Perinatal Stroke: Understanding Brain Reorganization Through Infant Neuroimaging and Neuromodulation
Conditions: Stroke, Hemiparesis
Sponsor: University of Minnesota

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Perinatal Stroke: Understanding Brain Reorganization through Infant Neuroimaging and 
Neuromodulation 
Principal Investigator: Bernadette Gillick 
Medical School- Rehabilitation Medicine 
420 Delaware Street SE, MMC 388 
Minneapolis, MN 55455 
612.626.3121 
612.625.4274 
gillick@umn.edu 
Co-Investigators: 
Michael Georgieff 
Bryon Mueller 
Mo Chen 
Jed Elison 
Raghavendra Rao 
Research Staff: 
Ellen Sutter 
Marie Hickey 
Alexander Opitz 
Kathleen Mantell 
Neely Miller 
Linda Krach 
Jensina Ericksen 
Jenna Wassenaar 
Martha DeMeules 
Annette Xenopoulos-Oddsson 
 
 
Biostatistician: 
Kyle Rudser 
Protocol Version Date:  01/21/2021 
 
 
 

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Project Summary 
Title 
Perinatal Stroke: Understanding Brain 
Reorganization through Infant Neuroimaging and 
Neuromodulation 
Short Title 
Perinatal Stroke: Understanding Brain 
Reorganization 
Principal Investigator                                                 Bernadette Gillick 
Study Design 
Cross-sectional study 
Study Duration 
5 years 
Study Centers 
University of Minnesota, Medical School, 420 
Delaware Street SE, Minneapolis, MN 55455 
Objectives 
Examine the brain reorganization after perinatal 
stroke and impact on  motor behaviors in infants 
between 3 and 24 months of (corrected) age 
Number of Participants 
50 with perinatal stroke and  10 past participants 
will be followed-up remotely 
Main Inclusion/Exclusion Criteria 
Primary Inclusion Criteria: 
Infants and children (<5 years old) with the 
diagnosis of perinatal stroke 
Primary Exclusion Criteria: 
Genetic disorders, metabolic disorders, neoplasm, 
disorders of cellular migration and proliferation, 
traumatic brain injury, indwelling, prior surgeries 
that constraint spontaneous movements, or other 
neurologic disorders unrelated to stroke including 
uncontrolled seizures  
Study Device 
TMS will not be used due to COVID-19 and 
limitations on in-person study visits.  
Duration of Device Exposure  
No TMS will be delivered as part of the remote 
study.  
Endpoint  
Safety, Cortical Excitability, Sensorimotor 
development 
Statistical Methods 
Sample size was based on a combination of 
enrollment feasibility in the available timeframe 
and what is appropriate given the preliminary 
nature of this pilot, safety and feasibility study.  
Note: No further data will be collected to address 
Aims 1-5 due to transitioning this study to take 
place remotely.  
Aim 1: The cortical map volumes of ipsilesional 
and contralesional hemispheres will be 
summarized and compared with a paired t-test 
Aim2: Differences in CST integrity (fractional 
anisotropy) between ipsilesional and 
contralesional hemispheres will similarly be 
evaluated with a paired t-test. The association of 
the cortical map volume with fractional 
anisotropy will be evaluated using generalized 

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estimating equations. Transformations and non-
identity link functions will be considered in 
exploratory analyses to evaluate non-linear 
relationships. 
Aim3: The association of movement quality with 
ipsilesional cortical excitability and relative tract 
integrity between hemispheres will be 
summarized with odds ratios from logistic 
regression. 
Aim 4: Safety outcomes will describe all adverse 
events, reporting the number and percentage along 
with seriousness, severity, frequency (within a 
participant), and relatedness. 
Aim 5: The association between lesion size and 
corticomotor excitability will be evaluated using 
linear regression with robust variance estimation 
for confidence intervals and P-values to determine 
if larger lesion size is associated with 
Corticomotor excitability. 
Aim 6: Use MRI and computational modeling to 
estimate individualized electric fields from each 
infant’s neuroanatomy.  This will be compared to 
modeling in 20 typically developing children 
acquired from the baby connectome project 
(BCP), and from at least one infant with perinatal 
stroke.  The association between lesion size and 
peak electrical field will be evaluated using linear 
regression and robust variance estimation. 
Aim 7. Determine relationship between 
presence/absence of an MEP at initial testing and 
initial motor assessment with development of CP. 
Aim 8. Describe the developmental trajectory of a 
case series of infants related to early imaging and 
neurophysiological assessments and later motor 
development 
 
 

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List of Abbreviations 
AE 
AHC-IS 
 
 
BCP 
BDAC 
BP 
CMRR 
CNBD 
CP 
CRF 
CST 
CT 
CTSI 
DTI 
 
EMG 
ERP 
FA 
GMA 
HARDI 
HCP 
HINE 
HR 
IHI 
MEP 
MRI 
MT 
NICU 
PEDI-CAT 
 
PHI 
RR 
SAE 
SGA 
SNN 
TMS 
UADE 
UMMCH 
UPIRTSO 
 
 
 
 
 
 
 
 
Adverse Event 
Academic Health Center’s Information Systems 
Baby Connectome Project 
Biostatistical Design and Analysis 
Blood Pressure 
Center for Magnetic Resonance Research 
Center for Neurobehavioral Development 
Cerebral Palsy 
Case Report Form 
Corticospinal Tract 
Computer Tomography 
Clinical and Translational Science Institute 
Diffusion Tensor Imaging 
 
Electromyography 
Event related potential 
Fractional Anisotropy 
General Movements Assessment 
High Angular Resolution Diffusion Imaging 
Human Connectome Project 
Hammersmith Infant Neuromotor Examination 
Heart Rate 
Interhemispheric Inhibition 
Motor Evoked Potential 
Magnetic Resonance Imaging 
Motor Threshold 
Neonatal Intensive-care Unit 
Pediatric Evaluation of Disability Inventory Computer Adaptive 
Test 
Protected Health Information 
Respiratory Rate 
Severe Adverse Event 
Small for Gestational Age 
Stereotactic Neuronavigation 
Transcranial Magnetic Stimulation 
Unanticipated Adverse Device Effect 
University of Minnesota Masonic Children’s Hospital 
Unanticipated Problems Involving Risk to Participants or Others 

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Background and Significance 
Perinatal stroke, which occurs between the 20th week of gestation and 28 days after birth, affects more 
than 1 in 2,300 live births.1, 2 Perinatal stroke is the most common cause of hemiparetic cerebral palsy 
(CP).3  Children with hemiparetic CP due to perinatal stroke show impaired motor function and sensation 
on one side of the body and usually their participation in daily activities suffers from this decreased 
function. In spite of presentation as young as in the neonatal period, and certainly within the first months 
of life, and even with prompt behavioral therapy, ongoing significant residual sensorimotor impairments 
are common. Therefore, innovative interventions that take advantage of the early critical window for 
optimizing outcomes are urgently needed—in infancy. These interventions would then occur during the 
time when the brain may be more neuroplastic and the development of corticospinal tract (CST) has not 
yet largely reorganized. Current pediatric studies have employed non-invasive brain stimulation, and most 
commonly use the single or paired-pulses of Transcranial Magnetic Stimulation (TMS) to evaluate and 
influence brain plasticity. TMS influences cortical excitability through electromagnetic depolarization of 
targeted cortical neurons through painless pulses delivered over the scalp.  However, these studies have 
mainly investigated older children with hemiparetic CP.4-6 
Corticospinal development continues postnatally over the first few years of life and damage to the system 
before, during, or after birth can have a resultant detriment to function throughout the individual’s 
lifetime.7, 8 Although initially the CST typically develops bilaterally, the integrity of the ipsilateral 
projections is compromised and control of the limbs develops predominately from the contralateral 
hemisphere. This loss in ipsilateral projections is driven by activity-dependent competition that exists 
between the two hemispheres. As the individual continues in movement and exploration of the 
environment through bimanual to unimanual activity, the crossed CST integrity continues to be 
strengthened. Typical interhemispheric inhibition (IHI) is progressively revealed as potent interaction 
between the motor cortices of the two hemispheres with accompanying corticospinal activation allows 
unimanual function. If a child incurs perinatal stroke on one side of the brain, the CST displays the 
potential for plasticity through reorganization of the two hemispheres. The ipsilesional hemisphere may 
lose the developing crossed-CST integrity and the contralesional hemisphere strengthens its ability to 
control bilateral movement. This adaptation however can have a negative impact on the quality and 
timing of hand function.9, 10 
The reorganization process of cortex and CSTs is believed to start from early infancy. Thus early 
inhibition of the exaggerated IHI from the contralesional hemisphere may be an efficacious way to both 
shape the reorganization optimally and improve long-term developmental outcomes in infants with 
perinatal stroke.  In order to understand brain reorganization and plasticity with perinatal stroke, 
investigation during infancy may allow exploration of the optimal time for intervention. Studies using 
TMS in infants have been safely performed, garnering information on tract integrity and cortical 
excitability.7, 11  To date, however, there is only one infant study using TMS to assess CST integrity with 
perinatal stroke.7  Indeed, more studies are needed to confirm and expand the current knowledge. As a 
unique aspect of investigation, combining Magnetic Resonance Imaging (MRI)/ Diffusion Tensor 
Imaging (DTI) and TMS, will provide an additional opportunity to assess reorganization of CST integrity 
and cortical excitability in infants with perinatal stroke.  Such information would contribute to the 
assessment of optimal timing of our interventions to improve motor outcomes. 
Identifying the association between laboratory assessment results and developmental outcomes is critical, 
first to understand the impact of brain injuries and reorganization on neurologic impairments in this infant 
population, and then to guide the direction of early neuromodulatory and combined behavioral 
interventions. In clinic, there are many standardized and reliable methods to assess motor outcomes in 
infants. The General Movement Assessment (GMA) is a quick and non-invasive way to evaluate motor 
performance in infants, before 20 weeks of age (corrected age for preterm infants), who are at risk for 
later neurologic impairments, such as those born preterm or with perinatal stroke.12  GMA has shown high 

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sensitivity to predict future diagnosis of motor dysfunction, and as a predictor of CP is considered cost-
efficient compared to MRI assessment.13  Thus, the GMA is an ideal tool to evaluate motor outcomes in 
infants with perinatal stroke. The Hammersmith Infant Neuromotor Examination (HINE) or Bayley may 
also be used for assessments at 3 and 24 months corrected age. The HINE is a valid and sensitive 
assessment for early prediction of CP as well as the type or severity of CP.14  The Pediatric Evaluation of 
Disability Inventory (PEDI), Gross Motor Function Classification Scale (GMFCS), and Mini-Manual 
Ability Classification Scale (mini-MACS), included in the remote follow-up portion of the study, will 
provide an assessment of fine and gross motor ability as well as participation in developmentally-
appropriate roles and activities. 
In instances of perinatal stroke, understanding not only the changes to the central nervous system but also 
the associated neurologic impairments during early infancy is a prerequisite before researchers and 
clinical practitioners can develop and provide timely and efficacious interventions. Therefore, the purpose 
of this study is to use MRI/DTI, and TMS to comprehensively examine both the CST integrity and 
cortical excitability in infants following perinatal stroke, and to identify association with sensorimotor 
outcome as evaluated by behavioral assessment. The remote component of the study will aim to relate 
neuroimaging and brain stimulation results to motor outcome in early childhood (age 2-5 years). This 
study will also investigate the relationship between modeled electric field and measured MT across 
hemispheres.  This may help identify anatomical markers that can predict electric field strength and thus 
could be used for dosing considerations for future neuromodulation interventions. We will also examine 
critical timing to provide future early neuromodulatory and combined behavioral interventions in infants 
with perinatal stroke. 
 
Specific Aims/Study Objectives 
No further data will be collected to address Aims 1-5 in the remote modification to the study, as 
TMS and MRI will not be used. However, results obtained for the participants from previous TMS 
and MRI sessions will be incorporated into the revised aims.  
Aim 1: Use TMS to index maladaptive cortical reorganization by assessing the relative excitability of 
corticospinal projections from each hemisphere to upper extremity musculature. 
Hypothesis: The ipsilesional hemisphere will have a smaller “map volume” (lower cortical excitability) 
than the contralesional hemisphere (larger map volume/higher cortical excitability). 
 
Aim 2: Index maladaptive cortical reorganization by evaluating the organizational integrity of the 
CSTs bilaterally via fractional anisotropy (FA), a standardized metric derived from DTI 
Hypothesis 1: Ipsilesional CST will have a lower value of FA than the contralesional CST. 
Hypothesis 2: Smaller cortical excitability volumes will be associated with lower values of FA. 
 
Aim 3: For infants with perinatal stroke, examine the relationship between movement quality derived 
from the GMA and cortical excitability and with CST integrity. 
Hypothesis: Atypical GMA outcome scores will be associated with a lower FA value and lower 
ipsilesional CST excitability. 
 
Aim 4: Monitor for adverse events during TMS cortical mapping and MRI scanning of infants with 
perinatal stroke. 
Hypothesis: No seizure or other serious adverse event related to TMS or MRI/DTI will occur in this 
study. 
 
Aim 5: Aim 1: Using TMS, define the relationship between lesion heterogeneity, corticomotor 
excitability and circuitry. 

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Hypothesis: We hypothesize that the larger the lesion, the higher the motor threshold and the greater the 
probability of atypical ipsilateral CST circuitry. 
 
Aim 6: Using MRI and computational modeling, estimate individualized electric fields from each 
infant’s neuroanatomy. 
Hypothesis 1: We hypothesize that the larger the lesion and motor threshold, the lower the modeled peak 
electric field.  
Hypothesis 2: We hypothesize that there is an association between the electric field and individual 
neuroanatomic characteristics. 
 
The following aims are included to transition this study to be completed remotely. These aims will 
contribute towards determining the relationship between biomarkers obtained via MRI and TMS in early 
infancy (<1 year) and later motor outcome (age 2-5 years) 
 
Aim 7. Determine relationship between presence/absence of an MEP at initial testing and initial motor 
assessment with development of CP. 
Hypothesis 1: We hypothesize that absence of an MEP from the more affected hemisphere at initial 
testing will be related to diagnosis of CP at age 2-4 years. 
Aim 8. Describe the developmental trajectory of a case series of infants related to early imaging and 
neurophysiological assessments and later motor development 
 
Hypothesis 1. Infants with greater asymmetries on early imaging and TMS assessments will have greater 
functional impairment  (as assessed with GMFCS, MACS, and PEDI-CAT) at age 2-4 years 
 
Device Description: 
Note: All in-person assessments have been deferred due to COVID-19. Transcranial Magnetic 
Stimulation devices will not be used in this remote study.  
Non-Invasive brain stimulation has been recently investigated for benefits in recovery of motor function 
in adults and more recently in children. One form, Transcranial Magnetic Stimulation (TMS), can be used 
in specific protocols either to test cortical excitability or as an intervention to attempt to influence cortical 
excitability. In this study we are using TMS only as a test to assess cortical excitability in the area of the 
brain known as the primary motor cortex or M1.  
Testing for Cortical Excitability (TMS): We will use a Magstim BiStim2 TMS stimulator with a coil to 
test the cortical excitability of the brain in infants with perinatal stroke. The center of the coil is hand held 
on the scalp over the desired region to be stimulated. An electrical current is pulsed through the electrode, 
which creates a magnetic field. This magnetic field, in turn, creates an electric field in the surrounding 
area, including inside the skull, which induces an ionic current to flow on the surface of the brain. 
Depending on the parameters of the stimulation and the excitability of the underlying cortex, the 
stimulation may or may not depolarize the nerve membrane to threshold. If it does depolarize, an action 
potential is generated and conducted to spinal motor neurons, which, depending on their own excitability, 
may transmit an action potential to muscle. Ultimately, the response is recorded as a motor evoked 
potential (MEP) with electromyography (EMG) electrodes located over the target muscle. 
Stereotactic Neuronavigation: In order to verify our exact location over the motor cortex we will be using 
a computerized method of location called Stereotactic Neuronavigation (SNN). (Brainsight Stereotactic 
Neuronavigation, Rogue Research, Montreal, Canada) Through the use of a locator situated atop the TMS 
device and a comparative participant- specific MRI image on a computer screen which shows the locator 
position, we will be able to specify the TMS hotspot location. 

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All investigational devices used in this study will have the following label statement: CAUTION – 
Investigational Device. Limited by Federal law to investigational use. 
Research Design and Methods 
Study Design and procedures overview 
Due to COVID-19, concern for the health and safety of participants, and the limited time remaining to 
complete the research, this study will be conducted remotely via virtual/remote assessments conducted 
during one ZOOM session with a parent/guardian.  
 
 
 
 
 
 
Anticipated Duration of the Clinical Investigation 
This study is expected to be completed within a two-year period beginning in August 2019. Submission 
of all indicated applications is presumed to occur over an initial 6-month period of time, with the potential 
for revisions within this timeframe. Recruitment of infants will be based over a 18 month period of time. 
Data analysis and write-up of results will occur during the last six months of this two-year period, as 
outlined in the table below.  
0-6 months 
6-12 months 
12-18 months 
18-24 months 
IRB 
 
 
Recruitment/Data Collection 
 
 
Data Analysis and Results Write-up 
If the trial ends prior to the study completion, all scheduled participants and families will be notified and 
study visits will be terminated.  The Clinical and Translational Science Institute (CTSI) will be notified 
and all future reserved dates for use of the CTSI will be canceled.  All research investigators on the study 
will be notified.  The CTSI funding agency will also be notified. 
Participants 
Sample Size: This follow-up study will be offered to all previous participants in the infant pilot study, 
with the aim of recruiting 10 infants for participation  
Inclusion Criteria: Participants will be eligible to participate in the study if the following conditions exist. 
1. Birth diagnosis of perinatal stroke by Cranial Ultrasound, Computer Tomography (CT), or MRI. 
2. Previous participant in the pilot study: Perinatal Stroke: Understanding Brain Reorganization through 
Infant Neuroimaging and Neuromodulation (parent/guardian indicated consent to be contacted for future 
studies) 
3.. Age less than or equal to 5 years 
Exclusion Criteria: 
1. Lack of wireless internet access or computer access to participate in virtual Zoom call. 
Exit/Discontinuation Criteria: 
1. Legal guardians of the infant voluntarily withdraws from the study 
2. Participant death 
3. Participant acquires any of the listed exclusion criteria 
4. Participant completes the protocol 
5. Participant is non-compliant with the protocol 
6. IRB recommendation 
Participants Recruitment Plan: Our primary recruitment method will be contacting families who 
previously participated in our pilot study in perinatal stroke who indicated on the pilot study signed 
consent form that they are open to being contacted for future studies. Parents/guardians of infant 
participants that did not indicate willingness to be contacted for future studies via the signed consent form 

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will not be contacted. Contacts will be initiated via email or phone via approved email/phone scripts. No 
new participants (that did not previously participate in the pilot study) will be recruited 
Procedures 
After a phone screen, the investigator will obtain the authorization forms from the legal guardian of the 
infant to request medical records from hospitals/clinics. Once we have determined eligibility for study 
criteria for the infant we will send the consent form via the approved UMN approved template e-consent 
within REDCap, and study staff will follow-up with a phone call to discuss any questions as needed.  If 
the parent or guardian deems appropriate, this can occur on the same day as the remote Zoom visit. The 
child participant will not need to be present during the Zoom visit. 
 
No MRI or TMS sessions will occur due to the study being conducted remotely in response to 
COVID-19.  
 
From the medical record, the research team will extract data regarding the following elements, as 
applicable:  
1. Diagnosis of cerebral palsy 
2. Recent movement or developmental assessments 
3. Types and amounts of rehabilitation therapies received 
4. Speech, cognition, or sensory assessments 
5. Surgeries or major procedures 
6. Recent imaging 
7. Comorbidities 
 
1. Questionnaires – completed over Zoom 
Questionnaires will be completed by the investigator in REDCap while on a virtual Zoom call with the 
parent or legal guardian of the participant. The child participant will not need to be present. In order to 
facilitate completion and comprehension of all questionnaires, the investigator will read the questions to 
the parent and enter the parent’s responses directly into REDCap. For the PEDI-CAT, the investigator 
will enter data into the Pearson Q-Global testing system (see below), but will not enter any identifying 
participant data to ensure anonymity of data entered into this system. The output of the PEDI-CAT will 
then be entered by the investigator into REDCap. The Zoom call will not be recorded. 
GMFCS: The GMFCS (https://canchild.ca/en/resources/42-gross-motor-function-classification-system-
expanded-revised-gmfcs-e-r) is a five-level classification system to describe the gross motor function of 
children with cerebral palsy. Distinctions between levels are based on functional abilities, assistive 
technology use, and quality of movement. The GMFCS Family and Self Report Questionnaire will be 
used for a parent/guardian to classify their child’s motor abilities. A format of the questionnaire is 
available for an age group of 2 to <4 years. This assessment takes < 5 minutes to complete.  
Mini-MACS: The Mini-MACS (https://www.macs.nu/files/Mini-MACS_English_2016.pdf) is a 
classification system to describe how children with cerebral palsy aged 1-4 years use their hands in daily 
activities. Ability is ranked on five levels based on the child’s self-initiate activity and their need for 
assistance/adaptation when handling objects. It will be completed by the researcher by asking the 
parent/guardian about their child’s manual abilities, as indicated by the assessment. This assessment takes 
< 5 minutes to complete.  
PEDI-CAT: The PEDI-CAT will be delivered using Pearson’s Q-global testing system 
(https://www.pearsonassessments.com/store/usassessments/en/Store/Professional-
Assessments/Behavior/Pediatric-Evaluation-of-Disability-Inventory-Computer-Adaptive-
Test/p/100002037.html) To deliver this assessment, the lab member will have access to the PEDI-CAT 
software, but will read the questions to the parent/guardian of the child and enter their responses into the 

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software. This delivery method has been chosen so that contact information of participants is not provided 
to an outside entity. No participant identifying information will be entered into the Pearson Q-global 
system. The PEDI-CAT software will elicit a document stating item responses and summary score, which 
will then be uploaded into REDCap by the study staff.   
 
The PEDI-CAT uses Item Response Theory statistical models to estimate a child’s ability from a minimal 
number of items. There are three functional domains that will be assessed: Daily Activities, Mobility, and 
Social/Cognitive. The Speedy form of the PEDI-CAT (less than or equal to 15 items per domain) will be 
used. It takes approximately 12 minutes to complete. The PEDI-CAT provides normative standard scores 
as age percentiles. It is appropriate for children age 0-21 years. Test-retest reliability is high for the three 
domains (>0.97) and has been found to have good construct validity and responsiveness to change.14, 15   
The single virtual visit, including time to complete questionnaires, is estimated to take <1 hour.   
 
Computational Modeling (offline analysis) 
Based on MRI data previously collected as part of the pilot study,. we will analyze the hypothetical TMS-
induced electric field strength (effective dose) and compare it across hemispheres. We will further test 
anatomical predictors for the modeled electric field. This will help to identify anatomical markers that can 
predict the effective TMS dose in pediatric stroke. Success in these efforts would identify anatomical 
markers that can predict electric field strength and thus could be used in dosing considerations for future 
neuromodulation interventions. 
To obtain greater data accuracy in our MRI processing and computational modeling we will include and 
use the iBEAT (Infant Brain Extraction and Analysis Toolbox) V2.0 software, as our current image 
processing software does not accurately correct for characteristics of an infant brain.  The software was 
developed in 2012 by the Developing Brain Computing Lab and the Baby Brain Mapping Lab in the 
University of North Carolina at Chapel Hill and is used specifically to process and correct structural infant 
and pediatric brain images, which typically exhibit low contrast.   
A one-time use of iBEAT V2.0 software will be used to process 4 de-identified pediatric brain image files 
from 1 participant that were taken at4 and 24 months (2 images from each time point).  The 4 de-
identified image files will be uploaded by our study staff from our secure BOX storage into the software 
program and processed, and those processed images will then be downloaded back into our secure BOX 
drive and used by our team for more accurate data analysis.  This will not compromise any PHI.  
iBEATV2.0 software website: https://ibeat.wildapricot.org/ 
 
Family/Infant Withdrawal: Families may discontinue participation at any time, for any reason.. The 
details surrounding the circumstances of the reason for withdrawing the participant from the study will be 
reported with no identifiers included. 
Safety and Adverse Events Monitoring 
Due to COVID-19 and the removal of in person assessments using TMS and MRI, risk of adverse 
events will be decreased.   
Adverse Events 

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Adverse Event (AE): An adverse event (AE) is any symptom, sign, illness or experience that develops or 
worsens in severity during the course of the study. Intermittent illnesses or injuries will be regarded as 
adverse events. Abnormal results of laboratory or diagnostic procedures are considered to be adverse 
events if the abnormality: 
 
Results in study withdrawal 
 
Is associated with a serious adverse event 
 
Is associated with clinical signs or symptoms 
 
Leads to additional treatment or to further diagnostic tests 
 
Is considered by the Investigator to be of clinical significance 
Serious Adverse Event (SAE) is any adverse event that is: 
 
Fatal 
 
Life-threatening 
 
Requires or prolongs a hospital stay 
 
Results in persistent or significant disability or incapacity 
 
A congenital anomaly or birth defect 
 
Important medical events are events that may not be immediately life-threatening, but are clearly of major 
clinical significance and may be SAEs. They may jeopardize the participant, and may require intervention 
to prevent one or the other serious outcomes noted above. 
Hospitalization: Hospitalization shall include any initial admission (even if less than 24 hours) to a 
healthcare facility as a result of a precipitating clinical adverse effect; to include transfer within the 
hospital to an intensive care unit. Hospitalization or prolongation of hospitalization in the absence of a 
precipitating, clinical adverse effect (e.g., for a preexisting condition not associated with a new adverse 
effect or with a worsening of the preexisting condition; admission for a protocol-specified procedure) is 
not, in itself, a serious adverse effect. 
Safety Monitoring Plan 
All research procedures will be performed by qualified personnel who have completed required training, 
including human participants training.  
All personnel will comply with all related regulations and laws, included, but not limited to 45CFR parts 
60 and 64, and HIPAA Privacy Regulations. Study data and information will be kept confidential and 
managed in accordance with requirements of HIPAA. All data will be stored in locked offices and not 
released without participant permission. 
AEs and SAEs will be assessed and followed throughout the study.  
Caregivers of participating infants will have contact information to enable them to easily contact study 
personnel.  
 
Anticipated Risks/Risk Mitigation: 
Study 
Procedures 
Anticipated Risks 
Risk Mitigation 
 
 
 

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Data 
collection 
Data breach 
All participant data will be secured in REDCap database, on 
Box servers, or in a locked file cabinet (for paper medical 
records) 
 
. 
Study Stopping Rules 
Anticipated Adverse Events: Participants will be parents/legal guardians of infants who sustained a 
congenital stroke before, during or shortly after birth. There are no anticipated adverse events for the 
infants, who will not be present for the study. The only anticipated risk is a risk of data breach.  
Adverse Event Reporting 
All AEs occurring during the study period must be recorded. The clinical course of each event will be 
followed until resolution, stabilization, or until it has been determined that study treatment or participation 
is not the cause. 
The Sponsor-Investigator will promptly review documented AEs and abnormal test findings to determine 
1) if the abnormal test finding should be classified as an AE; 
2) if there is a reasonable possibility that the AE was caused by the investigational device or, if 
applicable, other study treatment or diagnostic product(s); and 
3) if the AE meets the criteria for a SAE. 
If the Sponsor-Investigator’s final determination of causality is “unknown and of questionable 
relationship to the investigational device or, if applicable, other study treatment or diagnostic product(s)”, 
the adverse effect will be classified as associated with the use of the investigational device or study 
treatment or diagnostic drug product(s) for reporting purposes. If the investigator-sponsor’s final 
determination of causality is “unknown but not related to the investigational device or, if applicable, other 
study treatment or diagnostic product(s)”, this determination and the rationale for the determination will 
be documented in the respective participant’s case history. 
Adverse Events 
All observed or volunteered AEs and abnormal test findings, if applicable, or suspected causal 
relationship to the investigational device or, if applicable, other study treatment or diagnostic product(s) 
will be recorded in the participants’ case histories. For all AEs, sufficient information will be pursued 
and/or obtained so as to permit 
1) an adequate determination of the outcome of the effect (i.e., whether the effect should be classified 
as a serious adverse effect) and; 

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2) an assessment of the casual relationship between the AE and the investigational device or, if 
applicable, the other study treatment or diagnostic product(s). 
AEs or abnormal test findings felt to be associated with the investigational device or, if applicable, other 
study treatment or diagnostic product(s) will be followed until the effect (or its sequelae) or the abnormal 
test finding resolves or stabilizes at a level acceptable to the Sponsor-Investigator. 
AEs that do not qualify as ASE or as Unanticipated Adverse Device Effects will be reported the IRB with 
the continuing review progress report. 
Serious Adverse Events: Unexpected SAEs that are at least possibly related will be reported to the IRB 
within 10 days of learning of the event. 
If the AE is Serious, Unanticipated, Device Related, and determined by the Sponsor-Investigator to 
present an unreasonable risk to participants, the Sponsor must terminate the study within 5 working days 
of that determination. 
Unanticipated Problems Involving Risk to Participants or Others (UPIRTSO) 
Investigators are required to submit a report of UPIRTSO events to the IRB within 10 working days of 
first learning of the event. 
Statistical Considerations  
Sample size was based on a combination of enrollment feasibility in the available timeframe and what is 
appropriate given the preliminary nature of this pilot, safety and feasibility study. 
Aim 1: The cortical map volumes of ipsilesional and contralesional hemispheres will be summarized and 
compared with a paired t-test 
Aim2: Differences in CST integrity (FA) between ipsilesional and contralesional hemispheres will 
similarly be evaluated with a paired t-test. The association of the cortical map volume with FA will be 
evaluated using generalized estimating equations (to account for correlation of paired measurements from 
each participant: volume and FA from each hemisphere). Transformations and non-identity link functions 
will be considered in exploratory analyses to evaluate non-linear relationships. 
Aim3: The association of movement quality (atypical vs. typical movement) with ipsilesional cortical 
excitability and relative tract integrity between hemispheres (ratio of FA values) will be summarized with 
odds ratios from logistic regression. 
Aim 4: Safety outcomes will describe all adverse events (AEs), reporting the number and percentage 
along with seriousness, severity, frequency (within a participant), and relatedness. The statistical analyses 
were planned and will be conducted by Dr. Rudser (collaborator) at the Biostatistical Design and Analysis 
Center (BDAC). 
Aim 5:. The association between lesion size and corticomotor excitability will be evaluated using linear 
regression with robust variance estimation for confidence intervals and P-values to determine if larger 
lesion size is associated with corticomotor excitability. 
 
Aim 6: The association between lesion size and peak electrical field will be evaluated using linear 
regression and robust variance estimation.  This will be compared to modeling in 20 typically developing 
children acquired from the baby connectome project (BCP). 
Aim 7. Presence/absence of an MEP at initial testing will be compared with diagnosis of cerebral palsy. 
based on medical record. This relationship will be compared with a Chi Square test. 

NCT02743728 
10 
 
Aim 8. The developmental trajectory and assessment scores of a case series of infants will be presented 
with descriptive statistics.  
Data and Record Keeping 
All identifiable data are confidential and under protected.  Each participant will be assigned a number and 
all data collected forms will use only the assigned number for identification.. Password will also be used 
to protect digital data. 
All data will be kept for six years after the completion of this study. 
Confidentiality 
Information about study participants will be kept confidential and managed according to the requirements 
of the HIPAA of 1996. Those regulations require a signed participant authorization informing the 
participant of the following: 
 
What protected health information (PHI) will be collected from participants in this study 
 
Who will have access to that information and why 
 
Who will use or disclose that information 
 
The rights of a research participant or legal guardian to revoke their authorization for use of their 
PHI 
In the event that a participant or legal guardian revokes authorization to collect or use PHI, the 
investigator, by regulation, retains the ability to use all information collected prior to the revocation of 
participant authorization. For participants or their legal guardian that have revoked authorization to collect 
or use PHI, attempts should be made to obtain permission to collect at least vital status (i.e. that the 
participant is alive) at the end of their scheduled study period. 
Source Documents 
Source Data are the clinical findings and observations, laboratory and test data, and other information 
contained in Source Documents. Source Documents are the original records (and certified copies of 
original records); including, but not limited to, hospital medical records, physician or office charts, 
physician or nursing notes, participant diaries or evaluation checklists, pharmacy dispensing records, 
recorded data from automated instruments, x-rays, etc.. 
Data for this study will be entered by the research investigators and study coordinator directly into the 
electronic REDCap database. Any data collected on other electronic forms (PEDI-CAT) will then be 
entered within the next week into a REDCap database, which uses a MySQL database via a secure web 
interface with data checks used during data entry to ensure data quality. REDCap includes a complete 
suite of features to support HIPAA compliance, including a full audit trail, user-based privileges, and 
integration with the institutional LDAP server. All electronic documents not stored in REDCap will be 
stored securely on the Gillick Lab Box account, with access provided only to individuals specified in the 
study protocol as needed.  The MySQL database and the web server will both be housed on secure servers 
operated by the University of Minnesota Academic Health Center’s Information Systems group (AHC-
IS). The servers are in a physically secure location on campus and are backed up nightly, with the 
backups stored in accordance with the AHC-IS retention schedule of daily, weekly, and monthly tapes 
retained for 1 month, 3 months, and 6 months, respectively. Weekly backup tapes are stored offsite. The 
AHC-IS servers provide a stable, secure, well-maintained, and high-capacity data storage environment, 
and both REDCap and MySQL are widely-used, powerful, reliable, well-supported systems. Access to the 
study's data in REDCap will be restricted to the members of the study team by username and password. 
Record Retention 
The PI will maintain all records for 6 years. 

NCT02743728 
11 
 
Cited References 
1. 
Cardenas JF, Rho JM, Kirton A. Pediatric stroke. Child's nervous system : ChNS : official journal 
of the International Society for Pediatric Neurosurgery. Sep 2011;27(9):1375-90. doi:10.1007/s00381-
010-1366-9 
2. 
Raju TN, Nelson KB, Ferriero D, Lynch JK. Ischemic perinatal stroke: summary of a workshop 
sponsored by the National Institute of Child Health and Human Development and the National Institute of 
Neurological Disorders and Stroke. Pediatrics. Sep 2007;120(3):609-16. doi:10.1542/peds.2007-0336 
3. 
Lehman LL, Rivkin MJ. Perinatal arterial ischemic stroke: presentation, risk factors, evaluation, 
and outcome. Pediatric neurology. Dec 2014;51(6):760-8. doi:10.1016/j.pediatrneurol.2014.07.031 
4. 
Carey JR, Deng H, Gillick BT, et al. Serial treatments of primed low-frequency rTMS in stroke: 
characteristics of responders vs. nonresponders. Comparative Study 
Research Support, N.I.H., Extramural. Restorative neurology and neuroscience. 2014;32(2):323-35. 
doi:10.3233/RNN-130358 
5. 
Kirton A, Chen R, Friefeld S, Gunraj C, Pontigon AM, Deveber G. Contralesional repetitive 
transcranial magnetic stimulation for chronic hemiparesis in subcortical paediatric stroke: a randomised 
trial. The Lancet Neurology. Jun 2008;7(6):507-13. doi:10.1016/s1474-4422(08)70096-6 
6. 
Valle AC, Dionisio K, Pitskel NB, et al. Low and high frequency repetitive transcranial magnetic 
stimulation for the treatment of spasticity. Developmental medicine and child neurology. Jul 
2007;49(7):534-8. doi:10.1111/j.1469-8749.2007.00534.x 
7. 
Eyre JA, Smith M, Dabydeen L, et al. Is hemiplegic cerebral palsy equivalent to amblyopia of the 
corticospinal system? Ann Neurol. Nov 2007;62(5):493-503. doi:10.1002/ana.21108 
8. 
Martin JH. The corticospinal system: from development to motor control. Neuroscientist. Apr 
2005;11(2):161-73. doi:10.1177/1073858404270843 
9. 
Holmefur M, Krumlinde-Sundholm L, Bergstrom J, Eliasson AC. Longitudinal development of 
hand function in children with unilateral cerebral palsy. Developmental medicine and child neurology. 
Apr 2010;52(4):352-7. doi:10.1111/j.1469-8749.2009.03364.x 
10. 
Staudt M, Gerloff C, Grodd W, Holthausen H, Niemann G, Krageloh-Mann I. Reorganization in 
congenital hemiparesis acquired at different gestational ages. Annals of neurology. Dec 2004;56(6):854-
63. doi:10.1002/ana.20297 
11. 
Eyre JA, Miller S, Clowry GJ, Conway EA, Watts C. Functional corticospinal projections are 
established prenatally in the human foetus permitting involvement in the development of spinal motor 
centres. Brain : a journal of neurology. Jan 2000;123 ( Pt 1):51-64.  
12. 
Prechtl HF. General movement assessment as a method of developmental neurology: new 
paradigms and their consequences. The 1999 Ronnie MacKeith lecture. Developmental medicine and 
child neurology. Dec 2001;43(12):836-42.  
13. 
Einspieler C, Prechtl HF. Prechtl's assessment of general movements: a diagnostic tool for the 
functional assessment of the young nervous system. Mental retardation and developmental disabilities 
research reviews. 2005;11(1):61-7. doi:10.1002/mrdd.20051 
14. 
Dumas HM, Fragala-Pinkham MA, Haley SM, et al. Computer adaptive test performance in 
children with and without disabilities: prospective field study of the PEDI-CAT. Disabil Rehabil. 
2012;34(5):393-401. doi:10.3109/09638288.2011.607217 
15. 
Dumas HM, Fragala-Pinkham MA, Rosen EL, Lombard KA, Farrell C. Pediatric Evaluation of 
Disability Inventory Computer Adaptive Test (PEDI-CAT) and Alberta Infant Motor Scale (AIMS): 
Validity and Responsiveness. Phys Ther. Nov 2015;95(11):1559-68. doi:10.2522/ptj.20140339