Network Control and Functional Context: Mechanisms for TMS Response
Phase: NA
Conditions: Attention Deficit Hyperactivity Disorder, Attention Deficit Disorder, Working Memory
Sponsor: University of Pennsylvania

PROTOCOL TITLE 
Network Control TMS fMRI 
IRB PROTOCOL NUMBER 
830174 
PRINCIPAL INVESTIGATOR 
Desmond J. Oathes, PhD. 
Department of Psychiatry 
University of Pennsylvania 
FUNDING SPONSOR(S) 
National Institutes of Health 
INVESTIGATIONAL PRODUCT 
Transcranial magnetic stimulation (TMS) device 
that can stimulate brain regions noninvasively.  
•
MagVenture X100 Stimulator
•
Cool-B65 Butterfly TMS Coil
•
MRI-B91 TMS Coil
PROTOCOL VERSION 
V13 
DATED 
11/23/2022 
CLINICALTRIALS.GOV NUMBER NCT05736458 
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Page 2 of 25
Basic Info
 Protocol Number: :
830174
Principal Investigator:
OATHES, DESMOND J
Protocol Title:
Short Title:
Protocol Description:
RF1: Network Control TMS fMRI
Network Control TMS fMRI
In a sample of healthy young adults and those with ADHD we will use diffusion imaging to create 
individualized TMS targets by identifying brain regions with high and low regional 
controllability. We will directly compare the brain network responses to TMS targeted to these 
regions using single-pulse TMS/fMRI recordings. We will also evaluate the impact of using TMS 
during a working memory task with the aim of enhancing both network responses to stimulation 
and the impact of TMS on behavior.
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Study Personnel
Principal Investigator
Name:
OATHES, DESMOND J
Dept / School / Div:
10579 - PS-Center for the Neuroscience of Depression & Stress
Campus Address
Mail Code
3309
Address:
Richards Biomedical Building D306
3700 Hamilton Walk
City State Zip:
PHILADELPHIA PA 19104-6116
Phone:
215-573-9390
Fax:
215-573-0759
Pager:
Email:
oathes@mail.med.upenn.edu
HS Training Completed:
Yes
Training Expiration Date:
Name of course completed :
CITI Protection of Human Subjects Research Training - ORA
GCP Training Completed:
Yes
Training Expiration Date:
06/05/2022
Name of course completed :
Good Clinical Practice: An Introduction to ICH (GCP) Guidelines
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Study Contacts
Name:
FIGUEROA-GONZALEZ, ALMARIS
Dept / School / Div:
10579 - PS-Center for the Neuroscience of Depression & Stress
Campus Address
Mail Code
Address:
City State Zip:
Phone:
215-573-4229
Fax:
Pager:
Email:
almaris.ﬁgueroa-gonzalez@pennmedicine.upenn.edu
HS Training Completed:
Yes
Training Expiration Date:
Name of course completed :
CITI Protection of Human Subjects Research Training - ORA
GCP Training Completed:
Yes
Training Expiration Date:
06/23/2025
Name of course completed :
CITI Good Clinical Practice (GCP) - OCR
Name:
BLAINE, CAMILLE
Dept / School / Div:
10579 - PS-Center for the Neuroscience of Depression & Stress
Campus Address
Mail Code
Address:
City State Zip:
Phone:
Fax:
Pager:
Email:
Camille.Blaine@Pennmedicine.upenn.edu
HS Training Completed:
Yes
Training Expiration Date:
Name of course completed :
CITI Protection of Human Subjects Research Training - ORA
GCP Training Completed:
Yes
Training Expiration Date:
07/05/2025
Name of course completed :
Good Clinical Practice: An Introduction to ICH (GCP) Guidelines
NCT05736458 

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Other Investigator
Name:
SATTERTHWAITE, THEODORE D
Dept / School / Div:
4425 - PS-Neuropsychiatry
Campus Address
Mail Code
6021
Address:
Richards Medical Research Building
3700 Hamilton Walk
Ofﬁce A509
City State Zip:
PHILADELPHIA PA 19104-6021
Phone:
267-441-7145
Fax:
-
Pager:
Email:
sattertt@pennmedicine.upenn.edu
HS Training Completed:
Yes
Training Expiration Date:
Name of course completed :
CITI Protection of Human Subjects Research Training - ORA
GCP Training Completed:
No
Training Expiration Date:
Name of course completed :
Responsible Org (Department/School/Division):
10579 - PS-Center for the Neuroscience of Depression & Stress
Key Study Personnel
Name:
MURPHY, ANDREW
Department/School/Division:
Health System
HS Training Completed:
Yes
Training Expiration Date:
Name of course completed:
CITI Protection of Human Subjects Research Training - ORA
GCP Training Completed:
No
Training Expiration Date:
Name of course completed:
Name:
REBER, JUSTIN
Department/School/Division:
PS-Center for the Neuroscience of Depression & Stress
HS Training Completed:
Yes
Training Expiration Date:
Name of course completed:
CITI Protection of Human Subjects Research Training - ORA
GCP Training Completed:
Yes
Training Expiration Date:
09/17/2024
Name of course completed:
Good Clinical Practice: An Introduction to ICH (GCP) Guidelines
NCT05736458 

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Name:
GUR, RAQUEL E
Department/School/Division:
PS-Neuropsychiatry
HS Training Completed:
Yes
Training Expiration Date:
Name of course completed:
POR Recertiﬁcation Quiz - Full Board Review - SOM
GCP Training Completed:
Yes
Training Expiration Date:
12/28/2022
Name of course completed:
Good Clinical Practice: An Introduction to ICH (GCP) Guidelines
Name:
SHELINE, YVETTE I
Department/School/Division:
PS-Center for the Neuroscience of Depression & Stress
HS Training Completed:
Yes
Training Expiration Date:
Name of course completed:
CITI Protection of Human Subjects Research Training - ORA
GCP Training Completed:
Yes
Training Expiration Date:
03/23/2023
Name of course completed:
Good Clinical Practice: An Introduction to ICH (GCP) Guidelines
Name:
LINN, KRISTIN
Department/School/Division:
BE-Biostatistics Division
HS Training Completed:
Yes
Training Expiration Date:
Name of course completed:
CITI Protection of Human Subjects Research Training - ORA
GCP Training Completed:
Yes
Training Expiration Date:
12/07/2024
Name of course completed:
Good Clinical Practice: An Introduction to ICH (GCP) Guidelines
Name:
CIESLAK, MATTHEW
Department/School/Division:
PS-Neuropsychiatry
HS Training Completed:
Yes
Training Expiration Date:
Name of course completed:
CITI Protection of Human Subjects Research Training - ORA
GCP Training Completed:
No
Training Expiration Date:
Name of course completed:
Name:
DUPRAT, ROMAIN J
Department/School/Division:
PS-Center for the Neuroscience of Depression & Stress
HS Training Completed:
Yes
Training Expiration Date:
Name of course completed:
CITI Protection of Human Subjects Research Training - ORA
GCP Training Completed:
Yes
Training Expiration Date:
09/28/2024
Name of course completed:
Good Clinical Practice: An Introduction to ICH (GCP) Guidelines
NCT05736458 

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Name:
GRIER, JULIE
Department/School/Division:
PS-Center for the Neuroscience of Depression & Stress
HS Training Completed:
Yes
Training Expiration Date:
Name of course completed:
CITI Protection of Human Subjects Research Training - ORA
GCP Training Completed:
Yes
Training Expiration Date:
06/10/2025
Name of course completed:
Good Clinical Practice: An Introduction to ICH (GCP) Guidelines
Name:
PEREZ, GIANNA
Department/School/Division:
SM-SR-Biomedical Graduate Studies Financial Aid
HS Training Completed:
Yes
Training Expiration Date:
Name of course completed:
CITI Protection of Human Subjects Research Training - ORA
GCP Training Completed:
Yes
Training Expiration Date:
10/09/2023
Name of course completed:
Good Clinical Practice: An Introduction to ICH (GCP) Guidelines
Name:
BASSETT, DANIELLE S
Department/School/Division:
Bioengineering
HS Training Completed:
Yes
Training Expiration Date:
Name of course completed:
CITI Protection of Human Subjects Research Training - ORA
GCP Training Completed:
No
Training Expiration Date:
Name of course completed:
Name:
TAYLOR, JEROME
Department/School/Division:
PS-Psychiatry CHOP
HS Training Completed:
Yes
Training Expiration Date:
Name of course completed:
CITI Protection of Human Subjects Research Training - ORA
GCP Training Completed:
Yes
Training Expiration Date:
12/04/2022
Name of course completed:
Good Clinical Practice: An Introduction to ICH (GCP) Guidelines
Name:
CALKINS, MONICA E
Department/School/Division:
PS-Neuropsychiatry
HS Training Completed:
Yes
Training Expiration Date:
Name of course completed:
CITI Protection of Human Subjects Research Training - ORA
GCP Training Completed:
Yes
Training Expiration Date:
08/04/2023
Name of course completed:
Good Clinical Practice: An Introduction to ICH (GCP) Guidelines
NCT05736458 

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Name:
SYDNOR, VALERIE J
Department/School/Division:
Research Services
HS Training Completed:
Yes
Training Expiration Date:
Name of course completed:
CITI Protection of Human Subjects Research Training - ORA
GCP Training Completed:
Yes
Training Expiration Date:
02/18/2023
Name of course completed:
Good Clinical Practice: An Introduction to ICH (GCP) Guidelines
Disclosure of Signiﬁcant Financial Interests*
Does any person who is responsible for the design, conduct, or reporting of this research protocol have 
a FINANCIAL INTEREST?
No
Penn Intellectual Property*
To the best of the Principal Investigator's knowledge, does this protocol involve the testing, 
development or evaluation of a drug, device, product, or other type of intellectual property (IP) that is 
owned by or assigned to the University of Pennsylvania?
No
Certiﬁcation
I have reviewed the Financial Disclosure and Presumptively Prohibited Conﬂicts for Faculty 
Participating in Clinical Trials and the Financial Disclosure Policy for Research and Sponsored 
Projects  with all persons who are responsible for the design, conduct, or reporting of this research; and 
all required Disclosures have been attached to this application.
Yes
Biomedical Research
Clinical Trial*
Is this a clinical trial?
Yes
If Yes, please be aware that for each clinical trial conducted or supported by a Federal department or 
agency, one IRB-approved informed consent form used to enroll subjects must be posted by the 
awardee or the Federal department or agency component conducting the trial on a publicly available 
Federal Web site that will be established as a repository for such informed consent forms.
Investigator Initiated Trial*
Is this an investigator initiated trial?
No
Drugs or Devices*
Does this research study involve Drugs or Devices?
Yes: Investigational devices that may qualify as Non-Signiﬁcant Risk.
IND Exemption
For studies that fall under an IND exemption, please provide the number below
For studies including IND or IDE's, please provide the number(s) below
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IDE Review*
NOTE: For research involving investigational devices, you are required to review the guidance on 
Managing Research Device Inventory. Consult the Penn Manual for Clinical Research: https://
www.med.upenn.edu/pennmanual/secure/investigational-product-management-at-sites-not-using-
investigational-drug-services-(ids).html Please check the box Yes if you have reviewed the guidance.
Yes
Research Device Management*
Please indicate how research device(s) will be managed.
The device receipt, storage and dispensing is being conducted by the research team (please provide 
information in the protocol summary as to how this will be conducted)
Drug, Herbal Product or Other Chemical Element Management *
Please indicate how drugs, herbal products or other chemical entities will be managed.
Not Applicable (no drugs, herbal products or other chemical entities)
Radiation Exposure*
Are research subjects receiving any radiation exposure (e.g. X-rays, CT, Fluoroscopy, DEXA, pQCT, 
FDG, Tc-99m, etc.) that they would not receive if they were not enrolled in this protocol?
No
Gene Transfer*
Does this research involve gene transfer (including all vectors) to human subjects?
No
Human Source Material*
Does this research include collection or use of human source material (i.e., human blood, blood 
products, tissues or body ﬂuids)?
No
CACTIS and CT Studies*
Does the research involve Center for Advanced Computed Tomography Imaging Services (CACTIS) 
and CT studies that research subjects would not receive if they were not part of this protocol?
No
CAMRIS and MRI Studies*
Does the research involve Center for Advanced Magnetic Resonance Imaging and Spectroscopy 
(CAMRIS) and MRI studies that research subjects would not receive if they were not part of this 
protocol?
Yes
Investigational Agent or Device within the Operating Room*
Does the research project involve the use of an investigational agent or device within the Operating 
Room?
No
Cancer Related research not being conducted by an NCI cooperative group*
Does this protocol involve cancer-related studies in any of the following categories?
No
Processing of Materials*
Will the research involve processing (such as over encapsulating, or compounding)?
No
In-House Manufacturing of Materials*
Will the research involve processing (such as over encapsulating, or compounding)?
No
Medical Information Disclosure*
Does the research proposal involve the use and disclosure of research subject's medical information for 
research purposes?
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Yes
If the answer is YES, indicate which items is is provided with this submission:
Modiﬁed research informed consent document that incorporates HIPAA requirements
CHPS Resources*
Does the research involve CHPS resources?
No
HUP Inpatient Nursing Resources
Does this research include an inpatient admission at HUP?
No
Pathology and Laboratory Medicine Resources*
Will samples be collected by hospital phlebotomy and/or processed or analyzed by any of the clinical 
laboratories of the University of Pennsylvania Health System?
No
Research Involves Apheresis, Cell Collection, and/or Blood Product Collection*
Does this research involve collection of blood products in the Penn Donor Center and/or the use of 
apheresis for treatment or collection of cells or other blood components?
No
Research involving blood transfusion or drug infusions*
Will your research involve blood transfusion or infusion of study drug in 3 Ravdin Apheresis Unit for 
research purposes?
No
Trial in Radiation Oncology
Is this research a prospective trial being done in Radiation Oncology, and if so, has this protocol been 
approved by the Radiation Oncology Protocol committee?
N/A
Study in Radiation Oncology
Is this research a retrospective study being done in Radiation Oncology, and if so, has this project been 
reviewed by the Radiation Oncology Clinical Research Group?
N/A
Use of UPHS services*
Does your study require the use of University of Pennsylvania Health System (UPHS) services, tests or 
procedures*, whether considered routine care or strictly for research purposes?
Yes
Veteran's Affairs (VA) Patients or Subjects
Does your study involve data from Veteran's Affairs (VA) patients or subjects?
No
If yes, was this approved by the Philadelphia VA?
No
Out of State Research
Will any Penn personnel conduct any research activities outside of the State of Pennsylvania?
No
Research involving Virtua Health
Will any Penn personnel conduct any research activities at a Virtua Health site location, OR in 
collaboration with Virtua Health System personnel, OR using any Virtua Health System resources (e.g., 
medical records)?
No
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Primary Focus*
Other
Protocol Interventions
Sociobehavioral (i.e. cognitive or behavioral therapy)
Drug
Device - therapeutic
Device - diagnostic (assessing a device for sensitivity or speciﬁcity in disease diagnosis)
Surgical
x Diagnostic test/procedure (research-related diagnostic test or procedure)
Obtaining human tissue for basic research or biospecimen bank
Survey instrument
None of the above
The following documents are currently attached to this item:
There are no documents attached for this item.
Sponsors
Business Administrator
Name:
CASTELLANO, DANIEL
Dept / School / Div:
4435 - PS-Center for Tobacco Research
Phone:
215-573-5833
Fax:
215-573-6410
Pager:
Email:
dcastel2@pennmedicine.upenn.edu
Department budget code
000 - 000 - 0 - 000000 - 0000 - 0000 - 0000
Funding Sponsors
Funding sponsors billing address
If you have selected a commercial or industry sponsor, please provide the appropriate address and 
contact information for the Sponsor for the purposes of billing for IRB review fees (initial review, 
continuing review and convened modiﬁcation fees apply here). If the Sponsor is not industry/
commercial, this information is not necessary to provide with your application.
Funding sponsors gift
Is this research being funded by a philanthropic gift?
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Regulatory Sponsor
IND Sponsor
Name:
OATHES, DESMOND J
Dept / School / Div:
10579 - PS-Center for the Neuroscience of Depression & Stress
Phone:
215-573-9390
Fax:
215-573-0759
Pager:
Email:
oathes@mail.med.upenn.edu
Does the IND Sponsor (or his or her spouse or dependent children) have a SIGNIFICANT 
FINANCIAL INTEREST, as deﬁned above?
No
Industry Sponsor
None
Project Funding*
Is this project funded by or associated with a grant or contract?
Yes
Selected Proposals
Proposal No
Title
10064756-01
Network Control and Functional Context: Mechanisms for TMS Response
Sponsor Funding
Is this study funded by an industry sponsor?
No
Status of contract
The following documents are currently attached to this item:
There are no documents attached for this item.
Multi-Center Research
Penn as lead
1. Is this a multi-center study where Penn is serving as the Lead Site or the Penn PI is serving as the
Lead Investigator?
No
Management of Information for Multi-Center Research
Penn irb of record
2. Is this a multi-center study where the Penn IRB will be asked to serve as the IRB of Record for other
external study sites?
No
Other Sites
No other sites
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Protocol
Abstract
Transcranial magnetic stimulation (TMS) has evolved to become one of the most widely used 
approaches for non-invasive neuromodulation in humans and signiﬁcant data suggests that it may 
improve working memory performance. This study explores the concept of applying TMS to speciﬁc 
targets during speciﬁc states which may enhance its impact on behavior. We hypothesize that 
appropriate stimulation within a speciﬁc working memory context will enhance both network responses 
to stimulation and the impact of TMS on behavior.  In a sample of healthy adults and subset of young 
adults with ADHD, we will use diffusion imaging to create individualized TMS targets by identifying 
points in that brain that have high and low regional controllability. We will directly compare the brain 
network responses to TMS targeted to the high controllability and low controllability regions using 
single-pulse TMS/fMRI recordings. We will also evaluate the impact of using TMS to these regions 
during a working memory task (of both high and low memory load) with the aim of enhancing both 
network responses to stimulation and the impact of TMS on behavior. Participants will then receive 
repetitive TMS (rTMS) in the scanner to modulate these brain circuits. Following rTMS, we will re-
interrogate the same circuit using single-pulse TMS/fMRI and participants will repeat the working 
memory task.
Objectives
Overall objectives
We will use ultra-high resolution diffusion spectrum imaging (DSI) to map the structural connectome 
and identify brain regions with high and low regional controllability. We will directly test whether TMS 
targeted to control points using network control theory on a single-subject basis results in greater 
network responses in single-pulse TMS/fMRI recordings. Speciﬁcally, we will vary the stimulation 
target in a counterbalanced order across two days of TMS/fMRI, where stimulation of a prefrontal 
control point (with high regional controllability) is compared with stimulation of a prefrontal region 
with low regional controllability.  During each of these TMS/fMRI sessions, we will also evaluate the 
impact of functional context by stimulating under counterbalanced conditions of high or low working 
memory load. Critically, following these initial single-pulse experiments that interrogate network 
activation and interaction, each participant will receive rTMS in the scanner to modulate the system. We 
expect that rTMS targeted with network control theory and given immediately following high working 
memory load (a warm functional context) will produce greater improvements in working memory 
performance.  As an exploratory component, a subset of these experiments will be repeated in a sample 
of young adults with ADHD and documented executive dysfunction. As working memory dysfunction 
is a common and debilitating feature of many neuropsychiatric illnesses, these data will provide 
evidence of the potential clinical impact of next-generation personalized neuromodulatory therapies.
Primary outcome variable(s)
Brain network responses to single pulse TMS to prefrontal area with high regional controllability versus 
low regional controllability. Working memory performance pre- versus post-rTMS to a TMS target with 
high regional controllability versus a TMS target with low regional controllability.
Secondary outcome variable(s)
Brain network response to single pulse TMS in the context of high working memory load versus low 
working memory load. Working memory performance in patients with ADHD after rTMS to a high 
regional controllability point.
Background
For additional background information and source documentation, please refer to attachment 
(TDD_R01_Submitted_4IRB). Transcranial magnetic stimulation (TMS) has evolved to become one of 
the most widely used approaches for non-invasive neuromodulation. It is an FDA-approved therapy for 
treatment-resistant depression and signiﬁcant data suggests that it may improve working memory 
NCT05736458 

Page 14 of 25
performance in both clinical and non-clinical samples (O'Reardon et al., 2007; Brunoni & 
Vanderhasselt, 2014). The majority of neuroscientiﬁc studies seeking to understand brain responses to 
TMS ignore that the brain can be in many different states when stimulation is delivered; however, brain 
state is naturally modulated by the functional context of experiments based on their cognitive demands. 
Recent efforts measuring and controlling context have underscored the impact of functional context on 
TMS-induced changes in behavior (Bassett et al., 2011; Calhoun, Miller, Pearlson, & Adal, 2014). 
Notably, previous work from our group and others has shown that visualizing a motor response 
potentiates evoked responses to TMS stimulation to the motor cortex (Oathes, Bruce, & Nitschke, 2008; 
Sparing et al., 2002). As such, we infer that applying TMS at a particular moment during a cognitive 
task may allow us to manipulate the interaction between brain state and the effects of TMS on brain 
networks. Speciﬁcally, we hypothesize that stimulation within a speciﬁc functional context will enhance 
network responses to TMS as well as its impact on behavior, in particular working memory.  In addition 
to manipulating speciﬁc functional contexts of stimulation to enhance the impact of TMS on behavior, 
we also aim to explore the effect of speciﬁc stimulation sites on brain responses to TMS. Decades of 
cognitive neuroscience research have established a well-deﬁned network of brain regions that are 
essential for WM and executive processes, including regions within the fronto-parietal network (FPN), 
such as the dorsolateral prefrontal cortex (DLPFC) and the superior parietal cortex (Wager & Smith, 
2003; Rottschy et al., 2012; Owen, McMillan, Laird, & Bullmore, 2005). Furthermore, recent work 
from our group has demonstrated that accurate WM performance also depends on deactivation of 
regions within the default mode network (DMN) including the ventromedial prefrontal cortex and the 
posterior cingulate, and reduced functional connectivity between the FPN and the DMN (Satterthwaite 
et al., 2013). As in previous work, we call this constellation of activity and connectivity functional 
network segregation (Satterthwaite et al., 2013; Baum et al., 2017). Critically, earlier work by PI Oathes 
using TMS/fMRI has established that TMS can induce this same pattern of FPN activation and DMN 
deactivation (Chen et al., 2013). Thus, there is evidence of concordance between the brain circuits 
required for WM function and the brain circuits inﬂuenced using our TMS protocols. We hypothesize 
that stimulation during a WM task that instantiates this functional context will enhance both brain and 
behavioral responses to TMS. While our preliminary data guides our focus on WM, we anticipate that 
the interaction between functional context and stimulation may be a general mechanism of TMS 
response that could be extended to other brain networks and cognitive systems in future. Moreover, this 
study explores how we may be able to maximize the downstream brain network effects of TMS based 
on speciﬁc stimulation site. Speciﬁcally, we look at applying the network control theory to 
individualized TMS targeting. The network control theory (NCT) suggests that alterations in the 
activation of a single node in a brain network can lead to distributed and system-wide effects whose 
exact pattern depends on the structure of the network interconnecting all nodes (Liu, Slotine, & 
Barabasi, 2011; Muldoon et al., 2016). Originally developed in the ﬁeld of systems engineering, NCT 
provides a framework for understanding how key nodes, or control points, can exert disproportionate 
inﬂuence over system function (Liu et al., 2011). NCT is applicable in systems that are controlled 
through signals that originate at the control point and move through the network. This description is 
identical to the rationale for administering repetitive TMS to a speciﬁc brain area and expecting 
widespread effects on  brain and behavior.  Despite such widespread use in disparate ﬁelds and evident 
similarity to our understanding of how TMS inﬂuences human behavior, there has not yet been research 
exploring TMS in the context of network control theory (NCT). Efforts to test such a theory are critical, 
as validation could provide a generalizable mechanism of TMS that would prove essential for choosing 
the target of stimulation, titrating stimulation dose, and personalizing stimulation to the subjects 
intrinsic brain network architecture.  In a sample of healthy adults we will use ultra-high resolution 
diffusion imaging (DSI) to map the structural connectome and identify brain regions with high and low 
regional controllability. We will directly test whether TMS targeted to control points using NCT on a 
single-subject basis results in greater network responses in single-pulse TMS/fMRI recordings. 
Speciﬁcally, we will vary the stimulation target in a counterbalanced order across two days of TMS/
fMRI, where stimulation of a prefrontal control point (with high regional controllability) is compared 
with stimulation of a prefrontal region with low regional controllability. During each of these TMS/
fMRI sessions, we will also evaluate the impact of functional context by stimulating under 
counterbalanced conditions of high or low WM load. Critically, following these initial single-pulse 
experiments that interrogate network activation and interaction, each participant will receive rTMS in 
the scanner to modulate the system. We expect that rTMS targeted with NCT and given immediately 
following high WM load (a warm functional context) will produce greater improvements in WM 
performance. Furthermore, we predict that these behavioral changes will be mediated by functional 
network segregation. Importantly, a subset of these experiments will be repeated in a sample of young 
adults with ADHD and documented executive dysfunction. As WM dysfunction is a common and 
NCT05736458 

Page 15 of 25
debilitating feature of many neuropsychiatric illnesses (including ADHD, psychosis, and mood 
disorders), these data will provide evidence of the potential clinical impact of next-generation 
personalized neuromodulatory therapies (Shanmugan et al.,2016).
Study Design
Phase*
Not applicable
Design
We will use a 2x2x2 factorial design to probe the impact of network control theory guided targeting and 
functional context using single pulse TMS/fMRI. Within-session changes in working memory 
performance and network responses following neuromodulation with rTMS will be evaluated in healthy 
adults and in patients with ADHD. Healthy young adults will undergo four neuroimaging sessions. 
Following medical, clinical, and cognitive assessment, neuroimaging session one will consist of ultra-
high resolution diffusion spectrum imaging to map the structural connectome and identify control 
points. This initial session will be followed by two TMS/fMRI sessions which combine experiments 
that interrogate circuits with single-pulse TMS/fMRI as well as rTMS to modulate circuits. The two 
TMS/fMRI sessions will compare brain responses to stimulation targeted on the basis of high versus 
low regional controllability. Target location will alternate across neuroimaging sessions two and three in 
a counterbalanced fashion to test our hypotheses. For each of these two TMS/fMRI sessions, 
stimulation will occur within a counterbalanced functional context of high versus low working memory 
load. Within each TMS/fMRI session, initial interrogation using single-pulse stimulation will be 
followed by neuromodulatory rTMS. Single-pulse stimulation that was conducted pre-TMS will be 
repeated after neuromodulation, in order to evaluate the effect of network control theory targeting and 
the functional context of recent working memory load (warm rTMS) on working memory performance 
and network segregation. We will also study 35 patients with ADHD and working memory deﬁcits. In 
two scanning sessions, we will ﬁrst identify control points and then record responses to network control 
theory-guided rTMS administered during a functional context of high working memory load. Subjects 
can also complete an optional task while they undergo an fMRI scan if the task is available.
Study duration
Each healthy control subject will spend a total of approximately 7-12.5 hours of participation in the 
study over 4 or 5 experimental sessions. Each participant with ADHD will spend a total of 
approximately 5.5-10.5 hours of participation in the study over 3 or 4 experimental sessions.  Visit 1: 
Consent, screening, clinical interview and TMS demo (1-3 hrs)  Visit 2: Baseline MRI Scan: DSI, rest, 
T1 and assessments (2-4 hrs)  Assessments from Visit 1 and Visit 2 may be split onto multiple days in 
order to accommodate scheduling constraints.  Visit 3: TMS/fMRI scan (1.5-2 hrs)  Visit 4(-only 
healthy control subjects): TMS/fMRI scan 2 (1.5-2 hrs)  Visit 5(or 4 for ADHD patients) (OPTIONAL): 
Task fMRI scan (2 hrs)
Resources necessary for human research protection
Describe research staff and justify that the staff are adequate in number and qualiﬁcations to conduct 
the research. Describe how you will ensure that all staff assisting with the research are adequately 
informed about the protocol and their research related duties. Please allow adequate time for the 
researchers to conduct and complete the research. Please conﬁrm that there are adequate facilities for 
the research.
Staff will be trained on the protocol and inclusion/exclusion criteria. TMS protocols will involve direct 
training with the Principal Investigator and Center Director, who is an M.D. Facilities will include 
various laboratory spaces specializing in advanced computing and analysis of neuroimaging and 
cognitive datasets. Scans will be conducted on a Siemens Prisma 3 Tesla whole-body MRI with a 64- 
channel head/neck array, housed in the Center for Advanced Magnetic Resonance Imaging and 
Spectroscopy (CAMRIS). Additional MRI resources, such as a mock scanner, may be accessed from 
the Center for Functional Neuroimaging (CfN).
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Characteristics of the Study Population
Target population
This study will recruit 50 medically healthy young adults between the ages of 18 and 28 as well as 45 
patients with ADHD matched on age, sex, and race. A diagnosis of ADHD will be determined by the 
Young Adult Psychiatric Assessment (YAPA) or GOASSESS. We plan to enroll 95 participants in order 
to collect usable data from 40 healthy control participants and 35 patients with ADHD.
Subjects enrolled by Penn Researchers
95
Subjects enrolled by Collaborating Researchers
0
Accrual
Participants will be recruited from several sources. As detailed below, we have identiﬁed primary and 
secondary recruitment sources for both the healthy participants and ADHD patients.  1) Center for 
Neuromodulation in Depression and Stress (CNDS). The CNDS maintains a large pool of healthy 
volunteers who have indicated their interest in participating in studies of neuromodulation. Healthy 
participants will primarily be drawn from this source. Additional subjects, including those with 
symptoms of ADHD, will express interest by initiating contact with the research staff via phone or 
email for a phone-screening procedure or by completing an online screening form through Penn 
supported REDCap. The link for completion of online screening forms may be presented throughout all 
advertising mediums. All subjects ﬁtting inclusion criteria will be contacted by study staff with further 
information about the study. Follow-up may involve an additional pre-screening form for those subjects 
endorsing threshold criteria for 2 out of 3 questions about ADHD on the general screener. ADHD 
subjects will need to pass this pre-screener in order to be enrolled, as determined by a staff member 
according to GOASSESS criteria. 2) The Philadelphia Neurodevelopmental Cohort (PNC) 
(#810336).The PNC is a large-scale study of neurodevelopment conducted at Penn. PI Satterthwaite has 
led the neuroimaging efforts associated with this study, which included imaging n=1,601 participants 
ages 8-22. The PNC will provide the primary recruitment source for ADHD participants in this study, 
and a secondary source for healthy participants.  3) Subjects may also be drawn from a large pool of 
subjects who have agreed to be contacted for research as part of our Neuropsychiatry Programs center-
wide protocol (#813943). This protocol provides the Neuropsychiatry Program with common 
procedures including recruitment, screening, and clinical assessment. Please refer to protocol #813943 
for a complete description of all subject accrual procedures.  4) Adult ADHD clinic. The adult ADHD 
clinic at the outpatient psychiatry practices of the Department of Psychiatry will serve as a secondary 
recruitment source for ADHD patients. This will complement the participants provided by the PNC, and 
also provide a source of participants with more severe symptoms than the community-based sample 
provided by the PNC. We will provide clinicians with recruitment cards and brochures, whereby they 
can give study details and contact information to interested patients. There will also be information 
about the study on the clinic website. 5) Both healthy control volunteers and patients with ADHD will 
also be recruited through community advertising including ﬂyers and online postings (Craigslist, 
iConnect, CNDS website, Experiments@Penn, University of Pennsylvania School of Arts & Sciences 
UPenn Experiments). This sample should provide us with adequate data to compare the patient group to 
non-disordered group and compare across conditions within groups.
Key inclusion criteria
1. 18-28 years old at enrollment 2. Healthy participants: no current or past DSM-V Axis I or II 
diagnoses (besides past substance use disorders) 3. Healthy participants: no current use of psychoactive 
medication 4. ADHD participants: meets DSM-V criteria for ADHD according to the YAPA interview 
or GOASSESS 5. Right handed 6. For participants reporting daily use of more than 400mg caffeine/
day: willing to lower down to this level at least 1 week prior to screening visit and maintain throughout 
study visits 7. ADHD participants abstaining from psychostimulants: willing to not increase levels of 
caffeine use throughout study participation
Key exclusion criteria
1. Metallic implants, claustrophobia, or other contraindications to MRI/TMS (e.g. foreign metallic 
implants, pacemaker, shrapnel or other metal in/on the body that cannot be removed, claustrophobia, 
etc.).  2. Presence or history of medical or neurological disorders that may affect brain function. 
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Examples include history of signiﬁcant cardiac disease, endocrine disorders, renal disease, pulmonary 
disease, seizures, head trauma, CNS tumors, or visual impairment (e.g., blindness, glaucoma).  3. 
History of psychosis (schizophrenia, schizoaffective disorder) or bipolar disorder. 4. Signiﬁcant 
handicaps (e.g. intellectual disability) that would interfere with testing procedures 5. Recent substance 
use presenting the possibility of acute intoxication or withdrawal.  6. Pregnancy. 7. Not proﬁcient in 
English.  8. Any other factor that in the investigators judgment may affect patient safety or compliance 
(e.g. distance greater than 100 miles from procedure site) 9. Any reason that impairs ability to give 
informed consent 10. Healthy participants: psychoactive medication use. 11. Healthy participants: ﬁrst 
degree relative with psychosis. 12. ADHD participants: inability to refrain from stimulant medication 
within 24 hours of study sessions. 13. Active suicidality or current suicidal risk as determined by the 
investigator. 14. Opiate medication, antihypertensive medication, or any medication that interferes with 
fMRI recordings as per PI discretion 15. Unable to tolerate TMS 16. ADHD participants: Newly 
initiated psychotherapy as determined by investigator.
Vulnerable Populations
Children Form
Pregnant women (if the study procedures may affect the condition of the pregnant woman or 
fetus) Form
Fetuses and/or Neonates Form
Prisoners Form
Other
x None of the above populations are included in the research study
The following documents are currently attached to this item:
There are no documents attached for this item.
Populations vulnerable to undue inﬂuence or coercion
No subjects, including the economically disadvantaged, employees, and/or students at Penn, will be 
unduly inﬂuenced, encouraged, or coerced into participating in this study. These populations will not be 
targeted or excluded. If they are encountered and would like to participate, the appropriate measures 
will be taken in order to allow them the opportunity to provide consent.
Subject recruitment
1) Center for Neuromodulation in Depression and Stress (CNDS). The CNDS maintains a large pool of 
healthy volunteers who have indicated their interest in participating in studies of neuromodulation. 
Healthy participants will primarily be drawn from this source. Additional subjects, including those with 
symptoms of ADHD, will express interest by initiating contact with the research staff via phone or 
email for a phone-screening procedure or by completing an online screening form through Penn 
supported REDCap. The link for completion of online screening forms may be presented throughout all 
advertising mediums. All subjects ﬁtting inclusion criteria will be contacted by study staff with further 
information about the study. Follow-up may involve an additional pre-screening form for those subjects 
endorsing threshold criteria for 2 out of 3 questions about ADHD on the general screener. ADHD 
subjects will need to pass this pre-screener in order to be enrolled, as determined by a staff member 
according to GOASSESS criteria. 2) The Philadelphia Neurodevelopmental Cohort (PNC)(#810336). 
The PNC is a large-scale study of neurodevelopment conducted at Penn. PI Satterthwaite has led the 
neuroimaging efforts associated with this study, which included imaging n=1,601 participants ages 
8-22. The PNC will provide the primary recruitment source for ADHD participants in this study, and a 
secondary source for healthy participants.  3) Subjects will also be drawn from the Neuropsychiatry 
Programs center-wide protocol (#813943). In addition, subjects will be recruited from other protocols, 
including protocols #810336, #816281, #815814, #818621, #816275. Subjects who participated in these 
protocols indicated their willingness (or lack of) to be re-contacted for further research. We will 
preferentially recruit from subjects who have received detailed follow-up clinical phenotyping and 
baseline neuroimaging as part of those protocols 4) Adult ADHD clinic. The adult ADHD clinic at the 
outpatient psychiatry practices of the Department of Psychiatry will serve as a secondary recruitment 
source for ADHD patients. This will complement the participants provided by the PNC, and also 
provide a source of participants with more severe symptoms than the community-based sample 
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provided by the PNC. We will provide clinicians with recruitment cards and brochures, whereby they 
can give study details and contact information to interested patients. There will also be information 
about the study on the clinic website. 5) Both healthy control volunteers and patients with ADHD will 
also be recruited through community advertising including ﬂyers and online postings (Craigslist, 
iConnect, CNDS website, Experiments@Penn, University of Pennsylvania School of Arts & Sciences 
UPenn Experiments). All recruitment materials, including but not limited to ﬂyers, brochures, referral 
letters and online postings will be IRB-approved before distribution of any of these materials.
Will the recruitment plan propose to use any Penn media services (communications, marketing, etc.) for 
outreach via social media avenues (examples include: Facebook, Twitter, blogging, texting, etc.) or does 
the study team plan to directly use social media to recruit for the research?
Yes
Please identify which method(s) of social media you will utilize, the content of the text to be used, and 
the method(s) for posting this information (i.e., using Penn supported communication services). When 
proposing the text to utilize, please be aware of any social media limitations (i.e., number of characters 
allowed in a tweet) and any appropriate conﬁdentiality practices necessary to be compliant with posting 
research recruitment text.*
Both healthy control volunteers and patients with ADHD will be recruited through community 
advertising 
including 
ﬂyers 
and 
online 
postings 
(Craigslist, 
iConnect, 
CNDS 
website, 
Experiments@Penn, University of Pennsylvania School of Arts & Sciences UPenn Experiments). All 
recruitment materials, including but not limited to ﬂyers, brochures, referral letters and online postings 
will be IRB-approved before distribution of any of these material.
The following documents are currently attached to this item:
There are no documents attached for this item.
Subject compensation*
Will subjects be ﬁnancially compensated for their participation?
Yes
The following documents are currently attached to this item:
There are no documents attached for this item.
If there is subject compensation, provide the schedule for compensation per study visit or session 
and total amount for entire participation, either as text or separate document
Subjects will receive compensations for completing the following procedures.  Visit 1: Clinical 
Interview (=$40) and Test TMS Pulses (=$10) Visit 2: Baseline MRI Scan ($60) and assessments ($80) 
Visit 3: TMS/ MRI Scan $150  Visit 4 (for controls only): TMS/MRI Scan 2 $150 If participants have 
already completed some of the study procedures as a part of another study at the Center for 
Neuromodulation in Depression and Stress or through Neurodevelopment & Psychosis Section they 
will not have to complete these study procedures again and therefore will only be compensated based 
on new study procedures completed under this protocol. If they have already completed the clinical 
interview and assessments through a previous study, they may be able to complete Visit 2 assessments 
during Visit 1 and will be compensated $40 for Visit 1 and $60 for Visit 2. Unless the participant 
requests compensation after each study visit, subjects will be compensated at the end of their study 
participation.  Subjects may receive an additional $100 if the task for Visit 5 (or 4 for ADHD subjects): 
Task MRI Scan is available while they are enrolled in the study and they would like to complete it. In 
other words, if the task is not available by time the complete Visit 4 (or Visit 3 for ADHD subjects), 
their study participation will be considered complete and they will not receive the additional $100. 
Subjects will be compensated through University of Pennsylvania supported Greenphire ClinCard. This 
is a reloadable prepaid card (similar to a debit/credit card) which allows funds to be available 
immediately. Study staff will provide participants with a ClinCard Cardholder FAQ: US document 
(attached). Subjects who do not feel comfortable with the Greenphire ClinCard may be compensated by 
a check, in lieu of the ClinCard. We are not stating this option in the ICF, as we would prefer all 
participants to use the ClinCard for consistency; however, we acknowledge that not all individuals will 
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feel comfortable with this method and therefore, if a participant expresses discomfort, we will then 
verbally offer them the option of being paid with a check. If participants opt to have the payment 
provided to them in the form of a check; it will be mailed to their home address. Participants will be 
required to complete an electronic C-2 and a W-9, including providing their full social security number, 
in order to receive the study payment.
Study Procedures
Suicidal Ideation and Behavior
Does this research qualify as a clinical investigation that will utilize a test article (ie- drug or biological) 
which may carry a potential for central nervous system (CNS) effect(s)?
No
Procedures
Potential subjects showing an interest in participation for the study will be asked to answer questions on 
the CNDS general screener through Penn supported REDCap, if they have not already done so. A lead 
coordinator will review the results of this screener and refer them to this study if they meet basic 
eligibility criteria. For potential ADHD participants, this means meeting threshold for 2 out of 3 
questions asked about ADHD on the screening form. If they meet this threshold, they will be contacted 
and given a brief explanation of study procedures and time commitment involved in participation, and 
screened to exclude any individuals meeting clear-cut exclusion criteria. For ADHD participants, this 
involves ﬁlling out an additional online REDCap pre-screening form sent by a study coordinator. The 
questions and results of this pre-screener are determined by GOASSESS standards, and a staff member 
will mark the form pass or fail. The brief phone or online screen will last approximately 15 minutes. If 
basic eligibility criteria are met, and the pre-screener is passed, participants will be contacted to 
schedule their ﬁrst visit.  Visit #1- Consent and Screening Visit: This visit will involve both remote and 
in-person procedures. First, participants will be contacted to schedule a remote visit in which a 
coordinator will discuss the Informed Consent Form (ICF). After going through the ICF, participants 
will be asked to electronically sign the end of the ICF and complete a Remote ICF Attestation Form. 
After the ICF process, participants will be asked to complete multiple questionaries regarding their 
medical history, demographics, social security (for compensation), and eligibility to receive MRI scans 
and TMS. After the questionnaires, participants will undergo a clinical interview. If participants meet 
eligibility for these initial procedures, we will schedule an in-person meeting to test TMS tolerability. 
For the TMS demo, participants will receive several short rounds of TMS test pulses to the prefrontal 
cortex to ensure comfort. During this demonstration we will identify the participants resting motor 
threshold (MT). MT is deﬁned as the minimum magnetic ﬂux needed to elicit a response in a target 
muscle in 5 out of 10 trials. MT is the standard in the ﬁeld for measuring cortical excitability and to 
reduce seizure risk. While TMS is usually quite tolerable, a minority of participants (20%) cannot 
tolerate stimulation procedures. Tolerability screening will be assessed by giving test pulses of TMS 
that utilize 120% of each participants estimated motor threshold level. The information collected in this 
initial visit will determine if the subject meets all inclusion criteria.  Visit #2- Baseline MRI: During this 
visit, eligible participants will complete a 1 hour scan that will include ultra-high-resolution diffusion 
MRI and structural imaging. This ﬁrst session scan will allow for mapping the structural connectome, 
and used to identify regions of high and low controllability. These will serve as stimulation targets for 
the subsequent TMS/fMRI scan sessions. This visit will also involve multiple questionnaires and 
assessments, including neurocognitive testing. Assessments from Visit 1 and Visit 2 may be split onto 
multiple days in order to accommodate scheduling constraints. Participants who have previously and 
recently completed the screening assessment and neurocognitive battery through he Neurodevelopment 
& Psychosis Section will not need to complete these procedures and their data from those assessments 
will be shared for the current protocol only if they consent to the current study.  Visit #3-TMS/fMRI: 
Before TMS scans, a swim cap on each participant is marked overlying targeted brain regions as 
determined by neuronavigation (Brainsight). Motor threshold will be determined at the scanner just 
before the TMS/fMRI recordings to use in determining the 110% and 120% MT levels for TMS. 
Participants will have a 1-hour TMS/fMRI session including approximately 4 minutes total of repetitive 
stimulation as well as 2 rounds of single pulse TMS in scans each about 12 minutes. Target location 
(site of high controllability versus site of low regional controllability) will alternate across TMS/fMRI 
sessions and in a counterbalanced fashion. During this scan, participants will also perform a working 
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memory N-back task several times.  rTMS protocol: We will use the intermittent theta burst stimulation 
pattern (iTBS) of rTMS (Huang et al., 2005) at 110% resting motor threshold for each site for each 
participant. The iTBS will be administered using standard protocol pulse parameters: 2s of stimulations 
(30 stimulations) followed by 8s gaps and repeated 20 times for 600 stimulations total. fMRI recordings 
will be collected for 5 minutes before iTBS starts and also during each 8s gap so that cumulative dose 
as neuroplasticity is induced can be recorded. We have successfully employed 1, 5, and 20 Hz protocols 
as well as theta- burst rTMS using our in scanner rig without signiﬁcant heating of the coil elements. 
This is mainly due to the air cooling system that we developed and that is now an optional equipment 
purchase from Magventure for their MRI compatible TMS system.  Visit #4- TMS/fMRI 2 (for non-
symptomatic subjects only): This visit will be identical to visit #3, but the site of stimulation will be the 
opposite site from the ﬁrst TMS/fMRI session. Target location (site of high controllability versus site of 
low regional controllability) will alternate across TMS/fMRI sessions and in a counterbalanced fashion. 
We will use the motor threshold determined at the ﬁrst TMS/fMRI session for Visit #4.  Participant 
Monitoring During MRI/ TMS Procedure: For maximal safety we will have a medically trained 
individual (Dr. Sattherthwaite, TDB MD project staff or similarly trained nurse/physician) with 
advanced life support and TMS training on call at every study visit that includes rTMS with any 
participant (patient or healthy) to respond to any potential medical situations arising from doing TMS/
fMRI. Study staff will be trained by the study PIs (Oathes and Satterthwaite) to recognize the most 
common medical conditions arising from rTMS administration (syncope and seizure) and how to 
effectively report these outcomes as well as minimize discomfort for participants in the unlikely event 
that these events occur. Only individuals trained by the PIs will dispense TMS. The medical team 
member will also be available for consultation during these sessions for less medically urgent issues 
that participants may inquire about (e.g. common temporary headaches or discomfort from TMS). As 
part of our medical campus and for all scans, emergency personnel and equipment are immediately 
available to the MRI room should the need arise. In addition, an experienced technician and a member 
of the study team will administer TMS during the MR session and will ensure participant safety and 
well-being. If the participant complains of feeling claustrophobic or excessive discomfort from TMS 
and does not wish to complete the MRI, the study will be terminated.  Visit #5 (or #4 for ADD/ADHD 
patients)(OPTIONAL)- Task fMRI scan (for all subjects): This visit will only take place if the task is 
available, and the participant wants to complete it. This visit will take place over a 1-hour fMRI session. 
Participants will complete several fMRI scans while completing tasks relevant to attention and learning.
The following documents are currently attached to this item:
There are no documents attached for this item.
Deception
Does your project use deception?
No
International Research
Are you conducting research outside of the United States?
No
Analysis Plan
For the primary within-subjects analyses, a time (pre vs post rTMS) by working memory load (high vs 
low) by stimulation site (high vs low controllability) ANOVA will be done both on working memory 
performance (d prime sensitivity) as well as fMRI voxelwise brain responses. In addition, the group 
level factor (ADHD or Healthy) will be added to the same model for a separate mixed-effects ANOVA.
The following documents are currently attached to this item:
There are no documents attached for this item.
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Data conﬁdentiality
x Paper-based records will be kept in a secure location and only be accessible to personnel involved 
in the study.
x Computer-based ﬁles will only be made available to personnel involved in the study through the 
use of access privileges and passwords.
Prior to access to any study-related information, personnel will be required to sign statements 
agreeing to protect the security and conﬁdentiality of identiﬁable information.
x Wherever feasible, identiﬁers will be removed from study-related information.
A Certiﬁcate of Conﬁdentiality will be obtained, because the research could place the subject at 
risk of criminal or civil liability or cause damage to the subject's ﬁnancial standing, 
employability, or liability.
x A waiver of documentation of consent is being requested, because the only link between the 
subject and the study would be the consent document and the primary risk is a breach of 
conﬁdentiality. (This is not an option for FDA-regulated research.)
x Precautions are in place to ensure the data is secure by using passwords and encryption, because 
the research involves web-based surveys.
Audio and/or video recordings will be transcribed and then destroyed to eliminate audible 
identiﬁcation of subjects.
Subject Conﬁdentiality
Patients entering the study will be given a unique identifying code. This code will be used on all data 
obtained from scans or the medical record. Only one password protected document connecting the code 
with the participant name will exist. Everything will be immediately coded and this coded information 
will be stored in secure cabinets inside locked rooms or in password protected, IRB compliant online 
databases, such as REDCap.
Sensitive Research Information*
Does this research involve collection of sensitive information about the subjects that should be excluded 
from the electronic medical record?
No
Subject Privacy
Privacy refers to the person's desire to control access of others to themselves. Privacy concerns people, 
whereas conﬁdentiality concerns data. Describe the strategies to protect privacy giving consideration to 
the following: The degree to which privacy can be expected in the proposed research and the safeguards 
that will be put into place to respect those boundaries. The methods used to identify and contact 
potential participants. The settings in which an individual will be interacting with an investigator. The 
privacy guidelines developed by relevant professions, professional associations and scholarly 
disciplines (e.g., psychiatry, genetic counseling, oral history, anthropology, psychology). 
Participants will be recruited through the University of Pennsylvania and surrounding community. 
When applicable, they will be identiﬁed and contacted through that facility. For future contact, they will 
be asked if they prefer phone (and cell or home) or email. The study will be presented in a private room 
and the fMRI will also take place in a private room. All contact made with the participant will be done 
so when the coordinator(s) or investigator in private, as would be the case with a doctor making a call to 
their patient.
Data Disclosure
Will the data be disclosed to anyone who is not listed under Personnel?
Deidentiﬁed information may be shared with collaborating researchers within the University of 
Pennsylvania and at collaborating institutions (CHOP). Subjects who choose to participate in other 
projects at the Center for Neuromodulation in Depression and Stress will provide written permission 
(within ICF) to have their data shared between studies so that they do not need to repeat duplicate study 
procedures.  There will be no additional documentation for this study that identiﬁes these subjects as 
partaking in other studies.
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Data Protection*
x Name
x Street address, city, county, precinct, zip code, and equivalent geocodes
x All elements of dates (except year) for dates directly related to an individual and all ages over 89
x Telephone and fax number
x Electronic mail addresses
x Social security numbers
Medical record numbers
Health plan ID numbers
Account numbers
Certiﬁcate/license numbers
Vehicle identiﬁers and serial numbers, including license plate numbers
Device identiﬁers/serial numbers
Web addresses (URLs)
Internet IP addresses
Biometric identiﬁers, incl. ﬁnger and voice prints
Full face photographic images and any comparable images
Any other unique identifying number, characteristic, or code
None
Does your research request both a waiver of HIPAA authorization for collection of patient information 
and involve providing Protected Health Information ("PHI") that is classiﬁed as a "limited data set" 
(city/town/state/zip code, dates except year, ages less than 90 or aggregate report for over 90) to a 
recipient outside of the University of Pennsylvania covered entity?
No
Tissue Specimens Obtained as Part of Research*
Are Tissue Specimens being obtained for research?
No
Tissue Specimens - Collected during regular care*
Will tissue specimens be collected during regulator clinical care (for treatment or diagnosis)?
No
Tissue Specimens - otherwise discarded*
Would specimens otherwise be discarded?
No
Tissue Specimens - publicly available*
Will tissue specimens be publicly available?
No
Tissue Specimens - Collected as part of research protocol*
Will tissue specimens be collected as part of the research protocol?
No
Tissue Specimens - Banking of blood, tissue etc. for future use*
Does research involve banking of blood, tissue, etc. for future use?
No
Genetic testing
If genetic testing is involved, describe the nature of the tests, including if the testing is predicative or 
exploratory in nature. If predictive, please describe plan for disclosing results to subjects and provision 
NCT05736458 

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of genetic counseling. Describe how subject conﬁdentiality will be protected Note: If no genetic testing 
is to be obtained, write: "Not applicable."
Not applicable
Consent
1. Consent Process
Overview
Consent will be obtained by one of member of our research team. Because this study does not involve 
treatment, coercion is not a concern. Consent will be obtained remotely (via RedCap) where study staff 
members will discuss the Informed Consent Form, including the purpose of study, procedures, risks, 
and beneﬁts. They will explain that participating is completely voluntary and that not participating will 
not change access to treatment in any way. The subject will be given the option to consider study 
enrollment and will not be forced to make a decision the same day. At the end of the ICF, there will be a 
HIPAA-compliant eSignature ﬁeld following OCR- RedCap guidelines. By electronically signing the 
ICF, they will be consenting to participate in the study. Subjects will automatically receive an electronic 
copy of the ICF. Enrolled participants will be asked to complete the Remote ICF Attestation Form to 
ensure they understood all the procedures and risks associated with the study. After the ICF process, we 
will begin the screening procedures. If participant meets initial eligibility, they will be invited to an in-
person meeting where we can provide a paper copy of the ICF upon request.
Children and Adolescents
N/A
Adult Subjects Not Competent to Give Consent
N/A - we are looking for cognitively normal participants, so all will have the competency to give 
consent.
2. Waiver of Consent
Waiver or Alteration of Informed Consent*
Waiver of written documentation of informed consent: the research presents no more than minimal risk 
of harm to subjects and involves no procedures for which written consent is normally required outside 
of the research context
Minimal Risk*
Impact on Subject Rights and Welfare*
Waiver Essential to Research*
Additional Information to Subjects
Written Statement of Research*
No
If no written statement will be provided, please provide justiﬁciation
Request of waiver of documentation of informed consent for PRE-SCREENING activity only; phone 
and self-report screening will be captured via RedCap. Participants are informed of this and given the 
option to verbally consent; however, we will not be providing them a copy of this, as some individuals 
will not actually participate in the study and therefore the only link between the subject and the study 
would be the consent document and the primary risk is a breach of conﬁdentiality.
The following documents are currently attached to this item:
NCT05736458 

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There are no documents attached for this item.
Risk / Beneﬁt
Potential Study Risks
Clinical assessment: In the screening, we plan to ask if potential participants have had any diagnosis or 
treatment for a psychiatric or neurological condition. Some participants may experience emotional 
discomfort when answering some of the questions or talking about their personal feelings or life events. 
Participants may choose not to answer any question.  MRI Scan: There are no known risks associated 
with MRI scans for neurologically healthy subjects except that participants may experience discomfort 
as they will be required to lie still in a conﬁned area. Participants may experience claustrophobia (fear 
of enclosed spaces and/or anxious feelings accompanied by fast heart rate or shortness of breath) within 
the MRI scanner. In addition, the scanner produces a loud repetitive knocking noise during the study 
that some people ﬁnd bothersome even with ear plugs worn by all MRI study participants. If a subject 
has a problem with feeling uncomfortable while inside the scanner, they may stop this study.  Rare: 
Implanted medical devices and metallic foreign fragments inside the body may pose a risk if a subject 
were to enter the MRI magnet room. Devices such as Pacemakers, Internal Cardiac Deﬁbrillators, 
Insulin Pumps, and other medical devices may also prevent a safe MRI. Therefore, questions regarding 
medical and work history will be asked prior to your exam. Patients who have metallic devices in their 
bodies will not be permitted to be scanned using MRI. Although there are no known risks related to 
MRI on pregnant women or a fetus, there is a possibility of yet undiscovered pregnancy related risks so 
we will exclude any participants  TMS: Based on the latest safety guidelines for using TMS by a panel 
of experts in Neurology, Epilepsy, Psychology, Bioethics, Magnetic Resonance, Neuroscience, Hearing 
Disorders, and related disciplines (The Safety of TMS Consensus Group), a list of risk factors and 
guidelines for using TMS has been published (Rossi et al., 2004, 2009, 2021). The list recognizes TMS 
used in clinical as well as research applications, including TMS in an MRI environment. The most 
common side of effect of TMS is a mild headache, which approximately 25% of patients experience. 
We demonstrate TMS at the initial screening visit to ensure participants are comfortable receiving TMS. 
Headache intensity following administration of TMS could vary in severity from mild to intense. The 
effects of a more intense headache could last into the next day. Although uncommon, some subjects 
have experienced nausea, lightheadedness, and dizziness during the experiment. Seizure risk is the 
biggest safety concern in TMS research. For single-pulse TMS, this risk is listed as Rare. For high 
frequency rTMS (proposed here), the risk for seizure induction is listed as Possible but less than 1% in 
normals (healthy participants). With proper screening (outline above), and administering TMS to well 
over 100 participants, we have never induced a seizure. Consistent with these guidelines that list the risk 
of even transient cognitive or neurophsychological problems as overall negligible, most studies suggest 
a beneﬁt for cognitive performance with similar protocols and we expect a similar outcome (transient, 
up to 15 min) for our experimental task.  Risk of Breach of Conﬁdentiality: Breaches in conﬁdentiality 
could impact future insurability and/or employability if, for example, low cognitive performance is 
detected or a psychiatric/neurological condition is documented. An exception to conﬁdentiality is if a 
participant reports child abuse or neglect, or if they report suicidal or homicidal ideation or intent to the 
research team. Any information about child abuse or intent to harm oneself or others will be reported to 
authorities, as required by law.
Potential Study Beneﬁts
There is no promise of beneﬁt to subjects in this study. There is no beneﬁt to receiving the MRI scans or 
to the testing. The scans and testing are performed only for research and the results are not routinely 
shared with participants. However, in the event that MRI abnormalities are discovered, subjects will be 
informed of the ﬁnding. Participants experience the indirect beneﬁt of contributing to scientiﬁc 
knowledge.
Alternatives to Participation (optional)
The alternative to participation is to not participate.
Data and Safety Monitoring
1. Before any investigator or assistant is allowed to enter the scanner room, they are required to take an 
extensive MRI safety course (with annual refresher courses) that deal with powering down (or 
quenching) the magnet for patient safety and with established procedures for expediting participant 
contact with emergency medical personnel, should the need arise. These courses are run by CAMRIS as 
NCT05736458 

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a prerequisite for obtaining privileges to book and use scanner time. 2. Participants will already be lying 
down on the scanner bed during scans. In the event of a seizure, participants will be taken out of the 
magnet bore immediately and the barriers on both sides of the detachable bed will be raised to prevent 
injuries from falls. This event will qualify as a medical emergency and procedures outlined below will 
be followed: 3. Emergency responding in the scanner is facilitated by having two research staff running 
a scan. In the event of an emergency, one of these individuals remains with the participant and undocks 
the scanner bed from the magnet bore. This bed can easily be wheeled out of the scan room to facilitate 
speedy access to arriving emergency medical personnel. The second researcher calls 9-1-1 from the 
scanner suite and gives details of the participant's level of medical distress and location. This person 
next calls the Faculty Administrator for CAMRIS, Mark Elliot, Ph.D., to notify him of the event and to 
make use of his expertise in scanner emergencies. Next, this person goes out to the front of the scanner 
building to ﬂag down arriving emergency personnel and to direct them to the participant. 4. Dr. 
Theodore Satterthwaite MD, is a licensed physician and will be on call during all scans (or another 
medically trained individual) to respond to any more subtle potential medical situations arising from 
doing TMS/fMRI. Drs. Satterthwaite and Oathes will be involved in training research personnel in 
proper use of TMS/fMRI equipment and in detecting the onset of seizures. 5. These guidelines are in 
full agreement with CAMRIS safety protocols and with published guidelines by a panel of experts in 
conducting TMS/rTMS and TMS/neuroimaging work for both research and clinical purposes (Rossi et 
al., 2009). MRI compatible TMS equipment is used in a novel experimental context but well within 
recommendations by the equipment manufacturer who continues to work closely with the CNDS and 
the applicant.
The following documents are currently attached to this item:
There are no documents attached for this item.
Risk / Beneﬁt Assessment
There is essentially zero risk of harm from the research procedures (MRI,TMS, computerized tasks). 
The potential beneﬁt to society through the increased understanding of the effects of TMS on cognition 
far outweighs the potential risk from the MRI and TMS procedures. Additionally, those who would be 
unable to tolerate TMS or an MRI scan will be screened out.  In this study we will be using single 
pulses of TMS and short rounds of high frequency rTMS. For single pulse TMS, the risk is considered 
as rare. For high frequency the risk for seizure induction is listed as possible but less than 1% in healthy 
participants (Rossi et al. 2021) There is no evidence of increased risk for using single pulse and rTMS 
on unmedicated patients with ADHD.
NCT05736458