Investigation of Low-intensity Focused Ultrasound Parameters
Phase: NA
Conditions: Development of LIFU for Clinical Purposes
Sponsor: Virginia Polytechnic Institute and State University

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Investigation of Low-intensity Focused Ultrasound Parameters 
NCT: NCT05134233 
09/12/2024 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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INSTRUCTIONS: 
● Use this “TEMPLATE PROTOCOL (HRP-503)” to prepare a study protocol 
outlining your research plan.  
● Depending on the nature of your study, some major sections might not be 
applicable to your research. If so, simply mark as “N/A.” For example, a simple 
survey might have many sections with “N/A.”  For subsections (e.g., 1.x or 8.x) 
you can mark as “N/A”if you are certain that the subsection is not applicable. 
● Once the IRB/HRPP approves your submission, your latest approved version of 
the protocol will be stored in the IRB Protocol Management online system.  
● If your research plan changes and you need to modify the protocol, please submit 
an amendment to Protocol Management with the requested modifications. 
Download your current protocol from Protocol Management and indicate the 
changes/revisions using the track changes feature in order to make review of the 
modifications easier to follow. If you are unable to use track changes, please 
create a new paragraph wherever you need to make a change, and indicate 
“Amendment: Date” before making a change to any section. Protocol 
management will store the older versions of your protocol if the IRB or HRPP 
staff need to compare them during the review. 
PROTOCOL TITLE:  
Include the full protocol title.  
 
Investigation of low-intensity focused ultrasound parameters 
 
PROTOCOL NUMBER:   
Include the number assigned in Protocol Management (verify this has been added 
before submitting protocol to HRPP).  
 
 
21-882 
 
PRINCIPAL INVESTIGATOR: 
Full Name and Degrees: Wynn Legon PhD 
Department: Fralin Biomedical Research Institute at VTC 
Telephone Number: 540-526-2184 
Email Address: wlegon@vt.edu 
 
FUNDING: 
 
Sponsor(s): N/A 
 
Funded already or in the proposal phase?: Proposal phase 
Is Virginia Tech the primary awardee or the coordinating center of this grant or 
contract? If not, list the primary institution: Yes 
 
 

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VERSION NUMBER/DATE:  
Include the version number and date of this protocol. Versions should start at 1.0. 
 
1.1 
 
REVISION HISTORY:  
Use this table to keep track of changes. Add more rows as needed. 
 
Revision 
# 
Version Date 
Brief Summary of Changes  
(i.e., the different sections) 
Consent 
Change? 
1 
01/31/2022 
Section 7 & 8, added physiology 
measurements, added set of questionnaires. 
Section 15, timeline/compensation from 
questionnaire addition. Section 20, added BDI 
risk.  
Y 
2 
07/28/2022 
Adding respiratory and ECG physiology 
collection. Section 10, added that participant 
will be offered a copy of their MR images on 
CD.  
Y 
3 
01/11/2023 
Adding foreign participant payment details & 
FDA NSR determination 
Y 
4 
05/16/2024 
Adding menstruation questions 
N 
 

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Table of Contents 
1.0 
Study Summary 
5 
2.0 
Objectives 
5 
3.0 
Background 
6 
4.0 
Study Endpoints 
7 
5.0 
Study Design and Statistical Analysis Plan 
8 
6.0 
Setting 
8 
7.0 
Study Intervention(s)/Investigational Agent(s) 
9 
8.0 
Procedures Involved 
14 
9.0 
Data and Specimen Long Term Storage and Use 
19 
10.0 Sharing of Results with Subjects 
21 
11.0 Study Timelines 
21 
12.0 Inclusion and Exclusion Criteria 
22 
13.0 Vulnerable Populations 
24 
14.0 Number of Subjects 
25 
15.0 Recruitment Methods 
26 
16.0 Withdrawal of Subjects 
28 
17.0 Risks to Subjects 
28 
18.0 Potential Benefits to Subjects 
32 
19.0 Data Management and Confidentiality 
32 
20.0 Provisions to Protect the Privacy Interests of Subjects 
34 
21.0 Provisions to Monitor the Data to Ensure the Safety of Subjects 
35 
22.0 Compensation for Research Related Injury 
36 
23.0 Economic Burden to Subjects 
36 
24.0 Consent Process 
37 
25.0 Process to Document Consent in Writing 
40 
26.0 Resources Available 
41 
27.0 Multi-Site Research 
43 
 
 
 

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1.0 
Study Summary 
 
Study Title 
Investigation of low-intensity focused ultrasound parameters 
Study Design 
Systematic study of set parameters in a multiple visit study 
Primary Objective 
Understanding the interaction of varying ultrasound 
parameters 
Secondary 
Objective(s) 
Document the tolerability of the parameters 
Study Population 
Healthy volunteers aged 18-65 
Sample Size 
80 
Research 
Intervention(s)/ 
Investigational 
Agent(s)  
Low-intensity focused ultrasound, Transcranial magnetic 
stimulation, EMG will be used to record motor responses. 
Study Duration for 
Individual 
Participants 
7 total study sessions, ~2.5 hours per session, for a total of 
~17.5 hours.  
Acronyms and 
Definitions  
LIFU = low-intensity focused ultrasound  
TMS = transcranial magnetic stimulation 
MRI = magnetic resonance imaging 
CT = computed tomography 
EMG = electromyography 
ECG = electrocardiogram 
 
2.0 
Objectives 
2.1 Describe the purpose, specific aims, or objectives of this study: 
 
An understanding of the interaction of ultrasound parameters on human brain function is 
critical to rationally design clinically useful therapeutic methods that result in predictable 
outcomes. Experiments in small and large animal are confounded by small cranial vault 
size, anesthesia and thinner and differently shaped skulls making translation to human 
uncertain. Human studies remove translation and scaling issues and can be directly 
related for clinical use. Here, we will systematically test ranges of ultrasound parameters 
(intensity, duration, duty cycle, pulse repetition frequency) in a fully parametric design 
delivered to the primary motor cortex (M1) in healthy human volunteers. This will allow 
for an evaluation of what parameters change effect (and by how much), and determine 
how they interact with other parameters. Studies will be conducted in a cortical brain area 
using different outcome measures to test robustness and reproducibility. 
 
2.2 State the hypotheses to be tested:  
 
We hypothesize that duty cycles between 10 and 30% will result in inhibition and duty 
cycles > 50% will result in excitation independent of intensity and duration. We further 
hypothesize that longer durations will result in inhibition whereas shorter duration will 

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results in excitation. Finally, we hypothesize that 1000 Hz is the optimal PRF for these 
effects. 
3.0 
Background 
3.1 Summarize the relevant prior research on this topic and gaps in current 
knowledge within the field of study: 
 
Ultrasound has a rich parameter space. In addition to the fundamental frequency, 
parameters include intensity (directly relates to pressure), duration, number of cycles 
(relates to pulse duration), duty cycle and pulse repetition frequency (PRF). There are 
multiple studies in small and one in large animals explicitly testing how different 
parameters affect neuromodulation. King et al. (in mice) found that the product of 
intensity and duration best predicted success rates, Kim et al. (in rats) found a strong 
inter-dependency on duration and duty-cycle such that 300 milliseconds of LIFU at 50% 
duty cycle was most effective, and Yoo et al. (in rabbits) found PRF interacted with duty 
cycle such that high duty cycles (50%) at low PRFs (10 Hz) resulted in excitation 
whereas higher PRFs (100 Hz) at low duty cycle (5%) resulted in inhibition. In large 
animal (sheep), Yoon et al. reported inhibition was best achieved with a 3 and 5% duty 
cycle at PRFs of 60 and 100 Hz respectively and that 0.5 milliseconds at 70% duty cycle 
to be most effective for excitation. There are now several studies in primate and human 
showing neuromodulatory effect, though parameters have not been explicitly been tested. 
 
Additionally, we have conducted a retrospective study of symptoms and safety in TMS 
and LIFU, which reported no serious adverse events in any of the studies monitored (Sci 
Rep 2020 Legon).  
 
3.2 Describe any relevant preliminary data: 
 
Primary motor cortex. We have collected N = 6 healthy participants under a full-
parametric design looking at 3 intensities (6 W/cm2, 12 W/cm2, 24 W/cm2 Isppa in the 
head), 6 duty cycles (1%, 5%, 10%, 30%, 50%, 70%), 3 durations (100 msec, 500 msec, 
1000 msec) and 4 PRFs (10 Hz, 100 Hz, 500 Hz, 1000 Hz) delivered to the primary 
motor cortex using concurrent and concentric TMS/LIFU (Sci Rep 2018 Legon). 
Experiments were conducted at the University of Minnesota and University of Virginia, 
and reviewed by the corresponding university IRBs. Preliminary analysis revealed duty 
cycle to be a critical parameter (DC 30% = inhibition of ~10-15%; DC 50 – 70% = 
facilitation of ~15 – 25%). Interestingly, duty cycle does not look to interact with 
intensity but does so with duration. These effects were independent of PRF. The results 
have similarities to a theoretical model that takes into consideration how pressure affects 
cell membranes (eNeuro 2016 Plaskin).  
 
3.3 Based on the existing literature, provide the scientific or scholarly 
rationale for and significance of your research and how will it add to 
existing knowledge: 

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Neurological and psychiatric diseases are on the rise and present an immense challenge 
for health services globally. Current treatment methods are limited in their efficacy, 
particularly for patients with advanced or drug-resistant disorders, leaving a critical need 
to develop effective new treatment pathways. Low-intensity ultrasound is a new method 
of brain modulation that can be focused anywhere in the brain with precise targeting to 
alter brain activity and potentially repair dysfunctional brain circuits. Before this promise 
can be fulfilled, the development of tools and methods to aid in precise and predictable 
energy delivery are critical. This project will develop new means for precise, predictable 
delivery and determine effective ultrasound parameters for robust and reproducible 
neuromodulation. This information will help to progress ultrasound as a future targeted 
therapeutic that could be useful for a range of psychiatric and neurological disorders. 
 
4.0 
Study Endpoints 
4.1 Describe the primary and secondary study endpoints. See links below for 
discussion of study endpoints and how they may differ from study 
objectives. These are most common in clinical trials but are sometimes 
applicable to other types of biomedical research, as well as social, 
behavioral, or educational research. See link below for a discussion. 
https://docs.google.com/document/d/1Wocz7K7a0hCQJPPO_khh5l1
SQQjhGDDGHzcOPRHR5Tw/edit?usp=sharing  
 
Primary endpoint: Waveform combinations that induce reliable excitation and 
inhibition 
Secondary endpoint: Documentation of tolerability of waveforms 
 
4.2 Describe any primary or secondary safety endpoints. These should be 
included for all studies that are greater than minimal risk. (Minimal risk: 
The probability and magnitude of harm or discomfort anticipated in the 
research that are not greater in and of themselves than those ordinarily 
encountered in daily life or during the performance of routine physical or 
psychological examinations or tests.): 
 
Primary safety endpoint: Subjective report questionnaire on neurological/physiological 
feelings.  
Participants can request study procedures be stopped at any point throughout the 
experiment.  
Based upon previous literature from our lab in humans we expect the LIFU effect to last 
up to 30 minutes. There is no evidence as yet that the proposed administration lasts 
longer than 30 minutes. All participants will be involved in laboratory procedures during 
this interval and be queried via the attached Report of Symptoms Questionnaire for any 
signs or symptoms from the LIFU intervention pre and post intervention.  

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Post-stimulation Monitoring: 
Participants will be monitored for at least 30 minutes after stimulation has ended. 
Participants will complete a Report of Symptoms questionnaire prior to leaving the 
facility. Responses will be monitored with each given session and the change of any 
symptom to 'severe' on the post-stimulation questionnaire compared to the pre-
stimulation questionnaire will require PI evaluation.  
5.0 
Study Design and Statistical Analysis Plan 
5.1 Describe the basic study design/approach (e.g., qualitative study using five 
focus groups of first year students to describe assimilation into the 
university community; randomized controlled trial of a behavioral change 
intervention to increase dietary intake of whole grains; pre- post-test 
evaluation of new pedagogical techniques to improve adult literacy): 
 
A total of 80 participants will be enrolled in study procedures. We will examine the 
interaction of ultrasound parameters through repeat testing of set parameters of low-
intensity focused ultrasound (LIFU) while administering transcranial magnetic 
stimulation (TMS) to generate motor evoked potentials (MEP) which will be detected by 
electromyography (EMG). This study will be collected through multiple study visits. 
Visit 1 includes anatomical scans which will include 3T MRI and CT scans. Additional 
study visits will consist of LIFU/TMS parameter testing. It is anticipated participants will 
complete 7 study sessions, depending on participant availability.  
 
5.2 Describe corresponding data analysis plan/approach (e.g., content analysis 
of focus group transcripts; descriptive analysis followed by linear 
regression modeling; nonparametric analysis of pre- and post-test 
measures): 
 
MEP and SEP amplitude data will be analyzed separately using 4-way ANOVAs 
(intensity ×3, duty cycle ×6, duration ×3, PRF ×4) to determine significant main effects 
and interactions. Interactions will be decomposed using appropriate post-hoc examination 
(2/3-way ANOVA, t-tests, Tukey etc.). We will also employ stepwise regression. 
Iterative linear, quadratic and polynomial models will be tested for fit. Phase-plane 
diagrams will be produced for significant models.  
 
6.0 
Setting 
6.1 Describe the sites or locations where your research team will conduct the 
research.  Consider each of the items listed below: 
● 
Identify where your research team will identify and recruit potential 
subjects. 
● 
Identify where the team will perform the research procedures. 
● 
Describe the composition and involvement of any community 
advisory board(s). 
● 
For research conducted in other locations, describe: 

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o 
Site-specific regulations or customs affecting the research at 
those locations. 
o 
Local scientific and ethical review structure at those locations.  
Examples include work in other cultures or ethnic groups 
(within or outside of the U.S.) and work with churches. The 
HRPP will provide additional guidance for international 
research. 
 
Participants will be recruited from the general public in Roanoke, VA and surrounding 
areas. Participants will be recruited independently of other studies being conducted in the 
Legon lab. 
 
All research procedures will be conducted at the Fralin Biomedical Research Institute at 
VTC in Roanoke, VA. 
 
7.0 
Study Intervention(s)/Investigational Agent(s) 
7.1 Describe the study interventions (including behavioral interventions) and/or 
investigational agents (e.g., drugs or devices) to be used in this study.  Consider 
each of the items listed below:  
● 
Drug/Device Handling: If the research involves drugs or devices, 
describe your plans to store, handle, and administer the drugs or 
devices so that they will be used only on subjects, and only by 
authorized investigators. 
● 
Describe whether any of the following will be used: microwaves, X-
rays, DEXA scans, general anesthesia, or sedation 
● 
If control of the drugs or devices used in this protocol will be 
accomplished by following an established, approved organizational 
SOP (e.g., Research Pharmacy SOP for the Control of 
Investigational Drugs, etc.), please reference the SOP in this section. 
 
LIFU: The primary procedure involves the use of a Low-intensity focused ultrasound 
(LIFU) device. Ultrasound energy will be used. The device can only be activated by a 
computer controlled by the researchers. Study staff will be properly trained to operate this 
device.  
 
TMS: The primary procedure involves the pairing of LIFU with TMS. A stimulating coil 
produces an electric current via electro-magnetic induction of a specific brain region to 
cause MEPs. Study staff will be properly trained to operate this device.  
 
MRI: Participants will also undergo an MRI scan. Staff will review safety issues related 
to MRI with the subject and answer any questions. The MRI scanner used has a magnet 
strength of 3T, which has been approved for clinical use by the FDA. Participants will be 
able to communicate with study staff via an intercom. Staff operating the MRI have been 
trained to do so through both classroom and hands on education.  
 

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CT: Participants will undergo a head CT to obtain necessary images of their skull.  CT 
scans will be a low-dose scan with expected radiation dose of about 2mSv. This dose 
gives a lifetime cancer risk of about 1 in 10,000. The lifetime natural incidence rate is 
about 1 in 2. Equipment will be operated by trained personnel only.  
 
Stereotaxic Neuronavigation: Stereotaxic neuronavigation is the process of using a 
subject-specific anatomical MRI/CT images and co-registering them to their actual head 
and the LIFU transducer and TMS coil for real-time navigation of the treatment. The 
subject is fitted with a head-band that contains 3D infrared tracking bulbs. The LIFU 
transducer is also fitted with these tracking bulbs. Both the subject and treatment device 
are then tracked in real-time using an infrared camera. This procedure allows for precise 
targeting of specific brain regions using the subject-specific MRI and is wholly 
noninvasive. This procedure is ongoing throughout the experiment during the LIFU and 
TMS intervention.  
 
7.2 List the name of all drugs (including any vitamins, supplements, herbs, or 
nicotine) to be used in the study.  Indicate whether they have FDA 
approval, and list any limitations for their use:  
 
N/A 
 
7.3 List all devices, how they will be used, their purpose in the study, and if 
they will be used in a manner consistent with their approved uses. If they 
will be used in ways that are not yet FDA approved, indicate whether they 
need an IDE or a determination that they are exempt from the IDE 
Determination. If a determination of significant risk or non-significant risk 
is needed for any of the devices, include the researcher’s recommendation 
for each of those devices:  
 
LIFU: In its current state, ultrasound for neuromodulation follows the safety guidelines of 
the Food and Drug Administration (FDA) for obstetric diagnostic ultrasound and adult 
cephalic applications.  The device is not FDA approved for neuromodulation. . The 
device has been deemed a nonsignificant risk (NSR) by the FDA. These include derated 
limits of spatial peak pulse average (Isppa) of 190 W/cm2, a spatial peak temporal 
average of 720 mW/cm2 (94 mW/cm2 for adult cephalic) and a mechanical index (MI = 
peak negative pressure/√fc) of 1.9. MI is an indication of the ability to produce cavitation 
related bio-effects and can be used as an indication for potential micromechanical 
damage. We will use less than 50 W/cm2 (4x lower Isppa) for these studies. 
 
In addition to settings listed above, the following parameters are to be tested in this study. 
3 Intensity (I) settings (6, 12, and 24 W/cm2), 6 duty cycle (DC) settings ranging from 1-
70%, 3 duration (Dur) settings ranging from 100ms-1s, and 4 pulse repetition frequency 
(PRF) settings ranging from 10-1000Hz. As this is a parametric design, we are testing 
216 ultrasound settings. Though each setting will take less than 1 minute to test, testing is 

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expected to be divided between 6 study sessions (up to 36 per session) to reduce burden 
to the participant.  
 
These levels of energy are adhered to in human ultrasonic neuromodulation studies 
though there are no specific guidelines for energy deposition for ultrasonic 
neuromodulation and indeed, explicit expository and dosimetry for diagnostic and 
therapeutic applications, despite their prevalence and long history, has proven 
challenging and is still largely lacking.  Ultrasound for transient neuromodulation is 
different from the use of ultrasound for surgery where very high intensities are used to 
thermally ablate tissues or for blood-brain barrier (BBB) opening where high intensities 
are also used in combination with contrast agents to intentionally produce cavitation as a 
means of opening the BBB.  To date, a total of N = 179 in 8 published studies of healthy 
neurologically intact participants (plus one 1 TBI patient) have undergone a variant of 
LIFU for neuromodulation with no published report of severe adverse events. We have 
published on minor adverse events from LIFU (Legon et al. 2020).   
 
We recently compiled a qualitative report of side effects and symptoms from a subset of 
participants (N = 64) that have participated in one or more of our LIFU studies. We 
queried participants about their experience/tolerability with LIFU and any symptoms they 
experienced immediately after the intervention and also out to 22 months in a sub-cohort. 
There were no reports of any serious adverse events. The most common reported side 
effects were sleepiness, mild neck pain, headache and scalp tingling (Figure). These 
extinguished rapidly and no new symptoms were reported upon follow-up out to 1 month. 
We subsequently compared this side effect profile to other forms of non-invasive 
neuromodulation such as TMS, deep TMS and transcranial direct current stimulation 
(tDCS). We found the symptom profile to be similar to other forms of non-invasive 
neuromodulation. Over 300 healthy volunteers have undergone a variant of LIFU to 
different brain regions demonstrating that LIFU is safe and effective for transient non-
invasive neuromodulation in humans. 
 

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As currently employed, human neuromodulation with LIFU typically involves coupling a 
single (or multiple) focused single-elements usually in the ~ 250 to 600 kHz range (for 
efficient energy transfer through skull) to the scalp to target a desired cortical brain 
region. Transducers for cortical targeting are generally small (~ 30 mm diameter with a ~ 
30 mm focal length); produce a ~ 3-4 millimeter lateral and ~1 – 2 centimeter axial 
resolution, and can be placed anywhere on the head similar to other current methods of 
noninvasive brain stimulation.  
 
Ultrasound is also capable of reaching brain targets deep to the cortical surface as the 
acoustic waves can be focused to any desired depth with certain limits. Transducers for 
deep brain modulation are typically larger (~ 70 mm diameter) to achieve this deeper 
focal length at reasonable axial resolutions. In addition to adjusting focal lengths, there 
are a number of parameters that can be manipulated when using ultrasound including the 
acoustic frequency, amplitude, duration, duty cycle, pulse repetition frequency etc. and 
the efficacy of some of these for successful neuromodulation has been addressed in small 
animal studies though the precise mechanism of acoustic energy for neuronal modulation 
is largely theoretical and the impact of parameter space in humans is not yet well-
described.  The bioeffects of ultrasound for neuromodulation in humans as described here 
is likely largely mechanical as opposed to thermal as the parameters used are of low 
intensity and duration and do not generate sufficient temperatures for thermal 
modulation. As described, our study does not meet any of the definitions of a significant 
risk device as outlined by the FDA or VT and therefore does not require an IDE.  
 
TMS: Transcranial Magnetic Stimulation (TMS) is a neurophysiologic device that allows 
for non-invasive stimulation of the human brain (Rossi et al. 2009). We use the (Magstim 
2002, Magstim Inc. Morrisville NC, USA). TMS is minimal risk as deemed by the FDA. 
Possible adverse risks are described in risk section below. During TMS, the stimulating 
coil is held over a subject’s head and produces an electric current in the subject’s brain 
via electro-magnetic induction. Single-pulse TMS is used to probe the state of the motor 
system. The TMS coil is placed over the motor cortex and a single-pulse (120% of 
individual maximum threshold) is conducted. This is repeated 10 – 20 times at an inter-
stimulus-interval (ISI) of 5 – 10 seconds. The FDA approved TMS parameters for the 
treatment of major depression is 10Hz stimulation with 120% motor threshold; 4-second 
pulse trains; 26-second intertrain intervals, and each treatment session is last for 37.5 
minutes, this is a total of 3,000 pulses.  The proposed TMS parameters will stay below 
parameters for safety consideration. 
 
LIFU and TMS have been paired in numerous studies in the past, resulting in no serious 
adverse events. Transcranial focused ultrasound neuromodulation of the human primary 
motor cortex (Sci Report 2018 Legon et al), Systematic examination of low-intensity 
ultrasound parameters on human motor cortex excitability and behavior (Elife 2020 
Figure Preliminary self-report of symptoms in N = 64 healthy volunteer participants in LIFU studies in our lab (Legon 
et al. 2020). ‘Feelings’ refers to the question asking about experiencing any unusual feelings, attitudes or emotions. 
Please note the instance of severe ‘feelings’ in one individual was followed up by a neurologist and deemed 
unrelated to the intervention.      Data excerpted from Legon et al. (2020) 

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Fomenko et al), and Time course of the effects of low-intensity transcranial ultrasound on 
the excitability of ipsilateral and contralateral human primary motor cortex (NeuroImage 
2021 Xia et all).  
 
MRI: Participants will receive an MRI scan. The Siemens 3T scanner has been approved 
by the FDA and will be used in a manner consistent with approval.  
 
CT: Participants will receive a CT scan of their head. The Somatom Confidence RT Pro 
scanner has been approved by the FDA and will be used in a manner consistent with 
approval.  
 
In addition to study interventional devices listed above, the following device is utilized to 
obtain subject data throughout the experiments.  
 
EMG: Electromyography (EMG) involves attaching disposable surface electrodes to the 
skin overlying muscles of interest of the hand/ forearm in order to record muscular 
activity. Identification of the muscle is achieved by asking the participant to hold a light 
tonic contraction. The skin is prepared with a mild abrasive gel to remove surface debris 
and subsequently disinfected with rubbing alcohol. EMG electrodes are held in place 
with double-sided tape. We utilize the BrainSight device from Rogue Research. 
 
BP: Blood pressure will be measured using the QardioArm blood pressure monitor. This 
is a noninvasive smart blood pressure sleeve that is placed around the arm at the bicep 
and is controlled through a phone app. The QardioArm is FDA approved for BP 
monitoring. 
 
GSR and PPG: The galvanic skin response (GSR) sensor is used for real-time GSR 
biofeedback. The Shimmer GSR+ sensor monitors skin conductivity noninvasively 
between two reusable electrodes attached to two fingers of one hand. A stimulus causes 
the sweat glands to become more active, increasing moisture on the skin and allowing the 
current to flow more readily by changing the balance of positive and negative ions in the 
secreted fluid (increasing skin conductance). The Shimmer GSR+ unit also collects PPG 
data via an optical pulse sensor attached to a finger or earlobe. 
 
ECG: Two ECG leads will be applied, to collect an electrocardiogram (ECG). This will 
noninvasively record electrical heart activity. This device will be operated by trained 
study staff. 
 
Respiratory: A commercial respiration belt (SleepSense) will be wrapped around the 
chest to collect continuous respiration data. The belt uses Velcro closure and is 
noninvasive.  
 
7.4 If the drug is investigational (has an IND) or the device has an IDE or a 
claim of abbreviated IDE (non-significant risk device), include the 
following information: 
● 
Identify the holder of the IND/IDE/abbreviated IDE. 

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● 
Explain procedures followed to comply with sponsor requirements 
for FDA regulated research for the following: 
 
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 
 
 
N/A 
 
8.0 
Procedures Involved 
8.1 Describe and explain the study design: 
 
This is a systematic study of set parameters in a multiple visit study.  
 
Session 1: MRI and CT anatomical scans 
Session 2-7: LIFU parameter testing with TMS and EMG while utilizing 
neuronavigation and physiological data collection such as PPG, BP, ECG, Respiration, 
and/or GSR.  
8.2 Provide a description of: 
● 
All research procedures being performed  
● 
If the study has more than one procedure, session, and/or subject 
population, describe each procedure, session, and/or study 
population separately. For complex studies, you are encouraged to 
include a figure or chart. 
 
Recruitment and Screening: Individuals indicating interest in participating in this research 
study will complete a screening and demographic form as part of the screening process  
(see Safety Screening Form and Demographic Form). This information will be reviewed 
to determine eligibility and to screen for any contraindications to MRI, CT, and TMS.  
 
Consent: Participants will be asked to sign a consent form upon arrival for their first 
study visit. Participants will have as much time as they need to review the consent form 
and may ask questions of the PI or study team prior to participation.  
 
Pregnancy Screening: Prior to any study procedures, female participants will provide a 
urine sample which will be screened for pregnancy. As indicated in the consent form, if 

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testing indicates the participant is pregnant, they will be notified and excluded from the 
study.  
 
Participants will be healthy adults age 18-65 with no contraindications to MRI, CT, or 
TMS. We will enroll approximately 80 individuals.  
 
This study includes low-intensity focused ultrasound (LIFU), transcranial magnetic 
stimulation (TMS), magnetic resonance imaging (MRI), and computed tomography (CT). 
Additionally, stereotaxic neuronavigation is utilized. 
 
Study Procedures:  
 
Session 1 
Session 2-7 
Imaging 
36 Parameter Trials 
MRI & CT 
LIFU + TMS 
2.5 hours 
2.5 hours 
*parameters per session will be chosen randomly within the set values 
 
Session 1 - An MRI and CT exam will be performed and questionnaires will be 
administered.  
 
Sessions 2-7 - Utilizing imaging collected on previous visit, subjects will complete a 
testing session. These sessions will involve LIFU and TMS stimulation. Additionally 
EMG, PPG, BP, ECG, Respiration, and GSR will be collected. Questionnaires will be 
administered at each session.  
 
Follow up - An electronic questionnaire of Report of Symptoms will be sent about 1 
week following final study participation. If requested, this questionnaire can be 
completed verbally on the phone with study staff.  
 
MRI session: Participants will receive an MRI scan to obtain a high-resolution image of 
their head to be used for proper setup of LIFU parameter sessions. During the MRI 
session, the experimenter and participant are able to communicate with one another at all 
times, ensuring the comfort of the subject. In addition, participants are provided with an 
emergency ‘squeeze bulb’ which can terminate the scanning procedure at any time.  
 
CT session: Participants will receive a CT scan to obtain detailed imaging of the skull. 
CTs are collected as this is the only current option to properly image the skull. This is 
necessary for our computer models of acoustic wave propagation to ensure accurate 
intracranial intensities for each individual. 
 
Stereotaxic neuronavigation: Stereotaxic neuronavigation allows us to track the 
positioning of the ultrasound transducer on the subject's head in real time using the 
MR/CT images for guidance.   
 

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LIFU: Low-intensity focused ultrasound (LIFU) is a method of brain neuromodulation 
using ultrasonic acoustic energy. An ultrasound transducer is placed on the participant's 
head and is tracked using the neuronavigation system. Brief ultrasound pulses are 
delivered to the desired brain area. A small amount of ultrasound gel will be placed on 
the face of the single-element focused ultrasound transducer. The transducer will then be 
fitted on the scalp over the desired brain area and held in place with a mechanical arm. 
Brief pulses (0.1-1.0 seconds; duty cycle 1 – 70%; pulse repetition frequency 10 – 1000 
Hz) of low-intensity (< 50 W/cm2 Isppa), sub-thermal ultrasound (0.3 - 0.5 MHz) will be 
delivered in order to determine the area of activation, as well as the patterns of brain 
activity generated. Subjects may experience a mild buzzing sensation on their scalp 
depending upon stimulation parameters used. Participants will be familiarized with the 
sensations before formal testing. The ultrasound intensity used will be below the 
intensities recommended for the safe use of ultrasound by the FDA (190 W/cm2 Isppa) 
and will be brief in duration at these low-intensities as not to generate any heating. While 
no discomfort is anticipated, participants will be informed if they experience any 
warming sensation on their scalp or discomfort to notify the investigator and the 
procedure will be immediately terminated. Participants may be given ear plugs to wear 
during the procedure and/or a white noise machine may be utilized in the testing space. 
This is to provide ear protection and noise cancellation to reduce participant focus on 
LIFU device function. We have significant experience using LIFU including our 
published reports of human neuromodulation experiments. 
 
TMS: transcranial magnetic stimulation (TMS) is a noninvasive method of stimulating 
the brain using magnetically induced electrical currents. The stimulating coil is placed 
over a subject's motor cortex and a single pulse is conducted. This is repeated 10-20 
times at an inter-stimulus interval of 5-10 seconds per trial. A threshold setting will be 
determined for each participant before each study session to obtain an average motor 
evoked potential of approximately 0.75mV, measured with EMG recordings. This will be 
the setting used throughout the testing session.  
 
EMG: Electromyography (EMG) involves attaching disposable surface electrodes to the 
skin overlying muscles of interest of the hand and forearm in order to record muscular 
activity. Identification of the muscle is achieved by asking the participant to hold a light 
tonic contraction. The skin may be prepared with a mild abrasive gel to remove dead skin 
and surface debris and subsequently disinfected with rubbing alcohol. EMG electrodes 
are held in place with double sided tape. This signal is used to detect LIFU effects and 
TMS amplitude.  
 
PPG, GSR, ECG, BP, Respinration: Photoplethysmograph (PPG) and galvanic skin 
response (GSR) will be collected using a lightweight wearable Shimmer3 GSR+ unit and 
blood pressure will be collected using a wireless blood pressure monitor (QardioArm). A 
commercial respiration belt (SleepSense) will be wrapped around the chest to collect 
continuous respiration data. Electrocardiogram (ECG) will be collected using two leads. 
This data is collected to assess for any effects of ultrasound but more importantly as a 
monitor of the state of the participants’ autonomic nervous system as a potential 
contributor/confound that may affect responses. 

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Questionnaires: Questionnaires will be collected either electronically using a VT 
approved platform such as Redcap, or on paper. The following questionnaires will 
generally be completed during the imaging and consent visit but may be completed at 
following visits if time does not allow during the first visit: Beck Depression Inventory-II 
(BDI), Beck Anxiety Inventory (BAI), State Trait Anxiety Inventory (STAI), 
International Physical Activity Questionnaire (IPAQ), Medical Outcomes Survey Short 
Form-8 (SF-8), Sleep Scale from the Medical Outcomes Study, Patient Health 
Questionnaire-2 (PHQ-2), Generalized Anxiety Disorder 2-item (GAD-2), Tobacco, 
Alcohol, Prescription medications, and other Substance Tool (TAPS), and Perceived 
Stress Scale (PSS). Questionnaires may be used as a means of documenting potential 
confounds such as anxiety, fear, depression, etc. Questionnaires are estimated to take 30-
45 minutes to complete. Additionally, the STAI (state only), Experience Questionnaire, 
Daily Questionnaire, and Report of Symptoms questionnaires will be administered at all 
stimulation sessions (sessions 2-7). The Daily Questionnaire exists to help quantify any 
variance between participant sessions. This includes items such as amount of sleep, 
hormone changes, and caffeine intake. Lastly, subjects will be contacted up to one month 
following the final session to complete the participant Report of Symptoms questionnaire. 
All questionnaires are attached to this application. 
 
8.3 Describe: 
● 
Procedures or safeguards intended to reduce the probability and 
magnitude of risks. (For example: Reducing the risk of injury in a 
virtual reality study either by having the subjects sit during the study 
or by providing an obstacle-free space for walking.) 
● 
Be sure to describe all drugs and devices used in the research, when 
they will be administered or used, and their purpose.  
● 
Methods used to collect data about subjects. Please upload all data 
collection forms to Protocol Management. Some common examples 
are: 
● Screening questionnaires  
● Survey(s), including online surveys 
● Demographic questionnaire(s) 
● Interview guide(s), e.g., questions or pool of questions for semi-
structured interviews  
● Focus group guide(s) 
● Other documents used to collect data  
 
Every effort will be made to ensure the subject's comfort and to reduce any risk. Subjects 
will be thoroughly screened to ensure that MR and CT contraindications are not present. 
All females will be screened for pregnancy.  If, at any time, subjects experience 
discomfort, dizziness, or claustrophobia they will be able to discontinue immediately.  
 

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During MRI scanning subjects will have access to an emergency squeeze bulb they can 
indicate at any time. Staff operating the MRI undergo Advanced MR/Operator Training. 
This is required for persons wishing to conduct research on the Human Neuroimaging 
Lab (HNL) MRIs. Training consists of presentations, observation, and hands-on practice. 
Topics include safety and emergency procedures, subject screening and preparation, 
scanner set-up and operation, and troubleshooting. Each person must also complete at 
least 4 hours of observation (to include 2 different studies) and at least 16 hours of 
supervised scanning (to include 4 different studies). Certification is granted upon 
completion of the training and passing of a competency exam.  
 
During CT scanning subjects will be in communication with the trained technician. A 
trained and certified radiology technician will operate the CT.  
 
During LIFU stimulation sessions participants will be in constant communication with 
the study staff. Staff operating the LIFU device, TMS device, and 
EMG/PPG/BP/GSR/ECG/Respiratory recording device will undergo training under the 
direction of the PI. Additionally, participants will be reminded they can terminate the 
session at any time. Screening for side effects will take place pre and post all stimulation 
sessions.  
 
Methods used to collect data: 
We will collect questionnaires and screening information (see attached forms and 
questionnaires) using an electronic Virginia Tech approved system such as Redcap or 
Qualtrics, or via paper form.  
 
The MRI and CT will be used to collect brain images, and EMG will be used to collect 
muscle contraction signals. Standard devices will be used to collect PPG, BP, ECG, 
Respiration, and GSR data. All data will be stored on FBRI servers with the subject 
coded identifier.  
 
8.4 What data will you collect during the study and how you will obtain them? 
Please include descriptions of electronic data collection, database 
matching, and app-based data collection: 
 
Images will be obtained of the subjects' head/brain from MRI and CT scans. EMG signals 
will be collected using standard EMG equipment. Photoplethysmograph (PPG), blood 
pressure, heart rate, respiration, and galvanic skin response data will be collected using 
standard equipment. Electronic data such as questionnaires or screening forms may be 
collected through secure web-based survey tools, such as RedCap, provided by Virginia 
Tech. The Daily Questionnaire exists to help quantify any variance between participant 
sessions. This includes items such as amount of sleep, hormone changes, and caffeine 
intake. Additionally, questionnaire or screening data may be recorded on paper, entered 
into a digital database and then stored securely. All data will be stored on secure FBRI 
servers.  
 

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8.5 Who will transcribe or code audio and/or video recordings?: 
 
N/A 
 
8.6 Include a description of any deception to be used in the study. Include 
justification for the use of deception (why the deception is necessary), 
describe the debriefing process, and describe how the study meets all the 
following criteria  for alteration of consent (deception is considered an 
alteration of informed consent): 
• The research involves no more than minimal risk to the subjects 
• The alteration will not adversely affect the rights and welfare of the 
subjects 
• The research could not practicably be carried out without the 
alteration/deception 
• (Optional but encouraged in most cases) Subjects will be provided with 
additional pertinent information after participation (i.e., debriefing for 
studies involving deception)  
N/A 
 
8.7 If the study involves long-term follow-up (once all research related 
procedures are complete), describe what data will be collected during the 
follow up period and when it will occur:  
 
N/A 
 
9.0 
Data and Specimen Long Term Storage and Use 
9.1 If you will store data or specimens for future use, describe where you will 
store the data or specimens, how long they will be stored, and how and by 
whom the data or specimens will be accessed: 
 
All data collected from subjects will be assigned a coded designation. MRI, CT, EMG, 
and behavioral data will be stored on secure FBRI servers indefinitely. All of this data 
will have no identifying information.  Only the code will link it to the PII of the subject. 
The de-identified data will be made available to authorized study staff, and may be stored 
elsewhere such as Dropbox, iCloud, or a local drive on a desktop or laptop. Further, after 
publication of results, de-identified data may be made available to the public in 
accordance with funding and publication requirements, or otherwise.  
 
9.2 For specimens, list the data to be stored or associated with each 
specimen: 
 
N/A 

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9.3 Describe the procedures to release data or specimens outside of the 
research team, including the process to request a release, approvals 
required for release, who can obtain data or specimens, and what data 
will be provided with specimens: 
 
Prior to publication of results, de-identified data will be made available to study staff as 
listed on the approved IRB. After publication, de-identified data may be made public as 
required by funding sources, journals, or otherwise.  
 
9.4 Describe the identifiers to be included with stored data or specimens, as 
well as any key or code that could be used to make them identifiable. 
Describe where the code will be stored, who will have access to it, and 
when it will be destroyed: 
 
Data will be coded using a randomly generated identifier. The study key linking name to 
identifier is stored digitally under password access, only accessible by authorized 
members of the research team.  
 
Participant Social Security Number (or Taxpayer ID) and street address are collected in 
order to compensate participants, via W9 form or W-8BEN. This information is entered 
into the ClinCard system, which is a HIPAA compliant payment system approved by 
Virginia Tech. After entry the form is stored by central administration at Virginia Tech to 
be used if it is required. Study staff do not store documents with SSN or address long 
term. International participants will also be asked to provide a copy of passport, visa 
documents, any work authorizations, as well as the Foreign National Data Form. 
 
Documents with other identifiers, such as name, phone number, email, or elements of 
dates are stored separately from de-identified study data, either via encryption or in a 
locked file cabinet, accessible only by study staff.  
 
9.5 Please select the identifiers you will obtain (whether directly from 
participants or from another source), including but not limited to: 
 
☒ 
Name 
☒ 
Geographical subdivisions smaller than a state, including street address, 
city, county, precinct, zip code, and equivalent geocodes (note, the initial 
three digits of a zip code are not considered identifiable) 
☒ 
Elements of dates (except year) for dates directly related to an individual, 
including birth date, admission date, discharge date, date of death, and 
single year of age over 89 and all elements of dates (including year) 
indicative of such age (note, such ages and elements may be aggregated 
into a single category of age 90+) 

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☒ 
Phone numbers 
☐ 
Fax numbers 
☒ 
Electronic mail addresses (e-mail) 
☒ 
Social Security numbers 
☐ 
Medical record numbers 
☐ 
Health plan beneficiary numbers 
☐ 
Account numbers 
☐ 
Certificate/license numbers 
☐ 
Vehicle identifiers and serial numbers, including license plate numbers 
☐ 
Device identifiers and serial numbers 
☐ 
Web Universal Resource Locators (URLs) 
☐ 
Internet protocol (IP) address numbers 
☐ 
Biometric identifiers, including finger and voice prints (audio recording) 
☐ 
Full face photographic images and any comparable images (including 
video recording) 
☐ 
Student record number or identification number   
☐ 
User name for online or computer accounts 
☒ 
Any other unique identifying number, characteristic, or code (note this 
does not mean the unique code assigned by the investigator to code the 
data): Passport ID   
 
10.0 Sharing of Results with Subjects 
10.1 Describe whether you will share results (study results or individual subject 
results, such as results of investigational diagnostic tests, genetic tests, or 
incidental findings) with subjects or others (e.g., the subject’s primary care 
physician). If so, describe how you will share the results and include this 
information as part of the consent document. Upload materials you will use 
to explain the results to subjects: 
 
Study results will not be shared with participants directly as they are de-identified prior to 
analysis and/or publication. Participants will be offered a CD with raw (non-analyzed) 
MRI structural images, if desired. It is explained in the consent that these images are not 
reviewed by a physician and participants must go through their medical provider for any 
neurologic evaluations.   
 
11.0 Study Timelines 
11.1 Describe: 
● 
The duration of an individual subject’s participation in the study (for 
example, 1 hour, 2-4 weeks, 3-5 years). 
● 
The amount of time expected to enroll all study subjects (weeks, 
months, years, etc.) 
● 
The amount of time expected for the investigators to complete this 
study including primary data analyses. 

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Participants will be asked to participate in 7 study sessions lasting from 2-2.5 hours each. 
Participants will complete scanning tasks (MRI and CT), parameter tasks (LIFU/TMS), 
and/or questionnaires in any given session. It is anticipated that there will be a minimum 
of 1 week between a first and second study session to allow for image processing. Total 
study participation is expected to last 2-4 weeks per subject. Timeline for study data 
collection and primary analysis is two years.  
 
12.0 Inclusion and Exclusion Criteria 
12.1 Describe how you will screen individuals for eligibility. When will 
screening occur and what procedures will you use? Upload any screening 
scripts or surveys to Protocol Management:  
 
Subjects will be screened with electronic screening forms prior to scheduling a study visit 
to determine study, MRI, and CT eligibility. Study screening forms are attached. Once 
consented, female subjects will be screened for pregnancy by study staff.  
 
12.2 Describe the eligibility criteria that define who will be included and who 
will be excluded from enrollment for each procedure of your study. 
Include any geographic criteria (e.g., Virginia Tech undergraduate 
students, a national sample of adults with engineering degrees, minors 
aged 8-12 in the New River Valley, university faculty in Virginia and 
Paris, France): 
 
Inclusion criteria: Healthy volunteers, age 18-65. Both females and males of all 
ethnicities, who understand and speak English.  
 
Exclusion criteria:  
The exclusion criteria below are regularly implemented in MRI, CT, and TMS 
experiments for the safety of the subjects and for data quality assurance.  
1. Claustrophobia (scanning environment may be uncomfortable). 
2. Contraindications to MRI: including pacemaker, aneurysm clips, neurostimulators, 
cochlear implants, metal in eyes, steel worker, or other implants.  
3. Contraindications to CT: pregnancy. 
4. Active medical disorder or treatment with potential CNS effects (e.g. Alzheimer's) 
5. History of neurologic disorder. (e.g. Parkinson's, Epilepsy, or Essential Tremor)  
6. History of head injury resulting in loss of consciousness for >10 minutes. 
7. History of alcohol or drug dependence (through self-report).  
8. Failure to provide a Social Security Number or Tax ID Number. This is required for 
tax purposes or payment cannot be processed.  
 
Healthy individuals will include any persons who are not excluded based on the above 
listed criteria.  
 

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The minimum age for inclusion is 18 years. This is based upon literature citing that the 
safety of non-invasive brain stimulation in children/adolescents is unknown (Krishnan et 
al. 2015). There is evidence that the structural (Caviness et al. 1996) anatomy and 
importantly the mechanical properties of the child/adolescent brain is different from the 
adult (Chatelin et al. 2012). This is critical when using ultrasound as the effect of 
ultrasound is directly linked to the mechanical properties of tissue (Tyler 2012). Thus, 
studies in children/adolescents may not relate similarly to adult and thus the findings may 
not translate to the general population. 
 
The maximum age for inclusion is 65 years. Non-invasive brain stimulation looks to be 
safe in the elderly (Krishnan et al. 2015) and may have benefit (Legon et al. 2017). 
However, structural anatomy in the elderly is different including enlarged ventricles and 
CSF space (Ambarki et al. 2010; Sullivan et al. 2002). This may increase pressure from 
ultrasound in the brain and/or produce cavitation and/or unwanted standing waves – all of 
which are potential safety hazards. Functional anatomy of the elderly brain also shows 
differences from the adult brain (Hafkemeiger et al. 2013; Madden et al. 1999) that may 
affect outcomes measures of this study and not relate to the general population. The skull 
of the elderly is also different in that it may contain greater calcification. This is a 
potential safety hazard as it can heat abnormally from ultrasound. 
 
Chatelin, S., Vappou, J., Roth, S., Raul, J. S., & Willinger, R. (2012). Towards child 
versus adult brain mechanical properties. Journal of the mechanical behavior of 
biomedical materials, 6, 166-173. 
Krishnan, C., Santos, L., Peterson, M. D., & Ehinger, M. (2015). Safety of noninvasive 
brain stimulation in children and adolescents. Brain stimulation, 8(1), 76-87. 
Legon, W., Punzell, S., Dowlati, E., Adams, S. E., Stiles, A. B., & Moran, R. J. (2016). 
Altered prefrontal excitation/inhibition balance and prefrontal output: markers of aging in 
human memory networks. Cerebral Cortex, 26(11), 4315-4326. 
Ambarki, K., Israelsson, H., Wåhlin, A., Birgander, R., Eklund, A., & Malm, J. (2010). 
Brain ventricular size in healthy elderly: comparison between Evans index and volume 
measurement. Neurosurgery, 67(1), 94-99. 
Sullivan, E. V., Pfefferbaum, A., Adalsteinsson, E., Swan, G. E., & Carmelli, D. 
(2002). Differential rates of regional brain change in callosal and ventricular size: a 4-
year longitudinal MRI study of elderly men. Cerebral Cortex, 12(4), 438-445. 
Hafkemeijer, A., Altmann-Schneider, I., Oleksik, A. M., van de Wiel, L., Middelkoop, H. 
A., van Buchem, M. A., ... & Rombouts, S. A. (2013). Increased functional connectivity 
and brain atrophy in elderly with subjective memory complaints. Brain connectivity, 3(4), 
353-362. 
Madden, D. J., Turkington, T. G., Provenzale, J. M., Denny, L. L., Hawk, T. C., Gottlob, 
L. R., & Coleman, R. E. (1999). Adult age differences in the functional neuroanatomy of 
verbal recognition memory. Human brain mapping, 7(2), 115-135. 
 
12.3 Indicate specifically whether you will include or exclude each of the 
following special populations: (You may not include members of these 
populations as subjects in your research unless you indicate them in the 
description of your subject population.) 

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● 
Minors, as defined by state law where the study is performed 
(infants, children, teenagers) 
● 
Pregnant women (can be included in minimal risk studies by 
mentioning in section 13.1) 
● 
Prisoners (including all incarcerated individuals) 
● 
Adults not capable to consent on their own behalf 
 
Pregnant women, minors, prisoners, and adults unable to consent on their own behalf will 
be excluded.  
 
13.0 Vulnerable Populations 
13.1 If the research involves individuals who are vulnerable to coercion or 
undue influence, please describe additional safeguards you will include to 
protect their rights and welfare. Consider the applicable items listed 
below: 
● 
If the research involves Virginia Tech students, indicate whether 
these are students of any of the investigators. If so, describe whether 
the activities will take place during class time as part of the 
curriculum and the steps you will take to reduce the possibility that 
students feel obliged to participate in order to improve their course 
grade. The HRPP can provide further guidance as needed. Describe 
whether you will request access to student records (e.g., SAT, GPA, 
GRE scores). 
● 
If the research involves employees of Virginia Tech or the research 
sponsor, describe steps you will take to ensure that the employees 
are freely participating and describe how their data will be 
protected from inspection by their supervisors.  
● 
If the research involves Virginia Tech NCAA athletes, you must 
obtain approval from the athletic department.  
● 
For research involving Montgomery County Public Schools, you 
must obtain county approval (after obtaining contingent Virginia 
Tech approval). Other locales have different requirements; please 
check on these and describe here. Approval is typically granted by 
the superintendent, principal, and classroom teacher (in that order). 
Approval by an individual teacher is insufficient. School approval, in 
the form of a letter or a memorandum should be uploaded as a 
supporting document. 
● 
If the research involves pregnant women, review “CHECKLIST: 
Pregnant Women (HRP-412)” to ensure that you have provided 
sufficient information in this protocol. 
● 
If the research involves prisoners, review “CHECKLIST: Prisoners 
(HRP-415)” to ensure that you have provided sufficient information 
in this protocol. 
● 
If the research involves persons who have not attained the legal age 
for consent to treatments or procedures involved in the research 

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(minors), review the “CHECKLIST: Minors (HRP-416)” to ensure 
that you have provided sufficient information in this protocol. 
● 
If the research involves cognitively impaired adults, review 
“CHECKLIST: Cognitively Impaired Adults (HRP-417)” to ensure 
that you have provided sufficient information in this protocol. 
 
All subjects will be informed of the purpose of the study, the potential value to society, 
the lack of value to the subject personally, and all potential risks to the subject.  It will be 
explained to the subject that they are under no obligation to participate, and that they may 
discontinue at any time during the study, without penalty.  Employees will be told that 
their employment status will in no way be affected by their decision to participate in the 
study. Students will be advised that their decision to participate will not affect their 
student status, grades, coursework, or extra-curricular activities.  
 
14.0 Number of Subjects 
14.1 Indicate the total number of subjects to be enrolled and how this number 
was determined (e.g., sample size calculation [show], number of available 
subjects in a finite pool, number of tests funding award would allow):  
 
We anticipate enrolling 80 subjects in this study. This population size should allow for 
adequate statistical significance and analysis.  
 
It is anticipated that 70 percent of participants will complete the study sessions. To 
account for this we anticipate enrolling 80 participants to yield approximately 56 
participants.   
 
Based upon preliminary data (N = 5) and only two variables (duty cycle and duration) we 
found maximal changes of motor evoked potential amplitudes of 46.35% ± 12.33 and -
25.54% ± 15.56 depending upon variable selection. Minimal changes with change of 
variables was 5.99 ± 7.87. We propose an N = 56 and while N is not sufficient to detect a 
statistically significantly difference of ~ 6% an N = 56 is sufficient with a power of 0.8 
and a p = 0.05 to detect a ~15% that we suggest is the minimal significant change that is 
required for potentially clinically significant change.  
 
14.2 If this is a multi-site study, indicate the number of subjects to be enrolled 
at this site and the total to be enrolled from all sites: 
 
N/A 
 
14.3 If applicable, indicate the number of potential subjects you expect to 
screen for enrollment, and the number of subjects you will need to 
complete the research procedures: 
 

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It is anticipated that 70 percent of participants will complete the study sessions. To 
account for this we anticipate enrolling 80 participants to yield approximately 56 
participants. 
 
14.4 If the study has more than one procedure, indicate the total number of 
subjects to undergo each procedure separately: 
 
It is anticipated that all participants will complete all study procedures, given subject 
interest.  
 
15.0 Recruitment Methods 
15.1 Describe when, where, and how you will recruit potential subjects: 
 
Subjects aged 18-65 years old will be recruited from the general population.  
 
Interested individuals will be invited to complete an online set of screening and 
demographic forms using an approved VT platform such as Redcap or Qualtrics. See 
attached screening forms.  
 
Subjects that meet eligibility criteria for both the study, and MRI, CT, and TMS safety, 
will be invited to participate and enrolled in the study.  
 
Subjects will be recruited through flyers in the community, word of mouth, and electronic 
communication. For example, invitation to participate in research studies are posted on 
the FBRI at VTC webpage, Facebook, and Twitter. Only IRB approved images and 
wording will be utilized.  
 
Communication with subjects will occur both through phone and electronic means such 
as email.  
 
15.2 Describe the source of subjects (for example, clinic patients with specific 
conditions, students in the library, community members at a gathering, or 
members of a local gym): 
 
Subjects will be recruited through the Fralin Biomedical Research Institute at VTC, as 
well as the general public.  
 
15.3 Describe the methods that you will use to identify potential subjects: 
 
Interested study volunteers will be invited to complete an electronic screening form 
(attached), which will be stored on a secure server.  Study personnel will review 

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screening forms to locate eligible subjects which will then be contacted by email or 
phone to invite them to participate in the research.  
 
15.4 Describe materials that you will be use to recruit subjects. Attach copies 
of these documents with this protocol in Protocol Management and be 
sure to include the IRB protocol number on each document.  
● For flyers, attach the final copy of printed flyers.  
● For Virginia Tech News, Facebook postings and ads, newspaper ads, 
websites, MTurk/SONA/online survey systems, etc., attach the final 
wording and graphics to be used.  
● For email recruitments, please include the subject line.  
● For advertisements meant for audio broadcast, please submit the 
wording of the advertisement prior to taping (to avoid having to re-
record with approved language) and submit the final recorded version 
for IRB review before use.  
● Describe any compensation to subjects. Separate compensation into 
appropriate categories, such as: reimbursement for expenses, time and 
effort, and additional incentives for study participation.  For each 
category, specify the amount (including any pro-rated amount), schedule, 
and method of payment. 
 
See attached recruitment document, flyers, and images.  
 
Compensation: Subjects will be compensated for their time in the research study.  
Subjects will be compensated $20 for the first hour, and $10 for each additional half hour 
of study procedures after the initial hour of participation. This compensation applies for 
each study session, including all study procedures. In the event of a screen fail, standard 
compensation procedures still apply. There is an electronic questionnaire that can be 
completed remotely, which once confirmed is an additional $10 in compensation. 
Subjects will be informed of this payment scheme prior to participation. Subjects are able 
to withdraw at any time, without penalty.  
 
Study payments will be loaded onto an electronic Clincard.^  
 
Expected compensation is as follows: 
 
Session 1 - MRI and CT scan, 2.5 hours, $50 
Session 2-7 - LIFU/TMS/EMG, 2.5 hours per visit, $50 per visit 
Follow up - Online questionnaire, <15 minutes, $10 
 
Total - $360  
 
^ International subjects will be paid via Hokiemart and processing may take a few 
business days. Amount of compensation will not change. 
 

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16.0 Withdrawal of Subjects 
16.1 Describe circumstances under which you anticipate subjects could be 
withdrawn from the research without their consent: 
 
As is standard with MRI and TMS research, if subjects experience unusual sensations, 
they will be withdrawn. In some cases, due to the magnetic field (as described in risks 
below), subjects may experience peripheral nerve stimulation, e.g. tingling or twitching. 
They will be withdrawn from the study if this occurs. Researchers reserve the ability to 
withdraw a subject at any point in the study.  
 
16.2 If applicable, describe any procedures for orderly termination (e.g., 
discontinuation of a study drug or debriefing after a behavioral 
intervention): 
N/A 
 
16.3 Describe procedures that you will follow when subjects withdraw from the 
research, including partial withdrawal from procedures with continued 
data collection (e.g., participant declines to continue with regular blood 
draws, but continues with periodic behavioral questionnaires): 
 
Subjects will be compensated for their time, as described above, regardless of completion 
of all study tasks.  
 
17.0 Risks to Subjects 
17.1 List the reasonably foreseeable risks, discomforts, hazards, or 
inconveniences to the subjects related the subjects’ participation in the 
research. Include for the IRB’s consideration a description of the 
probability, magnitude, duration, and reversibility of the risks. Consider 
physical, psychological, social, legal, privacy, and economic risks. Do not 
indicate “No risk” or “N/A.” Instead, for studies with very low risk (e.g., 
anonymous online questionnaire on a mundane topic) indicate “The 
investigators are not aware of any risks from participation in this study.” 
or “No more than risks than are found in everyday life.” The example 
consent form presents a tabular method for risk information, which you 
can also use here. Common risk types include: 
● Physical (e.g., potential for pain, discomfort, infection) 
● Psychological (e.g., potential for stress, discomfort, and/or 
embarrassment) 
● Social (e.g., potential for discrimination or stigmatization and 
disruption of personal and family relationships) 
● Legal (e.g., potential for disclosure of illegal activity, negligence) 

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● Privacy (e.g., potential for personal information being accessed, used, 
or disclosed without the subjects’ knowledge or consent, breach of 
confidentiality/security) 
● Economic (e.g., potential for individuals to lose access to economic 
services, employment, insurability) 
 
MRI Data Collection: Movement or heating of metallic implants is a potential risk; 
Subjects will be screened to exclude people with metallic implants, fragments, or 
pacemakers. Some individuals experience claustrophobic reactions in the scanner. 
Subjects will be informed of this prior to the study. Any subject experiencing 
claustrophobia will be removed from the scanner immediately. The Siemens 3 Tesla (T) 
scanner has been approved by the FDA. However, there may be additional risks 
associated with scanning at 3 T compared to the conventional clinical scanners in the 1.5-
2.0 T range. These include: 
 
1. Effect of the static field. There is no conclusive evidence for irreversible or hazardous 
bioeffects to acute, short-term exposures of humans up to 2.0 T (Shellock and Kanal, 
1996). Studies have indicated some side effects at 4.0 T, namely unusual sensations 
including nausea, vertigo, and metallic taste (Schenck, 1992). However, there is no 
evidence that this is either irreversible or harmful. If subjects experience unusual 
sensations, they will be withdrawn. 
 
2.  Effect of the gradient field. MRI operates by rapidly changing small additional fields, 
called gradients. This will induce small electrical currents in any conductor, and thus 
could theoretically induce mild peripheral nerve stimulation. However, this is not 
substantially different at higher magnetic fields since the gradients are separate from the 
main magnet. There is no evidence that the effect of the gradients is any different at 3 T 
than at 1.5 T. However, if subjects experience peripheral nerve stimulation, e.g. tingling 
or twitching, they will be withdrawn. 
 
3.  Effect of the Radio Frequency (RF) electromagnetic field. The 3.0T magnetic field 
strength requires higher RF frequency pulses to excite the protons in the subject's brain. 
The limits of RF energy that humans can be safely exposed to are outlined by the FDA 
and the IEEE International Committee on Electromagnetic Safety: a) The exposure to RF 
energy below the level of concern is a Specific Absorption Rage (SAR) of 4 W/kg or less 
averaged over the body, and 10.0 W/kg or less spatial peak in any 10 g of tissue, and 3.2 
W/kg or less average over the head; or b) The exposure to RF energy that is sufficient to 
result in a core temperature increase of 1 degree C and localized heating to no greater 
extent than 38 degrees C in the head, 39 degrees C in the trunk, and 40 degrees C in the 
extremities, except for patients with impaired systemic blood flow and/or perspiration 
(Institute of Electrical and Electronics Engineers, 2006) The scanners used have a large 
monitor indicating the RF power level which can be limited to a specific maximum; We 
will adhere to the approved limits for the head. 
 
4. Acoustic Noise Levels. Rapid changes in the currents in the gradient coils of the MRI 
scanner produce significant levels of acoustic noise. The levels of noise approximately 

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range between 65 and 95 dB, but could have higher peaks. Communications with subjects 
takes place with the standard pneumatic headphones provided by the scanner 
manufacturer. These headphones provide some degree of noise reduction. Foam ear plugs 
with a Noise Reduction Rating of 31 dB will be provided.  
 
While in the scanner, participants lie still for approximately 15 minutes so that we may 
take images of their brain. They will be asked to relax and remain still, thus no physical 
harm can reasonably be expected from this procedure, other than perhaps mild stiffness 
from remaining still. 
 
All individuals who will be operating the scanners are required to pass an fMRI safety 
training course. However, it should be noted that over the past several years and over 
3000 imaging sessions, we have had no scanner-related emergencies. 
 
CT Data Collection: Participants will undergo a head CT to obtain necessary images of 
their skull.  CT scans will be a low-dose scan with expected radiation dose of about 
2mSv. This does gives a lifetime cancer risk of about 1 in 10,000. The lifetime natural 
incidence rate is about 1 in 2. Equipment will be operated by trained personnel only.  
 
To reduce both time burden and ionizing radiation exposure, if previous MRI or CT scans 
have been taken with the Legon lab, they can be used in this study and the first study visit 
procedures may be omitted.  
 
Low-Intensity Focused Ultrasound: Brief pulses (0.1-1.0 seconds; duty cycle 1 – 70%; 
pulse repetition frequency 10 – 1000 Hz) of low-intensity (< 50 W/cm2 Isppa), sub-
thermal ultrasound (0.3 - 0.5 MHz) will be delivered in order to determine the area of 
activation, as well as the patterns of brain activity generated. Subjects may experience a 
mild buzzing sensation on their scalp depending upon stimulation parameters used. 
Participants will be familiarized with the sensations before formal testing. The ultrasound 
intensity used will be below the intensities recommended for the safe use of ultrasound 
by the FDA (190 W/cm2 Isppa) and will be brief in duration at these low-intensities as 
not to generate any heating. While no discomfort is anticipated, participants will be 
informed if they experience any warming sensation on their scalp or discomfort to notify 
the investigator and the procedure will be immediately terminated.  
   
Comparison between the LIFU parameters used in proposed study to those for obstetric 
diagnostic imaging: The FDA guidelines for obstetric diagnostic images include derated 
limits of spatial peak pulse average (Isppa) of 190 W/cm2, a spatial peak temporal 
average of 720 mW/cm2 and a mechanical index (MI = peak negative pressure/√fc) of 
1.9. This study will use less than 50 W/cm2 (4x lower Isppa) for these studies. We have 
significant experience using LIFU including our published reports of human 
neuromodulation experiments. 
 
Transcranial Magnetic Stimulation: Single-pulse TMS is used to probe the state of the 
motor system. The FDA approved TMS parameters for the treatment of major depression 
is 10Hz stimulation with 120% motor threshold; 4-second pulse trains; 26-second 

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intertrain intervals, and each treatment session is last for 37.5 minutes, this is a total of 
3,000 pulses.  The proposed TMS parameters will stay below parameters for safety 
consideration. The device creates a clicking noise which can result in tinnitus. Hearing 
protection will be provided to participants to reduce this risk. Participants should not feel 
any discomfort, but will feel a small twitching movement in their hand. This may lead to 
residual soreness. Some people experience headaches or dizziness, which may be due to 
excessive muscle tension of the face and neck. Breaks will be taken where possible to 
reduce this tension. TMS may cause lightheadedness or fainting. We will encourage 
participants to eat a full meal and hydrate before study visits. There is a remote 
possibility that TMS can induce a convulsion even in the absence of neurological disease, 
epilepsy or other risk factors for seizures.  
 
Electromyography: EMG may involve skin prep with a mild abrasive gel to remove dead 
skin and surface debris and subsequently disinfection with rubbing alcohol. This may 
cause mild skin irritation.  
 
Due to the investigative nature of this study there may be other risks that are currently 
unknown.  
 
Personally Identifiable Information (PII) Collection: There is the risk that personally 
identifiable information (associated with the research materials) could be compromised. 
Study staff will take recommended and industry approved precautions to ensure 
confidentiality and security of the data. 
 
17.2  Indicate the measures you will use to minimize risks and monitor subjects 
for safety. (e.g., asking a subject at regular intervals to rate how they are 
feeling from 1 to 10, or to slowly crouch in order to check their balance.) 
 
Participants will be screened for safety and any MRI, CT, TMS or ultrasound 
contraindications, including pregnancy testing. MRI and CT operators will utilize a 
microphone/headphone system to communicate after positioned in the scanner, while the 
scanner is not operating. A squeeze bulb is provided during MRI in order for the 
participant to indicate that they would like to stop or are uncomfortable. Study staff will 
be present throughout all LIFU/TMS procedures and they will be halted if the subject 
experiences any unexpected sensations. Breaks will be offered periodically to reduce 
participant discomfort. Monitoring for side effects will take place pre and post all 
stimulation sessions.  
 
17.3 If applicable, indicate which procedures might have risks to the subjects 
that are currently unforeseeable. This will be rare, and usually applicable 
when testing a new drug or device or a new use of an existing drug or 
device: 
 
N/A 
 

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17.4 If applicable, indicate which procedures might have risks to an embryo or 
fetus should the subject be or become pregnant: 
 
CT should not be performed in pregnant women. Ionizing radiation can cause 
developmental problems in fetuses, particularly in the first trimester. Risks of using TMS 
with pregnancy women are currently unknown. Pregnant women will be excluded from 
this study. At the first study visit, study staff will screen for pregnancy in all females.  
 
17.5 If applicable, describe risks to others who are not subjects (e.g., collection 
of sensitive health data that might affect sexual partners if disclosed, 
mandatory reporting of abuse, DNA testing that might affect family 
members or relationships): 
 
N/A 
18.0 Potential Benefits to Subjects 
18.1 Describe the potential benefits that individual subjects might experience 
from participating in the research. Include the probability, magnitude, and 
duration of the potential benefits, as this will be useful to the IRB’s 
risk:benefit analysis. Do not include benefits to society or others. Do not 
list monetary or non-monetary compensation for participation, as this is 
not a benefit These should be included in section 2 or 3 of this document: 
 
There are no anticipated direct benefits for participants.  
 
18.2 If applicable, specify that there are no anticipated direct benefits for 
participants:  
There are no anticipated direct benefits for participants.  
 
19.0 Data Management and Confidentiality 
19.1 Describe procedures that you will use for quality control to ensure validity 
of collected data: 
 
All research staff conducting study procedures are trained to do so, through Human 
Subjects Protections, MRI safety training, and device specific operation trainings. All CT 
scans will be performed by a trained radiology technician.  
 
19.2 Describe any existing data or biospecimens you will obtain as part of this 
study. Include:  
● 
Variables or samples to be obtained  

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● 
Source of the data or specimens 
● 
Your authorization to access or receive the data or biospecimens 
● 
Whether the data or biospecimens are publicly available 
● 
Whether the data or specimens you receive will contain identifiers  
 
N/A 
 
19.3 Describe the steps that you will take to handle and secure study data 
during data collection, storage, use, and transmission.  Include 
information about training of study staff, authorization of access, 
password protection, encryption, physical controls, certificates of 
confidentiality, separation of identifiers and data, etc.: 
 
Each subject will be assigned a coded designation. All study data to be used in analysis 
will be de-identified using this coded designation, and contains no biographical data that 
can be linked to individuals. The key for study codes is stored in a secure server 
accessible only by limited authorized personnel. Any screening forms collected on paper 
will be stored in a locked filing cabinet within the Legon lab space. All electronic data 
collected will be stored on secure servers.  
 
MRI, CT, EMG, and behavioral data will be stored on secure FBRI servers.  
 
Participant screening and questionnaire data will be collected and stored on the secure 
platform Redcap.  
 
The MRI, CT, EMG, and behavioral data files will have no identifiable information 
stored within them. Only the participant coded designation, whose key is only 
accessible by authorized study personnel, links these data to the participant. These de-
identified data will be available to authorized personnel for data analysis, and may be 
made available to the public as required by funding source and journal used for study 
publication. 
 
19.4 For multi-site studies, describe how data or specimens will be handled 
and secured for each site (e.g., central or disseminated data storage, data 
coordinating center): 
 
N/A 
 
19.5 Describe the plan for data disposition following the conclusion of the 
study (e.g., long term maintenance of data, data destruction methods).  

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● 
What information will be included in the long term storage of data 
or specimens? 
● 
How long will the data or specimens be stored? 
● 
Where and how data or specimens will be stored? 
● 
Who will have access to the data or specimens during long term 
storage? 
● 
Who is responsible for receipt or transmission of the data or 
specimens? 
● 
How will data or specimens be shared or transported? 
● 
When and how will personal identifiers be destroyed? 
 
Data may be stored and archived indefinitely for future analysis. MRI, CT, EMG, and 
behavioral data is de-identified, coded, and contains no specific biographical 
information which can be related back to the individual. The study key is stored on a 
secure server which cannot be accessed unless specifically authorized.  Questionnaire 
and screening data will be collected and stored on the secure platform Redcap. 
 
20.0 Provisions to Protect the Privacy Interests of Subjects 
20.1 Describe the steps that you will take to protect subjects’ privacy interests. 
“Privacy interest” refers to a person’s desire to place limits on with whom 
they interact or to whom they provide personal information (e.g., 
collecting the minimal amount of private information required to complete 
the study, protecting the data once it is obtained):  
 
Only information required for study purposes will be collected. This includes subject 
screening, participation, and payment information. Once obtained these data are stored 
securely, accessible only by authorized personnel. Documents with subject name, such as 
the consent form, will be stored in a separate locked cabinet from files containing subject 
data with coded identifiers. The study key is only accessible by authorized staff.  
 
20.2 Describe steps that you will take to make subjects feel at ease with the 
research situation in terms of the questions being asked and the 
procedures being performed. “At ease” does not refer to physical 
discomfort, but the sense of intrusiveness a subject might experience in 
response to questions, examinations, and procedures (e.g., use of a same 
gender investigator to place sensors on the torso, a private changing area 
if clothing must be changed, sensitivity when discussing  pregnancy testing 
with subjects, making it clear on surveys that participants can discontinue 
at any time, not asking questions about private or sensitive issues unless 
necessary for the research): 
 
Research staff will check in with participants throughout study sessions to ensure any 
concerns are addressed immediately. Study procedures do not involve any questionnaires 

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or tasks that are anticipated to be emotional in nature. During the consenting process, 
staff will ensure participants understand that they can discontinue at any time.  
 
20.3 Describe how you plan to access existing sources of information about the 
subjects (e.g., medical records, grades) and how you will protect 
participant privacy through the data security plan: 
 
N/A 
 
20.4 Describe any required reporting that might occur as a result of your 
research questions, study populations, and data collection methods. 
Examples for Virginia and Virginia Tech include: 
• Any suspicions (e.g., circumstantial, disclosed) of child abuse (physical, 
emotional, sexual) and neglect  
• Sexual discrimination and/or sexual violence that involves a student 
• Disclosure or signs of intention to harm oneself (i.e., suicidal ideation 
and/or plan) 
• Disclosure or signs of desire to harm others (i.e., homicidal ideation 
and/or plan) 
• Suspected abuse, neglect or exploitation of vulnerable adults (e.g., 
individuals with a disability, elderly persons) 
 
The Beck Depression Inventory is included in our assessments. We will provide 
information with suicide hotline numbers as indicated by participants' responses.  
 
The data we are collecting is for research purposes only, not for clinical diagnosis. As 
such, the data collected, including that from the Beck Depression Inventory (BDI), will 
not be reviewed by a physician, and will not be analyzed for some time after the 
participants visit. However, to ensure participants safety, the study personnel 
administering the BDI will check a participant answer to item 9 on the BDI (Suicidal 
Thoughts or Wishes). If the participant answers "2 I would like to kill myself." or "3 I 
would kill myself if I had the chance." the study staff administering the questionnaire will 
put them in touch with the appropriate resources. We have also added language in the 
consent form informing the participant that if they feel distressed that we will put them in 
touch with the appropriate mental health resources. Further, we state that upon request we 
will provide them with a number for a mental health hotline: (1-800-950-6264) – The 
National Alliance on Mental Illness Help Line. 
 
21.0 Provisions to Monitor the Data to Ensure the Safety of Subjects 
Safety monitoring is required when research involves greater than minimal risk 
and is sometimes appropriate for other studies. 
21.1 Describe: 

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● 
The plan to periodically evaluate the data collected regarding both 
harms and benefits to determine whether subjects remain safe  (e.g., 
periodic reporting to the IRB, establishing a data monitoring 
committee, reporting data monitoring committee findings to the IRB 
and the sponsor). 
● 
What data you will review, including safety data, unexpected events, 
and data that show the ability to produce the intended results. 
● 
How the safety information will be collected (e.g., with case report 
forms, at study visits, by telephone calls with subjects). 
● 
The frequency of data collection, including when safety data 
collection starts. 
● 
Who will review the safety data and with what frequency. 
● 
The statistical tests for analyzing the safety data to determine 
whether harm is occurring. 
● 
Any conditions that will trigger an immediate suspension of the 
research (e.g., a serious adverse event). 
 
The PI will be responsible for continuous data and safety monitoring of all participants 
enrolled in this study. All report of symptoms questionnaires will be reviewed as the 
study progresses. Any unexpected events will be reviewed by the study PI. In the event 
of a serious adverse event, all data collection will be stopped until safety can be 
reviewed by the PI and IRB. 
  
22.0 Compensation for Research Related Injury 
22.1 If the research involves more than minimal risk to subjects, describe the 
available compensation in the event of research-related injury, if any: 
 
N/A 
 
22.2 Provide a copy of contract language, if any, relevant to compensation for 
research-related injury. At Virginia Tech, this is most common for 
sponsored research: 
 
N/A 
 
23.0 Economic Burden to Subjects 
23.1 Describe any costs that subjects might be responsible for because of 
participation in the research, including any uncompensated costs for items 
such as transportation, missed work, and childcare: 
 
Participation in the research study will take approximately 2-2.5 hours per session. 
Participants will be compensated for their time as described above.  
 

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24.0 Consent Process 
24.1 Indicate the process by which you will obtain consent for study 
participation. Please upload all consent, parental permission, and assent 
forms, documents, and scripts referenced in this section to Protocol 
Management. 
Describe the following: 
● 
Where the consent process will take place (e.g., clinic waiting area, 
classroom, online) 
● 
The time interval between sharing the consent information with the 
prospective subject and obtaining consent. For lab, interview, and 
focus group studies, the Virginia Tech IRB prefers that subjects have 
at least 24 hours to review the consent form and study information 
before the appointment where consent will be obtained. For simple 
online survey studies, you can typically present the consent 
information immediately before subjects begin participation. 
● 
If applicable, processes to ensure ongoing consent or assent (e.g., 
for multiple sessions; for research in which a minor will turn 18 
during the study; for longitudinal research with minors who will 
later be asked to provide or affirm their assent). 
● 
Please review “SOP: Informed Consent Process for Research (HRP-
090)” for recommended procedure. Describe your process, being 
sure to include: 
o 
The name and role of all study personnel who will be trained 
and certified by the PI to conduct the consent process 
o 
The time that will be devoted to the consent discussion 
o 
Steps that you will take to minimize the possibility of coercion 
or undue influence 
o 
Steps that you will take to gauge or ensure the subjects’ 
understanding 
 
Subjects who express interest in the study through recruitment efforts may be contacted 
by follow-up phone or email. If verbally screening, participants will provide verbal 
permission for study staff to collect screening information to determine study eligibility.  
If, after screening, participants are eligible for further participation, subjects will be asked 
to provide informed consent. 
 
Consent will be obtained on-site prior to the first study visit in a quiet area. Once written 
consent is obtained, participants do not need to undergo the consenting process again for 
additional study visits. As this study involves seven study visits, this is designed to be 
considerate of participants' time.  
 
Participants will be given as much time as they request to review the consent documents 
and ask questions. Consent documents for in person visits will be emailed to the 
participant at least 24 hours prior to their first visit. In order to determine understanding, 

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staff will discuss each section with the participant, verifying their understanding through 
conversation throughout.  
Staff will confirm they have had all questions answered prior to obtaining the participants 
signature.   
 
Participants will consent to the follow up questionnaire during the initial consent. A 
reminder of all relevant consent sections will be provided prior to questionnaire 
completion - see attached document. Report of Symptoms questionnaire will be sent to 
participants following in-person study participation.  If preferred, this questionnaire can 
be completed verbally via phone with study staff, in which case the consent process will 
involve a verbal consent reminder as documented by study staff initials. In this instance, 
study staff will review the reminder consent document with participants prior to 
completing the verbal questionnaire. 
 
Non-English Speaking Subjects 
● 
Indicate what language(s) other than English are understood by 
prospective subjects or representatives. 
● 
If non-English speakers will be recruited, describe the process you 
will use to ensure that the oral and/or written consent information 
provided will be in a language that they understand.  
● 
If you translate consent forms and study materials, please provide a 
certified translation of the form as well as the certification 
document. 
● 
Indicate the spoken language that study personnel obtaining consent 
will use. Describe how you will assess fluency of personnel obtaining 
consent to ensure that the translation is accurate. 
 
Subjects must be able to understand and read English, as that is the language in which the 
screening documents and study instructions will be presented. They are not required to be 
native English speakers in order to participate in the research. 
 
Waiver or Alteration of Consent Process (consent will not be obtained, 
required information will not be disclosed, or the research involves 
deception) 
● 
Review the “CHECKLIST: Waiver or Alteration of Consent Process 
(HRP-410)” to ensure you have provided sufficient information for 
the IRB to make these determinations (i.e., that it meets the criteria 
for a waiver or alteration of the consent process). 
 
N/A 
 
Subjects who are not yet adults (minors: infants, children, teenagers) 

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● 
Describe the criteria that you will use to determine  legal age for 
consent to treatments or procedures involved in the research under 
the applicable law of the jurisdiction in which the research will be 
conducted (e.g., in Virginia, individuals under the age of 18 years). 
o 
For research conducted in Virginia, review “SOP: Legally 
Authorized Representatives, Minors, and Guardians (HRP-
013)” to determine which individuals in the state meet the 
definition of “minor.” 
o 
For research conducted outside of the state, please describe 
the legal requirements for the definition of “minor.”  
● 
Describe the process for obtaining parental permission.  
o 
Permission from one parent is acceptable for studies that 
involve no greater than minimal risk OR involve greater than 
minimal risk but present the prospect of direct benefit to the 
minor subject. 
o 
Permission from both parents is required in all other 
cases (unless one parent is deceased, unknown, 
incompetent, or not reasonably available, or when only 
one parent has legal responsibility for the care and 
custody of the minor). 
● 
Describe whether you will obtain permission from individuals other 
than parents or Legally Authorized Representatives, and if so, who 
will be allowed to provide permission. Describe the process you will 
use to determine these individuals’ authority to consent to the 
minor’s general medical care. 
● 
Indicate whether you will obtain assent from all, some, or none of 
the minors. If you will obtain assent from some minors, indicate 
which minors will be required to assent. Consider chronological age 
and intellectual capacity when determining who will be required to 
provide assent (e.g., infants are unable to assent. However, 
teenagers are likely able to read and sign an assent form). 
● 
When assent of minors is obtained, describe whether and how you 
will document it.  Will minors sign an assent form or give verbal 
assent? 
● 
Attach parental permission and minor assent forms or scripts in 
Protocol Management.  
 
N/A 
 
Adults Unable to Consent  
● 
Describe the process you will use to determine whether an individual 
adult is capable of consent. 
● 
List the individuals from whom you will obtain permission in order 
of priority (e.g., durable power of attorney for health care, court 
appointed guardian for health care decisions, spouse, and non-
minor child). 

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o 
For research conducted in the Virginia, review “SOP: Legally 
Authorized Representatives, Minors, and Guardians (HRP-
013)” to determine which individuals in the state meet the 
definition of “legally authorized representative.” 
o 
For research conducted outside of Virginia, please describe 
the legal requirements for obtaining permission from a legally 
authorized representative in the state where the research will 
occur. 
● 
Describe the process for assent of the subjects. 
o 
Indicate whether you will require assent from all, some, or 
none of the subjects. If some, indicate which subjects will be 
required to assent and which will not. 
o 
If you will not obtain assent from some or all subjects, please 
provide justification for not obtaining assent. 
o 
Describe whether and how you will document assent.  
 
N/A 
 
25.0 Process to Document Consent in Writing 
25.1 Consult “SOP: Written Documentation of Consent (HRP-091)” for 
recommended procedures, and describe whether and how consent of the 
subject will be documented in writing: 
 
Consent will be documented through participant printed name and signature on the 
informed consent form.  For the follow-up questionnaire, electronic reminder of consent 
will be provided prior to questionnaire completion, or verbal reminder of consent will be 
indicated by study staff initials. All consent forms submitted.  
 
25.2 If the research presents no more than minimal risk of harm to subjects and 
involves no procedures for which written documentation of consent is 
normally required outside of the research context, you can request that the 
IRB waive the requirement to obtain written documentation of consent 
(e.g., consent to participate is indicated by pressing a button for an online 
questionnaire – after the consent information is presented and before the 
questionnaire begins): 
 
For study screening data collection, a waiver of consent is requested. Participants will be 
informed their data is being collected to determine study eligibility. Procedures will be 
explained to the participant by trained and authorized study staff and then the participant 
will be given as much time as they request to review the form and ask any questions prior 
to written consent. Follow up questionnaire reminder of consent will be provided either 
electronically or verbally per participant preference prior to questionnaire. If consent is 
reviewed verbally, reminder of consent will be documented with study staff initial. The 
consent forms are included in this application. 

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25.3 If you will document consent in writing, attach a consent document with 
places for signatures. If you will obtain consent, but not document consent 
in writing, please attach the consent script or text. Review “CHECKLIST: 
Waiver of Written Documentation of Consent (HRP-411)” to ensure that 
you have provided sufficient information. You should use “TEMPLATE 
CONSENT DOCUMENT (HRP-502)”to create the consent document or 
script: 
 
Written and Electronic/verbal reminder of consent forms attached.  
 
26.0 Resources Available 
26.1 Describe the resources available to conduct the research. For example, as 
appropriate: 
● 
Describe the PI’s availability to supervise the research. 
● 
Justify the feasibility of recruiting the required number of suitable 
subjects within the agreed recruitment period. For example, how 
many potential subjects do you have access to? What percentage of 
those potential subjects do you need to recruit? 
● 
Describe the time that you will devote to conducting and completing 
the research. 
● 
Describe your facilities. 
● 
Describe the availability of medical or psychological resources that 
subjects might need as a result of an anticipated or unanticipated 
consequence of participation in the research. 
● 
Describe your process to ensure that all persons assisting with the 
research are adequately informed about the protocol, the research 
procedures, and their duties and functions (e.g., training plans, 
detailed study notebooks). 
 
The PI is a research-dedicated Faculty member at the Fralin Biomedical Research 
Institute at VTC.  
 
PI Legon’s lab is part of the Fralin Biomedical Research Institute at Virginia Tech 
Carilion (FBRI at VTC) at Virginia Tech, located in Roanoke, Virginia. The Research 
Institute was founded in 2010 as part of a commitment to biomedical sciences by Virginia 
Tech.  Primary institute faculty including Legon have a primary faculty appointment 
within a traditional department at Virginia Tech, but are funded through and housed at 
the FBRI. Primary faculty comprise a broad interdisciplinary group working in a variety 
of areas such as neural computation, psychiatric and developmental disorders, genetics, 
substance abuse and molecular virology and biology. The FBRI also provides to the 
faculty an administrative staff of individuals with expertise in grants management, 
personnel management, supply ordering/tracking, web systems management, desktop 
support, laboratory animal care, IRB support, software development and facilities and 
operations support and planning as well as general administrative support.  
 

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The Legon lab is actively recruiting postdoctoral as well as graduate students. It is 
anticipated that undergraduate students will be involved in the lab as well to gain 
valuable research experience. As these individuals are incorporated into our research 
studies they will be added to the appropriate protocols.  It is the intention of the lab to 
diligently recruit and run participants, while still providing sufficient time for PI 
oversight and ongoing data analysis. 
 
Computing Resources: 
The FBRI has dedicated data centers in the primary Riverside 2 facility as well as the 
Biomedical Research Addition (BRA / Riverside 4) opened in 2020.  Both are secured 
with dual-factor biometric access and provide redundant and backup power through 
enterprise-class uninterruptible power supplies (UPS) and facilities-based generators.   
[Updated 4.22.2020] 
Research Technology and Computing Resources 
Dell / Intel HPC Cluster -SLURM (Dirac): 
 20 compute nodes, 960 cores, 3,840 GB RAM, 40Gb Interconnect 
Dell / Intel HPC Cluster - SLURM (Hawking): 
4 compute  nodes totaling 192 cores, 768 GB RAM, 40Gb Interconnect 
2 GPU nodes totaling 4 NVIDIA Tesla V100 16G Passive GPUs, 56 cores, 768 GB 
RAM, 40Gb Interconnect 
10+ dedicated Linux servers (48 core AMD Opteron-based, 192GB RAM) are available 
for image and data analysis 
Virtualized infrastructure using VMware vSphere with built-in redundancy between data 
centers serving Linux and Windows virtual machines available for general and scientific 
computing and image and data analysis 
40 and 100Gbit/s storage connectivity for research data 
10,40 and 100 Gbit/s Internal Local Area Network between file servers and cluster 
10 Gbit/s Wide Area Network for access to Virginia Tech main campus / Internet 
1.9 Petabytes of NAS centralized disk storage 
1.2 Petabytes of off-site storage for disaster recovery 
400 Terabytes of encrypted storage for scientific workloads 
Nightly backups, snapshots, and off-site data retention 
2.4Ghz / 5Ghz secure wireless network 
1 Gbit/s commodity Ethernet network 
Data Analysis Tools: MATLAB, SPM, AFNI, FSL, MRIcro, xjView, R, SAS, Graphpad 
Prism, SPSS 
Productivity Tools: Adobe Suite, Microsoft Office Suite, vi, vim, emacs, etc. 
  
MRI Scanning Resources (FBRI): 
Virginia Tech has three research-dedicated Siemens 3T MR scanners (2 Siemens 
Magnetom TIM Trios, and 1 PRISMA-FIT) available. Each scanner bay is equipped with 
the following stimulation and response interfaces: 
behavioral response: two-hand, eight-button optical response pads with USB, serial, and 
TTL output (Current Designs, Inc.) video stimulation: rear-projection video display 
(Hitachi CP-SX635) corrective lenses for use with video stimulation: MR-compatible 
frames with insertable polycarbonate lenses (prescriptions range from -8.00 to +8.00) 

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(Solo Bambini) stimulus delivery: dedicated computers for experiment presentation (Dell 
Optiplex 980) audio delivery: MRI compatible headphones. 
 
CT Scanning Resources (FBRI):  
Virginia Tech has a Siemens Somatom Confidence RT Pro CT Scanner available.  
 
Mental Health Resources: In the unlikely and unexpected event that a participant requires 
or requests mental health resources, the research staff will offer a national mental health 
hotline number (National Alliance on Mental Illness helpline: 1-800-950-6264). Those 
staff and volunteers are trained to transfer calls to crisis management, if needed or work 
to answer questions about education programs, treatment options, symptoms of mental 
health conditions and more (additional information may be found here: 
https://www.nami.org/find-support/nami-helpline). In the event of a mental health or 
other emergency, the local hospital system, Carilion Clinic is located approximately 1 
mile from the FBRI and is accessible by the public.  
 
Training: Study staff are trained in Human Research Protections through approved 
programs, such as CITI. Additionally, study procedures, such as participant task 
instructions, staff instructions to introduce and/or present and start computer tasks, and 
visit checklists are developed for each study in order to maintain consistency across 
participants and ensure all procedures are completed and documented. All staff 
consenting and administering research tasks review both the approved protocol and 
consent form prior to study startup and participant recruitment. If there are amendments 
or changes, staff review the new documents. Study coordinators review the consent 
process and procedures on an ongoing basis. 
 
27.0 Multi-Site Research 
Contact the HRPP for multi-site research (involving multiple institutions) and 
the details required for this section will be provided. Otherwise, indicate N/A. 
 
N/A