Motor and Neurophysiological Changes After Ischemic Conditioning in Individuals With Stroke
Phase: NA
Conditions: Stroke
Sponsor: University of Illinois at Chicago

Motor and Neurophysiological Changes after Ischemic Conditioning in Individuals with 
Stroke 
 
 
 
Cover Page  
 
Official Study Title  
Motor and Neurophysiological Changes After Ischemic Conditioning in Individuals With 
Stroke 
 
NCT Number  
NCT05906602 
 
Document Type  
Study Protocol and Statistical Analysis Plan  
 
Document Date  
February 4, 2025  
 
Sponsor  
University of Illinois-Chicago  
 
Principal Investigator  
Dr. Sangeetha Madhavan, PT, PhD Professor, Department of Physical Therapy 
University of Illinois-Chicago 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Motor and Neurophysiological Changes after Ischemic Conditioning in Individuals with 
Stroke 
 
 
Table of Contents 
 
Table of Contents………………………………………………………………………….2 
List of Abbreviations……………………………………………………………………...3 
1.0 
Study Summary ........................................................................................................ 5 
2.0 
Objectives* .............................................................................................................. 6 
3.0 
Background* ............................................................................................................ 7 
4.0 
Study Endpoints* ..................................................................................................... 9 
5.0 
Study Intervention/Investigational Agent .............................................................. 11 
6.0 
Study Timelines* ................................................................................................... 11 
7.0 
Inclusion and Exclusion Criteria* ............................................................................ 9 
8.0 
Vulnerable Populations* ........................................................................................ 15 
9.0 
Number of Subjects ................................................................................................ 11 
10.0 Recruitment Methods ............................................................................................. 16 
11.0 Procedures Involved* ............................................................................................. 18 
12.0 Data and Specimen Banking* ................................................................................ 32 
13.0 Sharing of Results with Subjects* ......................................................................... 32 
14.0 Withdrawal of Subjects* ........................................................................................ 33 
15.0 Risks to Subjects* .................................................................................................. 33 
16.0 Potential Benefits to Subjects* .............................................................................. 35 
17.0 Data Management* and Confidentiality ................................................................ 36 
18.0 Provisions to Monitor the Data to Ensure the Safety of Subjects* ........................ 37 
19.0 Provisions to Protect the Privacy Interests of Subjects .......................................... 37 
20.0 Compensation for Research-Related Injury ........................................................... 38 
21.0 Economic Burden to Subjects ................................................................................ 39 
22.0 Consent Process ..................................................................................................... 39 
23.0 Process to Document Consent in Writing .............................................................. 39 
24.0 Setting .................................................................................................................... 39 
25.0 Resources Available ............................................................................................... 40 
26.0 Multi-Site Research* ............................................................................................. 41 
 
 
 

Motor and Neurophysiological Changes after Ischemic Conditioning in Individuals with 
Stroke 
 
 
LIST OF ABBREVIATIONS  
10MWT  
 
10-meter walk test 
AHS   
 
Applied Health Sciences 
AMT                           Active motor threshold 
BDNF  
 
Brain derived neurotrophic factor 
BP  
 
 
Blood Pressure 
CCTS                          Center for Clinical and Translational Science (CCTS) 
CME   
 
Corticomotor excitability 
EMG   
 
Electromyography 
FDA   
 
Food and Drug Administration 
FMLE  
 
Fugl Meyer Lower Extremity Scale 
HIPAA  
 
Health Insurance Portability and Accountability Act 
HR  
 
 
Heart rate 
HRR                            Heart rate reserve 
IC  
 
 
Ischemic Conditioning 
iSP  
 
 
Ipsilateral silent period 
M1  
 
 
Lower limb primary motor cortex 
MEP   
 
Motor-evoked potential 
MMSE  
 
Mini-Mental State Examination 
MRC   
 
Medical Research Council 
MRI 
 
 
Magnetic resonance imaging 
MVC                           Maximum voluntary contraction 
MVIC   
 
Maximum voluntary isometric contraction 

Motor and Neurophysiological Changes after Ischemic Conditioning in Individuals with 
Stroke 
 
 
MVT                           Maximum voluntary torque 
NIH   
 
National Institutes of Health 
PAR-Q  
 
Physical Activity Readiness Questionnaire 
PI  
 
 
Principal Investigator 
RMT   
 
Resting motor threshold 
RPE   
 
Rating of perceived exertion 
SICI                            Short intracortical inhibition 
TA  
 
 
Tibialis anterior 
TCI  
 
 
Transcallosal inhibition 
tDCS                           Transcranial direct current stimulation 
TMS   
 
Transcranial magnetic stimulation 
UIC   
 
University of Illinois at Chicago 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Motor and Neurophysiological Changes after Ischemic Conditioning in Individuals with 
Stroke 
 
 
1.0 
Study Summary 
Functional ambulation remains a top priority for many stroke survivors living with 
chronic gait impairments. Current rehabilitation techniques to restore ambulatory 
capacity in stroke have shown promising, yet varying, results, and there is a critical need 
to maximize current benefits by designing optimal interventions. Neuromodulation is 
increasingly investigated as a promising strategy to promote neuroplasticity and 
accelerate motor recovery in stroke; however, no motor priming modality has emerged as 
the most effective method to prime the central nervous system for rehabilitation. Aerobic 
exercise is an effective neuromodulatory approach and advantageous for gait recovery in 
stroke, but some patients, especially those with moderate or severe impairments, lack the 
functional capacity to perform aerobic exercise. Thus, there is a need for alternative 
modalities. Ischemic conditioning (IC) is a procedure when the limb is exposed to brief, 
repeated bouts of reduced blood flow immediately followed by restored blood flow. 
Ischemic conditioning is a possible neuromodulatory technique that has shown to 
increase muscle hypertrophy, improve aerobic capacity, and increase walking speeds in 
both healthy and clinical populations. However, research investigating ischemic 
conditioning in stroke rehabilitation is limited. In the current study, our aim is to quantify 
the effectiveness of ischemic conditioning as a neuromodulatory modality to promote gait 
rehabilitation in individuals with stroke. Outcome measures will include gait variables, 
lower limb strength, lower limb muscle volume, ankle motor performance, and 
neurophysiological measures of corticomotor excitability (CME), intracortical inhibition, 
and transcallosal inhibition measured from the tibialis anterior (TA) muscles using 
transcranial magnetic stimulation (TMS).  
 
2.0 
Objectives* 
Aim 1. To quantify changes in CME and TCI of the paretic TA following a single session 
of IC in comparison to sham IC in individuals with stroke.  
Hypothesis 1. Individuals with stroke will display greater increases in CME of the 
paretic TA and greater increases in TCI from the lesioned to the non-lesioned hemisphere 
after IC in comparison to sham IC.  
 
Aim 2. To quantify changes in lower limb strength and ankle motor control following a 
single session of IC in comparison to sham IC in individuals with stroke.   
Hypothesis 2. Individuals with stroke will show greater improvements in lower limb 
strength and ankle motor control following IC in comparison to sham IC.   
 
3.0 
Background* 
Stroke is the leading cause of serious long-term disability in the United States 
resulting in mild to severe chronic gait impairments, such as hemiparesis, reduced 
gait speeds and endurance, and instability during gait (Jørgensen et al. 1995; 
Olney et al., 1996; Mayo et al. 1999). The primary focus of gait rehabilitation has 
been the development of interventions to restore ambulatory capacity which has 
shown promising results, but there is a critical need to maximize benefits of 
current gait rehabilitation. The concept of neuromodulation has emerged as an 
adjuvant tool to enhance the effects of stroke rehabilitation by modulating neural 

Motor and Neurophysiological Changes after Ischemic Conditioning in Individuals with 
Stroke 
 
 
activity to restore cortical balance and enhance behavioral outcomes (Stoykov & 
Madhavan, 2015). Neuromodulatory modalities can be categorized as movement-
based (continuous passive or active movements), stimulation-based (non-invasive 
brain and spinal stimulation), motor imagery and action observation, sensory-
based (electrical stimulation, vibration), and pharmacological-based (Stoykov & 
Madhavan, 2015). To date, no neuromodulatory modality has emerged as the 
most effective method to prime the central nervous system for rehabilitation. Due 
to the limited number of studies in stroke, the effects and cortical mechanisms of 
neuromodulatory modalities particularly targeting the lower limb primary motor 
cortex (M1) are still not completely understood. 
 
Aerobic exercise is considered a movement-based modality that may upregulate 
corticomotor pathways and enhance the effects of subsequent motor training (Stinear et 
al., 2014; Stoykov et al., 2017). In healthy populations, previous studies demonstrated 
that a single session of aerobic exercise increased corticospinal excitability (Hendy et al., 
2022), enhanced performance on a perceptual learning task and simple motor task (Perini 
et al., 2016), improved implicit motor learning (Mang et al., 2014), enhanced motor 
memory retrieval (Mang et al., 2016), enhanced motor skill consolidation (Stavrinos et 
al., 2017), and facilitated responses to neuromodulation (McDonnell et al., 2013; Mang et 
al., 2014; Singh et al., 2014). Previous research in stroke demonstrated that a single 
session of aerobic exercise increased responses to subsequent therapies by increasing 
lesioned hemisphere motor cortical excitability (Boyne et al., 2019; Li., et al 2019) and 
circulating levels of brain derived neurotrophic factor (BDNF) (Boyne et al., 2019) - a 
neural substrate underlying motor learning. Aerobic exercise has led to positive outcomes 
in the studies previously mentioned, however, other studies have reported mixed results. 
In one instance, aerobic exercise increased walking speeds but suppressed corticomotor 
excitability (Madhavan et al., 2020). Another study found aerobic exercise had no 
influence on motor learning (Snow et al 2016). One explanation for the inconsistency 
could be exercise intensity. Stroke literature suggests exercising at higher intensities for 
optimal outcomes (Boyne et al., 2019; Luo et al., 2019; Munari et al., 2018), however, 
many stroke patients, especially those with severe impairments, lack the mechanistic 
properties required to perform high-intensity exercise. Furthermore, individuals with 
stroke lack the aerobic capacity necessary to perform most aerobic exercise protocols. 
Mixed results, inconsistencies in current aerobic exercise protocols, and the lack of 
neuromodulatory procedures for those with severe impairments demand investigation 
into alternative methods for individuals with stroke.  
 
Ischemic conditioning (IC) could be a potential modality to improve function post-stroke. 
In IC, the limb is exposed to brief, repeated bouts of ischemia (reduced blood flow) 
immediately followed by reperfusion. Priming procedures increase the brain’s 
responsiveness to subsequent training protocols (Stoykov & Madhavan, 2015), and 
previous studies have revealed the neuromodulatory effects of IC. In rats, aerobic 
exercise and IC share mechanisms to induce neuroprotection and stimulate 
neuroplasticity by increasing levels of neurotrophic factors like BDNF and proteins 
responsible for building new connections within the central nervous system to support 
motor learning (Wang et al., 2020). Additionally, prior research suggests short (0-12 

Motor and Neurophysiological Changes after Ischemic Conditioning in Individuals with 
Stroke 
 
 
hours) and long (24-72) windows of action following IC (Koch et al., 2014; Durand et al., 
2019), and it has been implied by several studies that the delayed, or long-term, action 
may be more robust, especially as applied to neural plasticity (Perez-Pinzon, 2004; 
Dirnagl et al., 2009; Koch et al., 2014). In humans, IC has shown to improve muscle 
performance in healthy populations (Paradis-Deschênes et al., 2016). Local and remote 
IC performed in healthy individuals improved motor learning (Cherry-Allen et al., 2015), 
increased fatigue resistance (Barbosa et al., 2015), enhanced running performance 
(Bailey et al., 2012), and increased maximal power output (De Groot et al., 2010). Given 
the positive results in healthy populations, IC could potentially exert even larger effects 
in clinical populations with diminished motor output like stroke. In fact, an acute 
exposure to IC increased paretic muscle strength and muscle activation in individuals 
with stroke (Hyngstrom et al., 2018). Also in chronic stroke, prolonged IC exposure 
improved walking speed, cognitive function, and reduced paretic muscle fatigue (Durand 
et al., 2019; Feng et al., 2019). Increased fatigue resistance at submaximal contraction 
levels following IC may be due to increased neural activation which may be particularly 
beneficial following cortical reorganization after stroke (Hyngstrom et al., 2018). 
 
Thus, the objective of this work is to establish IC as an acute neuromodulation 
modality by measuring changes in corticomotor outcomes and subsequent motor 
performance in individuals with stroke after a single session of IC and sham-IC. 
This study is unique as it seeks to address the need for alternative priming modalities to 
promote motor function in individuals with stroke, particularly individuals with severe 
impairments. This study aims to develop a rehabilitation technology which can enhance 
motor outcomes for any severity of stroke by supplying an alternative method to 
traditional motor priming procedures.  
 
4.0 
Study Endpoints*  
 
Primary 
Corticomotor excitability (CME): Motor evoked potentials (MEPs) recorded from 
the TA muscles of the paretic limbs for individuals with stroke using single-pulse 
TMS targeting the lower limb primary motor cortex.  
 
Transcallosal inhibition (TCI): TCI from the stimulated hemisphere to the non-
stimulated hemisphere will be quantified as a measure of the ipsilateral silent 
period (iSP). During a 50% maximum voluntary contraction, single-pulse TMS 
will be delivered to the lower limb primary motor cortex ipsilateral to the active 
lower limb. The iSP in the active lower limb will be defined as the time after the 
MEP when electromyography (EMG) activity is below 25% of the background 
EMG.  
 
 
Muscle Strength: Ankle dorsiflexion and plantarflexion strength will be measured 
using a simple hand-held strength testing device (dynamometer) and using the 
Medical Research Council (MRC) Scale for muscle strength.  
 

Motor and Neurophysiological Changes after Ischemic Conditioning in Individuals with 
Stroke 
 
 
Ankle Motor Control: With a custom-built ankle tracking device, we will measure 
reaction time using a choice reaction time task. While seated, subjects will 
perform ankle dorsiflexion or plantarflexion using the paretic foot as quickly as 
possible in response to a rising or falling visual bar signal displayed on a screen. 
Bar signals will show in a random order and interval. EMG activity will be 
recorded during the task. Participants will perform a total of 30 trials with a 60-
second rest after every five trials. Reaction time will be defined as the duration 
from the signal presentation to the onset of the EMG response. 
 
Secondary 
Pain: Subjective measures of pain will be reported during IC using a Numerical 
Rating Scale (NRS) from 0 (no pain) to 10 (worst pain). If cuff inflation becomes 
too painful for the participant, the session will be terminated.  
 
5.0 
Study Intervention/Investigational Agent  
 
Ischemic Conditioning  
A rapid inflation cuff (Hokanson SC12 thigh cuff), similar to those used to measure 
blood pressure, will be placed on the proximal thigh of the paretic leg while subjects are 
seated in a chair. Prior to IC procedures, the cuff will be inflated to determine each 
subjects’ limb occlusion pressure (leg receiving IC) and will last <1-minute. For all Aims 
in the proposed study, the cuff will be inflated to 225mmHg for real IC and to 25mmHg 
for sham IC. The exact same set up used for real IC will be used for sham IC (same cuffs, 
same device, same body positions, etc.). The only difference between real and sham IC 
will be the amount of pressure in the cuff (225mmHg vs. 25mmHg). For all Aims in the 
proposed study, the cuff will be inflated for 5 minutes followed by 5 minutes of no 
inflation (0mmHg). Each cycle lasts 10 minutes (5 minutes of inflation followed by 5 
minutes of no inflation). Subjects will complete 5 cycles of real and sham IC for a total of 
50 minutes. These exact methods have been used previously in stroke patients without 
any adverse events or negative feedback from participants (Hyngstrom et al., 2018; 
Durand et al., 2019; Hyngstrom et al., 2020). A more detailed description of IC 
procedures is provided under Section 11.0 ‘Procedures Involved’. 
 
The equipment used for IC will be stored in a locked room in Dr. Madhavan’s laboratory. 
Only key research personnel will have key access to the storage room. 
 
For Aim 2, to distinguish the acute effects of both neuromodulatory modalities (sham IC 
and real IC) we will record measures of ankle strength and ankle motor control after one 
session of sham IC and real IC. Force output will be used to measure ankle (dorsiflexion 
and plantarflexion) strength. Ankle motor control (ankle dorsiflexion and plantarflexion 
reaction time) will be measured with a custom-built ankle-tracking device.   
 
6.0 
Study Timelines*  
In Aims 1 and 2, subjects will make three visits to the lab. The first lab visit will 
be for screening and clinical measures and will last approximately 2-3 hours. If 

Motor and Neurophysiological Changes after Ischemic Conditioning in Individuals with 
Stroke 
 
 
deemed eligible, subjects will make two more visits to the lab: 1 sham IC session 
and 1 real IC session. Each priming session will last 3-4 hours (including 50 
minutes of sham IC and real IC). 
We anticipate enrolling all study subjects within 3-5 years. Primary analyses will 
be completed one year following the completion of subject recruitment.  
7.0 
Inclusion and Exclusion Criteria* 
During recruitment procedures, when potential subjects contact the Brain Plasticity Lab, 
key research personnel will explain the study and answer all questions. Before admission 
to the study, subjects will undergo a brief screening pertaining to the inclusion and 
exclusion criteria listed below to assess their qualification to participate in the study. If 
the individual is interested, they will be screened over the phone using the attached 
screening documents (Supplemental_Phone Screen Stroke). If the individual is 
determined to be eligible over the phone using the eligibility criteria listed below, they 
will be scheduled for a visit to the laboratory for an in-person screening 
(Supplemental_Screening Stroke). All subjects will be screened in person in the Brain 
Plasticity Lab regardless of the initial mode of recruitment (i.e., initial phone screens will 
be screened again in person). Screen failures will be excluded from the study. To ensure 
that subjects continue to meet the eligibility criteria of this study, at the start of each 
session, subjects will be asked to notify the investigators of any change in their medical 
or physical condition or change in their prescription medications. All screening and 
patient consent will be done by key research personnel at the University of Illinois at 
Chicago (UIC).  
To determine whether potential subjects are to be excluded from the current study based 
on the presence of thrombosis, including deep vein thrombosis (DVT), we have included 
two additional risk assessment questionnaires, the Wells clinical prediction guide and the 
Caprini risk assessment model for venous thromboembolism. The Wells clinical 
prediction guide quantifies the probability of deep venous thrombosis (DVT). The Wells 
clinical prediction guide incorporates risk factors, clinical signs, and the presence or 
absence of alternative diagnoses to enable physicians to reliably stratify patients into 
high-, moderate-, and low-risk categories (McLendon et al., 2017). The Caprini Risk 
Assessment Model is an ordinal scoring tool used to quantify and categorize a patient's 
risk for venous thromboembolism (VTE—an aggregate disease that includes both 
pulmonary embolism [PE] and deep vein thrombosis [DVT]). Similar to the Wells 
prediction guide, the Caprini Risk score stratifies patients into risk categories: very low 
risk, low risk, moderate risk, and three separate high-risk categories. Any potential 
subject that scores higher than moderate risk, will be excluded from the study.  
In addition to pre-study assessments, to continuously monitor risks for DVT, we have 
incorporated safety measures during the ischemic conditioning procedure including 
safety checks for skin integrity (bruising or blistering on the skin), measures of blood 
pressure, oxygen saturation, and pain. 

Motor and Neurophysiological Changes after Ischemic Conditioning in Individuals with 
Stroke 
 
 
Additionally, we will assess potential subjects’ risk for vascular disease using the ankle-
brachial index (ABI) test. The ankle-brachial index (ABI) is a non-invasive tool for the 
assessment of vascular status (McClary & Massey, 2022). It consists of the ratio between 
the systolic blood pressure of the lower extremity, specifically the ankle, and the upper 
extremity (McClary & Massey, 2022). The ankle-brachial index test compares the blood 
pressure measured at the ankle with the blood pressure measured at the arm to determine 
if patient’s have narrowed arteries or significant reductions in blood flow to the arms and 
legs. This ratio compares the resistance of the blood vessels, with one of the primary 
factors being the diameter of the vessels (McClary & Massey, 2022). To calculate the 
ankle brachial index, the blood pressure in an artery in the leg is divided by the blood 
pressure in an artery in the arms. The final product is a ratio representative of subject’s 
potential risk for vascular disease. A low ankle brachial index number can indicate 
narrowing or blockage of the arteries in the legs. The opposite is true if blood pressure 
from the upper limb is divided by blood pressure from the lower limb (i.e., to determine 
narrowing in the arms). If the lower limb to upper limb ratio is less than 0.9, it may mean 
that a person has vascular disease in the blood vessels in his or her legs (McClary & 
Massey, 2022). If potential subjects’ ratios are less than 0.9, they will be excluded from 
the current study. 
 
Prior to enrollment of stroke subjects, we will also request access to medical records 
(Supplemental_Authorization for Release of Medical Information Cover Letter) to verify 
subject’s history of medical conditions prior to enrollment in the study.    
 
Eligibility Criteria: 
 
 
Inclusion Criteria: 
• Age >21 years old 
• Single, monohemispheric stroke > 6 months since onset 
• Residual hemiparetic gait deficits (e.g., abnormal gait pattern) 
 
 
Exclusion Criteria: 
• Lesions affecting the brainstem or cerebellum 
• Other neurological disorders that may interfere with motor function 
• Unhealed decubiti, persistent infections that may interfere with ability to 
perform test procedures 
• Significant cognitive or communication impairment (Mini-Mental State 
Examination (MMSE<21)), which could impede the understanding of the 
purpose of procedures of the study 
• Botulinum toxin (Botox) treatments to the lower limb within the past 6 
months  
• Pregnant women  
• Contraindications to TMS or IC (Listed below) 
 
TMS General Exclusion Criteria: 
• Previous adverse reaction to TMS 

Motor and Neurophysiological Changes after Ischemic Conditioning in Individuals with 
Stroke 
 
 
• Skull abnormalities or fractures 
• Concussion within the last 6 months 
• Unexplained, recurring headaches 
• Implanted cardiac pacemaker 
• Metal implants in the head or face 
• History of seizures or epilepsy 
• Use of medications that could alter cortical excitability or increase risk of 
seizure (e.g., antidepressants, antipsychotics, anxiolytics, anticonvulsants) 
• Current pregnancy 
 
IC General Exclusion Criteria: 
• History of thrombosis (i.e., blood clots) including venous thrombosis or deep 
vein thrombosis (DVT). 
• Blood clots in the leg, or any condition in which compression of the thigh or 
transient ischemia is contraindicated (i.e., open wounds in the leg, bruising, 
nerve damage, etc.) 
• Peripheral arterial grafts in the lower extremity 
• History of uncontrolled hypertension  
• History of peripheral vascular disease or hematological disease  
8.0 
Vulnerable Populations* 
Pregnant women and children below the age of 18 will be excluded from the research. 
TMS is contraindicated in women who are pregnant as the effect of TMS on the unborn 
fetus is unknown. Women of childbearing age will be asked their pregnancy status during 
phone screening procedures and answers will be recorded in the appropriate phone screen 
documents (Supplemental_Phone Screen Healthy; Supplemental_Phone Screen Stroke; 
Supplemental_Phone Screen 2week IC Stroke). When women of childbearing age visit 
the lab, they will be given a pregnancy test to confirm they are not pregnant prior to 
enrollment. Results of the pregnancy test will be recorded in the appropriate screening 
documents (Supplemental_Screening Healthy; Supplemental_Screening Stroke; 
Supplemental_Screening 2week IC Stroke). Children are excluded from this study 
because of concerns regarding maturation of the nervous system that could introduce 
confounding variables into the TMS related measures in the study.  
9.0 
Number of Subjects   
50 individuals with stroke will be required to attend up to one screening session 
and two training sessions (sham IC and real IC). All subjects will complete both 
conditions (sham IC and real IC) prior to corticomotor (CME and TCI) and 
behavioral (lower limb strength and ankle motor control) testing, and the order 
will be randomized, counterbalanced, and separated by at least one week.    
As this study intends to include individuals with stroke of all severities, we expect 
most screened subjects to be enrolled. Those with contradictions to TMS or IC 

Motor and Neurophysiological Changes after Ischemic Conditioning in Individuals with 
Stroke 
 
 
during screening will not be included. In total we expect to screen 75 individuals 
with stroke and anticipate enrolling 50 individuals with stroke.  
 
10.0 Recruitment Methods 
Individuals with stroke regardless of gender, racial or ethnic status will be recruited using 
a flyer (Supplemental_Flyer Stroke) and email announcement (Supplemental_Email 
Announcement Stroke), which will be posted at UIC, the Chicago metropolitan area, and 
via the web (UIC Announcements, UIC-AHS labs webpage, UIC Massmail). In addition, 
we will make in-person vocal announcements regarding our research in classrooms on the 
UIC campus for additional recruitment. Flyers (Supplemental_Flyer Stroke) and email 
announcements (Supplemental_Email Announcement Stroke) will also be shared with 
stroke support groups and outpatient clinics for additional recruitment of individuals with 
stroke. Flyers (Supplemental_Flyer Stroke) and email announcements 
(Supplemental_Email Announcement Stroke), will provide contact information for 
interested individuals to directly contact a member of the research team. When potential 
subjects contact the Brain Plasticity Lab, key research personnel will explain the study 
and answer all questions. If the individual is interested, they will be screened over the 
phone using the attached screening documents (Supplemental_Phone Screen Stroke). If 
the individual is determined to be eligible over the phone, they will be scheduled for a 
visit to the laboratory for an in-person screening (Supplemental_Screening Stroke). All 
subjects will be screened in person in the Brain Plasticity Lab regardless of the initial 
mode of recruitment (i.e., initial phone screens will be screened again in person). Screen 
failures (phone or in-person) will be excluded from the study, and data from screen 
failures will be securely disposed. 
Furthermore, individuals with stroke will also be recruited by physician referral from the 
Department of Neurology at UIC. Physicians will inform eligible patients about the study 
during their routine visits to the clinic by providing them with a copy of the flyer 
(Supplemental_Flyer Stroke). It will be made clear that the study is solely being 
conducted for research purposes and will in no way provide treatment for their 
symptoms. If the patient is interested in knowing more about the study, the patient will 
initiate contact with key research personnel. Screening and informed consent will be 
conducted by key research personnel only and not by the referring physician (to avoid 
possible coercion by the treating neurologist who may be the patient’s primary care 
physician).   
To aid recruitment, we will also use the UI Health EPIC electronic health record system. 
Specifically, we will use EPIC to identify potential participants who have had a stroke 
and have been treated at UI Health. Individuals who have had a stroke and meet other 
study inclusion criteria will be contacted first with one email (Supplemental_Email 
Script). After 7 days, if the research team has not received a response to the email, we 
may contact the individual with one phone call (Supplemental_Phone Script). No 
additional attempts will be made to contact potential subjects if no response is received to 

Motor and Neurophysiological Changes after Ischemic Conditioning in Individuals with 
Stroke 
 
 
the email or phone call. If a response is received from the individual indicating interest in 
the study, they will undergo screening procedures.  
Subjects will receive $20 per screening session and $20 per training session up to $60 for 
three sessions. Compensation will be provided in cash immediately at the end of each 
visit. If subjects discontinue, we will arrange to send payment in the mail or arrange for 
subjects to pick up payments. 
 
 
11.0 Procedures Involved*  
 
Subjects will be screened for study eligibility prior to participation in all Aims.  
All key research personnel will be provided the adequate training and equipment needed 
to carry out the study. Training will be repeated as necessary. Data collection and 
analyses will be performed by authorized personnel only. Subjects will be identified 
using a unique alpha-numeric code. Only the authorized study personnel will have access 
to the name associated with this code. This code and name will be in a secure, password 
protected database accessible only to study personnel.  
The principal investigator (PI) will be primarily responsible for monitoring the safety of 
subjects, and the safety and confidentiality of data. This will be done by following the 
best practices to ensure that we strictly adhere to the inclusion and exclusion criteria, and 
protections against risks outlines. The safety of each subject will be assessed on an 
individual basis throughout his or her involvement in the study. Any decline in function 
or subject responses that indicates a potential adverse effect will be reviewed 
individually. In the case of a subject being excluded from research participation based on 
TMS, or IC safety questionnaires, the PI will maintain confidentiality of these data.   
A member of the study team will be available to each subject throughout testing and will 
be monitoring participant safety. Subjects will be instructed to immediately inform study 
personnel if any adverse effects of treatment are experienced. We will ask subjects to 
provide us with a phone number of a caregiver (or friend or family member) to contact in 
case of emergency. Any adverse events or unanticipated problems will be recorded and 
communicated to all study personnel as soon as possible. Subjects will be removed from 
the study if the study procedures threaten the subjects’ safety or study procedures are 
unbearable. Any adverse events will be noted within the subject file. 
Any unexpected experience, adverse event or outcome related to the research will be 
closely monitored by the research personnel and reported to Dr. Madhavan immediately. 
Dr. Madhavan will take necessary action according to the nature of unforeseen problem 
which may include reporting of adverse events to the IRB and funding agency (if 
funded), suspension of research procedures in currently enrolled subjects; modification of 
research procedures for new subjects; changes of the informed consent document/process 
to ensure subject safety and privacy, modification of inclusion or exclusion criteria to 
mitigate the newly identified risks; implementation of additional procedures for 
monitoring subjects; and/or suspension of enrollment of new subjects.  

Motor and Neurophysiological Changes after Ischemic Conditioning in Individuals with 
Stroke 
 
 
General Overview: 
Aims 1 and 2 are a repeated measures cross-over study design with each subject 
undergoing two sessions of IC (real and sham).  
Aims 1 and 2:  
If potential subjects are deemed eligible for the study through phone 
screening, subjects will visit the lab for on-site screening (see details 
below). Once qualified, clinical measurements including motor 
impairment, ankle range of motion, cognition, quality of life, disability, 
and walking analyses (walking endurance and spatiotemporal 
characteristics) will be assessed. All of the tests to be used are commonly 
used in the clinic to measure motor and cognitive function as well as 
quality of life in individuals with stroke. A research investigator will be in 
attendance and will ensure safety at all times during the session. 
After screening procedures, each subject will come to the lab on two separate 
occasions separated by at least one week (2 weeks total). Subjects will experience 
one session of sham IC and one session of real IC (randomized order). Baseline 
measures of TMS followed by lower limb strength and ankle motor control will 
be recorded to begin both sessions (sham IC and real IC). The duration of sham 
IC and real IC will be 50 minutes in total (cycles of 5-min of occlusion followed 
by 5-min of reperfusion). TMS, strength, and ankle motor control will be recorded 
again immediately after sham IC and real IC procedures as well as 30-minutes 
post both procedures. To maintain subject safety and study validity, subjects with 
severe impairments who cannot perform the 10MWT safely, will not perform 
tests of gait speed (10MWT) but will experience all other study endpoints 
(corticomotor excitability, transcallosal inhibition, muscle strength, ankle motor 
control). If subjects with severe impairments are able to perform 10MWT safely 
using an assistive device (i.e., cane or walker), then gait speed will be collected 
using the 10MWT. Subjects with mild or moderate impairment levels will 
experience all study endpoints including gait speed. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Motor and Neurophysiological Changes after Ischemic Conditioning in Individuals with 
Stroke 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 1: Aims 1 & 2 Study Design. Stroke subjects will be randomized to receive either sham IC or real 
ICseparated by at least one week (2 weeks total). For IC sessions, with subjects in a seated position, the 
cuff will be placed over subjects’ paretic thigh and inflated to either 225mmHg (real IC) or 25mmHg (sham 
IC) for 5 minutes followed by 5 minutes of no inflation (0mmHg). This will be repeated five times for a total 
of 50 minutes. Measures of TMS, lower limb strength, and ankle motor control will be recorded prior to, 
immediately after, and 30-minutes after both procedures (sham IC and real IC). 
1 week of separation  
Baseline 
Measures: 
TMS, 
Strength, & 
Ankle Ctrl 
Screening 
At least 1 day  
in between 
Random 
30-
min 
Post:  
TMS, 
Strength, & 
Ankle Ctrl 
Follow Up:  
TMS, 
Strength, & 
Ankle Ctrl 
50-min 
5-min 
5-min 
0mmHg  
Sham 
IC: 
25mmHg 
5-min 
5-min 
0mmHg  
Sham 
IC: 
25mmHg 
5-min 
5-min 
0mmHg  
Sham 
IC: 
25mmHg 
5-min 
5-min 
0mmHg  
Sham 
IC: 
25mmHg 
5-min 
5-min 
0mmHg  
Sham 
IC: 
25mmHg 
50-min 
5-min 
5-min 
0mmHg  
Real 
IC: 
225mm
Hg  
5-min 
5-min 
0mmHg  
Real 
IC: 
225mm 
Hg  
 
5-min 
5-min 
0mmHg  
Real 
IC: 
225mm 
Hg  
 
5-min 
5-min 
0mmHg  
Real 
IC: 
225mm 
Hg  
 
5-min 
5-min 
0mmHg  
Real 
IC: 
225mm 
Hg  
 

Motor and Neurophysiological Changes after Ischemic Conditioning in Individuals with 
Stroke 
 
 
 
Screening Procedures: 
Aims 1 and 2: 
Subjects will be screened to determine if they qualify for the study using the listed 
inclusion and exclusion criteria. We will interview subjects and use their medical 
records to obtain stroke-related, demographic, and descriptive information. For 
subjects seen at UI Health, stroke-related and descriptive information will be 
obtained through the UI Health EPIC electronic health record system. For subjects 
not seen at UI Health, we will complete a separate authorization form 
(Supplemental_Authorization for Release of Medical Information Cover Letter) 
requesting their non-UI doctor to give the information to Dr. Sangeetha 
Madhavan. We will also have subjects complete the ‘Supplemental_Screening 
Stroke’ document which includes the TMS and IC safety questionnaire to ensure 
safety with all study procedures. Once subjects are determined to be eligible to 
participate, we will obtain informed consent from subjects and perform clinical 
assessments of movement impairment, ankle range of motion, cognitive function, 
quality of life, disability, and walking analyses (walking endurance and 
spatiotemporal characteristics). See below for detailed explanations. During the 
screening process, we will collect contact information for each subject, including: 
name, address and zip code, phone numbers, and email addresses 
(Supplemental_Screening Stroke). 
Ankle Range of Motion: Ankle range of motion will be tested by a trained 
evaluator using a manual range of motion testing tool (goniometer). We will test 
ankle dorsiflexion and plantarflexion range in the supine lying position (active 
and passive).  
 
Cognitive Function: Cognitive function will be assessed with the Mini-Mental 
State Examination (MMSE), a quantitative assessment of cognitive impairment. 
 
Motor Impairment: Lower extremity impairment will be measured using the Fugl 
Meyer Lower Extremity Scale (FMLE) - a series of tests of movement, reflex 
activity, coordination/ speed, sensation, and range of motion.  
 
Walking Endurance: Walking endurance will be measured using the 6-Minute 
Walk test. Subjects will walk as far as possible within 6 minutes.  
 
Walking spatiotemporal characteristics: During the 6-Minute Walk test, 
spatiotemporal parameters of walking will be assessed using APDM wearable 
sensors. Outcome measures of walking capacity will include cadence, stride 
length, individual step lengths, step times, and the absolute and relative times of 
stance and swing phases. Measures of interlimb symmetry, defined as ratios of 
paretic to nonparetic values of the spatial and temporal variables, will be 
calculated. 
 

Motor and Neurophysiological Changes after Ischemic Conditioning in Individuals with 
Stroke 
 
 
Quality of life: Quality of life will be measured with the EuroQol-5D (EQ-5D), a 
questionnaire with questions designed to assess aspects of quality of life. 
 
Disability: Global disability will be measured with the modified Rankin Scale 
(mRS), a simple 0-6 rating scale. Disability will also be measured using the 
Barthel Index which assesses a person’s ability to perform activities of daily 
living by assigning a numerical score based on individual performance in tasks 
such as feeding, bathing, grooming, dressing, using the toilet, transferring from a 
bed to a chair, walking, and climbing stairs. Scores typically range from 0 to 100, 
with lower scores indicating greater disability.   
 
Transcranial Magnetic Stimulation (TMS) Procedure: 
TMS is a safe, non-invasive, and painless method of brain stimulation that has 
been widely used to study the physiology of the muscle representations in the 
motor cortex in healthy and neurologically disordered individuals (Anand & 
Hotson, 2002). Very short duration (<1 ms) magnetic pulses are applied via an 
insulated wire coil placed on the intact scalp overlaying the motor cortical area 
projecting to a target muscle. Each pulse induces a MEP in the target muscle that 
can be readily monitored by recording EMG with electrodes taped to the muscle 
of interest. 
Prior to the start of TMS testing, while seated, maximum voluntary isometric 
contractions (MVIC) for each target muscle will be obtained with the ankle in 
neutral position restricted by a tightened metal clamp attached to a wooden board. 
EMG electrodes will be applied over the muscle bellies of each target muscle. 
Standard skin preparation techniques (light abrasion and cleansing with alcohol) 
will be completed prior to application of the electrodes. A ground electrode will 
be applied over the patella or other bony prominence. The ground electrode will 
be placed over a bony prominence at the level of the 7th cervical vertebra (C7) or 
below. This ground electrode will require small amounts of ultrasound 
transmission gel (Park Laboratories Inc, Fairfield, NJ, USA) which may be 
uncomfortable for some subjects, but the area will be cleaned thoroughly with 
paper towels and alcohol wipes upon session completion. EMG recordings will be 
amplified (Bagnoli, Delsys, Boston, MA), band-pass filtered (10-1000 Hz), and 
sampled at 2000 Hz. EMG activity will be collected from the all the muscles 
bilaterally. Three five-second contractions will be conducted with real-time visual 
feedback.  
Magnetic stimuli will be delivered via a double cone coil (diameter 110mm) with 
a posterior-anterior orientation connected to a Magstim 200 unit (Magstim 
Company, Boston MA). A double cone coil is typically used to deliver focal 
magnetic pulses to a number of scalp sites over the cortical area representing a 
muscle of interest. First, the TMS coil will be systematically moved over the 
targeted M1 to identify the location of the “hotspot”, defined as the location with 
the largest, consistent contralateral MEP, while maintaining a tonic contraction 
corresponding to 10% MVIC of the target muscle. For stroke subjects, the hotspot 

Motor and Neurophysiological Changes after Ischemic Conditioning in Individuals with 
Stroke 
 
 
location of the lesioned M1 will be mirrored from the location determined for the 
non-lesioned M1. Resting motor threshold (RMT) for the muscle of interest will 
be defined as the stimulator output intensity that can elicit a MEP with peak-to-
peak amplitude of at least 0.075 mV in four out of eight trials. It will be 
determined by increasing stimulus intensity in steps of 1% stimulator output. 
Active motor thresholds (AMT) will also be determined with the same protocol 
and defined by the lowest stimulus intensity required to elicit a MEP with a peak-
to-peak amplitude of at least 0.1 mV in four out of eight trials with the subject 
contracting the muscle of interest to about 10% MVIC. 
CME of the paretic TA muscle representations will be measured with single pulse 
TMS (Magstim, Dyfed, Wales, UK). To assess corticospinal excitability of the 
M1, the double cone coil will be placed over the M1 cortical area (near the vertex 
of the head), and the subject will then receive 15 stimuli at intensities 
corresponding to 130% of rest and active motor threshold at each designated 
timepoint (See Figures 1, 2, and 3). Changes in descending CME will be 
quantified from TMS as changes in mean peak-to-peak MEP amplitude. These 
measures will assist the investigators to assess the contribution of the motor 
cortex to lower limb muscles.  
Transcallosal inhibition (TCI) will also be measured with single-pulse TMS to 
assess the changes in interhemispheric inhibition from the lesioned to non-
lesioned hemisphere at designated timepoints (See Figure 1): before/ after real IC 
and sham IC. TCI from the stimulated hemisphere to the non-stimulated 
hemisphere will be quantified as a measure of the ipsilateral silent period 
(Davidson et al., 2016). During TCI, the participant will be instructed to maintain 
~ 50% maximum voluntary contraction while a suprathreshold pulse (130% of 
active motor threshold) is delivered to the hemisphere ipsilateral to the active 
muscle. This would enable the measurement of the ipsilateral silent period (iSP) 
which serves as a measure of TCI. The iSP in the contralateral TA is defined as 
the time after the MEP when EMG is below 25% of the background EMG. We 
will perform 5 trials to obtain iSP with an interval of ~60 seconds between trials 
to avoid fatigue. 
 
Ischemic Conditioning Procedure:  
A rapid inflation cuff (Hokanson SC12 thigh cuff) similar to those used to measure blood 
pressure, will be placed on the proximal thigh of the paretic leg while subjects are seated 
in a chair. 
Prior to IC procedures, the cuff will be inflated to determine each subjects’ limb 
occlusion pressure (leg receiving IC) which will last <1-minute. For all Aims in the 
proposed study, the cuff will be inflated to 225mmHg for real IC, and 25mmHg for sham 
IC. The exact same set up used for real IC will be used for sham IC (same cuffs, same 
device, same body positions, etc.). The only difference between real and sham IC will be 
the amount of pressure in the cuff (225mmHg vs. 25mmHg). For all Aims in the 
proposed study, the cuff will be inflated for 5 minutes followed by 5 minutes of no 
inflation (0mmHg). Each cycle lasts 10 minutes (5 minutes of inflation followed by 5 

Motor and Neurophysiological Changes after Ischemic Conditioning in Individuals with 
Stroke 
 
 
minutes of no inflation). Subjects will complete 5 cycles of real and sham IC for a total of 
50 minutes. These exact methods have been used previously with stroke participants 
without any adverse events or negative feedback from participants (Hyngstrom et al., 
2018; Durand et al., 2019; Hyngstrom et al., 2020). During IC, we will visibly monitor 
signs of skin integrity by loosening the cuff after the first inflation cycle to examine for 
any bruising or blistering on the skin. For all Aims in the proposed study, ratings of 
fatigue (0-10 scale) and pain (0-10 scale) will be monitored throughout the protocol and 
the pressure will be reduced or stopped completely if intolerable. Likewise for all Aims, 
signs of nerve compression will be monitored throughout IC procedures via verbal 
feedback regarding tingling or numbness. If these symptoms persist during periods of 
reperfusion (no cuff inflation), the activity will be stopped immediately. Blood pressure 
(BP), heart rate (HR), and oxygen saturation levels will be monitored throughout, and the 
activity will be stopped immediately if necessary. Participants will be contacted the day 
after their first IC treatment to follow-up regarding any current or lingering symptoms 
from the procedure.  
 
The equipment used for IC will be stored in a locked room in Dr. Madhavan’s laboratory. 
Only key research personnel will have key access to the storage room. 
 
Summary of Procedures 
  
 
Aims 1 and 2: 
• Visit # 1 (2-3 hours) - Subjects will undergo:  
o Screening using the appropriate documentation 
(Supplemental_Screening Stroke) which will collect 
information related to demographics, study eligibility criteria, 
medical conditions (Medical Screening Questionnaire), and IC 
and TMS safety. 
o Clinical assessments of movement impairment (FMLE), ankle 
range of motion, cognitive function (MMSE), quality of life 
(EQ-5D), disability (modified Rankin scale, Barthel Index), 
and walking analyses (walking endurance and spatiotemporal 
characteristics).  
• Visits # 2 and 3 (3-4 hours) - Subjects will undergo:   
o (Pre/ Baseline) TMS measures of CME and TCI   
o (Pre/ Baseline) assessments of lower limb strength and ankle 
motor control  
o 50 minutes of real IC or sham IC  
o (Post) TMS measures of CME and TCI   
o (Post) assessments of lower limb strength and ankle motor 
control 
o (30-minute Follow Up) TMS measures of CME and TCI   
o (30-minute Follow Up) assessments of lower limb strength and 
ankle motor control 
 
For Studies that Collect Existing or Prospective Data: 

Motor and Neurophysiological Changes after Ischemic Conditioning in Individuals with 
Stroke 
 
 
We will be collecting prospective data from our participants, at the time points outlined 
above. Hard copies of any data will be stored in a locked office in a locked file cabinet in 
the UIC College of Applied Health Sciences (AHS), and all digital data will be stored in 
a password-protected computer on the AHS server. Data entered in any spreadsheet, 
either digital or print, will be presented de-identified via subject’s unique alphanumeric 
code, save for the original screening forms and consent documents, which will contain 
participants names and contact information. Only authorized study personnel will have 
access to this data. All hard copies of data will be properly disposed of 10 years after the 
completion of the study. 
 
12.0 Data and Specimen Banking* 
 
NA 
 
13.0 Sharing of Results with Subjects* 
If requested, results of the experiments will be shared with subjects. However, raw data 
will not be shared with subjects. Study information from this study may be reviewed by 
representatives of the study group at University of Illinois at Chicago, the Institutional 
Review Board (IRB) at the University of Illinois at Chicago, and perhaps, the U.S. Food 
and Drug Administration (FDA), or the National Institutes of Health (NIH). Study 
records will be kept confidential to the extent provided by law. Names of individual 
subjects or any other identifying data will not be used in any report or publication of this 
study. 
14.0 Withdrawal of Subjects* 
 
Subjects will be reassured of their right to withdraw from the study at any time. The 
voluntary nature of participation will be reiterated, and subjects will be informed that 
their decision about participation will not affect their relationship with the UIC or any of 
its related entities. Subjects will be removed from the study if the study procedures 
threaten the subject’s safety or study procedures are unbearable. Subjects will be 
compensated for completed sessions. All previously collected data for a subject will be 
de-identified and used for the final analysis following their withdrawal from the study. 
All personal identifiable data will be destroyed 10 years after study completion. Results 
published will not include names of subjects.  
 
Any unexpected experience, adverse events or outcomes related to the research will be 
closely monitored by the research personnel and reported to Dr. Madhavan immediately. 
Dr. Madhavan will take necessary action according to the nature of the unforeseen 
problem which may include suspension of research procedures in currently enrolled 
subjects; modification of research procedures for new subjects; changes of the informed 
consent document/process to ensure subject safety and privacy, modification of inclusion 
or exclusion criteria to mitigate the newly identified risks; implementation of additional 
procedures for monitoring subjects; and/or suspension of enrollment of new subjects.  
 

Motor and Neurophysiological Changes after Ischemic Conditioning in Individuals with 
Stroke 
 
 
15.0 Risks to Subjects* 
The measurements made in this study present a minimal risk. The following specific risks 
exist for this study: 
Risks associated with TMS: 
 
1) Seizures: rare cases have reported the development of seizures during or 
immediately after magnetic brain stimulation. Individuals who have a history of 
seizures or have been diagnosed with epilepsy will be excluded from this research 
study. Single and paired-pulse TMS that we use in this study have been deemed to 
carry little risk beyond occasionally causing local discomfort. Our stimulation 
procedures follow published safety guidelines. Seizure activation is extremely 
unlikely with the single/ paired-pulse low numbers of stimulation proposed in the 
current investigation. 
2) Discomfort: a small number of people find TMS uncomfortable, particularly at 
high intensities of stimulation. If individuals report feelings of discomfort, 
stimulation intensity will be reduced or, if not feasible, testing will be terminated. 
3) Muscle twitching: subjects may feel twitches in the muscles of the arm, leg or 
face during the magnetic stimulation.  
4) Noise: a loud click during magnetic stimulation may be heard. Subjects will be 
provided with foam earplugs that can effectively prevent this discomfort. 
5) Pregnant women: the risks of TMS on pregnant women are unknown. If there is 
any doubt, TMS testing will not be initiated until the nonpregnancy is confirmed. 
Pregnant women will be excluded from TMS. 
6) Skin irritation: there is a risk of mild skin irritation at the location where the 
electrode sensors have been placed, but this usually consists of minor redness that 
will go away quickly after they are removed. 
Risks associated with clinical assessments:  
1) Muscle soreness or fatigue: during or following clinical assessments, subjects 
may experience muscle soreness 24-72 hours after testing or general fatigue. We 
will always check with the subject before proceeding with testing or training. 
Clinical assessments or exercise will be terminated if muscle soreness or fatigue 
becomes intolerable.  
2) Loss of balance, falls, and/or orthopedic injuries: subjects may lose their balance 
while getting up from sitting or walking during study procedures. Subjects also 
have a risk of falling and/or orthopedic injuries during clinical assessments, 
although the risks are no more than those experienced in everyday life. All 
clinical assessments will be conducted under the supervision and instruction of 
study personnel.  
Risks associated with ischemic conditioning: 
 

Motor and Neurophysiological Changes after Ischemic Conditioning in Individuals with 
Stroke 
 
 
1) Discomfort: subjects may experience discomfort due to the pressure of the blood 
pressure cuff.  
2) Bruising and skin irritation: there is a risk of bruising and skin irritation around 
the area where the IC cuff is placed. To monitor signs of skin integrity, the cuff 
will be loosened after the first inflation cycle to examine for any bruising or 
blistering on the skin. 
3) Tingling: subjects may experience tingling of the limb and feet and a rare but 
potential risk of nerve damage. Signs of nerve compression will be monitored 
throughout IC via verbal feedback regarding tingling or numbness. If these 
symptoms persist during periods of reperfusion, the activity will be stopped 
immediately. Subjects will be contacted the day after their first IC treatment to 
follow-up regarding any current or lingering symptoms from the procedure. 
 
Other Risks: 
1) Worsening of pre-existing medical condition: if a subject notes a worsening of a 
pre-existing medical condition because of IC or TMS, they will be instructed to 
notify study personnel immediately. Although the exact safety plan may be 
specific to the subject’s underlying medical condition, information regarding an 
emergency contact number and contact details for the nearest clinic/hospital will 
be provided. Study procedures will be terminated immediately.  
2) Loss of privacy or confidentiality: medical information and other study related 
data that is collected may be unintentionally accessed by non-study personnel. 
Subject data will be coded and stored in locked filing cabinets (paper format) or 
on password-protected computers (excel format) which are located in a locked 
office (AHSB Rm 810) to minimize this risk. Data access will be limited to key 
research personnel. 
3) Uncomfortable emotions: subjects may experience mild anxiety or embarrassment 
in answering questions of personal nature regarding their health or well-being. 
However, all information collected through study questionnaires will be kept 
confidential and all personal identifiers will be removed. In addition, only the 
study’s key personnel will have access to this information. 
 
 
16.0 Potential Benefits to Subjects* 
 
There are no direct benefits to individuals participating in this research project.  
 
17.0 Data Management* and Confidentiality 
Data and Statistical Analysis:  
Strength will be represented as raw force output values and comparisons will be made 
between the paretic and nonparetic legs for stroke subjects. Ankle motor control will be 
measured as reaction time using the paretic ankle which will be defined as the duration 
between visual signal presentation and the onset of the EMG response in the TA muscle.   

Motor and Neurophysiological Changes after Ischemic Conditioning in Individuals with 
Stroke 
 
 
Changes in descending CME will be quantified from TMS as changes in mean peak-to-
peak MEP amplitude obtained from the TA muscle in the paretic lower limb. TCI from 
the stimulated hemisphere to the non-stimulated hemisphere will be quantified as a 
measure of the ipsilateral silent period (Davidson et al., 2016).  
Based on previous studies, a statistical power analysis was conducted for sample size 
estimation using G*Power software. We used change in peak MEP amplitude after TMS 
as the primary outcome measure. For a meaningful change in peak MEP amplitude, the 
estimated sample size is 35 which provides at least 80% power with α = 0.05. Based on 
our previous experiences with attrition rates, we will recruit 45 subjects to achieve the 
desired power.  
Normality of outcome distributions will be confirmed using Shapiro–Wilk tests for all 
dependent variables. Baseline comparisons of neurophysiological and behavioral 
outcomes between the two experimental conditions (real IC and sham IC) will be 
evaluated using change scores and paired samples t-tests. To assess the main effects and 
interactions of condition (IC vs. sham-IC) and time (pre, post, post-30), two-way 
repeated-measures ANOVAs will be conducted separately for each outcome variable 
(CME, TCI, strength, and motor control). When significant main effects or interaction 
terms are observed, follow-up pairwise t-tests will be performed. Statistical analyses will 
be conducted using RStudio (version 4.0.2) and statistical significance will be set at a p-
value of 0.05. Effect sizes will be calculated for ANOVAs using eta squared (η²) for 
ANOVA models and interpreted according to Cohen’s benchmarks: small (η² = 0.01), 
medium (η² = 0.06), and large (η² = 0.14) (Cohen, 1988).  
Data Management and Security: 
The research will be conducted in compliance with state and federal laws, including the 
Health Insurance Portability and Accountability Act (HIPAA) which require researchers 
to protect an individual’s health information. Data will be stored and analyzed in the 
Brain Plasticity Lab (Rooms 810, 834, 447), 1919 W. Taylor St., Chicago, IL 60612. To 
minimize the risk of the loss of privacy and confidentiality, subject data will be coded 
and stored on a secure HIPAA compliant application (Box for Healthcare – UIC Health 
Data Box folder). Data will be processed and stored under the assigned participant code. 
The key code linking the subject’s participant number to his/her identity will be stored on 
a secure HIPAA compliant application (Box for Healthcare – UIC Health Data Box 
folder) separate from the data and destroyed ten years after study completion. All study 
personnel will have access to the key code and raw data. Study information from this 
study may be reviewed by representatives of the study group at University of Illinois at 
Chicago, the Institutional Review Board (IRB) at the University of Illinois at Chicago, 
and perhaps, the U.S. Food and Drug Administration (FDA), or the National Institutes of 
Health. Study records will be kept confidential to the extent provided by law. Names of 
individual subjects or any other identifying data will not be used in any report or 
publication of this study.  

Motor and Neurophysiological Changes after Ischemic Conditioning in Individuals with 
Stroke 
 
 
The principal investigator will be primarily responsible for monitoring the confidentiality 
of data. Authorized study personnel will have access to the raw data.  The raw data will 
not be made available to any other individuals.   
Quality Control Procedures: 
 
We will employ several quality control procedures to maximize the validity and 
reliability of protocol delivery and outcome assessments namely written protocols for the 
research personnel, and training research personnel. Dr. Madhavan will be actively 
involved in supervising and monitoring the study daily. She will meet with all study 
personnel at least once a week to ensure that there is strict adherence to study protocol 
and outcome assessments. All key research personnel will be provided the adequate 
training and equipment needed to carry out the study. Training will be repeated as 
necessary. Dr. Madhavan will check and regularly review any adverse events or 
deviations from protocol. Study personnel will monitor subject compliance to the 
protocol and losses to follow up. 
 
18.0 Provisions to Monitor the Data to Ensure the Safety of Subjects* 
 
NA. The measurements made in this study present a minimal risk. 
 
19.0 Provisions to Protect the Privacy Interests of Subjects 
 
The PI will be primarily responsible for monitoring the safety of subjects. This will be 
done by following the best practices to ensure that we strictly adhere to the inclusion and 
exclusion criteria, and protections against risks outlines. The safety of each subject will 
be assessed on an individual basis throughout his or her involvement in the study. Any 
decline in function or participant responses that indicates a potential adverse effect will 
be reviewed individually. 
Screening and testing of subjects will be conducted in private rooms. Subject’s privacy 
will be protected at all times by ensuring that only key research personnel are present 
during sessions. An alphanumeric code will be used to identify each subject. Authorized 
research personnel will maintain a master sheet which has the subject's name linked to 
his/her code (initials followed by a number). This sheet will be maintained on the lab 
computer in a password protected file that only the research team directly working on the 
project has access to. Other data will be maintained on the lab computers which only 
authorized personnel have access to. Security of these computers are maintained by the 
College of Applied Heath Science IT personnel. All personal identifiable data will be 
destroyed 10 years after study completion. Results published will not include names of 
subjects.  
A member of the study personnel will be available to each participant throughout testing 
and will be monitoring subject safety. Subjects will be instructed to immediately inform 
study personnel if any adverse effects of treatment are experienced. We will ask subjects 
to provide us with a phone number of a caregiver (or friend or family member) to contact 

Motor and Neurophysiological Changes after Ischemic Conditioning in Individuals with 
Stroke 
 
 
in case of emergency. Any adverse events or unanticipated problems will be recorded and 
communicated to all study personnel as soon as possible. Subjects will be removed from 
the study if the study procedures threaten the subject’s safety or study procedures are 
unbearable. Any adverse events will be noted within the subject file. 
 
Subjects will be reassured of their right to withdraw from the study at any time. The 
voluntary nature of participation will be reiterated, and subjects will be informed that 
their decision about participation will not affect their relationship with the UIC or any of 
its related entities.  
 
Subjects will continuously be reminded of the rare/ minimal risks associated with study 
procedures and reminded that all information they supply is voluntary. 
 
20.0 Compensation for Research-Related Injury 
A member of the research team will be available to the subject throughout testing and 
will be monitoring subject safety throughout. We will ask subjects to provide us with a 
phone number of a person to contact in case of emergency. In the event of injury related 
to this research, treatment will be available. However, the subject or his/her third-party 
payer, if any, will be responsible for payment of this treatment. In the unlikely event that 
the subject requires emergency medical care during a study visit, 911 will be called 
immediately. There is no compensation and/or payment for such medical treatment for 
such injury except as may be required by law. 
21.0 Economic Burden to Subjects 
Participants will be required to provide their own means of travel and will be 
responsible for any travel-related costs which may be partially reimbursed. 
 
22.0 Consent Process 
Subjects will be provided with a written consent form and may be assisted with 
understanding by the research therapist, the investigators, attending clinicians, or family 
members. Voluntary, informed consent will be obtained from all subjects by key research 
personnel prior to participation in any study procedures. As part of the informed consent 
process, the key research personnel will discuss the written informed consent document 
approved by the IRB at UIC. All study information, including purpose, procedures, risks, 
and benefits will be reviewed. Subjects will be given sufficient time to understand the 
form and will have the opportunity to ask any questions during and after the consent 
process. Subjects will be reassured of their right to withdraw from the study at any time. 
The voluntary nature of participation will be reiterated, and potential subjects will be 
informed that their decision about participation will not affect their relationship with the 
UIC or any of its related entities. Only individuals with the capacity to consent will be 
included in the study. The research personnel will ask specific questions about the study 

Motor and Neurophysiological Changes after Ischemic Conditioning in Individuals with 
Stroke 
 
 
to assess whether the participant understands the involved procedures. If they choose to 
participate in the study, subjects will provide informed written consent in the presence of 
the investigators. Subjects will be provided with a copy of the informed consent, so they 
can reference any information or contact details. 
Written consent will be obtained in person at Brain Plasticity Lab (Rooms 810, 834, 447), 
1919 W. Taylor St., Chicago, IL 60612. Study personnel will explain the study, and 
subjects will review the informed consent document. All questions regarding the study 
will be answered by the study personnel obtaining informed consent. Informed consent 
will be obtained in English using lay language. The subject will receive a copy of the 
signed informed consent document, and the investigator will keep the original copy in the 
research records. The informed consent document will be accessible by all study 
personnel. 
 
23.0 Process to Document Consent in Writing 
 
We will be documenting consent in writing with HRP-091-SOP-Written Documentation 
of Consent. 
 
24.0 Setting 
All subject recruitment and research procedures will be performed at the UIC Brain 
Plasticity Lab located at 1919 W. Taylor St., Rooms 447/ 810/ 834 (Applied Health 
Sciences Building) Chicago, IL 60612.  
25.0 Resources Available 
The Brain Plasticity Lab has excellent access to subject recruitment due to its 
location in the Illinois Medical District of Chicago, near the John H Stroger 
Hospital of Cook County, Rush University Medical Center, University of Illinois 
Medical Center, and the Jesse Brown VA Medical Center. Subjects for this study 
will be recruited from the various outpatient clinics in the greater Chicagoland 
area, including the University of Illinois at Chicago, Shirley Ryan Ability Lab, 
Rush University Medical Center, Schwab Rehabilitation Hospital, and the 
University of Chicago. Through Dr. Madhavan’s well-established working 
relationships with neurologists at UIC, we have access to a stroke registry 
maintained by the Department of Neurology at UIC. This registry gives us access 
to an additional ~1000 individuals with stroke who have given their consent to 
share their contact information with research personnel. The database is extremely 
useful for recruitment since it includes detailed medical information, such as 
lesion location and impairment level. Dr. Madhavan has also cultivated 
collaborative relationships with other hospitals in the area resulting in participant 
recruitment from these sites as well. In the past, previously mentioned recruitment 
resources have resulted in a complete R01-funded clinical trial (with strict 
recruitment criteria) with over 80 participants. Based on the resources above, we 
do not anticipate any problems in recruiting the 100 individuals required for the 

Motor and Neurophysiological Changes after Ischemic Conditioning in Individuals with 
Stroke 
 
 
proposed study. We anticipate enrolling all study subjects within 3-5 years, and 
primary analyses will be completed one year following the completion of subject 
recruitment.  
 
Resources are available for consequences of human research. Measures of HR, 
BP, oxygen saturation, pain, and RPE will be taken during sessions to mitigate 
potential consequences of human research and monitor any serious adverse 
events. Additionally, during IC procedures, the rapid inflation cuff will be 
loosened to inspect any damage to the skin and subjects will be asked to give 
feedback regarding painful sensations. All study procedures will be stopped if the 
study safety criteria are violated. Water, Gatorade, snacks, and first aid kits are 
available in the event of non-serious medical events. The Brain Plasticity Lab 
contains plenty of seating and a physical therapy bed in case subjects need to rest 
in certain positions at any point during the study procedures. In the event a subject 
needs immediate medical attention, they will be taken to the University of Illinois 
Hospital (1740 W Taylor St, Chicago, IL 60612) located 0.4 miles from the Brain 
Plasticity Lab.    
 
The Brain Plasticity Lab has a long history with priming procedures including 
stimulation-based priming (i.e., tDCS) and movement-based priming via ankle 
movements and aerobic exercise on either a treadmill or recumbent stepper. We 
have successfully completed numerous priming procedures without any serious 
adverse events. We will employ several quality control procedures to maximize 
the validity and reliability of protocol delivery and outcome assessments namely 
written protocols for the research personnel, and training research personnel. Dr. 
Madhavan will be actively involved with supervising and monitoring the study on 
a day-to-day basis. She will meet with all study personnel at least once a week to 
ensure that there is strict adherence to study protocol and outcome assessments. 
Dr. Madhavan will also hold bi-monthly journal club meetings to ensure that all 
key personnel are abreast of the scientific literature in the area and the importance 
of the current research and thereby motivate staff to ensure their best performance 
during training and assessment. All key research personnel will be provided the 
adequate training needed to carry out the study. Training will be repeated as 
necessary. Dr. Madhavan will check and regularly review any adverse events or 
deviations from protocol. Study personnel will monitor subject compliance to the 
protocol. In addition to quality control procedures, research personnel will have 
access to the UIC Center for Clinical and Translational Science (CCTS) which 
provides strategic services related to research design and analysis, research 
dissemination and implementation, biostatistics, community engagement, clinical 
research, regulatory and bioethics, recruitment and retention, and funding advice 
and support. Additionally, CCTS also helps young investigators navigate complex 
research processes and manage logistics. 
26.0 Multi-Site Research* 
NA  

Motor and Neurophysiological Changes after Ischemic Conditioning in Individuals with 
Stroke 
 
 
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Stroke