High-dose Accelerated Repetitive Transcranial Magnetic Stimulation to Cognitive Control Neurocircuitry in Mild Cognitive Impairment: A Safety and Feasibility Study
Phase: NA
Conditions: Mild Cognitive Impairment
Sponsor: Medical University of South Carolina

 
 
 
 
 
 
 
 
 
 
Protocol 
Version #10; 1-28-2022 
 
 
High-dose Accelerated rTMS to Cognitive Control Neurocircuitry in MCI: A Safety and 
Feasibility study 
 
Short Title:   
Plasticity Using Stimulation and Habit:  
A Pilot Open-label rTMS Study for MCI (PUSH-Pilot)  
 
NCT04503096 
IRB Protocol #: Pro00100536 
  
PI: Andreana Benitez, Ph.D.  
 

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PROTOCOL TITLE: 
 
High-dose Accelerated rTMS to Cognitive Control Neurocircuitry in MCI: A Safety and 
Feasibility study 
 
PRINCIPAL INVESTIGATOR: 
• 
Andreana Benitez, Ph.D.  
 
 
 
  
 
 

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1.0 OBJECTIVES / SPECIFIC AIMS 
 
The objective of this study is to establish the safety, feasibility, tolerability, and acceptability of 
high-dose accelerated intermittent theta burst (iTBS) repetitive transcranial magnetic stimulation 
(rTMS) to the left dorsolateral prefrontal cortex (dlPFC) in patients with amnestic Mild Cognitive 
Impairment (aMCI). We also seek to obtain preliminary efficacy data as well as feasibility / 
acceptability data of computerized cognitive training as an adjunct to iTBS rTMS. The long-term 
goal of this project is to obtain preliminary data to support future empirical studies of iTBS rTMS 
for aMCI, including future randomized controlled trials to devise the optimum rTMS therapeutic 
delivery (with variations in dosing parameters, cortical targeting, and MCI syndrome indications), 
with the ultimate goal of dementia prevention. The scientific merit of this pilot study has been peer-
reviewed and subsequently recommended for funding through the National Center of 
Neuromodulation for Rehabilitation (NC NM4R). 
 
AIM 1: Establish the safety of an accelerated rTMS protocol for neurocognitive 
rehabilitation in aMCI. We hypothesize that accelerated rTMS will be safe as indexed by 
1) no clinically significant structural brain changes; 2) no decrements in neurocognitive 
function; 3) no significant adverse events. 
AIM 2: Establish the feasibility, tolerability, and acceptability of an accelerated rTMS 
protocol for neurocognitive rehabilitation in aMCI. We hypothesize that 1) aMCI 
patients will consider the treatment acceptable and that 2) recruitment and retention will be 
feasible (> 80% retention). 
EXPLORATORY AIM: Establish the preliminary efficacy of an accelerated rTMS protocol 
for neurocognitive rehabilitation in aMCI. We hypothesize that aMCI patients will 
demonstrate modest improvements on neurocognitive testing and self-reported affective 
symptoms and quality of life from pre- to post-treatment. 
EXPLORATORY AIM: Establish the feasibility, acceptability of computerized cognitive 
training as an adjunct to accelerated rTMS in MCI. We hypothesize that aMCI patients 
will complete a range of exercises between sessions and at home (feasibility) and will rate 
the intervention as productive (acceptability). 
 
 
2.0 BACKGROUND 
 
Mild Cognitive Impairment (MCI) is the pre-dementia stage in which individuals remain functionally 
intact yet demonstrate the early cognitive and behavioral changes of neurodegenerative diseases. 
Over half of those with MCI develop dementia within 10 years1, but an intervention that can delay 
dementia onset by 5 years may cut dementia prevalence by a third and decrease healthcare 
costs2. However, the diagnosis and treatment of MCI is hampered by its variability in underlying 
etiology 
and 
clinical 
presentation. 
That 
is, 
the 
neuropathology 
of 
MCI 
is 
markedly 
heterogeneous3,4, 
and 
neuropsychiatric 
symptoms 
are 
also 
highly 
comorbid, 
including 
depression, anxiety, apathy, and  sleep dysfunction5–7. Thus, the ideal MCI intervention must suit 
a pathologically and behaviorally heterogeneous condition and have a high potential to be 
disseminated for dementia prevention. 
 
Repetitive transcranial magnetic stimulation (rTMS) to left dorsolateral prefrontal cortex (dlPFC) 
is one such potential intervention. One hypothesized mechanism of action of this approach is the 
enhancement of cognitive control by targeting the neurocircuit substrates, leading to improved 

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affect regulation8. If so, then rTMS should be a powerful transdiagnostic intervention for both 
affective and cognitive symptoms. Indeed, rTMS has been shown to reduce these symptoms in 
various neuropsychiatric syndromes9 including geriatric depression10, with the specific literature 
on rTMS for MCI currently nascent yet promising11.  
 
Conventionally, a course of rTMS is 30-40 minutes of treatment each weekday for 4-6 weeks. To 
lessen burden while leveraging established outcomes, newer high-dose accelerated intermittent 
theta burst (iTBS) rTMS protocols increase the number of sessions per day, reducing the 
treatment course by >50% and yielding more rapid response and remission12,13 while retaining 
safety, feasibility, acceptability, and effectiveness14–18. However, the safety and feasibility of this 
delivery schedule has yet to be established for MCI.  
 
In this open-label, safety and feasibility trial, we will recruit 40 amnestic MCI (aMCI) patients 
(target completers N=30) through memory disorders and neuropsychology clinics, as overseen 
by PI and neuropsychologist Dr. Benitez. We will recruit clinically well-defined participants who 
will meet stringent actuarial neuropsychological criteria for aMCI19. This study will employ 
identical procedures to an ongoing IRB-I approved NC NM4R pilot, Neuromodulation and 
Plasticity in Cognitive Control Neurocircuitry in Chronic Stroke (PI: McTeague; Pro 83136). 
Specifically, neuronavigation-based targeting of the left dorsolateral prefrontal node of the 
cognitive control network will be performed. This study will utilize accelerated rTMS using a 
MagVenture MagPro TMS System. All participants will receive treatment for eight, 3-min sessions 
of iTBS on each of three days within an eight-day span. Each session would be separated by 10 
mins or more per participant comfort and convenience. To collect preliminary feasibility and 
acceptability data for a planned follow-up combinatorial intervention study, participants will 
complete computerized cognitive exercises in the intervening periods between same-day rTMS 
sessions. At pre- and post-treatment, participants will undergo brain MRI (FLAIR, diffusion, 
T2*/gradient, volumetric scans, resting state) and computerized neurocognitive testing. As an 
open-label pilot study, there is no sham control group.  
 
 
3.0 INTERVENTIONS TO BE STUDIED 
 
Accelerated rTMS. We will utilize an LTP-like accelerated iTBS rTMS targeted to left dlPFC in 
aMCI using a MagVenture MagPro TMS System. All participants will receive treatment for eight, 
3-minute sessions on each of three days within an eight-day span. Each session will be 
separated by 10 minutes, according to participant comfort and preference. As an open-label 
pilot investigation, there is no sham control group.  
 
RATIONALE: Transcranial magnetic stimulation (TMS) is a means of non-invasively activating 
neuronal elements in the brain. Repetitive TMS (rTMS) in particular causally influences neural 
networks and produces acute neuroplastic periods that reliably persist after the termination of 
stimulation and promote cortical remodeling22,23. The evidence base for therapeutic rTMS has 
been most persuasive in the case of depression treatment. Proposed as a means of up-regulating 
prefrontal control over dysregulated limbic activation, high-frequency rTMS is most often applied 
to left dorsolateral prefrontal cortex24 (dlPFC). Several meta-analyses have now shown that open-
label effects sizes are large, while comparisons to sham stimulation are at least moderate to large 
among even patients highly resistant to pharmacotherapy25,26. In geriatric depression, the FDA-

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approved course of rTMS has been found to be safe, tolerable, and yield commensurate response 
rates10,27,28.  
 
The proposed mechanism by which rTMS remediates depression implies that rTMS should also 
be a powerful transdiagnostic intervention for both cognitive and affective dysregulation. The left 
dlPFC site typically targeted with rTMS is seated in an area of cortex integral to intact higher order 
cognition29 (i.e., executive function). Co-I Dr. McTeague has shown in a large meta-analytic study 
that this left dlPFC region (as well as the rest of the cognitive control or multiple demand network) 
is commonly hypo-activated during cognitive tasks across neuropsychiatric disorders30. While 
dementia was not included in this meta-analysis, a similar meta-analysis of task-based fMRI 
identifies prominent hypoactivation in MCI in the same frontoparietal network31. Thus, it is 
unsurprising that other meta-analyses and reviews of mild to moderate AD have shown that rTMS 
improves cognitive ability32 and neuropsychiatric symptoms33 with no adverse cognitive effects34. 
Although research into using rTMS as a treatment for MCI is in its infancy11, it is an ideal disease 
stage for dementia prevention using rTMS particularly given that 25-40% of MCI patients have 
comorbid depression35 which in turn increases risk of further cognitive decline and dementia36. 
Thus, there is abundant preliminary data supporting our rationale to use rTMS of the dlPFC to 
target neurocircuitry integral to cognitive and affective dysfunction, although its delivery could be 
better optimized to support clinical application.  
 
A therapeutic course of rTMS typically consists of 30-40 minutes of high-frequency (i.e. 10 Hz) 
treatment on each weekday, for 4-6 weeks. This schedule can be burdensome and reduce 
adherence. To improve upon this conventional approach, Co-I Dr. George et al. pioneered 
accelerated rTMS, demonstrating that delivering 3 high-dose sessions per day (i.e. 10 Hz; 3,000 
pulses for 30 mins; 18,000 pulses/day total) on three consecutive days was safe, feasible, and 
suggestive of rapid antidepressant effects14. More recently, a number of groups have 
demonstrated the feasibility, acceptability, and effectiveness of this form of delivery in which 
sessions are repeated daily, typically spaced by at least 30 minutes, to reduce total days of 
treatment. Safety has also been assessed with both structural and metabolic imaging as well as 
neurocognitive testing, which has shown no adverse effects and modest gains in cognition13,17. 
Furthermore, acceptability studies show that accelerated rTMS increases adherence and 
decreases interruptions to daily obligations while yielding faster response15–18. Importantly, critical 
to the success of this project is the fact that the procedures proposed in this study have already 
been approved by the MUSC Institutional Review Board for an NM4R pilot grant (PI: McTeague; 
Pro 83136). As such, all methods are already established and running, personnel trained, and, 
importantly, we will be able to compare the results in two prevalent and functionally impairing 
neurodegenerative disorders.   
 
Computerized Cognitive Training. To collect preliminary feasibility/acceptability data for a 
planned follow-up combinatorial intervention study, participants will complete computerized 
cognitive exercises in the intervening periods between same-day rTMS sessions. Clinical trials 
using the online system Brain HQ (https://www.brainhq.com/world-class-science/science-team) 
have been shown to be associated with cognitive function in older adults58,59. Each exercise 
takes approximately 3-10 minutes and adapts to the individual’s progress. The exercises fall 
under one of six categories: processing speed, memory, attention, people skills, cognitive 
flexibility and spatial navigation. During breaks between treatments, participants will complete 
exercises for a total of 20 minutes of exercises per day and 60 minutes of exercises over the 

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three days of treatment. Afterwards, participants will be asked to complete at least 20 minutes 
of these exercises per day at home during the 4 weeks following treatment completion.  
 
RATIONALE: Because accumulating work suggests that the 10-60 minute window following 
excitatory rTMS is a window of particular neuroplasticity37, the longer-term plan of this line of work 
is to utilize rTMS as an adjunct for multimodal interventions including computerized cognitive 
training and behavioral interventions to optimize neuroplasticity, cognitive remediation, and quality 
of life. Toward this goal, we will collect preliminary acceptability/feasibility data of computerized 
cognitive exercises, interleaved between rTMS sessions. 
 
Team expertise for ensuring safety and integrity:  
 
Dr. Benitez (PI) is a licensed clinical neuropsychologist who conducts patient-oriented 
research using neuropsychological and MRI methods. She is also an attending clinical faculty 
member in the Neuropsychology Clinic within the MUSC Department of Neurology and the 
research director of the newly formed Rapid Access Memory Clinic. She is ideally suited to 
ensuring that stringent study inclusion/exclusion criteria are met and to monitor the safety of 
participants during and following participation. 
 
Dr. McTeague (Co-I) is a licensed clinical psychologist and an expert in the functional 
architecture of the cognitive control network and its relationship to deficits in neuropsychiatric 
populations, as well as the application of accelerated, high-dose rTMS in neuropsychiatric and 
neurodegenerative disorders. She will ensure that all rTMS procedures are implemented 
according to best-practice safety guidelines, replicability, and rigor.  
 
Dr. Revuelta (Co-I) is an expert in utilizing rTMS in neuropsychiatric disorders, with a 
special emphasis in Parkinson’s Disease. He is also an associate professor in the MUSC 
Department of Neurology and the director of the Deep Brain Stimulation Program.  
 
Dr. Liu (Co-I) is a Professor of Neuroscience at MUSC and over the last 10 years has 
pioneered techniques for personalized mapping of functional networks. His techniques will be 
utilized to complement structural imaging data in assessing safety, while also providing 
preliminary evidence of the potential to modify the cognitive control and related networks in aMCI. 
 
Dr. Antonucci (Co-I) is an associate professor in neuroradiology at MUSC. He will be 
responsible for providing clinical neuroradiological reads of structural imaging scans, to assess 
and changes pre- to post-treatment. 
 
 
4.0 STUDY ENDPOINTS 
 
AIM 1: Establish the safety of an accelerated rTMS protocol for neurocognitive 
rehabilitation in aMCI.  
Primary Outcomes: Clinically significant structural brain changes; Neurocognitive 
performance changes; Adverse events 
Secondary Outcomes: Psychopathology symptom changes 
AIM 2: Establish the feasibility, tolerability, and acceptability of an accelerated rTMS 
protocol for neurocognitive rehabilitation in aMCI.  

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Primary Outcomes: Patient perception of treatment acceptability; Recruitment rates; 
Retention rates 
EXPLORATORY AIM: Establish the preliminary efficacy of an accelerated rTMS protocol 
for neurocognitive rehabilitation in aMCI.  
Primary Outcomes: Neurocognitive performance changes 
Secondary 
Outcomes: 
Subjective 
psychopathology 
symptom/Quality 
of 
Life 
changes 
EXPLORATORY AIM: Establish the feasibility, acceptability of computerized cognitive 
training as an adjunct to accelerated rTMS in MCI. We hypothesize that aMCI patients 
will complete a range of exercises between sessions and at home (feasibility) and will rate 
the intervention as productive (acceptability). 
Primary Outcomes: Rate of usage 
Secondary Outcomes: Game performance change; subjective acceptability  
 
 
5.0 INCLUSION AND EXCLUSION CRITERIA/STUDY POPULATION 
 
Participants will be recruited through outpatient memory disorders and neuropsychology clinics 
staffed by neurologists and neuropsychologists at MUSC/DVA. (No procedures will be performed 
at the DVA; only recruitment materials will be provided.) Clinic providers will be trained on study 
criteria and procedures and will be provided with recruitment materials. Dr. Benitez will oversee 
recruitment and will ensure that participants meet the following eligibility criteria: 
 
Inclusion Criteria: 
 
i. 
Age 60-85 
ii. English as a first/primary language 
iii. Has been diagnosed with MCI by a healthcare provider within the past two years per NIA-
AA criteria40: (1) Concern regarding cognitive decline reported by patient, informant, or 
clinician, (2) Objective evidence of impairment for age in 1+ cognitive domains, typically 
memory, (3) Preserved independent function, (4) no dementia. 
iv. Has met actuarial neuropsychological criteria for aMCI: (1) ≥2 impaired scores (i.e. ≤16th 
%ile) within one cognitive domain, or (2) ≥1 impaired scores (i.e. ≤16th %ile) in ≥3 
cognitive domains, using demographically-corrected normative data41–43. (1) and (2) must 
include the Memory domain. 
v. The primary suspected etiology of aMCI must be neurodegenerative, with competing 
differential diagnoses (e.g. psychiatric disorder, movement disorder, reversible causes, 
substance use) ruled out as the primary etiology/ies following a clinical evaluation by a 
healthcare provider.  
vi. Ability to provide independent informed consent, consistent with the MCI diagnostic 
criterion of preserved independent function. 
 
Exclusion Criteria: 
 
i. 
Dementia diagnosis per DSM-5 or NIA-AA44 criteria. 
ii. Daily/weekly use of anticholinergics, neuroleptics, sedatives, or bupropion. Stimulant use 
may be allowed pending investigator review. Cholinesterase inhibitors, NMDA receptor 

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antagonists, and antidepressants are allowed if on a stable regimen of four weeks prior to 
enrollment. 
iii. History of significant or unstable condition/s that may impact cognition such as significant 
cardiac, cerebrovascular, or metabolic disease, severe mental illness (e.g. bipolar 
disorder, psychoses), alcohol or substance use disorder, developmental disorder, or 
other neurologic disease (e.g. severe brain injury, seizures). 
iv. MRI and TMS contraindications (e.g., implants, claustrophobia, conditions/treatments that 
lower seizure threshold, taking medications that have short half-lives, no quantifiable 
motor threshold, active substance use disorder, bipolar disorder). 
v. Is enrolled in a clinical trial and/or has received an investigational medication within the 
last 30 days. 
 
 
6.0 NUMBER OF SUBJECTS 
 
The target completion is 30 participants. To contend with attrition, we propose to enroll 40 
participants. 
 
 
7.0 SETTING 
 
All procedures will take place in private assessment and rTMS treatment rooms at the MUSC 
Center for Biomedical Imaging at 30 Bee Street. The MRI scanning will also occur at the Center 
for Biomedical Imaging at 30 Bee Street on the MUSC campus. Certain procedures, such as 
consenting and questionnaire completion may be completed virtually through telehealth using an 
MUSC approved electronic platform (e.g. musc.doxy.me or REDCap). 
 
 
8.0 RECRUITMENT METHODS 
 
Recruitment 
 
Participants will primarily be recruited through outpatient memory disorders and neuropsychology 
clinics staffed by neurologists and neuropsychologists at MUSC/DVA. Clinic providers will be 
trained on study criteria and procedures and will be provided with recruitment materials. A study 
coordinator will be on-call to facilitate rapid recruitment should a potential participant indicate 
his/her interest to the recruiting provider. Dr. Benitez will oversee recruitment and will ensure that 
participants meet eligibility criteria. 
 
Participant recruitment will also include flyers, handouts, electronic and physical bulletin board 
postings, social media/message boards (i.e., Craigslist, MUSC Broadcast Research studies 
section of Yammer, Instagram, Facebook), web-based recruitment tools (e.g., ResearchMatch, 
Trial Match), newsletter/newspaper/media advertisements, and recruitment talks at local 
community events/organizations and surrounding community. All approvals will be obtained prior 
to displaying flyers at the VA, and approvals will be obtained in other community locations if/as 
needed. 
 

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This project will also use an Epic-based tool that allows investigators to query clinical data for 
recruitment. The study team will receive a recruitment report from the Biomedical Informatics 
group containing a list of patients who potentially meet eligibility criteria. Study staff will then 
perform a chart review on these patients to further assess inclusion/exclusion criteria. Patients 
who appear to meet eligibility criteria and have opted in to being contacted about research will be 
contacted by the study team via phone, postal mail, and/or email.   
 
Participants who make contact based on recruitment efforts will be given a description of the study 
purpose, procedures, and potential risks and benefits of the study by phone. The potential 
participant will be invited to ask questions until they are satisfied and can make a decision to 
proceed or not with the eligibility phone screen. If the potential participant agrees to continue, a 
phone screen will be conducted to determine eligibility for the next phase of the study. 
 
Eligibility Phone Screening 
 
Trained study staff will review the eligibility criteria with potential participants. The potential 
participants’ aMCI diagnosis will be verified by Epic chart review (if he/she is an MUSC patient) 
or by a formal request for medical records initiated by the patient and provided to study staff. PI 
and neuropsychologist Dr. Benitez will personally review all potential participants’ medical records 
to ensure that each MCI patient will meet the detailed inclusion/exclusion criteria, which 
necessitates that the patient has a comprehensive clinical history and neuropsychological test 
results on file. Should a potential participant not have an established MCI diagnosis, or have 
incomplete data in support of this diagnosis to the extent that his/her eligibility cannot be readily 
ascertained, study staff will recommend that he/she complete a clinical evaluation with a clinical 
neuropsychologist at MUSC or elsewhere, as convenient to him/her. 
 
 
9.0 CONSENT PROCESS 
 
Following recruitment and screening, the potential participant will be given a copy of the informed 
consent form (ICF) in-person, via postal mail, or e-mail for review. There is no required timeline 
between their receipt of the ICF and deciding whether or not to participate. Participants will be 
encouraged to take their time to decide.  
 
Informed consent will take place on the MUSC campus or through telehealth by trained research 
staff (eConsent). If consenting through telehealth using an IRB-approved electronic/online 
platform (i.e. REDCap or musc.doxy.me; all future references to an “electronic/ online platform” 
hereafter refer to these), the study staff will first confirm that participants have the appropriate 
technology to complete the electronic consent process. In the case of eConsent, the participant 
will be asked to locate a private and interruption-free environment in order to complete the 
appointment. The participant will receive a copy of the signed e-consent by email from the 
research personnel. If consenting in-person, the visit will take place in laboratory or Center for 
Biomedical Imaging space at 30 Bee Street.  
 
To ensure ongoing consent, participants will be queried at the start of any procedure about their 
comfort and willingness to continue.  
 
 

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10.0 STUDY DESIGN AND METHODS 
 
A summary and timeline of all procedures are outlined and described below.  
 
 
Session 
Number 
Task Description 
Location  
Approximate 
Time 
Commitment 
0 
Screening 
Epic and/or medical record review 
Keel TMS Safety Screen 
 
Telephone 
 
 
30 minutes 
 
1 
Pre-treatment Neurocognitive/Neuropsychiatric Assessment 
 
Consent/Safety 
Consent* 
Keel TMS Safety Screen* 
TMS Motor Threshold Test 
Credibility/Expectancy Questionnaire (Pre-treatment) 
 
Cognition 
Montreal Cognitive Assessment (MoCA)  
NIH Cognition Toolbox 
NINDS-CSN 30-Minute Neuropsychological Protocol (Hachinski et al., 2006, 
which includes Semantic and phonemic fluency, Digit Symbol-Coding, Digit 
Span, Hopkins Verbal Learning Test-Revised, Trail Making Test) 
WASI-II (Vocabulary, Matrix Reasoning)* 
 
Affective Function/Quality of Life 
Lawton Instrumental Activities of Daily Living Scale (IADL)* 
Mini-International Neuropsychiatric Interview (M.I.N.I)* 
Columbia Suicide Severity Rating Scale (CSSRS) 
Geriatric Depression Scale (GDS)* 
Hamilton Depression Rating Scale (HAM-D)* 
Young Mania Rating Scale (YMRS)* 
PROMIS Measures: Anxiety, Depression, Applied Cognitive Abilities, Social 
Participation, General Life Satisfaction, and Fatigue* 
Center for 
Biomedical 
Imaging 
3 – 3.5 hours  
2 
Pre-treatment MRI Scans 
FLAIR, diffusion, T2*/gradient, volumetric scans, resting-state fMRI 
Center for 
Biomedical 
Imaging 
1 – 2 hours 
3-5 
rTMS Treatment Sessions 
Review of systems adverse events questionnaire (Yaejee et al., 2015) 
Momentary Assessment of TMS 
8, 3 min sessions rTMS, interspersed with BrainHQ exercises 
 
Center for 
Biomedical 
Imaging 
2 – 3 hours 
per day, for 3 
days within a 
8-day span 
6 
Post-treatment Neurocognitive/Neuropsychiatric Assessment 
 
Cognition 
NIH Cognition Toolbox 
Montreal Cognitive Assessment (MoCA)  
NINDS-CSN 30-Minute Neuropsychological Protocol (Hachinski et al., 2006) 
 
Affective Function/Quality of Life 
Lawton Instrumental Activities of Daily Living Scale (IADL)* 
Mini-International Neuropsychiatric Interview (M.I.N.I)* 
Columbia Suicide Severity Rating Scale (CSSRS) 
Geriatric Depression Scale (GDS)* 
Hamilton Depression Rating Scale (HAM-D)* 
Young Mania Rating Scale (YMRS)* 
PROMIS Measures: Anxiety, Depression, Applied Cognitive Abilities, Social 
Participation, General Life Satisfaction, and Fatigue* 
Center for 
Biomedical 
Imaging 
2 - 3  hours  

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*Option to complete remotely, such as due to COVID-19 precautions. Components of sessions 
1&2 and 6&7 may be combined.. 
 
Session 1: In-person Pre-treatment Neurocognitive/Neuropsychiatric Assessment (2 - 3 
hours). Participants will complete computerized cognitive tests from the NIH Toolbox32 (30-40 
minutes). Each of these tests has been extensively normed, compared to traditional 
neuropsychological measures. Tests from different batteries will be utilized in this study for 
optimizing a comprehensive but efficient, reliable, and minimally burdensome subset of tests for 
MCI patients.     
 
For further sample characterization with more traditional and more extensively normed 
neuropsychological measures, participants will complete the Montreal Cognitive Assessment 
(MoCA)47 and the 30-minute battery recommended by the National Institute of Neurological 
Disorders and Stroke-Canadian Stroke Network (NINDS-CSN) Vascular Cognitive Impairment 
Harmonization Standards49: Semantic and phonemic fluency, Digit Symbol-Coding, Digit Span, 
Trail Making Test A & B, and Hopkins Verbal Learning Test-Revised. Full scale IQ will be 
assessed with the Vocabulary and Matrix Reasoning subtests of the WASI-II56. 
 
During this session, the Lawton Instrumental Activities of Daily Living Scale (IADL)57 will be 
administered in order to verify the participants’ functional independence per MCI criteria.  
 
To assess neuropsychiatric symptoms and conditions often concomittant with aMCI, participants 
will then complete the Mini-International Neuropsychiatric Interview (M.I.N.I)50. The Columbia 
Suicide Severity Rating Scale (CSSRS) 52 will be administered in order to assess suicide risk. The 
Geriatric Depression Scale (GDS) Hamilton Depression Rating Scale (HAM-D), and Young Mania 
Rating Scale (YMRS) will be administered. The computer adaptive test versions of the Anxiety, 
Depression51, Applied Cognitive Abilities53, Social Participation55 and Fatigue54 PROMIS 
Measures will also be administered. The PROMIS measures have been selected, specifically for 
the low-burden nature of the computerized adaptive form and the extensive normative data. 
Neuropsychiatric conditions other than psychotic disorders and substance use disorders will not 
Credibility/Expectancy Questionnaire (Post-treatment)* 
TMS Experience Questionnaire* 
BrainHQ Experience Questionnaire* 
Review of systems adverse events questionnaire (Yaejee et al., 2015) 
 
7 
Post-treatment MRI Scans 
FLAIR, diffusion, T2*/gradient, volumetric scans, resting-state fMRI 
Center for 
Biomedical 
Imaging 
1 - 2 hours 
8 
1 – 3 weeks post-treatment completion 
Review of systems adverse events questionnaire (Yaejee et al., 2015) 
PROMIS Measures: Anxiety, Depression, Applied Cognitive Abilities, Social 
Participation, General Life Satisfaction, and Fatigue* 
 
BrainHQ exercises 
REDCap 
 
 
 
Online 
10 – 20 
minutes 
 
 
>20 minutes 
per day 
9 
4 weeks post-treatment completion 
PROMIS Measures: Anxiety, Depression, Applied Cognitive Abilities, Social 
Participation, General Life Satisfaction, and Fatigue* 
Montreal Cognitive Assessment (MoCA)*  
TMS Experience Questionnaire* 
BrainHQ Experience Questionnaire* 
 
 
REDCap 
 
Video 
Conference 
30 min – 1 
hour 

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result in exclusion. The Edinburgh Handedness Inventory will be administered to assess hand 
preference on several forms of manual activity51. 
 
The option to remotely complete the M.I.N.I, MoCA, WASI-II, Demographics, Keel TMS Safety 
Screen, IADL questionnaire, GDS, HAM-D, YMRS, and the PROMIS measures will be given to 
participants if they are unable to physically come to the Center for Biomedical Imaging for the time 
being, such as due to COVID19 precautions. Phone calls or video conferencing through 
musc.doxy.me will be utilized in order to administer and oversee the completion of these 
assessments.  
  
Comfort 
and 
reliability 
considerations: 
During 
the 
administration 
of 
some 
of 
the 
neuropsychological assessments, the participants’ verbal responses will be audio recorded for 
quality control purposes. During all in-person sessions, snacks and water will be offered between 
testing administrations in order to improve energy, limit fatigue, and promote comfort. 
Furthermore, multiple breaks will be offered. Finally, participants will be given the option to 
schedule sessions on the same day, with a break, if additional visits/travel would be burdensome. 
 
Session 2: MRI Scanning (1 - 2 hours). At pre- and post-treatment participants will complete 
FLAIR, diffusion, T2*/gradient, perfusion and volumetric scans for assessment of structural 
changes. Participants will also complete a resting-state fMRI scan.  
 
Sessions 3-5: rTMS (2 – 3 hours). A MagVenture MagPro TMS System will be utilized. All 
participants will receive open-label treatment for approximately eight, 3-minute sessions of 
intermittent theta burst rTMS on each of three days within an eight-day span. A single 
session=600 pulses at 120% rMT, iTBS triplets at 50 Hz for 2 s and repeated every 10 s for a total 
of 190 s to left dlPFC. Total pulses=14,400. To enable adherence and retention, the days do not 
need to be contiguous. Same day sessions will be separated by 10-15 minutes, but more 
accounting for participant comfort. After each day of treatment, participants will be asked to 
complete an rTMS acceptability questionnaire. During treatment breaks participants will complete 
Momentary Assessment of TMS and 10-15 minutes of Brain HQ exercises between each session 
and will also have the option of completing tasks at home on intervening days during the treatment 
schedule. At the end of the final treatment session, participants will be asked to rate the exercises 
based on difficulty and enjoyment.  
 
Session 6: In-person Post-treatment Neurocognitive/Neuropsychiatric Assessment (2 - 3 
hours). Within one week following treatment, participants will repeat the pre-treatment 
neuropsychiatric and neurocognitive assessment for assessment of pre/post treatment changes.  
 
Session 7: Post-treatment MRI Scans (1 - 2 hours). Within one week following treatment, 
participants will repeat the pre-treatment MRI scans for assessment of pre/post treatment 
changes.  
 
Session 8: 1 – 3 weeks post-treatment completion. During the intervening weeks after 
Sessions 6/7 and before Session 9, the participants will be asked to remotely complete surveys 
using REDCap. Participants will also be provided with a research account for BrainHQ and asked 
to engage in at least 20 minutes of brain exercises daily until Session 9.   
 
 

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Session 9: 4 weeks post-treatment completion. Participants will again be asked to complete 
surveys using REDCap. Particiants will also be asked to complete the MoCA remotely, as well as 
acceptability/satisfaction questionnaires regarding the rTMS and BrianHQ interventions. 
 
Participant Compensation. Participants will be compensated as follows:  
 
Consent & Session 1: 
$40 for screening and pre-treatment assessments 
Session 2: 
 
  
$50 for the pre-treatment MRI 
Sessions 3 to 5: 
 
$120 for rTMS treatment (i.e. $40/day) 
Sessions 6 and 7: 
 
$100 for post-treatment assessments and MRI 
Session 8: 
 
  
$42 for post-treatment questionnaires (i.e. $14/wk over 3 weeks) 
Computerized Exercises: 
$4.5/completed 20-minute session (up to $126) 
Session 9: 
 
  
$22 for post-treatment questionnaires at 4 weeks follow-up 
 
Total:  $500 per participant upon the completion of all procedures. 
 
You will receive payments after completion of each Session and after 3 days of TMS.  Payment 
for study visits will be made using a pre-paid debit card, called a ClinCard. It works like a bank 
debit card and participants may use the card to purchase goods or services everywhere Debit 
MasterCard is accepted. Participants will be given a ClinCard at the beginning of the study. Each 
time they receive payment for participation in this study, the money will be added to the card, as 
outlined in the payment schedule above. In the event that any portion of the study is completed 
remotely, the ClinCard will be mailed to the participant. 
 
11.0 SPECIMEN COLLECTION AND BANKING (Not Applicable) 
 
 
12.0 DATA MANAGEMENT 
 
Analysis 
 
Aim 1. FLAIR, diffusion, T2*/gradient, perfusion and volumetric scans will be reviewed by Dr. 
Antonucci for any new signal abnormality. Adverse events will be surveyed and summarized.  
 
Aim 2. Retention (i.e., defined as completion of all study sessions) will be determined. Participants 
will also complete a survey regarding acceptability, including qualitative responses for treatment 
modification.  
 
Exploratory Aim 3. Neurocognitive performance and affective symptoms/quality of life will be 
analyzed with repeated-measures mixed models.  
 
Exploratory Aim 4. BrainHQ usage/retention, performance, and acceptability will be analyzed with 
repeated-measures mixed models.  
 
Power Considerations. The aims of this study are to determine safety and feasibility. The 
retention rate of 80% was determined to ensure that recruitment in the planned follow-up studies 
would be feasible in the longer time span allowed by future grants. Although these results will not 
be as compelling in the absence of a sham control, these data will give us an estimate of the 

Version #10; 1/28/2022 
 
 
 
 
 
Page 13 of 26 
potential effect sizes and response variability that we can anticipate in future randomized 
controlled trials. 
 
 
13.0 PROVISIONS TO MONITOR THE DATA TO ENSURE THE SAFETY OF SUBJECTS 
 
The PI will be responsible for the overall monitoring of the data and safety of study participants. 
The PI’s plan for ensuring safety and data integrity follows.  
 
Quality Control. QC will include regular data verification at weekly meetings with the PI, Co-Is and 
study personnel. This will include verification of the documentation (Integrity of the Consent and 
HIPPA, scores on the assessments, MRI scanning information), study progress and participant 
status, any adverse events, and any protocol deviations.  Events determined by the PI to be 
unanticipated problems involving risks to subjects or others (UPIRTSOs) will be reported by the 
PI to the IRB as soon as possible and no more than 10 working days per policy. 
 
Safety Training. 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 cover 
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 the MUSC Center for Biomedical Imaging and are a prerequisite for obtaining 
privileges to book and use scanner time. Prior to administering TMS all personnel must be trained 
and certified by Drs. McTeague (Co-I) and Revuelta (Co-I).  
 
Medical Emergencies: 
 
1. 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. 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. 
 
2. Drs. Revuelta and Antonucci are licensed physicians and will be on call during all sessions and 
rTMS sessions (or a similarly trained physician) to respond to any subtler potential medical 
situations. 
 
3. These guidelines are in full agreement with the Center for Biomedical Imaging 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).  
 
Suicidal Intent. Participants who have made a suicide attempt in the past year will be excluded. 
Also, suicidal intent will be assessed at the initial assessment phase of the study (during MINI 
Depression module) and with the Columbia Suicide Severity Rating Scale-Screen Version with 
Triage Points. At the initial assessment, the “Lifetime/Recent” version will be used. Consistent 
with the triage points determined by the scale authors, any positive endorsement to items 3 – 6 
will necessitate immediate consultation with the PI. Any positive endorsement of items 4 – 6 and 

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Page 14 of 26 
participation will be discontinued. Depending upon the follow-up to endorsement of item 3 
(passive ideation), participation may also be discontinued. Any participant endorsing these items 
will be referred to immediate consultation with the PI and provided appropriate referrals and 
follow-up contact to ensure engagement in care. For imminent suicidal intent, an emergency 
outpatient appointment or an in-house psychiatric consult will be arranged.  MUSC police will be 
called directly in the event that the clinician deems the participant to be imminently of risk of 
harming him/herself and refuses to cooperate with a plan to report to the emergency psychiatric 
consult.  
 
Ethical Research Practices. Ethical guidelines for clinical research will be followed strictly and all 
information obtained in the study will be kept strictly confidential. Data will be assigned coded 
identifiers and all names will be removed from study assessment and outcome data. Files linking 
participant names or identifying information to the coded identifier will be stored in a password-
protected file, on a password protected desktop computer in a locked laboratory. Demographic 
and other identifying information will be stored separately from consent forms to eliminate the 
possibility of participant identification; signed consent forms will be locked in secure cabinets 
separate from data files. The files linking names to IDs will be deleted at the conclusion of the 
research project. De-identified data will be stored indefinitely following the conclusion of the 
project. Only the PI and active research staff will have access to the de-identified data. The PI 
and all research staff and mentors will be responsible for and will comply with mandated reporting 
rules. All researchers will be obligated to demonstrate that they have remained abreast of all 
guidelines and rules related to the Health Insurance Portability and Accountability Act (HIPAA). 
Each member of the research staff will complete focused training on each task for which they are 
responsible and will perform ongoing quality control for others performing similar work. The PI 
and/or study coordinator will produce quarterly administrative reports describing study progress 
including accrual, demographics, and participants’ status. Reports will describe adherence to 
inclusion/exclusion criteria and the study protocol in addition to any unanticipated problems in the 
category of risks to participants or others as well as any adverse events. All collected data will be 
obtained for research (and participant safety) purposes only.  
 
Confidentiality. Any discussion of identifying sensitive and information will occur in private rooms 
at MUSC. Regarding documentation, participants’ names will appear only on the IRB-approved 
Consent, HIPAA, and payment forms, initial screening form, and in a separate key file that links 
individual participant names and contact information to a random participant identification code. 
The participant identification code will be assigned to the individual during Visit 1 and all 
subsequent data collection will reference this code. The key linking individual identifying 
information to the participation code will be maintained in an electronic database accessible only 
to the PI and their designees in a password-protected file on an encrypted and password protected 
network (MUSC LAN). The questionnaire data collected through REDCap will be referenced by 
participant ID only and collected via a HIPAA compliant interface and downloaded to the MUSC 
server once a participant has completed participantion. If a participant consents to participate at 
the interview, the initial screening form will be entered into a secure electronic database according 
to the assigned participation code and then locked a secure office, separate from payment and 
consent forms including heath information. If a participant declines consent or is lost to follow-up 
(i.e., defined as not appearing for intake within 1 month of screen), the screening form will be 
securely shredded.  The consent, HIPAA, and payment forms will be kept in a locked cabinet in a 
locked office. All other collected paper (e.g., interview responses) and electronic (e.g., 
questionnaire, neurocognitive, MRI data) files, including audio recording files, will be identifiable 

Version #10; 1/28/2022 
 
 
 
 
 
Page 15 of 26 
only by participant code and stored in locked file cabinets or on the secure MUSC LAN at the 
Institute of Psychiatry (non-MRI data) and Center for Biomedical Imaging (MRI data). The key file 
linking names to IDs will be deleted after data collection is complete. 
 
Consent and HIPAA forms will be kept on file for 6 years. Contact information is kept on file for 6 
years if the participant consents to allowing their information to remain active in our files, or the 
contact information is destroyed immediately after the study is completed if participants chose 
that option on the consent form. Although individual-subject analyses may be written up in 
publications, the individual subjects producing that data will never identified by name or initials, or 
any other identifying information. 
 
Other protections against risk.  In designing this trial, the research team sought to maximize data 
collection within the overall priority of maintaining participant comfort and safety. As was 
discovered in the pilot study by George and colleagues19, the proposed design is feasible, does 
not impose unreasonable expectations of time or effort, or expose patients to risks or limit them 
from the best available care. In the very unlikely event that a subject endorses transient alcohol 
or substance abuse during the course of this study, the coordinator will confer with a physician 
co-investigator prior to proceeding with any treatment. 
 
Adverse Events & Trial Safety. Potential conflicts of interest will be reported using the NIH rules 
for disclosure. Adverse Events (AEs)/Serious Adverse Events (SAEs) occurring during the course 
of the project will be collected, documented, and reported in accordance with protocol and IRB 
reporting requirements. All research staff involved with adverse event reporting will receive 
general and protocol specific AE/SAE training including identification, assessment and evaluation, 
and documentation and reporting. Any potential adverse events will be identified during the course 
of the study from participant self-report and administration of the visit assessments and 
procedures. Research staff will identify adverse events and obtain all available information to 
assess severity, seriousness, study relatedness, expectedness, outcome and the need for change 
or discontinuation in the study intervention.  
  
 
An Adverse Event (AE) is defined as any unwanted change, physically, psychologically or 
behaviorally, that occurs in a study participant during the course of the trial is an adverse event. 
A Serious Adverse Event (SAE) is defined as an adverse event that has one of the following 
outcomes: 
• 
Results in death, 
• 
Is life-threatening, 
• 
Requires 
inpatient 
hospitalization 
or 
prolongation 
of 
existing 
hospitalization, 
• 
Results in persistent or significant disability/incapacity, OR 
• 
Requires intervention to prevent one of the above outcomes. 
 
 
 
Adverse events are generally documented on AE Logs and AE Case Report Forms (CRFs). 
Additional relevant AE information if available should be documented in a progress note in the 
research record as appropriate to allow monitoring and evaluating of the AE. 

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Page 16 of 26 
 
 
When a reportable SAE is identified, the research staff will notify the MUSC Institutional Review 
Board (IRB) and DSMB within 24 hours and complete the AE report form in conjunction with the 
PI. The MUSC IRB meets monthly and is located at 1 South Park Circle, Bldg 1, Suite 401, 
Charleston, SC 29407. Communication with the IRB is through email, memos, official IRB forms, 
and online reporting.  
 
If complete information is not available when the initial 24-hour SAE report is disseminated, follow-
up information will be gathered to enable a complete assessment and outcome of the event. This 
information may include hospital discharge records, autopsy reports, clinic records, etc. The 
research staff will attach copies of source documents to the SAE report for review by the PI. 
  
We will report adverse events to the Medical University of South Carolina (MUSC) Institutional 
Review Board (IRB) as soon as possible, but no later than 10 working days after the investigator 
first learns of the event. The MUSC IRB AE reporting requirements are as follows: All deaths that 
occur during the study or 30 days post termination from the study are required to be reported as 
adverse events even if they are expected or unrelated. Other adverse events are reportable to 
the MUSC IRB if the AE is 1) unexpected AND 2) related or possibly related AND 3) serious or 
more prevalent than expected. All three criteria must be met for an AE to be reported to the MUSC 
IRB. The IRB definition of unexpected is that the AE is not identified in nature, severity or 
frequency in the current protocol, informed consent, investigator brochure or with other current 
risk information. The definition of related is that there is a reasonable possibility that the adverse 
event may have been caused by the drug, device or intervention. Reportable AEs are reviewed 
by the IRB Chair and reported to the IRB Board at the next meeting. 
 
The potential risks and benefits and methods to minimize these risks are outlined above. The 
research staff will report any unexpected AEs or any scores of “severe” on the side-effect 
symptom rating form or any FDA-defined serious AEs to the PI within 24 hours so that the PI can 
decide on the appropriate action. All unexpected AEs will be monitored while they are active to 
determine if treatment is needed. Study procedures will follow the FDA’s Good Clinical Practice 
Guidelines (www.fda.gov/oc/gcp).    
 
Data and Safety Monitoring Procedures.  
 
The PI will choose a group of faculty at MUSC to monitor the data on a bi-annual basis with 
respect to subject safety issues throughout the award period. The data and safety monitoring plan 
will include an internal Data Safety Monitoring Committee (DSMC), an external Data and Safety 
Monitoring Board (DSMB), and the Institutional IRB.  The purpose of the DSMC, DSMB, and IRB 
are to ensure the safety of participants and the validity and integrity of the data.  
 
Data Safety Monitoring Committee (DSMC). The internal DSMC will consist of the PI and co-
investigators/consultants on the proposal. The functions of the DSMC will include: 1) providing 
scientific oversight; 2) reviewing all adverse effects or complications related to the study; 3) 
monitoring enrollment; 4) reviewing summary reports relating to compliance with protocol 
requirements; and 5) providing advice on resource allocation. The DSMC will meet quarterly, 
remotely or in-person. The recommendations of the DSMC will be reviewed and the PI will take 
appropriate corrective actions as needed. 

Version #10; 1/28/2022 
 
 
 
 
 
Page 17 of 26 
 
Data and Safety Monitoring Board (DSMB). A DSMB will be established and will consist of 
professionals with appropriate expertise, who are willing to participate and who do not have any 
conflicts of interest. The DSMB will include: 1) two experts in the area of TMS, 2) a biostatistician 
with expertise in the conduct of clinical trials, and 3) two members with expertise in the treatment 
of MCI patients. The DSMB will meet on a bi-annual basis. The DSMB will perform the following 
activities: 
 
• 
Review the research protocol and plans for data and safety monitoring. 
• 
Evaluate the progress of the intervention, including periodic assessments of data quality 
and timeliness, participant recruitment, enrollment, and retention, participant risk versus 
benefit, integrity of the intervention, and other factors that can affect study outcome. 
• 
Consider factors external to the study when interpreting the data, such as scientific or 
clinical developments that may impact the safety of study participants or the ethics of the 
study. 
• 
Make recommendations to the internal DSMC and MUSC IRB for continuation or 
termination of the trial. 
• 
Protect the confidentiality of study data and monitoring. 
 
The DSMB will have the authority to temporarily or permanently discontinue the trial if it perceives 
that harm is occurring due to the intervention. The DSMB will meet with the internal DSMC yearly 
to review adverse event reports, patient complaints if any, and enrollment rates. Data will be 
provided at these meetings by the investigators on key variables that may indicate harm. The 
DSMB biostatistician will evaluate the confidentiality and integrity of the database and the 
procedures for recording and storing confidential files. The DSMB will also review the elements 
of the plan to manage emergencies. 
 
Institutional Review Board (IRB).  The MUSC IRB will review and approve the funded protocol; 
review patient and provider consent forms, ensure protection of patient privacy and safety, and 
monitor the study on an ongoing basis. Adverse events will be reported to MUSC IRB as they 
occur.  Annual reports to MUSC IRB will indicate enrollment rates, adverse events, new findings 
that may influence continuation of the study, and reports of the DSMB. 
 
 
 
14.0 WITHDRAWAL OF SUBJECTS 
 
Early withdrawal of study subjects.  As stated on the Informed Consent, all subjects reserve the 
right to withdraw from the clinical investigation at any time. The PI for any of the following reasons 
may discontinue subjects from the study: 
 
• 
Subject is found to have entered the study in violation of the protocol. 
• 
Subject withdraws consent to participate in the study. 
• 
Subject is unable to tolerate the pre-treatment MRI. 
• 
Subject is noncompliant with procedures set forth in the protocol. 
• 
Subject experiences an Adverse Event that warrants withdrawal from the study. 
• 
It is in the PI’s opinion that it is not in the subject’s best interest to continue. 

Version #10; 1/28/2022 
 
 
 
 
 
Page 18 of 26 
• 
Subject displays other abnormal laboratory, medical or clinical findings for which clinical 
intervention should take precedence over study participation including: 
 
a) Development of mania/hypomania 
 
b) Generalized seizure 
 
c) Inpatient hospitalization 
 
d) Unable to complete desired treatment in the designated time frame 
 
If a participant is lost to follow up, three documented attempts will be made to contact the 
participant. 
 
 
15.0 RISKS TO SUBJECTS 
 
Challenges will include patient tolerability to TMS, the MRI scanner, and the study clinical and 
neurocognitive assessments. The primary safety concern, the same as that for conventional once-
daily rTMS, is risk of seizure. However, all reported TMS-induced seizures during conventional or 
accelerated protocols have been self-limiting, and NONE required further intervention to stop the 
seizure; no post-seizure sequelae or recurrent seizures developed. Extensive precautions with 
regard to suicidal ideation/homicidal ideation risk will be followed. 
 
Due to the novel nature of the proposed study, the following table is included to provide a 
representative range of the stimulation parameters and populations examined with accelerated 
rTMS. The dosing range of these studies covers the range proposed in this study. In these as well 
as other accelerated rTMS studies, the authors have demonstrated the safety, feasibility and 
acceptability of accelerated, high-dose studies of rTMS in neurologically intact samples. Of 
pertinence to the issue of safety as well as the conceptual model proposed here, Holtzheimer et 
al.6 showed reliably enhanced neuropsychological performance on the Repeatable Battery for the 
Assessment of Neuropsychological Status (RBANS) from baseline to six weeks after an 
accelerated, high-dose rTMS protocol in patients with major depression. Furthermore, Baeken et 
al.18,30 as well as Herremans et al.29 and Williams et al.28 additionally collected structural and 
functional imaging and demonstrated no adverse changes pre- to post-accelerated rTMS. Taken 
together, these studies demonstrate that the potential risks of accelerated rTMS are likely similar 
to conventional once-daily rTMS.   
 
Representative accelerated rTMS studies for neuropsychiatric conditions. 
Study 
Total 
Pulses 
Days 
Total 
# 
Sessions 
Stimulation 
Intensity 
Disorder 
Frequency 
 N 
Holtzheimer 
et 
al.6 
15,000 
2 
15 
100% 
Major 
Depression 
10 Hz; 5s train, 
25s ITI 
14 
Baeken et al.18 
31,200 
4 
20 
110% 
Major 
Depression 
20 Hz; 1.9s train; 
12s ITI 
15 
Herremans 
et 
al.29 
31,200 
3 
15 
110% 
Alcohol 
Use 
Disorder 
20 Hz; 1.9s train; 
12s ITI 
19 
Desmyter 
et 
al.39 
32,400 
4 
20 
110% 
Major 
Depression 
54 
bursts 
of 
three; 2s train; 8s 
ITI s 
50 
Duprat et al.40 
32,400 
4 
20 
110% 
Major 
Depression 
54 
bursts 
of 
three; 2s train; 8s 
ITI s 
50 
George et al.19 
54,000 
3 
9 
120% 
Suicidal 
ideation 
10 Hz;  
41 

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Weighing potential risks related to TMS. Based on previous clinical applications of left prefrontal 
rTMS in depression and in various other psychiatric disorders, as well as risks published by 
researchers and communicated experiences, it is hypothesized that left prefrontal rTMS is likely 
to be effective in reducing psychosocial impairment. This study is an important necessary step to 
characterize the safety, feasibility, and tolerability of the proposed neurocognition enhancing 
effect. 
 
Potential worsening of neuropsychiatric symptoms with TMS. Several studies have thus far 
demonstrated the feasibility of using rTMS in depression without any alarming indicators of 
exacerbation of symptoms. The research team will work closely with patients to familiarize them 
with the nature of this experimental setup. All staff will also be trained to be alert to any worsening 
of neuropsychiatric symptoms and/or psychosocial impairment. Bipolar patients have at times 
shown hypomanic or manic switches in the course of once-daily rTMS, as such patients with 
bipolar type I will be excluded. Additionally, all patients will be assessed throughout each day for 
worsening symptoms. Participants will similarly be queried for worsening suicidal ideation/intent. 
Drs. Benitez or McTeague will additionally assess each patient once per week in-person or via 
telephone during rTMS treatment and the one month study involvement to assess mood, 
functioning, and safety.  
 
Potential risk of a seizure with TMS. There is a risk that TMS can cause a seizure; but it is rare. 
The risk of seizure induction is related to the intensity, duration, frequency and rest interval of 
stimulation. Following the adoption and widespread use of the safety guidelines from a National 
Institute of Neurological Disorders and Stroke (NINDS) workshop on TMS, only 20 seizures have 
been reported since 1997, and they usually involved parameters of "higher settings" than the "safe 
range". To our knowledge, stimulation with the parameters and settings proposed in this study 
should not cause seizures. Each subject’s stimulus intensity is determined by his or her motor 
threshold and will be carefully calculated before beginning treatment. In this study participants will 
receive rTMS to the prefrontal cortex, a region far less prone to seizure. Nonetheless, we will 
watch participants closely for any signs of seizure throughout all procedures. Additionally, our 
study patients will be free from using known stimulants and medications that are known to 
increase the risk of seizure (e.g., theophylline).  
 
Other potential effects of TMS on brain tissue. TMS is thought to be safe, with no brain damage, 
despite extensive use in humans and other animals. Dr. George and colleagues35 have recently 
completed a case report of a maintenance treatment of rTMS for depression over a year, where 
a depressed patient received a total of [(16,000 x 2 trials) + (8,000 x 12 trials)] = 32,000 + 96,000 
= 128,000 stimuli over a year period. The patient's MRI showed no structural changes at the end 
from baseline. The patient experienced no seizures and had tolerated the procedure equally 
throughout the successive trials.  Dr. George and colleagues have also reported a safety study44 
looking at the MRI scans before and after 2 weeks of daily left prefrontal rTMS for depression. 
McGirr et al.41 
60,000 
10 
20 
120% 
Major 
Depression 
10 Hz; 5s train, 
25s ITI 
27 
Modirrousta 
et 
al.42 
90,000 
3 
30 
110% 
Major 
Depression 
10 Hz; 5s train, 
25s ITI 
18 
Williams et al.28 
90,000 
5 
10 
90% 
Major 
Depression 
54 
bursts 
of 
three; 
2s 
train; 
10s ITI  
7 
Schulze et al.43 
120,000-
180,000 
10-15 
20-30 
120% 
Major 
Depression 
20 Hz; 2.5s train; 
10s ITI 
65 

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Specifically, no structural changes were found in the left prefrontal lobe of patients who received 
active rTMS compared to placebo. More specific to the current study, Baeken et al.18,30 as well as 
Herremans et al.29 and Williams et al.28 additionally collected structural and functional imaging 
and demonstrated no adverse changes pre- to post-accelerated rTMS. Taken together, these 
studies demonstrate that the potential risks of accelerated rTMS are likely similar to conventional 
once-daily rTMS.   
 
Potential changes in cognitive function. There have been no reports of deleterious changes (more 
than a minute) in cognitive function (memory, attention, etc.) in rTMS studies. Safety studies 
specifically looking for these changes did not find any effects of rTMS. Holtzheimer et al.6 showed 
reliably enhanced neuropsychological test performance from baseline to six weeks after an 
accelerated, high-dose rTMS protocol in patients with major depression. Similar effects have been 
observed in Alzheimer’s Disease and schizophrenia21. This study will assess for potential changes 
in cognitive function with pre- and post-treatment cognitive batteries designed to look for potential 
TMS effects, if they exist. 
 
Potential hearing loss. The discharge of the rTMS coil generates a high-energy click that may 
cause cochlear damage. Humans exposed to rTMS have shown temporary increases in auditory 
threshold (especially at high frequencies) lasting at least 5 minutes and less than 4 hours37. Foam 
earplugs can protect against these changes and will be worn by the patients and researchers 
present during TMS sessions. Due to high dosage delivery in this proposal, participants will be 
instructed to ensure proper fit of earplugs prior to each session. 
 
Risk of facial twitching and skin irritation. The TMS coil can cause facial twitching, skin irritation, 
or both, which can be acutely unpleasant. This typically often reduces over the course of 
treatment. Additionally, all patients will have a foam insert placed between the coil and their scalp 
for comfort and this typically reduces this discomfort. Furthermore, facial twitching and skin 
irritation are typically only acute and subside with the end of stimulation.  
 
Risk of a first-degree burn. The TMS coil can heat up during use.  The machine used in this study 
has two major protective engineering features: (1) an external heat monitor that will shut down 
the system if the coil gets too warm; and (2) a liquid-coiled coil design that keeps the coil much 
cooler than previous models.  Additionally, all patients will have a foam insert placed between the 
coil and their scalp for comfort and also to act as additional thermal protection. The TMS treater 
will periodically monitor coil temperature during each treatment.  
 
Potential risks related to delaying other psychotropic treatments. The investigators are sensitive 
to the ethical concerns of withholding changes in antidepressant medication from depressed 
patients or withdrawing them from antidepressants in an acute crisis due to their participation in 
a clinical trial. Thus in this trial, patients are allowed to stay on medications and to have their 
physicians adjust doses or even start new medications. The rationale is that the effects of 
medication changes or new medications are rarely visible within the ‘trial’ of acute TMS. Thus, 
ethically treatment as usual will be allowed and also address our hypothesis, without subjecting 
patients to slower medication adjustments by participating in the trial.  
 
MRI risks. Exposure to magnetic field strengths used in the present study is not shown to be a 
significant health risk. Risks to an unborn fetus from exposure to the MRI field strength used in 
the proposed research (3 Tesla) are unknown. Participants will be asked to lie still and awake for 

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50-60 minutes in the scanner and this can occasionally result in soreness, stiff back, etc. 
Participants will be queried approximately every 10 minutes about their comfort. The main risk 
associated with MR imaging is the possibility of introducing metal to the magnet or its close 
proximity. Participants are thoroughly screened to prevent metal being brought into the MR 
environment. Other potential hazards of MRI scanning include: collision hazards, noise, 
neurostimulation at rapid sampling rates (i.e., short TRs), body temperature changes, helium, and 
nitrogen hazards. The MRI facility is tested regularly by internal and external safety monitoring 
teams. These risks are minimal, and the facility is run within FDA guidelines. All investigators and 
research assistants running participants in the Center for Biomedical Imaging are thoroughly 
trained in MR safety as a requirement to run scans. 
 
Confidentiality Risks. There is a risk of a loss of confidentiality of personal information as a result 
of participation in any study. This is why all study records and audio recordings will be placed in 
a locked, secure, limited access location. Participation in the study and the information provided 
will be treated as confidential. The information we collect will contain a code number and not a 
name to protect confidentiality. Codes linking numbers and names will be kept in a locked secure 
location and will not be accessible to anyone outside the research team. Despite these efforts to 
maintain subjects’ anonymity and confidentiality, there is always some minimal risk of people other 
than the study investigators gaining access to health information. Every effort will be made to 
ensure that health information will be collected and stored in a manner that ensures the highest 
level of protection of confidentiality. 
 
 
16.0 POTENTIAL BENEFITS TO SUBJECTS OR OTHERS 
 
High frequency repetitive TMS (rTMS) is FDA-approved for the treatment of major depression. 
Work by the investigative team as well as others has shown that the left dorsolateral prefrontal 
(dlPFC) site targeted with rTMS to remediate depression is seated in an area of cortex integral to 
efficient and adaptive higher order cognition (i.e., executive function). Furthermore, Co-I Dr. 
McTeague has demonstrated that this left dlPFC region is commonly hypoactivated during 
cognitive tasks across disorders. Thus, it is not surprising that cognitive improvements have been 
reported as ancillary benefits to rTMS treatment for depression. We propose that because rTMS 
to dlPFC is targeting cognitive neurocircuitry integral to adaptive functioning, that promoting 
neuroplasticity in this network with rTMS could be optimized to improve neurocognitive impairment 
in MCI. At present there is no FDA-approved treatment for cognitive impairment in MCI; all 
clinically available interventions (e.g. medication, cognitive rehabilitation) specific to ameliorating 
cognitive decline are either provided off-label or have limited efficacy per the literature. 
 
 
17.0 SHARING OF RESULTS WITH SUBJECTS 
 
We will inform participants of any new or relevant information that might influence their desire to 
continue participating in the study. We will also provide participants with an oral summary of their 
clinical outcomes should it be desired by the participant. 
 
 
18.0 DRUGS OR DEVICES 
 

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We will use a MagVenture MagProsystem with a Cool-B65 coil to deliver iTBS to subjects. Access 
to the device will be limited to those who are trained to deliver the treatment and have been 
certified by Mark George, M.D. 
 
Prefrontal rTMS at this intensity, frequency and number of stimuli has been considered "non-
significant risk" by the FDA and the MUSC IRB for well screened depressed patients or healthy 
adults. (See the uploaded letter from the FDA; FDA_George.pdf). It is also FDA approved (Oct 
2008) for the treatment of depression. 
 
 
 
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