Safety and Efficacy of an Accelerated Protocol of Intermittent Theta Burst Transcranial Magnetic Stimulation (TMS) to Enhance Performance and Promote Resilience in Astronauts: Study 1
Phase: NA
Conditions: Cognition, Stress Reaction
Sponsor: Medical University of South Carolina

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NCT04123496 
Protocol Version 6 IRB Approval: 03/23/2021 
PROTOCOL TITLE: 
Safety and Efficacy of an Accelerated Protocol of Intermittent Theta Burst Transcranial 
Magnetic Stimulation (TMS) to Enhance Performance and Promote Resilience in 
Astronauts (TRISH BRASH) 
 
PRINCIPAL INVESTIGATOR: 
 
Donna Roberts, M.D. 
 
 
 

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1.0 
Objectives / Specific Aims 
To address the major challenges in maintaining behavioral health and performance of crews on 
exploration-class missions, NASA has conducted extensive research in the areas of crew 
selection, training, and identifying behavioral issues in extreme environments1,2. However, 
evidence from US and Russian spaceflight experience and data from space analog 
environments indicate that performance and behavioral issues are a significant risk for human 
space flight, no matter how well selected and trained crew members may be2. While these 
symptoms may result in minor disruptions in Earth-based work environments, their significance 
becomes greatly magnified by the remoteness of space, potentially jeopardizing mission success 
and putting astronauts’ lives in danger. Future exploration-class missions, such as a mission to 
Mars, are characterized by long mission durations (2 to 5 years); extreme isolation; hostile 
environment; extended periods of time within the confinement of the spacecraft; lack of contact 
with family; and limited social interactions beyond one’s team members. There will be extreme 
performance pressures on crew members who must work optimally together as a team at all 
times. Therefore NASA must identify and validate countermeasures to promote behavior health 
and performance  (NASA  Human Research Roadmap: BMed1, BMed6). NASA has considered 
the inclusion of psychoactive medications for this purpose, however drugs may have expiration 
dates shorter than the mission length and the pharmacokinetics of drug administration in 
microgravity is poorly understood3 making non-pharmacological approaches desirable. 
High frequency repetitive transcranial magnetic stimulation (rTMS) to left prefrontal cortex is a 
FDA-approved non-invasive brain stimulation for the treatment of major depression. A therapeutic 
course of rTMS typically consists of approximately 30-40 minutes of high-frequency (i.e., 10 Hz) 
treatment on each weekday, for 4 to 6 weeks. This protracted schedule often creates logistical 
hurdles for patients. Recently, a number of investigators have examined accelerated rTMS 
delivery. Sessions are repeated on the same day to reduce total days of treatment. Accelerated 
protocols have typically endeavored to fit the conventional dosing scheme (i.e., 54,000-60,000 
pulses over 4-6 weeks) into a shorter time period ranging from 3 days to 2 weeks. In the case of 
either conventional or accelerated rTMS, there has been no systematic examination of dose 
response.  
We propose that similar to novel drug development, advancing accelerated rTMS for enhancing 
neurocognitive function, stress resilience and to prevent the onset of neuropsychiatric symptoms 
(e.g., anxiety, depression, anger, irritability) fundamentally necessitates establishing the dose-
response function for neurocognitive enhancement. Establishing this dose-response curve would 
enable the overall goal of study to develop and establish the efficacy of accelerated rTMS to left 
dlPFC as a non-pharmacological method for enhancing cognitive performance and resilience of 
high-performing, healthy adults of astronaut age and to extrapolate results to a spaceflight 
relevant environment (parabolic flight).   
Aim 1. Establish the dose-response curve for an accelerated rTMS protocol to left dlPFC for 
enhancing neurocognitive performance and resilience in a group of adults that mimic the astronaut 
population. We hypothesize that neurocognitive performance and resilience to stress and 
psychopathology will show similar dose-response curves and that a dose that maximizes efficacy 
while minimizing burden will be demonstrated.  

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Aim 2. Examine the efficacy and safety of accelerated rTMS to left dlPFC for enhancing cognitive 
performance and resilience. We hypothesize that relative to sham TMS, accelerated rTMS to left 
dorsolateral prefrontal cortex (dlPFC) will show neurocognitive performance (primary outcome) 
and resilience enhancements (secondary outcome) in a group of healthy adults that mimic the 
astronaut population. We additionally hypothesize that accelerated rTMS will be safe as indexed 
by 1) no clinically significant structural brain changes; 2) no decrements in neurocognitive or 
affective function; 3) no significant adverse events. We hypothesize that frontal midline theta (and 
intersite phase synchrony) will be enhanced during successful feedback learning as shown on 
post- relative to pre- treatment EEG and more so under stress. Under threat, we also expect to 
see reduced stress as indexed by physiological measures of defensive reactivity (autonomic and 
startles reflex responding). We additionally hypothesize that active stimulation will be related to 
lower levels of self-reported stress and neuropsychiatric symptoms and greater resilience.  
Aim 3. Assess the biological efficacy of TMS in a microgravity environment. During parabolic flight, 
resting motor threshold (rMT) will be measured for 10 subjects and compared to rMT obtained 
before and after flight on the ground. Any change in rMT during flight compared with pre- and 
post-flight values will be interpreted as an indicator of an altered physiological response to TMS 
during microgravity and will guide extension of the optimal ground-based accelerated rTMS 
protocol for spaceflight.  
 
2.0 
Background 
 
A1. Transcranial magnetic stimulation. Transcranial magnetic stimulation (TMS) is a medical 
device that can safely and non-invasively stimulate the brains of awake individuals to induce 
neuroplasticity4 and is currently under investigation for numerous applications in behavioral 
health and performance5. Led by the pioneering efforts of our co-Investigator, Dr. Mark George, 
TMS first received approval from the U.S. FDA in 2008 for the treatment of depression6,7 and is 
now used in psychiatric departments throughout the US and Canada8. TMS is able to focally 
stimulate the cortex by creating a dynamic magnetic field generated by a brief but powerful 
electrical current passed through an electromagnetic coil9. The magnetic field induced by  TMS  
diminishes rapidly as distance increases away from the coil. This allows TMS to be used in 
environments with complex equipment (like a space capsule) without interfering with other 
devices. For example, we have successfully used TMS to treat pain conditions inside the 
crowded intensive care unit10,11. 
TMS pulses induce a transient electric field in underlying excitable neuronal tissue. The affected 
area is approximately 2 to 3 cm below the device in superficial cortex12, but neural effects are 
then triggered in interconnected brain areas. TMS pulses cause depolarization of cortical 
neurons at the stimulation site, which then propagate through connected network nodes13. Thus, 
TMS influences not only regional or local cortex, but also distributed neural networks. Repetitive 
TMS (rTMS) can further causally influence neural networks with the added power to produce 
neuroplastic periods of lasting excitation and/or inhibition that reliably persist after the termination 
of stimulation14. 
The evidence-base for rTMS as a means of prompting therapeutic neuroplasticity 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 

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dorsolateral prefrontal cortex (dlPFC)15. 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 pharmacotherapy16,17.  
A2. Repetitive TMS to 
target cognitive 
enhancement and 
resilience. The proposed 
mechanism by which rTMS 
remediates depressive 
symptoms (i.e., up-
regulating prefrontal control 
over dysregulated limbic 
activation) implies that 
rTMS should not only 
remediate depression, but 
should be a powerful 
transdiagnostic intervention 
for affective and cognitive 
dysregulation.  In fact, high-
frequency rTMS to left  
dlPFC is effective in 
reducing symptoms as   far 
ranging as pain18, to 
craving19, posttraumatic stress disorder20, borderline personality disorder21, and compulsive food 
restriction22. 
The left dlPFC site typically targeted with rTMS is seated in  an area  of cortex integral to intact 
higher order cognition (i.e., executive function)23.  Co-I McTeague has demonstrated that this left 
dlPFC region (as well as the rest of the cognitive control or multiple demand network) is commonly 
hypoactivated during cognitive tasks across neuropsychiatric disorders.  This was observed in a 
transdiagnostic 
functional 
neuroimaging 
meta-
analysis of more than 11,000 neuropsychiatric 
patients and matched control participants (Figure 
1)24.  Furthermore, we have observed during 
functional magnetic resonance imaging (fMRI) 
concurrent with TMS, that TMS pulses to the left 
dlPFC cause BOLD activation in distributed regions 
of the cognitive control or multiple demand network 
(Figure 2; Badran et al., in preparation).  
Even among healthy individuals for whom 
neurocognitive performance has a more restricted 
range, improved working memory performance has been observed after only a single session of 
excitatory rTMS25,26.  Regarding neurocircuit based effects, multiple sessions (i.e., 2 weeks) of 
excitatory rTMS to left dlPFC among a separate sample of healthy participants have been 
shown to enhance the efficiency of the cognitive control network during working memory 
performance27. 

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Taken together, it is not surprising that cognitive improvements have been reported as ancillary 
benefits to conventional28-30 as well as accelerated31 therapeutic rTMS for cognitively intact 
depressed patients. Accordingly, rTMS has also been shown to improve cognition as the primary 
outcome in studies of mild cognitive impairment32. 
We propose that because rTMS to dlPFC is targeting cognitive neurocircuitry integral to adaptive 
cognitive functioning, that promoting neuroplasticity in this network with rTMS could be better 
optimized to both improve neurocognitive performance as well as enhance resilience to stress 
and neuropsychiatric dysfunction. 
A3. Accelerated theta burst rTMS: Lessening intervention burden toward enhancing 
adherence amidst the demands of space flight. A therapeutic course of excitatory rTMS 
typically consists of a single treatment session on each weekday for four to six week. A single 
session lasts approximately 37.5 minutes with stimulation consisting of 10 Hz trains delivered for 
4 seconds on and 26 seconds off. This schedule can be burdensome and reduce adherence. 
More recently, a number of groups have examined the safety, feasibility, acceptability, and 
effectiveness of accelerated rTMS delivery31,33-35 during which sessions are repeated on the 
same day to reduce total days of treatment, typically spaced by at least 30-60 minutes or more. 
Safety has also been assessed with both structural and metabolic imaging as well as 
neurocognitive testing, which has shown no adverse effects on neural integrity and, in fact, gains 
in cognition31,33-35.  Furthermore, acceptability results have suggested that accelerated protocols 
could increase adherence and decrease interruptions to daily obligations31,33-35. 
In a recent further innovation, intermittent theta burst (iTBS) rTMS has been shown to be as 
efficacious as 10 Hz rTMS in remediating depression36.  Notably, a  single session of 
excitatory iTBS rTMS entails 600 pulses in merely 3 minutes.  More specifically, pulses are 
delivered in triplets at 50 Hz for 2 s (i.e., 5 Hz triplets) and repeated every 10 seconds for a total 
of 190 seconds (600 pulses). Based on animal work, it has been proposed that theta burst 
stimulation may be particularly effective in inducing synaptic long-term potentiation due to 
potential mimicry of endogenous theta rhythms37. Cortical theta rhythms as characterized in 
electroencephalography (EEG) are especially important in the support of human cognitive 
control38,39.  Furthermore, among healthy participants theta burst stimulation to left dlPFC has 
been shown to enhance working and recognition memory performance40,41. 
While the use of iTBS in accelerated protocols is only now emerging for the remediation of 
neuropsychiatric dysfunction, accumulating safety and efficacy results are promising, even 
among the most impaired and vulnerable patients42. From a practical standpoint, theta burst 
sessions are typically spaced by approximately 30 minutes to one hour or more with no 
requirements on the intervening time period. As such, astronauts could undergo multiple 3-
minute sessions in a single day with limited interference on space flight demands. 
To establish an efficacious intervention, tailored to the logistical demands of spaceflght, we 
propose two studies (Aims 1 & 2), each of which would implement a cutting-edge high-dose 
accelerated theta burst protocol for the application of rTMS to enhance neurocognitive 
performance and resilience to stress and neuropsychiatric dysfunction. 

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A4. A principled, empirical approach for determining rTMS dose. In the case of either 
conventional or accelerated rTMS, there has been no 
systematic examination of dose  response.  Rather,  prior 
rTMS investigations have relied upon rational decision 
trees in determining TMS dose. For example, emerging 
accelerated protocols have typically endeavored to fit the 
conventional dosing scheme (i.e., 54,000- 60,000 pulses 
over 4-6 weeks) into a shorter time period ranging from 3 
days33 to 2 weeks31.  While dose-response curves are 
typically interrogated as a function of efficacy relative to 
toxicity, it is also possible to model efficacy in the absence 
of  toxicity, which would be most appropriate in the case of 
rTMS. 
We propose that establishing the dose-response curve for 
enhancing neurocognitive performance among  healthy,  
high  functioning  individuals, will most efficiently enable us 
to pinpoint the most efficacious and least burdensome dose 
to be administered. 
A5. TMS and microgravity. Living in a microgravity environment has significant physiological 
effects on the human body43-45. For example, the pharmacokinetics of drug administration is 
altered in microgravity46 and psychotropic medications are known to have reduced efficacy during 
spaceflight3. Likewise, there is the potential that TMS may operate differently in a microgravity 
environment. For example, studying the MRI brain scans of astronaut before and following 
spaceflight,   we   have   recently shown there is a shift of brain tissue within the skull post-flight47. 
This observed upwards shift  of brain tissue could potentially alter the dosing of TMS as the 
effectiveness of TMS depends on the distance from the TMS coil (which is placed on the scalp) 
to the underlying cortex48. In addition, cephalad fluid shifts which occur in astronauts49 and during 
parabolic flight50-52 may alter the neurophysiological  response  to  TMS. Therefore, as part of this 
study we will investigate the physiological response to TMS in a microgravity analog environment 
(parabolic flight). 
Several TMS measures of cortical excitability have been described; however the most basic 
is determination of the TMS resting motor threshold (rMT).  The rMT is the minimal magnetic 
pulse causing muscle contraction as detected by electromyography (EMG) recordings. It is 
more formally defined as the amount of TMS machine output (intensity) necessary to produce 
a motor evoked potential (MEP) that exceeds a defined peak-to-peak amplitude (usually 50 
μV) 50% of the time in a finite number of trials. The rMT is believed to be an indicator of 
neuronal membrane excitability53. Accurate estimation of rMT is of utmost importance in both 
research and clinical studies as it is the unit most commonly used for rTMS dosing54. 
Inaccurate estimation of rMT can lead to subject/patient over- or under-dosing. 
A6. Conceptual Model and Rationale for Design. We hypothesize that through up regulating 
cognitive control circuitry with rTMS that an astronaut would have enhanced capacity for 
successfully contending with the rigors of spaceflight. This would be evidenced foremost in 
enhanced cognitive control performance. The neurocircuitry undergirding efficient cognitive 
control overlaps with the neurocircuitry undergirding emotion regulation55, and as reviewed, 
rTMS to dlPFC remediates a broad range of affective dysfunction. Thus, we further propose that 

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accelerated rTMS will promote stress resilience and prevent the onset of neuropsychiatric 
symptoms (e.g., anxiety, depression, anger, irritability).  
Study Arm 1 would establish the dose-
response 
for 
enhancing 
cognitive 
performance with accelerated rTMS to left 
dlPFC. Stress resilience will be utilized as a 
secondary outcome. Given the model it would 
also be reasonable to first establish the 
objective point at which resilience is up 
regulated by rTMS. We anticipate that healthy 
participants analogous to astronauts would 
likely show little variability in baseline 
resilience and affective dysfunction. We also 
anticipate that rTMS as proposed here could 
prevent 
the 
onset 
of 
stress 
and 
neuropsychiatric symptoms and thus we will 
longitudinally follow participants for the 
emergence. 
Study Arm 2 would utilize the dose established in study one that maximizes cognitive 
performance gains while minimizing side effects and burden in a double blind, randomized 
controlled trial. Primary (neurocognitive performance) and secondary (resilience) outcomes 
would be identical to study 1.  In addition, the impact of active versus sham iTBS on cognitive 
control and resilience under stress will be demonstrated during a challenging learning paradigm 
under threat of shock. EEG will be used to assess the impact on of iTBS on neurocircuit structure 
and function. Response stability will be assessed at 6 months and one year. To assess safety, 
structural MRI adverse event reporting, and cognitive measures will be collected over a long-
term 6-month follow up period. 
Study Arm 3 study would assess the biological efficacy of TMS in a microgravity environment 
during parabolic flight. 
Study Arm 4 would establish the dose-response for enhancing cognitive performance with 
accelerated rTMS to left dlPFC, as well as assessing safety. In addition, the impact of each dose 
of iTBS on cognitive control and resilience under stress will be demonstrated during a challenging 
learning paradigm under threat of shock. MRI and EEG will be used to assess the impact on of 
iTBS on neurocircuit structure and function. Response stability will be assessed at 1 month post-
treatment. Approval to combine studies 1 and 2 into a 4th arm was approved by our sponsor, 
due to recruitment delays caused by COVID-19. 
 
B. INNOVATION AND ADVANTAGES AND RELEVANCE TO ASTRONAUTS 
 
B1. Establishing a dose-response curve for rTMS. We propose to innovate in terms of 
establishing the dose-response curve for rTMS, instead of relying upon rational decision trees 
typically founded upon the rTMS for depression literature. At present there exists no empirical 
information as to the dose for maximal benefit in neurocognitive enhancement and stress 
resilience.  

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B2. Utilizing an accelerated rTMS delivery schedule. We propose to utilize an accelerated 
(high-dose) delivery schedule to lessen burden, increase adherence, and promote the utilization 
of this intervention during space flight with the counter measures NASA already has in place to 
promote behavior health and performance. Specifically, we propose to examine a range of rTMS 
doses all within a one-week delivery schedule. 
B3. Utilizing an intermittent theta burst stimulation pattern. We propose to innovate by 
utilizing intermittent theta burst (iTBS), excitatory stimulation, which has been shown to be non-
inferior to 10 Hz stimulation in the treatment of depression, but requires only three 
minutes/session.  
3.0 
Study Endpoints 
Study Arms 1 2 & 4 neurocognitive performance is the primary treatment outcome measure. 
Stress resilience and acceptability/tolerability are secondary treatment outcome measures. For 
Study Arm 3, biological efficacy of TMS in microgravity is the primary treatment outcome 
measure. Recruitment for Study Arm 1 will cease once 40 participants have completed all 
procedures and fulfilled randomization to all doses. Recruitment for Study Arm 2 will cease once 
60 participants have completed all procedures and fulfilled randomization to all doses. 
Recruitment for Study Arm 3 will cease once 10 participants have completed all procedures. 
Recruitment for Study Arm 4 will cease once 50 participants have completed all procedures and 
fulfilled randomization to all doses. 
 
 
4.0 
Inclusion and Exclusion Criteria/ Study Population 
Participants who are aged 22-55 (inclusive), who mimic the demographics of the astronaut 
population. We conservatively expect an 80-90% retention rate, as dropout is typically fewer 
than 10% in double-blind trials of conventional daily (87) as well as accelerated rTMS (86, 89). 
Study Arms 1 2 & 4 will all have the same inclusion/exclusion criteria.  Study Arm 3 will have 
similar inclusion/exclusion criteria with additional criteria involving exposure to parabolic flight.å 
 
Study Arms 1 2 & 4 Inclusion Criteria. Participants must be 22-55 years of age: endorse good 
health with no history of mental or physical illness or implanted metal; college graduates 
(associates degree or higher); negative urine pregnancy test if female of childbearing potential; 
English is primary language; capacity to consent; willingness to adhere to rTMS schedule and 
assessments.   
Study Arms 1 2 & 4 Exclusion Criteria. Participants will be excluded for the following: any current 
psychiatric diagnosis or current Clinical Global Impression ratings of psychiatric illness > 1; 
neurodevelopmental disorders; current physical illness; history of CNS disease, concussion, 
overnight hospitalization, or other neurologic sequelae), tumors, seizures, meningitis, 
encephalitis, or abnormal CT or MRI of the brain; frequent or severe headaches; history of a 
continuing significant laboratory abnormality; any psychotropic medication taken within 5 half-lives 
of procedure time; pregnancy or intention to become pregnant during rTMS or follow-up period; 
any head trauma resulting in loss of consciousness; visual impairment (except glasses); inability 
to complete cognitive testing; currently breast feeding; active participation or plan for enrollment 
in another evidence-based clinical trial affecting psychosocial function; repeated abuse or 
dependence upon drugs (excluding nicotine and caffeine) currently taking medications that lower 
the seizure threshold; taking either of the medications including stimulants, modafinil, thyroid 

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medication, or steroids; implanted devices/ferrous metal of any kind; history of seizure or seizure 
disorder; inability to determine motor threshold; claustrophobia or other condition that would 
prevent the structural MRI assessment of pre and post-treatment, and 6 months later.  
Study Arm 3 Inclusion/Exclusion Criteria. Study Arm 3 will have modified inclusion criteria 
regarding age, as the participants must be 23-61 years of age, as well as identical exclusion 
criteria with the following additional exclusion criteria related to the experience of parabolic flight:  
Participants will be excluded for the following: History of motion sickness and/or motion 
discomfort; fear of flying or previous inability to tolerate flying; visual impairment (except glasses), 
ear disease, hearing loss or balance disorders; neck, back or other spinal problems; diabetes; 
history of GERD or other blood disorders; high or low blood pressure; heart or vascular trouble, 
stroke, history of angina or chest pain; stomach, liver, esophageal or intestinal trouble; weakened 
limbs or joints or broken bones within the past year; subthreshold behavioral health issues, such 
as panic attacks, fear of heights, fear of flying or fear of closed spaces; currently pregnant; 
dizziness, blackouts, fainting spells, or loss of consciousness for any reason; recent severe 
illness, surgery, or admission to hospital; medical rejection, medical discharge from military or 
other disabilities; lung disease, breathing problems, asthma or others. 
5.0 
Number of Subjects 
Study Arm 1: Dose-finding (enrollment n = 50 to complete assessments and treatment for n=40): 
To contend with dropout we propose to enroll 50, with the aim of completing assessments and 
treatment for 40 participants. We conservatively expect an 80-90% retention rate, as dropout is 
typically fewer than 10% in double-blind trials of conventional daily87 as well as accelerated 
rTMS86,89. Recruitment would cease once 40 participants have completed all procedures and 
fulfilled randomization to all doses.  
Study Arm 2: Efficacy & Safety (enrollment n = 70 to complete assessments and treatment for 
n=60): To contend with dropout we propose to enroll 70, with the aim of completing assessments 
and treatment for 60 participants. We conservatively expect an 80-90% retention rate, as dropout 
is typically fewer than 10% in double-blind trials of conventional daily87 as well as accelerated 
rTMS86,89. Recruitment would cease once 60 participants have completed all procedures and 
fulfilled randomization to the most efficacious dose determined by Study Arm 1. 
Study Arm 3: Biological Efficacy of TMS in Microgravity (n = 10): To contend with dropout 
we propose to enroll 10 participants.   
Study Arm 4: Dose-finding & Safety (enrollment n = 60 to complete assessments and treatment 
for n=50): Due to recruitment delays due to COVID-19, we have proposed to our sponsor (and 
have received approval) to combine studies 1 and 2. To contend with dropout we propose to enroll 
60, with the aim of completing assessments and treatment for 50 participants. We conservatively 
expect an 80-90% retention rate, as dropout is typically fewer than 10% in double-blind trials of 
conventional daily87 as well as accelerated rTMS86,89. Recruitment would cease once 50 
participants have completed all procedures and fulfilled randomization to the most efficacious 
dose determined by Study Arm 1. 
 
6.0 
Setting 

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Study Arms 1 2 & 4: All procedures will take place in private assessment and rTMS 
treatment rooms at the MUSC Brain Stimulation Laboratory (BSL) in the Institute of 
Psychiatry. The MRI scanning for Study Arm 2 and 4 will occur at the Center of Biomedical 
Imaging at 30 Bee Street on the Medical University of South Carolina campus.  
The option to remotely complete the consenting process and SCID interview will be given 
to participants in order to limit in-person visits for a multitude of reasons, including 
COVID19 precautions. Phone calls or video conferencing through Webex will be utilized in 
order to properly administer and oversee the completion of these assessments. 
Study Arm 3: Screening, interview and assessments will take place in private assessment 
rooms at the MUSC Brain Stimulation Laboratory (BSL) in the Institute of Psychiatry.  The 
study treatment procedures will take place at Sanford, Florida - The ZERO-G Experience® 
 
7.0 
Recruitment Methods 
Participant recruitment for Study Arms 1, 2, 3 & 4 will include flyers, handouts, electronic and 
physical bulletin board postings, social media/message boards (i.e., Craigslist, MUSC Broadcast 
Research studies section, Yammer, Facebook, Twitter, Instagram), newsletter/media 
advertisements, and recruitment talks at local community events/organizations and surrounding 
community as well as through the MUSC Psychiatry. The flyers will be used as the advertisement 
for all the different recruitment platforms. Participants who make contract through the QR code 
will be directed to a secure REDCap survey asking for their preferred contact date and time to 
discuss the study. 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 phone screen. If the potential participant agrees to 
continue, a phone screen will be conducted to determine eligibility for the next phase (in-person 
clinical interview) of the study. 
8.0 
Consent Process 
Informed Consent. If the potential participant passes the telephone screen and decides to come 
in for the interview, a signed informed consent will be necessary at the outset before beginning 
the interview. The PI, Dr. Roberts or trained study staff will administer the consent process in an 
office at the MUSC Department of Radiology or the Institute of Psychiatry. The consent form 
describes the study procedures and ensures participants of the confidentiality of their responses. 
The consent form further reminds participants that they have the option to withdraw from the study 
at any time and will receive proportional payment or they can refuse to answer certain questions 
and continue in the study with full compensation. The consent form contains thorough descriptions 
of the research protocol including the procedures, benefits and risks, compensation, right to non-
participation, review processes, emergency medical treatment, financial responsibility, and 
privacy issues. Prior to beginning the clinical assessment session or any scan, participants must 
demonstrate ability to read, verbalize understanding of, and sign informed consent 
documentation. Two fields within the consent form enables participants to consent to whether 
study personnel may keep their contact information and contact them in the future regarding other 
research studies. Enrollment is not contingent upon responses to this query. Participants will be 

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allowed to take the consent form home for further review. Each day participants will be queried 
about their comfort with continuing the study. 
9.0 
Study Design / Methods 
This study involves three aims divided into four separate study arms. Study Arm 1 Dose Finding; 
Study Arm 2 Efficacy & Safety; Study Arm 3 Biological Efficacy of TMS in Microgravity; Study 
Arm 4 Dose Finding & Safety.  
 
Recruitment, Screening & Intake Assessment. For Study Arms 1, 2, 3 & 4, healthy participants 
would be recruited from the local and surrounding community. Eligibility would be screened in-
person or via phone. Participants who meet probable inclusion criteria endorse good health, 
demographics of astronauts with no history of mental illness, neurological disorders, substance 
abuse or implanted metal as determined Telephone Screening-Control would be invited for an 
intake assessment. The Telephone Screening-Control questionnaire would include a TMS safety 
screener, the 4-item Patient Health Questionnaire (PHQ-4 item), PTSD Checklist Screener (PCL-
6), and 7-item Generalized Anxiety Disorder (GAD-7). E-consent will be an option if the 
coordinator does not feel the participant is able to come into the laboratory for consenting for any 
reason, but primarily due to safety precautions surrounding the COVID-19 pandemic. The e-
consent will be emailed through REDCap and approved research personnel will go through the 
e-consent with the participant over the phone or over video conferencing. The participant will 
receive a copy of the signed e-consent by email from the research personnel. The coordinator will 
offer to send the consent form to the participant in advance to provide ample time for review. 
Following the consent, the remainder of the intake assessment can also be performed remotely. 
This includes the Structured Clinical Interview for DSM-5. Study Arm 3 participants will have 
additional assessments to assess capability to be in parabolic flight. 
Study Arm 1: Dose Finding 
rTMS dosing parameters, targeting, and rationale for proposed design. We chose to alter dose as 
a function of sessions, with a single session defined as 600 pulses at 120% motor threshold, 50 
Hz triplets for 2 s, and repeated every 10 s for a total of 190 s to left dlPFC (Table 1). Ten doses 
would be block randomized to participants (block size to be determined by Dr. Ramakrishnan) to 
ensure that the upper and lower doses are acquired in tandem in approximately equal rates.  
Table 1. Dosing Parameters by Weekday and Total for Determining Dose-Response Curve 
                                 # of Active Sessions     
                                            by day* 
                                                   Total 
Dose 
Step 
Monday 
Tuesday 
Wednesday 
Thursday 
Friday 
# 
Active  
Sessions 
# Active 
Pulses 
# 
Sham 
Sessions 
1 
1 
1 
1 
1 
1 
5 
3000 
45 
2 
2 
2 
2 
2 
2 
10 
6000 
40 
3 
3 
3 
3 
3 
3 
15 
9000 
35 
4 
4 
4 
4 
4 
4 
20 
12000 
30 
5 
5 
5 
5 
5 
5 
25 
15000 
25 
6 
6 
6 
6 
6 
6 
30 
18000 
20 
7 
7 
7 
7 
7 
7 
35 
21000 
15 
8 
8 
8 
8 
8 
8 
40 
24000 
10 
9 
9 
9 
9 
9 
9 
45 
27000 
5 
10 
10 
10 
10 
10 
10 
50 
30000 
0 
*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.  

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A MagVenture MagPro TMS System would be utilized and is already in place at the Brain 
Stimulation Laboratory. To control for differences in treatment time for the different doses, all 
participants would be in the TMS chair for the same duration. That is, all participants would 
perceive receiving treatment for ten, 3-minute sessions on each weekday for one-week. Each 
session would be separated by at least 10 minutes or more depending on stimulator availability 
and participant schedule. In addition to block randomization to dosing parameters, Dr. 
Ramakrishnan would randomize each participant’s daily active/sham sessions.  For example, if a 
participant were assigned to receive two active sessions in a given day, five sessions must be 
sham. This would further maintain the integrity of the blind. Additionally, a focal electrical sham 
developed by Co-I Dr. George and colleagues77 would be used which simulates the sound and 
sensation of active TMS. This entails a pre-treatment individualized titration of electrical 
stimulation until sham and active blocks of rTMS are indistinguishable to participants. Participants 
then receive an individualized level of sham stimulation throughout treatment. This has been 
shown in a series of trials to bolster the integrity of the blind78-80. Guided by existing studies, the 
dose range is 3,000-30,000 pulses for a total of 5 to 50 active rTMS sessions. Each participant 
would perceive ten 3-minute sessions (each separated by 10 minutes) over each of five 
contiguous days. A single session=600 pulses of iTBS at 120% rMT, triplets at 50 Hz for 2 s and 
repeated every 10 s for a total of 190 s (600 pulses) to left dlPFC targeted via F3 of the 10-20 
system. Probabilistic coil placement to left dlPFC via F3 was chosen as opposed to individualized, 
neuronavigation-based targeting to the participant’s structural scan to maximize the potential to 
readily implement the approach by crewmembers in during spaceflight. In order to further prove 
the precision of using neuronavigation equipment compared to using cap measurements alone, 
coordinators will concurrently run an observational study during the treatment visits which will not 
require additional invested time by the participant. 
To assess intervention acceptability, participants would be asked to rate pain and discomfort on 
a visual analog scale after each session86. At the end of treatment participants would also 
complete a 5-item questionnaire about confidence in treatment procedures and mechanisms. To 
assess intervention safety, adverse events would be examined. To assess intervention feasibility, 
recruitment and retention rates would be examined. To assess intervention efficacy, 
neurocognitive, resilience, and symptom measures would be repeated after the last treatment 
session, and at 1 month post- treatment.   
To assess neurocognitive performance, participants would complete the WinSCAT battery60 (a 
computerized battery which takes about 10 minutes to complete and includes tests of reaction 
time, short term memory, and visual memory and is used by NASA to assess cognitive function 
in astronauts during International Space Station flights), the NIH Toolbox62 (a comprehensive set 
of neuro-behavioral measure that assess cognitive, emotional, sensory, and motor functions), as 
well as subtests from the Penn Computerized Neurocognitive Battery61. The battery includes well-
validated computer- adaptations of neuropsychological tests (approximately 60 - 90 minutes total). 
Tasks assess domains including: information-processing speed, sustained attention/vigilance, 
verbal memory, working-memory capacity, cognitive flexibility, episodic memory, performance 
monitoring, resistance to interference, spatial memory, set shifting, inhibition/impulsivity, verbal 
learning, episodic memory, sensorimotor function and processing speed. 
To assess resilience, stress, and affective function, participants would complete the Connor-
Davidson Resilience Scale63, a 25-item scale assessing hardiness, sense of control, adaptability, 

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stress endurance and self-confidence. The 17-item Hamilton Scale for Depression (HAM-D)The 
10-item Perceived Stress Scale64 would be completed to assess subjective stressors and their 
impact. The 99-item self-report Inventory of Depression and Anxiety Symptoms (IDAS-II)65 would 
be completed as a broad measure of psychopathology and related functional impairment. The 
measure includes 18 non-overlapping factor-analytically-derived symptom subscales covering a 
wide range of psychopathology dimensions such as anxiety, depression, mania, insomnia, 
appetite). 
To further characterize the sample, participants would complete Structured Clinical Interview for 
DSM-566 and two sections of the Wechsler Abbreviated Scale of Intelligence-II (WASI-II)67 Matrix 
Reasoning and Vocabulary. To assess substance use and abuse, the Fagerstrom Test for 
nicotine dependence, Drug Abuse Screening Test (DAST‐10) Questionnaire, and Alcohol Use 
Disorders Identification Test (AUDIT). 
To assess trajectory of changes in symptoms and psychosocial function, the abbreviated 7-item 
IPF (Brief Inventory of Psychosocial Functioning; B-IPF) would be administered at intake, after 
the last treatment session, and then via telephone or RedCap survey, each week for four weeks 
following treatment completion. The 6-item Patient Reported Outcome Measurement Information 
System (PROMIS), 4-item Patient Health Questionnaire (PHQ-4), Generalized Anxiety Disorder-
7 (GAD-7), and 6-item PTSD Checklist (PCL-6) would also be administered. These measures 
would be revised to query the last 7 days. Weekly symptom changes and demographic data would 
be assessed via RedCap.  
Table 2. Visit Summary Study Arm 1: Dose Finding 
 
Session 
Number 
Task Description 
Location at MUSC 
Visit Duration 
0 
 
Eligibility Screening 
Telephone 
30 minutes 
1 
Consent* 
 
Interview* 
 
Neurocognitive 
Battery 
 
Questionnaire 
Battery 
 
Motor Threshold 
Testing 
MUSC Brain Stimulation 
Laboratory in the Institute 
of Psychiatry 
20-30 minutes 
 
30 minutes 
 
90 minutes 
 
1 hour 
 
10-15 minutes  
2 
rTMS day 1 
MUSC Brain Stimulation 
Laboratory in the Institute 
of Psychiatry 
Ten 3-minute 
treatment sessions 
separated with10 
minutes or more 
between each 
session.  

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Total Time: –2 - 4 
hours 
3 
rTMS day 2 
MUSC Brain Stimulation 
Laboratory in the Institute 
of Psychiatry 
Ten 3-minute 
treatment sessions 
separated with 10 
minutes or more 
between each 
session.  
 
Total Time: –2 - 4 
hours 
4 
rTMS day 3 
MUSC Brain Stimulation 
Laboratory in the Institute 
of Psychiatry 
Ten 3-minute 
treatment sessions 
separated with 10 
minutes or more 
between each 
session.  
 
Total Time: –2 - 4 
hours 
5 
rTMS day 4 
MUSC Brain Stimulation 
Laboratory in the Institute 
of Psychiatry 
Ten 3-minute 
treatment sessions 
separated with 10 
minutes or more 
between each 
session.  
 
Total Time: –2 - 4 
hours 
6 
rTMS day 5 
 
 
 
MUSC Brain Stimulation 
Laboratory in the Institute 
of Psychiatry 
Ten 3-minute 
treatment sessions 
separated 10 
minutes or more 
between each 
session.  
 
Total Time: –2 - 4 
hours 
7 
Neurocognitive 
Battery 
 
Questionnaire 
Battery  
MUSC Brain Stimulation 
Laboratory in the Institute 
of Psychiatry 
90 minutes 
 
1 hour 
 
8 
1 month post-
treatment 
Neurocognitive 
Battery 
MUSC Brain Stimulation 
Laboratory in the Institute 
of Psychiatry 
90 minutes 
 
 
1 hour 

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*Option to complete remotely due to COVID-19 precautions. 
Study Arm 2: Efficacy & Safety  
Assessment & rTMS. The assessment and TMS methods from study 1 will be identical, except 
that 60 participants (enrollment n=70 to complete assessments and treatment for n=60 to 
contend with drop out) will be randomized to one dose of active or sham  iTBS rTMS. The dose 
will be determined as the most efficacious dose from Study 1, minimizing side effects and 
burden. In addition, to determine longer-term safety of the intervention, participants will complete 
neurocognitive, resilience and symptom measures pre- and immediately post-treatment as well 
as 1, 2, and 6 months later. 
MRI assessment. To more specifically examine safety, participants who received active 
stimulation will undergo MRI sessions (FLAIR, diffusion, T2* and volumetric sequences) for 
assessment of structural changes at pre- and post-treatment, and 6 months later. 
Physiological assessment. The impact of active versus sham iTBS on function will be further 
assessed with electrocortical and physiological activity during a challenging feedback-based 
response-learning paradigm39,70. This learning task is essentially a more difficult version of the 
Wisconsin Card Sorting task. More specifically, participants must dynamically learn different 
categories of stimuli as well as the exceptions. Participants receive feedback (correct/incorrect) 
on each trial to shape learning. Intermittently, and disproportionately on incorrect trials to 
increase stress, participants are instructed to increase performance speed. Additionally, trials 
are embedded in counterbalanced blocks of threat of unpredictable shock. Half of the blocks are 
“No Shock” probability blocks, whereas half of the blocks are “Unpredictable Threat of Shock.” 
Thus, in addition to performance demands participants must contend with a psychologically 
threatening and unpredictable context during performance. Typically, more efficient learning and 
performance is predicted by increased midline theta oscillations (4-8 Hz) and increased intersite 
phase synchrony during feedback, and further enhanced under threat or stress among those 
with successful performance39. Responses to blocks of unpredictable threat and no threat will be 
compared in terms of autonomic measures (heart rate and skin conductance) as well as the 
responses to 50 ms, 98 dB white noise probes, which elicit a blink response (i.e., startle reflex)  
measured with electromyography (EMG). The reactions captured in these measures reliably 
increase as a function of stress and aversion as well as lack of resilience71-74. In summary, we 
predict that EEG metrics of cognitive control will be enhanced pre- to post-treatment in the active 
relative to sham group, and more pronounced under threat, indicative of enhanced cognitive 
control and resilience. We predict that concurrent physiological metrics of stress reactivity during 
unpredictable relative to no threat of shock will be reduced pre- to post-treatment in the active 
relative to sham group, indicative of improved resilience. Shock level will be individually titrated 
prior to the learning procedure. EEG will be assessed pre- and immediately post-treatment as 
well as 1 and 6 months later (64-channel Brain Products ActiChamp System). Startle, heart rate 
and skin conductance will be assessed with Biopac EMG, EKG, and EDA modules. 
 
Table 3. Visit Summary Study Arms 2 and 4: Dose-finding/Efficacy & Safety  
 
1 month post-
treatment 
Questionnaire 
Battery 

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Session 
Number 
Task Description 
Location at MUSC 
Visit Duration 
0 
 
Eligibility Screening 
Telephone 
30 minutes 
1 
Consent 
 
Interview 
 
Neurocognitive 
Battery 
 
Questionnaire Battery 
 
Motor Threshold 
Testing 
MUSC Brain 
Stimulation Laboratory 
in the Institute of 
Psychiatry 
20 – 30 minutes 
 
30 minutes 
 
90 minutes 
 
 
1 hour 
 
10 – 15 minutes 
2 
MRI Safety Screen 
 
Pre-treatment 
Structural MRI and 
functional MRI  
 
EEG assessment 
MUSC Center for 
Biomedical Imaging 
5 minutes 
 
 
1 – 2 hours 
 
 
1-2 hours 
3 
rTMS 
MUSC Brain 
Stimulation Laboratory 
in the Institute of 
Psychiatry 
Up to ten 3-minute 
treatment sessions 
separated with 20-30 
minutes or more 
between each 
session.  
 
Total Time: 3 - 5 
hours 
4 
rTMS 
MUSC Brain 
Stimulation Laboratory 
in the Institute of 
Psychiatry 
Up to ten 3-minute 
treatment sessions 
separated with 20-30 
minutes or more 
between each 
session.  
 
Total Time: 3 - 5 
hours 
5 
rTMS 
MUSC Brain 
Stimulation Laboratory 
in the Institute of 
Psychiatry 
Up to ten 3-minute 
treatment sessions 
separated with 20-30 
minutes or more 
between each 
session.  
 

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Total Time: 3 - 5 
hours 
6 
rTMS 
MUSC Brain 
Stimulation Laboratory 
in the Institute of 
Psychiatry 
Up to ten 3-minute 
treatment sessions 
separated with 20-30 
minutes or more 
between each 
session.  
 
Total Time: 3 - 5 
hours 
7 
rTMS  
 
 
MUSC Brain 
Stimulation Laboratory 
in the Institute of 
Psychiatry 
 
Up to ten 3-minute 
treatment sessions 
separated with 20-30 
minutes or more 
between each 
session.  
 
Total Time: 3 - 5 
hours 
8 
Post-treatment 
Neurocognitive 
Battery 
 
Post-treatment 
Questionnaire Battery 
 
MUSC Brain 
Stimulation Laboratory 
in the Institute of 
Psychiatry 
 
90 minutes 
 
 
 
1 hour 
9 
MRI Safety Screen  
 
Post-treatment 
Structural MRI and 
functional MRI 
 
EEG assessment 
MUSC Center for 
Biomedical Imaging 
 
5 minutes 
 
 
1 – 2 hours 
 
 
1 – 2 hours 
 
10 
1 month post-
treatment 
Neurocognitive 
Battery 
 
1 months post-
treatment 
Questionnaire Battery 
 
EEG assessment 
MUSC Brain 
Stimulation Laboratory 
in the Institute of 
Psychiatry 
90 minutes 
 
 
 
 
1 hour 
 
 
 
1 – 2 hours 
 
Study Arm 3: Biological Efficacy of TMS in Microgravity 

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To assess the biological efficacy of TMS during microgravity, we will determine resting motor 
threshold (rMT) in 10 subjects before, during and following parabolic flight (sessions 1-3). To 
determine rMT, we will briefly apply single pulse TMS.  We will use a standard clinical algorithm 
(adaptive parameter estimation by sequential testing) to determine rMT of the abductor pollicis 
brevis muscle in an automated fashion. The measurement takes 20 seconds to perform (20 stimuli 
using single pulse TMS)75,76.   
Pre-flight data collection:  First, on the ground pre-flight, the optimal location for stimulus induction 
will be identified. This location will be marked on the scalp in order to facilitate quick and 
reproducible identification of this site during the in-flight and post-flight sessions. At this location 
the TMS coil will be fixed firmly in place and the rMT will be determined.  The subjects will also 
undergo a 10 minute standard computerized cognitive battery (WinSCAT) used by NASA to 
assess cognitive function in astronauts during International Space Station flights60.   
In-flight data collection:  The in-flight rMT measurement will be performed by placing the coil in 
the same location identified pre-flight. The coil will be secured in place using stabilization 
hardware developed with Zero-G similar to the fixation hardware in use in our lab. The flight profile 
includes 30 parabolas each with approximately 25 seconds of microgravity. This will allow up to 
2-3 in-flight measurements per subject providing a margin for human error.  
Post-flight data collection:  The same procedure will also be utilized to obtain the post-flight 
measurement.  The subjects will also undergo a computerized cognitive battery (WinSCAT) post-
flight. 
Any significant change (based on established values in normal controls54) in rMT during flight 
compared with pre- and post-flight values will be interpreted as an indicator of an altered 
physiological response to TMS during microgravity. 
The research team (Drs. George and Roberts and trained research assistants) will be aboard the 
flight and perform all research procedures.  Drs. George and Dr. Roberts are licensed physicians 
who have extensive experience safely performing TMS.  Dr. Roberts has previous parabolic flight 
experience. The research assistants will come from the brain stimulation laboratory and will have 
been trained in all aspects of TMS application and safety prior to the flight.  In addition, they will 
have been responsible for the application of TMS in the brain stimulation laboratory gaining 
expertise in applying TMS during ongoing TMS trials prior to the parabolic flight. 
Additional data collection:  The same procedures will be utilized to obtain the rMT in three different 
body positons (upright, supine, Trendelenburg) and WinSCAT cognitive battery. 
Experimental set up 
See the figure which shows our set up on the ground.  To record motor evoked potentials, signals 
will be amplified using a 1902 amplifier, digitized with a 1401 ADC and displayed using Signal 
Software (Cambridge Electronic Design, Cambridge, England) which will be used on loan from 
our laboratory. For cortical stimulation, a portable TMS system will be used.  A laptop computer 
will be used to control the automated software.  Zero G Corporation will work with the research 
team to install this hardware in the aircraft and to perform safety checks.   
Zero-G has extensive experience with the aircraft and implementing hardware setups.  NASA has 
used Zero-G parabolic flights to train astronauts and certify spaceflight hardware for more than 
15 years.  Zero-G Corporation has performed a feasibility analysis and has given preliminary pre-

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approval for this study.  Approximately 2 months prior to the flight, a detailed structural review of 
the experimental set up will be performed.  As a commercial airline, Zero-G is regulated by the 
FAA.  Any structural change to the aircraft such as bringing experimental equipment on board 
must be approved by the FAA.  Therefore our experimental set up will undergo structural analysis 
by the FAA as part of a designated engineering review.  Upon receiving approval from the FAA, 
we will be confirmed for a flight date.   
On the day prior to the flight, the study team members will work with Zero G to load the study 
equipment into the aircraft and to perform safety checks assuring the test equipment is ready for 
flight (See study schedule below).  During this time, the participants will have free time.   
 
Research activities during parabolic flight 
Upon entering the aircraft, subjects and the research team will be directed to an area in the back 
of the plane which contains standard aircraft seating.  Subjects and the research team will remain 
in this area during take-off and flight until the aircraft reaches an appropriate altitude.  The subjects 
and research team will stay seated until signaled by Zero G personnel that it is time to move to 
the section of the plane where all experimental procedures will take place.  At that time, the 
parabolic portion of the flight will begin.  
For each parabola, Zero-G personnel provide the study team with adequate notice that the 
microgravity portion of the flight is approaching.  This gives the research team time to get the 
subject in place in preparation for the upcoming TMS application.  During TMS, the subject will be 
seated in a chair fixed to the floor of the aircraft and wear a seatbelt.  (See the figure).  The TMS 
coil will be securely fixed in place using an adjustable arm attached to the chair.  The subject will 
place his/her head in a chin rest and forehead rest attached to the chair.  The subject will hold 
their head against the TMS coil for the 20 seconds of TMS.  One member of the research team 
will start the software which will control application of the TMS pulses and ensure the subject’s 
head is in the appropriate position against the TMS coil.  Another member of the research team 
(Dr. George or Dr. Roberts) will closely monitor the subject for any discomfort or adverse event.  
After the 20 seconds of TMS, the subject will move from the experimental set up to the nearby 
designated location where subjects remain when not actively involved in the study as the research 
team prepares the next subject for the next parabola.     
During parabolic flight, go-pro cameras will be used to video record the study. 
All emergencies are handled in accordance with FAA regulations.  Throughout the flight Drs. 
George and Roberts will observe the subjects for any sign of an adverse event requiring medical 
attention.  If such an event occurred, Dr. George or Roberts will notify the Zero-G flight director 
who will inform the pilot to end the parabolic flight maneuvers and to go immediately to the closest 
airport to get medical treatment for the subject.  Drs. George and Roberts will ensure the subject 
is in a safe position and monitor the subject until emergency personnel arrive. All Zero-G 
personnel are trained in basic life support and cardiopulmonary resuscitative equipment is 
available on the plane. 

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Travel/transportation 
The parabolic flight will take place in Sanford, Florida.  Participants will be required to make their 
own transportation arrangements to Sanford, Florida and for the return trip to the Charleston area.  
The study will reimburse subjects for gas mileage from the Charleston area to Sanford, Florida 
and for the return.  Participants should plan on travel to Sanford, Florida the day before the 
planned study date.  A hotel reservation will be made for the participants by the study team and 
the cost of the hotel stay for two nights will covered by the study.  Participants will also be 
reimbursed a per diem for meals. Reimbursement rates will be per MUSC policy (currently 58 
center per mile and $32 per day per diem pro-rated).  This has been reviewed and approved by 
MUSC Risk Management and the approval email from Risk Management is attached. 
 
Study schedule 
Listed are the activities of each day and who will be involved (study team and/or participants). 
Day prior to study   Travel to Sanford, Florida 
Study team 
Participants 
 
 
 

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Day 1: Test Readiness Review                                                
8:00am:   
Arrive 
Study team 
Participants 
8:30am:  
Mission Briefing 
Study team 
Participants 
9:15am:     
Experiment set-up 
Study Team 
Participant - Free Time 
9:30am:     
Test Readiness Review 
(TRR) 
Study Team 
Participant - Free Time 
12:00pm:   
Finalize TRR 
Study Team 
Participant - Free Time 
2:00pm:       
Load experiments on G-
FORCE ONE     
Study Team 
Participant - Free Time 
5:00pm:     
Complete experiment 
loading 
Study Team 
Participant - Free Time 
 
 
Day 2: Flight Day                                                
8:00am:   
Check-in 
Study team 
Participants 
8:30am:  
Pre-flight data collection 
Study team 
Participants 
9:00am:     
Security Check & Boarding 
Study Team 
Participants 
10:00am:     
ZERO-G Weightless Lab 
Flight 
Study Team 
Participants  
12:30pm:   
Post-flight data collection 
Study Team 
Participants 
1:00pm:       
Return to Charleston area 
Study Team 
Participants 
 
Study Arm 4: Dose Finding  
Assessment & rTMS. The assessment and TMS methods from study 1 will be identical, except 
that 50 participants (enrollment n=60 to complete assessments and treatment for n=50 to 
contend with drop out) will be randomized to one of ten doses of active  iTBS rTMS. In addition, 
to determine longer-term safety of the intervention, participants will complete neurocognitive, 
resilience and symptom measures pre- and immediately post-treatment as well as 1 month later. 
MRI assessment. To more specifically examine safety, all participants will undergo MRI sessions 
(FLAIR, diffusion, T2* and volumetric sequences) for assessment of structural changes at pre- 
and post-treatment,. 
Physiological assessment. The impact of each dose of iTBS on function will be further assessed 
with electrocortical and physiological activity during a challenging feedback-based response-

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learning paradigm39,70. This learning task is essentially a more difficult version of the Wisconsin 
Card Sorting task. More specifically, participants must dynamically learn different categories of 
stimuli as well as the exceptions. Participants receive feedback (correct/incorrect) on each trial 
to shape learning. Intermittently, and disproportionately on incorrect trials to increase stress, 
participants are instructed to increase performance speed. Additionally, trials are embedded in 
counterbalanced blocks of threat of unpredictable shock. Half of the blocks are “No Shock” 
probability blocks, whereas half of the blocks are “Unpredictable Threat of Shock.” Thus, in 
addition to performance demands participants must contend with a psychologically threatening 
and unpredictable context during performance. Typically, more efficient learning and 
performance is predicted by increased midline theta oscillations (4-8 Hz) and increased intersite 
phase synchrony during feedback, and further enhanced under threat or stress among those 
with successful performance39. Responses to blocks of unpredictable threat and no threat will be 
compared in terms of autonomic measures (heart rate and skin conductance) as well as the 
responses to 50 ms, 98 dB white noise probes, which elicit a blink response (i.e., startle reflex)  
measured with electromyography (EMG). The reactions captured in these measures reliably 
increase as a function of stress and aversion as well as lack of resilience71-74. In summary, we 
predict that EEG metrics of cognitive control will be enhanced pre- to post-treatment as a function 
of dose, and more pronounced under threat, indicative of enhanced cognitive control and 
resilience. We predict that concurrent physiological metrics of stress reactivity during 
unpredictable relative to no threat of shock will be reduced pre- to post-treatment, more so at 
higher doses, indicative of improved resilience. Shock level will be individually titrated prior to 
the learning procedure. EEG will be assessed pre- and immediately post-treatment as well as 1 
month later (64-channel Brain Products ActiChamp System). Startle, heart rate and skin 
conductance will be assessed with Biopac EMG, EKG, and EDA modules. 
 
10.0 Data Management  
Confidentiality. Any discussion of identifying sensitive information will occur in private rooms at 
the Brain Stimulation Laboratory, 30 Bee Street Center for Biomedical Imaging, or the Department 
of Radiology. 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 her 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 in the PI’s 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 
the PI’s locked office. All other collected paper (e.g., interview responses) and electronic (e.g., 
questionnaire, neurocognitive, MRI data) files will be identifiable only by participant code and 
stored in locked file cabinets or on the secure MUSC LAN at the Institute of Psychiatry (non-MRI 

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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. 
All study personnel will complete all annual MUSC CITI training concerning confidentiality 
and research ethics.  
The PI will monitor data quality on a weekly basis to ensure integrity, completeness, and 
fidelity to the IRB protocol.  
Statistical Plan.  
Arms 1 and 4. Dose-response relationships for the primary and secondary efficacy endpoints of 
change in neurocognitive performance (composite measure), EEG, and resilience, stress and 
symptoms would be assessed using the multiple comparisons procedure with modeling (MCP-
Mod) approach for 1 and 2 month outcomes. To determine the reliability of a dose response, 
MCP-Mod fits a set of pre-specified candidate dose-response curves to the data using a multiple-
comparisons technique. The pre-specified dose-response curves to be tested for resilience and 
neurocognitive performance would be Emax, logistic, and linear. Significant curves would then 
be used to develop inferences on optimal doses for the randomized controlled trial in aim 2. 
Descriptive statistics would be performed on acceptability ratings, adverse events, and dropout 
rates. Linear mixed- effects models would assess the trajectory of pain/discomfort ratings. 
The rationale for participant/dose ratio. Dose-response studies are not powered in the traditional 
manner. In order to resolve the shape of the continuous dose response function, it is statistically 
more efficient to select more doses as opposed to more participants57,58. The number of 
observations within each dose is primarily to account for sampling variability, which could be 
achieved with a minimum of 2 to 3 observations. Capturing variability is essential to the planned 
analyses, which underweight the points of greatest variability in estimating the response curve. 
To contend with dropout we propose to enroll 60, with the aim of completing assessments and 
treatment for 50 participants. We conservatively expect an 80-90% retention rate, as dropout is 
typically fewer than 10% in double-blind trials of conventional daily59 as well as accelerated 
rTMS31. 
Arm 2. Descriptive statistics would be performed on acceptability ratings, adverse events, and 
dropout rates. Linear mixed-effects models would assess group x pre/post rTMS change in 
neurocognitive performance, resilience and stress self-report measures, and EEG and ERP 
metrics. Regarding statistical power, we based predicted effect sizes on findings of 
neurocognitive enhancement by Holtzheimer et al.31 in an accelerated rTMS protocol, 
specifically, reliable change of 5 standard units on the RBANS (SD=8.9). Specifically, group 
sample sizes of 27 achieve 80% power to detect a difference of 5.000 (SD=8.9) in a design with 
3 repeated measurements having a Compound Symmetry covariance structure, the correlation 
between observations on the same subject is 0.300, and alpha level is 0.050. We propose to 
enroll 70 people to contend with dropout with target completion reached with 30 participants 
each completing active and sham conditions (60 participants total). 

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Arm 3. A power analysis was performed to determine the number of subjects needed to study 
physiological effects of simulated microgravity on motor threshold determination. With our study 
design, each subject will be his/her own control. For calculation of the study’s power, we used 
data of Wassermann54 who examined session-to session variability of motor threshold in 19 
subjects on three separate occasions and computed the average coefficient of variation in motor 
threshold across sessions as 0.058±0.036. Based on this data, a total of 10 subjects will have a 
99% chance (at a two sided 5% significance level) to detect a change in motor threshold due to 
an experimental intervention (parabolic flight) with an effect size of 1.61.  
 
11.0 Provisions to Monitor the Data to Ensure the Safety of Subjects 
The principal investigator 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 Dr. George/Dr. Roberts.  
Seizure Risk. Participants will already be lying down on the scanner bed during scans or reclined 
in a chair during rTMS. In the event of a seizure in the scanner, participants will be taken out of 
the magnet bore immediately and the barriers on both sides of the detachable bed will be raised 
to prevent injuries from falls. This event will qualify as a medical emergency and procedures 
outlined below will be followed. 
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. Dr. George and Dr. Roberts are licensed physicians and will be on call during all sessions and 
rTMS sessions (or a similarly trained physician) to respond to any more subtle potential medical 
situations arising from doing TMS/fMRI. Dr. George will be responsible for training research 
personnel in detecting the onset of seizures. 

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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 purposes95.  
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.  
Other protections against risk.  In designing this trial, the research team constantly struggled with 
the tension between adding more tests or interventions and participant burden. As was discovered 
in the pilot study by George and colleagues86, this 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. 
 
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. A research specialist will identify any potential adverse events 
during the course of the study from participant self-report and administration of the visit 
assessments and procedures. The research assistant will provide information to the PI, who will 
be responsible for AE/SAE assessment and evaluation including a determination of seriousness 
and study relatedness.  
 
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, 

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• 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. 
 
AEs/SAEs are documented and reported as per protocol and IRB requirements. 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. 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. If the AE 
meets the definition for serious, appropriate SAE protocol specific reporting forms are completed 
and disseminated to the appropriate persons and within the designated timeframes as indicated 
above. For each AE/SAE recorded, the research staff will follow the AE/SAE until resolution, 
stabilization or until the participant is no longer in the study as stated in the protocol. When a 
reportable SAE is identified, the research staff will notify the MUSC Institutional Review Board 
(IRB) within 24 hours and complete the AE report form in conjunction with the PI. The MUSC IRB 
meets monthly and is located at 165 Cannon Street, Rm. 501, Charleston, SC  29425. 
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), 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 unexpected AND related or possibly related AND 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 Plan (DSMP). The PI, Dr. Roberts will be in charge of 1) providing 
scientific oversight; 2) reviewing all adverse effects or complications related to the study; 3) 

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monitoring enrollment; 4) reviewing summary reports relating to compliance with protocol 
requirements; and 5) providing advice on resource allocation. Dr. Roberts will meet quarterly in-
person and as necessary with the CoI-s as an internal Data Safety Monitoring Committee (DSMC) 
to review progress. The recommendations of the DSMC will be reviewed and the PI will take 
appropriate corrective actions as needed. At each meeting the DSMC will: 
 
• Review the research protocol and plans for data and safety monitoring. 
• Evaluate the progress of the three studies, 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 
developments that may impact the safety of study participants or the ethics of the study. 
• Make recommendations to the MUSC IRB for continuation or termination of the studies. 
• Protect the confidentiality of study data and monitoring. 
 
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. 
 
  
12.0 Withdrawal of Subjects  
Early withdrawal of study subjects.  As stated on the Informed Consents, all subjects reserve the 
right to withdraw from the clinical investigation at any time.  The Investigator 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 noncompliant with procedures set forth in the protocol. 
• Subject experiences an Adverse Event that warrants withdrawal from the study. 
• It is in the Investigator’s opinion that it is not in the subject’s best interest to continue. 
• Subject displays other abnormal laboratory, medical or clinical findings for which clinical 
intervention should take precedence over study participation including: 
a) Development of significant neuropsychiatric symptoms   
b) Generalized seizure 
c) Inpatient hospitalization 
d) Unable to complete treatment in the designated time frame 
 
Any participant who informs research staff of an intention to withdraw from the study will be asked 
to return for a final safety visit, whereby the complete range of post-treatment assessments will 
be performed. If a participant is lost to follow up, three documented attempts will be made to 
contact the participant. 
 
 
13.0 Risks to Subjects 

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Risks associated with TMS and MRI.  
 
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, Table 4 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.81 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.82,83 as well as Herremans et al.84 and Williams et al.85 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.   
 
 
Table 4 . Representative accelerated rTMS studies for neuropsychiatric conditions. 
 
Study 
Total 
Pulses 
Days 
Total 
# 
Sessions 
Stimulation 
Intensity 
Disorder 
Frequency 
 N 
Holtzheimer et al.81 
15,000 
2 
15 
100% 
Major 
Depression 
10 Hz; 5s 
train, 25s 
ITI 
14 
Baeken et al.82,83 
31,200 
4 
20 
110% 
Major 
Depression 
20 Hz; 1.9s 
train; 12s 
ITI 
15 
Herremans et al.84 
31,200 
3 
15 
110% 
Alcohol Use 
Disorder 
20 Hz; 1.9s 
train; 12s 
ITI 
19 
Desmyter et al. 92  
32,400 
4 
20 
110% 
Major 
Depression 
54 bursts of 
three; 2s 
train; 8s ITI 
s 
50 
Duprat  et al.  9 3 
32,400 
4 
20 
110% 
Major 
Depression 
54 bursts of 
three; 2s 
train; 8s ITI 
s 
50 
George et al. 8 6 
54,000 
3 
9 
120% 
Suicidal 
ideation 
10 Hz; 
41 
Mc Girr et al.  3 4 
60,000 
10 
20 
120% 
Major 
Depression 
10 Hz; 5s 
train, 25s 
ITI 
27 

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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 (as 
proposed) is likely to be effective in enhancing cognition. This study is an important necessary 
step to characterize the safety, feasibility, efficacy and also durability of the proposed quality of 
life enhancing effect. 
 
Potential worsening of neuropsychiatric symptoms with TMS. Several studies have thus far 
demonstrated the feasibility of using rTMS in depression without any indicators of exacerbation 
of symptoms. The research team will work closely with participants to familiarize them with the 
nature of this experimental setup. All staff will also be trained to be alert to any emergence of 
neuropsychiatric symptoms and/or psychosocial impairment.  An ethical issue concerning the use 
of variable doses was considered at length; however, this concern is made easier by 
understanding that all participants will be given an active course of rTMS.  Thus, even the lowest 
doses have previously shown efficacy in treating depression and may improve cognition among 
healthy participants in the study 1. Additionally, all participants will be assessed throughout each 
day for emerging side effects.  
 
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" then 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. 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 colleagues90 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 study88 
Modirrousta et al. 94 
90,000 
3 
30 
110% 
Major 
Depression 
10 Hz; 5s 
train, 25s 
ITI 
18 
Williams et al. 85 
90,000 
5 
10 
90% 
Major 
Depression 
54 bursts of 
three; 2s 
train; 10s 
ITI 
7 
Schulze et al. 91 
120,00
0-
180,00
0 
10-15 
20-30 
120% 
Major 
Depression 
20 Hz; 2.5s 
train; 10s 
ITI 
65 

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looking at the MRI scans before and after 2 weeks of daily left prefrontal rTMS for depression. 
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.82,83 as well as 
Herremans et al.84 and Williams et al.85 additionally collected structural and functional imaging 
and demonstrated no adverse changes pre- to post-accelerated 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.81 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. 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 hours89. 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. 
 
Safety in case of pregnancy. This protocol will exclude pregnant and breastfeeding women 
(women of child bearing age will undergo a pregnancy test prior to enrollment). 
 
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.  
 
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. Therefore, pregnant females and those who may 
become pregnant (unwilling to follow study restrictions limiting chances of conception) will not be 
allowed to participate. Participants will be asked to lie still and awake for 30 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 

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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.  
 
Risks associated with the parabolic flight (ZERO-G Experience®).  
 
Injury or Illness. There is risk of injury or illness from sudden changes in gravity, altitude and/or 
turbulence, and could include physical contact of one’s body with the interior of the aircraft and 
other participants during weightlessness, as well as objects and liquids floating in the aircraft.  
There is the danger of property damage, personal injury or illness (minor or serious) and/or death 
resulting from weightlessness, the conduct of the ZERO-G Experience®, flight malfunction or 
mechanical failure and/or anything else related to the ZERO-G Experience®.  The risks of such 
Injuries & Damages are involved in such high adventure programs as the ZERO-G Experience® 
and subjects may have to exercise extra care for their own person and for others around them in 
the face of such hazards and that despite exercising such care Injuries & Damages may occur.  
 
Hazards and Risks Unforeseen and Foreseen.  This experience involves exposure to a variety of 
hazards and risks foreseen and unforeseen, which are inherent in or may result from each ZERO-
G Experience® and some of which cannot be eliminated without destroying the unique character 
of the ZERO-G Experience®. 
 
Lack of Medical Personnel. There may not be rescue or medical personnel on board the aircraft 
to address and treat the Injuries & Damages to which the participants (subjects and study team 
personnel) may be exposed to as a result of the ZERO-G Experience®.  However, Drs. George 
and Roberts will be aboard the flight and all Zero-G personnel are trained in basic life support and 
cardiopulmonary resuscitative equipment is available on the plane. 
 
Nausea or Vomiting due to Motion Discomfort. Motion discomfort can lead to nausea or vomiting. 
During the preflight training, the ZERO-G Experience® staff will provide some useful tips on in-
flight movements that will help participants to reduce their chance of motion discomfort. Unlike 
the astronauts in training, the flyers will experience 30 parabolas, which is enough to provide a 
pleasurable experience but not enough to cause motion discomfort. An often-made mistake by 
flyers is not eating prior to the flight.  ZERO-G provides a flight- friendly meal and encourages all 
participants to eat before and during the preflight training. Flying on an empty stomach is not 
recommended and can aid in creating motion discomfort. 
 
The Zero-G Experience Risks of Other Persons. Injuries & Damages can occur by natural causes 
or activities of other persons, other participants, the Mission Director and Coaches, assistants, 
the study team personnel, or other third parties, as a result of negligence, the conduct of the 
ZERO-G Experience® or because of other reasons.  
 
Decompression and Loss of Consciousness. While the probability of an explosive decompression 
on the ZERO-G aircraft is similar to any other Part-121 operation, commercial airplane operation, 
the implications of not getting oxygen into the body immediately could be significant including 
permanent brain damage or death. 
 

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Unknown Risk of Performing single pulse TMS during Parabolic Flight 
Subjects will be exposed to TMS during parabolic flight for at most 40 seconds.  However, as TMS 
has previously not been performed in a microgravity environment, all risks associated with TMS 
during parabolic flight cannot be known. Microgravity may result in unknown altered cerebral 
physiology which may alter the response to TMS and it is for this reason that study arm 3 is being 
performed.   
 
Nevertheless, the investigators have taken several precautions to reduce the chance that a 
subject would be exposed to any serious risks from combined TMS and parabolic flight: 
 
– First and foremost, only single pulse TMS will be performed.  As discussed above, the risk 
of seizure induction with TMS is related to the intensity, duration, frequency and rest 
interval of stimulation.  For study arm 3, only single pulse TMS will be performed such that 
TMS pulses will be spaced 1 second apart. 
 
– The intensity of TMS will be very low.  The intensity will be set to be at most just above the 
amount needed to cause a brief thumb twitch. 
 
– The subjects will be exposed to a small number of TMS pulses (at most 40 TMS pulses 
total during parabolic flight) 
 
– The duration of exposure to TMS during parabolic flight will be very brief.  During parabolic 
flight, resting motor threshold will be determined. This will take at most only approximately 
40 seconds total per subject. 
 
– Drs. George and Roberts will be present on the flight and in constant observation of the 
subjects.  At any sign of an adverse event requiring medical attention, they will notify Zero-
G flight personnel who will inform the pilot to end the parabolic flight maneuvers and return 
to the airport to get medical treatment for the subject.  911 will be called and emergency 
personnel will meet the team at the airport. 
 
 
 
14.0 Potential Benefits to Subjects or Others 
Establishing the dose-response curve for enhancing neurocognitive performance with accelerated 
rTMS could efficiently identify the most efficacious range of doses and thus significantly advance 
the capacity for successfully contending with the rigors of spaceflight for astronauts. Participants 
in this study may or may not individually experience neurocognitive enhancement.  While all doses 
are in the demonstrated therapeutically effective range, some doses may be more effective than 
others. Some people might consider parabolic flight (approximately $5000 value) as a potential 
benefit. 
 
15.0 Sharing of Results with Subjects  

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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 a summary of their clinical 
outcomes. 
 
 
16.0 Drugs or Devices (if applicable)  
We will use a MagVenture MagProsystem with a Cool-B65 coil to deliver TBS 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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Slack, K.J., et al., Risk of Behavioral and Psychiatric Conditions, in Human Health 
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Michael Faraday, L.P. Williams, Editor. 1965, Basic Books: New York. p. 531. 
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Roth, B.J., S. Momen, and R. Turner, Algorithm for the design of magnetic 
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Hallett, M., Transcranial magnetic stimulation: a primer. Neuron, 2007. 55(2): p. 187-
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