Brain Networks of Turning Performance With Aging and Stroke
Phase: NA
Conditions: Aging
Sponsor: VA Office of Research and Development

Cover Page 
O+icial Title: Brain Networks of Turning Performance with Aging and Stroke 
NCT Number: NCT05475236 
Document Date: 10/13/2022 

IRB Version Date: 3/9/2004 
PI version date:10/13/2022 
IRB study number: IRB202200959 
 
Protocol 
 
1. Project Title 
Brain Networks of Turning Performance with Aging and Stroke 
 
2. Investigator(s): 
Clayton W. Swanson, PhD 
David J. Clark, ScD 
Dorian Rose, PhD 
Damon Lamb, PhD 
 
3. Abstract: 
 
The objective of this study is to examine the neural control of turning while walking, which is 
often impaired for older adults and people who have had a stroke. Leveraging the 
infrastructure of Dr. David Clark’s IRB approved ongoing Merit Review study called the 
CONTROL Study (IRB201803010 - Cerebral networks of locomotor learning and retention 
in older adults) this study adds one additional (optional) assessment visit to measure 
brain function using transcranial magnetic stimulation (TMS) which is a form of non- 
invasive brain stimulation. The CONTROL Study collects multiple forms of turning 
performance data in older adults; however, the it does not perform or collect transcranial 
magnetic stimulation (TMS) data to assess excitatory and inhibitory neurophysiological function 
in motor networks of the brain. 
 
Recent work demonstrates significant associations between brain excitatory/inhibitory function 
and turning performance in older adults, although these results remain largely preliminary. 
Therefore, the objective of this proposal is to further elucidate associations between 
neurophysiological function (measured with TMS) and measures of turning performance. 
Specific Aim 1 will test the hypothesis that greater cortical inhibitory function will be associated 
with faster turn speed and shorter turn duration for 360˚, 180˚, and 90˚ turns. Specific Aim 2 
will test the hypothesis that greater cortical inhibitory function will be associated with greater 
segmental turning strategies (i.e., head leads in the turn followed by shoulders, trunk, etc.) of 
the axial skeleton. Specific Aim 3 will test the hypothesis that participants with greater baseline 
cortical inhibition will demonstrate larger 360 ̊, 180 ,̊ and 90˚ turning performance gains. This 
pilot study will enroll 40 mobility compromised older adults and 10 participants post-stroke which 
will provide preliminary data for a future grant submission, proposing a larger scale clinical trial 
of turning rehabilitation for mobility compromised adults. 
 
4. Background: 
Gait and balance impairments during straight ahead walking are well documented in older 
adults and post-stroke survivors, but rarely is turning factored into either the assessment or 
intervention. Nearly all tasks performed throughout the day require some amount of turning. In 
fact, people over the age of 65 execute between 300-1500 turns per day. Even with the 
abundance of turning in daily life, there remains a relative paucity of research targeted to 
understanding age and stroke related turning deficits, or the potential for achieving turning 
improvements following an intervention. Recent research has documented significant 
differences in 360 ̊ and 180 ̊ turning performance between neurotypical young and older adults, 
such that older adults were found to turn more slowly and to have a reduced peak velocity. 
Moreover, our recent research as shown that compared to conventionally measured straight 

IRB Version Date: 3/9/2004 
PI version date:10/13/2022 
IRB study number: IRB202200959 
 
ahead walking variables (i.e., walking speed), performance on the 360 ̊ turn test provides 
excellent ability to discern between neurotypical middle-age and older adults. This finding 
indicates that turning ability may be more sensitive to lower limb motor control differences 
between these populations. Similarly, stroke related research demonstrates increases in the 
duration and number of steps needed to complete 360 ̊ turns. 
We propose to use transcranial magnetic stimulation (TMS), which is a non-invasive brain 
stimulation technique to measure motor cortex neurophysiology during a single study visit . 
Specifically, we are interested in three measures associated with inhibitory activity respectively 
termed the cortical silent period (cSP), short interval intracortical inhibition (SICI), and long 
interval intracortical inhibition (LICI). These measures represent inhibitory activity, specifically 
gamma-aminobutyric acid (GABA) which is the primary inhibitory neurotransmitter in the brain. 
Although there are certain unique features for each of these measures. Specifically, the cSP is a 
single pulse TMS measure which assesses GABA-B corticospinal inhibitory activity while both 
SICI and LICI are paired pulse TMS measures which are thought to measure cortical (rather 
than corticospinal) levels of inhibitory activity. Moreover, the two paired pulse TMS measures 
assess different GABAergic subtypes. Specifically, SICI measures GABA-A activity while LICI 
measures GABA-B activity. Notably, my prior research is the first to demonstrate associations 
between the cSP and turning performance for older adults, such that those older adults with 
greater levels of inhibition (i.e., longer silent periods) demonstrate better turning performance 
(i.e., shorter turn duration). Although the precise mechanism linking cortical inhibition to turning 
performance remains unclear, there is emerging evidence that motor cortex inhibition predicts 
performance on tests of motor response-inhibition (i.e., the termination or prevention of 
movement). In the context of turning (e.g., 90˚, 180˚, and 360 ̊ turns), response-inhibition may 
help facilitate transitioning away from “automatic” straight ahead walking allowing for 
neuromuscular control to initiate a change in direction. This concept has been demonstrated for 
other complex walking tasks, such as obstacle avoidance or sudden step length adjustments. 
Together, these results indicate that cortical inhibition likely plays an important role in gait 
related performance. However, no research has assessed all three inhibitory measures and 
their associations to turning performance. Moreover, no studies have assessed whether 
baseline levels of motor cortex inhibitory activity are predictive of turning performance gains or 
tDCS induced neuroplastic alterations. 
5. Specific Aims: 
 
The specific aims are developed around the premise of incorporating turning data 
collected from the CONTROL Study and incorporating those data with the unique TMS 
data collected from this study. 
Specific Aim 1: Determine the extent to which cortical inhibition is associated with 90˚, 
180˚, and 360˚ turn duration and velocity in older adults. 
Hypothesis 1: Greater levels of cortical inhibitory activity will be associated with shorter turn 
duration and faster peak turn velocity for 90˚, 180˚, and 360˚ turns. 
Specific Aim 2: Determine the extent to which cortical inhibition is associated with 
segmental turning strategies in older adults. 
Hypothesis 2: Greater levels of cortical inhibitory activity will be associated with greater degrees 
of segmental specific turning strategies for 90˚, 180˚, and 360˚ turns. 
Specific Aim 3: Determine the extent to which cortical inhibition is predictive of turning 
performance changes post-intervention. 

IRB Version Date: 3/9/2004 
PI version date:10/13/2022 
IRB study number: IRB202200959 
 
Hypothesis 3: Participants with greater cortical inhibitory activity at baseline will demonstrate 
larger improvements on the 360 ̊ and 180 ̊ turn tests. 
 
6. Research Plan: 
Study Overview 
This study will recruit zero participants. 
• 
Please refer to Table 1 outlines what measures will be shared from the CONTROL Study 
and which measures are unique to the current study. 
Table 1: Shared and Unique methods and metrics between the CONTROL Study and this study. 
 
 
Participant Screening 
Recruitment will coincide with the CONTROL Study. Specifically, participants will be screened 
by the CONTROL Study staff to determine if they meet the study criteria. This includes 
participants between the ages of 65 – 95 years for the older adult participants and 65 – 85 for 
the post-stroke participants. The exclusion criteria include participants who have 
contraindications to non-invasive brain stimulation (i.e., TMS). This would include having metal 
in the head, a pacemaker, a wound on the scalp, or a history of seizures. Additionally, 
medications affecting the central nervous system including, but not limited to, benzodiazepines, 
anti-cholinergic medication and GABAergic medication will be exclusionary as they could 
influence the results of TMS. 
 
Informed Consent and Onsite Screening Visit 
Participants will undergo informed consent for the CONTROL Study and at that time will be 
invited to undergo an additional informed consent for this study. Prior to the participant signing 
the additional consent form research staff will explain the TMS study protocol to participants. 
For participants who wish not to participate in the TMS visit they may continue with the 
CONTROL Study protocol. 
At the discretion of the Principal Investigator, any individual may be deemed ineligible for further 
participation in this study if there are concerns about the individual’s capability to perform study 
procedures or if it may be unsafe for the volunteer to participate in the study. 
 
Transcranial Magnetic Stimulation (TMS) Visit 
Various assessments of muscle strength, neural control, and health and independence will be 
made during the TMS assessment visit. These assessments include: 
Maximal Force Assessment 
Participants will perform a series of maximal voluntary contractions (MVCs) to determine the 
maximal tibialis anterior strength output for each leg. On separate trials, participants will be 
encouraged to produce as much force during a dorsiflexion as possible with each tibialis 

IRB Version Date: 3/9/2004 
PI version date:10/13/2022 
IRB study number: IRB202200959 
 
anterior muscle. Once force output for subsequent trials is within 10% the largest force 
producing trial will be recorded and used during the cSP TMS trials. 
 
Electromyography (EMG) 
EMG electrodes will be placed on each tibialis anterior muscle which will be used to measure 
muscle activity during the TMS trials. Please see the section Transcranial Magnetic Stimulation 
below for more information. 
Transcranial Magnetic Stimulation (TMS) 
Prior to starting TMS, participants will first complete a 
TMS safety screening questionnaire. The answers to 
this safety screening will be reviewed and approved 
by the researcher performing TMS and/or the PI. Like 
figure 1 but on the tibialis anterior muscles rather than 
the vastus medialis oblique’s participants will have two 
surface EMG electrodes placed on each muscle belly 
and one on a boney landmark (e.g., patella). 
Participants will be seated in the TMS chair. Then 
research staff will measure the participants head to 
locate the center. This is completed by identifying the 
middle points when measuring from the nasion to 
inion and from tragus to tragus. Once the center of the 
head is determined we will measure laterally 1 cm on 
both cortical hemispheres this point will denote the 
starting spot for stimulation. After locating the general location, the research staff will work to 
identify a more precise location for stimulation by incrementally increasing the stimulation 
intensity and systematically moving the TMS coil around until stimulation results in a consistent 
muscle response. Once an initial muscle response is observed stimulation intensity will be 
determined to consistently generate an appropriate muscle response and amplitude. This 
procedure will be conducted on both cortical hemispheres. 
Following the determination of location and intensity for stimulation the tibialis anterior muscles, 
the 6 TMS trials will be performed at random. Each of these trials will be roughly three minutes 
in length and will include collection of the cortical silent period, short interval intracortical 
inhibition, and long interval intracortical inhibition for each hemisphere independently. 
 
Questionnaires 
We will administer two questionnaires aimed at assessing self-reported measures of health and 
independence when performing activities of daily living. Both are short, simple, paper-based 
questionnaires. Specific examples include: 
• 
Short Form-36 – is a set of 36 questions aimed at assessing self-reported measures of 
health. 
• 
Katz Index of Independence – is a set of questions aimed at assessing one’s level of 
independence when performing activities of daily living. 
 
Possible Discomforts and Risks: 
There is a risk that participants may find the questionnaires uncomfortable or embarrassing if they 
feel uncomfortable with their answers. In an attempt to alleviate these feelings participants may 
skip any question that they do not wish to respond do. 
 
 
 
 
 
 
 
 
 
 
 
Figure 1: Example of TMS 
participant set up 

IRB Version Date: 3/9/2004 
PI version date:10/13/2022 
IRB study number: IRB202200959 
 
Falls. While we do not anticipate a fall occurring there is the potential that a participant could fall 
while getting into or out of the Biodex seat (Figure 1). To mitigate this risk the Biodex seat rotates 
and lowers. Additionally, study staff will be present to help participants safely navigate their body 
position into the seat. Once seated, participants will be securely harnessed in (similar to a seatbelt 
in a vehicle). 
Headache. Although rare, the most common side effect from TMS brain stimulation is headache. 
However, individuals should not, participate if they have a history of migraine or other types of 
severe or frequent headaches. It is also possible that participants may experience some neck 
stiffness or neck pain. This is believed to be due to the straight posture of the head and neck we 
will require during the experiment. 
TMS is a safe, non-invasive brain stimulation technique that can be used for both diagnostic and 
therapeutic procedures. The single and paired pulse TMS techniques that will be performed in this 
study have been used extensively in thousands of research studies and on tens of thousands of 
subjects in the United States and around the world. Single and paired pulse TMS techniques are 
considered very safe when accepted guidelines are followed, and no long-term risks have been 
reported involving the use of single and paired pulse TMS. For most people, the stimulation is not 
painful, but occasionally slight discomfort or headache can occur. The headaches go away quickly 
with nonprescription medication. TMS produces a clicking sound when a current is passed 
through the stimulation coil. During repetitive TMS stimulation this click can result in ringing in the 
ear and temporary shifts in your ability to determine the pitch and loudness of sounds if no 
protection is used. Hearing damage is possible, and one subject suffered permanent hearing 
damage when hearing protection fell out, although this was done using repetitive TMS (rTMS). 
This study does NOT include rTMS and only single and paired pulse TMS will be employed in this 
study. Animal and human studies have shown that earplugs or headphones can effectively 
prevent the risk of hearing disturbance due to TMS. Therefore, participants will be fitted with 
earplugs during TMS. If individuals find the procedure too uncomfortable, they may discontinue at 
any time. 
TMS can interfere with implanted medical devices and will not be done in people who have 
pacemakers, implanted pumps, or stimulators, such as cochlear implants or in people who have 
metal objects inside the eye or skull (dental work such as fillings and similar procedures do not 
pose a risk and are acceptable). If participants have an implanted device or metal object that is 
not safe for TMS, they will not be allowed to participate. 
In general, the risks associated with TMS are very minimal, but research has shown that there is a 
very small risk of seizures if repetitive TMS (rTMS) is done with very intense, high frequency 
stimulation or with trains of stimulation separated by a second or less. Such intensity, frequency, 
and repetition rate will not be used in this study as the study does NOT include rTMS and only 
single and paired pulse TMS methods will be employed. Finally, there is no medical risk 
associated with the surface EMG recordings of the muscle responses to TMS. 
 
8. Possible Benefits: 
There is no direct benefit to the participant. 
9. Conflict of Interest: 
None. 
 
10. Statistical analysis and sample size calculations 

IRB Version Date: 3/9/2004 
PI version date:10/13/2022 
IRB study number: IRB202200959 
 
For each aim, the objective of this pilot study is to calculate variance of response and 
confidence intervals of effect sizes to be used as preliminary data for a future grant submission 
which will incorporate a clinical trial for turning specific rehabilitation. The proposed sample size 
of 50 per group for the older adults is considered sufficient for providing stable and reliable 
estimates of variability and effect size. The proposed sample of 10 stroke participants will allow 
for the assessment of feasibility. 
 
Data and Safety Monitoring Plan 
Adverse Event Reporting 
Adverse events will be reported according to the guidelines of the University of Florida 
Institutional Review. 
Reporting within 5 days of the PI becoming aware will apply to adverse events that meet all of 
the following criteria: 
• 
Serious 
• 
Unexpected 
• 
Related or the Relationship is “more likely than not” 
Adverse events will be added to the cumulative event table and reported at continuing review 
when they meet either of the following criteria: 
• 
Serious (but expected) and related or the relationship is “more likely than not”. 
• 
Unexpected (but not serious) and related or the relationship is “more likely than not”. 
A serious adverse event is any adverse event that results in any of the following outcomes: 
• 
death, 
• 
a life-threatening adverse event, 
• 
inpatient hospitalization or prolonging existing hospitalization, 
• 
a persistent or significant disability/incapacity, 
• 
or a congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse event when the event may jeopardize the 
patient or subject and/or may require medical or surgical intervention to prevent one of the 
outcomes listed in the definition above. 
An unexpected adverse event is any adverse event that is not consistent with the current 
investigator brochure, protocol, consent form, or is not part of the normal disease progression. 
In addition, known adverse events may occur more frequently than expected. If so, then this 
meets the definition of “unexpected” and must be reported to the IRB. 
Protection Against Risk 
Staff training: All personnel will be thoroughly trained in the study procedures by the Principal 
Investigator or other appropriate member of the research team and will complete all required 
trainings concerning human subjects research at the University of Florida. 
Health monitoring and medical response: Volunteers at risk of health problems due to recent 
history of medical conditions (e.g., serious cardiac or pulmonary conditions) will be excluded, as 
noted above in the inclusion/exclusion criteria. Any adverse events will be recorded and 
monitored as required by our University of Florida Institutional Review Board. In the event of a 
medical emergency at the VA Hospital (our study site) we will call the hospital emergency 

IRB Version Date: 3/9/2004 
PI version date:10/13/2022 
IRB study number: IRB202200959 
 
response line, 6-9-1-1 and alert them to a code blue (medical emergency). Subjects will be able 
to terminate a study session at their request at any time without prejudice. Minimization of risk 
during neurorehabilitation and assessments will be accomplished by monitoring vital signs, with 
prescribed criteria for termination of the testing session. Vital signs will be monitored before, 
during and after assessment. Contraindications for participation will include resting heart rate 
>100 bpm or <50 bpm, resting systolic blood pressure >180 mmHg or <100 mm Hg or resting 
diastolic blood pressure >100 mmHg. Indications to terminate physical activity will include 
subject complaints of shortness of breath, light-headedness, dizziness, confusion, severe 
headache, dyspnea or onset of angina. If any of these conditions are greater than mild or persist 
after rest, the patient’s primary physician will be called and patient referred for evaluation. If the 
patient complains of angina at rest, loss of consciousness occurs, or cardiac arrest, emergency 
medical services through 911 will be called immediately. Portable defibrillators are available. 
Confidentiality: Data will be used only in aggregate and no identifying characteristics of 
individuals will be published or presented. Confidentiality of data will be maintained by using 
research identification numbers that uniquely identify each individual. Safeguards will be 
established to ensure the security and privacy of participants’ study records. Appropriate 
measures will be taken to prevent unauthorized use of study information. Data other than 
demographic information will not use names as an identifier. The research ID number will be 
used. The research records will be kept in a locked room in the study site. The files matching 
participants' names and demographic information with research ID numbers will be kept in a 
locked file that uses a different key from that of all other files. Only trained and certified study 
personnel will have access to these files, and they will be asked to sign a document that they 
agree to maintain the confidentiality of the information. Electronic records will be stored on 
password protected network server maintained by the university information technology 
department. In compliance with the Health Insurance Portability and Accountability Act (HIPAA) 
and the Standards for Privacy of Individually Identifiable Health Information of the Department of 
Health and Human Services, we access personal health information and medical records only 
after receiving signed informed consent. 
TMS Safety: Our protocol uses stimulation parameters that are considered standard practice for 
single- and paired- pulse TMS. These parameters have been used safely in thousands of prior 
research studies. The most common side effect of TMS is a headache. To minimize risks 
associated with TMS, participants will complete a pre-TMS screening form and will be monitored 
throughout the stimulation session. Additionally, participants will be asked to report any 
discomforts. If stimulation is or becomes uncomfortable, the stimulation levels will be decreased 
to a comfortable level or will be stopped. 
Questionnaire administration: Questionnaire data are collected in secure spaces where the 
interview cannot be overheard. Participants will be informed that they are not required to answer 
questions that they do not wish to answer.