Assessing Cognitive Improvements, Brain Neuroplasticity and the Role of Genetic Factors After Aerobic Exercise in Sedentary Adults
Phase: NA
Conditions: Sedentary Behavior
Sponsor: University of Miami

Principal investigator: Joyce Gomes 
Protocol Title: Assessing Cognitive Improvements, Brain Neuroplasticity and the Role of Genetic 
Factors After Aerobic Exercise in Sedentary Adults 
IRB Number: 20180926 
NCT: NCT03804528 
Document Version Date: 2/22/2021 

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1) Protocol Title
Assessing Cognitive Improvements, Brain Neuroplasticity and the Role of Genetic Factors 
After Aerobic Exercise in Sedentary Adults
2) Objectives
The overall goal of the proposed study is to evaluate the effects of an 8-week aerobic exercise
program on cognition and determine the relationship between cognitive improvements and 
neuroplasticity. Limited to Option A (See Study Options section), we will also explore the effect 
modification of BDNF levels and BDNF allelic status, and APOE4 status on cognitive response after 
exercise.
Aim 1: Quantify improvements in cognitive performance after 8 weeks (150 min per 
week) of moderate intensity aerobic exercise in sedentary adults ≥ 55 years of age. H1: We 
hypothesize that we will see improvements in overall cognitive performance after exercise, and 
greater improvements in some of the cognitive domains (e.g., in executive function and processing 
speed, as opposed to memory or language).
Aim 2: Determine an association between changes in plasticity, aerobic capacity, and 
cognitive performance overall and by cognitive domain, after 8 weeks of moderate intensity 
aerobic exercise in sedentary adults ≥ 55 years of age. H2: We hypothesize that a greater response in 
the brain plasticity will be associated with greater improvements in cognitive performance overall and 
in executive function after exercise. 
Aim 3 (Option A): Explore the effect modification of BDNF (levels and Val66Met) and 
APOE e4 on cognitive response after exercise. H3: We hypothesize that individuals with greater levels 
of BDNF, being Val carriers or APOE e4carriers will have greater improvement in cognitive 
performance after exercise. 
3) Study Plan/Options
Due to challenges posed by the COVID-19 pandemic, social distancing practices, and aiming to
create a feasible scenario to continue the current study, we propose an additional option to safely adapt 
study methods to deliver the study in a home-based, fully remote manner. Importantly, this scenario also 
presents as an opportunity to collect meaningful data on our specific aims while translating this 
successful research program into a remote/home-based mode of delivery. A remote/home based option 
may also yield valuable preliminary data that will be relevant for planning future exercise studies in 
aging adults in the present “new normal”. 
Therefore, this research project will continue using a two-option design consisting of:

Option A: Current, IRB-approved, in-person methods pending appropriateness based on
current University of Miami recommendations and standard operating procedures as it relates
to the COVID-19 pandemic.

Option B: Remote option of current methods to maximize recruitment. This will be the only
option until the study team obtains approval to resume Option A (as per University’s safety
guidelines, as mentioned above).
4) Background
Individuals 65 and older will reach 30% of the global population over the next 30 years,
totaling approximately 2 billion people.1 Many will develop age-related cognitive decline, a condition 
for which there is no effective prevention or treatment. Therefore, the development of successful 
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strategies to support cognitive health and remediate age-related cognitive decline is critically needed. 
Exercise is effective at improving cognitive performance,2–4 but there is considerable inter-individual 
variability in cognitive outcomes after exercise. A greater understanding of this variability, the 
mechanisms, exercise dose and type is necessary to improve the effectiveness of exercise in prevention 
and remediation of age-related cognitive decline. 
Improvements in cognition after exercise are attributed to neuroplasticity, which is generally 
defined as the reorganization of the functional connections and structure of the nervous system to adapt 
to changes in experience and environment. Neuroplastic changes after exercise include: neurogenesis,5 
angiogenesis,6 synaptogenesis,7 and production of neurotrophic molecules such as brain derived 
neurotrophic factor (BDNF).8,9 All of these changes contribute to synaptic neuroplasticity that represents 
an increase in the efficacy of synaptic transmission in intracortical circuits related to cognitive function, 
learning and memory. Long-term potentiation (LTP)10 is a form of synaptic neuroplasticity defined as 
an increased synaptic efficacy following a direct electrical current stimulus of hippocampal neurons. 
LTP may explain synaptic activity implicated in improved cognition after exercise.11 
Transcranial magnetic stimulation (TMS) is a non-invasive device that applies a brief magnetic 
field close to the cranium to induce a very low amplitude current in the brain.12–14 TMS is FDA approved 
for the treatment of drug-resistant depression, neurosurgery mapping, migraines and has been used in 
research settings since 1984.13,14 TMS allows for an assessment of neuroplasticity that was modeled 
after the animal experiments of LTP synaptic plasticity in hippocampal neurons, but is performed 
through non-invasive stimulation of the motor cortex.15–17 In our pilot work, we established the 
feasibility and safety of TMS neuroplasticity measures in exercise and cognition research in middle-
aged adults,18 and demonstrated that TMS plasticity assessment can identify individuals who derived 
greater cognitive benefits in executive function after 4 weeks of aerobic exercise with no adverse 
events.18 However, TMS neuroplasticity has not been used to investigate exercise-mediated cognitive 
improvements in aging adults. Option A, we have been using TMS to gain insights into brain plasticity 
that may be relevant for exercise-induced cognitive improvements.
For Option B, we will use transcranial alternating current stimulation (tACS), which is one 
specific form of transcranial electrical stimulation (tES) combined with electroencephalography (EEG) 
to measure neuroplasticity that is similar to TMS neuroplasticity measurements. In both paradigms, the 
brain’s response to a mild electrical stimulus is recorded. With TMS, a mild electrical stimulus is 
delivered with electromagnetic induction, and the response is measured with electromyography surface 
electrodes. With tACS, a mild electrical current is delivered with small electrodes placed on the scalp, 
and measured with electromyography surface electrodes. These two methods are under the same 
neurophysiological principles, and thus, yield comparable data. 
The practical application of tACS is simple: a low intensity (1-2 mA) alternating electrical 
current is applied to the scalp to influence underlying cortical excitability, which is measured with non-
invasive surface EEG electrodes. Direct current stimulation is presently FDA-approved for extracranial 
use, and FDA applications for cranial stimulation for management of mood disorder and chronic pain 
are in progress. The stimulator used in this study is the STARSTIM®-Home system (Neuroelectrics, 
Inc), a tES home-base system that recently received FDA approval for the Investigational Device 
Exemption supplemental protocol in a study for tES to be used to treat patients with Major Depression 
Disorder (MDD) due to COVID-19 related restrictions. STARSTIM®-Home system is capable of 
recording EEG before, during and after tACS stimulation. 
Genetic factors may modify cognitive response to exercise. A common single nucleotide 
polymorphism of the BDNF gene (Val66Met) impairs activity-dependent release of BDNF.19 We and 
others have demonstrated that the Val66Met allele attenuates improvements in cognitive performance 
after exercise, both in young18,20 and old adults21. Furthermore, carriers of the apolipoprotein E (APOE) 
e4 alleles exhibit greater cognitive benefits after exercise through unknown mechanisms,22,23 although 
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they have greater risk for AD.24,25 The effects of genetic factors on response to exercise will only be 
evaluating in the Option A. 
Our prior work has demonstrated that the link between exercise and cognitive improvements in 
older adults is largely based on cardiovascular fitness.4 Therefore, we will quantify cognitive 
improvements following an aerobic exercise intervention in sedentary adults aged 55+ years, and 
determine the relationship between cognitive improvements and neuroplasticity. We will also explore 
the effect modification of BDNF levels and BDNF allelic status, and APOE4 status on cognitive 
response after exercise for Option A only.
This project is supported by a KL2 Career Development Grant from the Miami Clinical and 
Translational Research Institute at UM that is funded until December 2020. With the additional Option 
B of the study, our goal is to maximize the opportunities to gain valuable data that will be necessary for 
an R-type NIH submission in early 2021. Given the increasing use of ubiquitous mobile technologies in 
aging and older adults, especially in light of the COVID-19 pandemic, the addition of a remotely 
delivered clinical research program may facilitate recruitment, address barriers to participation, and 
accelerate the translation of our findings to a broader audience and clinical application. 
5) Inclusion and Exclusion Criteria
Subjects will be screened by collecting information to ensure the participant’s eligibility in the 
study. Screening will be considered visit/session #1. 
Inclusion Criteria:

age ≥ 55years

no clinically detectable cognitive impairment (MoCA score ≥ 24)

sedentary (defined as ‘low’ category using the International Physical Activity Questionnaire 
(IPAQ) short last 7 days).

basic computer skills (accessing an e-mail or using the internet).
Exclusion Criteria:

any unstable medical condition (i.e.: uncontrolled hypertension or uncontrolled diabetes)

medical contraindication to physical exercise

Contraindication to neuroplasticity assessment (TMS and tACS):
a.
Any current history of a psychiatric illness
b. No medication is an absolute exclusion from TMS and tACS. Medications will be reviewed 
by the Principal Investigator and a decision about inclusion will be made based on the 
following:
i. The subject’s past medical history, drug dose, history of recent medication changes 
or duration of treatment, and combination with other CNS active drugs.
c.
Any metal in the brain, skull or elsewhere unless approved by the responsible MD
d. Any medical devices (i.e. Cardiac pacemaker, deep brain stimulator, medication infusion 
pump, cochlear implant, vagal nerve stimulator)
e.
Intracranial lesion
f.
Substance abuse or dependence within the past six months
g. Exclusively for Option A: TMS Neuroplasticity assessment, as per the TMS Safety 
Guidelines.13
i. History of fainting spells of unknown or undetermined etiology that might constitute 
seizures
ii. History of seizures, diagnosis of epilepsy, history of abnormal (epileptiform) EEG 
or family history of treatment resistant epilepsy  
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
Pregnant women

Vulnerable populations such as prisoners

People unable to consent themselves

Subjects who, in the Investigator’s opinion might not be suitable for the study
6)Number of Subjects
This is not a multi-center study. We will recruit a total of 80 adults. We will use a multifaceted 
approach by recruiting participants from the Evelyn F. McKnight Brain Institute community memory 
clinic, and by advertising the study using flyers throughout the University of Miami Miller School of 
Medicine (UMMSM) and Coral Gables Campuses, the Miami community and participant registries. We 
will also recruit via online research database tool including the ResearchMatch.org. In addition, we will 
access University Research Informatics Data Environment (URIDE), and potential subjects will be 
identified and contacted via the Consent to Contact Initiative. 
With a significance level of 0.05, our sample of 80 individuals will provide 80% power to detect 
a Cohen effect size of 0.36 using a two-sided paired t-test for Aim 1, the effect size associated with 
improvements in executive function in a recent meta-analysis of healthy adults 55+,26 and an attrition of 
20%, not uncommon in exercise intervention trials. In addition, a sample of 80 participants will provide 
80% power to detect a correlation of 0.34 between the change in neuroplasticity and the change in 
cognitive performance. 
7)Study Timelines
The total time for a participant to complete this study will vary based on participant 
availability but is feasible to be completed within 10 weeks total (the intervention portion of the study 
is 8 weeks, with week 1 designated for pre-testing and week 10 for post-testing). Subjects will be 
recruited utilizing an open enrollment process over the course of 2 years. The following timeline will 
be utilized to guide and track intervention based on participant visit/session number and option 
selected as described in the following figure.
OPTION A: This option follows the current study timeline.
Visit #1: Screening process (may be partially done over a phone interview, but requires one visit in 
person to consent and collect physical measures, completed in week 1)

Information will be collected to ensure that the participant is eligible to participate in the study. 
Estimated total time: 40 minutes [20 minutes (in person or phone interview, Attached) and 20 
minutes in person]. These include:
OPTION A
OPTION B
Supervised in-person by a study member
*Currently not available
Remotely supervised by a study member 
*Adaptation of current methods meeting the 
practice of social distancing
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o
Demographic information and medications/drugs in use
o
Montreal Cognitive Assessment27 (MoCA) 
o
International Physical Activity Questionnaire (IPAQ)28 and self-report body mass index 
(BMI) measurement
o
TMS screening and description of the study and overview of inclusion/exclusion criteria 
(may be done via phone with corresponding documentation)
o
Medical History, Physical Ability Readiness questionnaire, Vital Signs Sheet. The decision 
to participate in the study will be made upon a review of the potential participant’s medical 
history, vital signs sheet and, physical ability readiness questionnaire and a systems review 
performed by a licensed Physical Therapist who is a member of the Laboratory. Based on the 
results of this evaluation, if the subject is found to require further medical clearance, they 
will be referred to their physician for further evaluation and the assessment of potential 
eligibility in the present study. 
o
Exercise Questionnaires (literacy, self-efficacy, barriers/motivators)
Visit #2 Pretest assessment- Part 1 (estimated time: 3 hours, completed in week 1, may be performed on 
same visit as Part 2)

Blood draw 

Gait and postural control assessment

Review of the adverse effects

TMS plasticity measures

Review adverse effects post TMS
Visit #3 Pretest assessment- Part 2 (estimated time: 1.5 hours, completed in week 1, may be performed 
at same visit as Part 1)

Cognitive test battery

Exercise testing

Exercise Questionnaires (literacy, self-efficacy, barriers/motivators)
Visits #4-15: Physical exercise Intervention-Moderate Intensity (estimated time per visit: 60 minutes 3 
times per week for weeks 2-5, total of 4 weeks of Moderate Intensity Exercise)

Assessment of vitals (blood pressure, heart rate)

60 minutes of aerobic exercise (includes 5 minute warm-up/5 minute cool-down) 

Re-assessment of vitals
Visits #16-27: Physical exercise Intervention-High Intensity (estimated time per visit: 60 minutes for 
weeks 6-9, total of 4 weeks of High Intensity Exercise)

Assessment of vitals (blood pressure, heart rate)

60 minutes of aerobic exercise (includes 5 minute warm-up/5 minute cool-down) 

Re-assessment of vitals
Visit #28 Posttest assessment- Part 1 (estimated time: 3 hours, maybe completed on same day as Part 2, 
completed in week 10)

Blood draw

Gait and postural control assessment

Review of the adverse effects

TMS plasticity
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
Review adverse effects post TMS
Visit #29 Posttest assessment- Part 2 (estimated time: 1.5 hours, may be completed on same day as Part 
1, completed in week 10)

Cognitive test battery

Exercise Testing

Exercise Questionnaires (literacy, self-efficacy, barriers/motivators)
Optional Test visits: 

An additional testing combining TMS and EEG during pre and post testing will be offered to 
participants. This testing is performed to gather information about direct measure of neuronal 
activity. This would add approximately two hours to each visit. 
Visit #4: TMS/EEG pretesting measure (estimated time: 2 hours)

Review of adverse events

Single pulse TMS plasticity measures

EEG recording

Review adverse effects post TMS
Visit #31: TMS/EEG post testing measure (estimated time: 2 hours)

Review of adverse events

Single pulse TMS plasticity measures

EEG recording

Review adverse effects post TMS
OPTION B: This option is an adaptation of the current methods that includes updating testing 
timeline to include a familiarization session. We updated our assessment to include outcome measures 
that are appropriate for remote delivery. We eliminated our genetic testing as it not possible to be 
performed remotely. In this option, in-person visits will be replaced with remote sessions.
Adaptations of the current timeline include: 
Session #1a: Screening process:

A virtual consenting process will be completed using zoom for healthcare and REDCap e-
consent as approved through the Clinical and Translational Science Institute (CTSI). The 
individual will be sent a REDCap link either through a secure email or through the chat 
feature of zoom. Once the individual opens the link, they will be asked to share their screen. 
At that time a trained study personnel will review the informed consent with the individual 
and answer any question the individual may have about the study. If the individual agrees to 
participate in the study, they will be asked to sign the e-consent form and provide the study 
personnel remote access of their web browser to also sign the consent form. The individual 
will then certify the information and submit the consent. At that time, they will have the 
option to download or print the completed consent form. A copy can be mailed at the 
individual’s request. Participants will then be mailed a study kit.
Session #1b: Familiarization session- Review items delivered to place of residence using secured 
zoom (estimated time: 1.5 hours, completed in week one, follow up session may be scheduled as 
needed)
o
Familiarize participant with all of the tools in the study kit. 
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o
The participant will learn to take their own blood pressure, oxygen saturation, put on the 
heart rate monitor, and proper safety and cleaning procedures.
o
Participants will learn various zoom functions such as sharing screens which will be later 
utilized in the study.
o
Participant will learn how to put on the EEG cap and how to operate the tablet. 
Session #2 and #28 Pretest and Post assessment Part 1 (estimated time: 2 hours, completed in week 
1)

TMS plasticity assessment will be replaced with the tACS/EEG plasticity assessment. 

TMS-EEG will not be offered for Option B of the study.
Session #29 Posttest assessment- Part 2 (estimated time: 2 hours, completed in week 1).

Return Study Kit. 
8) Study Endpoints  
Neuroplasticity Measures

TMS Plasticity Measures
o
An index of the duration of the TBS-induced modulation of corticospinal excitability (the time-
point at which the normalized mean MEP amplitude returns to baseline values) will be defined 
for each participant.

TMS-EEG
o
The TMS-EEG integration provides real-time information on cortical reactivity and 
connectivity. EEG provides exquisite temporal resolution, a direct measure of neuronal 
activity, and is capable of differentiating inhibitory and facilitatory effects in response to 
TMS. Contrasting the results of TMS on EEG before and after TBS provides information 
about cortical plasticity (at the site of stimulation) and resulting network dynamic 
adaptations.
o
Brain functional connectivity and inter-regional coordination can be directly estimated from 
EEG’s. Spontaneously occurring potentials across EEG channels will be detected prior and 
following stimulation using already developed event detection algorithms. Measurements 
following single-pulse TMS provide insights on cortical excitability. The EEG cap will 
be placed at the beginning of the session and will remain on for the duration of the visit.

tACS/EEG Plasticity
o
An index of change in the tACS-induced modulation of cortical excitability will be defined for 
each participant. Brain functional connectivity and inter-regional coordination can be directly 
estimated from EEG’s. Spontaneously occurring potentials across EEG channels will be 
detected prior to and following stimulation using already developed event detection 
algorithms.
Cognitive performance

Cognitive performance will be assessed using a neuropsychological test battery. Executive 
function will be assessed using the Digit Span subtest of the Wechsler Adult Intelligence Scale 
– Fourth30, processing speed will be assessed using the Trail-Making Test Part B31and the Stroop 
color-word test29, global cognition will be assessed with the repeatable neuropsychological 
battery (RBANS)30; and the Delis-Kaplan Executive Function System (DKEFS)31 will test for 
language.
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
Option B: the same cognitive battery, except for the Stroop color-word test, and with 
the addition of a TestMyBrain.org32 battery of Digit Symbol Matching, Simple and 
Choice Reaction Time, and Gradual Onset Continuous Performance Test will be used 
via a secured Zoom Platform. 
Gait and postural control

The Timed Up-and-Go (TUG) test will be completed. Four, 90-second trials of walking will then 
be completed to assess gait under normal and cognitive dual task conditions. Standing postural 
control will be assessed by measuring postural sway with mobile sensors during 2 repetitions 
each of 30-second trials of standing—two with eyes open, two with eyes closed, and two while 
performing the serial subtraction cognitive task.

Option B: The Timed Up-and-Go (TUG) test will be completed and supervised via a 
secured Zoom Platform.
Genetic Testing

Blood samples will be collected for BDNF levels and DNA to assess brain-derived 
neurotrophic factor (BDNF) Val66Met polymorphism and the presence of 
apolipoprotein-E (APOE) e4 allele. We will store blood samples for future examination 
of other potential genetic, epigenetic, metabolic or pro-inflammatory markers.
Aerobic Capacity

The Incremental Shuttle Walking Test (ISWT) will be performed to determine maximal walking 
velocity and walk distance. These values will be used to predict VO2 peak changes over time as 
a measure of aerobic capacity. The test will be used to dose the aerobic exercise intensity. 
Additionally, changes in VO2 peak will assessed for relationship with neuroplasticity and 
cognitive changes. The participants will be closely monitored (Heart rate, Blood pressure, rate 
of perceived effort) prior, during and after the test.

Option B: We will adapt our exercise assessment to a submaximal aerobic capacity assessment 
using the 1-minute Sit-to-Stand Test (1-MSTST)33 which can be completed in the participant’s 
home. The 1-MSTST will be performed to determine maximal repetitions completed in one 
minute without using upper limbs. These values will be used to predict changes in aerobic 
capacity over time. The test is submaximal and will be used to dose the aerobic exercise intensity. 
Additionally, changes in aerobic capacity will be assessed for any relationship with 
neuroplasticity and cognitive changes. The participants will be closely monitored (heart rate, 
blood pressure, rate of perceived effort, and oxygen saturation) prior to, during and after the test.
9)Procedures Involved* 
Study Design
This is an investigator-initiated open label study in neurologically healthy sedentary adults.
Participants will undergo a total of 29 or 31 sessions, including the screening session, three to four 
pretest (baseline) assessments, 24 aerobic exercise sessions and three to four post-test assessments. For 
option A, assessments will take place at the Neuromotor Plasticity Lab located at Lois Pope Life 
Center located at 1095 14th Terrace, 1st Floor, Miami, FL 33136 and aerobic exercise visit will take 
place at either the UMMSM Medical Wellness Center or the UM Coral Gables Wellness Center. For 
option B, assessments and exercise sessions will take place in the participant home as they are 
monitored by a trained study member.  An illustration of the experimental design is provided below:
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Methods:
Subjects will participate in the Option A pending appropriateness based on current University of 
Miami recommendations and standard operating procedures as it relates to the COVID-19 pandemic. 
Given the COVID-19 pandemic, it is worth of note that potential participants may remain less 
enthusiastic about in-person procedures for an undetermined length of time. Thus, even in the event that 
the study team obtains approval to resume activities as per Option A based on University guidelines, we 
would like to continue to offer Option B according to participant preference. All testing procedures 
described for the Option A will be adapted (as feasible) for the Option B. Testing procedures that differ 
for the Option B are described and noted in the Option B methods. 
OPTION A METHODS
TMS Plasticity 
Subjects will come in for a total of 2 plasticity visits (pre and post training). We will measure 
plasticity in the motor cortex of the dominant hand. 
Subjects will be set up in a chair with EMG electrodes placed on the first dorsal interosseus (FDI) 
on the dominant hand to measure motor threshold over in the corresponding (contralateral) motor 
cortex (M1). The motor threshold serves as the basis for the following TMS-measures over the motor 
cortex. When administering TMS, the figure of eight coil will be placed tangentially to the scalp with 
the handle pointing posterior for all stimulations. We will proceed with determining motor threshold 
and conduct TMS (single pulse TMS and TBS) over the dominant motor cortex. After removing the 
EMG equipment from the subject, a post TMS safety evaluation will be conducted.
During each of the TMS/plasticity visits, the following procedures will take place:
Single Pulse TMS
TMS will be delivered using a biphasic figure of eight coil. This stimulation phase will consist 
of 3 batches of 30 TMS pulses delivered every 5-7 seconds at 120% of resting motor threshold (RMT) 
prior to TBS stimulation as a baseline. RMT will be defined as the minimum stimulus intensity that 
produced a small MEP (about 50 μV in 50% of 10 trials) during relaxation of the tested muscles. 
After TBS has been administered, batches of single pulse TMS will be administered at timed intervals 
for 40 minutes over the motor cortex.
TBS
For this study subjects will receive intermittent Theta Burst Stimulation (iTBS) over the motor 
cortex.   iTBS consists of bursts of 3 pulses at 50 Hz repeated at intervals of 200ms for a total of 2 
seconds (1 train) each train will be repeated every 10 seconds for 20 times for a total of 600 stimuli. 
Screening
Pre-test
High 
intensity 
exercise
(4 weeks)
Moderate 
intensity 
exercise
(4 weeks) 
Post-test
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After TBS is applied to the motor cortex in an intermittent fashion (iTBS), TMS-induced potentials 
show increased amplitude for a period of 20-30 minutes.  
Stimulation intensity will be delivered at 80% of active MT (AMT). AMT will be defined as 
the minimum stimulus intensity that produces a small MEP (about 200 μV in 50% of 10 trials) during 
isometric contraction of the tested muscles, at about 20% of maximum voluntary contraction.
Transcranial Magnetic Stimulation (TMS) and EEG
EEG provides exquisite temporal resolution, is a direct measure of neuronal activity, and can be 
correlated with cognitive performance, and is capable of differentiating inhibitory and faciliatory effects 
in response to TMS. Resting EEG will be compared with neuropsychological testing and imaging data. 
Event related potentials (ERPs) will be measured by EEG during TMS stimulation to assess for 
electrophysiologic response during testing. A TMS compatible EEG system would be set up and left in 
place for the duration of the visit. The TMS-EEG integration provides real-time information on central 
physiologic responses such as cortical reactivity and connectivity. 
Subjects will be set up in a chair with EMG electrodes placed on the right hand for collection of 
motor evoked potentials (MEPs) during stimulation over the left primary motor cortex (M1). The EMG 
electrodes will remain in place throughout the TMS session. In order to keep the brain target constant 
throughout the stimulation session, we will use a frameless stereotactic neuronavigation system.
Baseline EEG Measures:
A 64 channel, TMS compatible EEG system will be set up at the beginning of the visit. Resting 
state EEG measures will be collected that includes a 3.5-min recording with eyes opened followed by 
a 3.5-min recording with eyes closed.
TMS with EEG measures:
Assessment of Motor Threshold:
Resting motor threshold (RMT) will be determined by applying single pulses of TMS to M1. RMT 
will be defined as the minimum stimulus intensity that produces a motor evoked potential (MEP) of at 
least 50 µV and up to 1 mv in the hand muscles in at least 5 of 10 trials. MEPs will be measured by 
electromyography (EMG) during relaxation of the tested muscles. Determination of RMT will be used 
to guide intensity to be used for single and paired pulses as described below. The optimal position for 
obtaining MEPs will be identified at the beginning of the assessment of RMT. 
TMS Assessments of Intracortical Inhibition and Facilitation Using Single TMS Pulses:
Cortical reactivity will be assessed by applying paired and single pulses of TMS to the cortex and 
intracortical inhibition and facilitation will be assessed using a paired pulse technique. Paired pulse 
techniques measure the influence of a sub- or supra-threshold conditioning TMS pulse to M1 or DLPFC 
on a supra-threshold TMS pulse to M1 or DLPFC. TMS intensity will be set at 120% of each 
individual’s resting motor threshold for reactivity measures with single pulses and sub- and supra-
threshold TMS pulses will be set to 80% and 120%, respectively for paired pulse measures. Cortical 
reactivity will be assessed via EEG measures (TMS-evoked potentials - TEPs) and cortico-motor 
reactivity will be assessed at M1 by measuring peak-to-peak amplitude of MEPs (motor-evoked 
potentials as measured by EMG) induced in the hand muscles in response to the TMS. 
Neuropsychological Test Battery
Participants will undergo 2 neuropsychological test visits (pre-test and post-test) to assess the 
influence of physical exercise on cognitive performance. This assessment will last approximately 1.5 
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hour.

Visuomotor processing speed and cognitive flexibility/task switching: This will be assessed 
using the Trail Making Test (TMT),34,35  is a two-part test (parts A and B). Part A consists of a 
series of circles with the numbers 1- 25 scattered on a sheet of paper. Individuals are asked to 
draw a line from one circle to the next following the sequential order of the numbers until all the 
encircled numbers are connected. They are asked to complete each of these tasks as quickly as 
they can without making mistakes. Part B consists of encircled numbers (1-13) and letters (A-
L). Individuals are asked to connect the circles alternating between numbers and letters as quickly 
as they can without making mistakes. Each part is scored according to the number of errors made 
and the time (in seconds) to completion.  

Response inhibition, mental flexibility, and attentional control: This will be assessed using the 
Stroop Color Word Test29. The test consists of three components, each component consisting 
of 100 items, presented in five columns.  On the first portion, participants are asked to read words 
printed in black ink (RED/GREEN/BLUE).  On the second portion, participants are asked to 
identify the color of ink in which a series of Xs are printed.  On the final section, participants are 
asked to identify the color of ink the color words are printed in.  Participants are asked to 
complete each component as quickly and as accurately as possible.  Each section is scored based 
on number of items completed accurately within a 45 second period.  

Attention and working memory: The Digit Span subtest of the Wechsler Adult Intelligence 
Scale - Fourth edition36 will be used to asses this construct. This measure consists of three parts; 
namely, Digit Span Forward (DSF), Digit Span Backward (DSB), and Digit Span Sequencing 
(DSS). Participants are read increasingly longer lists of numbers (starting with 2 digits and 
increasing in difficulty up to 9 digits) and asked to repeat them verbatim, in backward order, and 
sequentially (i.e., from smallest to largest) on DSF, DSB and DSS respectively. Each portion is 
discontinued when participants cannot accurately repeat 2 consecutive trials of equal difficulty. 

Global Cognition: The Repeatable Battery for the Assessment Neuropsychological Status 
(RBANS) Update30 is a brief battery used to measure an individual’s cognitive state. The battery 
is 
composed 
of 
five 
cognitive 
domains 
including: 
Immediate 
memory, 
Visuospatial/Constructional, Language, Attention, and Delayed Memory. The whole assessment 
is completed in approximately 25 minutes.
Immediate memory is assessed through a list learning task of 10 words and a short story. 
Participants are asked to repeat a list of 10 words over a series of four learning trials. The 
score is dependent on the number of correctly recalled words over the four trials. 
Participants are then read a short story and asked to recall as many details from the story 
that they can remember over 2 trials. The score is based on the number of correct key 
details the participant can recall. 
Visuospatial/Constructional is assessed using a figure copy and line orientation task. 
Participants are asked to copy a figure as accurately as they can while being timed. The 
score is based solely on the exactness of the copy of the figure. Participants are then shown 
13 lines that are numbered 1 to 13 and are arranged in a fan shape that are 15 degrees apart 
from each other at the top of a page. Participants are shown a series of two lines, isolated 
from the fan shape, and asked to identify what numbers they correspond to on the fan 
shape. Participants are awarded one point for each time they correctly match the lines. 
Language is assessed through picture naming and semantic fluency. Participants are asked 
to identify the name of ten different figures. The score is based on the number of figures 
the participant names correctly. Participants are then asked to name as many items from a 
specific category as they can for one minute. One point is awarded for each unique 
response. 
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Attention is composed of a digit span and coding task. Participants are read a series of 
numbers increasing in length in which they are asked to repeat. Participants are awarded 
one point for each series of number they correctly recall. Coding is comprised of a key of 
nine symbols that are associated with a number one through nine. The participant is then 
asked to use the key to assign numbers to a list of matching symbols below, where the 
numbers are missing.  One point is given for each symbol correctly assigned to a number 
based on the key. 
Delayed memory is measured by recalling the ten words and short story from the 
immediate memory task, recalling the figure copied during the visual spatial 
constructional task, and identifying the ten words from the list learning task among twenty 
other words. 

Verbal Fluency: The Verbal Fluency subtest of the Delis-Kaplan Executive Function 
System (D-KEFS)31 will be used to assess verbal fluency. This subtest is comprised of letter 
fluency, category fluency, and category switching. During the letter fluency portion, 
participants are asked to name as many words as they can that begin with a certain letter of 
the alphabet within one minute. There are three trials with three different letters and the 
participant is awarded one point for each unique, appropriate response. For Category fluency, 
participants are asked to name as many items as they can that correspond to the category 
provided within one minute. Participants complete two trials with two different categories 
and are awarded one point for each unique, appropriate response. During the category 
switching the participant is asked to switch between naming items from two different 
categories within one minute. Participants are awarded one point for each unique appropriate 
response given for each category as well as each time they correctly switch between 
categories.  
Postural Control assessment
Participants will undergo a functional evaluation of to assess the influence of physical exercise on 
postural control and gait. The duration of these assessments is approximately 0.5 hours.

For the functional assessment, participants will be outfitted with wireless accelerometers 
(Mobility Lab, Seattle, WA) secured with Velcro straps to the wrists, ankles, sternum and 
lower back. The Timed Up-and-Go test will be completed, which is a valid and reliable test of 
mobility37 that requires the subject to stand from a chair, walk 3 meters, turn and sit back down. 
Four, 90-second trials of walking will then be completed along a 35x4m indoor hallway to 
assess gait under normal and cognitive dual task conditions. The cognitive dual task will be 
verbalized serial subtractions of 7 from a random 3-digit number. Finally, standing postural 
control will be assessed by measuring postural sway (i.e., center-of-pressure fluctuations) 
during 6, 30-second trials of standing—two with eyes open, two with eyes closed, and two 
while performing the serial subtraction cognitive task.  
Exercise Testing
A test of maximal aerobic capacity will be obtained using the Incremental Shuttle Walking Test38 
and prediction equations to determine VO2 peak changes over time. Dr. Lawrence Cahalin, PT, PhD 
Professor of Physical Therapy and a leader in cardiorespiratory fitness testing and training, will serve as 
a consultant on this proposal and will oversee the development and implementation of the exercise 
testing and training, and guide the analysis and interpretation of the results.
Blood Collection 
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Items included in the “Study Kit’
Blood samples will be collected for BDNF levels and DNA to assess brain-derived neurotrophic 
factor (BDNF) Val66Met polymorphism and the presence of apolipoprotein-E (APOE) e4 allele. We 
will store blood samples for future examination of other potential genetic, epigenetic, metabolic or pro-
inflammatory markers. DNA will be extracted by standard methodology and the prepIT L2P reagent.39 
The SNPs of the BDNF gene (rs6265, rs429358 and rs7412) and APOE4 will be analyzed using TaqMan 
genotyping assays. Blood samples will be delivered to the lab on ice within 2 hours of collection, 
centrifuged and stored at -80 °C until processing.
Physical exercise Intervention
The physical exercise intervention will be administered at the University of Miami Miller School 
of Medicine Wellness Center. Participants will be given a time slot, which will be preferred for the 
duration of the study but flexibility with the intervention time frame will be provided. Participants will be 
supervised by a member of the study team during all times and all sessions. Each participant will engage 
in 60 minute daily sessions delivered 3 times/week for 8 consecutive weeks (a total of 24 sessions). 
Participants will be fitted with a heart rate monitor and will be instructed to walk (or trot) to 
maintain 55-64% of maximal heart rate (determined by exercise test) for the first 4-weeks of exercise or 
to maintain 65-90% of maximal heart rate (determined by exercise test)  for the second 4-weeks of exercise 
during each session. Participants will be supervised at all times 
during the exercise sessions, and will be given the opportunity to 
rest if they indicate that they are uncomfortable. During all 
exercise sessions a research personnel who is trained in Basic Life 
Support or Cardiopulmonary Resuscitation (CPR) and First Aid 
certified will be present on site. During this session, heart rate and 
participant’s exerted effort (measured with the Borg scale40 will 
be monitored prior to the session, every 10 minutes of the 50 
minute session and 5 minutes after the end of the session. The 
Borg scale is a numerical scale where 6 represents rest (no effort), 
and 20 represents maximal effort (see photo on the right). 
A PT will be available by phone if subjects are reporting 
excessive discomfort in need of evaluation, and an appropriate 
referral will be made as necessary. In the event of an absence, 
participants will have the opportunity to make up the missed 
session. 
Exercise Questionnaires:
We will perform the Lifetime Physical Activity Questionnaire, Exercise Self-Efficacy, and 
Barriers and Motivators to Exercise questionnaires. 
OPTION B METHODS 
Study Kit
Participants will receive a study kit including items 
that have been previously sanitized using alcohol-based 
solution greater than 70% will be shipped to the participant’s 
home. The study kit will include: 
1. a sphygmomanometer (OMRON BP7350, Omron 
Healthcare, Inc.)
2. a heart rate monitor (Polar H10, Polar Electro Inc., Lake 
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Success, NY, USA)
3. a pulse oximeter (Diagnostix™ 2100 Fingertip Pulse Oximeter)
4. a physical activity monitor (Actigraph GT9X-BT Link, ActiGraph LLC, Pensacola, FL, USA)
5. a tape measure, masking tape, alcohol prep pads Isopropyl Alcohol 70%
6. a non-invasive brain stimulation/EEG hybrid STARSTIM®-Home (Neuroelectrics, USA) that 
includes a tablet.
7. a pre-paid return shipping label
When the study kit arrives, before beginning any assessments or intervention, we will schedule 
a remote meeting utilizing zoom for healthcare, to familiarize the participant with all of the tools in the 
study kit. The participant will learn to take their own blood pressure, oxygen saturation, put on the heart 
rate monitor, put on the EEG cap, and proper safety and cleaning procedures. If needed, we may schedule 
multiple meetings to ensure the participant is properly familiarized with all of the materials in the study 
kit. 
Adaptations to Our Testing Procedures 
tACS Plasticity
Subjects will come in for a total of 2 plasticity visits (pre and post training). 
Subjects will be set up in a chair and will don the STARSTIM®-Home (Neuroelectrics, USA). 
The practical application of tACS is simple: a low intensity (1-2 mA) alternating electrical current is 
applied to the scalp to influence underlying cortical excitability, which is measured with non-invasive 
surface EEG electrodes. The study investigator will remotely supervise the session utilizing a tablet and 
zoom for healthcare that comprises the STARSTIM®-Home system (Neuroelectrics, Inc). The 
neuroplasticity assessment will follow the current guidelines for the safe application of 
neurophysiological 
measures 
recommended 
by 
the 
International 
Federation 
of 
Clinical 
Neurophysiology.13,14
Following the familiarization session, the study investigator will remotely supervise the session 
utilizing a tablet that comprises the STARSTIM®-Home system. TACS will be performed over two sites, 
approximately covering the scalp over the frontal lobe, and the test will last for approximately 30 
minutes. STARSTIM®-Home is capable of recording EEG before, during and after tACS stimulation. 
The STARSTIM®-Home system can only be used at pre-specified times, determined and approved by 
the study investigator. In accordance with the safe application of neurophysiological measures 
recommended by the International Federation of Clinical Neurophysiology, we will collect and monitor 
adverse events. 
During each of the tACS plasticity visits, the following procedures will take place:
Baseline Resting EEG
Resting EEG recordings will take place for 2 minutes with participant’s eyes open and for 2 
minutes with participant’s eyes closed while the participant is seated. 
tACS
A low intensity (1-2 mA) alternating current will be applied to the scalp approximately over the 
frontal lobe for 2 minutes via the STARTSTIM®-Home system (Neuroelectrics, Inc) as directed by the 
study investigator while the participant is seated. 
 
tACS Plasticity EEG
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Resting EEG recordings will take place for 2 minutes with participant’s eyes open and for 2 
minutes with participant’s eyes closed after receiving tACS stimulation. A change in baseline resting 
EEG potentials will be compared to post tACS-EEG potentials to determine neuroplasticity.
Neuropsychological Test Battery
This assessment will be performed in the same manner as previously described for Option A, 
except all testing will be delivered via a secured Zoom for Healthcare Platform. The Stroop Color-
word test will be omitted from Option B. Additionally, Option B will use an additional battery from 
TestMyBrain.org.32

TestMyBrain.org: As there are some tests that are not appropriately delivered via zoom, 
a few additional tests will be utilized for option. A TestMyBrain (TMB) link will be sent 
to participants during their assessment visit, and the investigator will guide them through 
the test. Overall this portion of the test will require 10 minutes.
o
Processing Speed is assessed using the TMB Digit Symbol Matching. Participants 
are shown symbols that match a corresponding number. Participants must quickly 
and accurately select the appropriate the number. They have 90 seconds to 
complete as many symbols as possible. 
o
Basic psychomotor response speed will be measured with TMB Simple Reaction 
Time. Participants will be shown either “GO!” or “WAIT!”. Participants must 
press the space bar on the computer as rapidly as possible, only when the word 
“GO!” is presented. 
o
TMB Choice Reaction Time will be used to measure processing speed, response 
inhibition, and attention. Participants are shown 3 boxes with arrows inside of 
them. Two boxes have the same color, and one is different (odd color). 
Participants must rapidly select the direction of the arrow in the odd colored box. 
o
TMB Gradual Onset Continuous Performance Test assesses sustained attention, 
response inhibition, and cognitive control. Participants asked to press a key when 
a city picture appears, and to not press when a mountain image appears. The 
images rapidly transition from one to the next with mountains appearing only 10-
20% of the time. 
Postural Control assessment
We will continue to use the Timed Up-and-Go as a measure of functional mobility in the same 
manner previously described. The participant will be instructed to set-up the chair and measure a 3-
meter space with the provided tape measure and tape to complete this assessment in their home and the 
investigator will guide the timed up-and-go procedure and record their performance. 
Exercise Testing
We will adapt our exercise assessment to a submaximal aerobic capacity assessment using the 1-
min sit-to-stand test41 which can be completed in the participant’s home. Participants will be asked to 
join a zoom meeting where they will be asked to confirm their current geographical location and phone 
number. Participants will put on the heart rate monitor (Polar) and activity monitor (Actigraph). After 
this, vitals will be taken after 3-5 minutes of seated rest. Blood pressure, heart rate, and oxygen saturation 
will be documented by the investigator, and participants will complete a daily exercise questionnaire. 
The participant will then be asked to stand up and sit down from a sturdy chair for one-minute while 
being monitored by a trained study member. The number of sit-to-stands performed in 1 minute will be 
recorded. The participant’s heart rate will be monitored continuously throughout the test and heart rate 
and blood pressure will be taken and documented immediately after the assessment. Heart rate and blood 
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pressure will be taken again after 5 minutes of seated rest and will be continued to monitored until the 
participant has returned within 20% of their baseline measurement.
Exercise Questionnaires
Questionnaires and surveys will be completed by the participant using a REDCap link sent via a 
secured email. We are expanding our questionnaire to include a battery of structured surveys used to 
assess the 7 ‘pillars’ of Brain Health (cognitive function, physical exercise, nutrition, comprehensive 
health, socialization, sleep, and vital plan [perceived meaning in life]), developed by the Barcelona Brain 
Health Initiative.42
Adaptation of Our Physical exercise Intervention
We have modified our 2-month, 3x/week in-person exercise intervention to be safely delivered 
as a home-based exercise program. The study team will setup a zoom call to discuss the plan the exercise 
delivery modes, which will be individually planned, based on each participant’s available resources and 
personal situations. For instance, participants whom have access to aerobic exercise equipment at home 
(treadmill, elliptical, or stationary bike) will be able to use them in the same manner as option A with a 
remote investigator monitoring and instructing. Individuals who do not have exercise equipment at home 
will be given a routine of exercises that do not require any equipment, and can be done safely in their 
homes. The body-weight exercise program was developed by a group of 4 physical therapists (one who 
is the Principal Investigator of the study) who are part of this study team. Modifications for each exercise 
will be tailored individually based on participant’s ability levels and safety. Regardless of mode of 
exercise, the participant will warm up for 5 minutes, have 40 minutes of exercise, and 5 minutes to cool 
down. Mandatory rest and water breaks will be incorporated into the exercise session every 8 minutes 
for two minutes each, for a total of 10 minutes of rest breaks during the exercise session. The following 
figure shows a sample of exercise types for both scenarios. 
Each session, participants will join a zoom meeting with a trained study personnel to ensure 
safety and guide the participant through the exercise session. The participant will be asked to put on the 
heart rate monitor and provide their geographical location and phone number as per our safety of exercise 
Individuals who have access to exercise equipment at home (treadmill, stationary
bike, elliptical)
Scenario 01
Personal Equipment
Scenario 02
No Equipment
Individuals who do not have equipment at home will be given a sequence of free
weight and machine exercise, for example with marching in place, and body
weight exercise.
Marching in place
Walking and running on treadmill
Elliptical
Stationary bike
Stationary recumbent bike
Sit to stand
Whole body
Jumping jacks
Squat
Wall push-ups
Exercise parameters for both scenarios: Moderate to vigorous (5 minutes warm-up, 40 minutes of continuous exercise in the target zone, and a 5-
minute cool-down); RPE 11-13 (somewhat hard) weeks 1-4, and 13-15 (hard) weeks 5-8; Target Heart Rate 54-65% weeks 1-4, 65-89% weeks 5-8
*Other exercise options and modifications for each exercise will be made available based on participant’s ability and safety.
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plan. Heart rate, oxygen saturation, and blood pressure will be documented by study personnel after 5 
minutes of seated rest.  Participants will then complete the daily exercise questionnaire to ensure it is 
safe to begin exercising. The participant will have continuous heart rate monitoring throughout the 
intervention sessions using the heart rate monitor (Polar) and activity monitor CentrePoint Software 
(Actigraph, USA) permitting investigators the ability to monitor patients remotely and in near real-time. 
Participants heart rate and rate of perceived exertion at will be recorded at frequent intervals. Mandatory 
rest and water breaks will be implemented to ensure proper hydration. 
Exercises will follow a standard format to ensure safety and adherence to study goals (See 
following table). All participants will complete a guided 5-minute warm-up. The intervention will be 
structured in five, 10-minute timed blocks consisting of eight minutes of exercise and two minutes of 
rest. For the body-weight group, participants will be shown two exercises. They will perform exercise 
“A” for one minute then exercise “B” for one minute. The participant will then repeat A-B sequence 
three more times for a total of 8 minutes of exercise. The participant will then take a rest and water break 
for two minutes to complete block one. The participant will complete five blocks using this format, 
completing a total of 10 unique exercises. The participant will then be guided through a cool down where 
they will slowly decrease exercise vigor to bring their heart rate down to baseline levels. Following 
exercise, the participant will be asked to take their blood pressure, heart rate and oxygen saturation and 
will monitored until the participant has returned within 20% of their baseline measurement. 
10) Data and Specimen Banking*
Data will be stored indefinitely at the Lois Pope Life Center located at 1095 14th Terrace, 1st 
Floor, Miami, FL 33136. Data will be stored in a secured area within a locked cabinet accessed by 
only IRB-approved personnel.
For Option A, samples will be stored indefinitely at the John P. Hussman Institute for Human 
Genomics, University of Miami located at 1501 NW 10th Ave, Miami, FL 33136. Tubes will be 
labeled and managed according to the Laboratory Information System. Sample log-in and tracking 
will assign a unique sample ID to each specimen. The samples will be stored in a -80 freezer. Samples 
will be accessed only by IRB-approved personnel and PI designees. The release of data or samples 
will need prior authorization by the PI.
11) Data Management
Time
Personal Equipment Group
Time
Body Weight (No Equipment) Group
Minutes
 0:00-4:59
Warm-up 5 Minutes
Minutes 
0:00-4:59
Warm-up 5 Minutes
Total Time=10 minutes
Total Time=10 minutes
Work= 8 minutes
Work= 8 minutes
Minutes
 5:00-14:59
Block 1 Steady 
State Aerobic
Rest and Water= 2 minutes
Minutes 
5:00-14:59
Block 1 Body 
Weight A/B
Rest and Water= 2 minutes
Total Time=10 minutes
Total Time=10 minutes
Work= 8 minutes
Work= 8 minutes
Minutes 
15:00-24:59
Block 2 Steady 
State Aerobic
Rest and Water= 2 minutes
Minutes 
15:00-24:59
Block 2 Body 
Weight C/D
Rest and Water= 2 minutes
Total Time=10 minutes
Total Time=10 minutes
Work= 8 minutes
Work= 8 minutes
Minutes 
25:00-34:59
Block 3 Steady 
State Aerobic
Rest and Water= 2 minutes
Minutes 
25:00-34:59
Block 3 Body 
Weight E/F
Rest and Water= 2 minutes
Total Time=10 minutes
Total Time=10 minutes
Work= 8 minutes
Work= 8 minutes
Minutes 
35:00-44:59
Block 4 Steady 
State Aerobic
Rest and Water= 2 minutes
Minutes 
35:00-44:59
Block 4 Body 
Weight G/H
Rest and Water= 2 minutes
Total Time=10 minutes
Total Time=10 minutes
Work= 8 minutes
Work= 8 minutes
Minutes 
45:00-54:59
Block 5 Steady 
State Aerobic
Rest and Water= 2 minutes
Minutes 
45:00-54:59
Block 5 Body 
Weight I/J
Rest and Water= 2 minutes
Minutes 
55:00-60:00
Cool-down 5 Minutes
Minutes 
55:00-60:00
Cool-down 5 Minutes
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Data Monitoring
Data will be stored in accordance with University Policies. It will be kept in a locked cabinet, 
and the only people who will have access to this data are personnel approved by the IRB to work on 
this study. Data will be stored indefinitely at the Lois Pope Life Center located at 1095 14th Terrace, 
1st Floor, Miami, FL 33136 and at 5915 Ponce de Leon Blvd, 5th Floor, Coral Gables, FL 33146. 
Data will also be stored using approved digital storage such as Box, Microsoft OneDrive, the data 
capturing system REDCap. The release of data or samples (only collected from in person) will need 
prior authorization by the PI. Data collection will be halted if the participant requests it. If this occurs, 
subject will be taken off the study and the reason of discontinuation will be documented.
Data Analysis:
With a significance level of 0.05, our sample of 80 individuals will provide 80% power to 
detect a Cohen effect size of 0.36 using a two-sided paired t-test for Aim 1, the effect size associated 
with improvements in executive function in a recent meta-analysis of healthy adults 55+,42 and an 
attrition of 20%, not uncommon in exercise intervention trials. In addition, a sample of 80 participants 
will provide 80% power to detect a correlation of 0.34 between the change in TMS neuroplasticity 
and the change in cognitive performance for Aim 2, and 80% power to detect an R-Squared of 0.11 
attributed to a genetic modification in the change in cognitive performance using an F-Test for Aim 
3 (Option A only). We expect an overall improvement in cognitive performance after aerobic 
exercise. Most robust improvements are expected in executive function as previously shown in 
elderly, but also in other cognitive domains such as processing speed and attention. 11
Baseline characteristics will be summarized as means ± standard deviation or medians 
(interquartile ranges) for continuous variables and as frequency (%) for categorical variables. 
Normality for the distributions of continuous variables will be visually assessed and statistically 
tested. If the normality assumption is questionable, Box-Cox transformation will be used to reduce the 
skewness in the indicated analyses or non-parametric tests will be used. All statistical tests will be 
conducted against a 2-sided alternative hypothesis, employing a significance level of 0.05.
In the univariate analysis, we will compare the cognitive performance (overall and by 
domain) before and after exercise, using paired t-test to test for Specific Aim 1. For Specific Aim 2, 
we will examine the relationship between the change in TMS neuroplasticity and the change in 
cognitive performance using Pearson product-moment correlation coefficient. For Specific Aim 3, 
we will compare mean change in cognitive performance across subgroups by genotype using F- test. 
In the multivariable analyses, we will adjust for baseline characteristics (age, sex, race- ethnicity, 
education) using mixed effect modeling to quantify improvements in cognitive performance after 
exercise (Specific Aim 1), and to determine an association between changes in TMS plasticity, 
cognitive performance and changes in aerobic capacity (Specific Aim 2). We will use modification 
models by including interaction terms (time-by-genotype) to explore the relationship between change in 
cognitive performance after exercise and BDNF levels, Val66Met, and APOE e4 status (Specific Aim 3- 
Option A only). 
12) Provisions to Monitor the Data to Ensure the Safety of Subjects*
Monitoring the safety of participants with respect to TMS neuroplasticity assessment 
TMS has been used in a growing number of laboratories worldwide since 1984. A series of 
adverse events have been identified since then, and have been thoroughly reviewed for the 
development of recommended safety guidelines and precautions for the use of TMS, first at a 
consensus conference at the NIH in June, 1996 and, more recently, in 2008 in Siena (Italy), in a 
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meeting of an international panel of TMS experts (The Safety of TMS Consensus Group).
The principal investigator will ensure that these guidelines are well-known by all study 
investigators and will carefully follow these updated safety guidelines in the present study. 
Additionally, we will track and report any adverse events that may occur.
Monitoring the safety of participants with respect to tACS neuroplasticity assessment 
Transcranial Alternating Current Stimulation (tACS) is a form of Transcranial Electrical 
Stimulation (tES). TES is uniquely suited for a home-based remote intervention as it can be delivered 
with a lightweight, portable and inexpensive device. Importantly, tES stimulation is painless and has 
a favorable safety profile. Two independent papers that represent broad consensus efforts between 
experts in the field, have concluded that tES is safe if appropriate guidelines are followed, that it lacks 
serious adverse effects and that it is well tolerated. These consensus efforts include the paper by Bikson 
et al. (2016)43 that considered 33,200 tES sessions across 1000 subjects undergoing repeated sessions. 
This report included data from healthy individuals and diverse clinical populations. It also includes 
the paper by Antal et al. (2017)44 reflecting the outcome of a consensus meeting, which took place in 
Göttingen, Germany, on September 6-7, 2016 and follow-up committee work by email 
correspondence. The committee reviewed safety, ethical, legal, regulatory considerations, and 
provided application guidelines for tES. The data considered included over 18,000 tES courses of 
multiple sessions administered to healthy subjects, neurological and psychiatric patients. The 
conclusion of both these large consensus efforts – and reflecting a true consensus between all 
participants in both groups – is that tES represents a minimal risk intervention.
As previously mentioned, participants will have a familiarization session where they will be 
instructed on how to appropriately place the EEG cap. The study investigator will remotely supervise 
the session utilizing a tablet that comprises the STARSTIM®-Home system. The STARSTIM®-Home 
system can only be used at pre-specified times, determined and approved by the study investigator. In 
accordance with the safe application of neurophysiological measures recommended by the 
International Federation of Clinical Neurophysiology, we will collect and monitor adverse events. 
Monitoring the safety of participants with respect to Exercise
The decision regarding ability to perform exercise will be made upon a review of the potential 
participant’s medical history, vital signs sheet, Physical Activity Readiness Questionnaire (PAR-Q) 
and a systems review performed by a licensed Physical Therapist. Based on the results of this 
evaluation, if the subject is found to require further medical clearance, they will be referred to a 
Medical Physician for further evaluation and the assessment of potential eligibility in the present 
study.
All exercise intervention will be performed by trained study personnel, under the guidance 
of a Physical Therapist to ensure participant safety during exercise and to respond appropriately in 
case of an adverse event. There are three physical therapists on our team. As participants will have 
been screened prior to study enrollment and only subjects appropriate for exercise will be included, 
no more than minimal risk is present in regards to exercise intervention.
13) Withdrawal of Subjects*
The principal investigator will withdraw participants who become ineligible to participate in 
the study (as per study inclusion and exclusion criteria), or if there is a safety concern for the 
participant or study investigators. When subjects withdraw from the study any data already collected 
will still be used, but further data will not be collected.
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14) Risks to Subjects*
All risks involved in study procedures are outlined below. As some testing is specific to either 
the Option A or the Option B only, these designations are stated. If no designation is present than these 
risks are inherent to both options. Each option will have a specific Informed Consent Form that will 
identify the unique risk based on their option participation.
Risks associated with TMS (Option A Only):
TMS has been used in a growing number of laboratories worldwide since 1984. A series of adverse 
events have been identified since then, and have been thoroughly reviewed for the development of 
recommended safety guidelines and precautions for the use of TMS, first at a consensus conference at 
the NIH in June, 1996 and, more recently, in 2008 in Siena (Italy), in a meeting of an international panel 
of TMS experts (The Safety of TMS Consensus Group). We will carefully follow these updated safety 
guidelines in the present study.
More Common

Headaches and/or Neck Pain: Up to 20%-40% of subjects undergoing TMS experience 
headaches or neck pain, which are believed to be due to muscle tension. All prior cases of 
headaches induced by TMS have promptly resolved with a single dose of acetaminophen 
(Tylenol®) or aspirin. In some cases, TMS may cause facial discomfort on the same side 
of stimulation. 
Rare
Seizures: TMS can cause a seizure; however, this is an extremely rare problem. Repetitive 
TMS can induce a seizure even in the absence of pre-existing brain lesions, epilepsy, or 
other seizure risk factors, both in patients and healthy subjects. From the several thousands 
of studies that have used TMS to date, a total of 16 cases have been reported, of which 9 
cases occurred after the 1998 safety guidelines. Based on the available data, the reported 
risk of seizures is less than 1 in 1000 for repetitive TMS. Additionally, TMS has been rarely 
associated with seizure-like events and syncope. Nevertheless, this is a very concerning 
complication and to make the subjects’ risk as small as possible, the investigators will 
follow precautions that are recommended by the International Society for Transcranial 
Stimulation and mentioned in the 2008 updated safety guidelines of The Safety of TMS 
Consensus Group.

Hearing Problems: TMS produces a loud clicking sound when the current is passed through 
the stimulation coil. This loud click can result in ringing in the ear and short-term decreased 
hearing if no protection is used. In order to prevent this potential adverse effect subjects 
will be given earplugs. Animal and human studies have demonstrated that earplugs can 
effectively prevent the risk of hearing disturbance due to TMS.  In one case45 a subject’s 
hearing protection fell out and resulted in permanent hearing loss during a 1Hz rTMS 
session at 120% of the motor threshold.  The authors were using a special TMS coil called 
the H-coil that is designed to reach deep into the subject’s brain and is shaped like a helmet 
fitted onto the subject’s head.  However, the authors claimed that the loudness of the H-
Coil they were using was not different from other coils. This type of coil will not be used 
in this study.  In order to inform and protect the subjects, we will take the following 
precautions: 
o
Inform subjects of the risk of permanent hearing loss, if an earplug should loosen, 
become detached, or fall out. 
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o
Inform subjects that they should immediately report to the investigator any 
loosening or detachment of an earplug during TMS. 
o
Immediately stop TMS to replace earplugs if the subject reports or if an investigator 
observes that an earplug has loosened or has fallen out.  
o
Ask the subject if they are experiencing any hearing problems following every 
session of TMS
o
Prompt referral for auditory assessment of all individuals who complain of hearing 
loss, tinnitus, or aural fullness following completion of TMS.
The risk of hearing loss with our TMS coil is very low with no reported incidence of 
transient or lasting problems using the methods outlined in this study.  

Syncope: Syncope can occur due to anxiety and psycho-physical discomfort during testing 
and treatment with TMS. This is reported less than seizure activity but the true number may 
be higher due to under-reporting. Subjects will be monitored for feeling any signs or 
symptoms of a pending syncopal event (i.e. feeling dizzy or lightheaded). TMS will 
immediately be stopped and the subject will be assisted. 

Memory: TMS could induce short-term changes in memory, attention and other cognitive 
and mental functions. This is a rare risk, as safety studies conducted found these events to 
be rare and transient. 
Mood: Acute psychiatric effects have been described in patients receiving rTMS. Although 
single cases suggest a causal relationship between rTMS and mania, the overall rate (13 
cases) across 53 randomized controlled studies in depression appears to be low (0.84% 
mania for active rTMS vs. 0.73% for sham rTMS) and even below natural switch rates in 
patients with bipolar disorders receiving mood stabilizers (2.3–3.45%). Similarly, cases 
ofrTMS induced psychotic symptoms, anxiety, agitation, suicidal ideation and insomnia, 
have been reported, but it is unknown whether these occur at higher rates compared to the 
natural course of disease being treated or associated with other interventions. Psychotic 
symptoms and suicidal ideation have never been described in normal subjects during or 
after rTMS. Subjects with psychiatric problems will not be included in this study, so mood 
changes are not anticipated.
Dental Pain: The possibility of dental pain during rTMS has been reported. This potential 
adverse effect of TMS would occur during the application of the stimulation itself. Should 
such discomfort occur, we encourage the participant to alert the study investigator. The 
stimulation session will be immediately terminated, and the participant will be encouraged 
to seek a dental evaluation. This is a very rare occurrence, but it may point to the presence 
of a cavity that may require care. This adverse effect should not lead to any lasting problems 
or complications.

Finally, even though TMS has been used in several laboratories worldwide since 1984, 
there could be some unforeseen complications, and the patients will be informed about this 
possibility.
Risks associated with tACS (Option B Only):
As mentioned before in the ‘Monitoring the safety of participants with respect to tACS 
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neuroplasticity assessment’ section, there is a consensus that tACS as in the form of tES is painless and 
has a favorable safety profile. Also, two independent papers that represent broad consensus efforts 
between experts in the field, have concluded that tES is safe if appropriate guidelines are followed, that 
it lacks serious adverse effects and that it is well tolerated, representing a minimal risk intervention.
In accordance with the safe application of neurophysiological measures recommended by the 
International Federation of Clinical Neurophysiology, we will collect and monitor adverse events. 
Possible adverse events can include:

Mild tingling sensation

Slight Itch

Temporary mild redness under cap
Electroencephalography (EEG): There are no risks associated with an EEG. The test is painless and 
safe.
Risks of Gait and Postural Testing
Potential risks of standing and walking include fall, fatigue, muscle strains, sprains, muscle 
soreness and light headedness. Participants will be supervised at all times during physical function 
testing, and will be given the opportunity to take breaks if they indicate not feeling well. Typically, 
muscle soreness is temporary and is resolved within a few days, but if muscle soreness persists, we will 
do our best to accommodate a “make up” session.
Risks of Exercise Testing and Physical Exercise Intervention
Potential risks of exercise and exercise testing include fatigue, muscle strains, sprains, muscle 
soreness and light-headedness. There are possible, but infrequent complications of the training 
exercises such as dizziness, fainting, fall, irregular heartbeat, and very rarely, heart attack, cardiac 
arrest, or death. Participants will be supervised at all times during the physical exercise intervention 
and physical exercise testing, and will be given the opportunity to take breaks if they indicate not 
feeling well. Typically, muscle soreness is temporary and is resolved within a few days, but if muscle 
soreness persists, we will do our best to accommodate a “make up” session.
The standard procedure for handling emergencies at the University of Miami Medical Wellness 
Center is to call 911 (emergency response system). Additionally, all study personnel who will be 
supervising exercise sessions will be trained in CPR. 
We have developed a new safety plan specifically for option B to ensure participant wellbeing 
throughout the intervention which includes confirming the participant’s geographical location and 
phone number at every session. In the event that the participant experiences any adverse event, the 
trained study personnel will follow the original study protocol, which states to call 9-1-1. The study 
team will use this geographical information collected prior to the session to assist emergency 
personnel. We will be enforcing mandatory rest and water breaks during exercise to promote proper 
hydration and rest. We have created a daily exercise questionnaire to provide strict guidelines for 
when someone should or should not engage in exercise. The daily exercise questionnaire and 
participant vitals will be used to determine if participants are appropriate and safe to proceed with 
the exercise intervention. We have also developed a strict guide to recognize when to stop an 
exercise.
Electromyography (EMG, Option A only):
The sticky pads used for the test may cause skin irritation or redness.  Taking the sticky pads off 
causes discomfort similar to when taking off a band-aid.
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Neuropsychological (Cognitive) Testing:
Participants may feel tired or frustrated during the cognitive tests, and will be given breaks as 
needed.
Psychological Stress
Some of the questions we will ask you as part of this study may make participants feel 
uncomfortable. They have the option to refuse to answer any of the questions and take a break at any 
time during the study. In addition, participants will be made aware that they may stop participation 
in the study at any time.
Collection of Blood (Option A only)
There are minor risks associated with having blood draw n for laboratory testing (risks not 
higher than for any routine blood sampling). The risks of blood drawing include: fainting, the occurrence 
of temporary discomfort and/or bruise at the site of puncture; rarely, infection or the formation of a small clot 
or swelling to the vein and surrounding area may occur. 
Unforeseeable Risks
There may be unforeseen risks that the investigators are not aware of. In the event this happens, 
these will be responded to appropriately for subject safety and reported to the IRB.
15) Potential Benefits to Subjects
It is not possible to predict whether subjects will benefit directly from participation in this study. 
However, participating in regular exercise has been demonstrated to improve overall feelings of well-
being and fitness.
16) Vulnerable Populations
This study will not enroll pregnant women, prisoners or children. Subjects have to be able to 
sign and personally (Option A) or digitally (Option B) date the written/digital ICF as approved by 
the CTSI. Subjects should be able to follow instructions for exercise interventions and assessment 
battery.
17) Sharing of Results with Subjects*
Study information will be shared in the format of academic presentations, scientific 
manuscripts and poster presentations. As this study will involve community recruitment outside 
of the UHealth system, study results and information will not be uploaded into UChart.
18) Setting
Option A

Screening and TMS procedures will take place at the Lois Pope Life Center located 
at 1095 14th Terrace, 1st Floor, Miami, FL 33136.

Exercise interventions will take place at the University of Miami (Medical and 
Coral Gables Wellness Centers).
Option B

Screening, assessments, and exercise sessions will take place at the participant’s 
place of residence. A study kit including items needed to complete assessments 
will be mailed to the participant. Participants will be asked their geographical 
location and phone number at the beginning of every assessment and exercise 
session. 
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19) Resources Available
All investigators, trainees, and staff will be required to be trained and up to date in the CITI 
course for the Responsible Conduct of Research, Conflict of Interest and other modules related to 
patient oriented research, as per University policy. Prior to any participant activities, the study will be 
reviewed and approved by the University of Miami Human Subjects Research Office, and all Key 
Personnel, including investigators, trainees, and staff will be listed in the protocol.
Contact information for the Principal Investigator and other designees will be provided to all 
participants and we will make sure they understand whom to contact in case of any emergencies, 
adverse events, or other questions. We will monitor adverse events in all participants throughout the 
interventions, and will review these regularly.
Dr. Joyce Gomes-Osman. PhD, PT is the principal investigator in this study. She is a research 
neuroscientist with extensive experience in clinical research and non-invasive brain stimulation 
approaches, which include transcranial magnetic stimulation (TMS) and electroencephalography 
(EEG). Dr. Gomes has a publication record that include studies utilizing non-invasive brain 
stimulation to characterize the neurophysiology and induce neurostimulation (as a potential 
therapeutic approach) in individuals with neurologic impairments from spinal cord injury. Her 
experience in clinical trials are a result of 6 years working at the Miami Project to Cure Paralysis, 
University of Miami, where she was a project coordinator for two R01 grants, while working on her 
doctoral studies. Dr. Gomes has expanded her knowledge in Neurology and non-invasive brain 
stimulation techniques during her postdoctoral fellowship with Dr. Alvaro Pascual-Leone, an 
internationally recognized leader in this field, at the Berenson-Allen Center for Non-Invasive 
Stimulation at Beth Israel Deaconess Medical Center at Harvard Medical School. She remains 
affiliated as a research scholar, and is currently conducting studies to investigate the effects of aerobic 
exercise on neuroplasticity and cognitive function in healthy individuals. In addition, she is a lecturer 
at the “Intensive Course in Transcranial Magnetic Stimulation”, organized by this Center.
Dr. Lawrence Cahalin, PT, PhD, will CCS is Board Certified in Cardiopulmonary Physical 
Therapy. He has 33 years of clinical experience in physical therapy. His clinical practice has focused 
on independent exercise testing, cardiac and pulmonary rehabilitation, physical therapy for patients 
with end-stage heart and lung disease before and after heart or lung transplantation, and breathing 
retraining. Dr. Cahalin has an interest and expertise in exercise testing, exercise training, and 
assessment of functional capacity. His training in both physical therapy and gerontology has provided 
him with clinical and research skills to better appreciate and understand the effects of aging in older 
adults with and without heart and lung disease. Much of his work has examined the dynamic 
interaction between the cardiac and pulmonary systems at rest and during exercise with the goal of 
improving diagnoses, functional performance, and quality of life. He has made significant 
contributions to science and clinical research addressing (1) the safety of exercise testing, (2) the 
clinical utility of the 6-minute walk test in heart failure and end-stage lung disease, (3) inspiratory 
muscle testing and training in heart failure, (4) the clinical utility of heart rate recovery during 
maximal and submaximal exercise, and (5) promoting the development and implementation of 
worksite health and wellness programs as vehicles to prevent non- communicable disease and 
provide cardiac rehabilitation.
Dr. Jordyn Rice, PT, DPT is the lead physical therapist in this study. She is a research associate 
in the Neuromotor and Plasticity lab currently working to complete her PhD studies in Physical 
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Therapy under the supervision of Dr. Joyce Gomes-Osman. She has a clinical background working in 
a variety of settings and has an active PT practice.
Trainees: Several trainees are planned to come in contact with participants. Our team has 
extensive experience with successful mentoring and we have designed an excellent educational 
program that runs throughout the fellowship.
20) Prior Approvals
No approvals need to be obtained prior to commencing the research Recruitment Methods.
21) Recruitment Methods
Participants for this study will be recruited via a recruitment flyer on the Miller School of 
Medicine Campus, University of Miami Coral Gables Campus, and greater Miami community. In 
addition, online research database tool (ResearchMatch.org) and the Consent to Contact Initiative 
will be used as recruitment methods. Individuals who are interested in participating in the study will 
be instructed to contact study staff via email or telephone to discuss the study details. At this time, 
the study will be explained to the potential participants. If subjects appear to fulfill eligibility criteria 
and are showing further interest in participating, a meeting will be scheduled to take place at the Lois 
Pope Life Center located at 1095 14th Terrace, 1st Floor, Miami, FL 33136 or virtually via Zoom. 
During this meeting, individuals will have the opportunity of choosing (or not) to enroll in the study.
Option A:
Participants will be compensated $60 at the beginning of the study and $60 upon completion 
of the study for a total of $120. Additionally, for the Option A only, participants will be compensated 
$2 for parking or transportation cost during their visits. Parking payments will be paid at the end of 
each week (ie: if participants attended 3 exercise sessions, they will receive $6 on their last visit of 
the week).
Option B:
Participants will be compensated $120 upon termination of all study visits via a gift card. 
22) Local Number of Subjects
Approximately 80 participants will be enrolled in this study.
23) Confidentiality
Data will be stored indefinitely at the Lois Pope Life Center located at 1095 14th Terrace, 
1st Floor, Miami, FL 33136 in a locked cabinet. For the Option A only, the BDNF and APOE4 
samples will be analyzed and stored indefinitely at the Hussman Institute for Human Genomics 
(HIHG) Biorepository, 1501 NW 10th Avenue Biomedical Research Building(BRB) Rm 448 
Miami, FL 33136. Identifiers will be removed from blood samples that are collected during this 
research and may be store and used for future research studies.
24) Provisions to Protect the Privacy Interests of Subjects
Information about study patients will be kept confidential and managed according to HIPAA 
requirements. Regulations require a signed patient HIPAA Authorization informing the participant of 
the following:

What protected health information (PHI) will be collected

Who will have access to that information and why
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
Who will use or disclose that information
If a participant withdraws consent or revokes authorization to collect or use PHI, following 
regulations, the investigator retains the ability to use all information collected prior to revocation of 
patient authorization.
All of the subjects PHI will be kept secure with paper information in a locked cabinet and all 
electronic data password protected, and only used as necessary for study purposes. This will be 
explained to subjects at the beginning of the study.
25) Compensation for Research-Related Injury
In the event of an injury, individuals will be instructed to follow-up with their medical 
insurance in the event of an injury.
26) Economic Burden to Subjects

Option A: Participants are required to transport themselves to all study visits and pay 
for transportation and parking costs as necessary but will be reimbursed for $2 each 
study visit. 

Option B: Participants will not incur any economic burden and will be provided with 
all resources necessary to participate in this study. 
27) Consent Process
Option A: The informed consent process will take place when the potential participant comes in 
for visit #1 at the Lois Pope Life Center located at 1095 14th Terrace, 1st Floor, Miami, FL 33136. The 
study team will thoroughly discuss the study aims, requirements, schedule, procedures, possible benefits, 
potential risks and alternatives. If subjects remain interested in participating, they will be given an 
informed consent document, and ample time to review it in privacy. After the potential participant has 
indicated that he/she has completely read the document, they will have the chance to ask any questions 
before deciding to give written consent. 
Option B: A virtual consenting process will be completed using zoom for healthcare and 
REDCap e-consent as approved through the Clinical and Translational Science Institute (CTSI). The 
individual will be sent a REDCap link either through a secure email or through the chat feature of 
zoom. Once the individual opens the link, they will be asked to share their screen. At that time a 
trained study personnel will review the informed consent with the individual and answer any question 
the individual may have about the study. If the individual agrees to participate in the study, they will 
be asked to sign the e-consent form and provide the study personnel remote access of their web 
browser to also sign the consent form. The individual will then certify the information and submit 
the consent. At that time, they will have the option to download or print the completed consent form. 
A copy can be mailed at the individual’s request. 
The investigator will emphasize to each potential participant that his/her participation is 
voluntary and there is no consequence to refusing participation. Ample time will be taken to 
familiarize potential subjects with procedures.
Only when they declare that they are comfortable with all aspects of the study and its 
procedures, will they be allowed to offer consent. The subject will be interviewed for their 
introspections and comments about the experiment to confirm their understanding. At that point the 
potential participant will share their screen and electronically sign the informed consent document. 
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They will then give the study member remote access to their browser and allow the study member to 
also sign the consent form. The potential participant will then verify the information and submit the 
consent. At that point they will be given the option to download a copy or print the signed informed 
consent. The participant may also request a mailed copy be sent to them. 
The consent form document will not have the UM footer as the research team will not be 
inserting or extracting any data from the participant’s medical record.
28) Process to Document Consent in Writing
Only the study personnel listed on this protocol and designated by the PI to consent patients 
are authorized to conduct the IC process.
Informed consent will be obtained in accordance with US 21 CFR 50.25 and ICH Good 
Clinical Practice. HSRO Investigator Manual HRP-103 guidance will be followed, as well as HSRO 
guidance for Informed Consent. COVID-19 mitigation HSRO consenting process will used to obtain 
remote consent.
29)Authorization for Use and Disclosure of Protected Health Information (HIPAA)
Type of Request:
  Waiver of Authorization for access to medical record for subject 
identification/recruitment.
Waiver of Authorization for access to medical record to obtain data for the research.
Confirm that you will destroy or de-identify the information you collect at the earliest 
opportunity.
   I confirm
Confirm that the information you collect will not be reused or disclosed to any other person 
or entity, except as required by law, for authorized oversight of the research study or for 
other research for which the use or disclosure of PHI is permissible.
    I confirm
30) Drugs or Devices
Device: Magpro X100, MagVenture Corporation, Farum, Denmark
This device was purchased by the Department of Physical Therapy for the Neuromotor Plasticity 
Laboratory, directed by Dr. Gomes-Osman. 
The Transcranial Magnetic Stimulator is the original device developed by the Magstim 
Corporation for the purpose of electromagnetic neural tissue stimulation in 1984. The devices consist 
of a bank of capacitors that can be charged up to a predetermined amount of energy and then quickly 
discharge via solid state switches into a coil of copper wire. This coil of copper wire is encased in 
plastic. As the current passes through the coil, a magnetic field is generated following Faraday Laws. 
This magnetic field will in turn induce a secondary current in any tissue with capabilities to conduct 
electricity that is placed in the proximity of the induced magnetic field. For the purpose of brain 
stimulation, the coil is held over the subject’s head and as the current passes through it, i.e., a magnetic 
field is generated that penetrates the scalp and skull without being attenuated. This magnetic field 
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induces a flux of current in the brain. This secondary current induced in the brain influences neuronal 
activity by virtue of mostly transsynaptic effects. The effects induced by the stimulation of the brain 
depend on the site of stimulation, since different areas of the brain control different functions. In 
addition, stimulation parameters such as focality of the magnetic field, stimulus intensity and 
stimulus frequency also condition the induced effects in the brain. The Transcranial Magnetic 
Stimulator has no electric contact with the patient or subject. There is no failure mode of the device 
that could result in the delivery of an excessive amount of stimulation intensity or number of stimuli 
given a circuit breaking safety device. Therefore, the device allows noninvasive stimulation of the 
human brain without the use of direct electrical contact between the device and the subject. In 
principle, this device provides the means of an electrodeless, noninvasive, and painless stimulation 
of the human brain. It is used in cognitive research and treatment of some neurologic and psychiatric 
conditions.
Support for non-significant risk device
The non-invasive brain stimulation device (TMS) utilized in the present study has been 
cleared by the FDA for the treatment of depression. There have been nearly 2,000 research 
studies published utilizing this technique, and the safety of this device has been established. 
The First International  Safety Conference  on Transcranial  Magnetic Stimulation took place at 
the National Institutes of Health in Bethesda, MD, in June 1996. Representatives of the Food and 
Drug Administration (FDA) were present at that meeting and they shared the consensus that the 
evidence accumulated over the previous 10 years supports the safety of TMS. More recently in 
2008, an international panel of TMS experts (The Safety of TMS Consensus Group) met for a 
consensus conference to review and update safety guidelines in TMS based upon review of 
published data (Rossi et al., 2009). The  evidence reviewed by this group of experts in the field 
continues to support the safety of TMS with the application of recommended guidelines. These 
TMS guidelines and recommended safety screening are incorporated into this study of physiologic 
measures. In the present study, we will strictly follow the Safety Guidelines to TMS.
Storage and usage of device
The Magpro X100 will be stored at the Lois Pope Life Center located at 1095 14th Terrace, 
1st Floor, Miami, FL 33136. The device will be used by the principal investigator, and only be used 
by members of the Laboratory following adequate training.
tACS Device Related Information 
Applicable to:
FDA Regulation
IND Studies
IDE studies
Abbreviated 
IDE studies
21 CFR 11
X
X
21 CFR 54
X
X
21 CFR 210
X
21 CFR 211
X
21 CFR 312
X
21 CFR 812
X
X
21 CFR 820
X
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This device will be purchased or rented by the Department of Physical Therapy for the Neuromotor 
Plasticity Laboratory, directed by Dr. Gomes-Osman. Transcranial Alternating Current Stimulation 
(tACS) is a form of Transcranial Electrical Stimulation (tES).
For over a decade tACS has been used in a growing number of studies due to its cost effectiveness 
and overall feasibility as a form of non-invasive brain stimulation. TACS is a brain stimulation technique 
that is designed to target and manipulate brain oscillations. An alternating sinusoidal current is applied 
between two electrodes which can vary on the strength, position, and frequency of the current. Only a 
fraction of the current enters the brain which in turns causes the membrane potential of a group of 
neurons to change which changes the probability of the generation of an action potential. In conjunction 
with EEG readings, tACS can provide us insights into the brain functioning.46 TES is uniquely suited 
for a home-based remote intervention as it can be delivered with a lightweight, portable and inexpensive 
device. Importantly, tES stimulation is painless and has a favorable safety profile. Based on the 
conclusion of large consensus efforts – and reflecting a true consensus between all participants in both 
groups – is that tES represents a minimal risk intervention.
The practical application of tACS is simple: a low intensity (1-2 mA) alternating electrical 
current is applied to the scalp to influence underlying cortical excitability, which is measured with non-
invasive surface EEG electrodes. The study investigator will remotely supervise the session utilizing a 
tablet and zoom for healthcare that comprises the STARSTIM®-Home system (Neuroelectrics, Inc). The 
neuroplasticity assessment will follow the current guidelines for the safe application of 
neurophysiological 
measures 
recommended 
by 
the 
International 
Federation 
of 
Clinical 
Neurophysiology.13,14 STARSTIM®-Home is capable of recording EEG before, during and after tACS 
stimulation. The STARSTIM®-Home system can only be used at pre-specified times, determined and 
approved by the study investigator. In accordance with the safe application of neurophysiological 
measures recommended by the International Federation of Clinical Neurophysiology, we will collect 
and monitor adverse events. 
Support for non-significant risk device
Transcranial Alternating Current Stimulation (tACS) is a form of Transcranial Electrical 
Stimulation (tES). TES is uniquely suited for a home-based remote intervention as it can be delivered 
with a lightweight, portable and inexpensive device. Importantly, tES stimulation is painless and has 
a favorable safety profile. Two independent papers that represent broad consensus efforts between 
experts in the field, have concluded that tES is safe if appropriate guidelines are followed, that it lacks 
serious adverse effects and that it is well tolerated. These consensus efforts include the paper by Bikson 
et al. (2016)43 that considered 33,200 tES sessions across 1000 subjects undergoing repeated sessions. 
This report included data from healthy individuals and diverse clinical populations. It also includes 
the paper by Antal et al. (2017)44 reflecting the outcome of a consensus meeting, which took place in 
Göttingen, Germany, on September 6-7, 2016 and follow-up committee work by email 
correspondence. The committee reviewed safety, ethical, legal, regulatory considerations, and 
provided application guidelines for tES. The data considered included over 18,000 tES courses of 
multiple sessions administered to healthy subjects, neurological and psychiatric patients. The 
conclusion of both these large consensus efforts – and reflecting a true consensus between all 
participants in both groups – is that tES represents a minimal risk intervention.
The stimulator used in this study is the STARTSTIM®-Home device (Neuroelectrics, 
Inc), a tACS home-base system that recently received FDA approval for the Investigational 
Device Exemption (IDE) supplemental protocol in a study for tACS to be used to treat patients 
with Major Depression Disorder (MDD) due to COVID-19 related restrictions. Several devices 
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that enable direct current stimulation are cleared by the FDA for extracranial use, particularly 
aiming for iontophoretic medication delivery. Pivotal studies aiming to gain FDA approval for 
different tCS devices for treatment of major depression, epilepsy, and chronic pain are in 
progress. It is important to note that the IDE in this instance was requested by the company 
because they are conducting a pivotal study for tCS in epilepsy and could not risk endangering 
their effect and thus wanted to ensure coordinated action with the FDA. Both the company and 
the FDA felt it valuable to issue the IDE as part of the concerted effort to highlight targeted 
actions to address the COVID-19 pandemic and its impact on mental health. 
Storage and usage of device
The STARTSTIM®-Home device (Neuroelectrics, Inc) will be mailed to participants’ homes 
for pre and post assessments. Participants will then mail the device back to the investigator using a 
pre-paid return label for sanitization and storage at the Lois Pope Life Center located at 1095 14th 
Terrace, 1st Floor, Miami, FL 33136. The device supervision and application will only be performed 
by the principal investigator, and only be used by members of the Laboratory following adequate 
training.
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