Individualized Closed Loop Transcranial Magnetic Stimulation (TMS) for Working Memory Enhancement
Phase: NA
Conditions: Memory
Sponsor: University of Pennsylvania

Page 1 of 23 
 
 
 
 
 
 
CLINICAL RESEARCH PROTOCOL 
 
INVESTIGATIONAL PRODUCT 
Transcranial Magnetic Stimulation (TMS): MagPro 
X100 Stimulator/ Cool-B65 Butterfly Coil/ MRI-B91 
TMS Coil 
PROTOCOL TITLE Individualized Closed Loop TMS for Working 
Memory Enhancement 
IRB PROTOCOL NUMBER 832891 
PRINCIPAL INVESTIGATOR 
Desmond J. Oathes, PhD. 
Department of Psychiatry 
University of Pennsylvania 
FUNDING SPONSOR(S) National Institutes of Health (NIH) 
PROTOCOL VERSION V7.2 August 2023 
DATED September 8, 2023 
CLINICALTRIALS.GOV NUMBER NCT04402294 
 
 
 
 
 
 
 
 

Page 2 of 23 
 
 
Protocol Details 
 
Basic Info 
 
Confirmation Number: 
djabjdjj 
Protocol Number: 
832891 
Created By: 
LYU, MENGQUN 
Principal Investigator: 
OATHES, DESMOND J 
Protocol Title: 
Optimizing Neuromodulation through Individualized Stimulation Frequencies 
Short Title: 
Individualized Loop TMS 
Protocol Description: Transcranial Magnetic Stimulation (TMS) is  a  non-invasive  mechanism  for  stimulating  the  human 
brain. TMS can potentiate or inhibit activity in various brain regions, and it allows researchers to 
exert causal control over neural pathways. We will use real-time fMRI brain readout to optimize 
TMS delivery and measure changes in behavioral and brain response following the neuromodulation 
in healthy participants. 
Submission Type: 
Biomedical Research 
Application Type: 
EXPEDITED Category 1 
 
 
 
Study Personnel 
Principal Investigator 
Name: 
OATHES, DESMOND J 
Dept / School / Div: 
10579 - PS-Center for the Neuroscience of Depression & Stress 
Campus Address 
3309 
Mail Code 
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 

Page 3 of 23 
 
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: 
06/21/2022 
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 

Page 4 of 23 
 
Other Investigator 
Name: 
FAN, YONG 
Dept / School / Div: 
4452 - RA-Radiology 
Campus Address 
6116 
Mail Code 
Address: 
Richards Building, 7th Floor 
3700 Hamilton Walk 
City State Zip: 
PHILADELPHIA PA 19104-6116 
Phone: 
215-746-4065 
Fax: 
215-573-1811 
Pager: 
Email: 
yong.fan@uphs.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: 
04/17/2024 
Name of course completed : 
Good Clinical Practice: An Introduction to ICH (GCP) Guidelines 
 
Responsible Org (Department/School/Division): 
 
10579 - PS-Center for the Neuroscience of Depression & Stress 
 
Key Study Personnel 
Name: 
Department/School/Division: 
HS Training Completed: 
Training Expiration Date: 
Name of course completed: 
GCP Training Completed: 
Training Expiration Date: 
Name of course completed: 
DAVATZIKOS, CHRISTOS 
RA-Radiology 
Yes 
CITI Protection of Human Subjects Research Training - ORA 
No 
Name: 
LI, HONGMING 
Department/School/Division: 
RA-Radiology 
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: 

Page 5 of 23 
 
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: 
FIGUEROA-GONZALEZ, ALMARIS 
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: 
06/21/2022 
Name of course completed: 
CITI Good Clinical Practice (GCP) - OCR 
Name: 
TROTH, JILLIAN L 
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: 
03/28/2026 
Name of course completed: 
CITI Good Clinical Practice (GCP) - OCR 
Name: 
HAMMETT, ETHAN C 
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: 
06/20/2026 
Name of course completed: 
CITI Good Clinical Practice (GCP) - OCR 
Name: 
ELLIOTT, MARK A 
Department/School/Division: 
RA-Radiology 
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: 

Page 6 of 23 
 
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: 
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 
Name: 
WOLF, DANIEL 
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: 
12/04/2023 
Name of course completed: 
CITI Good Clinical Practice (GCP) - OCR 
Name: 
GARCIA, SARAI 
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: 
06/12/2026 
Name of course completed: 
CITI Good Clinical Practice (GCP) - OCR 
Name: 
Department/School/Division: 
HS Training Completed: 
Training Expiration Date: 
Name of course completed: 
GCP Training Completed: 
Training Expiration Date: 
Name of course completed: 
SATTERTHWAITE, THEODORE D 
PS-Neuropsychiatry 
Yes 
CITI Protection of Human Subjects Research Training - ORA 
No 

Page 7 of 23 
 
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 
 
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? Please note the following definition:Clinical trial is defined as a research study in 
which one or more human subjects are prospectively assigned to one or more interventions (which may 
include placebo or other control) to evaluate the effects of the interventions on biomedical or behavioral 
health-related outcomes. See CFR 45.46.102(b) 
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. For more guidance, please 
see: https://irb.upenn.edu/homepage/how-to-submit/initial-submission/2018-common- rule. Please see: 
https://irb.upenn.edu/clinicaltrials for additional clinical trial requirements. 
 
Investigator Initiated Trial* 
Is this an investigator initiated trial? Please select "Yes" if ALL the following conditions are met:The 
research is subject to FDA regulations for human subjects research.The individual PI both initiates  (plans 
and designs) and conducts an investigation and under whose immediate direction the investigational agent 
is administered or dispensed. The individual investigator has absolute  responsibility and accountability 
and designs, conducts, monitors, manages the data, prepares reports  and oversees all regulatory and ethical 
matters. See 21 CFR 312.3 
Yes 

Page 8 of 23 
 
If Yes, please be aware that the investigator may be required to create and manage a record of this trial  
in https://clinicaltrials.gov. 
 
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 
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 solely because they are enrolled in this protocol? 
(e.g. X-rays, CT, Fluoroscopy, DEXA, pQCT, FDG, Tc-99m, etc.)?IF YES, the protocol must be 
approved by the RRSC (Radiation Research Safety Committee). Consult EHRS web site: 
www.ehrs.upenn.edu/protocols/radiohuman.html for more information.If you have questions, email 
jjesik@ehrs.upenn.edu or kavyap@upenn.eduIf your protocol includes Nuclear Medicine Procedures, 
the protocol must be reviewed by the Nuclear Med Operations Committee: https://redcap.link/NMOPS 
No 
 
Gene Transfer* 
Does this research involve gene transfer (including all vectors) to human subjects? IF YES, the protocol 
must be approved by the Institutional Biosafety Committee. Consult EHRS web site: 
www.ehrs.upenn.edu/protocols/bio_humans.html for submission requirements If you have questions, call 
215-898-4453. The protocol may also require review by the Senior Vice Provost for Research's Human 
Research Advisory Committee(HRAC). The IRB will notify the PI and study staff if this review is 
warranted. 
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)? IF YES, consult the EHRS web site: www.ehrs.upenn.edu/programs/ 
bio/bbpathogens.html for information on OSHA Bloodborne Pathogens requirements (training, 
vaccination, work practices and Exposure Control Plan). If you have questions, call 215-898-4453. 
No 
 
Image Guided Biopsies* 
Does the research involve imaging guided biopsy? IF YES, please contact the Clinical Imaging Core.  See 
https://www.med.upenn.edu/cbi for more details. Any questions should be directed to the Director  of 
Research Operations, Dept of Radiology, Kathleen Thomas. 
No 

Page 9 of 23 
 
Computerized Tomography (CT) Studies* 
Does the protocol involve CT scans that are not considered standard of care and are being performed for 
research purposes?IF YES, complete the CACTIS Committee Application: https://is.gd/CACTIS and 
consult CACTIS website: http://www.uphs.upenn.edu/radiology/research/labs/cactis/ for application 
requirements. 
No 
 
CAMRIS and MRI Studies* 
Is an MRI scan being performed for research only and NOT considered standard of care (example: specific 
scanner, parameters or solely for the purposes of research)?NOTE: Research/non-standard use  of MRI 
may include but is not limited to any of the following: Situations in which MRI results may impact subjects 
current clinical care plan or treatment decisions, such as:The study requires a  customized report with 
specifics regarding the study protocol (i.e., specific measurements or details); Introduction of a device of 
any kind during the MRI that is not used during a 'standard of care' type scan.Your MRI is not consistent 
with standard care time points for MRI imaging.Your MRI is not paid for by insurance.IF YES, consult 
CAMRIS website: https://www.med.upenn.edu/camris/application- and-faq.html for application 
requirements and required institutional consent form language. 
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? Therapeutic, 
Prevention, Supportive Care, Screening, Early Detection, or Diagnostic, Epidemiologic, Observational, 
Outcome, Ancillary or Correlative. For a description of these categories, see http://www.ctsrmc.org/ 
submitting_a_protocol.php NCI Cooperative Groups are as follows:Alliance for Clinical Trials in 
OncologyNCI Clinical Trials Group (Canadian Cancer Society) (NCCTG)Children's Oncology Group 
(COG)NRG Oncology GroupECOG-ACRIN Cancer Research GroupSouthwest Oncology Group 
(SWOG) IF YES, the protocol must be submitted to the Cancer Center's Clinical Trials Scientific Review 
Committee for scientific review and approval prior to obtaining IRB approval. Consult the CTSRMC 
website: www.ctsrmc.org for application requirements 
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 
 
HIPAA / Protected Health Information 
Does the research proposal involve accessing (viewing / using), collecting, or disclosing of protected 
health information (PHI) directly from participants or their medical or dental record for research purposes? 
Yes 
 
Indicate which item is provided with this submission: 
 
Modified research informed consent document that incorporates HIPAA requirements 
Cohort/data analysis tools used 
Remote Study Visits 
Does the research proposal involve conducting research visits remotely via any type of video 
conferencing software? 
Yes 

Page 10 of 23 
 
Conference software used 
Zoom 
 
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? (UPHS includes all Penn 
hospitals and clinical practices, including the Clinical Care Associates network of  community  practices). 
Examples of UPHS services/tests/procedures includes the Clinical Translational Research Center (CTRC), 
laboratory tests, use of the pathology lab, cardiovascular imaging tests or radiology imaging tests (whether 
being billed via the Service Center or through UPHS), other diagnostic tests & procedures and associated 
professional services, etc. 
No 
 
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., 

Page 11 of 23 
 
medical records)? 
No 
 
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: 
4412 - PS-Psychiatry 
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? 
 
Regulatory Sponsor 
IND Sponsor 
 
none 

Page 12 of 23 
 
000 - 000 - 0 - 000000 - 0000 - 0000 - 0000 
 
Industry Sponsor 
 
None 
 
Project Funding* 
Is this project funded by or associated with a grant or contract? 
Yes 
 
Selected Proposals 
Proposal No 
Title 
10070605 
Individualized Closed Loop TMS for Working Memory Enhancement 
 
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 
 
 
 
 
 
 
 
Protocol 
Abstract 
Transcranial magnetic stimulation (TMS) is a non-invasive mechanism for stimulating brain regions in 
humans. TMS can potentiate or inhibit activity in various brain regions, and it allows researchers to  exert 
causal control to explore and define network connectivity among brain regions. Using real-time brain 
readouts combined with interleaved TMS/fMRI, we will compare the optimal and the  least  optimal 
stimulation frequency based on individualized functional connectivity networks. By comparing brain and 
behavioral changes after three days of neuromodulation at optimal and least optimal 

Page 13 of 23 
 
stimulation frequency, we aim to explore whether optimal stimulation frequency will lead to more 
robust brain and behavior responses to repetitive TMS (rTMS). 
 
Objectives 
Overall objectives 
We aim to evaluate whether optimized frequency (compared to the least-optimized frequency) of excitatory 
TMS will generate better results in behavior and brain activity among healthy participants. Specifically, 
we will develop a novel tool to compute individualized multi-scale functional connectivity networks using 
data from baseline resting and task-evoked brain states. Building on that, we will utilize recurrent neural 
networks (RNN) with long short-term memory (LSTM), a promising deep learning technique, to generate 
brain decoding models and obtain real-time readouts of brain states. We will then establish a closed loop 
of rTMS and brain readouts, fine-tuning the rTMS frequency to determine the optimal stimulation 
frequency for each participant. Participants will receive their optimal stimulation frequency of rTMS over 
a three-day neuromodulation session and their least optimal stimulation frequency (the frequency least 
successful in moving their brain state) over another three-day neuromodulation session (order 
counterbalanced across subjects). We hypothesize that  optimal frequency will drive performance 
improvements and brain changes more than the least optimal frequency. 
 
Primary outcome variable(s) 
Behavior change (task performance) and brain activity change (in-scanner brain readouts during the 
working memory task or at rest) in response to neuromodulation. 
 
Secondary outcome variable(s) 
Correlation between changes in behavioral measures and changes in network connectivity before and 
after the neuromodulation. 
 
Background 
Repetitive TMS (rTMS) has been widely adopted to non-invasively stimulate the brain to improve working 
memory (WM) performance in both clinical and non-clinical samples (Brunoni & Vanderhasselt, 2014). 
However, behavioral and symptom responses to TMS remain heterogeneous and the factors governing the 
strength and direction of rTMS effects across individuals remain largely unknown. Accumulating evidence 
has demonstrated that TMS efficacy hinges upon the precision of TMS targeting, and individualized 
functional connectivity networks (FCNs) may help accurately  identify TMS targets for individuals (Fox, 
Buckner, White, Greicius, & Pascual-Leone, 2012; Fox, Liu, & Pascual-Leone, 2013; Weigand et al., 
2018) since effects of stimulation are propagated throughout both local and distributed brain networks 
(Herbsman et al., 2009; Kloppel et al., 2008). The functional brain state varies across individuals and 
within individuals over time (Bassett, Wymbs, Porter, Mucha, Carlson, & Grafton, 2011; Calhoun, Miller, 
Pearlson, & Adal, 2014; Finn, Scheinost, Finn, Shen, Papademetris, & Constable, 2017), which could 
substantially alter the impact of TMS. Preliminary research suggests that manipulating brain states during 
the delivery of repetitive TMS (rTMS) neuromodulation augments the behavioral impact of rTMS (Luber 
et al., 2017). Through manipulation  of brain state with a related behavioral task and using fMRI as the 
feedback signal, it may be possible to tune rTMS delivery to maximally impact the desired brain states in 
awake behaving study participants   in a highly individualized manner. Therefore, improved efficacy of 
TMS could be achieved through precise TMS targeting and optimal TMS delivery tailored for individuals 
and optimized online based on real-time readouts of brain states. FCNs derived from functional MRI have 
demonstrated promising performance for identification of reproducible individualized targets. However, 
existing methods are limited in that they typically identify group-level functional connectivity networks 
(FCNs) and focus on resting state fMRI alone. Our recent work suggests that individualized, sparse, non-
negative FCNs provide enhanced ability for characterizing the functional brain of individual subjects (Li, 
Satterthwaite, & Fan, 2017). Moreover, recent evidence suggests that task fMRI can improve upon within-
subject and between-subject estimates of stable brain network representations as compared with resting 
state fMRI only (Finn, Scheinost, Finn, Shen, Papademetris, & Constable, 2017). Based on these findings, 
current study will focus on both resting and task-evoked brain states and individualized, multiscale, 
hierarchical functional neuroanatomy, and we will extend upon our recent published work (Li et al., 2017, 
2016; Li, Zhu, & Fan, 2018) using deep matrix decomposition techniques (Trigeorgis, Bousmalis, 
Zafeiriou, & Schuller, 2014; Zhao, Ding, & Fu, 2017). This strategy will yield a set of individualized FCNs 
that   share similar spatial patterns across subjects at multiple scales with a hierarchical organization, 

Page 14 of 23 
 
facilitating individualized precise TMS targeting. Another major innovation that will facilitate optimal 
TMS delivery is the brain decoding for real-time online brain readouts. Recent studies have  demonstrated 
promising brain decoding performance of prediction models built upon functional connectivity measures 
among FCNs within time windows with a fixed width (Shirer, Ryali, Rykhlevskaia, Menon, & Greicius, 
2012; Richiardi, Eryilmaz, Schwartz, Vuilleumier, & Van De Ville, 2011). However, such fixed time 
windows are not likely optimal over different brain states that change  at unpredictable intervals. 
Meanwhile, recurrent neural networks (RNNs) with long short-term memory (LSTM) (Hochreiter & 
Schmidhuber, 1997) have achieved remarkable advances in sequence modeling (Lipton, Berkowitz, & 
Elkan, 2015), and these techniques have been successfully applied to EEG and ECoG data analysis (Glaser, 
Chowdhury, Perich, Miller, & Kording, 2017; Schwemmer et al., 2018). Our recent study has demonstrated 
that brain decoding models built upon individualized FCNs using LSTM RNNs accurately decode fine-
grained WM tasks and motor tasks in real time (Li & Fan, 2018). Therefore, here we will build brain 
decoding models to obtain real-time readouts of brain states using LSTM RNNs. Besides TMS targeting, 
rTMS frequency has clear neurobiological consequences successfully measured in-vivo in non-human 
animal brains in a landmark study (Allen, Pasley, Duong,  & Freeman, 2007). Our team has adopted the 
interleaved TMS/fMRI technique which will allow stimulation of specific nodes while recording fMRI 
responses from all other brain regions (Chen et al., 2013; Fonzo et al., 2001; Nahas et al., 2001). Building 
on this basic strategy and the innovative methodology mentioned above, we can fine-tune the TMS 
frequency based on real-time feedback of TMS induced effects on the brain. Specifically, we will target 
FCNs identified by a brain decoding model built using LSTM RNNs, apply short trains of in-scanner 
rTMS, monitor the resulting brain response with fMRI, and tune TMS delivery accordingly. As a result, 
we can optimize noninvasive brain stimulation through individualized target and frequency. By comparing 
behavioral and brain responses with optimized and non-optimized stimulation frequencies, this study will 
provide us novel insight to variability in response to TMS and will potentially enhance the capabilities of 
the existing device. 
 
Study Design 
Phase* 
Not applicable 
 
Design 
This study will recruit 38 healthy participants, who will be recruited through the community via study 
advertisements. Prior to any study visits, all subjects will be pre-screened through a phone interview  with 
a trained member of the study team or an online self-report screening, both through REDCap. The study 
involves 11 study visits. The first study visit will consist of a consenting and extended screening visit. All 
participants will have the opportunity to ask questions before signing the electronic consent form. We will 
complete a semi-structured clinical interview and will demonstrate TMS to ensure the participant is 
comfortable with all study procedures. This visit will be completed both remote and in- person. The second 
study visit will involve a 1-hour MRI scan. During the scan, the participant will complete multiple 
computerized tasks. The MRI scan will include both structural and functional scans, and those scans will 
be used to localize the stimulation target for the subsequent sessions. The third  study visit will be a 2-hour 
TMS/fMRI session, and the participant will engage in behavioral tasks   while interleaved rTMS rounds 
are delivered at different excitatory frequencies (frequency range: 2Hz-20Hz). This scan will be used to 
determine the optimal stimulation frequency for the individual participant. The fourth, fifth, and sixth study 
visits will involve neuromodulation with either the optimized frequency or the frequency least successful 
in moving a participants brain state,  as  determined from the third study visit. Each subject will receive 
~3000 pulses in each session, including the pulses from the motor threshold determination. We will 
determine the adjusted MT by  using the Stokes equation, which accounts for differences in cortical 
distance from the site relative to motor cortex (where the motor threshold is found). The stimulation 
amplitude will be equivalent to 110% of the adjusted MT. Prior studies have safely utilized TMS with such 
design (VanDerwerker et al., 2018; Cristancho, Trapp, Siddiqi, Dixon, & Lenze, 2018). The seventh study 
visit will involve a 1-hour TMS/fMRI session while the participant is engaging in a behavioral task.. This 
visit is designed to examine brain and behavioral changes after the first round of neuromodulation.  The 
seventh and the eighth visit will be scheduled at least one week apart. The  eighth, ninth, and tenth study 
visits will mirror the fourth, fifth, and sixth study visits and will involve neuromodulation with either the 
optimized or least-optimized individual frequency. The order of optimized and least-optimized frequencies 
will be counterbalanced across participants between Visit    4-6 and Visit 8-10 (i.e., half of the participants 
will receive stimulations of the two frequencies in one order, and the other half will receive stimulations 
of the two frequencies in the reverse order). The 

Page 15 of 23 
 
eleventh visit will mirror the seventh visit and will examine brain and behavioral changes after the second 
round of neuromodulation. 
 
Study duration 
Each subject will spend a total of approximately 13.5-20 hours of participation in the study over 11  study 
sessions. The study schedule is as follows: Visit 1: Consent/Screening (1-3 hours)  Visit  2: Baseline MRI 
(1.5-2 hours) Visit 3: TMS/fMRI (2-2.5 hours) Visit 4-6: 1st Neuromodulation Session (1-1.5 hours each) 
Visit 7: TMS/fMRI (1.5-2 hours) Visit 8-10: 2nd Neuromodulation Session (1-1.5 hours each) Visit 11: 
TMS/fMRI (1.5-2 hours). 
 
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 the study physician, Ted Satterthwaite, M.D. Facilities will 
include Penn 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, 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). 
 
 
 
Characteristics of the Study Population 
Target population 
38 healthy control participants to collect useable data from 28 healthy participants. 
 
Subjects enrolled by Penn Researchers 
38 
 
Subjects enrolled by Collaborating Researchers 
0 
 
Accrual 
All recruitment will be conducted through the University of Pennsylvania and the surrounding community 
to find a total of 38 healthy participants. It is assumed that there will be some participants who screen fail, 
are lost to follow up, withdraw, or complete without usable scanner data. Therefore, we estimate that we 
will need to consent/enroll up to 38 participants overall, in order to adequately test the hypotheses on at 
least 28 participants. 
 
Key inclusion criteria 
1)18-60 years old 2) Right handed 3) No psychiatric history as diagnosed by the SCID-V 4) Normal 
cognition 5) Capacity to give informed consent and follow study procedures 6) Sufficient command of 
English language to understand and respond to written as well as verbal instructions 
 
Key exclusion criteria 
1) History of neurological disorder or traumatic brain injury (other than mild)  2) Unable to have an  MRI 
scan, or current or prior medical condition that could interfere with the collection or interpretation of MRI 
data 3) Unable to receive TMS 4) Implanted devices, such as an aneurysm clip or cardiac pacemaker 5) 
History of stroke, epilepsy, or brain scarring  6) Recent use of psychoactive medications, as determined 
by investigators 7) Pregnant, nursing, or trying to become pregnant (self-attestation  alone) 8) Color 
blindness 9) Otherwise determined by investigator to be unfit for study 

Page 16 of 23 
 
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. 
 
Participant recruitment 
Please describe the plan to equitably identify and recruit a diverse group of participants that is reflective of 
the population under study. If this is a multicenter protocol, the recruitment plan should describe the local 
(Penn) site's plan. Describe:how potential participants may be identified (review of medical records, Slicer 
Dicer, DAC reports including referrals from physician offices and clinics);who may approach potential 
participants;methods to achieve sample diversity and inclusiveness;what information may be presented to 
or discussed with them; andthe context and setting in which recruitment will happen. 
All participants will be recruited through the University of Pennsylvania and the surrounding community. 
Subjects will be recruited through flyers, brochures, online advertising (CNDS website, Facebook, 
Craigslist, iConnect). All recruitment materials, including but not limited to  flyers,  brochures, referral 
letters, online postings, and email templates will be IRB-approved  before  distribution of any of these 
materials. Study coordinators may also contact participants  from  past studies at the CNDS who indicated 
they would be willing to be contacted about participating future studies at the center. Individuals 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  on  REDCap. All subjects meeting basic inclusion 
criteria will be scheduled for a remote screening visit. In order to facilitate the enrollment of interested 
subjects in multiple studies, center-wide general pre- screening forms, phone screen and self-report screen 
will be used. The Center for Neuromodulation in Depression and Stress has numerous studies that all are 
closely related, in both purpose and eligibility criteria, a general pre-screening (both phone and self-report) 
has been created. Many participants will   be eligible for multiple studies and will be presented with the 
opportunity to participate in all studies  that they are eligible for. An additional benefit of a shared or 
general pre-screening is that participants who do not qualify for a specific study can be informed of other 
studies they are eligible for. It will be clearly explained to all individuals that this pre-screening is for 
multiple studies and that their information will be stored in REDCap (option given to have screening done 
on paper). Additionally, subjects will be recruited through Penn's Office of Clinical Research iConnect 
volunteer registry. Volunteers who have consented to be contacted regarding studies of interest will be 
sorted by relevant diagnoses and invited by study team members to fill out an online survey to determine 
eligibility. 
 
Recruitment Materials 
Is the research team using any recruitment materials? These may include but are not limited to: phone call 
scripts, radio/video scripts, flyers/brochures, internet postings, email, letters to potential  participants, 
letters to patient physicians, My Penn Medicine (MPM), other direct messaging, etc. For guidance 
regarding recruitment materials, please review the IRB's guidance on Participant Recruitment Materials 
online:https://irb.upenn.edu/mission-institutional-review-board-irb/guidance 
Yes 

Page 17 of 23 
 
Use of Penn Media & Social Media Services 
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.NOTE: Penn Medicine must utilize one of the centralized PM Facebook 
Pages:ClinicalResearch@Penn Facebook pagePenn Medicine Facebook page@PennCancer Facebook 
pageAll clinical research paid Facebook ads must be listed on Clinical Research @ Penn Facebook 
page,www.facebook.com/ClinicalTrialsAtPenn. Exceptions to the above must get approval from the Penn 
Medicine Social Media Committee: pennmedicinesocialmediacommittee@uphs.upenn.edu. 
We will post flyers and place brochures throughout the local community to recruit for this study. In 
addition, participants will be recruited through advertisements in print (e.g. local newspapers), online 
media/websites (e.g. craigslist.com, researchmatch.org, Penn Medicine, CNDS website, Facebook, and 
Google ads), as well as radio or TV ads. All recruitment materials, including but not limited to flyers, 
brochures, referral letters, online postings, and email templates will be IRB-approved  before  distribution 
of any of these materials. 
 
The following documents are currently attached to this item: 
Subject  recruitment (03.15.2019_flyer_initialsubmission.docx) 
 
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 
 
Total compensation for completing all study visits is $720.00. Subjects will receive additional 
compensation ($0.17-$150) depending on the choices they make during the incentive-based tasks of the 
Neuromodulation Sessions. We will explain the details of the compensation before they begin the task. 
Subjects will receive compensation at the end of their study completion. If subjects do not  fully complete 
the study, they will receive compensation for the parts of the study they did complete, based  on the 
following outline: Visit 1: Clinical Interview ($20.00) Visit 2: Baseline MRI ($50.00) Visit 3 TMS/fMRI 
($150.00) Visit 4-6: 1st Neuromodulation Session ($50.00 x 3 = $150.00) Visit 7: TMS/ fMRI ($100.00) 
Visit 8-10: 2nd Neuromodulation Session ($50.00 x 3 = $150.00) Visit 11: TMS/fMRI ($100.00). Subjects 
will be compensated through University of Pennsylvania supported Greenphire ClinCard. This is a 
reloadable virtual or physical 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 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. If participants choose to participate in multiple studies at the center, 
some similar/identical study visits (mainly screening visit and baseline MRI) may not need to be repeated. 
If this is the case, participants will only be compensated for the new study procedures/visits they complete. 

Page 18 of 23 
 
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)? Centeral nervous system(CNS) 
effect: the ability of a test article to enter into and potentially interact with the central nervoous system 
(brain and spinal cord). Clinical Investigation: Any experiment that involves a test article and one or more 
human subjects that either is subject to requirements for prior submission to the Food and Drug 
Adminstration (FDA) under section 505(i) or 520(g) of the Federal Food, Drug, and Cosmetic Act, or is 
not subject to the requirements for prior submission to the FDA under these sections of the act, but, the 
results of which are intended to be submitted later to, or held for inspection by, the FDA as part of an 
application for a research or marketing permit. 
No 
 
Procedures 
All participants will be recruited through the University of Pennsylvania and the surrounding community. 
Subjects will be pre-screened for eligibility through phone or online self-report screener in REDCap. 
Eligible subjects will be invited in for a screening visit. Visit 1 will be a consent/ screening session. This 
visit will involve remote and in-person procedures. During the remote visit, a coordinator will discuss the 
Informed Consent Form with the participant. After going through the ICF, participants will be asked to 
electronically sign at the end of the ICF and complete a Remote ICF Attestation form   to ensure they 
understood all the procedures and risk associated with the study. If they agree to participate, they will 
complete questionnaires related to their medical history, demographics, and eligibility to receive MRI 
scans and TMS. After completing the questionnaires, participants  will  undergo a clinical interview. This 
interview could be done in person or remote. If participants meet eligibility for these initial procedures, we 
will schedule an in-person meeting to test TMS. 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. Screening data will be recorded in REDCap; 
this data will be retained indefinitely until the study enrollment is completed. The information collected in 
this initial visit will  determine  if  the subject meets all inclusion criteria. If participants screen-fail or 
withdraw, we will assign the clinical interview compensation to their virtual Greenphire Clincard. Upon 
meeting all criteria for inclusion in the study, subjects will then return to complete a 1-hour baseline MRI 
scan at Visit 2. All MRI imaging protocols will be reviewed and approved by CAMRIS. An experienced 
technician and a member of the study team will be present during the MR session to ensure participant 
safety and well-being. If the participant complains of feeling claustrophobic and does not wish to complete 
the MRI, the study will  be terminated. Emergency personnel and equipment are immediately available to 
the MRI room should the need arise. It is possible that during the course of the research study, the research 
staff may notice unexpected findings on an MRI scan. Should this occur, the findings will be assessed by 
a trained radiologist. The study doctor will inform research subjects of any significant findings. Visit 3 will 
include fMRI and interleaved TMS/fMRI. During this scan, the participant will perform a working memory 
N-back task several times. Brain data from the baseline MRI scan (stimulation target in individualized 
brain space) will be calibrated with the skin and scalp using a Polaris Vicra camera (Brainsight 
neuronavigation) to allow marking of the stimulation site on a swim cap for the TMS/fMRI session. During 
the MRI scan, participants will receive interleaved TMS/fMRI probes to the brain targets. The purpose of 
this TMS/fMRI scan is to probe and modulate and measure activity in targeted neural circuits following 
our established methods (Chen et al., 2013). Moreover, by building brain decoding models using LSTM 
RNNs deep-learning technique, we can establish a closed loop of rTMS and brain readouts. As a result, 
we will be able to fine-tune the rTMS frequency to achieve optimal   brain state and maximized working 
memory performance during this session. Our MRI-compatible   TMS system (MagPro X100 Stimulator, 
MRI-B91 TMS coil) is housed in Stellar Chance (SC3T) and  the Hospital of the University of 
Pennsylvania (HUP 6) at the 3-Tesla MRI machine. The apparatus was installed under the supervision of 
Mark Elliott, Ph.D. a member of CAMRIS. TMS in an MRI scanner involves no additional risks to the 
subject. Visits 4-6 will involve excitatory rTMS delivered in the 

Page 19 of 23 
 
same interleaved pattern at the same stimulation site as the TMS/fMRI session but with either the 
optimized frequency determined from that session or the frequency least successful in moving their  brain 
state (half of the participants will receive optimized stimulation frequency, and the other half of  the 
participants will receive least-optimized stimulation frequency during these sessions). The present study 
utilizes the same FDA-approved devices (Magventure Cool-Coil B65, MagVenture X100 Stimulator) to 
administer TMS. The TMS system is housed in the Richards Biomedical Building. Only individuals trained 
by the Principal Investigator (Desmond Oathes, Ph.D.) and, Ted  Satterthwaite  (M.D.) will dispense TMS. 
In addition to receiving TMS, participants will complete questionnaires and computerized tasks during 
these visits. The tasks will assess reaction time, working memory, decision- making. The decision-making 
task will be incentive-based and the amount the participant earns will be added to their final study 
compensation. During some of the tasks, we may ask subjects to wear a  passive eye-tracking device to 
record the location of your gaze at any particular time. The order of tasks will be randomized for each 
participant. Visit 7 will involve a 1-hour TMS/fMRI session. Participants will complete the working 
memory N-back task while inside the scanner. The purpose of this visit is to examine the brain and 
behavioral changes after the first round of neuromodulation. Visit 8-10 will  mirror Visit 4-6 and will 
involve neuromodulation with either the optimized or least-optimized  individual frequency. The order of 
optimized and least-optimized frequencies will be counterbalanced across participants between Visit 4-6 
and Visit 8-10 (i.e., half of the participants will receive  stimulations of the two frequencies in one order, 
and the other half will receive stimulations of the two frequencies in the reverse order). Visit 7 and the 
Visit 8 will be scheduled at least one week apart.In addition, unless the MRI is unavailable or we encounter 
scheduling constrains, Visit #3-Visit #7 will be scheduled within the same work week, such as Visit #3 is 
on Monday, Visits #4-7 are Tuesday/ Wednesday/Thursday, respectively, and Visit #7 is on Friday. 
Similarly, Visit #8-Visit #10 will be scheduled 4 work-days in a row, either Monday-Thursday or Tuesday-
Friday. Visit  11 will mirror Visit  7 and examine brain and behavioral changes after the second round of 
neuromodulation. Monitoring  will include: (1) successful recruitment, retention; (2) subject adherence; 
(3) safety and tolerability. 
 
The following documents are currently attached to this item: 
 
There are no documents attached for this item. 
 
Deception 
Does your project use deception? Deception could be considered any direct misinformation presented to 
the subject or omission of key information pertaining to the design or nature of the project. 
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 condition (optimized vs least- 
optimized frequency) ANOVA will be done both on task performance as well as fMRI voxelwise brain 
responses. 
 
The following documents are currently attached to this item: 
 
There are no documents attached for this item. 

Page 20 of 23 
 
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 
Subjects entering the study will be given a unique identifying participant ID. Most data obtained will   use 
this ID to remain de-identified. Any electronic forms (i.e., status log form) connecting the ID with  the 
participant name will be stored in REDCap, a password protected, IRB compliant online databases, with 
identifier fields flagged for confidentiality. Any paper forms connecting the ID with the participant name 
(i.e., consent, MRI form) will be stored in secure cabinets inside locked rooms. 
 
Sensitive Research Information* 
Does this research involve collection of sensitive information about the subjects that should be excluded 
from the electronic medical record? [NOTE: This does not apply to: 1) research information that would 
not normally be included in the electronic medical record or 2) information that is in the electronic medical 
record as part of clinical care.] 
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 
their preferred contact method. 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. Participants will 
further be informed & required to provide verbal consent to have their phone screen information (written 
consent within online self-report screener) retained in REDCap. 
 
Disclosures 
Will any data or specimens from Penn participants OR other research generated work product (e.g., 
intellectual property) be disclosed to any individuals, entities, or vendors, etc. outside of Penn? 
No 

Page 21 of 23 
 
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 

Page 22 of 23 
 
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 a 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 potential participant 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. 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 the participant meets initial eligibility, they 
will be invited to an in-person meeting where we will provide a paper copy of the ICF on request. The 
patient will be reminded before and after enrolling, and before  any research procedure that their 
participation is optional and has no impact on the care they can expect. 
 
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* 
Yes 
 
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: 

Page 23 of 23 
 
There are no documents attached for this item. 
 
 
Risk / Benefit 
Potential Study Risks 
There is a small risk of loss of confidentiality. 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. Clinical Interview and Assessment: Some discomfort may be associated with  the clinical 
assessments conducted in this study. Participants may experience emotional discomfort when answering 
some questions in the questionnaires or when talking about personal  information.  Participants may choose 
not to answer any of the questions and to terminate their participation. MRI scan: Likely/Common: 
Subjects 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. If a subject has a problem 
with feeling uncomfortable while inside the scanner, they may stop this study.  To lessen the noise, earplugs 
will be provided. 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. There are no known risk factors associated 
with MRI scans for healthy subjects. 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. Since there is no possible 
benefit from participating in this protocol for a pregnant woman, we will exclude pregnant women. A MRI 
scan requires subjects to be in a partially enclosed space inside the scanner. Some people may find this to 
be uncomfortable and claustrophobic. Participants will be instructed to inform the doctor ordering the scan, 
or the study staff, if they suffer from claustrophobia. The MRI scanner produces different types of noises 
during a scan. Since the noise level can be loud, participants may be given special earplugs to reduce the 
noise. A MRI scanner has a strong magnet which attracts certain metals. If anyone has these types of metal 
in their body, the MRI's strong magnetic field can cause them to move which may cause injury. The MRI 
will not be performed on anyone having these types of metal in their body. To prevent an injury, participants 
will be asked questions or given a form requesting information about any metal in their body and if they 
work with metals. Some dyes in tattoos and permanent eyeliner contain metals which may move during 
the MRI scan causing the area with the tattoo to become irritated and swollen. No metal objects are allowed 
to   be brought into the MRI scan room at any time, because the MRI magnet will quickly and strongly 
pull those items into the scanner. To prevent any injury to patients and staff and any damage to the MRI 
scanner, participants will be asked to remove all jewelry and clothing containing metal before you enter 
the MRI scan room. Also, since the MRI magnet will erase credit cards, they must not be taken into the 
scan room. Once participants are positioned in the scanner, the door to the room will be closed to  prevent 
anyone with any metal object entering the scan room. TMS: TMS is considered to be a low-risk procedure. 
The most common side effect of TMS (approx 25% of patients) is a mild headache. Other side effects may 
include scalp discomfort at the site of stimulation and/ or muscle tenderness as a result of the TMS 
stimulation. They may also experience temporary and local bruising, swelling or pain from the swim cap 
and/ or muscle activation by TMS. This muscle activation may induce jaw or eyebrow movement during 
the TMS stimulation. If the TMS target is near the eye muscles, TMS stimulation   may induce tear 
formation. Although studies have found no hearing impairments as a result of this sound, some subjects 
experience a mild temporary effect on their hearing. To minimize this possibility, subjects will be given 
protective earplugs. The most significant side effect associated with TMS is a TMS-induced seizure. 
However, in the most recent TMS safety guidelines (Rossi et. al, 2021), they  show that a TMS-induced 
seizure in an individual without identifiable risks is very unlikely (1/100,000 sessions). Moreover, even 
though individuals with risk factors (history of epilepsy, brain lesion, brain scarring, or medication use) 
have a slightly higher risk of a TMS-induced seizure, the risk is still low (67/100,000 sessions). There are 
no known long-term adverse effects reported with the use of this  device. There may be long-term risks 
due to TMS that are currently unknown. Rarely, device malfunction could result in a scalp burn. The effects 
of TMS on a fetus are unknown. Therefore, we require that females of child-bearing potential attest at the 
time of participation that they are not pregnant. TMS/fMRI: There is no added risk by performing TMS 
and fMRI together. 

Page 24 of 23 
 
Potential Study Benefits 
This study will provide no direct benefit to individual participants. 
 
Alternatives to Participation (optional) 
The alternative to participation is to not participate. 
 
Data and Safety Monitoring 
The PI will monitor the study for any serious and adverse events. All serious events (SAE) will be reported 
to the IRB: a) Death immediately b) Life-threating and all other SAEs within 7 calendar days. Should there 
be a serious event that occurs that increases the risks to the participants the study will be stopped, an 
investigation will be conducted, and a findings report will be generated before the study is resumed. 
Detailed Data Safety Monitoring Plan: This section describes the Data and Safety Monitoring Plan and 
quality assurance (QA) procedures that will be used for this proposed study. This monitoring plan details 
the frequency of monitoring visits, regulatory document review, and compliance review. Monitor Selection: 
One monitor will be assigned for this study and will be responsible to complete the monitoring process. 
The monitor will be a research coordinator at the center who is not  the  lead research coordinator for this 
study. An updated CV will be kept on file in the Research Personnel regulatory binder to document the 
qualifications of the monitor. The following activities will be completed by the monitor to close out the 
study: Ensure all data has been reviewed and collected; Confirm all reports of unanticipated problems have 
been reported to the IRB(s); Review the regulatory documentation and subject files for completeness and 
compliance with all applicable  federal  regulations; Ensure that all continuing review reports were 
submitted to and approved by the IRB(s); Review requirements for record retention with the investigator 
and the clinical staff. The checklist will be signed by the monitor and included in the regulatory files. Data 
Management: All data will be deidentified and only qualified research personnel will be having access. 
Records will be kept electronically on password protected servers. Safety Monitoring: All unanticipated 
problems will be reported to the Principal Investigator or delegated research staff for the duration of the 
study. The Principal Investigator has the front-line responsibility for identifying potential adverse events 
experienced by study participants, making adjustments accordingly, and reporting the experience. The 
P.I. is responsible for tracking these reports and relaying them as required to the IRBs and other 
investigators. Data integrity, safety, and privacy will be monitored by the PI and the coordinators. 
 
The following documents are currently attached to this item: 
 
There are no documents attached for this item. 
 
Risk / Benefit Assessment 
There is minimal risk from the research procedures (MRI, TMS, behavioral tasks). The potential benefit 
to society through the increased understanding of TMS 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.