent 
behaviors, emergency evaluation will occur, and an appropriate plan of action will 
be followed, e. g. referral to psychiatric emergency room (see supplemental 
suicide protocol). The PI will be contacted and will join the decision-making 
process about how to manage the suicidal thoughts or behaviors. 
3) The reading portion of the Wide-Range Achievement Test (68) to assess general 
educational attainment. 
4) Digit span task (70) to assess executive function. 
5) Beck Depression Inventory II(66) to assess sub-clinical mood symptoms.** 

 
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6) Short Form 12(67) to assess general health status.** 
 
Preparation for MRI scans, mock scanner and task practice: The subject will enter a "mock 
scanner" to practice the task. The mock scanner has a moving table that takes the subject 
inside a large tube, similar to the real MRI scanner.  Study personnel can stay in the room as 
the subject learns and practices the task.  Subjects find the mock scanner less intimidating, 
although the experience familiarizes them with the scanner environment and helps to de-
sensitize them to the actual scanner. 
 
For subjects who complete the screening process, we will provide them with a schedule and 
instructions to set up expectations we have about being in a consistent frame of mind for each 
session. We will counsel participants to abstain from alcohol on the evenings prior to the 
TMS/MRI sessions and obtain a full night of sleep. We will ask them to maintain their usual 
caffeine habits, and not deviate from session-to-session. 
 
This session should take approximately 1 hour. 
 
6.3 Visit 2: Baseline MRI session #1   
Staff and participants will follow the fMRI Lab COVID-19 safety guidelines. 
 
This session will occur at the fMRI laboratory on North Campus. This visit will follow the 
screening session by up to ~2 weeks, depending upon availability of the fMRI and TMS suite. 
During the visit, we will acquire baseline MRI data, including localization data using the n-back 
task. We will also obtain motor threshold in the adjacent TMS suite and give subjects an initial 
exposure to iTBS stimulation to ensure tolerability. 
 
This session should last approximately 2 – 3 hours. 
 
6.3.1 Safety assessment: We will review the subject’s safety screening forms for fMRI and TMS 
to make sure nothing has changed since the initial assessment. We will also record sleep and 
ingestions of psychoactive substances (caffeine, alcohol, nicotine).  We will prepare them for the 
MRI scan, ensuring that they remove all metal from their person (lockers are provided at the 
fMRI laboratory to store personal items such as wallets, cell phones). 
 
6.2.2 MRI Image acquisition: Scanning will be performed at the UM Functional Magnetic 
Resonance Imaging Laboratory (fMRI Lab) on a 3T MR 750 scanner (Waukesha, WI) using a 
32-channel coil.  
When we position a subject in the scanner, head movement will be minimized through: 
(a) instructions to the participant; and (b) packing the head inside the head coil with a system of 
foam padding and pillows that we have found is well-tolerated by the participants, yet limits 
movement.  Extra care will be taken to ensure that the participant’s head is positioned as 
straight as possible since that eases the task of identifying landmarks used in positioning slices 
to be acquired in the fMRI scans. A mirror or MR-compatible goggle system projects the 
computer display output into the bore of the scanner. Stimuli are controlled and responses 
recorded either by E-Prime (PST, Inc., Pittsburgh, PA) or Presentation (Neurobehavioral 
Systems, Albany CA) lab software. Participants will wear a response claw on their hands with 
buttons in order to make button-press responses during cognitive tasks. The stimulus-
presentation and response-collection systems have been tested to ensure that no artifacts are 
introduced and that there has not been an increase in the image-level noise. The goggle system 
may contain an eye tracking camera, which can permit the monitoring and possible analysis of 
eye movements during the scan. In addition, MR-compatible earphones may be used and 
physiological sensors may be attached. These sensors consist of a strain gauge, or strap that 

 
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goes around the torso, to measure respiration, and plastic finger cuff, to measure heart rate by 
plethysmography and CO2 monitor (although latter may not be used if it is redundant with pulse 
oximeter). These non-invasive sensors are FDA-approved components (except for the CO2 
monitor) of the scanner, and the fMRI Center has begun to incorporate the physiological 
information into the acquisition sequences in order to improve image reconstruction. Because 
this is an area of data analysis that remains under development, we may not employ these 
sensors in all scans. Once in the scanner, subjects can communicate via intercom with the 
technician running the scanner in the control room. A window separates the control room from 
scanner room, which is sealed off from the outside by a light vacuum seal. In addition to the 
intercom system, subjects are given a squeeze bulb. They are informed that should they need 
to exit the scanner immediately or gain the attention of the technicians, they can trigger an 
alarm in the control room by squeezing the bulb. 
After localizer scans, subjects will undergo 3 scans: 1)  BOLD-weighted fMRI (EPI, 
TR=800 ms, FOV=23, slice=2.4mm, 96x96 matrix) for the n-back task (8 minutes); 2) BOLD-
weighted resting state scan for 10 minutes to obtain data for functional connectivity analyses 
(eyes open, looking at fixation cross); 3) pseudo-continuous ASL (pCASL) sequence following 
the recommendations of the ISMRM consensus(75). Our pCASL implementation will use a 3D 
stack of spirals acquisition(76) with 6 interleaves (TR=5000 ms, TE=4 ms, BW=125kHz, 
FOV=22 cm) preceded by a 1800 ms labeling period and an 1800 ms delay to allow the label 
spins to clear the arteries and enter the capillary/tissue compartment.   Two hyperbolic secant 
inversion pulses at 600 and 1300 ms after labeling will suppress background signals, after first 2 
frames to permit collection of spin density images for quantification.  We will acquire 20 pCASL 
control-label image pairs, which will be reconstructed to a 128x128 matrix. Since the excitatory 
effects of iTBS have been demonstrated to last up to 60 minutes,(30) data acquisitions will 
occur in the appropriate time frame to capture iTBS effects. The last scan in the sequence will 
be a high-resolution structural scan (SPGR) for image normalization, as well as a T1 scan in the 
same prescription as the BOLD scans to facilitate normalization.   
The scans and acquisition parameters described here are representative of what will be 
employed, although the actual acquisitions may differ slightly. Power-monitoring software on the 
scanner will ensure total energy delivered to the subject will remain within FDA guidelines. 
Specifically, the specific absorption rate (SAR) will be not greater than: 1) 4 W/kg averaged over 
the whole body for any period of 15 minutes; 2) 3 W/kg averaged over the head for any period 
of 10 minutes; 3) 8 W/kg in any gram of tissue in the head or torso; 4) 12 W/kg in any gram of 
tissue in the extremities, for any period of 5 minutes.  
 
6.2.3 Visit 2 TMS session: This session will follow the MRI session for visit 2.  
 
6.2.3.1 Motor threshold: Motor threshold will be obtained to calibrate the intensity of stimulation 
delivered for the TBS TMS sessions.  Motor evoked potentials (MEPs) elicited using biphasic 
posterior-anterior stimulation will be recorded from right first dorsal interosseous (FDI) using 
surface electromyography (Rogue Research, Montreal, Canada). The motor cortical hotspot will 
be defined as the site of stimulation in left motor cortex that elicits the largest, consistent 
response in the FDI with the coil oriented at 45 degrees to the coronal plane.  Active motor 
threshold (AMT) will be obtained as the percentage of stimulator output that elicits an MEP of ≥ 
200 μV peak-to-peak on ten out of twenty trials while the subject is contracting the FDI muscle 
at approximately 20% of their maximum.(77) 
 
6.2.3.2 Trial run of iTBS: In order to see if subjects can tolerate iTBS, we will do a 2-3 minute 
run of iTBS to the dorsolateral prefrontal cortex (approximate location). If a subject cannot 
tolerate iTBS, they will be withdrawn from the protocol (but receive payment for the 2 visits they 
completed). 
 

 
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6.3 Visits 3,4,5, Combined TMS/MRI sessions   
 
These sessions involve the experimental manipulation, using iTBS TMS prior to the MRI 
session, in order to test hypotheses described in the Aims.  These visits will also occur at the 
fMRI laboratory, which houses the TMS suite, across the hall from the MRI magnet.  Each TMS 
session will differ, depending upon how iTBS is delivered and what the subject is doing while 
receiving stimulation. The MRI sessions will be identical.  
 
We will seek to test participants at the same time of day to reduce circadian variability, 
separated by 1 to ~4 days.  We will also work to schedule the 3 sessions in the same week, 
avoiding Monday. Each session will last approximately 2-3 hours.  Below, we describe what 
happens for each of the three visits. 
 
6.3.1 Safety assessment: We will review the subject’s safety screening forms for fMRI and TMS 
to make sure nothing has changed since the prior session. We will also record sleep and 
ingestions of psychoactive substances (caffeine, alcohol, nicotine).  We will prepare them for the 
MRI scan, ensuring that they remove all metal from their person (lockers are provided at the 
fMRI laboratory to store personal items such as wallets, cell phones). 
 
6.3.2 Neuronavigation for TBS sessions: To determine the site for stimulation, we will use 
neuronavigation, with structural and functional information to account for individual variability in 
recruitment of the FPN. BOLD mages acquired from the first MRI session (Visit #2) will be 
analyzed with standard methods to determine the activation of 2-back minus 1-back, and 
aligned with the subject’s high resolution SPGR structural scan.  These data will be transferred 
to the Brainsight Frameless system (Rogue Research, Montreal CA).  For the dlPFC target, we 
will locate the junction of the anterior and middle third of the left middle frontal gyrus (MFG), 
which corresponds to Brodman area 46,(78, 79), and within a zone that is 1/3 the length of the 
MFG, will search for the locus of greatest activation in BOLD activation (2-back minus 1-back, or 
1-back minus 2-back) for each subject, using those coordinates as the site of stimulation. The 
Brainsight system will be used to identify the overlaying scalp position. For the vertex (control) 
target, we will locate the approximate vertex, according to standard 10-20 system, but in a 
region where no BOLD change is detected. 
 
6.3.3 TMS session:  We will deliver iTBS, which has been shown to increase cortical 
excitability,(30) using 3 pulses of stimulation at 50 Hz, repeated every 200 ms, for 2 sec trains, 
repeated every 10 sec, giving a total of 600 pulses in 190 sec. Stimulation will be delivered at 
80% of AMT, which is within consensus recommendations for safety,(80) and used in published 
work.(81)  
 
In counter-balanced order, subjects will receive one of three iTBS sessions on each of 
the 3 days:  1) Vertex stimulation and subjects will be instructed to maintain gaze on a fixation 
screen and rest; 2) dlPFC stimulation (from neuronavigated target described above, subjects 
will be instructed to maintain gaze on a fixation screen and rest; or 3) dlPFC stimulation 
augmented with an n-back task. A computer screen will display an n-back task, using the 2-back 
condition.  Letters will appear for 0.5 sec every 2 seconds, and presentation will be 
synchronized with the iTBS stimulation, which will occur 0.5 sec before the onset of every 5th 
letter. Actual parameters may differ slightly when delivered in the experiment. 
 
6.3.4 MRI session:  MRI sessions will be identical to Visit #2.  The MRI will follow immediately 
after the iTBS TMS session.  
 
 
6.4 Reimbursement of subjects 
 

 
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In order to make participation worth the subjects’ time, they will be reimbursed $20 for the 
assessment sessions and $50 for each MRI/TMS (total $220/subject). We have found that this 
amount provides a good incentive to encourage ongoing participation. 
 
6.5  Participant discontinuation/withdraw 
 
During the pre-screening process, subjects who are found to be non-eligible, before signing the 
consent form, will be considered not enrolled, and all data related to that subject will be 
destroyed.  Subjects who consent, and are found not eligible during the assessment and 
screening will be considered screen failures, and all research and identifying data will be 
destroyed, except for the consent form and limited information to document the screen failure 
(age, gender, diagnosis, specific reason for exclusion). Subjects will receive a subject number at 
the time of consenting. Subjects who pass screening will be considered enrolled. Subjects who 
leave the study after signing the informed consent, and after being deemed 
eligible/enrolled/randomized, will be considered withdrawn. Subjects may withdraw from the 
study at any time and for any reason.  Subjects may be withdrawn by the investigator when 
continued participation would present an unacceptable risk to the subject. Based on previous 
experience, we expect that most subjects will be compliant with the study protocol.   
 
 
7.0 Assessment of Safety and Regulatory Reporting 
 
7.1 Data and Safety Monitoring Plan 
 
7.1.1 Overall framework of monitoring: Study monitoring is conducted to ensure that the rights 
and well-being of trial participants are protected, that the reported trial data are accurate, 
complete, and verifiable, and that the conduct of the trial is in compliance with the currently 
approved protocol/amendment(s), with International Conference on Harmonization Good 
Clinical Practice (ICH GCP), and with applicable regulatory requirement(s) 
 
7.1.2 Roles and responsibilities for regular operations 
 
 
PD/PI: The PI, a board-certified psychiatrist, will meet with study staff on a weekly basis 
to monitor the progress of the study.  During phases when subject recruitment is occurring, the 
PI will review screenings and scheduling of assessments, as well as strategies to improve 
recruitment yield.  Issues around maintaining confidentiality and privacy of participants during 
screening, assessment and data collection will be reviewed. Any protocol deviations and 
adverse events will be reviewed at this weekly meeting.  For serious adverse events, the PI will 
be notified as soon as the SAE comes to the attention of study staff. 
 
 
 Study coordinator/research assistant: This bachelors level individual will carry out the 
screening and informed consent, and they will provide additional study information, all under the 
supervision of the PI.  The individual will be trained in screening, administering consent and 
information to the participants. Questions about eligibility will be discussed with the PI. This 
individual will administer surveys and neuropsychological tests, monitor the participants during 
the procedure and administer the experimental intervention (TMS).  They will receive training in 
the administration of TMS to ensure they can safely operate the device, are aware of potential 
side effects and can execute the seizure protocol if this is necessary.  They will conduct any 
necessary follow-up interviews. 
 
Clinical Assessor:  Screenings will include thorough assessment of psychiatric health by 
a masters-level clinician with experience in administration of psychiatric interviews.  They will 
ensure the absence of any neuropsychiatric conditions in the subjects, as well as health 
conditions that would be a contra-indication to TMS or MRI procedures. 

 
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7.1.3 Frequency and type of other study monitoring: 
 
 
Institutional Review Board monitoring: Approval of all procedures, advertisements and 
materials given to subjects will be secured from the University of Michigan IRBMED.  Annual 
reviews will be conducted by IRBMED, including the number of subjects screened, enrolled and 
withdrawn.  The IRB will also review protocol deviations, adverse events (according to the 
reporting timetable of IRBMED) and complaints that arise in connection with the study. 
 
TMS Safety Committee monitoring: The TMS Safety Committee (see eResearch 
application for composition of group and charter) will review the protocol prior to initiation of the 
first subject.  The committee will receive an initial report after the first 3 subjects, and then semi-
annual reports afterwards. The reports will include a log of all adverse events recorded during 
the study, number of subjects studied, and details of the specific TMS protocols employed.  The 
committee will also review protocol deviations and any unanticipated events reported to the IRB. 
If the committee has concerns about subject safety, these concerns will be conveyed to 
IRBMED.   
 
Data monitoring: Data entry will be audited by study staff, who were not involved in 
primary data entry.   
 
7.1.4 Adverse events arising in the course of participation:  
 
 
7.1.4.1 Adverse Events Review: Monitoring will occur by the clinical study coordinator. 
The coordinator will then bring all possible AEs to the attention of the PI for evaluation, 
gradation and appropriate reporting.  AE’s will be assessed for severity (mild, moderate, 
severe), expectedness (expected, unexpected) and relatedness (definitely related, possibly 
related, unlikely related, not related).  A log of all AE’s will be maintained by the study 
coordinator. 
 
7.1.4.2 Adverse Events Definitions and reporting timetable: A Serious Adverse Event 
(SAE) in this study will be defined as an event that results in death, is life-threatening, requires 
hospitalization or prolongation of existing hospitalization, or results in persistent or significant 
disability or incapacity. The degree of probable relation between study procedures and the SAE 
will be carefully evaluated and documented. 
 
Serious adverse events will be reported to the IRB within 7 days of occurrence (or 
notification) of the event if they are definitely or possibly related to the study interventions and 
unexpected.  If the SAE is expected, it will be reported within 14 days.  For SAEs that are not 
related to the study, reporting will occur at the time of scheduled continuation, or not at all if 
determined to be expected, per standard reporting timetable of the University of Michigan IRB. 
Unexpected adverse events in this study will be defined as any adverse events for which 
the nature and severity are not consistent with expected or anticipated adverse events resulting 
from participation in the protocol.  
 
Adverse events will be assessed as severe, moderate or mild. Moderate is defined as 
any non-serious event which causes discomfort and requires treatment, but does not pose any 
significant or permanent risk or harm to the subject or require in-patient hospitalization, including 
social or psychological trauma causing moderate or temporary distress, significant 
embarrassment, stigmatization of individual or community/ group, disruption of familial/social 
relationships or nontrivial emotional distress or upset.  Moderate AEs will include evaluation in 
the emergency room not leading to hospitalization.  Mild is defined as any non-serious event of 
less than moderate severity.   
 
Moderate and mild AEs that are expected will not be reported to the IRB.  Moderate/mild 
AEs that are unexpected and definitely or possibly related will be reported to the IRB at the time 

 
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of scheduled continuing review.  Moderate AEs that are unexpected and definitely not related 
will not be reported to the IRB. 
 
7.1.5 Quality assurance and quality control for data acquisition 
 
 
Clinical assessments:  Assessors will be trained on assessment instruments and 
established according to laboratory standards and good inter-rater reliability 
 
MRI data:  The fMRI lab maintains weekly schedule of calibration runs to assure 
consistent operation.  Processing pipelines and standard operating procedures are in place 
ensure that data is processed in a uniform manner.  Quality control at each step will be carried 
out by study staff to verify, through multiple metrics, image quality.  Databases will track 
processing steps, in addition to automatically generated log files. 
 
7.1.6 Confidentiality and security of data 
 
 
Confidentiality of data:  Multiple steps are taken to ensure the confidentiality of sensitive 
information.  Subjects are reminded that they do not have to answer questions that make them 
feel uncomfortable, which reinforces the voluntary nature of their participation.  The 
confidentiality of all information gathered directly from subjects or obtained from the patient's 
medical records is assured by assigning records a coded research number and identifying all 
computer and paper files only by this code.  A single tracking file will link the codes with subject 
identifiers, such as name and hospital number.  In addition, consent forms and payment forms 
will be kept in a separate, locked room, apart from research data.  All files will be kept in locked 
file drawers in locked rooms, to which only authorized research personnel have access.  
Electronic records will be kept on secure servers, and records with identifying information will be 
kept separate from records used to collect research data.  Only staff members who have a need 
to know personal identifying information will have access to this information.  All research staff 
are trained in research ethics and HIPAA regulations pertaining to protected health information.  
Screening forms for subjects who do not qualify for the study will be destroyed, except for 
anonymous information unlinkable to the subjects (such as age, gender and education).  After 
the completion of data analysis, the record linking subjects to the research codes will be 
destroyed, thereby anonymizing the data. 
 
7.2 Event Windows, Missed Assessments, Missed Sessions and Protocol Deviation Reporting 
 
Any safety-related assessments (TASS, fMRI screening) which are missed will be reported to 
the IRB as a protocol deviation. For the other assessments, missing assessments will not be 
reported as protocol deviations unless they constitute > 10% of the total assessments. In order 
to accommodate inevitable scheduling conflicts, holidays, etc., study team members will be 
allowed to schedule Motor Threshold (MT) and/or fMRI procedures with discretion as needed.  
 
These deviations are expected to be minor and will not be reported, although they will be 
recorded. These allowances should affect neither the scientific integrity nor the safety 
monitoring provisions of the protocol.  
 
8.0 Statistical analysis 
 
Analyses described below represent planned analyses for primary and secondary measures.  
However, actual implementation of these analyses may differ slightly from what is described 
below, although the primary and secondary outcome measures will be as described. 
 
Specific Aim 1: Localize neural effects of dlPFC iTBS  

 
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Primary outcome measures:  
 
Primary outcome #1, BOLD activation: 2-back minus 1-back BOLD activation, voxelwise  in FPN  
Analysis Plan:  MRI data analysis and strict quality control will use validated and established 
routines implemented in our laboratory. For processing BOLD images, we will use well-tested 
routines from FSL 5.0.1 and SPM12 for slice timing and realignment algorithms and spatial 
normalization (MNI-152) procedures implemented in VBM8. First-level analysis will use the 
general framework of the modified General Linear Model,(82) implemented in SPM12 with 
temporal convolution.  For the n-back data the first-level design matrix will include regressors for 
2-back and 1-back, iTBS/MRI session and 12 realignment parameters (including temporal 
derivatives of 6 realignment parameters). Second-level, between-subject analysis will consist of 
two-sided, one-sample t-tests for primary effects. For statistical inference across the FPN, and 
the entire brain, we will use topological false discovery rate (FDR)(83) providing corrected 
probabilities at p<0.017 (0.05/3, accounting for testing of 3 primary MRI measures). Given a 
priori hypotheses about FPN, a mask of activation (2-back minus 1-back, p<0.001uncorr) at the 
group level, using all 4 MRI runs to provide the most representative mask, will be used as small 
volume correction.  
 
(H1.1):  iTBS to dlPFC, compared to vertex stimulation, will increase fMRI activation in the FPN 
during the n-back.  To examine the effect of iTBS on FPN, we will directly contrast the MRI 
session following dlPFC stimulation with the session following vertex stimulation, with subjects 
in an unconstrained, resting state for both conditions. (2-back minus 1-back contrast, voxelwise 
analysis in SVC-corrected FPN mask).  We are using two-sided tests, because unpredicted 
results have been described in the literature, where inhibitory cTBS has resulted in increased 
perfusion,(42) and increased connectivity,(44) and excitatory 5 Hz TMS to dlPFC demonstrated 
reduced BOLD activation.(84) For a secondary measure to test H1.1, we will examine whole 
brain activation, since change may occur outside this region of interest. For example, dlPFC 
stimulation has been observed to induce changes in a limbic anterior-cingulate network.(85)   
Exploratory analysis:  We will conduct exploratory analyses with a generalized psychophysical 
interaction (gPPI). To test for interaction between task and session, we will extract the time-
course at the site of stimulation, deconvolve it with the canonical hemodynamic response 
function (HRF), and then generate an interaction regressor (task X time-course) which is tested 
(after-reconvolution with HRF) across the entire brain.(86) gPPI tests for changes in the slope of 
connectivity coefficients with task, so it reflects how task modulates connectivity. Testing for 
effects of iTBS will test for a modulation of this modulation. Statistical correction will use 
topological false discovery rate (FDR)(83), at p <0.05, corrected for whole brain search.  
 
Primary outcome measure #2, BOLD connectivity: FPN connectivity to dlPFC iTBS stimulation 
target 
Analysis Plan: Data processing of fMRI BOLD resting scans will begin with standard pre-
processing steps.  All scans will be slice-time corrected and realigned (FSL 5.0.9) to the 10th 
image acquired during a scanning session.(87)  Subsequent processing will be performed with 
the Statistical Parametric Mapping SPM8 package (R4667; Wellcome Institute of Cognitive 
Neurology, London).  Anatomic segmentation will be performed with the VBM8 toolbox in SPM8, 
using the high resolution SPGR T1 image, subsequently normalized to an MNI template using 
DARTEL.  Normalizing warps to the MNI152 template are applied to the co-registered functional 
volumes, which are re-sliced and smoothed with an 8 mm isotropic Gaussian smoothing kernel. 
To assess and manage movement, we will calculate the frame-wise displacement (FD (88)) 
from the translation and rotation parameters from the realignment file, which is the sum (in 
millimeters) of the absolute values of frame displacement, i.e. successive 3D volumes, for all 6 
parameters of rotation and translation.  Rotational displacements are converted from degrees to 
millimeters moved on the surface of a 50 mm sphere.  We use a ‘scrubbing routine’ to censor 

 
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any frame with FD > 0.5 mm from the regression analysis described below, yielding a scrub 
ratio for each subject.  As it has been demonstrated that as many as 60% of frames can be 
removed and still yield analyzable results,(88, 89) we will use 60% deleted frames as a cutoff for 
analyzable subjects.  Three-compartment segmentation of the high-resolution structural image 
from the VBM8 normalization will be applied to the functional time series to extract cerebral 
spinal volume (CSF) and white matter (WM) compartments, which will be subjected to a 
principal component analysis to identify the top 5 components in each,(90) which corresponds 
to heart rate and respiratory effects on the blood oxygenation level-dependent signal.(91) 
Adjusted time courses will be derived from sequential regressions of the time series with the 
following:  Linear trend, 6 motion parameters, their temporal derivatives, the quadratics of these 
12 parameters, 5 components from the PCA of CSF, 5 components of PCA of WM, followed by 
band pass filtering from 0.01 – 0.1 Hz, and then motion scrubbing. ICA-AROMA will be used to 
de-noise the data and remove additional, residual motion artifacts.(92) Global signal regression 
(GSR) will not done because of concerns about non-uniform transformation of correlations 
introduced by GSR, problematic for group comparisons.(93) For the primary analysis, the time-
course from a 6 mm radius sphere at the site of stimulation will be entered into the multiple 
regression and correlated with every other gray-matter voxel time-course in the brain for each 
subject. Correlation coefficients are Z-transformed and then entered into the second level, 
between-subject analyses as two-sided, paired t-tests to compare between sessions.  Statistical 
inference will be controlled as above. 
 
(H1.2) iTBS to dlPFC, compared to vertex stimulation, will increase FPN connectivity during 
resting state BOLD. Because TMS effects are observed away from the site of stimulation,(38-
41) we are testing functionally-defined FPN networks.  We recognize that the FPN defined by n-
back will not be identical to the FPN defined by a dlPFC seed-based connectivity, although the 
two significantly overlap. 
 
Exploratory analysis, global brain connectivity: We will examine a graph-theoretic measures 
known as global brain connectivity (GBC).(94)  GBC reflects the strength of local connectivity, 
similar to degree connectivity, except that no arbitrary thresholding of connections (‘edges’) is 
required; rather, the value of the connection strength (r-to-Z transformed) is summed.  GBC in 
the dlPFC has been shown to decrease with electro-convulsive therapy, with the degree of 
change related to symptom improvement;(95) thus, we will test to see if iTBS to the dlPFC has 
an effect on GBC in the dlPFC. Two types of analyses will be conducted.  In the first, we will 
average the connectivity for the 6 mm radius sphere at the site of stimulation and compare that 
for dlPFC stimulation and vertex stimulation. Alpha level will be p<0.05, two-sided.  In the 
second analysis, we will search for network effects. Time courses will be extracted from 10 mm 
diameter spheres based on a set of 264 nodes distributed throughout the brain,(96) generating 
a cross-correlation matrix of Pearson r-values. Z-transformed r-values (connectivity strengths) 
for each of the 264 nodes with every other node (global brain connectivity) are summed, and 
connectivity strengths with the nodes within 13 specified networks are also summed.  
Connectivity measures (13 per subject) will then be entered into second level repeated 
measures ANCOVA, with gender as between factor, network and session (dlPFC, vertex) as 
within-factors, and meanFD and age as a co-variates, testing the hypothesis of change in GBC 
by network.  We will also test exploratory effects across all 13 networks (with alpha level set to 
0.05/13=0.0038), and we will test for effects on GBC (connectivity between all nodes). 
 
 
 
Primary outcome measure #3, rCBF at stimulation target 
Analysis plan: The pCASL images will be realigned using SPM12 realignment routines and 
denoised using compCor(90) and then used to calculate the perfusion rate at each voxel using a 

 
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two-compartment model, assuming gray matter T1 of 1400 ms. and 90% labeling efficiency. 
ROI analysis of the CBF images will occur in native space, using the FPN mask derived from n-
back activation, warped to individual anatomy. A two-sided, paired t-test will test for effect of 
sessions, with p<0.017 as alpha.  Secondary analyses will be performed on 6 cm radius sphere 
at the site of stimulation, in addition to a whole brain, voxel-wise search for changes in gray-
matter tissue, using topological FDR to correct for multiple comparisons to p<0.017corr. 
 
(H1.3) iTBS to dlPFC, compared to vertex stimulation, will increase resting perfusion at the site 
of stimulation.  PET studies of high frequency TMS have reported increased CBF at the 
dlPFC,(97) a finding which motivates our hypothesis here.  However, a cTBS study by our co-
investigator (T.L.) also found increased CBF after supposedly inhibitory stimulation of 
dlPFC,(98) so we will be performing a two-tailed t-test here. While the primary analysis will 
focus on the site of stimulation, a secondary analysis will focus on the FPN network, defined by 
the n-back task. 
Exploratory analysis, amplitude of low frequency fluctuations (ALFF): ALFF, and fractional ALFF 
(fALFF), measures the magnitude of low frequency BOLD fluctuations, generally from 0.01 to 
0.1 Hz.(99) fALFF measures the fractional strength (relative to the full spectrum) of BOLD 
fluctuations.   ALFF is correlated with CBF,(100, 101) so this measure provides an alternative to 
supplement the pCASL analysis. This is a potentially important measure for brain stimulation, as 
fALFF/ALFF abnormalities have been reported in psychiatric disorders,(102-104) and fALFF in 
the subgenual cingulate gyrus has been shown to predict response to electroconvulsive 
therapy.(105) This analysis will use the BOLD resting data as above, except that frame 
censoring (scrubbing) will not be performed, since censoring can affect the frequencies in a run 
of BOLD-acquired MRI data. Each voxel’s BOLD time series will be transformed into the 
frequency domain and the mean amplitude of the spectrum over the frequency range of 0.01–
0.1 Hz will determine ALFF. fALFF for two bands (slow-4; 0.027-0.073 Hz; and slow-5, 0.01-
0.027 Hz) will be calculated as the magnitude for that band over the magnitude of the full 
spectrum. This analysis will focus on the 10 mm diameter sphere under the site of stimulation. 
Alpha level for this analysis will be set at 0.017 (0.05/3), two-tailed. 
Exploratory analyses, between measures: Exploratory analyses will also test for correlations 
between the three MRI measures, to provide a richer picture of iTBS effects.  Lastly, we 
recognize that vertex stimulation, here being used as a control condition for dlPFC stimulation, 
may have some effects on brain networks, although it was selected to avoid the FPN. With 
some caveats (effect of order, since baseline is not counter-balanced), we can use baseline 
measures from the first MRI session (no preceding TMS session), to see if iTBS differences 
represent a change in the dlPFC-stimulated condition or the vertex-stimulated condition.  An 
additional exploratory analysis will compare stimulation over the ‘activated target’ (2-back minus 
1-back) versus the ‘deactivated target’ (1-back minus 2-back), based on how the target was 
selected. 
 
Specific Aim 2: Demonstrate modulation of the effect of dlPFC iTBS by a cognitive task  
Primary outcome measures:  
To examine state-dependency and modulation of iTBS effects by task, we will contrast MRI 
measures following iTBS applied to the dlPFC while subjects perform the n-back with MRI 
measures following iTBS compared to when they are in an unconstrained, resting state. The 
general analysis plan will use the same work-up of the imaging data as described above, the 
only difference being the MRI sessions that are compared with each other.  Although directions 
of change are difficult to predict, we are predicting increasing activity as has been reported for 
iTBS applied during a deep encoding memory paradigm and not observed during shallow-
encoding.(106)  However, it is possible that cortex may become more efficient and less 
activation may be seen. The following primary hypotheses will be tested: 
 

 
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Primary outcome #1, BOLD activation: 2-back minus 1-back BOLD activation, voxelwise in FPN  
 (H2.1) For dlPFC stimulation during performance of a n-back task, compared to dlPFC 
stimulation in a resting, unconstrained mental state, FPN activation to the n-back task will be 
greater.  For this analysis, the region of interest will be the FPN taken from the activation mask, 
as described above. For a secondary measure to test H2.1, we will examine whole brain 
activation, since change may occur outside this region of interest. 
 
Primary outcome measure #2, BOLD connectivity: FPN connectivity to dlPFC iTBS stimulation 
target 
(H2.2) For dlPFC stimulation during performance of a n-back task, compared to dlPFC 
stimulation in a resting, unconstrained mental state, connectivity with the dlPFC site of 
stimulation will increase.  For this analysis, the region of primary interest will be connectivity to 
site of stimulation. 
 
Primary outcome measure #3, rCBF at stimulation target 
(H2.3) For dlPFC stimulation during performance of a n-back task, compared to dlPFC 
stimulation in a resting, unconstrained mental state, resting perfusion at stimulation site will 
increase.  The primary region of interest will be the site of stimulation, and secondary analyses 
will focus on the FPN, defined by n-back activation.   
 
Specific Aim 3: Demonstrate improvement in cognitive control with iTBS, modulated by 
cognitive task during stimulation   
 
Primary outcome measure: accuracy to 2-back 
Analysis plan: For analysis of n-back performance, our primary performance measure will be 
accuracy to the 2-back condition. Secondary measures will be d-prime, to capture the sensitivity 
to the target and not bias to respond, and median reaction time. Although we found significant 
effects on d-prime for our list learning paradigm, that memory task was very different from the 
more demanding n-back, which requires updating and manipulation in short-term storage, while 
our list learning task involved only incidental memory. For each measure, we will conduct a 
repeated measures ANCOVA, with the performance measure across the three iTBS conditions 
as the repeated measure, and sex as a fixed, between-subject factor and age as a co-variate. 
Post-hoc, paired t-tests will used for specific contrasts. 
 
(H3.1) 2-back accuracy will be greater for dlPFC stimulation (no task during iTBS) relative to 
vertex stimulation  
(H3.2) 2-back accuracy will be greater for dlPFC stimulation applied while subjects carry out an 
n-back during iTBS stimulation during stimulation, compared to when they receive stimulation 
alone.  The same hypotheses will be applied to d-prime, our secondary measure. Two-sided 
tests will be used, because it is also possible that performance may worsen, either with 
stimulation alone, or when combined with subjects performing the n-back. It would be critical to 
know, for example, that performance of a cognitive control task was degraded by combining 
TMS with a task. Although a commercial device is being tested on dementia patients, relying on 
the assumption that the combination is beneficial,(18)  we are not aware of this assumption 
being tested as we propose to do here.  
Exploratory analyses around performance correlations:  In addition to testing questions about 
performance, we will also examine correlations between performance and the MRI measures 
from Aims 1 and 2, testing important questions around mechanism. Since we will systematically 
test for correlations between both performance measures and the three primary measures from 
each aim (18 correlations), alpha will be set at 0.05/18 = 0.0028. 
 
9.0 Ethics and Protectionn of Human Subjects 

 
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9.1 Ethical Standard and IRB Review  
 
The investigator will ensure that this study is conducted in full conformity with the principles set 
forth in The Belmont Report: Ethical Principles and Guidelines for the Protection of Human 
Subjects of Research, as drafted by the US National Commission for the Protection of Human 
Subjects of Biomedical and Behavioral Research (April 18, 1979) and codified in 45 CFR Part 
46 and/or the ICH E6; 62 Federal Regulations 25691 (1997) and the Declaration of Helsinki and 
Good Clinical Practice (GCP). 
All protocol amendments must be IRB approved prior to implementing, except when 
change is for patient safety. 
 
9.2 Subject Confidentiality 
 
Study staff will make every effort to limit identifiable information on potential subjects during 
recruitment. The minimum amount of information will be recorded, and staff are alerted to the 
dangers of printing, faxing and emailing sensitive information.  Phone conversations with 
potential research subjects will occur behind closed doors, and staff will ask callers if they are in 
a location where sensitive information can be discussed without danger of revealing confidential 
information.  Any information gathered on subjects who prove ineligible will be destroyed as 
soon as possible (a list of patients who have declined or screened out will be maintained 
through the recruitment phase in order to avoid contacting these subjects again). 
 
9.3 Potential Risks and Minimization of Risks 
 
9.3.1 Potential Risks 
 
9.3.1.1 Issues around confidentially and the disclosure of sensitive information:  
Subjects will grant the experimenters access to protected health information.  
They will also reveal sensitive information about themselves, which will include their 
psychiatric status and any history of substance abuse.  Subjects may feel uncomfortable 
revealing this information, and there is a risk of losing confidentiality. Subjects will also 
be informed in the consent document that confidentiality will be limited in cases where 
the subject reveals intentions to harm themselves or others, and the investigator feels 
that the proper authorities may need to be notified in order to prevent the occurrence of 
harm to the subject, or others. 
 
9.3.1.2 The risks associated with the MRI study are:   
1) A minor risk of discomfort or anxiety from being in the confined space of the 
MRI scanner.  
2) Fast imaging sequences, such as those employed in this study, have the 
potential to induce peripheral nerve stimulation (PNS).  PNS can be described as a light 
touching sensation on the skin surface and may cause mild discomfort but is not harmful 
to the subject.  
3) Risks of hearing damage due to loud noises produced by the scanner.  
4) Risk that the magnetic resonance image will reveal a minor or significant 
lesion in the brain, e. g. a tumor, previously unknown to the subject, and requiring 
additional follow-up. 
5) Risk of injury from objects accelerated by the strong magnetic field of the 
magnet, striking the subject; or metallic substances on the skin or foreign bodies 
implanted deliberately or accidentally in the subject that acquire kinetic or thermal 

 
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energy from the magnetic or radiofrequency emissions of the MRI, causing tissue injury 
to the subject.   
6) Sometimes, subjects report a temporary, slight dizziness or light-headedness 
when they come out of the scanner. 
7) Potential risk for pregnant women:  According to the NIMH Council Workgroup 
on MRI research and Practices (September, 2005), “there is no known risk of MR brain 
scanning of a pregnant woman to the developing fetus for scanning at 4T or less, and no 
known mechanism of potential risks under normal operating procedures.”  Nevertheless, 
subjects should be warned about potential risks, not yet discovered. 
 
 
9.3.1.3 The risks associated with TMS: 
1) Local scalp pain near stimulation site (common, not serious): Activation of 
muscles and nerves near the site of stimulation can cause substantial pain and 
discomfort, depending on the intensity and frequency of stimulation.  
2) Headache or neck pain (common, not serious): Headache and neck pain, 
typically lasting up to a few hours on the day of stimulation, are the most frequent side 
effects of TMS.  
3) Sound exposure (rare, serious): When producing a magnetic pulse train, the 
stimulating coil produces a series of brief clicks. No evidence of hearing loss has been 
found in humans exposed to TMS, despite extensive exposure to repeated stimulations 
over several years. 
4) Risk of Seizure Induction (rare, serious): The major safety concern about TMS 
is the possibility of eliciting a seizure, although TMS has rarely been associated with the 
induction of seizure, even in patients with epilepsy. For example, a recent international 
consensus conference rated the risk of seizure inductions during low-frequency rTMS as 
“rare, and usually protective.”  Thus, seizure risk, while not zero, is so low as to be 
difficult to estimate.  Even with rTMS therapy for depression, patients are routinely 
treated on psychotropic medications, and the risk of seizure induction is estimated at 
1/30,000 treatments.(7) 
5) Syncope (rare, not serious):  In the setting of altered sensory stimulation, 
subjects occasionally experience brief loss of consciousness, usually attributable to 
vasovagal syncope. 
6) For women of child-bearing potential: It is unknown if TMS can pose a risk to 
fetuses.  
 
9.3.2 Protections Against Risk 
 
9.3.2.1 Confidentiality of data:   
Multiple steps are taken to ensure the confidentiality of sensitive information.  
Subjects are reminded that they do not have to answer questions that make them feel 
uncomfortable, which reinforces the voluntary nature of their participation.  The 
confidentiality of all information gathered directly from subjects or obtained from the 
patient's medical records is assured by assigning records a coded research number and 
identifying all computer and paper files only by this code.  A single tracking file will link 
the codes with subject identifiers, such as name and hospital number.  In addition, 
consent forms and payment forms will be kept in a separate, locked room, apart from 
research data.  All files will be kept in locked file drawers in locked rooms, to which only 
authorized research personnel have access.  Electronic records will be kept on secure 
servers, and records with identifying information will be kept separate from records used 
to collect research data.  Only staff members who have a need to know personal 
identifying information will have access to this information.  All research staff are trained 
in research ethics and HIPAA regulations pertaining to protected health information.  
Screening forms for subjects who do not qualify for the study will be destroyed, except 

 
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for anonymous information unlinkable to the subjects (such as age, gender and 
education).  After the completion of data analysis, the record linking subjects to the 
research codes will be destroyed, thereby anonymizing the data. 
 
 
9.3.2.2 Risks from MRI scanning:   
 
1) The risk of discomfort and anxiety will be minimized by custom pads and 
pillows to make the subject as comfortable as possible. The subject is allowed to 
communicate with the machine operator via an intercom and may trigger an audible 
alarm at any time.  Before the subject rolls into the bore of the magnetic, he or she is 
always reminded that they are free to stop the study at any time if they become 
uncomfortable.  If they were to experience an anxiety reaction, the study would be 
halted, and the participant would receive immediate counseling from staff, with option to 
meet with the P.I. or another study psychiatrist.  Participants find that once outside of the 
scanner, they experience immediate relief of any anxiety and discomfort. If the study 
team has any doubts about relief of anxiety, follow-up telephone calls would be made 
later that day or 1-3 days after the session to confirm the transient nature of their 
reaction. 
2)  The MRI machine is operated within FDA guidelines so the potential for 
inducing PNS is low. 
3)  All subjects are required to wear foam earplugs to reduce the risk of hearing 
damage.  
4)  In the event of anomalous finding on MRI, the PI would contact the subject 
and explain that the subject should contact their primary care provider to obtain a clinical 
MRI scan.  A protocol for managing incidental findings has been developed, and it 
includes the following: 
 
I. 
Discovery of a finding: Incidental findings that arise in the course of 
assessment, such as an abnormal finding in the MRI, will be brought to the 
immediate attention of the PI.   
II. 
Gathering additional information: The PI will review the finding and seek 
consultation with a neuroradiologist who consults for the fMRI laboratory.  
III. 
Informing the subject: If the PI is available while the subject is being scanned 
and can assess the finding and make a determination about informing the 
subject, that will be done immediately.  If the PI is not available for a face-to-
face meeting with the subject, study staff are instructed to complete as much 
of the protocol as is reasonable, without revealing the existence of an 
anomaly.  The intention here is to control the circumstances by which the 
subject is informed of the anomaly, making sure that the PI (a board certified 
psychiatrist) is the person who talks to the subject, can answer questions and 
gauge the emotional reaction of the subject to the news.  The subject will be 
informed by the PI, personally, either through a phone call or a face-to-face 
meeting.  While a face-to-face meeting is preferred, this may not be 
immediately convenient for the subject, and the PI must weigh the relative 
benefits of the more personal setting versus anxiety engendered by 
anticipating a meeting to discuss something the subject did not expect to 
hear. 
IV. 
Informing the subject’s health care provider: Arrangements will be made to 
provide a summary of the finding to the subject’s personal physician, with the 
patient’s permission.  The information conveyed will recommend that a follow-
up, clinical MRI be obtained to evaluate the incidental finding. 
V. 
Informing the local IRB: The incidental finding will be reported to the IRB.    
 

 
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5)  The MRI suite is kept clear of all objects that could be picked up by the 
magnetic field.  MRI personnel are trained in safety procedures, which include training 
around the materials that cannot be brought into the scanner room.  The technician 
administering the scan is also trained to review each subject’s MRI safety form to assess 
their suitability to enter the MR environment.  Subjects are screened at multiple points.  
An initial phone screening is done, in which the MRI is explained, and subjects are 
excluded from participation if they have contraindications to an MRI scan.  On the day of 
the scan, the subject completes an MRI safety screening form, which is reviewed by 
study personnel and reviewed by the MRI technician.  Subjects are prompted at two 
points to remove all metallic objects from their person, soon after the subject arrives at 
the MRI center.  They are given instructions to empty their pockets, remove jewelry, 
watches, wallets, and shown a storage box where belongings can be safely stored.  
Immediately before entering the scanner room, they are prompted again, to ensure that 
they have removed any items that might interfere with the san or interact with the 
magnetic field. 
6)   To minimize risks from nausea, subjects are carefully eased out of the 
scanner, and a technician guides the subject from the scanner bed, counseling them to 
rise slowly, ensuring they have adequate balance. 
7)  Subjects are informed that pregnancy, or the intention to become pregnant, 
are contra-indications to receiving a research MRI scan.  At the initial phone screening, 
female subjects are asked about pregnancy or the possibility of pregnancy.  When the 
subject is consented for the study, language in the informed consent document mentions 
this exclusion, again.  All woman of child bearing age will be given an option for a urine 
pregnancy test the day of the fMRI scan, or they may decline this option and sign a form 
indicating that they do not believe they could be pregnant.   Woman with a positive 
pregnancy test will not be permitted to continue in the study.  
 
 
 
 
9.3.2.3 Risks associated with TMS 
 
1) Local scalp pain near stimulation site (common, not serious):  The first step 
will be slight coil rotations (< 10 degrees), which often reduce stimulation-related pain. If 
this does not work, the coil will be moved slightly or the stimulation magnitude will be 
turned down. 
2) Headache or neck pain (common, not serious): These side effects are usually 
managed well with standard analgesics (e.g., single doses of aspirin, acetaminophen, or 
ibuprofen). Subjects will be instructed to contact the investigators if the headache 
persists on the following day. 
3) Sound exposure (rare, serious): Earplugs will be used in this study in all 
subjects as a precautionary measure.  
4) Risk of Seizure Induction (rare, serious): For all studies, the parameters used 
will fall within the safety parameters established at the International Workshop on the 
Safety of Repetitive Transcranial Magnetic Stimulation from 2009 and updated in 
2009,(107) as well as the safety guidelines for TMS protocols that are not repetitive in 
nature (e.g., single pulse studies). Oberman et al(80) reviewed the available TBS 
literature to date. Out of over 1,000 participants, there was only 1 incidence of seizure 
reported. This incidence occurred after 50 trains (10 seconds) of TBS to the primary 
motor cortex at an intensity of 100% of resting motor threshold. Therefore, all TBS 
procedures used will stimulate at an intensity less than this level. While TBS does use a 
high frequency of stimulation, it is for a much shorter period of time than other types of 
TMS (typically 40 s for cTBS, 190 s for iTBS, versus 20 minutes of 1 Hz rTMS).  In 
experimental protocols, stimulation will be delivered at no greater than 80% of active 

 
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motor threshold.   Maximal frequency of stimulation will be the standard 3 pulses 
delivered at 50 Hz bursts.  Inter-train interval will be no less than 10 sec. 
In the event of a seizure, subjects would receive counseling about the low 
likelihood of a recurrent seizure. Mindful of the potential consequences of a report of a 
seizure in a medical record for a subject's insurability, driving, etc, medical 
documentation will include full details about the provoked nature of the seizure in an 
experimental protocol. Subjects will be informed of this possibility in the consent 
process, in addition to the possibility that a subsequent workup could reveal an 
increased risk of seizures.  
 
In addition. the following steps will be taken: 
 
Subject Screening: Rigorous screening of subject participants will be done to 
exclude individuals with an increased risk of developing a seizure. 
 
Training of all individuals who administer TMS: All personnel involved in TMS 
sessions will be familiar with the safety guidelines and with the seizure 
protocol. 
 
Seizure protocol: A seizure protocol will be posted in a visible location in the 
room where TMS will be delivered. The seizure protocol is as follows: 
 
Protect from injury: Pull back coil apparatus, tilt chair back to flatten. 
Protect head and body from injury using padding. Move any objects out of 
range that could potentially cause injury. Place a small folded blanket or 
other cushioning under the head if it is moving violently. Loosen any zips/ 
buttons close to the neck (e.g., jackets). If possible, turn subject on 
his/her side to prevent aspiration. 
 
ABC’s: (airway, breathing, circulation): Maintain a clear airway (head tilt, 
chin lift). Assess cardiorespiratory function (breathing and pulse). 
 
Activate EMS (Emergency Medical Services): Call Huron Valley 
Ambulance – 994-4111. If breathing and pulse are present, state, 
“Medical emergency at [location, building name and number].” If breathing 
and/or pulse are absent, state, “Cardiac arrest at [location, building name 
and number]”.  
 
Record time and duration of seizure. 
 
Do not: restrict movement, insert of force objects into the mouth. 
 
After the seizure: Maintain a clear airway: Subject to rest on his/her side 
to prevent aspiration. Help to reorient the subject: provide reassurance. 
Remain with the subject 1:1 until fully oriented and stable. Check vital 
signs. Have the subject transported to the Emergency Department for 
assessment. 
 
Documentation: When the subject is stabilized, document the following: 
Incident preceeding the seizure (stimulation parameters, duration of 
stimulation). Description of seizure (parts of the body involved in the 
seizure, types of movement, time, and duration of seizure). Medical 

 
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personnel notified and time. Treatment given or emergency measures 
taken. Any injury incurred during the seizure. Subject’s clinical status 
post-seizure. 
 
5)  Syncope:  Subjects are encouraged to be well-hydrated in advance of the 
sessions.  During breaks and upon completion of the protocol, they are advised to rise 
slowly from the chair and observed carefully for any signs of fading consciousness. 
6) For women of child-bearing potential: Participants are asked during their 
screening whether they are pregnant or are trying to become pregnant and are not 
enrolled in the study if they are. Sexually-active women of child-bearing potential will be 
asked to use a reliable birth control method for the duration of this study. 
 
 
9.4 Potential Benefits and Justification of Risk 
 
There are no direct benefits for the participants in this research. However, the proposed 
experiments should reveal important information about how TMS interacts with the brain, and 
this information may be used to design new or improve existing TMS treatments, which may 
benefit individuals suffering from neuropsychiatric disorders. The proposal will test the broad 
hypothesis that when TMS is applied to a brain in a controlled mental state, network changes 
induced by TMS will be facilitated, compared to stimulation when mental state is uncontrolled. 
Results from this study will be used to optimize TMS therapy for depression and other 
neuropsychiatric disorders by controlling mental state to improve the efficacy of TMS treatment. 
 
 
10.0  Data Handling and Record Keeping 
 
10.1 Data handling 
The investigator is responsible to ensure the accuracy, completeness, legibility, and timeliness 
of the data reported.  All source documents will be completed in a neat, legible manner to 
ensure accurate interpretation of data.  Dark ink is required to ensure clarity of reproduced 
copies.  When making changes or corrections, the original entry will be crossed with a single 
line, and initial and date the change.  For some assessments, subjects may enter information 
directly onto a computer, rather than a paper form.  Only research ID numbers will link these 
data with the subjects, and data will be stored in encrypted form on password-protected, secure 
computers.  Systems that are only used to collect data, such as laptop or tablet computers, will 
also have research files securely deleted after upload to the central database. 
Research data will be maintained on password protected computers, on a secure linux 
cluster maintained in the Psychiatry Affective Neuroimaging Laboratory (PANLab) or on secure 
UMHS-administered servers.   Backup procedures include RAID drives with mirroring, and off-
site backup. 
Recruitment tracking files are kept only for the duration of recruitment.  Paper records 
are kept in locked file drawers in a locked room, to which only authorized research personnel 
have access. Paper records with identifying information (consent form, payment records) are 
kept in locked file cabinets, physically separate from the research records. Computer records 
with identifying information are kept on secure, password protected servers.  Electronic 
databases will be used to store the coded data, and the key linking to identifiable subject 
information will be kept separate from the database with research data.  
 
10.2 Plans to destroy links between research data and subjects.   
 

 
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At the point where additional data collection becomes unlikely, the identifying links between 
subject identity and the research data will be destroyed. 
 
10.3 Data Sharing   
 
The value of this research is significantly enhanced by making the data available for the widest 
possible use, and because of the rapidly changing world of data analysis, it is impossible to 
predict what future research will do with data collected for any particular project in the present.  
By keeping the data indefinitely, it will become available for projects, yet to be determined.  
These include projects run by the investigators, as well as those outside the institution through 
data sharing plans or central repositories.  The NIMH, which funds this study, requires that data 
be uploaded into the NIMH Data Archive (NDA), which is a requirement of receiving funding.       
When data are transferred to co-investigators and data repositories, de-identification will be 
performed, removing all HIPAA identifiers from the files.  To prevent reconstruction of facial 
likenesses from structural image datasets, we will blur/obscure/strip the information from the 
MRI image around the face. 
Subjects will be informed in the consent document that the data will be stored and that it 
may be shared with other investigators, both at the University and outside the University, 
through central databanks.  The risk posed to subjects will be very, very small.  Storing the data 
for an indefinite amount of time will follow strict protocols, outlined above, that will ensure the 
safety of the data and minimize the risk of accidental disclosure.  Data that is shared or 
uploaded to central databanks will be de-identified and will be effectively anonymized, since 
investigators using these central databases will not have access to the keys linking individual 
subjects to the data.  Furthermore, no data will be shared without an agreement by stewards of 
the central databank to require data use agreements and prevent investigators from even 
attempting to identify subjects.  It is extremely unlikely that an investigator would even be able 
identify subjects from shared data, without already having access to a subject's identifiers.   
 
 
 

 
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