Task-dependent Effects of TMS on the Neural Biomarkers of Episodic Memory
Phase: NA
Conditions: Normal Physiology
Sponsor: National Institute of Neurological Disorders and Stroke (NINDS)

Protocol Title:  Task-dependent eﬀects of TMS on the neural biomarkers of episodic memory 
NCT#: NCT04694131  
Document Date:  11/15/2022 

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Abbreviated Title: Task-dependent TMS and memory 
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Abbreviated Title: Task-dependent TMS and memory 
Protocol #: 000196 
Version Date: 11.15.22 
Title: Task-dependent effects of TMS on the neural biomarkers of episodic memory 
 
NIH 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 
 
 
 

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TABLE OF CONTENTS  
TABLE OF CONTENTS ................................................................................................................ 2 
STATEMENT OF COMPLIANCE ................................................................................................ 5 
1 
PROTOCOL SUMMARY ...................................................................................................... 6 
1.1 
Synopsis ........................................................................................................................... 6 
1.2 
Schedule of Activities (SOA) ........................................................................................... 8 
2 
INTRODUCTION .................................................................................................................. 9 
2.1 
Study Rationale ................................................................................................................ 9 
2.2 
Background ...................................................................................................................... 9 
2.3 
Risk/Benefit Assessment ................................................................................................ 10 
2.3.1 
Known Potential Risks ............................................................................................ 10 
2.3.2 
Known Potential Benefits ....................................................................................... 13 
2.3.3 
Assessment of Potential Risks and Benefits ........................................................... 13 
3 
OBJECTIVES AND ENDPOINTS ...................................................................................... 13 
4 
STUDY DESIGN.................................................................................................................. 15 
4.1 
Concomitant Therapy ..................................................................................................... 23 
5 
STUDY POPULATION ....................................................................................................... 23 
5.1 
Inclusion Criteria ............................................................................................................ 23 
5.2 
Exclusion Criteria ........................................................................................................... 23 
5.3 
Inclusion of Vulnerable Participants .............................................................................. 24 
5.3.1 
Participation of Employees ..................................................................................... 24 
5.4 
Lifestyle Considerations ................................................................................................. 24 
5.5 
Screen Failures ............................................................................................................... 24 
5.6 
Strategies for Recruitment and Retention ...................................................................... 25 
5.6.1 
Costs ........................................................................................................................ 25 
5.6.2 
Compensation ......................................................................................................... 25 
6 
PARTICIPANT DISCONTINUATION/WITHDRAWAL .................................................. 26 
6.1 
Participant Discontinuation/Withdrawal from the Study ............................................... 26 
6.2 
Lost to Follow-up ........................................................................................................... 26 
7 
STUDY ASSESSMENTS AND PROCEDURES ................................................................ 27 
7.1 
Screening Procedures ..................................................................................................... 27 
7.1.1 
Screening activities performed prior to obtaining informed consent ...................... 27 

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7.1.2 
Screening activities performed after a consent for screening has been signed ....... 27 
7.2 
Clinical Evaluations ....................................................................................................... 27 
7.3 
Biospecimen Evaluations ............................................................................................... 27 
7.3.1 
Correlative Studies for Research ............................................................................ 28 
7.3.2 
Samples for Genetic/Genomic Analysis ................................................................. 28 
8 
STATISTICAL CONSIDERATIONS.................................................................................. 28 
8.1 
Statistical Hypothesis ..................................................................................................... 28 
8.2 
Sample Size Determination ............................................................................................ 29 
8.3 
Statistical Analyses ........................................................................................................ 29 
8.3.1 
General Approach ................................................................................................... 29 
8.3.2 
Analysis of the Primary Endpoints ......................................................................... 29 
8.3.3 
Analysis of the Secondary Endpoint(s) ................................................................... 29 
8.3.4 
Baseline Descriptive Statistics ................................. Error! Bookmark not defined. 
8.3.5 
Sub-Group Analyses ................................................ Error! Bookmark not defined. 
8.3.6 
Tabulation of individual Participant Data ............................................................... 30 
8.3.7 
Exploratory Analyses .............................................................................................. 30 
9 
REGULATORY AND OPERATIONAL CONSIDERATIONS ......................................... 30 
9.1 
Informed Consent Process .............................................................................................. 30 
9.1.1 
Consent/Assent Procedures and Documentation .................................................... 30 
9.1.2 
Consent for minors when they reach the age of majority ....................................... 30 
9.1.3 
Telephone consent .................................................................................................. 31 
9.1.4 
Telephone assent ..................................................................................................... 31 
9.1.5 
Considerations for Consent of NIH employees ...................................................... 31 
9.1.6 
Consent of Subjects who are/become Decisionally Impaired ................................. 31 
9.2 
Study Discontinuation and Closure ................................................................................ 31 
9.3 
Confidentiality and Privacy ............................................................................................ 31 
9.4 
Future use of Stored Specimens and Data ...................................................................... 32 
9.5 
Safety Oversight ............................................................................................................. 32 
9.5.1 
Principal Investigator/Research Team .................................................................... 32 
9.6 
Clinical Monitoring ........................................................................................................ 33 
9.7 
Quality Assurance and Quality Control ......................................................................... 33 
9.8 
Data Handling and Record Keeping ............................................................................... 33 

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9.8.1 
Data Collection and Management Responsibilities ................................................ 33 
9.8.2 
Study Records Retention ......................................................................................... 33 
9.9 
Unanticipated Problems ................................................................................................. 33 
9.9.1 
Definition of Unanticipated Problems (UP) ........................................................... 33 
9.9.2 
Unanticipated Problem Reporting ........................................................................... 34 
9.10 
Protocol Deviations and Non-Compliance ................................................................. 34 
9.10.1 NIH Definition of Protocol Deviation .................................................................... 34 
9.11 
Publication and Data Sharing Policy .......................................................................... 34 
9.11.1 Human Data Sharing Plan ....................................................................................... 34 
9.11.2 Genomic Data Sharing Plan .................................................................................... 35 
9.12 
Collaborative Agreements ........................................... Error! Bookmark not defined. 
9.12.1 Agreement Type ....................................................... Error! Bookmark not defined. 
9.13 
Conflict of Interest Policy ........................................................................................... 35 
10 ABBREVIATIONS .............................................................................................................. 35 
11 REFERENCES ...................................................................... Error! Bookmark not defined. 
 
 
 

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STATEMENT OF COMPLIANCE 
The protocol will be carried out in accordance with International Conference on Harmonisation 
Good Clinical Practice (ICH GCP) and the following:  
• United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 
CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812)  
National Institutes of Health (NIH)-funded investigators and trial site staff who are responsible 
for the conduct, management, or oversight of NIH-funded trials have completed Human Subjects 
Protection and ICH GCP Training. 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled.  Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study.  In addition, all changes to the consent form will be IRB-approved; a 
determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form. 
 
 

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1 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS 
Title: 
Task-dependent effects of TMS on the neural biomarkers of episodic 
memory 
  
Study Description: 
The Behavioral Neurology Unit studies the human brain systems 
underlying learning and adaptation with the goal of finding 
interventions to make these processes more efficient. In this study, 
we are interested in examining how the task state of the episodic 
memory network influences the effect of faciliatory TMS on memory 
and its EEG neural correlates. It is hypothesized that Network-
targeted parietal-TMS will improve memory performance and 
enhance EEG biomarkers of successful memory performance, but 
that these changes will be modulated by the ongoing task activity 
during stimulation. 
Objectives: 
 
 
 
Primary Objectives:   
• 
Investigate how TMS modulates EEG neural measures 
of successful memory and the association of this 
modulation with behavioral performance 
• 
Examine how memory task state influences 
susceptibility to plasticity via TMS and determine the 
optimal neural state for improving memory 
 
 
 
Exploratory Objectives:  
• Search for MRI predictors of the effects of TMS 
 
  
Endpoints: 
• 
Primary Endpoints: Memory performance, Late Positive Posterior ERP, 
evoked theta/alpha power (secondary), EEG functional connectivity 
(secondary) 
• 
Exploratory Endpoints:  fMRI resting state functional connectivity, 
fractional anisotropy 
  
Study Population: 
32 Healthy Volunteers ages 18-40. Referrals will occur from the NIH 
Clinical Research Volunteer program or through self-referrals to the 
protocol. 
 
Description of 
Sites/Facilities:  
 
 
Enrolling Participants: 
 
Protocol activities will occur at the OP5 clinic and 7SW clinic at the 
NIH clinical center. 
 
 
50 Healthy Volunteers ages 18-40 
 
 

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Study Duration: 
60 months 
 
Participant Duration: 
 
1 month 
 
 
 

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1.2 
 SCHEDULE OF ACTIVITIES (SOA) 
  
Procedures 
Enrollment/Scre
ening 
Day -7 to -1 
Baseline 
Visit 1, Day 1 
Study Visit 2  
Day 4 +/-3 day 
Final Study Visit 
3 
Day 13 +/-8 day  
Informed consent 
X 
 
 
 
Demographics 
X 
 
 
 
Medical history 
X 
 
 
 
Concomitant medication review 
X 
 
 
 
Physical exam 
X 
 
 
 
Vital signs 
X 
 
 
 
Height 
X 
 
 
 
Weight 
X 
 
 
 
3T MRI 
 
X 
 
 
EEG 
 
 
X 
X 
TMS 
 
 
X 
X 
Cognitive Tasks 
 
 
X 
X 
Pregnancy test b 
 
X 
 
 
Complete Case Report Forms 
(CRFs) 
 
 
 
X 
a:  
b: Urine pregnancy test (women of childbearing potential). 
 

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2 
INTRODUCTION 
2.1 
STUDY RATIONALE 
The Behavioral Neurology Unit studies the human brain systems underlying learning and 
adaptation with the goal of finding interventions to make these processes more efficient. This 
study will observe neural reorganization underlying episodic memory performance. The protocol 
will investigate how engaging in a memory task alters the activity and connectivity of the 
network and the relevance of those changes to successful task performance. Also, how this 
adaptation influences plasticity of the network will be examined. Using simultaneous TMS, 
EEG, and cognitive testing, this study will examine the network basis of memory processing, as 
well as elucidating potential mechanisms of TMS-induced memory improvement.  
The overall objective of this study is to (1) examine the effects of TMS on EEG biomarkers of 
successful memory performance and (2) investigate how the task state of the episodic memory 
network influences the effect of faciliatory TMS on memory. 
The results will answer basic science questions about the network basis of memory processing, 
with potential application to other cognitive networks and domains. Additionally, these data will 
provide a greater understanding of TMS as a tool for influencing the hippocampus, the network, 
and memory performance, allowing for optimization of stimulation for that purpose. Finally, this 
work will address clinical questions on how to improve memory and re-channel activity in 
networks via noninvasive stimulation for clinical purposes.  
 
2.2 
BACKGROUND  
Episodic memory provides a means by which we reflect on the past, make decisions about the 
future, and form a learned identity. Deficits in this system occur in a variety of neurological and 
psychiatric disorders1–5, making them one of the most debilitating problems in neurology6,7. 
However, there currently exist no effective treatments for memory impairment. A better 
understanding of how the brain adapts to perform a memory demand will not only expand our 
basic knowledge of memory processing but could inform novel treatments for individuals with 
memory impairments.   
Episodic memory depends on the hippocampus8,9 and a distributed set of regions which form the 
hippocampal-cortical network (HCN), including medial prefrontal, posterior cingulate, and 
medial and lateral parieto-occipital cortex10–13. This network shows changes in fMRI activity and 
connectivity in response to successful memory encoding and retrieval14–18.  Likewise, abnormal 
function of this network has been associated with memory impairment in many disorders, 
including traumatic brain injury19,20, epilepsy21,22, and Alzheimer’s disease23,24. Additionally, the 
HCN generates real-time EEG signatures of successful encoding and retrieval, most notably the 
Late Positive Posterior Event-Related Potential (ERP)25 and oscillatory activity in the theta/alpha 
band26.  
There has been substantial recent interest in using brain stimulation to manipulate brain 
networks, both to test the role of particular regions and networks in memory processing causally 
and as a potential therapeutic tool in treating memory disorders27–29. Noninvasive transcranial 
magnetic stimulation (TMS) has been used to manipulate activity and connectivity in the HCN 
and improve memory performance in healthy adults30–39. Repeated treatment over days produces 

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lasting effects30–36, but single sessions of cTBS have been effective37,38 and time-locked cTBS 
can produce facilitation at the trial-by-trial level39. However, while enhancement of connectivity 
in the HCN is positively correlated with memory improvement, how TMS treatment increases 
the retention of information in the HCN and particularly the hippocampus remains unknown. 
Additionally, while the effects of time-locked cTBS have been examined in relation to fMRI 
activity in the hippocampus39, the effect of HCN cTBS on EEG measures of successful memory 
has not been studied. Establishing these mechanisms will improve the basic understanding of 
how the brain successfully meets a memory demand and inform translational studies for the 
treatment of memory impairment. One goal of this project is to examine the effects of on-line 
TMS on the electrophysiological signatures of successful memory performance to provide more 
information on the mechanism by which TMS improves episodic memory to develop new and 
specific biomarkers of target engagement for future clinical studies. 
The effects of brain stimulation have been shown previously to vary depending on neural state, 
such as the phase of oscillations relevant to the stimulated network40,41 and network activation by 
simultaneous task performance42–44. However, the influence of brain state on HCN facilitation 
with TMS has not been investigated, despite its likely importance. A second goal of this project 
is to examine this question of task state-dependent modulation for the HCN and episodic 
memory. 
Using simultaneous EEG, TMS, and memory testing, we will investigate the EEG activity 
related to successful memory performance and examine how TMS modulates that activity. In 
healthy volunteers, we will deliver brief, facilitatory TMS before and during the encoding trials 
of a memory task to either the HCN, via an inferior parietal cortex site with maximal 
hippocampal connectivity, or to the vertex as a control.  We will additionally deliver stimulation 
during a control task with similar attentional demands and processing load, and there will be a 
no-stimulation condition for both tasks.  We will record task performance and time-locked EEG 
activity, focusing on episodic memory performance and the late positive posterior ERP, 
theta/alpha power, and EEG functional connectivity measured during encoding and retrieval as 
our outcome measures. 
  
2.3 
RISK/BENEFIT ASSESSMENT 
2.3.1 Known Potential Risks 
 
TMS 
Brief, self-limited, seizures were seen in early studies, before limits were established for 
combinations of delivery parameters and still occur occasionally. However, this risk has been 
reduced to the order of one in every 50,000 sessions in individuals without specific risk factors. 
For TMS, safety guidelines have been developed45 and updated46. These guidelines were 
incorporated into FDA’s Class II Special Controls Guidance Document: Repetitive Transcranial 
Magnetic Stimulation (rTMS) Systems in Table 2. Maximum Safe Train Duration (seconds) 
Limits for Avoiding Seizures. Furthermore, the study participants are a lower risk since 
participants with any neurological or psychiatric disorders, history of seizure or taking certain 
medications are excluded. cTBS was not included in the guidelines.  However, there is only a 

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single report of seizure with cTBS47. In that single patient, the study was conducted in at 
stimulation intensity levels higher than in this study.  
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 when hearing 
protection was used, in several normal participants who had been extensively studied with TMS 
was found, nor transient changes in several participants tested before, and immediately after 
stimulation48 and more recent has found no increase in auditory threshold from TMS49,50. All 
participants will wear earplugs to reduce the risk of cochlear damage.  
Other than this, TMS does not appear to pose any hazard beyond that of electrical brain 
stimulation, which has been in clinical use for decades.  
 
Behavioral measures  
There are no major risks associated with these memory tests other than frustration or 
embarrassment associated with the participants’ performance.  
 
EEG 
There are no major risks associated with EEG recording, however there is a possibility of 
discomfort from the electrode cap and abrading of the scalp during electrode application. 
Additionally, there may be electrode gel remaining in the hair following cap removal.  
 
 
 
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. Participants will be fitted with ear plugs. There are no 
known long-term risks of MRI scanning. 
 
Procedures to Minimize Risk 
TMS 
Study staff will be trained in TMS administration, TMS safety, and the measurement of the 
TMS-evoked potentials by Dr. Eric Wassermann. Study staff will be trained to recognize and 

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respond to signs of seizure and syncope. For each session, at least two TMS-trained personnel 
will be in the laboratory. A licensed independent practitioner (LIP), a physician or nurse 
practitioner trained in TMS, will be in house, specifically aware of the session, and reachable by 
phone for all TMS sessions. The TMS laboratory is in a clinic area with nursing and code team 
support. Each room has oxygen, suction, and an emergency call button. If a participant has a 
significant event, such as a seizure, the hospital emergency system (Code Blue) will be activated 
and treatment will be initiated as required. 
Study staff will monitor individuals during participation and participants will be encouraged to 
tell experimenters of any discomfort. At each session, participants will be asked whether 
stimulation was (1) tolerable, (2) tolerable with some discomfort, or (3) intolerable. If the 
participant responds that stimulation is intolerable, the participant will be withdrawn from the 
experiment. Any participant exhibiting distress or who wishes to stop the experiment for any 
reason will be allowed to stop. Nonprescription drugs may be used to alleviate headache or pain 
discomfort. 
Persons operating TMS equipment will have been certified by a NINDS TMS laboratory or the 
NIMH Noninvasive Neuromodulation Unit (NNU) in safe application of TMS. 
Standard training procedures used include training in TMS device operation, supervised repeated 
practice in TMS procedures, and testing for inter-rater reliability in motor threshold 
determination.  To be credentialed as a TMS user, an individual must have passed the following 
criteria, as assessed by senior BNU or NNU staff: 
 
1) Training in TMS device operation 
2) Supervised administration of at least 10 TMS procedures 
3) Demonstration of inter-rater reliability on motor threshold determination 
4) Current Basic Life Support certification  
5) Training on basic TMS safety and risks by TMS-trained physician 
6) Training on recognition and initial response to seizures 
 
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 at participant’s request.  
 
EEG 
To reduce discomfort during electrode application, the researcher will use care in securing the 
cap for comfort and in moving hair to clear access to the scalp. Additionally, after cap removal, 
participants will be provided with shampoo and sink space to clean gel from their hair should 
they desire.  

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MRI 
To mitigate the risk of damage 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, tattoos 
posing MRI risk, 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. 
2.3.2 Known Potential Benefits 
This study does not offer direct benefit to participants but is likely to yield generalizable 
knowledge about TMS and the effects on memory.  
2.3.3 Assessment of Potential Risks and Benefits 
Brief, self-limited, seizures were seen in early studies, before limits were established for 
combinations of delivery parameters and still occur occasionally. However, this risk has been 
reduced to the order of one in every 50,000 sessions in individuals without specific risk factors. 
Extensive training will be administered by Dr. Eric Wassermann, a neurologist and an expert in 
TMS, so study staff can effectively recognize and respond to adverse effects. Additionally, a 
licensed independent practitioner (LIP), a physician or nurse practitioner trained in TMS, will be 
in house, specifically aware of the session, and reachable by phone for all TMS sessions. 
Although this risk is more than minimal, the information to be gained is of great benefit. 
Episodic memory deficits occur in a variety of neurological and psychiatric disorders1–5, making 
them one of the most debilitating problems in neurology6,7. However, there currently exist no 
effective treatments for memory impairment. TMS has shown promise as a method of improving 
memory in healthy adults30–39, including older adults51. A better understanding of the effects of 
this tool on memory processing could inform novel treatments for individuals with memory 
impairments.   
 
3 
OBJECTIVES AND ENDPOINTS 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Primary 
 
 
1. Investigate how TMS 
modulates EEG 
1. Memory performance 
1. Memory performance 
measures will allow us to 

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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
neural measures of 
successful memory 
and the association of 
this modulation with 
behavioral 
performance 
 
2. Examine how 
memory task state 
influences 
susceptibility to 
plasticity via TMS 
and determine the 
optimal neural state 
for improving 
memory 
 
 
• Accuracy: Percentage of 
successful (later 
remembered hit and 
correct rejection) vs 
unsuccessful (forgotten 
miss and false alarm) trials 
for item recognition 
(remember/familiar/new) 
and context recollection 
(spatial location) 
• d’: Analysis of hits 
(correctly remembered as 
encoded) relative to false 
alarms (new objects 
labelled as encoded) for 
item recognition 
 
2. Late positive posterior ERP 
• ERP amplitude 500-700 
ms after trial onset 
(encoding and retrieval) 
over parietal and occipital 
electrodes 
 
3. Theta/alpha power 
(secondary) 
• Power in the 4-13 Hz band 
0-1000 ms after trial onset 
(encoding and retrieval) 
 
4. EEG functional connectivity 
(secondary) 
• Pearson correlation 
coefficients (r) between 
electrode time courses 
after trial onset (encoding 
and retrieval) 
 
examine the effects of 
TMS on performance, as 
well as to sort successful 
vs unsuccessful trials for 
EEG analyses 
 
2. The late positive posterior 
ERP has been previously 
shown to be a robust 
marker of successful 
memory performance25 
 
3. Task-induced changes in 
this frequency band have 
been previously associated 
with successful memory 
performance26 
 
4. fMRI functional 
connectivity modulation 
via network-targeted TMS 
has been previously 
associated with TMS-
induced memory 
improvement. Whether 
EEG functional 
connectivity will be 
similarly altered, and the 
relevance to memory 
changes, remains 
unknown  
Tertiary/Exploratory  
 
 
1. Search for MRI 
predictors of the 
1. Baseline fMRI functional 
connectivity 
It is hypothesized that TMS 
influences downstream targets 

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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
effects of parietal 
TMS 
 
• Resting state functional 
connectivity at baseline 
between the hippocampus 
and cortical regions 
 
2. Baseline DTI structural 
connectivity 
• Fractional anisotropy (FA) 
at baseline between the 
hippocampus and cortical 
regions 
 
(i.e., regions other than the 
stimulation site) via network 
connections. Associations 
between TMS outcomes and 
structural or functional 
connectivity would support 
this hypothesis, elucidating 
potential mechanisms of TMS 
effects 
 
4 
STUDY DESIGN 
This protocol is a single site study. The study will include a baseline 3T MRI session, and two 
experiments conducted during two sessions of simultaneous TMS, EEG, and cognitive testing 
(Figure 1). Both experiments will use the same participants to allow for within-subjects 
comparisons and the order of experiments will be counterbalanced. Participants who miss a 
session will be rescheduled or replaced (see Recruitment). Participants will make three visits to 
the lab, a baseline assessment session and two TMS/EEG sessions, for a time commitment of 
approximately 8 hours. TMS/EEG Session 1 will occur 1-31 days following the baseline visit 
and TMS/EEG Session 2 will occur 4-31 days following TMS/EEG Session 1 (Figure 1).  
 
Figure 1. Study Design 
 
On each TMS/EEG day, participants will undergo EEG recording using a 64-channel elastic cap. 
During recording, they will complete two blocks of a task, one for each experiment, which differ 
only in their timing of TMS delivery. Each block consists of  90 study trials of episodic memory 
encoding (45 trials) and spatial processing (45 trials) for a total of 180 trials (90 memory and 90 
spatial processing) per TMS/EEG session (Table 1).  
 
Table 1. Conditions and trial counts. 

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Parietal Stimulation 
Vertex Stimulation 
TOTAL 
Stim On 
Stim Off 
Stim On 
Stim Off 
Memory Spatial Memory Spatial Memory Spatial Memory Spatial 
Experiment 1 
30 
30 
15 
15 
30 
30 
15 
15 
180 
360 
Experiment 2 
30 
30 
15 
15 
30 
30 
15 
15 
180 
TMS will be paired with task trials and consist of 2-second trains of continuous theta burst 
stimulation (cTBS; see Study Procedures). In Experiment 1, TMS will be delivered during the 
rest phase immediately prior to trial onsets (Figure 2). In Experiment 2, TMS pulses will occur 
during the trial while participants are actively engaged in the task (Figure 2). The order of 
experiments will be counterbalanced across subjects within each session. TMS will be delivered 
to an episodic memory network-connected location in posterior parietal cortex (see 4.4.2. TMS, 
below) or to the vertex as an inactive control condition, and the order of stimulation location will 
be counterbalanced across TMS/EEG sessions. One-third of trials will contain no stimulation as 
an additional control to examine behavioral and neural effects in the absence of the TMS sensory 
artifact (Table 1). Participants will then be tested on encoded items, also with EEG recording. 
EEG data will be examined in an event-related design, with timeseries following trial onsets 
compared across task (memory encoding, spatial processing, and memory retrieval) and 
stimulation (parietal-TMS, vertex-TMS, and no-TMS) conditions. 
 
Figure 2. Experiment Design 
 
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 and via advertisements that will 
be pre-approved by the IRB. Although NIH employees will be allowed to participate, no direct 
solicitation of employees/staff by supervisors or co-workers will take place. Any recruitment 
material will be IRB approved. Participants who indicate interest will be pre-screened by phone. 
Pre-screening questions are listed in Appendix B. IRB-approved ads will be posted on NIH 
listservs with the permission of the moderator and IRB required statement on how the receiver 
was identified. Listservs may include NIH sponsored recruitment list serves such as (NIH HV 
recruitment list serv). Listserv announcement will include: 
“You are receiving this message because your email address is included in the above NIH 
Listserv/mailing list. The purpose of this message is to inform you of studies that are recruiting 

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volunteers at NIH, Bethesda, Maryland. The moderator of the listserv/mailing list has permitted 
its use for this distribution”. 
 
It is possible that some participants will miss a session. If this occurs, and the participant is still 
willing to participate, we will reschedule. If a participant no longer wishes to continue with the 
study, a new participant will be recruited for the full study. If they have data from one 
experiment, those data will still be included in analysis for that experiment but excluded from 
any comparisons across experiments.  
It is possible that technical problems may arise. If this occurs, and the participant is willing to 
continue with the study, we will reschedule. 
 
Screening  
Participants who pass pre-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 A.  
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.  
In some cases, consent, screening, and examination (when required) may be performed on the 
same day as the baseline MRI. 
 
Study procedures: 
 
Behavioral Tasks  
Memory Task: This is a test of episodic memory, including item recognition and context 
recollection30,52,53. In the task, participants will be shown a series of objects in one of four 
quadrants on the screen. They will be instructed to remember the objects and where they were 
located, both of which will be tested later. To ensure attention and for consistency with the 
spatial task (see below), they will be asked to indicate by button press whether the object is 
primarily used outdoors (e.g., a baseball) or indoors (e.g., a television). During the encoding 
phase, each object will be presented for 4 seconds with 4 seconds between trials. In Experiment 
1, TMS will occur during a 2 second cue before each trial and in Experiment 2, TMS will occur 
in the first 2 seconds of stimulus object presentation. There will be 180 encoding trials, 
interspersed with 180 trials of the spatial task (described below). Trial order will be randomized. 
The retrieval phase will occur following the end of encoding. Participants will be shown, 
sequentially and in randomized order, the 180 encoded objects and 180 new lure objects, for a 
total of 360 trials. For all trials, they will respond with whether the object was old (previously 
seen) or new (not previously seen) and their confidence on a scale of 1-6 (1=confident new, 

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6=confident old) as a measure of item recognition. If the object was previously seen, participants 
will then be asked which quadrant the item was presented in to provide a measure of context 
recollection. We will use two different versions of the task with different and non-overlapping 
sets of objects at the two test sessions and the order of versions will be counterbalanced across 
participants.  
 
Spatial Task: This is a test of spatial processing, which will serve as a control task to isolate 
neural markers of memory engagement, versus engagement in any task with similar visuospatial 
qualities. Notably, spatial processing activates a network of frontoparietal including the posterior 
parietal cortex regions54,55, allowing it to further serve as a control to isolate hippocampal 
network effects of TMS from the local effects of TMS on the stimulated region. In each trial of 
this task, participants will be shown an arrow pointing to one corner of the screen and displayed 
in one of four quadrants. They will be instructed to indicate by button press whether the arrow 
points to the corner in which it is displayed (“match,” e.g. pointing to the upper right corner in 
the upper right quadrant) or a different corner (“no-match,” e.g. pointing to the upper right corner 
in the upper left quadrant). Accuracy of match/no-match responses will be assessed. Each arrow 
will be presented for 4 seconds with 4 seconds between trials. In Experiment 1, TMS will occur 
during a 2 second cue before each trial and in Experiment 2, TMS will occur in the first 2 
seconds of stimulus presentation. There will be 180 trials, interspersed with encoding trials of the 
memory task. We will use two different versions of the task at the two test sessions.  
 
TMS 
The parietal target will be the region of the left posterior parietal cortex with the greatest 
connectivity with the left hippocampus derived from the baseline resting-state fMRI session31. 
This region was chosen because of its dense connections with the hippocampus56,57. Thus, 
stimulation of this location can modulate function of the hippocampal-cortical network30–36,38. 
 
The control target will be vertex, a commonly used active control site which does not influence 
neural or behavioral activity58. 
 
TMS 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 cortex31 will be used as our location of 
stimulation. To reduce the influence of diurnal variations in the responsiveness to neuroplasticity 
protocols59, we will make every effort to test subjects during the same time of day. 
 
Stimulation will be delivered during the encoding phase of the behavioral task, either prior to 
trial onset (Experiment 1) or simultaneously with trial onset (Experiment 2; see 4.4.1 Behavioral 
Tasks for timing) in the form of 2-seconds of theta-burst stimulation (50 Hz pulse triplets every 
200 ms; Figure 3) at 80% of the motor evoked potential threshold of the right abductor pollicis 
brevis muscle or 44% of maximum stimulator output, whichever is lower. This protocol has been 

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shown previously to particularly influence the hippocampal-cortical network and memory 
performance37–39. 
 
Figure 3. Theta-burst stimulation.  
 
 
EEG 
Participants will be fitted with a 64-channel elastic EEG cap for the duration of each experiment 
session. Data will be recorded continuously during the study and test phases of the behavioral 
experiment. The EEG signal will be amplified online, filtered, and digitized continuously along 
with stimulus onset codes used for subsequent analysis. Independent component analysis and/or 
other processing techniques will be performed to isolate and remove recurring artifacts from the 
signal. 
 
Single-trial waveforms will be screened for artifactual contamination. Trials will then be divided 
based on task type (spatial, memory encoding, accuracy of item recall (memory task) and spatial 
task performance. The timeseries from trials of the same type and/or accuracy will then be 
averaged, and the resulting waveforms will be compared across categories. For theta/alpha band 
analysis, we will additionally use time-frequency decomposition of the event-related averages.  
 
MRI 
We estimate a maximum of 1 hour for baseline scanning. Because scanner malfunctions and 
subsequent loss of data are common, we will not report these as unexpected problems. 
Participants whose data are lost due to scanner malfunctions will be rescheduled, if possible.  
Participants whose MRI sessions cannot be completed may enter the experiment if the MPRAGE 
(see below) data have been acquired.  They will be rescheduled for the other scans when 
possible. 
MRI anatomical scanning: All participants will have anatomical (MPRAGE) scans at baseline. 
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. 
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Resting-state scanning: All participants will receive a resting-state fMRI scan at baseline for 
identification of a TMS target. 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 10 min).  
Diffusion-weighted scanning: Participants will have a diffusion-weighted scan for diffusion 
tensor imaging (DTI) scanning at baseline to estimate white matter structural connectivity. This 
phase will take approximately 20 min.  This may be omitted in some cases due time constraints. 
 
Justifications for MRI and TMS non-significant risk (NSR) designation 
 
Research Pulse Sequences:  
a. These custom sequences all operate under the International Electrotechnical Commission (IEC) 
60601-2-33, First Level-Controlled Operating Mode. The IEC/FDA set operating mode limits on the 
MRI for RF heating (Specific Absorption Rate) and Time-varying magnetic field gradients (dB/dt) 
that are fully operational for all research pulse sequences. This device has not received pre-market 
approval or 510 (K) clearance by the FDA.  
 
MRI Research Analysis and Reconstruction Software:  
a. This software conforms to operate under the International Electrotechnical Commission (IEC) 
60601-2-33, First Level-Controlled Operating Mode. The IEC/FDA set operating mode limits on the 
MRI for RF heating (Specific Absorption Rate) and Time-varying magnetic field gradients (dB/dt) 
that are fully operational for all research pulse sequences. This device has not received pre-market 
approval or 510 (K) clearance by the FDA.  
 
 
Magstim Rapid2 with Air Film coil TMS (Magstim):  
 
a. This device is classified as an FDA cleared device with 510(K) clearance by the FDA #K143531, 
K162935. The indicated use according to the 510(K) is the treatment of Major Depressive Disorder 
in adult patients who have failed to achieve satisfactory improvement from prior antidepressant 
medication in the current episode. In this study, this device is intended to be used to investigate how 
TMS modulates EEG neural measures of successful memory and the association of this modulation 
with behavioral performance, and not for diagnostic purposes. Therefore, it does not conform to the 
510(k) label.  
 
 
BrainVision actiCHamp Plus EEG (Brain Vision): 
 
a. The Sponsor has confirmed with the manufacturer that there is no market clearance or approval for 
this device in the US and that the device does not meet criteria for exemption under 21CFR812. This 
device has not received pre-market approval or 510 (K) clearance by the FDA.  
 
According to 21 CFR 812.3 (m) and FDA “Information Sheet Guidance for IRBs, Clinical 
Investigators, and Sponsors: Significant Risk and Nonsignificant Risk and Nonsignificant Risk 
Medical Device Studies January 2006 (accessible at: 
http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126418.pdf) the use of 

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these devices in the study are a Non-significant Risk study. 21 CFR 812.3(m) enumerates four 
criteria for a Significant Risk Device Study; none of these apply to this study: 
1.  is intended as an implant and presents a potential for serious risk to the health, safety, or 
welfare of a subject; 
No.  All devices listed in this section are not intended as implants and do not 
present a potential for serious risk to the health, safety, and welfare of a 
subject 
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; 
No. All devices listed in this section are not purported or represented to be for 
3. a use in supporting or sustaining human life and presents no potential for serious risk to 
the health, safety, or welfare of a subject.is for a use of substantial importance in 
diagnosing, curing, mitigating, or treating disease, or otherwise preventing impairment of 
human health and presents a potential for serious risk to the health, safety, or welfare of a 
subject; or 
 
No. All devices listed in this section are not intended for use of substantial importance in 
diagnosing, curing mitigating, or treating disease, or otherwise preventing impairment of 
human health and presents no 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  
 
No. All devices listed in this section do not present a potential for serious risk to the health, 
safety, or welfare of subjects.  
  
The protocol will comply with the abbreviated IDE requirements under 21 CFR 812.2(b), 
available at:  
https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?fr=812.2 
 
Devices determined to be used on label or other exempted devices pursuant to 21CFR812.2(c):  
 
GE Discovery MR 750 System–3T. 510k: K163331 
 
a. This device and associated system carries an FDA 510(k) clearance . The Sponsor has 
determined that the device is used in the trial in accordance with this label.  
 
Primary Objective 
 
Primary Objective 1: Investigate how TMS modulates EEG neural measures of successful 
memory and the association of this modulation with behavioral performance  
• Hypotheses 

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o Network-targeted parietal-TMS will improve memory performance (context 
recollection; Primary Outcome Measure 1) on parietal-TMS relative to vertex-
TMS trials 
o Relative to vertex-TMS, parietal-TMS will also increase the Late Positive 
Posterior ERP (Primary Outcome Measure 2) and theta power (Secondary 
Outcome Measure 1) during encoding on successful trials, relative to unsuccessful 
trials 
o The EEG effects will correlate with memory improvement (Correlation, Primary 
Outcome Measure 1 and Primary Outcome Measure 2/Secondary Outcome 
Measure 1) 
o Additionally, parietal-TMS will alter EEG functional connectivity patterns 
(Exploratory Outcome Measure 1) at encoding during successful trials relative to 
unsuccessful trials 
o Parietal-TMS will not influence neural activity or accuracy for spatial trials, 
relative to vertex-TMS and no-TMS 
 
Primary Objective 2: Examine how memory task state influences susceptibility to plasticity via 
TMS and determine the optimal neural state for improving memory 
• Hypotheses 
o Network-targeted parietal-TMS during memory encoding will have a larger effect 
on source recollection (Primary Outcome Measure 1), relative to pre-trial parietal-
TMS and vertex-TMS during encoding 
o Exploratory Analyses:  
§ Parietal-TMS during memory encoding will increase the Late Positive 
Posterior ERP (Primary Outcome Measure 2) and theta-power (Secondary 
Outcome Measure 1), relative to pre-trial parietal-TMS and vertex-TMS 
during encoding  
§ Additionally, parietal-TMS will alter EEG functional connectivity patterns 
(Exploratory Outcome Measure 1) during later-remembered trials, relative 
to pre-trial parietal-TMS and vertex-TMS during encoding 
§ Network-targeted TMS will not influence neural activity during arithmetic 
trials, relative to vertex-TMS and no-TMS 
 
Exploratory Objective: 
Search for MRI predictors of the effects of parietal TMS 
•  Measurement of baseline resting-state functional connectivity (Exploratory Outcome 
Measure 3) and fractional anisotropy (Exploratory Outcome Measure 4) between the 
hippocampus and cortical regions of the episodic memory network, particularly the 
precuneus60 , and look for correlations with the effects of TMS on memory and task-
related EEG events across participants. 
 
 
End of participation 
Participants 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 

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clinical significance, e.g., significant pathology on MRI will be shared with participants and any 
provider whom they designate.  
 
4.1 
CONCOMITANT THERAPY 
Not applicable 
 
5 
STUDY POPULATION 
5.1 
INCLUSION CRITERIA 
In order to be eligible to participate in this study, an individual must meet all of the following 
criteria: 
1. Stated willingness to comply with all study procedures and availability for the duration of 
the study  
2. Ability of subject to understand and the willingness to sign a written informed consent 
document. 
3. Age 18-40 (inclusive) 
 
5.2 
EXCLUSION CRITERIA 
An individual who meets any of the following criteria will be excluded from participation in this 
study: 
1.) Any current major neurological or psychiatric disorder such as (but not limited to) 
stroke, Parkinson disease, Alzheimer disease, schizophrenia or major depression 
2.) History of seizure 
3.) Medications acting on the central nervous system, such as those that lowers the 
seizure threshold such as neuroleptics, beta lactams, isoniazid, metronidazole; 
benzodiazepines, tricyclic or other antidepressants; or prescription stimulants. 
4.) Inability to provide informed consent 
5.) Ferromagnetic metal in the cranial cavity or eye, implanted neural stimulator, 
cochlear implant, or ocular foreign body 
6.) Implanted cardiac pacemaker or auto-defibrillator or pump 
7.) Non-removable body piercing 
8.) Claustrophobia 
9.) Inability to lie supine for 1 hour 
10.) 
Pregnancy, or plans to become pregnant during the study. 
11.) 
Members of the NINDS BNU 
12.) 
Subjects who have contraindications to MRI will follow the NMR Center 
guidelines for MR safety  
 
An eligibility checklist is provided in Appendix A. 
 

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5.3 
INCLUSION OF VULNERABLE PARTICIPANTS 
5.3.1 Participation of Employees  
NIH employees may be enrolled in this study as this population meets the study entry criteria.  
Neither participation nor refusal to participate as a subject in the research will have an effect, 
either beneficial or adverse, on the participant’s employment or position at NIH. 
Every effort will be made to protect participant information, but such information may be 
available in medical records and may be available to authorized users outside of the study team 
in both an identifiable an unidentifiable manner. 
The NIH Information Sheet on Employee Research Participation will be made available.  Please 
see section 9.1.5 for consent of employees. 
 
5.3.2 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 of childbearing potential will have a pregnancy test before each MRI session.  
Women who are pregnant will be excluded and women who can become pregnant will be 
excluded following a positive pregnancy test.  
 
5.3.3 Adults who lack capacity to consent 
Adults who are unable to provide initial informed consent will be excluded from this study. 
Adults who permanently lose the capacity to provide on-going consent subsequent to giving 
initial consent will be removed from the study and compensated for what they have completed. 
 
5.4 
LIFESTYLE CONSIDERATIONS 
Not applicable  
 
5.5 
SCREEN FAILURES 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently entered in the study. A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure participants, to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, eligibility criteria, 
and any serious adverse event (SAE). 
Individuals who do not meet the criteria for participation in this study (screen failure) because of 
a medication or pregnancy may be rescreened. Rescreened participants should be assigned the 
same participant number as for the initial screening. 
 

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5.6 
STRATEGIES FOR RECRUITMENT AND RETENTION 
The protocol will study 32 healthy individuals. Participants who are withdrawn or drop out from 
the study will be replaced. NIH employees who are not members of the BNU will be allowed to 
participate. Based on current experience, the anticipated non-completion rate is 22%, due to 
screen failures, individual characteristics making stimulation impossible, such as very high 
motor evoked potential threshold, non-removable hair braiding, and other issues discovered after 
consenting. 
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. Any recruitment material will be IRB approved. Participants who indicate interest 
will be pre-screened by phone. Pre-screening questions are listed in Appendix B. 
It is possible that some participants will miss a session. If this occurs, and the participant is still 
willing to participate, they will be rescheduled. If a participant no longer wishes to continue with 
the study, a new participant will be recruited for the full study. If they have data from one 
experiment, those data may be included in analysis for that experiment but excluded from any 
comparisons across experiments.  
It is possible that technical problems may arise. If this occurs, and the participant is willing to 
continue with the study, they will be rescheduled. 
When data from a subject are not usable due to noise or other technical problems, a new 
participant will be recruited for the full study to achieve a sample of 32 complete subjects.  
5.6.1 Costs 
N.A. 
5.6.2 Compensation 
All participants will be compensated for time and research-related inconveniences in accord with 
NIH guidelines as follows:  
 
Compensation for time 
First hour 
 
 
$20 
 
Additional hours 
 
$10  
 
 
 
 
 
Compensation for inconveniences 
Participants will be paid $10.00 per one Inconvenience Unit (IU).  
 
fMRI testing (4 IU) 
 
 
$40 
TMS testing (4 IU)  
 
 
$40 
EEG testing (2 IU) 
 
 
$20 

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Behavioral Tasks (2 IU) 
 
$20 
Pregnancy Test (1 IU) 
 
$10 
 
Payment (check) will be mailed to participants after they complete the protocol, or by direct 
deposit if available. 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. 
6 
PARTICIPANT DISCONTINUATION/WITHDRAWAL  
6.1 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
Participants are free to withdraw from participation in the study at any time upon request.  
An investigator may discontinue or withdraw a participant from the study for the following 
reasons: 
• Significant non-compliance  
• If the participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation 
• Subject has completed the study follow-up period 
• Death 
• Screen Failure 
The reason for participant discontinuation or withdrawal from the study will be recorded on the 
Case Report Form (CRF). 
6.2 
LOST TO FOLLOW-UP 
A participant will be considered lost to follow-up if he or she fails to return for two scheduled 
visits and is unable to be contacted by the study site staff.  
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• The site will make one attempt to contact the participant and reschedule the missed visit 
within one week and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain if the participant wishes to and/or should continue in 
the study. 
• Before a participant is deemed lost to follow-up, the investigator or designee will make 
one attempt to regain contact with the participant either by email or telephone.   
• Should the participant continue to be unreachable, despite this attempt, he or she will be 
considered lost to follow-up. 

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• It is possible that a participant deemed lost to follow-up will recontact the investigators to 
return to the study. In this case, if it is within six months of their consent date, they will 
be rescheduled. The subject will keep their previously assigned subject number. 
 
7 
STUDY ASSESSMENTS AND PROCEDURES 
7.1 
SCREENING PROCEDURES 
7.1.1 Screening activities performed prior to obtaining informed consent 
Minimal risk activities that may be performed before the subject has signed a consent include the 
following:  
• Email, written, in person or telephone communications with prospective subjects.  
• Review of existing medical records to include H&P, laboratory studies, etc.   
• Review of existing MRI, x-ray, or CT images. 
7.1.2 Screening activities performed after a consent for screening has been signed 
The following activities will be performed only after the subject has signed the consent this 
study: 
• Pregnancy test 
• Clinical MRI scan, if none has been obtained within the last year 
7.2 
CLINICAL EVALUATIONS 
MRI: 3T MRI will take an estimated 1 hour for baseline scanning.  
MRI anatomical scanning: All participants will have anatomical (MPRAGE) scans at baseline. 
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.  
Resting-state scanning: All participants will receive a resting-state fMRI scan at baseline for 
identification of a TMS target. 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 10 min).  
Pregnancy testing: All participants of childbearing potential will undergo pregnancy testing 
before each MRI scan. 
Assessment of adverse events will be monitored, tracked, documented, and reported by study 
investigators and the PI 
 
7.3 
BIOSPECIMEN EVALUATIONS 
Not applicable 

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7.3.1 Correlative Studies for Research 
Not applicable 
7.3.2 Samples for Genetic/Genomic Analysis 
Not applicable 
8 
STATISTICAL CONSIDERATIONS 
8.1 
STATISTICAL HYPOTHESIS 
The primary aims are to investigate how TMS alters the EEG biomarkers of successful memory 
performance and how memory state-related neural changes influence plasticity of the brain. 
Secondary aims for this protocol will include examining the MRI connectivity predictors of TMS 
effects. 
• Primary Objective 1: Investigate how TMS modulates EEG neural measures of successful 
memory and the relevance of modulation to behavioral performance 
• Hypotheses 
a. Network-targeted parietal-TMS will improve memory performance (context 
recollection; Primary Endpoint 1) relative to vertex-TMS trials 
b. Relative to vertex-TMS, parietal-TMS will also increase the Late Positive 
Posterior ERP (Primary Endpoint 2) and theta power (Primary Endpoint 3) during 
encoding on successful trials, relative to unsuccessful trials 
c. Parietal-TMS will alter EEG functional connectivity patterns (Primary Endpoint 
4) at encoding during successful trials relative to unsuccessful trials 
d. The EEG effects will correlate with memory improvement (Correlation, Primary 
Endpoint 1 and 2-4) 
e. Parietal-TMS will not influence neural activity or accuracy for spatial trials, 
relative to vertex-TMS and no-TMS 
 
• Primary Objective 2: Examine how memory task state influences susceptibility to plasticity 
via TMS and determine the optimal neural state for improving memory 
• Hypotheses 
a. Network-targeted parietal-TMS during memory encoding will have a larger effect 
on memory performance (Primary Endpoint 1), relative to pre-trial parietal-TMS 
and vertex-TMS during encoding 
b. Exploratory Analyses:  
i. Parietal-TMS during memory encoding will increase the Late Positive 
Posterior ERP (Primary Endpoint 2) and theta-power (Primary Endpoint 
3), relative to pre-trial parietal-TMS and vertex-TMS during encoding  
ii. Additionally, parietal-TMS will alter EEG functional connectivity patterns 
(Primary Endpoint 4) during later-remembered trials, relative to pre-trial 
parietal-TMS and vertex-TMS during encoding 
iii. Network-targeted TMS will not influence neural activity during arithmetic 
trials, relative to vertex-TMS and no-TMS 
 

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• Exploratory Objective: Determine MRI predictors of the effects of noninvasive stimulation 
We will examine the correlations between stimulation effects on our behavioral and 
neural outcome measures (Primary Endpoint 1 and Primary Endpoints 2-4) and MRI 
measures of structural and functional connectivity (Exploratory Endpoints 1-2). For each 
participant, the Pearson correlation between (1) the difference in outcome measures 
paired with parietal-TMS and vertex-TMS and (2) hippocampal FA or hippocampal 
functional connectivity will be calculated. Thresholds for significant effects will be set at 
p<0.05 following FDR correction for multiple comparisons. 
 
8.2 
SAMPLE SIZE DETERMINATION 
All experiments in this protocol are powered based on the primary outcome, which relates to the 
effects of TMS on memory and its neural correlates.  
A power analysis was conducted using G*Power v3.1.9.7. We used a repeated-measures, within-
factors ANOVA based on a previous study with a similar design39. Like the proposed 
experiments, this study delivered 2-second trains of TMS prior to trials of memory encoding or a 
control task and examined the effects on later memory performance and on neural activity, in this 
case hippocampal fMRI activity, during encoding. They used a three-way repeated-measures 
ANOVA to examine the interactions between TMS presence (on vs off), frequency (theta-burst 
vs 12.5 Hz beta), and location (parietal cortex vs supplementary motor area) and found an effect 
size of theta burst parietal-TMS on memory performance of η2=0.44 and fMRI hippocampal 
activity of η2=0.28. As the proposed analyses will also use three-way repeated-measures 
ANOVAs (see Section 8.3.2), we calculated subject number based on these effect sizes, power of 
0.80, and α = 0.05 shared across two primary outcomes, memory performance and the late 
positive posterior ERP (α = 0.025 for each outcome). Thirty-two participants with complete data 
will be needed. To achieve n=32, we will recruit up to 50 subjects to account for potential non-
completion (e.g., screen failure, subject withdrawal) or unusable data (e.g., due to noise).  
 
8.3 
STATISTICAL ANALYSES 
8.3.1 General Approach 
The primary aims are to investigate how TMS alters the EEG biomarkers of successful memory 
performance and how memory state-related neural changes influence plasticity of the brain. 
Secondary aims for this protocol will include examining the MRI connectivity predictors of TMS 
effects. 
8.3.2 Analysis of the Primary Endpoints 
• Primary Endpoint 1: Investigate how TMS modulates EEG neural measures of successful 
memory and the relevance of modulation to behavioral performance 
This aim will examine behavioral and EEG neural outcome measures (Primary Endpoints 
1-4). We will perform 3x3 ANOVAs on each outcome measure with the factors trial type 
(successful/ unsuccessful/ spatial), stimulation site (parietal/ vertex/ none), and their 
interaction. We will particularly focus on the main effect of stimulation site to determine 

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the influence of parietal-TMS on memory performance and its neural correlates, and the 
interaction effect to determine the task specificity of TMS effects. Thresholds for 
significant effects will be set at p<0.025 following FDR correction for multiple 
comparisons. 
 
• Primary Endpoint 2: Examine how memory task state influences susceptibility to plasticity 
via TMS and determine the optimal neural state for improving memory 
This aim will examine behavioral and EEG neural outcome measures (Primary Endpoints 
1-4). We will perform 3x3x2 ANOVAs on each outcome measure with the factors trial 
type (successful/ unsuccessful/ spatial), stimulation site (parietal/ vertex/ none), 
stimulation timing (pre-trial and mid-trial) and their interaction. We will particularly 
focus on the interaction effect of stimulation site and timing to determine the influence of 
memory task-state parietal-TMS on memory performance and its neural correlates, and 
the three-way interaction effect to determine the task specificity of state-dependent TMS 
effects. Thresholds for significant effects will be set at p<0.025 following FDR correction 
for multiple comparisons. 
 
8.3.3 Tabulation of individual Participant Data 
Not applicable 
 
8.3.4 Exploratory Analyses 
Determine MRI predictors of the effects of noninvasive stimulation:  The correlations between 
stimulation effects on our behavioral and neural outcome measures (Primary Outcome Measures 
1-2, Secondary Outcome Measure 1, Exploratory Outcome Measure 1) and MRI measures of 
structural and functional connectivity (Exploratory Outcome Measures 2-3) will be examined. 
For each participant, the Pearson correlation between (1) the difference in outcome measures 
paired with parietal-TMS and vertex-TMS and (2) hippocampal FA or hippocampal functional 
connectivity will be calculated. Thresholds for significant effects will be set at p<0.05 following 
FDR correction for multiple comparisons. 
9 
REGULATORY AND OPERATIONAL CONSIDERATIONS 
9.1 
INFORMED CONSENT PROCESS 
9.1.1 Consent/Assent Procedures and Documentation 
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. 
 
The consent form contains all required elements. The consent form is submitted with this 
protocol.   
9.1.2 Consent for minors when they reach the age of majority  
Not applicable 

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9.1.3 Telephone consent  
Not applicable 
9.1.4 Telephone assent 
Not applicable 
9.1.5 Considerations for Consent of NIH employees 
Consent for NIH employees will be obtained as detailed above with following additional 
protections: 
Consent from employees will be obtained by an individual independent of the employee’s team 
whenever possible.  Otherwise, the consent procedure will be independently monitored by the 
CC Department of Bioethics Consultation Service in order to minimize the risk of undue 
pressure on the employee. 
9.1.6 Consent of Subjects who are/become Decisionally Impaired 
Not applicable 
9.2 
STUDY DISCONTINUATION AND CLOSURE 
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause.  Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to study participants, 
investigator, and regulatory authorities.  If the study is prematurely terminated or suspended, the 
Principal Investigator (PI) will promptly inform study participants, and the Institutional Review 
Board (IRB), and will provide the reason(s) for the termination or suspension.  Study participants 
will be contacted, as applicable, and be informed of changes to study visit schedule. 
 Circumstances that may warrant termination or suspension include, but are not limited to: 
• Determination of unexpected, significant, or unacceptable risk to participants 
• Insufficient compliance to protocol requirements 
• Data that are not sufficiently complete and/or evaluable 
• Determination that the primary endpoint has been met 
Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the IRB. 
9.3 
CONFIDENTIALITY AND PRIVACY 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, 
their staff, and the sponsor(s) and their interventions. This confidentiality is extended to cover 
testing of biological samples and genetic tests in addition to the clinical information relating to 
participants. Therefore, the study protocol, documentation, data, and all other information 
generated will be held in strict confidence.  
All research activities will be conducted in as private a setting as possible. 
The study monitor, representatives of the Institutional Review Board (IRB), and/or regulatory 
agencies may inspect all documents and records required to be maintained by the investigator, 

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including but not limited to, medical records (office, clinic, or hospital) and pharmacy records 
for the participants in this study. The clinical study site will permit access to such records. 
The study participant’s contact information will be securely stored at each clinical site for 
internal use during the study. At the end of the study, all records will continue to be kept in a 
secure location for as long a period as dictated by the reviewing IRB, Institutional policies, or 
sponsor requirements. 
Study participant research data, which is for purposes of statistical analysis and scientific 
reporting, will be transmitted to and stored at the NIH. This will not include the participant’s 
contact or identifying information. Rather, individual participants and their research data will be 
identified by a unique study identification number. The study data entry and study management 
systems used by clinical sites and by NIH research staff will be secured and password protected. 
At the end of the study, all study databases will be de-identified and archived at the NIH. 
To further protect the privacy of study participants, a Certificate of Confidentiality has been 
issued by the National Institutes of Health (NIH).  This certificate protects identifiable research 
information from forced disclosure. It allows the investigator and others who have access to 
research records to refuse to disclose identifying information on research participation in any 
civil, criminal, administrative, legislative, or other proceeding, whether at the federal, state, or 
local level. By protecting researchers and institutions from being compelled to disclose 
information that would identify research participants, Certificates of Confidentiality help achieve 
the research objectives and promote participation in studies by helping assure confidentiality and 
privacy to participants. 
9.4 
FUTURE USE OF STORED SPECIMENS AND DATA 
Study participant research data, which is for purposes of statistical analysis and scientific 
reporting, will be transmitted to and stored on password-protected computers or backed up on 
media stored in locked cabinets within locked BNU offices. Keys to participant identity will be 
stored in lab notebooks, available only to study investigators. Samples will not be stored under 
this protocol. All data will not include the participant’s contact or identifying information. 
Rather, individual participants and their research data will be identified by a unique study 
identification number. 
Genetic testing will not be performed.  
9.5 
SAFETY OVERSIGHT 
9.5.1 Principal Investigator/Research Team  
The clinical research team will meet on a regular basis (approximately weekly) when subjects are 
being actively enrolled/evaluated on the study to discuss each subject.   
All data will be collected in a timely manner and reviewed by the principal investigator or a lead 
associate investigator. Events meeting requirements for expedited reporting as described in 
HRPP Policy 801 will be submitted within the required timelines.  
The principal investigator will review all data on each subject to ensure safety and data accuracy. 
The principal investigator will personally conduct or supervise the investigation and provide 
appropriate delegation of responsibilities to other members of the research staff.  

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9.6 
CLINICAL MONITORING 
Not applicable 
9.7 
QUALITY ASSURANCE AND QUALITY CONTROL 
The NINDS Quality Assurance (QA) Audit Committee will periodically monitor the protocol. 
This protocol will undergo periodic review by the QA Audit Committee as outlined in the 
NINDS QA Standard Operating Procedure (SOP).  
The purpose of the QA audit is to assess compliance with applicable regulatory requirements, 
good clinical practice guidelines, NINDS/NIH policies, as well as to provide recommendations 
for improving the management of clinical research data. The protocol will be audited according 
to the decision algorithm as described in the NINDS SOP.  
 
9.8 
DATA HANDLING AND RECORD KEEPING 
 Data Collection and Management Responsibilities 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site investigator. The investigator is responsible for ensuring the accuracy, completeness, 
legibility, and timeliness of the data reported. 
All source documents should be completed in a neat, legible manner to ensure accurate 
interpretation of data.   
Hardcopies of the study visit worksheets will be provided for use as source document worksheets 
for recording data for each participant enrolled in the study.  Data recorded in the electronic case 
report form (eCRF) derived from source documents should be consistent with the data recorded 
on the source documents.  
Clinical data (including adverse events (AEs), concomitant medications, and expected adverse 
reactions data) and clinical laboratory data will be entered into CiSTAR, a 21 CFR Part 11-
compliant data capture system provided by the NINDS. The data system includes password 
protection and internal quality checks, such as automatic range checks, to identify data that 
appear inconsistent, incomplete, or inaccurate. Clinical data will be entered directly from the 
source documents. 
9.8.1 Study Records Retention 
Study documents should be retained as per the NIH Intramural Records Retention Schedule. No 
records will be destroyed without the written consent of the sponsor, if applicable. It is the 
responsibility of the sponsor to inform the investigator when these documents no longer need to 
be retained. 
9.9 
UNANTICIPATED PROBLEMS 
9.9.1 Definition of Unanticipated Problems (UP) 
Any incident, experience, or outcome that meets all of the following criteria: 
• Unexpected in terms of nature, severity, or frequency given (a) the research procedures 
that are described in the protocol-related documents, such as the Institutional Review 

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Board (IRB)-approved research protocol and informed consent document; and (b) the 
characteristics of the participant population being studied; and 
• Related or possibly related to participation in the research (“possibly related” means there 
is a reasonable possibility that the incident, experience, or outcome may have been 
caused by the procedures involved in the research); and 
• Suggests that the research places participants or others (which many include research 
staff, family members or other individuals not directly participating in the research) at a 
greater risk of harm (including physical, psychological, economic, or social harm) than 
was previously known or expected. 
9.9.2 Unanticipated Problem Reporting  
The investigator will report unanticipated problems (UPs) to the NIH Institutional Review Board 
(IRB) as per Policy 801. 
9.10 PROTOCOL DEVIATIONS AND NON-COMPLIANCE 
It is the responsibility of the investigator to use continuous vigilance to identify and report 
deviations and/or non-compliance to the NIH Institutional Review Board as per Policy 801.  The 
investigator is responsible for knowing and adhering to the reviewing IRB requirements. 
9.10.1 NIH Definition of Protocol Deviation 
A protocol deviation is any changed, divergence, or departure from the IRB-approved research 
protocol.  
• Major deviations: Deviations from the IRB approved protocol that have, or may have the 
potential to, negatively impact the rights, welfare or safety of the subject, or to 
substantially negatively impact the scientific integrity or validity of the study. 
• Minor deviations: Deviations that do not have the potential to negatively impact the 
rights, safety or welfare of subjects or others, or the scientific integrity or validity of the 
study. 
9.11 PUBLICATION AND DATA SHARING POLICY 
9.11.1 Human Data Sharing Plan 
This study will be conducted in accordance with the following publication and data sharing 
policies and regulations: 
National Institutes of Health (NIH) Public Access Policy, which ensures that the public has 
access to the published results of NIH funded research. It requires scientists to submit final peer-
reviewed journal manuscripts that arise from NIH funds to the digital archive PubMed Central 
upon acceptance for publication. 
This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of 
NIH-Funded Clinical Trial Information and the Clinical Trials Registration and Results 
Information Submission rule. As such, this trial will be registered at ClinicalTrials.gov, and 
results information from this trial will be submitted to ClinicalTrials.gov. In addition, every 
attempt will be made to publish results in peer-reviewed journals.  Data from this study may be 

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requested from other researchers after the completion of the primary endpoint by contacting Dr. 
Eric Wassermann. 
9.11.2 Genomic Data Sharing Plan 
Not applicable 
9.12 CONFLICT OF INTEREST POLICY 
The independence of this study from any actual or perceived influence is critical.  Therefore, any 
actual conflict of interest of persons who have a role in the design, conduct, analysis, publication, 
or any aspect of this trial will be disclosed and managed. Furthermore, persons who have a 
perceived conflict of interest will be required to have such conflicts managed in a way that is 
appropriate to their participation in the design and conduct of this trial.  The study leadership in 
conjunction with the NINDS has established policies and procedures for all study group 
members to disclose all conflicts of interest and will establish a mechanism for the management 
of all reported dualities of interest. 
10 ABBREVIATIONS 
 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
CFR 
Code of Federal Regulations 
CONSORT Consolidated Standards of Reporting Trials 
CRF 
Case Report Form 
cTBS 
Continuous Theta Burst Stimulation 
DCC 
Data Coordinating Center 
DTI 
Diffusion Tensor Imaging 
EC 
Ethics Committee 
EEG 
Electroencephalography 
ERP 
Event Related Potential 
eCRF 
Electronic Case Report Forms 
FA 
Fractional Anisotropy 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
ICH 
International Conference on Harmonisation  
ICMJE 
International Committee of Medical Journal Editors 
IRB 
Institutional Review Board 
MRI 
Magnetic Resonance Imaging 
NIH IC 
NIH Institute or Center 
OHRP 
Office for Human Research Protections 
PI 
Principal Investigator 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 

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SMC 
Safety Monitoring Committee 
SOA 
Schedule of Activities 
SOP 
Standard Operating Procedure 
TMS 
Transcranial Magnetic Stimulation 
UP 
Unanticipated Problem 
US 
United States 
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