Neural Circuitries of Motor Learning as a Target to Modulate Sensorimotor Recovery After Stroke
Conditions: Stroke, Sensorimotor Impairment
Sponsor: Medical University of South Carolina

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PI Name:  Dr. Kirstin-Friederike Heise 
 
Study Title:   NEURAL CIRCUITRIES OF MOTOR LEARNING AS A TARGET TO MODULATE 
SENSORIMOTOR RECOVERY AFTER STROKE   
 
NCT05511467 
 
 
Medical University of South Carolina 
Protocol 

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TABLE OF CONTENTS  
 
A. SPECIFIC AIMS__________________________________________________________________ ............... 3 
B. BACKGROUND AND SIGNIFICANCE_________________________________________________ .............. 4 
C. PRELIMINARY STUDIES___________________________________________________________ .............. 4 
D. RESEARCH DESIGN AND METHODS (including data analysis) __________________________ .................. 4 
D1. OVERVIEW OF STUDY STRUCTURE AND PROCEDURES ....................................................................... 4 
D1.1 
Sample Size Rationale & Recruitment Feasibility. ................................................................................ 4 
D1.2  
Participant Inclusion Criteria. ................................................................................................................. 5 
D1.3 
Participant Exclusion Criteria. ................................................................................................................ 5 
D1.4 Procedures ................................................................................................................................................. 5 
D2. TIMELINE ........................................................................................................................................................ 8 
D3. DATA ANALYSIS ............................................................................................................................................ 9 
D2.1 
Sample Size Justification. ...................................................................................................................... 9 
D3.2 
Analysis Plan. ...................................................................................................................................... 10 
D3.3 
Consideration of Sex as a Biological Variable. .................................................................................... 10 
D3.4 
Potential Challenges and Solutions. .................................................................................................... 10 
E. PROTECTION OF HUMAN SUBJECTS________________________________________________ ............ 10 
E1.  RISKS TO THE SUBJECTS ......................................................................................................................... 11 
a.  Human Subjects Involvement and Characteristics ...................................................................................... 11 
b.  Sources of Materials .................................................................................................................................... 11 
c.  Potential Risks ............................................................................................................................................. 11 
E2.  ADEQUACY OF PROTECTION AGAINST RISKS ...................................................................................... 12 
a.  Recruitment and Informed Consent ............................................................................................................ 12 
b.  Protection against Risk ................................................................................................................................ 13 
E3.  POTENTIAL BENEFITS OF THE PROPOSED RESEARCH TO THE SUBJECTS AND OTHERS ........... 14 
E4.  IMPORTANCE OF THE KNOWLEDGE TO BE GAINED ............................................................................ 14 
E5.  SUBJECT SAFETY AND MINIMIZING RISKS (Data and Safety Monitoring Plan) ..................................... 14 
E5.1 
Safety Training. .................................................................................................................................... 14 
E5.2 
Medical Emergencies. ......................................................................................................................... 14 
E5.3 
Ethical Research Practices. ................................................................................................................. 14 
E5.4 
Data Monitoring Procedures. ............................................................................................................... 14 
E5.5 
Data and Safety Monitoring Board....................................................................................................... 15 
E5.6 
Data Safety Monitoring Committee (DSMC). ....................................................................................... 15 
E5.7 
Data and Safety Monitoring Board (DSMB). ........................................................................................ 15 
F.  
REFERENCES/LITERATURE CITATIONS_________________________________________ ............... 15 
G. APPENDIX______________________________________________________________________ ............. 17 
 

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A. SPECIFIC AIMS__________________________________________________________________ 
 
Experience-dependent plasticity in neural networks is generally appreciated as a resource for recovery, but no 
interventional approach exists to prevent maladaptive plastic processes (e.g., resulting in learned disuse of the 
paretic hand)1. The problem is that the mechanisms that drive maladaptive plasticity during sensorimotor recovery 
are still incompletely understood2. Additionally, it remains an open question to what degree plastic changes during 
recovery and sensorimotor learning share common neural circuits3,4. Imaging and electrophysiological evidence 
support learning stage-specific dynamics (e.g., in early/late encoding, consolidation) within circuits of cortical and 
subcortical regions that engage in distinct types of motor learning (e.g., implicit, explicit) in the intact nervous 
system5–7.  
Despite increasing evidence for stroke-related neural network disruptions to predict impairment in many behavioral 
domains8, we still have a limited understanding of how brain lesions impact the dynamics within learning circuits 
and how this relates to maladaptive plastic changes. First data shows altered functional network characteristics 
suggesting deficient communication between task-relevant regions that are potentially linked to deficient integration 
of new (to be learned) information in stroke9,10. A separate line of research indicates a lesion-induced reorganization 
of the motor executive functional network connectivity that reflects the restoration of motor function11,12.  
A more comprehensive understanding of the interaction between a focal lesion and the dynamics within neural 
networks during sensorimotor learning will yield important information about the capacity to integrate new 
information and potentially avoid maladaptive mechanisms. While this is particularly relevant in the early phase 
post-stroke, during which these plastic changes supposedly develop2, investigating the chronic phase in a first step 
will allow including biomarkers of recovery as covariates into the analysis of network alterations.  
So far, the fields of sensorimotor rehabilitation research and motor-learning-related network science have not been 
integrated sufficiently13 but primarily conducted in isolation, thus rendering an inclusive view impossible. 
Additionally, suitable paradigms that systematically differentiate types of motor learning and learning stages have 
not been implemented systematically for populations with sensorimotor deficits, which precludes the identification 
of specific network dynamics and their relevance to sensorimotor recovery.  
Bringing together longstanding expertise in stroke rehabilitation, kinematic analyses of complex behavior, 
and advanced neuroimaging, Dr. Heise and the multi-professional COBRE team are uniquely positioned to 
advance the field of learning research as a diagnostic tool in the context of stroke rehabilitation. Dr. Heise 
(PI) combines expert knowledge in studying dynamics of complex motor control and learning using 
neurophysiological, neuroimaging techniques, and non-invasive brain stimulation in healthy and neurological 
populations14–17, with longstanding clinical experience in the field of stroke rehabilitation. 
We still do not know enough about how a focal lesion impacts the dynamics within brain circuits that govern motor 
learning and how this relates to maladaptive plastic changes. Filling this knowledge gap builds the basis for 
designing interventions that causally target experience-dependent maladaptive changes which negatively impact 
the patient’s recovery (e.g., leading to disuse of the paretic hand). With this JI project, we will generate pilot data 
serving as the first evidence for motor learning-related network dynamics in the chronic phase after stroke (aim 1) 
and their link with biomarkers of recovery of upper-extremity sensorimotor function (aim 2).  
AIM 1 To characterize motor learning (ML)-related neural network dynamics in the presence of a focal 
lesion, we will use a representational statistical modeling approach18 to describe learning-related connectivity 
changes based on task-based functional magnetic resonance imaging (fMRI) in stroke survivors (≥6 months post-
lesion, stroke group SG) and healthy volunteers of comparable age and gender (control group, CG). Functional 
connectivity patterns will be modeled throughout the acquisition phase to capture the temporal trajectory of 
encoding-related network changes. 
AIM 2 To understand the association between ML-related network dynamics and biomarkers of recovery, 
we will comprehensively describe upper-extremity sensorimotor functioning and impairment for the individuals in 
the SG and statistically integrate these biomarkers of recovery with the ML-related network dynamics within a 
separate representational model. 

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B. BACKGROUND AND SIGNIFICANCE_________________________________________________ 
 
Recovery of upper extremity function remains dissatisfying for the majority of stroke survivors with sensorimotor 
impairment19, which represents a major hindrance to independence in daily life20. Within the field of rehabilitation 
research, learning mechanisms have long been a major area of interest because they are considered one key 
player in functional recovery. This basic premise goes back to seminal work that established the brain’s capacity to 
change in response to environmental stimuli and learning, i.e., experience-dependent plasticity21,22.  
However, it is evident that plasticity does not have purely beneficial effects on recovery3 but that also negative 
consequences such as learned disuse of the paretic hand can be observed1. 
 
The proposed JI project implements a conceptually and methodologically innovative approach to characterize 
stroke-related alterations within functional circuits that govern sensorimotor learning and their link to recovery. The 
completion of this project will set the stage for the PI’s planned next steps. Altered network dynamics during learning 
in the SG will provide network-informed targets for non-invasive brain stimulation to further investigate their 
modifiability and behavioral relevance. Additionally, they justify the longitudinal investigation of network dynamics 
within learning circuits during the development of maladaptive plastic changes longitudinally in the early phase after 
stroke. 
C. PRELIMINARY STUDIES___________________________________________________________ 
 
The project describes a pilot study and serves as a proof-of-concept to generate preliminary data to support the 
planned follow-up R01 proposal.  
D. RESEARCH DESIGN AND METHODS (including data analysis) __________________________ 
 
D1. OVERVIEW OF STUDY STRUCTURE AND PROCEDURES 
 
D1.1 
Sample Size Rationale & Recruitment Feasibility. 
Before the main study described below, a short series of pilot experiments is planned to iteratively test the 
experimental paradigm with the goal to assure feasibility of all experimental procedures for varying levels of motor-
functional capacity in the stroke group. 
Initial pilot phase. For this initial phase, which precedes the main study, we anticipate recruiting a maximum of 
N=40 volunteers (patients and controls) to iteratively test and optimize the paradigm (the learning task) for use in 
the MRI environment. 
Main study. Target recruitment will include N=25 stroke survivors in the chronic phase (≥6 months after index 
lesion, stroke group) and N=15 healthy volunteers of comparable gender, age range and education level (control 
group). There will be no overlap with individuals of the initial pilot phase. Based on previous work, we anticipate 
that with these sample sizes it will be sufficient to determine the feasibility and effect sizes for the planned follow-
up R01 application (also see Sample Size Justification below).  
Recruitment. This study will recruit from the Registry for Stroke Recovery (RESTORE-Pro#00037803, IRB 
approved 9/6/14) which is a research tool sponsored by the National Institutes of Health (NIH) Center of Biomedical 
Research Excellence (COBRE) in Stroke Recovery with participants consented for future contact to support stroke 
recovery research conducted at MUSC. Trained RESTORE staff will query the registry for potential volunteers and 
provide the Principal Investigator (PI) or a member of the research team with the contact information of subjects 
who meet their criteria.  Since these patients have already consented to being contacted for future research, the PI 
or a member of the research team will contact potential volunteers to further screen for potential enrollment. Contact 
will be sought via the preferred option indicated by the patient in the registry, e.g., via phone or email.  

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Recruitment of patients is feasible as it will happen in collaboration with the QBAR Core therapist team and 
capitalizing on the RESTORE database with over 800 participants, potentially eligible for this study. Volunteers for 
the control group will feasibly be recruited through the same channel and from spouses of patients and word-of-
mouth to assure comparability concerning age, gender, and confounding variables such as education level. In 
addition, the potentially interested people will be accessed through flyers distributed digitally through MUSC 
information screens, the online platform Yammer.com, as well as through the MUSC Wellness Center. 
Participants. For the initial pilot phase and the main study, chronic stroke survivors (time since stroke greater than 
or equal to 6 months) will be recruited. Acute stroke survivors (time since stroke less than 6 months) are excluded 
to minimize confounding from the spontaneous recovery of cognitive functioning.  
D1.2  
Participant Inclusion Criteria.  
For all participants: Adult volunteers (age ≥18 years) with right-hand dominance23 will be recruited for the stroke 
and control group.  
Stroke-specific inclusion criteria are defined as (1) ischemic or hemorrhagic lesion with (2) subcortical or cortical 
tissue involvement, and (3) in the chronic phase (>6 months) after their index lesion, (4) voluntary whole-hand grip 
force (MRC, Medical Research Council scale for muscle force ≥224) and repeated release (standardized as a 
reduction of 50% of maximum voluntary contraction measured with a dynamometer).  
D1.3 
Participant Exclusion Criteria.  
For all participants: Any contraindication for MRI scanning is a general exclusion criterion irrespective of group. 
Primary intracerebral hematoma or subarachnoid hemorrhage, bi-hemispheric ischemic strokes, other concomitant 
neurological disorders affecting motor or cognitive function (e.g., dementia); moderate to severe global aphasia; 
visual impairment that precludes completion of scanner tasks; presence of any MRI risk factors such as an 
electrically, 
magnetically 
or 
mechanically 
activated 
metal 
or 
nonmetal 
implant 
including 
cardiac 
pacemaker, intracerebral vascular clips or any other electrically sensitive support system; pregnancy as the effect 
of MRI on the fetus is unknown; history of seizure disorder; claustrophobia; substance use disorder; psychotic 
disorders; moderate to severe traumatic brain injury  
Stroke-group specific exclusion criteria are defined as: Primary intracerebral hematoma, or subarachnoid 
hemorrhage; bi-hemispheric or cerebellar strokes; other concomitant neurological disorders affecting upper 
extremity motor function; documented history of dementia before or after stroke; severe aphasia, particularly of 
receptive nature (NIHSS Language subsection ≥225) affecting their ability to understand the purpose of the study 
and give informed consent; uncontrolled hypertension despite treatment; intake of tricyclic anti-depressants or 
neuroleptic medication. 
D1.4 Procedures 
Telephone Eligibility Screening (session 0). Potential participants of the stroke group will be pre-screened for 
eligibility regarding level of upper-extremity sensorimotor function and to exclude moderate or severe cognitive 
impairment. In lack of a validated phone proxy tool, we will use a questionnaire-based interview to estimate the 
level of sensorimotor function in a standardized and reproducible way (Appendix 1). Individuals reporting minimal 
voluntary whole-hand grip and release control will be invited for further assessment of in- and exclusion criteria if 
additionally identified as cognitively unimpaired, ambiguous, or mildly impaired by the Telephone Interview for 
Cognitive Status (TICS)26,27. Eligibility for MR imaging is screened (MRI safety screen). Individuals who are able to 
complete these tasks demonstrate intact decision-making capacity. Individuals identified by the TICS as moderately 
or severely impaired will not be invited. The telephone screening will be done by a member of the administrative 
member of the research team who is trained to perform the questionnaire-based interview. To ensure to recruit only 
eligible participants for the patient group, telephone eligibility screening needs to be performed prior to obtaining 
informed consent. Data generated during this initial phone interview for participants not included in the study, will 
not be stored. Data of participants who are recruited and consented will be stored with the participant’s data under 
the participant’s study identification number after removal of identifiable information (name, contact details). 

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In-person Eligibility Screening (session 0). In cases in which in-person screening is feasible, e.g., if potential 
participants are already at the study site and have expressed interest in participating in this study, potential 
participants will be pre-screened based on the same information as in the telephone screening. One exception is 
the cognitive screening, which will be done with the Montreal Cognitive Assessment (MoCA)36 instead of the 
Telephone Interview for Cognitive Status (TICS)26,27. In these cases, no TICS data will be collected. 
Informed Consent (session 1). Informed consent can be obtained in a written fashion by one of the members of 
the study team. Participants will be provided with ample time to review the consent document prior to discussion 
with a member of the study team. The nature of the study will be explained by a member of the study team in lay 
terms. If the participant or control agrees to participate in the study, they will sign and date the informed consent 
and HIPAA forms (or combined consent/HIPAA if applicable). They will also be informed that they may choose to 
withdraw from the study at any time. Participants will be informed that their decision regarding participation will not 
affect their clinical care in any way. A copy of the signed informed consent and HIPAA will be provided to 
participants. 
Alternatively, electronic consent (eConsent) will be obtained through the REDCap system. A member of the 
research team will reach out to the participant by phone to provide details of the study. If the participant agrees to 
participate, a link to the REDCap eConsent will be provided to the participant via a hyperlink (text or email), and a 
member of the study team will review the consent document over the phone or via videoconferencing with the 
participant. The participant will electronically sign the eConsent and submit the REDCap survey. The study team 
member will then electronically sign the eConsent and print a PDF of the document. The signed PDF willl be emailed 
or mailed to participants for their records. eConsent will be implemented at sites that support this method of consent. 
Multi-System Assessment (session 2). Following consent, participants of both groups will be assessed regarding 
their neuro-cognitive and emotional functioning to further assure eligibility. Handedness (for participants of the 
stroke group this relates to pre-morbid status) will be assessed with the Edinburgh Handedness Inventory23.  
In addition, participants of the stroke group undergo the assessment of their upper-extremity sensorimotor 
functioning as well as the evaluation of stroke-related quality of life (SIS-3.020,28). General severity of stroke-related 
symptoms will be quantified with the NIH Stroke Scale (NIH-SS)29,30. The NIH-SS will be performed by the PI or 
research staff certified for testing the NIH-SS. 
Physical Assessment of upper-extremity sensorimotor functioning. To comprehensively characterize a broad 
range of upper extremity sensorimotor control, a test battery will be used that captures the non-/low-functional up 
to fine-motor impairment level. Passive and active range of motion and movement-associated pain of the paretic 
upper extremity will be evaluated with the upper-extremity section of the Fugl-Meyer Assessment (UEFMA)31. To 
characterize grasp, grip, pinch, and gross-motor functioning with relevance to activities of daily living, the Action 
Research Arm Test will be used (ARAT)32,33. To quantify dexterity of individual finger movements, the Nine-Hole 
Peg Test (9HPT)34,35 will be used. To quantify maximum voluntary contraction (MVC) and repeated 
contraction/release of contraction, a digital dynamometer will be used. All physical examination will be performed 
by a study therapist trained in standardized testing of upper-extremity function. 
Neuro-Cognitive and emotion Assessment. To further ensure eligibility, an in-person session will take place. 
Following consent, the Montreal Cognitive Assessment (MoCA)36 will be completed. Participants will complete 
computerized cognitive tests from the NIH Toolbox39 (30-40 minutes). Each of these tests has been extensively 
normed compared to traditional neuropsychological measures. Tests from different batteries will be utilized in this 
study to optimize a comprehensive but efficient, reliable, and minimally burdensome subset of tests for chronic 
stroke patients. Participants of the SG presenting with aphasic symptoms will also complete the bedside Western 
Aphasia Battery (WAB)37, to measure levels of aphasia that would preclude valid assessment in all other domains. 
Similarly, participants will complete the Virtual Reality Lateralized Attention Test (VRLAT)38 if suspected of 
presenting with neglect symptoms. 
The Patient Health Questionnaire-9 Item (PHQ-9)41 will be administered to screen for depression and anxiety as 
these are relevant confounders for learning and memory.  

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All neuro-cognitive and emotion assessment will be performed by trained personnel and overseen by a licensed 
clinical psychologist (Dr. Lisa McTeague).  
Sleep and vigilance screening. General sleep quality is quantified with the Pittsburgh Sleep Quality Index (PSQI)43 
once in session 2. Sleep duration and quality of the night preceding each individual experimental session are 
assessed with the respective items of the St. Mary’s sleep questionnaire44. Before the task training and retest 
sessions, self-perceived vigilance is evaluated with the Stanford Sleepiness Scale (SSS)45 and additionally 
quantified objectively with the psychomotor-vigilance task (PVT)46. Except PSQI, all of the above-mentioned sleep 
and vigilance screening assessments are performed on both experimental sessions (session 3 and 4). All sleep 
and vigilance screening will be performed by the PI or a member of the research team.  
Additional Questionnaires will be used to collect information about the participant’s demographics including age, 
gender, level of education in addition to medication intake (Appendix 2). 
To reduce the burden for those participants who have participated in a study at the Stroke Recovery Research 
Center involving the same standardized assessments and questionnaires and consented to data sharing, we will 
use the already available data if these have been collected within ≤30 days. 
Two-layered Learning Task (sessions 3 and 4). We will adapt an established sequence learning paradigm47,48 
for the use in patients with sensorimotor impairment of the upper extremity. Two layers of implicit sequential 
information (Figure 1) are implemented in the experimental paradigm through visual stimuli on a computer screen 
to distinguish the two modes of implicit learning. Behavior is captured with whole-hand grip-force transducers (the 
hand-held interface) requiring minimal active range of motion and voluntary muscle force. 
 
Figure 1 Behavioral paradigm and participant flow. A) Experimental set-up showing visual stimuli with imperative cue (green) 
and force feedback (yellow) to implement the stimulus-response mapping of cue positions and input force level scaled relative 
to individual 
The force will be defined relative to maximum voluntary contraction for each hand separately. This allows even low-
functioning participants to perform the task with the paretic hand. The participants will receive the instruction to 
follow the imperative cue by adjusting their own grip force. Feedback will be provided about the actual grip force in 
real-time. Force adjustment happens in stepwise increments of the relative force, which allows to induce two 
different implicit learning modes. Specifically, the volunteers will learn the association between visual cue and 
individual force level (1st order) within standard serial reaction time task49, in which a sequence of force levels is 
provided repetitively and contrasted with random force levels. In addition, they will learn the hidden rule, i.e., the 2nd 
order sequence that can occur among both, the first-order sequential and the random force levels. This hidden 
regularity will be implemented through the sequential variation of cue intervals comparable to a morse code that 
occurs among otherwise uniform intervals. Based on the recorded muscle force (1000Hz sampling rate), the 
behavioral outcome (temporal/spatial accuracy) is monitored continuously throughout the learning phase. This 
procedure makes it possible to differentiate performance in the two learning modes. Furthermore, as left and right 
hand will be tested, it will be possible to estimate the impact of hand-dominance and side of lesion (non-/paretic 
hand) on the learning capacity for each learning mode. 

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Imaging Parameters (sessions 3 and 4). Scanning will take place at the Center for Biomedical Imaging on the 
Siemens 3T Prisma. Functional and structural scanning parameters are detailed in the NI Core. High-resolution 
structural, fluid-attenuated inversion recovery (FLAIR), diffusion-weighted (DWI), and arterial spin labeling (ASL) 
perfusion imaging will use in-house standard sequences and will be collected from all participants in session 3. The 
task-based fMRI sequence will be optimized for an event-related design with a TR of 2 seconds. For the resting-
state data, a TR of 0.8 seconds will be used. Task-based and resting-state imaging will be collected in session 4 
with varying protocols for participants of SG and CG as described in the timeline below and explicitly detailed in the 
information and consent form. All MRI sequences will be accompanied by electrical recording of physiological 
signals from the upper body (e.g., electrocardiogram, electrodermal analyses) to support processing of MRI data 
and for secondary analyses examining relationships between autonomic nervous system dysfunction, brain, and 
behavioral outcomes.  
D2. TIMELINE  
Participants of both groups (stroke, control) will undergo the same protocol, which includes 4 sessions (outlined in 
the table below). 
 
Session Number 
Task Description 
Location at Medical 
University of South 
Carolina 
Approximate Time 
Commitment 
0 
Telephone Eligibility Screening 
 
Sensorimotor function screening 
(Appendix 1) 
 
Cognitive screening (TICS26,27) 
 
MRI Safety Screen 
Via telephone 
30 minutes 
1 
Consent 
Stroke Recovery 
Research Center or 
remotely through 
electronic consent 
20-30 minutes 
2 
Multi-system Assessment 
All participants 
 
Pregnancy Test 
 
EHI§ 
 
Questionnaires (Appendix 2)§ 
 
Neuro-Cognitive and emotion 
Assessment 
Stroke group 
 
physical Assessment of upper-
extremity sensorimotor 
functioning 
 
NIH-SS 
Stroke Recovery 
Research Center or 
partly remotely§ 
3 – 3.5 hours 

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 
SIS§ 
3 
MRI scanning and task 
familiarization 
 
MRI Safety Screen 
 
Sleep and vigilance screening  
MRI sequences: 
 
FLAIR 
 
DWI 
 
ASL 
 
T2* weighted sequence (resting-
state) 
 
Physiological recordings 
Learning task: 
 
Task familiarization (in the mock 
scanner) 
Center for Biomedical 
Imaging 
 
 
2 – 2.5 hours 
4 
MRI scanning during task practice 
MRI Safety Screen 
Sleep and vigilance screening  
MRI sequences: 
 
High-resolution T1 weighted 
 
T2* weighted sequence (task-
based) during task practice 
 
Physiological recordings 
Center for Biomedical 
Imaging 
 
2 – 2.5 hours 
D3. DATA ANALYSIS 
D3.1 
Sample Size Justification.  
Given the scarcity of pilot data on stroke and control participants and fMRI-based dynamic connectivity during motor 
learning, justification has to be based on our best estimates and regarded with some caution. One of the primary 
goals of this project is to determine effect sizes for the follow-up grant proposal. For changes to latent connectivity 
characteristics induced by implicit motor learning (pre/post evaluation), empirically obtained effect size estimates 
were derived from the average effect size of published studies involving participants with chronic stroke9 and healthy 
volunteers50. Consequently, sample sizes of 25 and 15 in the stroke survivors and healthy volunteers will allow us 
to estimate the for the main effect of time (pre/post learning) the within-group effect sizes can be expected to be in 
the range of 0.33 - 0.52 at 90% confidence level. 

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D3.2 
Analysis Plan.  
Imaging Preprocessing. Data will be processed by the CBI Computational Core led by Dr. Hesheng Liu. 
Preprocessing parameters for the task-based fMRI data will be optimized to fit the requirements of the 
representational similarity analysis (RSA, described below), specifically smoothing will be reduced to allow for better 
multivariate pattern detection. Resting-state fMRI data will undergo in-house standard preprocessing. 
For the learning task-based data, a general linear model (GLM) will be fitted to each individual’s data serving as the 
basis for the representational similarity analysis (RSA). In addition to the regressors of interest (matched to the 
onset time of each regressor of the event-related design of the learning-paradigm: 1st and 2nd order sequence force 
cues, random force cues) six motion parameters will be included as nuisance covariates. Estimated beta-values 
will be extracted from the GLM for each stimulus and run for each region of interest (ROI) within subject. For each 
ROI, a neural matrix will be created by correlating (Pearson) the multi-voxel patterns between all possible 
combinations of pairs of stimuli of the learning task condition and then averaged across subjects within group (first-
order RSA51). In the second step, group-averaged matrices (only the upper diagonal elements) will be vectorized 
and correlated (Pearson) for all possible combinations of ROI pairs (second-order RSA51), which will allow to 
investigate the representational similarity between ROIs i.e., the clustering/networks of ROIs, with regard to the 
between-condition similarity in multi-voxel activation patterns. 
For the resting-state data, the connectivity analysis will be used to identify physiological biomarkers for recovery 
and potential predictors for learning efficiency. For this purpose whole-brain resting-state network fluctuations, 
based on BOLD signal time courses, will be extracted for cortical and subcortical ROIs. Nuisance regression will be 
performed to account for the effects of motion on functional connectivity (including six translation and rotation 
parameters from the motion correction transformation, average CSF, white matter, and whole-brain time courses, 
as well as the first derivatives, squares, and squared derivatives of each of these confound predictors52. To extract 
the dynamic modulation of connectivity over time, time courses will be divided into sub-blocks of multiples of the 
TR to allow capturing slow-frequency fluctuations by approximating the frequency envelope of the hemodynamic 
response at the given TR with the highest possible temporal precision. Connectivity will be quantified as the 
magnitude-squared coherence53,54 between each pair of ROI for each sub-block of time55. Network characteristics 
and their temporal dynamics will then be analyzed with dynamic network statistics following the approach given in 
reference55.     
D3.3 
Consideration of Sex as a Biological Variable.  
While this study will not be sufficiently powered to reveal sex differences, in planned follow-up analyses we will 
utilize sex as a covariate, as well as age, race, and ethnicity. 
D3.4 
Potential Challenges and Solutions.  
We expect that network definition across participants of the stroke group with varying lesion size and location will 
be methodologically challenging. Therefore, we will pursue a ROI-based approach in a first step, and we will take 
an exploratory approach to investigate the influence of lesion location and size on whole-brain networks. As RSA 
methodology benefits from large sample size, this pilot work includes the conventional univariate analysis of 
connectivity in its analysis pipeline. The implementation of the RSA analysis pipeline is one of the main purposes 
of this pilot study even though the results may not provide sufficient power for generalizability.  
 
E. PROTECTION OF HUMAN SUBJECTS________________________________________________ 
We are committed to conducting safe research that favors benefits over risks. The following sections describe how 
we will attend to safety and ethical issues involved in conducting the proposed research. 

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E1.  RISKS TO THE SUBJECTS  
a.  Human Subjects Involvement and Characteristics  
As described in section D1, the target sample of the main study will include a total of N=25 adult stroke survivors in 
the chronic phase, N=15 neurologically healthy adult volunteers, in addition to max. N=8 participants for the initial 
pilot phase (max. N=4 for stroke and control group).  
 
Inclusion of Women and Minorities.  
There is a relatively equal ratio of male to female stroke patients in South Carolina. In the duration of this project, 
forty (N=25 stroke group, N=15 control group) individuals will be enrolled. Consequently, 50% women will be 
assigned to each group. There will be no exclusion criteria with respect to ethnic background. Demographic data 
from the US Census Bureau (2016 estimates.) indicates the sex, race and ethnicity distribution in South Carolina 
as follows: 51.5% female, 48.5% male; 68.5% white persons not of Hispanic origin, 27.5% Black or African 
American, 0.5% American Indian and Alaska Natives, 1.6% Asian persons; with 5.5% persons of Hispanic origin). 
The goal in the proposed study is to construct a participant pool that matches population proportions in South 
Carolina. (2016; https://www.census.gov/quickfacts/SC). Consequently, we will seek to enroll a minimum of 31.5% 
minority representation per group. As necessary, advertisements will be placed in newspapers and radio stations 
with primarily African-American or Hispanic readership and audience.  
 
Comfort and reliability considerations:  
During the administration of some of the neuropsychological assessments, the participants’ verbal responses will 
be audio recorded for quality control purposes.  
 
Video recording of sensorimotor functional tests 
During all in-person sessions, snacks and water will be offered between testing administrations in order to 
improve energy, limit fatigue, and promote comfort. Furthermore, multiple breaks will be offered.  
Finally, participants will be given the option to schedule sessions on the same day, with a break, if additional 
visits/travel would be burdensome. 
b.  Sources of Materials  
Data collected from all participants will include responses to diagnostic interview, neuropsychological assessment, 
questionnaire responses, structural and functional brain images, behavioral performance from scanner tasks, heart 
rate, respiration, demographic information, health/medication information (to determine experiment counter-
indicators), contact information for scheduling appointments, personal address and other information for processing 
payment, and related information for the sole purpose of research and ensuring participant safety. Additionally, 
consent forms and HIPAA forms will be collected. 
c.  Potential Risks  
Risks of in-person visits due to COVID-19 
The option to remotely complete some of the sub-tests of the multi-system assessment (session 2), as for example 
the MoCA, the Stroke Impact Scale, the Edinburgh Handedness Inventory, and the BDI will be given to participants 
if they are unable to physically come to the Stroke Research Center for the time being, such as due to COVID19 
precautions. Phone calls or video conferencing through Microsoft Teams, Zoom (with HIPAA approved license 
using single sign‐on, or Doxy.me will be utilized to properly administer and oversee the completion of these 
assessments. 
MRI risks.  
There is a serious risk that MRI could move iron-containing objects in or around the face or head, which could in 
the process possibly harm the person. As such, these contraindications will be thoroughly screened at intake and 
at each scan. Participants are thoroughly screened to prevent metal being brought into the MR environment and 
are asked to change clothes into MR safe (no zippers, buttons, etc.) clothing before entering the MR chamber. In 

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the absence of risks related to metal, exposure to magnetic field strengths used in the present study is not shown 
to be a significant health risk. Electrodes used for physiological recordings are MRI safe, however may result in 
mild irritation to skin at the placement sites where adhesive is present.  
Risks to an unborn fetus from exposure to the MRI field strength used in the proposed research (3 Tesla) are 
unknown. Therefore, pregnant females and those who may become pregnant (unwilling to follow study restrictions 
limiting chances of conception) will not be allowed to participate. Participants will be asked to lie still and awake for 
up to 1.5 hours in the scanner and this can occasionally result in soreness, stiff back, etc. Participants will be queried 
approximately every 10 minutes about their comfort. All investigators and research assistants running participants 
in imaging center are thoroughly trained in MR safety yearly as a requirement to run scans.   
Claustrophobia.  
Some emotional discomfort may be anticipated due to the enclosed nature of the MRI. Participants will be screened 
and encouraged not to participate if he/she has a history of claustrophobia. To minimize participant distress and to 
ensure comfort and consistent communication with the experimenters and PI during all scans, participants will be 
queried between each imaging sequence. Procedures are interrupted or terminated when a patient reports or the 
experimenters and/or PI suspect undue stress.  
Risks related to questionnaire- and clinical assessment.  
Participants may experience an exacerbation of symptoms by being asked to discuss their histories and/or filling in 
questionnaires about their mood and health status. Testing will be performed by a licensed clinical psychologist. In 
the event of a participant becoming agitated or experiencing an exacerbation of symptoms, the testing psychologist 
will lead the participant in relaxation exercises and debriefing until subjective distress reduces to a comfortable 
level.  
Loss of confidentiality.  
Despite efforts to maintain participants’ anonymity and confidentiality, there is always some minimal risk of people 
other than the study investigators gaining access to protected health information.  
E2.  ADEQUACY OF PROTECTION AGAINST RISKS  
The PI and all members of the research team will complete MUSC training in human subjects protection in research. 
The protocol will include and follow guidelines for protection of participants in research. Additionally, all potential 
research participants will be informed of their rights as an experimental participant. 
 
a.  Recruitment and Informed Consent 
Measures taken to limit risk of coercion during recruitment and consent procedure. Participants will be recruited 
through the COBRE CTTR Core and RESTORE database and contacted through their preferred channel indicated 
in the registry (e.g., phone or email) to introduce the study and suggest participation. Potential participants will be 
invited to ask questions until they are satisfied and can make a decision to proceed or not with the phone screen. 
If the potential participant agrees to continue, a phone screen will be conducted to determine eligibility for the next 
phase (the assessment of cognitive, motor and emotional functioning) of the study. This screening session serves 
to assure the participants’ ability to read, verbalize understanding of the content discuss, make an informed decision 
about participation, and sign informed consent documentation. During recruitment care will be given to assess that 
participants are not coerced and are not motivated solely due to financial remuneration to limit the risk of recruiting 
primarily socioeconomically disadvantaged individuals. 
 
Informed Consent. If the potential participant passes the pre-screen and decides to come in for the assessment of 
cognitive, motor and emotional functioning, a signed informed consent will be necessary before beginning 
assessments. Time will be given between information and consenting to make a decision about participation. 
Potential participants will be encouraged to discuss the study with a person they trust (e.g., spouse or adult children) 
before making a decision about participation. E-consent will be an option if the participant is not able to come into 
the laboratory for consenting. The e-consent will be emailed through REDCap and approved research personnel 
will go through the e-consent with the participant over the phone or over video conferencing. The participant will 
receive a copy of the signed e-consent by email from the research personnel. The coordinator will offer to send the 

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consent form to the participant in advance to provide ample time for review. The consent form describes the study 
procedures and ensures participants of the confidentiality of their responses. The consent form further reminds 
participants that they have the option to withdraw from the study at any time and will receive proportional payment 
or they can refuse to answer certain questions and continue in the study with full compensation. The consent form 
contains thorough descriptions of the research protocol (physical and neuropsychological assessment, MRI, clinical 
interview, etc.) including the procedures, benefits and risks, compensation, right to nonparticipation, review 
processes, emergency medical treatment, financial responsibility, and privacy issues. The content of the consent 
will be verbally explained to the participant and the participant will be asked to raise any questions and concerns. If 
the person requests a waiting period, then one will be given. If the person desires to consent immediately, then the 
person will provide consent immediately.  
b.  Protection against Risk 
Tracking Participant Comfort/Wellbeing.  
If there are adverse effects during the laboratory sessions, the PI and/or research assistant will terminate the study, 
provide a debriefing, and contact PI or staff clinician (if PI is not present) for further assistance and follow-up for the 
participant. Only trained psychiatrists, psychologists and research staff will administer the subject screenings, 
assessments, and perform MRI scanning. These professionals will be sensitive to possible signs of subject fatigue 
or distress. Breaks from testing will be allowable, and the testing sessions may also be rescheduled. Upon study 
completion, participants will be fully debriefed on the rationale for the study. As part of the debriefing, each 
participant will also be given the opportunity to ask questions about the study and will be given the contact 
information of the PI.  
Strategies to Ensure Comfort and Retention.  
1) We will maintain communication. Specifically, the research coordinator will be in constant communication with 
participants. The coordinator will ensure the eligibility of the participant, safety of the participant, adherence to tasks, 
and contentment of the participant, throughout the study duration. The coordinator will explain all expectations and 
study details and re-explain throughout the study duration. In addition, upcoming visits will be reminded through 
phone calls or other communication methods of each participant’s preference. Change of schedule will also be 
accommodated and coordinated by the study coordinator. 2) Participants’ time and effort spent on research will be 
remunerated by the participation payment according to the payment schedule. 3) To maximize participants’ 
convenience, a waiting area is provided in the lobby of the CBI with convenient access to the restrooms. 
Participants’ parking is also accommodated in a parking lot adjacent to the research building. 4) We will ensure that 
our staff is well educated about the protocol and procedures by training and observing all procedures at least 
quarterly.  
 
Staff Safety Training.  
All research staff personnel will successfully complete IRB Certification training (CITI and GCP certification) and 
will be as forthcoming as possible with participants. Additionally, research staff will receive safety training in MRI by 
Center for Biomedical Imaging staff at MUSC. 
Confidentiality.  
All data except for the consent forms and HIPAA forms will be de-identified at the time of data recording. All 
electronic data will be stored in a password-protected research server that is accessible to study personnel only. 
The server is backed up every day and maintained 24/7 by IT specialists. All paper data with personally identifiable 
information including the consent forms and HIPAA forms will be stored in a key-locked cabinet in a key-locked 
room that is accessible to the study personnel only. Other paper data without personally identifiable information 
including testing sheets documenting testing sequences and notes will also be stored in a cabinet in a key-locked 
room that is accessible to study personnel only.  
 
Screening Measures & Emergency Room.  
Participants will be thoroughly screened for MRI eligibility multiple times (initial phone contact, intake interview, and 
again at each MRI scanning session). In the event of adverse effects related to MRI scanning, safety coordinators 
and medical staff have been trained how to quickly address any emergencies that may arise. 

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Close monitoring of participant stress and wellbeing will take place over all experimental sessions. 
Physiological Recording Equipment.   
Physiological recording devices meet all standards for non-invasive, scanner compatible materials. 
Incidental findings  
Incidental findings that may be uncovered from the MRI scan will be communicated directly to the participant 
immediately as they are found and explained by the investigator. 
E3.  POTENTIAL BENEFITS OF THE PROPOSED RESEARCH TO THE SUBJECTS AND OTHERS  
There may be no direct benefits from participating in this study.  
E4.  IMPORTANCE OF THE KNOWLEDGE TO BE GAINED  
With the precautions in place to select participants, we expect a very low risk of adverse events in our proposed 
participant cohort. This is relative to the substantial benefit in better understanding the effect of a focal lesion on 
neural network dynamics during sensorimotor learning in chronic stroke. Thus, the potential benefits for basic 
research and the expected findings’ implications for the future design of targeted treatment for post-stroke 
sensorimotor rehabilitation likely outweighs the mild discomfort, risks of more serious outcomes, and time spent by 
participants enrolled in the proposed research. 
E5.  SUBJECT SAFETY AND MINIMIZING RISKS (Data and Safety Monitoring Plan) 
E5.1 
Safety Training.  
The applicant along with the research assistant assisting with the scans will have taken first aid and CPR certification 
courses to assess and respond to participant emergencies within and outside of the scanner before beginning the 
study. Before any investigator or assistant is allowed to enter the scanner room, they are required to take an 
extensive MRI safety course (with annual refresher courses) that cover powering down (or quenching) the magnet 
for patient safety and with established procedures for expediting participant contact with emergency medical 
personnel, should the need arise. These courses are run by the MUSC Center for Biomedical Imaging and are a 
prerequisite for obtaining privileges to book and use scanner time.  
E5.2 
Medical Emergencies. 
 
Emergency responding in the scanner is facilitated by having at least two research staff running a scan (applicant 
and research assistant as well as the MR technologist). In the event of an emergency, one of these individuals 
remains with the participant and undocks the scanner bed from the magnet bore. This bed can easily be wheeled 
out of the scan room to facilitate speedy access to arriving emergency medical personnel. The second researcher 
calls 9-1-1 from the scanner suite and gives details of the participant’s level of medical distress and location. Next, 
this person goes out to the front of the scanner building to flag down arriving emergency personnel and to direct 
them to the participant. These guidelines are in full agreement with Center for Biomedical Imaging safety protocols.  
E5.3 
Ethical Research Practices.  
Ethical guidelines for clinical research will be followed strictly and all information obtained in the study will be kept 
strictly confidential. The PI and all research staff and mentors will be responsible for and will comply with mandated 
reporting rules. All researchers will be obligated to demonstrate that they have remained abreast of all guidelines 
and rules related to the Health Insurance Portability and Accountability Act (HIPAA). Each member of the research 
staff will complete focused training on each task for which they are responsible and will perform ongoing quality 
control for others performing similar work.  
E5.4 
Data Monitoring Procedures.  
The PI and/or study coordinator will produce quarterly administrative reports describing study progress including 
accrual, demographics, and participants’ status. Reports will describe adherence to inclusion/exclusion criteria and 
the study protocol in addition to any unanticipated problems in the category of risks to participants or others as well 

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as any adverse events. All collected data will be obtained for research (and participant safety) purposes only. MRI 
data will be processed biweekly to entail consistent quality and scanner characteristics.  
E5.5 
Data and Safety Monitoring Board.  
Data will be monitored on a bi-annual basis with respect to subject safety issues throughout the award period. The 
data and safety monitoring plan will include an internal Data Safety Monitoring Committee (DSMC), an external 
Data and Safety Monitoring Board (DSMB), and the Institutional IRB.  The purpose of the DSMC, DSMB, and IRB 
are to ensure the safety of participants and the validity and integrity of the data.  
E5.6 
Data Safety Monitoring Committee (DSMC).  
The internal DSMC will consist of the PI and co-investigators/consultants on the proposal. The functions of the 
DSMC will include: 1) providing scientific oversight; 2) reviewing all adverse effects or complications related to the 
study; 3) monitoring enrollment; 4) reviewing summary reports relating to compliance with protocol requirements; 
and 5) providing advice on resource allocation. The DSMC will meet quarterly and as necessary by telephone. The 
recommendations of the DSMC will be reviewed and the PI will take appropriate corrective actions as needed. 
E5.7 
Data and Safety Monitoring Board (DSMB).  
A DSMB will be established and will consist of professionals at MUSC with appropriate expertise, who are willing 
to participate and who do not have any conflicts of interest. The DSMB will include: 1) one expert in the area of MR 
imaging, 2) a physician with expertise in chronic stroke, 3) a stroke rehabilitation specialist (physical or occupational 
therapist). The DSMB will meet on an annual basis. The DSMB will perform the following activities: 
 
Review the research protocol and plans for data and safety monitoring. 
 
Evaluate the progress of the intervention, including periodic assessments of data quality and timeliness, 
participant recruitment, enrollment, and retention, participant risk versus benefit, integrity of the intervention, 
and other factors that can affect study outcome. 
 
Consider factors external to the study when interpreting the data, such as scientific or clinical developments 
that may impact the safety of study participants or the ethics of the study. 
 
Make recommendations to the internal DSMC and MUSC IRB for continuation or termination of the project. 
 
Protect the confidentiality of study data and monitoring. 
The DSMB will have the authority to temporarily or permanently discontinue the project if it perceives that harm is 
occurring due to the intervention. The DSMB will meet with the internal DSMC yearly to review adverse event 
reports, patient complaints if any, and enrollment rates. Data will be provided at these meetings by the investigators 
on key variables that may indicate harm. The DSMB will also review the elements of the plan to manage 
emergencies. 
F.  
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G. APPENDIX______________________________________________________________________ 
 
Appendix 1:  
Pre-Screening Telephone Questionnaire.  

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Appendix 2:  
Demographic, Education, Medication Questionnaire.