Functional Connectivity as a Biomarker of rTMS
Phase: PHASE1
Conditions: Traumatic Brain Injury
Sponsor: National Institute of Neurological Disorders and Stroke (NINDS)

CNS IRB Protocol Template (12.15.15 rev2)
Protocol Title: Functional connectivity as a biomarker of rTMS
Abbreviated Title: rTMS / functional connectivity
Protocol Number: 17-N-0055
Date of This Submission/Version:  November 13, 2019/ Version H
Principal Investigator: Eric Wassermann, MD
Behavioral Neurology Unit
National Institute of Neurological Disorders and Stroke
Building 10, Rm 7D41
9000 Rockville Pike
Bethesda, MD 20892
Phone: 301-496-0151
E-mail: wassermanne@ninds.gov
Human Research Protections Program Investigator and Staff Training:
For this protocol, the following “Just in time” human subjects protection training courses 
are required for investigators and staff:
•
CITI GCP modules
•
Unanticipated Problems and Reporting Requirements in Biomedical Research
Total requested accrual: 101 
101 Healthy Volunteers 
 
Project Uses Ionizing Radiation: 
x No 
□ Yes 
IND/IDE
x No 
□Yes 
Durable Power of Attorney 
x No 
□ Yes 
Multi-institutional Project
x No 
□ Yes
 
Data and Safety Monitoring Board  x No 
□Yes 
Technology Transfer Agreement 
x No 
□ Yes 
Samples are being stored 
x No  
□ Yes 
Flesch-Kincaid reading level of consent form: 8 (for HVs)

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PRÉCIS
Objective: To use resting state functional connectivity (FC) as a biomarker of synaptic 
modulation by repetitive transcranial magnetic stimulation (rTMS) in paradigms intended 
to improve memory and learning.  Ancillary outcomes include the effects of rTMS on the 
interaction between the explicit implicit memory systems.  
 
Study population: Healthy adult volunteers 
Design: The study contains two experiments.  Experiment 1 is designed to establish the 
number of rTMS sessions required to produce a meaningful change in resting parieto-
hippocampal FC in healthy subjects.  Experiment 2 will replicate a prior experiment 
which used rTMS to enhance the explicit memory system in healthy subjects, and look 
for potential effects on the implicit system.  This intervention will be contrasted with a 
negative control condition (vertex stimulation) in a between-groups design.  
Outcome measures: The primary outcome measures are the change in FC produced by 
serially applied rTMS and improvement in explicit memory.  We will explore whether 
enhancement of the explicit system has effects on resting state connectivity in the implicit 
system and whether white matter integrity predicts changes in FC in healthy subjects.  

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Table of Contents
List of Abbreviations
8
1.
Introduction and Background
9
a. Background
9
b. Functional Connectivity as a stable biomarker
10
c. Dose finding using continual reassessment method (CRM)
11
d. Examining the effect of rTMS stimulation on implicit and explicit 
memory systems
12
e. Restoring connections in patients with TBI
12
f. Measuring mentation during resting-state scans.
13
2.
Study Objectives and hypotheses
13
a. Aims
13
b. Hypotheses
14
i.
Primary Hypotheses
14
ii. Secondary hypotheses
14
Experiment 2:
14
3.
Subjects
14
a. Description of study populations
14
b. Inclusion criteria
14
c. Exclusion criteria
15
4.
Study Design and Methods
16
a. Study overview
16
b. Recruitment
16
i.
Healthy Volunteers
16
ii. Patients with TBI
17
c. Screening
17
d. Study procedures
18
i.
Behavioral tasks
18
vii. Experiment 1
21
viii. Experiment 2
24
viiii.  Experiment 3
25
x. Duration of Study
26
e. End of Participation
26
5.
Management of Data and Samples
27
ii. Data and Sample Sharing Plan
27
6.
Additional Considerations
28
a. Research with investigational drugs or devices
28
b. Gene therapy
28
7.
Risks and Discomforts
28
a. General
28
b. Study Procedures
28
i.
Behavioral measures
28
ii. MRI
28
iii. TMS
29
c. Procedures to Minimize Risk
29
i.
Behavioral measures
29

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ii. MRI
29
iii. TMS
29
8.
Subject Safety Monitoring
30
9.
Outcome Measures
30
a. Primary outcome measures
30
b. Secondary outcome measures
30
c. Exploratory outcome measures
30
10. Statistical Analysis
31
a. Analysis of data/study outcomes
31
i.
Experiment 1
31
ii. Experiment 2
32
b. Power analysis
34
11. Human Subjects Protection
35
a. Subject selection
35
b. Justification for exclusion of subjects
35
i.
Justification for exclusion of children
35
ii. Justification for exclusion of subjects above the age of 50
35
iii. Justification for the exclusion of non-English speakers/readers
35
iv. Justification for participants who have already participated in Experiment 1.
36
Because the persistence of the rTMS effect is unknown, participants from Experiment 1 
will not be invited to participate in Experiment 2.
36
c. Justification for the Exclusion of other Vulnerable Subjects
36
i.
Persons without consent capacity
36
ii. Women who are Pregnant, Plan to Become Pregnant, or are Breast-feeding
36
d. Justification of sensitive procedures
36
e. Safeguards for vulnerable populations
36
i.
Safeguard of vulnerable subjects (NIH employees)
36
f. Qualifications of investigators
36
12. Anticipated Benefit
38
14. Consent Documents and Process
39
a. Designation of Those Obtaining Consent
39
b. Consent Procedures
39
c. Consent Documents
39
15. Data and Safety Monitoring
39
16. Quality Assurance (QA)
40
a. Quality assurance monitor
40
b. Quality assurance plan
40
17. Reporting of Unanticipated Problems, Adverse Events and Protocol Deviations40
18. Alternatives to Participation
41
19. Privacy
41
20. Confidentiality
41
a. For research data and investigator medical records
41
b. For medical records
42

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21. Conflict of Interest
42
a. Distribution of NIH Guidelines
42
b. Conflict of Interests
42
c. Role of a Commercial Company or Sponsor
42
22. Technology Transfer
42
23. Research and Travel Compensation
42
a. Healthy Volunteers (HVs)
42
b. Patients with TBI
43
24. References
44
25. Attachments/ Appendices
47
a. Appendix A: Pre-screening Questions
47
i.
Healthy Volunteers
47
ii. Patients with TBI
47
b. Appendix B: Inclusion/Exclusion Checklist
48
TBI Patients
48
Inclusion criteria
48
Exclusion Criteria
48
Healthy Volunteers
48
Inclusion criteria
48
Exclusion Criteria
48
c. Appendix C: Timeline of Study
50
d. Appendix D: Assessment of Capacity to Provide Informed Consent / 
Surrogate Consent
53
e. Appendix E: Capacity assessment tool questions and scoring
54
f. Appendix F: Amsterdam Resting-State Questionnaire (ARSQ)
55
g. Appendix G : Timeline figures
57
26. Consent Forms
59

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List of Abbreviations 
rTMS
Repetitive Transcranial Magnetic Stimulation
fMRI
functional Magnetic Resonance Imaging
FC
Functional Connectivity
WPT-I
Weather Prediction Task Implicit Version
AMT
Associative Memory Task
DTI
Diffusion Tensor Imaging
FA
Fractional Anisotropy
ARSQ
Amsterdam Resting-State Questionnaire

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1. Introduction and Background
Justification for non-significant risk (NSR) designation for conventional TMS studies 
within published guidelines and theta-burst rTMS at up to MEP threshold intensity
21CFR812.2 SR states that a significant device
1. is intended as an implant and presents a potential for serious risk to the health, 
safety, or welfare of a subject
TMS is not an implantable device.
2. is purported or represented to be for a use in supporting or sustaining human life 
and presents a potential for serious risk to the health, safety, or welfare of a 
subject
TMS is not for use in supporting or sustaining human life. It does not present a 
potential for serious risk to the health, safety, or welfare of participants when 
used as described in this protocol.
3. is for a use of substantial importance in diagnosing, curing, mitigating, or 
treating disease, or otherwise preventing impairment of human health and 
presents a potential for serious risk to the health, safety, or welfare of a subject
TMS, as used under this protocol is not of substantial importance in diagnosing, 
curing, mitigating, or treating disease, or otherwise preventing impairment of 
human health and does not present a potential for serious risk to the health, safety 
or welfare of a subject.
4.  otherwise presents a potential for serious risk to the health, safety or welfare of a 
subject
TMS and its repetitive form, rTMS have been in use for over three decades and 
have been cleared by the FDA for treatment of several disorders.  Safety 
guidelines have been developed (Wassermann, 1998) and updated (Rossi, 
Hallett, Rossini, & Pascual-Leone, 2009) allowing its dissemination to a wide 
range of clinical and non-clinical settings.  For example, brief, self-limited, 
seizures were seen in early studies, before limits were established for 
combinations of delivery parameters.  However, this risk has been reduced to the 
order of one in every 40,000 sessions, including for paradigms (theta-burst 
stimulation) not included in the guidelines (Lerner, Wassermann, & Tamir, 
2019).  In the past 20 years, the FDA has generally waived pre-IDE inquiries for 
TMS/rTMS studies on an NSR device basis. Hence, the CNS IRB, like most US 
IRBs, has accepted NSR designation for TMS/rTMS studies within these 
limitations.  
Description of device

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No device is specified in this protocol. TMS is delivered using standard, commercially 
available, equipment and guided with a frameless stereotaxic system similar to that used 
for neurosurgical procedures. TMS devices are cleared by the FDA for a range of 
applications including deep nerve stimulation and the treatment of psychiatric disorders.
Reports of prior investigations with device
The use of TMS/rTMS for investigational and therapeutic purposes was pioneered in 
NINDS laboratories, work which has resulted in over 1,000 publications. Worldwide, it is 
in use in hundreds of laboratories. See references for relevant safety literature.
Investigational plan
The objective of this study is to use resting state functional connectivity (FC) as a 
biomarker of synaptic modulation by repetitive transcranial magnetic stimulation (rTMS) 
in paradigms intended to improve memory and learning. Ancillary outcomes include the 
effects of rTMS on the interaction between the explicit implicit memory systems.  
The study contains two experiments.  Experiment 1 is designed to establish the number of 
rTMS sessions required to produce a meaningful change in resting parieto-hippocampal 
FC in healthy subjects.  Experiment 2 will replicate a prior experiment which used rTMS 
to enhance the explicit memory system in healthy subjects, and look for potential effects 
on the implicit system. This intervention will be contrasted with a negative control 
condition (vertex stimulation) in a between-groups design.  
a. Background
Repetitive transcranial magnetic stimulation (rTMS) has been attempted as a treatment 
for cognitive deficits in a variety of disorders (Bonnì, Mastropasqua, Bozzali, 
Caltagirone, & Koch, 2013; Pachalska, Lukowicz, Kropotov, Herman-Sucharsaka, & 
Talar, 2011; Pape, et al., 2009).  Two assumptions underlie nearly all such studies.  The 
first of these is the notion that rTMS exerts its effects by increasing the excitability of 
local neurons.  This came from classical observations on the effects of rTMS on MEP 
amplitude (the motor evoked potential), which increased after high frequency (Pascual-
Leone, Valls-Solé, Wassermann, & Hallett, 1994) and decreased after low frequency 
(Chen, et al., 1997) stimulation.  This phenomenon was likely mediated by changes in 
synapses on neurons located in the motor cortex (M1) at or near the stimulated site.  Later 
attempts to influence other brain areas have generally assumed and relied on local effects 
and it is frequently observed that rTMS is only effective at modulating activity in 
superficially located areas within reach of the stimulating current.  The other, related, 
assumption is that stimulation has been actually delivered effectively to the target region 
or network simply because the stimulating coil was placed in its vicinity.  This premise 
often appears tautologically in post-hoc, mechanistic explanations of behavioral 
outcomes.  
If rTMS were a drug, preclinical evidence of “target engagement” would be expected 
before interventional trials.  For better or worse, however, the field of noninvasive brain 
stimulation has generally skipped this step.  While jumping directly to clinical outcomes 

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may have saved time, reliable biomarkers could have been helpful by providing surrogate 
endpoints and better mechanistic understanding.  The absence of biomarkers or similar 
surrogate endpoints has also made the dosing parameter space difficult to explore 
efficiently, since this would have to rely on behavioral endpoints in most cases.  In this 
context, it is notable that, despite intensive research, the field has delivered only one 
widely adopted use whose several delivery parameters have never been optimized.  
Biomarkers of target engagement or surrogate endpoints with less variability than 
behavioral outcomes might have avoided some of the blind alleys.  
Wang et al. (2014) have provided a paradigm, which may prove useful in solving these 
and other problems for noninvasive brain stimulation in the clinical domain.  As a way to 
target the hippocampus, a deep structure beyond the reach of TMS, they used a 
conventional functional magnetic resonance imaging (fMRI) measurement, functional 
connectivity (FC), to find an individually customized, upstream cortical target, connected 
by a known monosynaptic pathway from the parietal cortex to the hippocampus.  By 
individualizing the stimulation site using fMRI, Wang and colleagues eliminated the 
effect of inter-individual differences in anatomy, which can impact the results of a 
stimulation intervention (Karabanov, Chao, Paine, & Hallett, 2012).   By applying rTMS 
repeatedly to this target, they caused an increase in memory performance and a correlated 
change in FC between the stimulated area and the area of interest deep in the brain.  
Incidentally, rTMS also caused dramatically increased connectivity in a network of sites 
related to visual memory and outside the stimulated pathway.  Their work suggested that 
FC could be used as a marker of target engagement for noninvasive brain stimulation 
studies and, possibly, as an endpoint in clinical trials.  
This protocol is an attempt to use FC as an endpoint, first in a dose finding study aimed at 
determining the number of rTMS sessions required to produce a meaningful degree of 
modulation in the pathway studied by Wang et al., then in an experiment involving a 
different pathway, and finally in a clinical trial in amnestic TBI patients.  
This study is sponsored by the Center for Neuroscience and Regenerative Medicine 
(CNRM). To address the profound issues related to the diagnosis and treatment of TBI, 
the United States Congress, through Public Law 110–252, established the CNRM as a 
collaborative intramural program in May 2008. The CNRM is a collaborative intramural 
federal program involving the United States Department of Defense (DoD), the 
Uniformed Services University of Health Sciences (USUHS), and the National Institutes 
of Health (NIH) joining clinicians and scientists across disciplines to catalyze innovative 
approaches to TBI research. 
b. Functional Connectivity as a stable biomarker
Functional connectivity is stable across scanning sessions within individuals (Barch, et 
al., 2013; Finn, et al., 2015).  Data from 126 participants collected from the Human 
Connectome Project (Van Essen, et al., 2013) were used to demonstrate that participants’ 
pattern of resting state functional activity can be reliably identified amongst sets of 
participants and across days (Finn, et al., 2015).  For example, Finn and colleagues 
(2015) demonstrated that a machine classifier can identify whole brain patterns of resting 

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state functional connectivity across resting sessions with a success rate of at least 92.9% 
(see Figure 1).  High test-retest reliability has been found in several studies (Biswal, et 
al., 2010; Shehzad, et al., 2009; Zuo, et al., 2010; Zuo, et al., 2010) and the temporal and 
spatial measures of resting-state networks are stable across years (Choe, et al., 2015).  
Thus, we are confident that FC is stable enough to use as a biomarker for the effects of 
rTMS in serial test sessions.   
Figure 1.  Results from Finn et al. (2015).  Correct identification scores for machine classifier (y-axis) 
across eight different networks (x-axis) for FC patterns pulled from R1 and compared to the second session 
(R1; black bars) and for patterns pulled from the second session and compared to the first session (R2; gray 
bars).  1 = Medial  Frontal, 2 = Frontoparietal, 3 = Default Mode,  4 = Subcortical-Cerebellum, 5 = Motor, 
6 =  Visual 1, 7 = Visual 2, 8 = Visual Association
c.
Dose finding using continual reassessment method (CRM)
Wang and colleagues arbitrarily chose to deliver five sessions of rTMS.  However, there 
are no empirical data on the duration of rTMS required to induce meaningful synaptic 
changes.  Therefore, we will focus on the number of sessions as our rTMS parameter of 
interest while using the same stimulation parameters (e.g. frequency, intensity, duration) 
as Wang et al. (2014).  We are choosing to focus on optimizing the number of sessions, 
rather than the other delivery parameters, because only one parameter can be explored at 
a time and reducing the number of sessions will have the greatest effect on the feasibility 
of this and future studies.     
To find the minimum number of rTMS sessions required to produce a change in FC 
equivalent to that found by Wang et al., we will employ the continual reassessment 
method (CRM), a Bayesian, adaptive design, used to determine the dosing in Phase I 
drug trials.  It is felt to be more efficient and accurate than simple dose escalation studies 
at estimating target drug doses (Garrett-Mayer, 2006).   The parameter usually 
determined by this method is the minimum dosage expected to produce toxicity, or 
maximum tolerated dose (MTD).  In this case, the MTD corresponds to the minimum 
number of sessions expected to produce the criterion change in FC.  The logistical 

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function relating dose and effect and the MTD—the level where some predetermined 
proportion of subjects’ experience “toxicity”— is initially assumed from prior knowledge 
and then adjusted dynamically, based on response data from small cohorts of subjects 
dosed at successively higher or lower levels as the MTD is approximated.  Cohorts are 
run iteratively until either a pre-specified number of participants is run, or another 
stopping rule has been reached (see statistical analysis section).    
d. Examining the effect of rTMS stimulation on implicit and explicit 
memory systems 
Learning and memory rely on two primary systems, an “implicit” system, which supports 
learning by practice and experience under feedback conditions and an “explicit” system, 
which supports the storage of conscious knowledge.  Implicit memory relies on parallel 
cortical-basal ganglia loops, which operate under the modulatory influence of 
catecholaminergic projections from the midbrain.  The explicit system resides in the 
hippocampus, amygdala, and related areas.  These systems may be in some degree of 
competition (Ashby & Maddox, 2011; Ashby & Maddox, 2005; Packard & Knowlton, 
2002; Poldrack & Packard, 2003).  As noted above, Wang et al. (2014) targeted the 
hippocampus and used a test of the explicit memory system as a behavioral outcome.  
In our second experiment, we will use rTMS to increase connectivity in pathways an 
explicit memory task.  We will target the parieto-hippocampal pathway, as Wang et al. 
(2014) did.  We hypothesize that FC will increase only in the targeted pathways and that 
there will be a parallel dissociation in the effects on implicit and explicit memory.  This 
will confirm our overall hypothesis that pathways involved in specific cognitive 
processes can be targeted selectively.  We will also include a negative control condition 
(vertex stimulation) to control for sensory and other nonspecific effects of rTMS.
e.
Measuring mentation during resting-state scans.
Recent work has revealed that mentation patterns during resting state scanning correlates 
with functional connectivity measurements (Gregory et al., 2016).  Because differences in 
mentation between participants are difficult to control and could potentially explain our 
results, we have decided to include a measure of mentation (the Amsterdam Resting-State 
Questionnaire) as an exploratory measure to our protocol (see Appendix F).  
f.
Targeting the implicit learning system
The original version of this protocol included a dorsolateral prefrontal stimulation arm, 
the purpose of which was to attempt to enhance connectivity in the implicit learning 
system via fronto-striatal pathways. However, this proved infeasible, due to subject 
discomfort. This protocol now concentrates on the effects of parietal stimulation on FC 
and implicit and explicit learning.
g. Enhancing hippocampal network FC in TBI patients

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We originally planned to pilot the paradigm for explicit memory system enhancement in 
amnestic TBI patients.  This plan has been dropped because of time and resource 
constraints.
2. Study Objectives and hypotheses
The overall objective of this study is to determine whether functional connectivity can be 
used as a biomarker of rTMS synaptic modulation.  The experiments outlined in this 
protocol will not be used to demonstrate the clinical effects of rTMS.  
a. Aims
Experiment 1
Specific Aim 1: To determine the number of rTMS sessions required to produce a 
substantial change in FC between the parietal cortex and hippocampus in healthy 
subjects.
Experiment 2
Specific Aim 2: To determine whether rTMS delivered to the parietal cortex 
increases parietal-hippocampal FC in healthy subjects.
Specific Aim 3:  To measure the effect of parietal rTMS on AMT and  WPT-I, 
performance.  
Specific Aim 4:  To evaluate the relationship between fMRI connectivity and 
AMT and WPT-I outcomes after parietal rTMS in healthy subjects.
b. Hypotheses
i.
Primary Hypotheses
Experiment 2: rTMS of the left parietal cortex will increase FC between the left 
parietal cortex and the hippocampus compared to rTMS of the vertex. rTMS of 
the left parietal cortex will significantly increase explicit memory compared to 
rTMS of the vertex.
ii. Secondary hypotheses: 
 Experiment 2: rTMS of the left parietal cortex will decrease FC between the left 
caudate (head) and parietal cortex compared to rTMS of the vertex. rTMS of the 
left parietal cortex will significantly decrease implicit memory compared to rTMS 
of the vertex.

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3. Subjects
a. Description of study populations 
We will study 50 healthy individuals (Experiment 1: 18; Experiment 2: 32).  We are 
requesting up to 101 healthy volunteers as the accrual ceiling to account for dropouts and 
screening failures. 
b. Inclusion criteria
Healthy individuals in Experiments 1 and 2.
•
Age 18-50 (inclusive)
•
English speaking and writing
c.
Exclusion criteria
•
Any current major neurological or psychiatric disorder such as (but not limited to) 
stroke, Parkinson disease, Alzheimer disease, schizophrenia or major depression
•
History of seizure
•
Medications acting on the central nervous system
•
Ferromagnetic metal in the cranial cavity or eye, implanted neural stimulator, 
cochlear implant, or ocular foreign body
•
Implanted cardiac pacemaker or auto-defibrillator or pump
•
Non-removable body piercing
•
Claustrophobia
•
Inability to lie supine for 1 hour
•
Pregnancy, nursing, or plans to become pregnant during the study.
•
Members of the NINDS Behavioral Neurology Unit (BNU)
•
For Experiment 2: Participation in Experiment 1
Eligibility Checklist: See Appendix B. 
4. Study Design and Methods
a. Study overview 
This study will include 2 experiments, each using rTMS and MRI. Experiment 1 will use 
parietal rTMS.  Experiment 2 will involve parietal and vertex rTMS.  Experiments 2 will 
have the same learning and memory testing.  
Experiment 1 will require a maximum of 8 visits (contingent on the results of Experiment 
1) and a maximum time commitment of about 13 hours.

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Experiment 2 will require a maximum of 8 visits (contingent on the results of Experiment 
1) and a maximum time commitment of about 15 hours.
b. Recruitment 
Healthy participants will be recruited from the pool of individuals self-referring to the 
study directly and via the NIH Clinical Research Volunteer Program. Although NIH 
employees will be allowed to participate, no direct solicitation of employees/staff by 
supervisors or co-workers will take place.  All recruitment material will be IRB 
approved.  Participants who indicate interest will be pre-screened over the phone.  Pre-
screening questions will include the following questions (Appendix A):
Are you between 18 and 50 years of age?
Are you in good health?
Are you taking any medications?
Are you prone to seizures, stroke, or migraines?
Are you free of a history of significant neurological or psychiatric conditions?
Are you free of any metal in your body?
Are you comfortable doing a one-hour MRI?
Are you able to visit the lab for up to 8 visits in a two-week period, and up to 7 
visits in a week?  
Participants will not be invited to participate in more than one Experiment for this 
protocol.  Thus, participants in Experiment 1 will not be invited to participate in 
Experiment 2.  
It is likely that some participants will miss some sessions.  If this occurs, and the 
participant is still willing to participate, we will reschedule.  If the subject has already 
received rTMS, we will wait at least 30 days to reschedule the session so that the effects 
of stimulation wash out.  If a participant misses a session after baseline measures have 
been collected, baseline measurements will be performed again (e.g. MRI, behavioral 
assessments).  
The study is requesting a waiver of consent documentation to conduct phone pre-
screening on potential subjects prior signing main research consent to verify eligibility.
c.
Screening
Participants who pass initial screening will be invited to participate in the study and 
scheduled for consent and formal screening.  
Upon arrival to the screening appointment, written, informed consent will be obtained by 
an investigator and formal screening will be done according to Appendix B. 

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Volunteers who have not had a neurological exam from an NINDS provider within the 
past two years will receive a neurological examination from an NINDS physician or 
nurse practitioner.  This will not replace any exam the participant will receive for 
purposes of medical care; the exam will be for research purposes only.  All women of 
child-bearing potential will have a urine pregnancy test (not earlier than 24 hours) before 
each MRI scan.  
d. Study procedures
i.
Behavioral tasks
Weather Prediction Task (Implicit version; WPT-I) - This is a test of the ability to learn 
an implicit, stochastic, association by trial and error and recruits a brain network 
including the dorsolateral prefrontal cortex and the head of the caudate nucleus, primarily 
in the right hemisphere.  In the WPT, participants learn to predict a binary outcome, 
based on arbitrary stimuli with a hidden statistical link to that outcome.  One, two, or 
three-card combinations of four possible cards are presented on a computer and the 
subject is asked to predict the “weather;” i.e. whether it will be rainy or fine.  After each 
prediction, the subject receives corrective feedback.  Each card is independently 
associated with one outcome with a fixed probability.  For example, the probability of 
rainy might be 0.2 for squares, 0.4 for diamonds, 0.6 for circles, and 0.8 for triangles.  
We will use three different versions of the task at the three test sessions (see below).  The 
task has 150 trials, with breaks after every 50 trials and takes approximately 17 minutes. 
Associative Memory Task (AMT) – This is a test of the ability to learn and remember 
explicit associations between unrelated stimuli and involves the hippocampus and related 
visual processing areas.  Participants are shown 20 face-name combinations (study phase) 
and are instructed to encode as many of these combinations as possible.  Memory of the 
combinations is immediately assessed afterwards (test phase) by showing participants 
each individual face and asking them to recall the associated word.  As with the WPT, we 
will use three different versions of the task at the three test sessions.  The task takes 
approximately 10 minutes.  
ii. MRI
1. MRI Anatomical scanning
All subjects will have anatomical (MPRAGE) scans before and after rTMS and diffusion 
tensor imaging at the beginning of the study. Participants who have not had one in the 
past year will receive a standard clinical MRI scan of the head, which will be submitted 
to the Diagnostic Radiology Department CC for interpretation.  Depending on the 
requirement for a clinical scan, this phase will take 10-30 min.  
2. Resting State Functional Connectivity
During scanning, participants will be instructed to lie motionless with open eyes fixated 
on a cross that is presented on a screen visible through a mirror attached to the MR head 
coil (approximately 20 min). 

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We estimate a maximum of 3 hours for the first scan in all experiments, and one hour for 
subsequent scans.  Because scanner malfunctions and subsequent loss of data are 
common we will not report these as unexpected problems at the time of occurrence, but 
only at the time of continuing review.  Subjects whose data are lost due to scanner 
malfunctions will be rescheduled, if possible.
MRI and its use in this research will be used per its FDA approved indication and 
specified parameters.
iii. rTMS
In all experiments, rTMS will be delivered at 100% of the motor evoked potential 
threshold and 20 Hz in trains lasting 2 s for 20 min with 28 second rests in-between trains 
(similar to Wang et al., 2014).   If subjects are uncomfortable at 100% stimulation, the 
investigators will lower the stimulation by 5% increments up to 10% total decrease of 
stimulation. If subject is not comfortable at a 10% decrease, they will be withdrawn from 
the study.
The parietal target in all experiments will be the region of the left, lateral parietal area 
with the greatest connectivity with the left hippocampus derived from the baseline resting 
state fMRI session, as located using the targeting coordinates of Wang et al.  
As a negative control, identical rTMS will be delivered at the vertex in Experiments 2 
and 3.  We justify the use of vertex stimulation as a control over sham stimulation as 
follows.  A major criticism of sham procedures in rTMS neuromodulation studies is that 
conventional sham techniques do not reproduce the sensation of real rTMS on the scalp.  
This confound is so significant that basic validity of crossover designs has fallen into 
serious question.  It is the consensus in the community that a more rigorous and 
scientifically valid procedure is to use real rTMS over a scalp site that is not thought to be 
part of the targeted network.  This also serves as a control for nonspecific neural effects 
of the stimulation on the brain and further restricts the possibility of spurious or 
misinterpreted positive results (Sandrini et al., 2011; Ziemann et al., 2008).  
Importantly, our paradigm is based on that of Wang and colleagues (2014) who used off-
target stimulation as a control condition and found no significant effects on connectivity 
of behavior.  Using an inactive sham that failed to replicate the sensory effects of rTMS 
would invalidate our study as a replication and lead to other questions about the source of 
any effects of active stimulation on connectivity or behavior.
rTMS targets will be marked in the participant’s anatomical MRI volume and located 
with a frameless stereotaxic system.  If any experiment, for any reason, fails to produce useful 
individual targets, a literature-based location for the parietal cortex (Wang, et al., 2014) 
will be used as our location of stimulation.  In each experiment, rTMS will only delivered 
to the target in one hemisphere.  To reduce the influence of diurnal variations in the 
responsiveness to neuroplasticity protocols (Sale, Ridding, & Nordstrom, 2008), we will 
make every effort to test subjects during the same time of day.

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To allow participants the opportunity to experience rTMS at the parietal site and decide 
about continued participation, we will give them a “sample” before the first rTMS 
session.  We will then ask the participant if they wish to continue the study.
For all experiments, FC and explicit/implicit memory will be measured within a week 
before the first rTMS session and immediately after the last rTMS session.  Memory 
testing will be performed again 7-10 days after the last rTMS session.  Experiment 1, 
however, will include no memory testing.  
For all experiments rTMS and its use in this research will be used per its FDA approved 
indication and specified parameters.
iv. Cognitive Battery
All behavioral testing including the memory tests described above will take 
approximately three hours.  Experiment 2 will include a 75-minute computerized battery 
that will be administered in parallel with pre- and post-stimulation assessments.  The 
purpose of the battery is to detect effects on cognitive processes other than those targeted 
in the study.  The data will be treated as exploratory.  The battery includes the following 
tests: 
1) Flanker Inhibitory Control and Attention Test (executive function and attention) - 
Participants respond to the direction of a target arrow while inhibiting attention to 
arrows flanking the target arrow (~3 minutes).
2) the Dimensional Change Card Sort Test (executive function and set-shifting) – 
Participants must match pictures based on one of two rules.  These rules are transposed 
and participants’ set-shifting abilities are measured by their accuracy and reaction time 
(~4 minutes).
3) the List Sorting Working Memory Test (for working memory) – Participants are given 
two lists of items (e.g. animals and foods) and are asked to list the items in size order.  
The task requires the participant to concurrently remember the items while sorting (< 10 
minutes).
4) the Picture Sequence Memory Test (for story sequence memory) – Participants are 
given a list of objects and must remember the order of these objects in relation to each 
other.  For example, if object A is listed in position X, the participant must recall what 
object is in position X+1 (~7 minutes).
5) the Oral Reading Recognition Test (for language) – The participant is asked to read 
individual words and the researcher records whether the word is read correctly (~3 
minutes).  
6) the Picture Vocabulary Test (for language) – Participants are aurally presented with a 
word and must match that word with one of four pictures that best represents the meaning 
of the word.  The number of correct responses is recorded (~4 minutes).  

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7)  the Pattern Comparison Processing Speed Test (for processing speed) – Participants 
are presented with two pictures and must determine whether they are the same or 
different.  The number of correct responses in 90 seconds is recorded (~3 minutes).  
8) the Georgia Complex Figures task (for visual memory) – Participants are asked to 
copy a complex drawing, and reproduce it from memory after a 20-minute delay.  The 
number of successful elements of the complex figure are recorded (~ 5 minutes without 
delay).  
9) the Category Fluency test (for category fluency) – Participants are given a category 
(e.g. animals, tools) and are asked to name as many category members in 60 seconds as 
possible (~ 2 minutes).  
10) a verbal paired associates test (for verbal memory) – This test is similar to the AMT, 
but instead of new items used at each time point, the same pairs are retested at the end of 
the week of stimulation (~ 5 minutes).  
11) the Everyday Memory Questionnaire (EMQ) (a subjective memory assessment) – 
Participants are asked 13 questions to assess their impression of their memory function.  
For each question, participants rate how often a particular memory problem has occurred, 
e.g. not being able to recall a word, having to check something that has already been done 
(~ 3 minutes).  
12) Neuro-QOL forms: Depression, Fatigue, Sleep Disturbance, Cognition-General, 
Cognition-Executive (a subjective mental health assessment)– Participants report 
outcome measures through computer adaptive tests (CAT), short forms, or scales.  (~ 20 
minutes).
v. Amsterdam Resting-State Questionnaire
The ARSQ will be administered immediately after each resting-state scan and includes 50 
questions related to patterns of mentation that could occur during resting-state scanning 
(see Appendix F).  For each question, the participant is asked whether they agree or 
disagree with a statement related to their thoughts in the scanner.  This questionnaire 
generally takes < 8 minutes to complete.  
vii. Experiment 1 (Completed)
Experiment 1 will study only healthy volunteers.  During the first day of experimentation, 
all participants will have an initial scanning session where anatomical, resting-state, and 
DTI images will be collected.  This will be followed by 1-5 days of rTMS (20-minutes 
per day).  Participants may schedule the first MRI session, and the first session of rTMS 
anytime within two days.  On the day after the last rTMS session (within 12-36 hours), a 
final anatomical and resting-state-scan will be collected.  Immediately following each 

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resting-state scan, we will administer the ASRQ.  In this experiment, all participants will 
experience the same procedures, with the exception of the number of days where rTMS is 
administered (see Figure 2).  
The search for the optimal number (1-5) of rTMS sessions will be performed using a 
continual reassessment method (CRM) design (O'Quigley, Pepe, & Fisher, 1990) (see  
Statistical Analysis section, below).
Participants will be run in cohorts of 3 (5 cohorts, for a total of 15 participants). Each 
cohort’s FC results will be submitted to the CRM analysis, which will indicate how many 
rTMS sessions the next group will receive.  For example, if Cohort 1 experiences a large 
increase in FC after 3 rTMS sessions (e.g. if the change is above the optimal cutoff 
point), the CRM will likely recommend a drop in the number of sessions for the next 
cohort.  In this case, the CRM may recommend reducing the next cohort’s sessions by 1 
or 2.  Alternatively, if a slight or no increase in FC is observed, the CRM will likely 
increase the number of sessions by 0, 1 or 2.   
This procedure will be repeated until one of two stopping rules is achieved: 1) 15 
participants have been tested, or 2) The CRM has recommended the same dose as the 
previous cohort 3 times in a row (see Figure 3).  The first cohort will receive 3 sessions 
of rTMS.  If the CRM does not reveal clear results by the end of data collection (15 
subjects), we will default to 5 sessions of rTMS for Experiment 2.  

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Figure 2.  Procedures for Experiment 1.   Time are estimates.
Figure 3.  Flowchart of cohorts in Experiment 1.  The experiment begins with an initial cohort at dose level 
3 (3 sessions of rTMS).  When a stopping rule has been met, the final MTD is determined from the CRM.  

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FC will be measured before and after each course of rTMS and we will obtain an 
anatomical scan in the first session.  A timeline of each experiment is provided in 
Appendix C.
viii. Experiment 2
Experiment 2 will use a between-subjects design (see Figure 4) to study healthy 
volunteers.  All participants will have an initial scanning session on the first day of the 
study where anatomical, resting-state, and DTI images will be collected.  This will be 
followed by 1-5 days of rTMS (20-minutes per day).  The number of days of rTMS will 
be derived from the results of Experiment 1.  On the day after the last rTMS session 
(within 12-36 hours), a final anatomical and resting-state-scan will be collected.  
Immediately following each resting-state scan, we will administer the ASRQ. All 
participants will experience the same procedures, with the exception of the location of 
stimulation.  Depending on group assignment, the participant will either receive 
stimulation to the parietal cortex, or vertex.  
Contrary to Experiment 1, Experiment 2 will include behavioral testing at 3 different time 
points: 1) after the initial scanning session, 2) after the final scanning session, and 3) 
about a week after the last scanning session.  This will include memory testing using the 
WPT-I and AMT, as well as the cognitive battery described above.  
Subjects will be assigned to two groups (parietal and vertex), which will be balanced by 
age and sex.  We will blind volunteers to stimulation type (group assignment) by 
recruiting participant who are naïve to the study hypothesis.  Investigators scoring FC and 
behavioral data will be kept blind to rTMS assignment.  
Figure 4.  Procedures for Experiment 2.    Times are estimates.
viiii. Duration of Study 

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Participation for healthy participants in Experiments 1 and 2 will be no more than 8 
visits.  
e.
End of Participation
Volunteers will remain under the care of their own providers.  No care will be offered to 
those participating in this protocol, except for any acute care required for adverse events.  
Findings of clinical significance, e.g., significant pathology on MRI will be shared with 
participants and any provider whom they designate.  
5. Management of Data and Samples
i.
Storage
The results of testing will be stored on password-protected computers or backed up on 
media stored in locked cabinets. Keys to participant identity will be stored in lab 
notebooks, available only to study investigators. Samples will not be stored under this 
protocol. 
ii. Data and Sample Sharing Plan
This protocol is not subject to the Genomic Data Sharing (GDS) policy. The data will be 
shared at the time of publication, in response to a specific request to the PI. All data will 
be shared with the CNRM data repository and the Federal Interagency Traumatic Brain 
Injury Research (FITBIR) Informatics System upon study completion.  Also, data may 
also be shared with collaborating laboratories at NIH or submitted to designated 
repositories and databases if consent for sharing was obtained. 
All images will be transferred to a research picture archiving and communication system 
(PACS) located at the NIH Clinical Center.  PHI will be removed, and a study ID 
identical to the CNRM Global Unique Identifier (GUID) described below.  Imaging data 
will be processed and stored by the CNRM at the NIH Clinical Center.
The CNRM GUID is a number assigned by the CNRM Informatics Core.  The 
Informatics Core has established an encrypted system and will provide access to the site 
for generation of a GUID), developed locally at each site, from personal health identifiers 
(PHI) data. Only the local site will have access to PHI.  Local sites will maintain Master 
Keys matching GUIDs to PHI. Electronic/computer Master Keys will be kept on 
password protected terminal(s) in locked rooms with access limited to designated study 
personnel. 
Electronic Master Key records will be backed up electronically at each site at least 
monthly.  Physical print outs/copies of Master Keys will be kept in a locked cabinet in 
the office of a designated study investigator, and will be updated monthly or at more 
frequent intervals.  The mapping from PHI to GUID will not be stored by or known to the 

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CNRM Informatics Core or NIH CIT personnel, but the central registration of issued 
GUIDs will help ensure uniformity of identifiers across sites and the ability to identify 
the enrolling site.  
Subjects receiving follow up visits will retain initially-assigned GUIDs throughout their 
participation and all data will be stored linked to this GUID. Requirements or requests for 
subject future contact (re-identification) must pass through the enrolling site for GUID-
PHI Master Key deciphering.   CNRM Master Keys will contain the following 
information: GUID, last name, last 4 digits SSN, date of birth, and/or medical record 
number. 
De-identified data will be stored in the CNRM Data Repository housed at NIH.
Data will be stripped of identifiers and may be coded (“de-identified”) or unlinked 
from an identifying code (“anonymized”). When coded data is shared, the key to the 
code will not be provided to collaborators, but will remain at NIH.  Data and samples 
may be shared with investigators and institutions with an FWA or operating under 
the Declaration of Helsinki (DoH) and reported at the time of continuing review.  
Sharing with investigators without an FWA or not operating under the DoH will be 
submitted for prospective IRB approval.  Submissions to NIH-sponsored or 
supported databases and repositories will be reported at the time of Continuing 
Review.  Submission to non-NIH sponsored or supported databases and repositories 
will be submitted for prospective IRB approval.
6.Additional Considerations
a. Research with investigational drugs or devices
•
N/A
b. Gene therapy
•
N/A
7. Risks and Discomforts
a. General
The behavioral tasks, neuroimaging procedures, and screening procedures are minimal 
risks to the participant.  
b. Study Procedures
i.
Behavioral measures 
There are no major risks associated with these memory tests other than frustration or 
embarrassment associated with the participants’ performance.  

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ii. MRI 
People are at risk for injury from the MRI magnet if they have pacemakers or other 
implanted electrical devices, brain stimulators, some types of dental implants, aneurysm 
clips (metal clips on the wall of a large artery), metallic prostheses (including metal pins 
and rods, heart valves, and cochlear implants), permanent eyeliner, implanted delivery 
pump, or shrapnel fragments. Welders and metal workers are also at risk for injury 
because of possible small metal fragments in the eye of which they may be unaware.  
People with fear of confined spaces may become anxious during an MRI.  Those with 
back problems may have back pain or discomfort from lying in the scanner. The noise 
from the scanner is loud enough to damage hearing, especially in people who already 
have hearing loss.  There are no known long-term risks of MRI scanning.
iii. TMS
There is a small possibility of a seizure during TMS. TMS has been found to produce 
hearing loss in experimental animals, caused by the click produced by the stimulating 
coil.  However, no evidence of chronic hearing loss in several normal participants who 
had been extensively studied with TMS was found, nor transient changes in several 
participants tested before, and immediately after stimulation (Brasil-Neto, et al., 1992).  
All of our participants will wear earplugs to reduce the risk of cochlear damage.  Other 
than this, TMS does not appear to pose any hazard to the brain beyond that of electric 
stimulation, which has been in clinical use for decades.  The World Health Organization 
task group and the Food and Drug Administration concluded that brief exposure to static 
magnetic fields up to 2 Tesla have no adverse effects on human health ). 
c.
Procedures to Minimize Risk
i.
Behavioral measures
To minimize the risk associated with frustration or embarrassment, the researcher will 
maintain a positive attitude and observe the participants’ behavior to determine if they are 
overly frustrated.  Breaks will be encouraged if deemed necessary.  
ii. MRI
To mitigate the risk of damage from associated with exposure to a powerful magnet, all 
magnetic objects (for example, watches, coins, jewelry, and credit cards) must be 
removed before entering the MRI scan room.  In addition, participants will be screened 
for metal implants such as pacemakers or other implanted electrical devices, brain 
stimulators, some types of dental implants, aneurysm clips (metal clips on the wall of a 
large artery), metallic prostheses (including metal pins and rods, heart valves, and 
cochlear implants), permanent eyeliner, implanted delivery pump, or shrapnel fragments.
To minimize the risk of hearing damage, participants will be given earplugs or noise 
reducing headphones.  To confirm that our female participants are not pregnant, thus 
removing any unknown risks of MRI on a fetus, women of childbearing potential will 
have a urine pregnancy test within 24 hours of participation in the fMRI experiment.  
Female participants will not be allowed to participate if the test is positive.  There are no 
risks of pregnancy testing.

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iii. TMS
To reduce the risk of a headache, migraine, or pain associated with rTMS, participants 
will be asked periodically if they are experiencing any of these symptoms, although 
typically these symptoms tend to subside after a short time away from rTMS.  
To reduce the risks of hearing loss associated with rTMS, all subjects will be fitted with 
hearing protection.  
8. Subject Safety Monitoring
For healthy subjects, a credentialed physician or nurse practitioner will be on site for all 
rTMS administration and immediately available.  This is the standard of care in 
community and academic clinical and experimental rTMS centers, nationwide.  Study 
staff will be trained in rTMS administration, rTMS safety, and the measurement of the 
motor evoked potential threshold and will have performed 10 measurements under 
supervision.  Study staff will monitor individuals during participation and participants 
will be encouraged to tell experimenters of any discomfort. Any subject exhibiting 
distress or who wishes to stop the experiment for any reason will be allowed to stop.  
Participants may withdraw at any time. Data of those participants that have completed at 
least the first session of either Experiment 1-2 (i.e. both MRI scan and behavioral 
assessment) will be kept and analyzed. A researcher may end experimentation for the 
following reasons:
1)
Abnormal response to rTMS including the occurrence of a seizure, loss of consciousness, or 
excessive pain or headache produced by rTMS.  
2)
Withdrawal of consent and/or decision to terminate.
3)
Excessive frustration exhibited by participants on behavioral tasks.
4)
Decision by legal proxy or patient guardian to terminate participation.
5)
Subjects withdrawn due to high motor thresholds above the maximum capacity of the 
stimulator
6)
Subjects withdrawn due to discomfort of TMS
9. Outcome Measures
a. Primary outcome measures
•
Pre-to-post rTMS difference in FC between the left parietal cortex and the left 
hippocampus (Experiments 1-2) in healthy subjects (Experiments 1 and 2).   
•
Pre-to-post rTMS difference in AMT scores in healthy subjects (Experiment 2).
b. Secondary outcome measures
•
Pre-to-post rTMS difference in WPT-I scores after rTMS in healthy subjects 
(Experiment 2).

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c.
Exploratory outcome measures
•
Correlations between memory performance and white matter integrity (Experiment 
2).   
10. Statistical Analysis
a. Analysis of data/study outcomes
i.
Experiment 1
Specific Aim 1: To determine the number of rTMS sessions required to produce a 
substantial change in FC between the parietal cortex and hippocampus in healthy 
subjects.
We will use the continual reassessment method (CRM) design (O’Quigley et al., 1990) to 
find the optimal number of sessions to produce a clinically meaningful change in fMRI 
connectivity between the parietal cortex and hippocampus in healthy subjects.  The CRM 
is an adaptive design for dose finding studies, in which a “dose-toxicity” curve is fitted to 
the data and each patient will be assigned the dose most likely to be associated with the 
target toxicity level, designated as maximum tolerated dose (MTD)  (Garrett-Mayer, 
2006).  It is important to note that while we retain the toxicity terminology from the CRM 
literature in the following description, we have adapted the technique to finding the 
threshold for efficacy, not toxicity.
In our study, the escalation decisions will be based on the efficacy of the rTMS.  For the 
purpose of this study, the term dose will be used to mean the number of rTMS sessions. 
Similarly, the term toxicity will correspond to efficacy of the rTMS. 
First, we used the data by Wang et al. (2014) to determine the threshold value for a 
clinically meaningful change in connectivity. The optimal cut-point for dichotomizing FC 
change was 0.028, which was determined by maximizing the Youden’s index 
(sensitivity+specificity1) in the ROC analysis. 
The details and assumptions to implement CRM are as follows.
•
Dose limiting toxicity (DLT): We assume that a FC change equal to or greater 
than the threshold value 0.028 is an effective change. DLT will be defined as the 
FC change from baseline to post-stimulation ≥ 0.028 
•
Target toxicity level (TTL): The sensitivity for the dichotomized FC change (at 
0.028) in the parietal simulation group was 87.50% in Wang et el. (2014). TTL is 
set to 12.5%, which is equal to (1-sensitivity).  The MTD is then defined as the 
number of rTMS sessions that has a risk of DLT equal to the chosen TTL value of 
12.5%.
•
Dose levels:  The dose level refers to the number of consecutive rTMS sessions. 

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The range of sessions is 1 to 5. 
•
Number of healthy volunteers per dose level:  3 healthy volunteers per dose level
•
Dose-toxicity model: We propose to use a one-parameter hyperbolic-tangent 
dose-response model by O’Quigley et al. (1990), where a Gamma (1, 1) prior will 
be used.  
•
Starting dose:  3 sessions
•
Stopping rule: Healthy volunteers will continue to be recruited to the trial until a 
fixed sample size of 15 is achieved. 
The following aims will be investigated using the optimal sessions determined in Specific 
Aim1.
ii. Experiment 2
Specific Aim 2 (Primary Aim 1): To determine whether rTMS delivered to the parietal 
cortex increases parietal-hippocampal FC in healthy subjects.
For each healthy subject, the Pearson correlation coefficients (r) between time courses of 
BOLD activity in the parietal and hippocampal areas will be calculated to determine the 
functional connectivity before and after rTMS stimulation. They will be Fisher-
transformed to normalize r values. We will call this the z scores.  The change in the z 
scores from pre- to post- stimulation will be assessed using the one-tailed, paired t test. 
Specific Aim 3: To measure the effects of parietal rTMS on AMT and WPT-I.  
First, the change in the AMT scores from pre- to post- stimulation will be calculated.  
Then, the two sample t-tests will be used to compare the changes in the AMT scores 
between the parietal and the sham groups.  Additionally, we will consider using the 
Wilcoxon rank sum tests when the changes in the AMT scores are not normally 
distributed in each group.
Next, we will perform a similar analysis for WPT-I scores. 
Specific Aim 4:  To evaluate the relationship between fMRI connectivity and AMT and 
WPT-I outcomes in the parietal group in healthy subjects.
For each subject, the Pearson correlation coefficients (r) between time courses of the 
parietal and hippocampal regions will be calculated to determine the functional 
connectivity before and after rTMS stimulation. Then, the changes of the z scores (Fisher 
transformed r values) from pre- to post- simulation will be calculated. Similarly, the 
changes in AMT scores from pre- to post-simulation will be computed.  The linear 

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regression models will be used to examine the relationship between the change in 
functional connectivity and the change in AMT scores.  
Next, we will repeat a similar analysis using WPT-I scores. 
b. Power analysis 
Experiment 1:  The maximum number of healthy subjects for Experiment 1 is set at 15. 
Experiment 2: We propose to recruit 32 healthy participants (16 subjects in each of the 
parietal and control groups) to participate in Experiment 2. 
We based our sample size estimate on the behavioral results from the study we are 
replicating (Wang et al., 2014). In Wang et al. (2014), the effect size of the memory 
increases caused by PPC stimulation, compared to sham stimulation, was 0.75 (Cohen’s 
d). This was achieved using a within-subjects design. Using this effect size, to achieve a ß 
of 0.70 using the between subjects design described in this protocol (Experiment 2), 16 
participants are required.  
Sixteen subjects per group also achieves sufficient power to to detect FC changes. Wang 
et al. indicate that the mean difference in FC from post to pre stimulation in retrosplenial 
region was 0.1018 and its standard deviation was 0.09296.  Based on their data, we 
assume that the mean change will be between 0.1008 and 0.1028. We also assumed its 
standard deviation (SD) will be between 0.085 and 0.10.  A one-tailed, paired t-test was 
used at a significance level of 0.05. Computations were carried out using PASS (Hinze J. 
[2008] PASS, NCSS, LLC, Kaysville, Utah).
The following table shows estimates of power to address Primary Aim 1 given ten subjects 
per treatment group.  
Mean of paired 
difference
Estimated standard 
deviation of the 
difference
Power
0.1008
0.085
0.96440
0.1018
0.085
0.96698
0.1028
0.085
0.96940
0.1008
0.093
0.93446
0.1018
0.093
0.93833

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0.1028
0.093
0.94202
0.1008
0.100
0.90159
0.1018
0.100
0.90651
0.1028
0.100
0.91125
Table 1.  Estimated power for primary aim 1 (N=10 in parietal group)
A sample size of ten subjects per group achieves 93.8% power to detect a mean of paired 
differences of 0.1018 with an estimated standard deviation of differences of 0.093 and 
with a significance level of 5% using a one-sided paired t-test. Under other scenarios, the 
estimated powers were greater than 90%. 
Assuming a 50% dropout rate, we anticipate enrolling up to 101 healthy subjects (33 for 
Experiment 1; 64 for Experiment 2). 
11. Human Subjects Protection
a. Subject selection
We will recruit healthy participants through referrals from the NIH Clinical Research 
Volunteer program or through self-referrals to the protocol.  We will work to ensure 
equitable selection.  
b. Justification for exclusion of subjects
i.
Justification for exclusion of children
Children will not be included.  The study is predicated on the work of Wang et al. (2014) 
who studied participants over the age of 18.  Therefore, in order to replicate this result, 
we will recruit a sample of the same age.  
Because we intend to compare the results of Experiments 1 and 2 and because we will be 
attempting to replicate Wang et al. (2014), we will focus our analysis on subjects between 
the ages of 18-50.  
ii. Justification for exclusion of subjects above the age of 50
Because neuroplasticity is reduced in older adults (Fathi, et al., 2010) including subjects 
above the age of 50 would reduce our power for detecting change in FC.  Therefore, this 
group will be excluded.  
iii. Justification for the exclusion of non-English speakers/readers
We are excluding non-English speakers because differences in the ability to understand 
the task instructions might not be apparent to us when communicating via an interpreter, 

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but could affect performance significantly, introducing unpredictable differences between 
groups of subjects.  
iv. Justification for participants who have already participated in Experiment 
1.
Because the persistence of the rTMS effect is unknown, participants from Experiment 1 
will not be invited to participate in Experiment 2.
c.
Justification for the Exclusion of other Vulnerable Subjects
i.
Persons without consent capacity
Because there is a minor increment above minimal risk and no expectation of benefit, we 
do not feel it would be appropriate to include participants without the capacity to give 
informed consent.
ii. Women who are Pregnant, Plan to Become Pregnant, or are Breast-feeding
The effects of MRI on fetal development and the health of pregnant women is unknown.  
Therefore, women who are pregnant will be excluded and women who can become 
pregnant will be excluded following a positive pregnancy test.  
d. Justification of sensitive procedures
This study involves no sensitive procedures.  
e.
Safeguards for vulnerable populations
Since the effects of rTMS and MRI on fetal development are unknown, women of 
childbearing potential will have a pregnancy test before each rTMS and MRI session.  
i.
Safeguard of vulnerable subjects (NIH employees)
Protections for employees and staff participating in this study include 1) assuring that the 
participation or refusal to participate will have no effect, either beneficial or adverse, on 
the subject’s employment or position at the NIH, 2) giving employees and staff who are 
interested in participating the “NIH Information Sheet on Employee Research 
Participation” prior to obtaining consent, and 3) assuring that there will be no direct 
solicitation of employees or staff.   
Consent will not be obtained by a co-worker.  We will only enroll NIH employees and 
staff when they are not members of the Behavioral Neurology Unit in the National 
Institute of Neurological Disorders and Stroke.  This is the laboratory in which the 
research described in this protocol will occur.  NIH employees and staff who participate 
during work hours must have permission from their supervisor.  NIH employees and staff 
must either participate outside of work hours or take leave in order to receive 
compensation.  The last stipulation does not apply to the home-monitoring period.  
Women of childbearing potential will have a pregnancy test, which must be negative 
before proceeding

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12. Anticipated Benefit
This study does not offer direct benefit to participants but is likely to yield generalizable 
knowledge to the understanding of the effect of rTMS on FC in healthy adults.
13. Consent Documents and Process
a. Designation of Those Obtaining Consent
Study investigators designated as able to obtain consent are noted in the Study Personnel 
Document.  All study investigators obtaining informed consent have or will complete the 
‘Elements of Successful Informed Consent’ training prior to experimentation.
b. Consent Procedures
All participants will receive a verbal explanation in terms suited to their comprehension 
of the purposes, procedures and potential risks of the study and of their rights as research 
participants.  Participants will have the opportunity to review the written consent form 
carefully and ask questions regarding this study before signing.   
Consent will not be obtained by a co-worker.  
c.
Consent Documents
 The consent form contains all required elements.  Healthy Volunteer consent forms are 
submitted with this protocol.  
14. Data and Safety Monitoring
a.
        Data and safety monitor
Data and safety will be regularly monitored by the Principal investigator.  Dr Leonardo Cohen, a 
neurologist and an intramural NINDS investigator, will serve as the Independent Medical 
Monitor for this protocol.  
 
b.         Data and safety monitoring plan
Protocol investigators will evaluate the safety of study subjects throughout the conduct of the 
study and respond to adverse events (AEs) in a timely manner.  The IMM will be informed of 
serious adverse events within 7 days and sent a summary of adverse events at the time of each 
annual review
If no interval data were collected, the monitor will be informed and a report will not be required. 
The IMM will also be sent protocol updates and other pertinent documents relating to the study 
on an as-needed basis. The IMM may also be consulted in person and as needed to discuss 
clinical issues. In person consultations with the IMM will be documented.
 
c.
        Criteria for stopping the study or suspending enrollment or procedures
If, in the judgment of the PI or IMM, a study procedure is causing frequent unexpected or adverse 
outcomes, that procedure will be suspended until a review can be undertaken in consultation with 
the IRB. Depending on that consultation, the procedure may be dropped from the protocol via an 

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amendment, or specific language may be added to the protocol and consent forms to reflect the 
changing risk level.
15. Quality Assurance (QA)
a. Quality assurance monitor
The CNRM will monitor the protocol:
1) After 5 subjects have completed participation in the study.
2) Every 6 months after the first five subjects have completed participation in the 
study
3) At the close of the protocol.
b. Quality assurance plan
The protocol will be monitored by CNRM for regulatory compliance and data quality in 
accordance with the established monitoring plan.  The NINDS QA office will review the 
CNRM monitoring reports, but will not provide additional audits, unless deemed 
indicated by the findings of the CNRM monitor.
16. Reporting of Unanticipated Problems, Adverse Events and 
Protocol Deviations
Reportable events will be tracked and submitted to the IRB as outlined in Policy 801.
17. Alternatives to Participation 
Participants do not receive rTMS in this study or forego any treatment in order to 
participate in this study.  The alternative, therefore, is not to participate. 
18. Privacy
All research activities will be conducted in as private a setting as possible.  
19. Confidentiality
a. For research data and investigator medical records
All study investigators will have access to research records and data.  Hard copy 
research data/records will be coded, no individual will be identified by name, and the 
data will be stored in a locked filing cabinet locked to protect subject anonymity. 
Electronic data with identifiers (including neuroimaging) will be saved password-
protected NIH-issued computers on secured servers.  Neuroimaging data will be 
maintained on a secure internet-based server.  Only study investigators will have access 
to the data.  De-identified results from clinical trials will be posted on cctrials.gov.  

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Clinical data will be managed according to NIH Clinical Center’s standard policies 
(http://www.cc.nih.gov/participate/patientinfo/legal.shtml). Sensitive, private 
information (such as a urine drug test) will not be collected in this study, so no special 
protections for NIH employees and staff are necessary.  However, confidentiality 
protections for them will be the same as those for all subjects.  The PI  will instruct all 
study personnel  in the relevant SOPS and procedures to ensure  the privacy  of NIH 
employees and staff who participate in our study.  All investigators will be required to 
read the SOP on participation of NIH personnel.
Participant research data will be de-identified and stored on secure computer systems.   
The only entries in the medical record will be to document participation in the research 
study. In laboratory records, all personally-identifying information will be removed. 
Participants will be identified by a number code, the key to which will be accessible only 
to the investigators. The information gathered during this study will be kept confidential 
to the extent that the law allows. The lab results will be kept safe in a locked room. The 
subjects will be informed that these results may be published for scientific purposes, 
provided their identity is not revealed. 
Members of the CNRM, Uniformed Services University, Henry M Jackson Foundation, 
US Department of Defense and NIH, may have access to the study data for auditing 
purposes.
b. For medical records
Clinical data will be managed according to NIH’s Clinical Center’s policy 
(http://www.cc.nih.gov/participate/patientinfo/legal.shtml). 
20. Conflict of Interest
a. Distribution of NIH Guidelines
NIH guidelines on conflict of interest have been distributed to all investigators. 
b. Conflict of Interests
There are no conflicts-of-interest to report. 
c.
Role of a Commercial Company or Sponsor
There is no commercial company or sponsor.
21. Technology Transfer
N/A

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22. Research and Travel Compensation 
All participants will be compensated for time and research-related inconveniences in 
accord with NIH guidelines as follows: 
Experiment 1 
Number
Pay per 
Procedure
Total
Time for first hour
2-7
$20
40-160
Time for each additional hour
1-3
$10
30
rTMS
1-5
$60
60-300
MRI
2
$60
120
Urine pregnancy test
2-6
$10
20-60
Experiments 1 Total
$250-650
Experiment 2 
Time for first hour
3-8
$20
80-160
Time for each additional hour
6-11
$10
60
rTMS
1-5
$60
60-300
MRI
2
$60
120
Behavioral Tasks
3
$30
90
Urine pregnancy test
2-6
$10
20
Experiment 2 Total
$250-840
Payment (check) will be mailed to participants after they complete the protocol.  If 
participants are unable to finish the study, they will be paid for the portion of the study 
completed.  No reimbursement for travel or escort fee will be provided.
Employees and staff who participate during work hours must have permission from their 
supervisor. NIH employees must either participate outside of work hours or take leave in 
order to receive compensation
24. References

CNS IRB Protocol Template (12.15.15 rev2)
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Adams, J., Doyle, D., Ford, I., Gennarelli, T., Graham, D., & McLellan, D. (2011). 
Diffuse axonal injury in head injury: Definition, diagnosis and grading. 
Histopathology, 15(1), 49-59.
Adams, J., Graham, D., Gennarelli, T., & Maxwell, W. (1991). Diffuse axonal injury in 
non-missile head injury. 54(6), 481-483.
Alexander, G., DeLong, M., & Strick, P. (1986). Parallel organization of functionally 
segregated circuits linking basal ganglia and cortex. Annual Review of 
Neuroscience, 9, 357-381.
Barch, D., Burgess, G., Harms, M., Petersen, S., Schlaggar, B., Corbetta, M., . . . Van 
Essen, D. (2013). Function in the human connectome: Task-fMRI and individual 
differences in behavior. NeuroImage, 80(15), 169-189.
Biswal, B., Mennes, M., Zuo, X.-N., Gohel, S., Smith, S., Beckmann, C., . . . Milham, M. 
(2010). Toward discovery science of human brain function. PNAS, 107(10), 4734-
4739.
Bonnì, S., Mastropasqua, C., Bozzali, M., Caltagirone, C., & Koch, G. (2013). Theta 
burst stimulation improves visuo-spatial attention in a patient with traumatic brain 
injury. Neurological Science, 34(11), 2053-2056.
Brasil-Neto, J., Cohen, L., Panizza, M., Nilsson, J., Roth, B., & Hallett, M. (1992). 
Optimal focal transcranial magnetic activation of the human motor cortex: Effects 
of coil orientation, shape of the induced currect pulse, and stimulus intensity. 
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Buckner, R., Krienen, F., & Yeo, B. (2013). Opportunities and limiations of intrinsic 
functional connecitivity MRI. Nature Neuroscience, 16(7), 832-837.
Chen, R., Classen, J., Gerloff, C., Celnik, P., Wassermann, E., Hallet, M., & Cohen, L. 
(1997). Depression of motor cortex excitability by low-frequency transcranial 
magnetic stimulation. Neurology, 48, 1398-1403.
Choe, A., Jones, C., Joel, S., Muschelli, J., Belegu, V., Caffo, B., . . . Pekar, J. (2015). 
Reproducibility and temporal structure in weekly resting-state fMRI over a period 
of 3.5 years. PlOS One. doi:10.1371/journal.pone.0140134
Fathi, D., Ueki, Y., Mima, T., Koganemaru, S., Nagamine, T., Tawfik, A., & Fukuyama, 
H. (2010). Effects of aging on the human motor cortical plasticity studied by 
paired associative stimulation. Clinical Neurophysiology, 121(1), 90-93.
Finn, E., Shen, X., Scheinost, D., Rosenberg, M., Huang, J., Chun, M., . . . Constable, R. 
(2015). Functional connectome fingerprinting: identifying individuals using 
patterns of brain connectivity. Nature Neuroscience, 18(11), 1664-1671.
Garrett-Mayer, E. (2006). The continual reassessment method for dose-finding studies: a 
tutorial. Clinical Trials, 3(57), 57-71.
Karabanov, A., Chao, C.-C., Paine, R., & Hallett, M. (2012). Mapping different intra-
hemispheric parietal-motor networks using twin coil TMS. Brain Stimulation, 
6(3), 384-389.
Lerner, A. J., Wassermann, E. M., & Tamir, D. I. (2019). Seizures from transcranial 
magnetic stimulation 2012-2016: Results of a survey of active laboratories and 
clinics. Clin Neurophysiol, 130(8), 1409-1416. doi:10.1016/j.clinph.2019.03.016

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Levin, H., Gar, H., Eisenberg, H., Ruff, R., Barth, J., Kreutzer, J., . . . Marshall, L. 
(1990). Neurobehavioral outcome 1 year after severe head injury experience of 
the Traumatic Coma Data Bank. Journal of Neurosurgery, 73(5), 699-709.
Maxwell, W., Kansagra, A., Graham, D., Adams, J., & Gennarelli, T. (1988). Freeze-
fracture studies of reactive myelinated nerve fibres after diffuse axonal injury. 
Acta Neuropathologica, 76(4), 395-406.
O'Quigley, J., Pepe, M., & Fisher, L. (1990). Continual reassessment method: A practical 
design for phase 1 clinical trials in cancer. Biometrics, 46(1), 33-48.
Pachalska, M., Lukowicz, M., Kropotov, J., Herman-Sucharsaka, I., & Talar, J. (2011). 
Evaluation of differentiated neurotherapy programs for a patient after severe TBI 
and long term coma using event-related potentials. Medical Science Monitor 
Basic Research, 17(10), CS1290-CS128.
Pape, T., Rosenow, J., Lewis, R., Ahmed, G., Walker, M., Gurenon, A., . . . Patil, V. 
(2009). Repetitive transcranial magnetic stimulation-associated neurobehavioral 
gains during coma recovery. Brain Stimulation, 2(1), 22-35.
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rapid-rate transcranial magnetic stimulation of the human motor cortex. Brain, 
117, 847-858.
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(2001). Interactive memory systems in the human brain. Nature, 414, 546-550.
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K., . . . Sharp, D. (2011). Inflammation after trauma: Microglial activation and 
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(2009). The resting brain: unconstratined yet reliable. Cerebral Cortex, 19(10), 
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imaging of traumatic brain injury review: Implications for neurorehabilitation. 
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25. Attachments/ Appendices
a. Appendix A: Pre-screening Questions
i.
Healthy Volunteers
⬜
Are you between 18 and 50 years of age?
⬜
Are you in good health?
⬜
Are you taking any medications?
⬜
Are you prone to seizures, stroke, headaches, or migraines?
⬜
Are you free of a history of significant neurological or psychiatric conditions?
⬜
Are you free of any metal in your body?
⬜
Are you comfortable doing a one-hour MRI?

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b. Appendix B: Inclusion/Exclusion Checklist
Healthy Volunteers
Inclusion criteria
⬜
18 to 50 years of age
⬜
Able to speak and write in English
Exclusion Criteria
⬜
Pregnant/plans to be become pregnant during the study.
⬜
Major neurological or psychiatric disorder
⬜
History of seizure
⬜
Ferromagnetic metal or implanted device
⬜
Non-removable body piercing.
⬜
Claustrophobia or cannot lie supine for 1 hour.
⬜
Taking medications acting on the CNS.  
⬜
NINDS Behavioral Neurology Unit Employee or fellow
⬜
For Experiment 2: participation in Experiment 1 

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c.
Appendix C: Timeline of Study
The first rTMS session and consenting procedures may occur on the same day as the 
initial scanning session)
TIME
PROCEDURE
Experiments 1: Healthy Volunteers  
Day -30 to 1 
Screening Procedures: Demographics, Neurological 
exam (if HV has not had one in past 2 years).  
Informed Consent
Day 1
Resting-state fMRI: 20 minutes
Anatomical Scan: 10-30 minutes
DTI: 20-30 minutes
ARSQ: 8 minutes
Urine pregnancy test
Stimulation Days 1-5*
These procedures may occur on the 
same day as the baseline MRI or 
up to 4 days afterwards..
Resting Motor Threshold Measurement (30 
minutes)**
rTMS: (20 minutes)
Day 6 
Anatomical Scan: 10 minutes
Resting-state fMRI: 20 minutes
ARSQ: 8 minutes
Urine pregnancy test
Experiment 2: HVS
Day -30 to 1
Screening Procedures: Demographics, Neurological 
exam (if HV has not had one in past 2 years).  
Informed Consent
Day 1
Resting-state fMRI: 20 minutes
Anatomical Scan: 10-30 minutes
DTI: 20-30 minutes
Behavioral Tests: AMT, WPT-I 
Cognitive Battery (2.5 hours)
ARSQ: 8 minutes
Urine pregnancy test

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TIME
PROCEDURE
Stimulation Days 1-5*
These procedures may occur on the 
same day as the baseline MRI or 
up to 4 days afterwards..
Resting Motor Threshold Measurement (30 
minutes)**
rTMS: (20 minutes)
Day 6
Anatomical Scan: 10 minutes
Resting-state fMRI: 20 minutes
Behavioral Tests: AMT, WPT-I 
Cognitive Battery (2.5 hours)
ARSQ: 8 minutes
Urine pregnancy test
7 to 14 days after final scan
Behavioral Tests: AMT, WPT-I,Cognitive 
Battery (2 hours)
*The number of days of rTMS for Experiment 1 depends on the cohort of participants; 
HVs will receive between 1-5 sessions of rTMS.  For Experiment 2, this number will 
depend on the results of Experiment 1.
** This measurement will be taken once during the first rTMS session.

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d. Appendix D: Amsterdam Resting-State Questionnaire (ARSQ)
Here below are several statements regarding potential feelings and thoughts 
you may have experienced during the resting period in the scanner (when 
you were looking at the cross on the screen trying to think about nothing). 
Please indicate the extent to which you agree with each statement.
Questions
Completely 
Disagree
Disagree
Neither 
Agree nor 
Disagree
Agree
Completely 
Agree
I thought about my feelings
I felt restless
I felt tired
I felt sleepy
I felt comfortable
I felt relaxed
I felt happy
I felt ill 
I enjoyed the session
I had negative feelings 
I felt bored
I felt nothing
I felt the same throughout the session
I thought about my health
I thought about my work/study
I thought about my behavior
I had thoughts that I would not 
readily share with others
I had busy thoughts
I had similar thoughts throughout the 
session
I thought about others
I thought about myself
I thought about pleasant things
I had my thoughts under control 
I thought about solving problems
I thought about the aim of the 
experiment
I had difficulty staying awake
I had rapidly switching thoughts
I had superficial thoughts

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Questions
Completely 
Disagree
Disagree
Neither 
Agree nor 
Disagree
Agree 
Completely 
Agree
I thought about the past.
I thought about the present
I thought about the future
I had deep thoughts
I thought about nothing
I had difficulty holding on to my 
thoughts
I thought about people I like
I thought in images
I thought in words
I thought about things I need to do
I was conscious of my body
I thought about the sounds around me
I thought about the odors around me
I thought about my heartbeat
I thought about my breathing
I felt pain
I placed myself in other peoples’ 
shoes
I felt motivated to participate
I have difficulty remembering my 
thoughts
I have difficulty remembering my 
feelings 
I had my eyes closed 
I was able to rate the statements 

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e.
Appendix G : Timeline figures
Experiment 1 (from Section 4.d.vii)
Experiment 2 (from Section 4.d.viii)
26. Consent Forms
Consent documents uploaded in iRIS:

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-
Standard Consent Form