Modulating the Hippocampal and Striatal Memory Networks With rTMS
Phase: NA
Conditions: Normal Behavioral Patterns
Sponsor: National Institute of Neurological Disorders and Stroke (NINDS)

 
CNS IRB Protocol Template (5.4.17) 
 
 
Protocol Title: Modulating the hippocampal and striatal memory networks with rTMS 
Abbreviated Title: Memory systems and rTMS 
Protocol Number: 19-N-0114 
Date of This Submission/Version: 10.23.2020 Version 5 
 
Principal Investigator 
 
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 
 
 
Précis: 
 
Objective 
The Behavioral Neurology Unit studies the human brain systems underlying learning and adaptation with 
the ultimate goal of finding interventions to make these processes more efficient. We are interested in 
whether repetitive transcranial magnetic stimulation (rTMS) can alter functional connectivity (FC) and 
behavioral efficiency in two memory networks in the brain: the hippocampal network, which supports the 
storage and retrieval of recallable facts, concepts, and events, and the striatal network, which supports the 
storage and retrieval of skills and habits. Additionally, because these networks interact behaviorally and 
can interfere with each other, an important question is whether neuromodulation of one network changes 
connectivity and efficiency in the other network. Pilot data from our group suggest that exogenous 
stimulation of one network causes it to expand its range of FC and co-opt resources from the other, which 
is a potential mechanism for the observed behavioral interaction. This study is designed to test a) whether 
rTMS- modulates within-network FC and memory supported by that network, and b) whether this also 
causes FC and behavioral changes in the other network.  
 
Study population: Healthy Volunteers 
 
Design 
This study contains four between-subjects experiments and is a mixed inter-/intra subject design. 
Experiment 1 will use nominally excitatory stimulation targeting the hippocampal network to increase FC 
within the hippocampal network. We also expect to increase FC between the hippocampal and striatal 
networks, increased declarative memory, and a possible decrease in procedural, learning. Experiment 2 
will use excitatory stimulation targeted to the striatal network. We expect this to cause stronger within-
network FC in the striatal network, increased FC between the hippocampus and the striatal network and 
concomitant behavioral effects. Experiments 3 and 4 will be similar except that we will target nominally 
inhibitory stimulation to these networks and look for the inverse results. FC will be measured under 
resting and task-activated conditions and active rTMS will be compared to vertex sham. 
 
Outcome measures 

 
 
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The primary outcome measure is the change in FC produced by rTMS within the targeted network. 
Between-network FC changes and corresponding memory changes will be secondary outcomes. 
Exploratory measures will include correlations between individual cognitive differences (questionnaires 
and NIH Toolbox scores), and our primary and secondary outcome measures. 
 
 
 

 
 
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Table of Contents  
Précis: .................................................................................................................................................................... 13 
List of Abbreviations ........................................................................................................................................ 45 
1. 
Introduction and Background ............................................................................................................. 56 
2. 
Study Objectives ....................................................................................................................................... 89 
3. 
Subjects .................................................................................................................................................... 910 
4. 
Study Design and Methods .................................................................................................................... 10 
5. 
Management of Data and Samples ..................................................................................................... 15 
6. 
Additional Considerations .................................................................................................................... 15 
7. 
Risks and Discomforts ....................................................................................................................... 1615 
8. 
Subject Safety Monitoring ................................................................................................................ 1917 
9. 
Outcome Measures ............................................................................................................................. 1917 
10. 
Statistical Analysis ......................................................................................................................... 1918 
11. 
Human Subjects Protection ........................................................................................................ 2119 
14. 
Consent Documents and Process ................................................................................................... 22 
15. 
Data and Safety Monitoring ............................................................................................................. 22 
16. 
Quality Assurance (QA) ................................................................................................................ 2322 
17. 
Reporting of Unanticipated Problems, Adverse Events and Protocol Deviations ......... 23 
18. 
Alternatives to Participation ...................................................................................................... 2324 
19. 
Privacy ............................................................................................................................................... 2324 
20. 
Confidentiality ................................................................................................................................. 2324 
21. 
Conflict of Interest .............................................................................................................................. 24 
22. 
Technology Transfer ..................................................................................................................... 2425 
23. 
Research and Travel Compensation ........................................................................................ 2425 
24. 
References ............................................................................................................................................. 26 
25. 
Attachments/ Appendices ........................................................................................................... 3029 
26. 
Consent Forms ................................................................................................................................. 3433 
 
 
 

 
 
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List of Abbreviations  
rTMS  
repetitive Transcranial Magnetic Stimulation 
fMRI  
functional Magnetic Resonance Imaging 
BOLD  
Blood-Oxygen Level Dependency 
FC 
 
Functional Connectivity 
rsFC 
 
resting-state Functional Connectivity 
tbFC 
 
task-based Functional Connectivity 
WPT-F  
Weather Prediction Task Feedback Version 
WPT-O  
Weather Prediction Task Observational Version 
ARSQ  
Amsterdam Resting-State Questionnaire 
 
 

 
 
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1. Introduction and Background 
a. 
Background 
Memory deficits are among the most debilitating problems in neurology (Nestor et al., 2005; Vakil, 
2005), reduce quality of life for caregivers (Kreutzer et al., 1994), and tax the American public financially 
(e.g., $80-100 billion/yr for Alzheimer disease; CDC & NCCDPHP, 2000). Memory is affected 
disproportionately among cognitive functions in traumatic brain injury (TBI; Levin et al., 1988) and an 
estimated 3.2-5.3 million Americans are living with a TBI-related disability (Frieden et al., 2015). 
Because there are no accepted methods for improving memory in amnestic patients, new approaches are 
urgently needed. Additionally, the rise in popularity of “brain training” indicates a growing interest in 
improving memory amongst healthy adults (Rabipour & Raz, 2012). While behavioral approaches such as 
brain training have gained popularity, their utility to everyday human function is controversial (Simons et 
al., 2016).  
 
Cognitive functions, such as memory, reside in brain networks (Power et al., 2011) and brain disorders 
disrupt these networks, causing effects on behavior (Gratton et al., 2012). The two characterized memory 
networks are the striatum-centered memory system (Keele et al., 2003; Knowlton et al., 1996), and 2) the 
hippocampal-centered memory system (Knowlton et al., 1996; Raichle et al., 2001). The striatal system 
supports the encoding and retrieval of skills and habits through repetition (e.g., riding a bike; procedural 
memories), whereas the hippocampal system supports the encoding and retrieval of recallable facts 
related to objects, events, or concepts (e.g., knowing a bike has two wheels; declarative memories). 
Although commonly discussed as discrete systems, they interact (Mattfeld & Stark, 2010, 2015; Poldrack 
et al., 2001), and learning typically involves both declarative and procedural acquisition. (Ghilardi et al., 
2009). Evidence from neuroimaging (Mattfeld & Stark, 2010, 2015; Poldrack et al., 2001), behavioral 
studies in healthy subjects (Ashby & Crossley, 2010; Foerde et al., 2006, 2007) and patients (Foerde et 
al., 2013; Moody et al., 2004), and lesion experiments in rats (Lee et al., 2008; Packard & McGaugh, 
1996), support a competitive relationship between systems. For example, engaging in learning of one 
memory type can interfere with learning of the other (Brown & Robertson, 2007; Cohen & Robertson, 
2011). 
 
rTMS has been shown to improve declarative memory (Wang et al., 2014; Figure 1), but it is unknown 
whether this enhancement is associated with behavioral effects on procedural memory or whether 
modulation of the striatal network affects declarative memory. Although TMS has been used to show a 
double dissociation between stimulation of different cortical sites and their effects on procedural and 
declarative memory (Cohen & Robertson, 2011; Galea et al., 2010), these studies did not include a 
measure of target engagement. Therefore, these studies cannot be considered mechanistically informative. 
To optimize the effect of rTMS on learning and memory, a mechanistic understanding of how these 
improvements occur is required. We will attempt to fill this gap by using functional connectivity (FC) as 
a marker of target engagement, and measuring changes in procedural and declarative learning. Because 
understanding mechanistic changes are necessary to optimize the effect on behavior, changes in FC will 
serve as our primary outcome measure. 
 

 
 
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field, rTMS affects network-level activity beyond the site of stimulation (Fox et al., 2012). By applying 
rTMS to a cortical site known to be connected to a network of interest, it is possible to modulate the FC 
of that network (Eldaief et al., 2011; Rahnev et al., 2013; Steel et al., 2016; van der Werf et al., 2010; 
Vercammen et al., 2010). Wang, and colleagues (2014) delivered nominally excitatory (20 Hz) rTMS to 
the subject-specific posterior parietal cortex (PPC) site that was maximally connected to the anterior 
hippocampus and observed robust increases in hippocampal network FC. Specifically, this technique 
increased resting-state FC (rsFC) between the hippocampus and several cortical regions (Fig. 3 Image 
showing Stiumlation-dependent enhancement of hippocampal network). These changes were specific to 
the hippocampal network, and not the local site of stimulation, as the voxels throughout the brain with the 
highest baseline FC with the hippocampus showed the largest FC increase. Furthermore, these effects 
were present two-weeks later (Wang & Voss, 2015). The validity of using rsFC of a cortical area with a 
deep node (the hippocampus) as a subject-specific targeting guide and then using the change in FC as an 
outcome measure has been established by Wang et al (2014) and confirmed in our laboratory (see pilot 
data below).  
 
Using this technique, we will attempt to increase and decrease FC within the hippocampal and striatal 
memory systems by selectively targeting each network with rTMS in separate experiments. We predict 
that rTMS will cause changes in FC and memory in the targeted network, which correspond with the 
stimulation protocol: Nominally excitatory stimulation will cause enhancement of the targeted network, 
and nominally inhibitory stimulation will cause FC to decrease. Additionally, because these networks are 
known to interact in behavioral and 
imaging experiments (Brown & 
Robertson, 2007; Cohen & Robertson, 
2011; Mattfeld & Stark, 2010, 2015; 
Poldrack et al., 2001), we expect that 
altering the function of one network 
will cause changes in the pattern of FC 
in the other. Pilot data from our 
laboratory (Fig. 4 Connectivity changes 
with left Precuneus and medial 
Occipital Cortex) show that declarative 
 
network FC enhancement is accompanied by significantly increased rsFC between the striatum 
and the hippocampal network. “Capture” of one system by the other is a good explanation for why 
behavioral engagement in one learning type interferes with the other (Brown & Robertson, 2007; Cohen 
& Robertson, 2011).  
b. 
Pilot Data 
Pilot data from our laboratory show that enhancing the hippocampal network with rTMS via the PPC 
(Wang et al., 2014) is effective and replicable: Nine subjects tested showed significant FC increases 
between the hippocampus and regions that showed a group-level increase in FC with the hippocampus in 
Wang et al. (precuneus and medial occipital cortex; t(8) = 2.73, p < 0.05, d = 0.75; Fig. 4). To show that 
these effects were specific to the hippocampus, we calculated FC changes between the dorsolateral 
prefrontal cortex and the same regions (i.e. precuneus and medial occipital cortex), and found no change 
from pre- to post-stimulation (p = 0.22). Furthermore, the increase in hippocampus FC with the 
precuneus/medial occipital cortex were significantly greater than the change in global connectedness of 
the brain (t(8) = 2.62, p  < 0.05, d = 0.58), showing that these effects were network-specific.  
 
These pilot data, however, also suggest rTMS targeted to the hippocampus and connected areas also 
affects the striatal network. Figure 4 shows statistically significant FC increases between the caudate and 
the precuneus/medial occipital cortex. Thus, in addition to increasing FC in the hippocampal network, 
rTMS also caused the striatum to be pulled into tighter association with the hippocampal network. 
Figure 3. Hippocampal FC changes from Wang et al. (2014) 
 Stimulation-dependent enhancement of hippocampal network overlaid on a 
template brain from Wang et al. (2014). The highlighted regions represent the 
areas that increased in FC with the hippocampus caused by PPC stimulation.  

 
 
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Structural equation modeling, which can be used to determine the direction of influence between network 
nodes, indicated a robust increase in connectivity from the striatum to the precuneus and medial occipital 
cortex after stimulation. This may explain why behavioral engagement of the hippocampal network 
interferes with procedural learning (Brown & Robertson, 2007; Poldrack et al., 2001). Based on these 
preliminary findings, we will guide rTMS to the hippocampal network and examine the effects on both 
the hippocampal-dependent memory system and the striatal memory system. We will also target the 
striatal network, and look for similar effects on the hippocampal network.  
 
 
  Figure 4: Hippocampal FC changes from pilot data. 
 
 
c. 
Resting-State vs. Task-Based Connectivity 
The results of Wang et al. (2014) and data from our laboratory show that rTMS can enhance rsFC within 
a targeted network. However, it is unknown whether the same is true of tbFC. Because tbFC may be a 
better measure of stimulation-induced changes, we will include this measurement in our experiments and 
compare the results to rsFC.  
d. 
Measuring mentation during resting-state scans. 
Recent work has revealed that mentation patterns during resting-state scanning correlates with FC 
measurements (Gregory et al., 2016). Because differences in mentation between participants are difficult 
to control and could potentially explain our results, we will include a measure of mentation (the 
Amsterdam Resting-State Questionnaire) as an exploratory measure to our protocol.  
2. Study Objectives  
The overall objective of this study is to determine whether the hippocampal and striatal memory networks 
can be modulated using rTMS. We will also examine cross network changes in FC by guiding nominally 
excitatory and inhibitory stimulation to the striatal and hippocampal memory networks and measuring the 
effects on both the targeted and non-targeted one. The results will be used to inform future clinical trials 
of rTMS in patients with disorders of learning and memory and possibly to enhance and accelerate 
learning in healthy individuals.  
a. 
Primary aims 
Figure 4. Pilot data (N=9) demonstrating increases in FC 
between precuneus and medial occipital cortex and three 
separate brain regions.  
* - p < 0.05     

 
 
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Primary Aim 1: Determine whether nominally facilitatory stimulation of the hippocampus 
increases rsFC or tbFC within the hippocampal memory network (Experiment 1; Replication of 
Wang et al., 2014). 
Primary Aim 2: Determine whether nominally facilitatory stimulation of the striatum increases 
rsFC or tbFC within the striatal memory network (Experiment 2). 
Primary Aim 3: Determine whether nominally inhibitory stimulation of the hippocampus 
decreases rsFC or tbFC within the hippocampal memory network (Experiment 3). 
Primary Aim 4: Determine whether nominally inhibitory stimulation of the striatum decreases 
rsFC or tbFC within the striatal memory network (Experiment 4). 
b. 
Secondary aims  
Our secondary aims are to measure the effects of each type of stimulation at each site on 
declarative and procedural learning and memory and between network changes in task-based and 
resting-state FC.  
c. 
Exploratory aim  
We will search for predictors of the within and between network FC changes, including scores on 
the ARSQ, the NIH toolbox, and the procedural and observational versions of the Weather 
Prediction Task.  
3. Subjects 
a. 
Description of study population 
We will study 104 healthy individuals (26 in each experiment). We are requesting up to 122 healthy 
volunteers as the accrual ceiling to account for dropouts and screening failures. 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 previous experience, our anticipated dropout rate is 15%. 
b. 
Inclusion criteria 
• 
Age 18-40 (inclusive) 
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, such as those that lowers the seizure threshold 
such as neuroleptics, beta lactams, isoniazid, metronidazole; benzodiazepines, tricyclic or other 
antidepressants; or prescription stimulants. 
• 
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 2 hours 
• 
Pregnancy, or plans to become pregnant during the study. 
• 
Members of the NINDS BNU 
• 
Subjects that received rTMS under protocol 17-N-0055 are excluded in order avoid learning 
effects from previously being exposed to the same behavioral tasks 

 
 
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• 
Subjects who have contraindications to MRI (we will follow the NMR Center guidelines for MR 
safety). Some of the exclusions are:  
1. 
Have non-MRI compatible metal in the body, such as a cardiac pacemaker, brain 
stimulator, shrapnel, surgical metal, clips in the brain or on blood vessels, cochlear 
implants, artificial heart valves or ferromagnetic fragments in the eye or oral cavity as 
these make having an MRI unsafe.  
2. 
Unable to lie flat on the back for the expected length of the experiment (2 hours).  
3. 
Have an abnormality on the brain imaging or neurologic examination not related to the 
diagnosis.  
4. 
Non-removable body piercing or tattoo posing MRI risk 
5. 
Pregnancy (urine pregnancy test) 
 
An eligibility checklist is provided in Appendix A. 
4. Study Design and Methods 
a. 
Study overview 
This protocol will include four experiments, each using rTMS and MRI, in a between-subjects design 
(Table 1). Experiments 1 and 3 will use PPC rTMS. Experiments 2 and 4 will use M1 stimulation. 
 
 
Active 
Stimulation Type  
Active 
Stimulation Site 
Targeted 
Network 
Experiment 1 
Facilitatory (20-Hz) 
PPC  
Hippocampal 
Experiment 2 
Facilitatory (20-Hz) 
M1 
Striatal 
Experiment 3 
Inhibitory (cTBS or 1-Hz) 
PPC 
Hippocampal 
Experiment 4 
Inhibitory (cTBS or 1-Hz) 
M1 
Striatal 
Table 1. Experiment Details. PPC = Posterior Parietal Cortex, M1 = Motor Cortex. 
Table 2 shows the timeline of each experiment. Each study will include FC and memory testing at 
baseline, 24-hours after, and two weeks after three days of rTMS. The number of days of rTMS is based 
on pilot data where three days of stimulation produces significant enhancement of rsFC in the 
hippocampal network in five out of six individuals tested. Each participant will make a maximum of 6 
visits to the lab (not including screening), for a maximum time commitment of 14 hours. The 24-hour 
follow-up will occur between 12 and 48 hours after the last stimulation session, and the 2-week follow-up 
will occur 14-21 days after baseline measurements. Scanning will occur in the NIH NMRF. All visits will 
be outpatient. 
 
 
Baseline Day 
rTMS Sessions 
Post Stimulation Day 
2-week follow-up 
Group 1 
Baseline FC 
and Memory 
Active Stimulation 3-
sessions 
FC and Memory Testing 
FC and Memory 
Testing 
Group 2 
Baseline FC 
and Memory 
Vertex Stimulation 3-
sessions 
FC and Memory Testing 
FC and Memory 
Testing 
Table 2. Timeline of each experiment. 

 
 
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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 are listed in Appendix B. 
 
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 
volunteers at NIH, Bethesda, Maryland. The moderator of the listserv/mailing list has permitted 
its use for this distribution”. 
 
i. 
Participant rescheduling  
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 visit after 
baseline measures have been collected, besides the two week follow-up visit, baseline measurements 
(MRI and behavioral assessments) will be performed again. If a participant completes all visits, but is 
unable to attend the follow-up visit, their attendance in the study will be considered complete. 
c. 
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.  
d. 
Study procedures 
ii. 
Behavioral Tasks  

 
 
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Behavioral testing will occur at baseline, 24-hours, and two-weeks after stimulation. 
 
Weather Prediction Task (feedback version; WPT-F) - 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 200 trials, with breaks after every 50 trials.  
 
Weather Prediction Task (Observational version; WPT-O) – The observational version of the WPT 
resembles a paired associates test where the feedback and cards are displayed on the screen are shown on 
the screen together. After all pairs are shown the cards are again shown and the participant is asked to 
remember which feedback outcome (rain or fine) goes with that set of cards. Unlike the WPT-I, the WPT-
E recruits brain regions that support declarative memory. Both version each take approximately 20 
minutes. The order of the tasks will be counterbalanced across participants. 
iii. MRI 
We estimate a maximum of 2 hours for each scan in all experiments. 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. 
1. MRI Anatomical scanning 
All subjects will have anatomical (MPRAGE) scans at baseline, 24-hours, and 2-weeks after rTMS. 
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 FC 
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).  
3. Task-Based FC 
During scanning, participants will perform both versions of the WPT and tbFC will be measured. During 
the feedback version of the task, when a response is required, participants will respond using one of two 
buttons on a button box inside the scanner. Participants will respond verbally during the retrieval phase of 
the WPT-O. 
iv. rTMS 
The parietal target in Experiments 1 and 3 will be the region of the left PPC with the greatest connectivity 
with the left hippocampus derived from the baseline resting-state fMRI session, (similar to Wang et al. 
2014). The left PPC was chosen because of its dense connections with the hippocampus (Cavada & 
Goldman-Racic, 1989; Mesulam et al., 1977). 
 

 
 
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The target in Experiments 2 and 4 will be the M1 area of maximal connectivity with the right striatum. 
M1 has extensive projections to the striatum (Parent & Hazrati, 1995), and these regions are functionally 
connected at rest (Di Martino et al., 2008). 
 
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) or motor cortex will be used as our 
location of stimulation. 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. 
 
20-Hz Stimulation (facilitation) 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).  
 
Continuous Theta-Burst Stimulation (cTBS; inhibition) will be delivered at 80% of active motor threshold 
for 40 seconds (similar to Huang et al., 2005). cTBS consists of 50-Hz triplets separated by 200ms. 
 
Control stimulation. As a negative control, rTMS will be delivered to the vertex with the same delivery 
parameter values and neuronavigation. Wang and colleagues (2014) used vertex stimulation as a control 
condition and found no significant effects on rsFC or behavior. In addition, there is no evidence that 
vertex stimulation causes other changes in rsFC (Jung et al., 2016). 
 
Contingency for Experiments 3 and 4 if we are unable to inhibit each network. Because targeted 
inhibition of the hippocampal and striatal network with cTBS has not been demonstrated, it is possible 
that cTBS may not yield the expected inhibitory effects in Experiments 3 and 4. Thus, we will examine 
the results from the first three subjects receiving active stimulation in Experiments 3 and 4 and if there is 
no clear decrease of FC in the targeted network, we will run a cohort of 3 subjects using 1-Hz rTMS. We 
will proceed with the stimulation type that demonstrates the most reliable inhibitory effect.  
 
 1-Hz Stimulation. Stimulation will be delivered at 115% of the motor evoked potential threshold at 1-Hz 
continuously for 16 minutes (similar to Chen et al., 1997). 
v. 
Cognitive Battery 
The purpose of the battery is to detect effects on other memory processes other than those targeted in the 
study, characterize participants cognitive abilities at baseline, and to monitor for unexpected deleterious 
effects of stimulation. The data will be treated as exploratory. Some tasks will only be included at 
baseline (indicated below). These tests will not be given inside of the scanner. 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). This test will only be given at baseline. 
 
2) 
 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). This test will only be 
given at baseline. 
 
3) 
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 

 
 
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participant to concurrently remember the items while sorting (< 10 minutes). This test will only 
be given at baseline. 
 
4) 
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) 
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). This test will only be 
given at baseline. 
 
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). This test will only be given at baseline. 
 
7) 
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). This test will only be given at baseline. 
 
8) 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) 
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) Verbal paired associates test (for verbal memory) – This test is similar to the WPT-O, 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) 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 – Participants report outcome 
measures through computer adaptive tests (CAT), short forms, or scales. (~ 20 minutes). 
vi. 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 C). 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.  
 
All clinical rating scales can be performed using an interpreter in any language.   Interpreters will also be 
available for other protocol procedures as necessary. 
 
e. 
End of participation 

 
 
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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 
a. 
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.  
b. 
Data  
This protocol is not subject to the Genomic Data Sharing (GDS) policy. Data may also be shared with 
collaborating laboratories at NIH or outside of NIH and/or submitted to NIH-designated repositories and 
databases if consent for sharing was obtained 
 
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 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 
• 
Magnetic resonance imaging system operating in research mode 
• 
Magstim Rapid2 Therapy System and the  
• 
Magstim Air Film Coil 
 
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 
these devices in the study are a Non-signficant 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; 
None of the three devices are implants.  
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; 
None of the three devices are for use in supporting or sustaining human life.  
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; or 

 
 
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The investigational use of the three devices is not of substantial importance in 
diagnosing, curing, mitigating, or treating disease, or otherwise preventing impairment 
of human health.  
4. 
otherwise presents a potential for serious risk to the health, safety or welfare of a subject  
The use of the legally marketed MRI system in research mode will be performed under 
operating conditions below each of the limits (field strength, Specific Absorption Rate, 
time rate of change of gradient fields and sound pressure levels) deemed to be significant 
risk by the FDA as stated in the FDA guidance document, Criteria for Significant Risk 
Investigations of Magnetic Resonance Diagnostic Devices. 
 
The Magstim Rapid2 Therapy System is legally marketed, indicated for “the treatment of 
Major Depressive Disorder in adult patients who have failed to achieve satisfactory 
improvement from prior antidepressant medication in the current episode.” The Magstim 
Air Film Coil is legally marketed as “a stimulating coil solely intended for use with the 
Magstim® Rapid2 Stimulating Unit for the purposes of peripheral nerve stimulation. The 
Air Film Coil is an accessory of the Magstim® Rapid2 Unit.” Both are used in 
combination in rTMS. Their use in this study is not within the labeled indications. The 
major risk of rTMS and cTMS is the risk of seizure. 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 50,000 sessions. For 
rTMS, safety guidelines have been developed (Wassermann, 1998) and updated (Rossi, 
Hallett, Rossini, & Pascual-Leone, 2009). 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. The rTMS and and 1-Hz Stimulation in this study are below the 
limits defined in these documents. Furthermore, the study subjects are a lower risk since 
subjects 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 single report of seizure with cTBS (Lerner, Wassermann, & Tamir, 2019; 
Oberman et al., 2011, Rossi et al., submitted manuscript). In that single patient, the study 
was conducted in at stimulation intensity levels higher than in this study. Over the past 20 
years, the FDA has generally waived pre-IDE inquiries for TMS/rTMS studies on an NSR 
device basis.  
 
All subjects will wear hearing protection. 
 
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  
 
b. 
Gene therapy 
• 
N/A 
7. Risks and Discomforts 
b. General 
 
rTMS, as delivered under this protocol, involves more than minimal risk to participants. The 
behavioral tasks, neuroimaging procedures, and screening procedures are minimal risks to the participant.   
c. 
Study Procedures 

 
 
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i. 
Behavioral measures  
There are no major risks associated with these memory tests other than frustration or embarrassment 
associated with the participants’ performance.  
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. Participants will be fitted with ear 
plugs. 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 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 stimulation (Pascual-Leone et al., 1992) and more recent has found no increase in 
auditory threshold from TMS (Janicak et al., 2008; Levkovitz et al., 2007). 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 ).  
d. 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 at 
subject’s discretion.  
ii. 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. 
iii. TMS 

 
 
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Study staff will be trained in rTMS administration, rTMS safety, and the measurement of the TMS-
evoked potentials by Dr. Eric Wassermann. Study staff will be trained to recognize and respond to signs 
of seizure and syncope. For each session, at least two rTMS-trained personnel will be in the laboratory. A 
licensed independent practitioner (LIP), a physician or nurse practitioner trained in rTMS, 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. 
 
Syncope will be treated safely by immediately placing the participant in a lying position with legs 
elevated. Should any participant become faint, the LIP covering the study will be called immediately.  
 
Although no long-term deleterious effects of rTMS cognition have been reported, we will monitor 
cognition with the NIH Toolbox. This is a standardized assessment with age-adjusted normative values. 
An investigator will review NIH Toolbox results for each participant at the post-stimulation and 2-week 
follow-up assessments. If a participant experiences a significant drop from baseline, the IMM will be 
informed and the test(s) repeated in a few days. If the deficit persists, the participant will be withdrawn 
from the study and referred for clinical neuropsychological evaluation. If, in the judgment of Dr. 
Wassermann or IMM, a study procedure is causing frequent unexpected or adverse events of any kind, the 
study will be suspended until a review can be undertaken in consultation with the IRB. Depending on the 
outcome, the protocol may be amended, and/or specific language added to the protocol and documents to 
reflect the altered risk. 
 
TMS Training 
In accordance with safety guidelines, the TMS operator is a TMS-trained technician who operates under 
the supervision of the PI and/or Medically Responsible Investigator.  Examples of TMS operators include 
medical assistants, technicians with relevant experience, psychologists, physicists, physiotherapists, 
engineers, physician assistants, nurses, nurse practitioners, and physicians.   
 
Persons operating TMS equipment will have been certified by a NINDS laboratory 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 technician, an individual must have passed the following criteria (as assessed by a 
designated BNU TMS instructor): 
 
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) In-service training on basic TMS safety and risks by TMS-trained physician 
6) In-service training on recognition and initial response to seizures 
 

 
 
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8. Subject Safety Monitoring 
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 any experiment (i.e. both MRI scan and 
behavioral assessment) will be kept and analyzed. A researcher may end experimentation for the 
following reasons: 
• 
Abnormal response to rTMS including the occurrence of a seizure, loss of consciousness, 
or the participant’s unwillingness to continue or headache produced by rTMS.  
• 
Withdrawal of consent and/or decision to terminate. 
• 
The experiment will be ended if the participant is unwilling to continue due to pain, or 
frustration with the procedures 
9. Outcome Measures 
a. 
Primary outcome measures 
• 
Pre-to-Post rTMS differences in rsFC and tbFC within the targeted memory network.  
b. 
Secondary outcome measures 
• 
Pre-to-Post rTMS differences in WPT-O scores  
• 
Pre-to-Post rTMS differences in WPT-F scores  
• 
Pre-to-Post rTMS differences in rsFC and tbFC between memory networks.  
c. 
Exploratory outcome measures 
• 
Correlations between network FC changes and: 
o 
ARSQ scores 
o 
NIH Toolbox Scores 
o 
WPT-F scores 
o 
WPT-O scores 
10. 
Statistical Analysis 
a. 
Analysis of data/ study outcomes 
Our primary aim is to examine stimulation-dependent changes in FC within the targeted network in each 
study. Secondary aims for this protocol will include all behavioral change data from the WPT-F and 
WPT-O and changes in FC to the non-targeted network, and between networks.  
 
To calculate FC from resting-state scans, the Pearson correlation coefficients (r) between time courses of 
BOLD activity in a seed region (i.e. hippocampus or striatum) will be calculated to determine the FC 
before and after rTMS stimulation. They will be Fisher-transformed to normalize r-values. 
 
To calculate FC from task-based scans, the time series from a seed region will be inputted into a general 
linear model analysis as a regressor along with a regressor indicating when the task is occurring. For the 
WPT-F, this will include both the choice phase and the feedback phase during learning. For the WPT-O, 
this will include the observational trials and the retrieval trials. This analysis will be performed on each 

 
 
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individual to create a spatial map of beta values indicating the strength of the association between the 
seed and other regions during task performance.  
 
Statistical analysis for Experiments 1 and 3 (targeting the hippocampal network)  
iv. Preliminary Aims 
 
 
Primary Aim 1 
To confirm modulation of the hippocampal network, the average timeseries of the left 
hippocampal seed will be correlated with all other voxels with available data before and 
after stimulation. These data will be submitted to AFNI’s 3dLME linear mixed effects 
function, which will be used to reveal potential areas of significant change in rsFC and 
tbFC.  
v. 
Secondary Aims 
 
 
Secondary Aims 
Behavioral data will be submitted to a 3 x 2 x 2 ANOVA using timepoint (Pre-
stimulation, post-stimulation, and follow-up), group (PPC vs. Vertex), and learning type 
(procedural and declarative) as factors. A significant interaction (p < 0.05) between time, 
group, and learning type will confirm network-dependent modulation of each memory 
type.  
 
To confirm changes in FC, a similar analysis will be performed as Primary Aim 1, except 
that the timeseries of the right striatum seed will be used instead of the hippocampal seed. 
 
Statistical Analysis for Experiments 2 and 4 (targeting the striatal network) 
i. 
Preliminary Aims 
 
 
Preliminary Aim 1 
To confirm modulation of the striatal network, the average timeseries of the right striatum 
seed will be correlated with all other voxels with available data before and after 
stimulation. These data will be submitted to AFNI’s 3dLME linear mixed effects 
function, which will be used reveal potential areas of significant change in rsFC and 
tbFC.  
ii. 
Secondary Aims 
 
 
Secondary Aims  
Behavioral data will be submitted to a 3 x 2 x 2 ANOVA using timepoint (Pre-
stimulation, post-stimulation, and follow-up), group (M1 vs. Vertex), and learning type 
(procedural and declarative) as factors. A significant interaction (p < 0.05) between time, 
group, and learning type will confirm network-dependent modulation of each memory 
type.  
 
 
 
To confirm changes in FC, a similar analysis will be performed as Primary Aim 1, except 
that the timeseries of the left hippocampus seed will be used instead of the striatal seed. 
 
Interim Analysis for Experiments 3 and 4. The data from 3 initial participants in Experiments 3 and 4 will 
be examined to confirm that cTBS is inhibiting our networks of interest. FC will be calculated within the 
targeted networks and analyzed by study investigators. If, in the opinion of the study team, inhibition of 
these networks is unreliable, a cohort of 3 subjects will be run and will receive 1-Hz stimulation instead. 
Following this cohort, the results will be compared between stimulation protocols and the study team will 
make an informed decision about whether to continue with cTBS or to switch to 1-Hz stimulation instead.  

 
 
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b. 
Power analysis (All experiments) 
All experiments in this protocol are powered based on the primary outcome, which relates to modulating 
FC within the targeted networks.  
A power analysis was conducted on our preliminary data using G*Power v3.1. We used a repeated-
measures ANOVA model with FC changes between the hippocampus and the precuneus/medial occipital 
cortex as my dependent variable. The precuneus/medial occipital cortex was used because these regions 
showed the most robust response to stimulation in Wang et al., (2014). Based on these data (Mean 
Difference = 0.16, Pooled Standard Deviation = 0.21, Cohen’s d = 0.75), and assuming power of 0.80 and 
α = 0.05, 26 right-handed healthy participants between 18 and 40 years of age will be needed (13 per 
group) for each experiment (104 total). To account for attrition (estimated ~15%), we will request an 
accrual celling of 122.  
 
There were no preliminary data to conduct a power analysis for stimulation involving the striatal network. 
Thus, we propose to have 13 analyzable subjects in the M1 group, the same number as in the parietal 
group from Experiments 1 and 3. We also plan to obtain 13 subjects in the control group, resulting in 26 
analyzable healthy subjects (13 per group).  
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 children 
Children will not be included. The study is predicated on the work of Wang et al. (2014) and Poldrack et 
al. (2001; 2003), preliminary data from our laboratory for participants above the age of 18. Therefore, we 
will recruit a sample of the same age.  
c. 
Justification for exclusion of subjects above the age of 40 
Because neuroplasticity is reduced in older adults (Fathi, et al., 2010), including subjects above the age of 
40 would reduce our power for detecting change in FC. A lower age of 40 years old for the upper limit, as 
older brains have less memory capability . Therefore, this group will be excluded.  
d. 
Justification for the Exclusion of other Vulnerable Subjects 
i. 
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.  
e. 
Justification of sensitive procedures 
This study involves no sensitive procedures.  
f. 
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 

 
 
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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.  
 
All investigators and staff authorized to consent subjects will complete consent training prior to obtaining 
consent. 
 
12. 
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.  
13. 
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. 

 
 
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c. 
Criteria for stopping the study or suspending enrollment or procedures 
If a study procedure is causing serious adverse events, or unanticipated problems it will be suspended.  If 
there is a serious adverse event the study 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 amendment, or specific language may be added to the protocol and consent forms to 
reflect the changing risk level.  
 
14. 
Quality Assurance (QA) 
a. 
Quality assurance monitor 
The NINDS Quality Assurance (QA) Audit Committee will periodically monitor the protocol. 
b. 
Quality assurance plan 
This protocol will undergo periodic review by the QA Audit Committee as outlined in the NINDS QA 
Standard Operating Procedure (SOP).  
 
This protocol will undergo random review by the NINDS Quality Assurance (QA) Office as outlined in 
the NINDS QA Standard Operating Procedure. 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. This protocol is classified as 
“more than minimal risk” and thus will be audited with a target frequency of once during the first year 
following IRB approval, and then approximately every three years thereafter. 
15. 
Reporting of Unanticipated Problems, Adverse Events and 
Protocol Deviations 
Reportable events will be tracked and submitted to the IRB as outlined in Policy 801. 
 
 
16. 
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.  
17. 
Privacy 
All research activities will be conducted in as private a setting as possible.  
18. 
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 in 
a locked office 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. Clinical data will be managed 
according to NIH Clinical Center’s standard policies 

 
 
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(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.  
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).  
19. 
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. 
20. 
Technology Transfer 
N/A 
21. 
Research and Travel 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 
Subjects will be paid $10.00 per one Inconvenience Unit (IU). No payment will be offered for the 
screening visit.  
 
fMRI testing (4 IU) 
 
 
$40 
TMS testing (4 IU)  
 
 
$40 
Behavioral Tasks (1 IU)  
 
$20 
Pregnancy Test (1 IU)  
 
$10 
 

 
 
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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 
 
 

 
 
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22. 
References 
Ashby, F. G., & Crossley, M. J. (2010). Interactions between declarative and procedural-learning 
categorization systems. Neurobiology of Learning and Memory, 94(1), 1–12. 
https://doi.org/10.1016/j.nlm.2010.03.001 
Brown, R., & Robertson, E. (2007). Off-Line processing: Reciprocal interactions between declarative and 
procedural memories. Journal of Neuroscience, 27(39), 10468–10475. 
https://doi.org/10.1523/JNEUROSCI.2799-07.2007 
Cavada, C., & Goldman-Racic, P. S. (1989). Posterior parietal cortex in rhesus monkey: I. Parcellation of 
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c. 
Amsterdam Resting-State Questionnaire 
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 
 
 
 
 
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 
 
 
 
 

 
 
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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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24. 
Consent Forms 
Healthy Volunteer Consent