Baby Brain Recovery Study

Study Overview
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Brief Summary
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This study will be a longitudinal multiple-visit observational study, done to identify possible bioindicators of recovery and repair of motor corticospinal pathways which may be targeted by future interventions in infants with perinatal stroke. 65 participants will be recruited and complete 1 visit at time point 1 (0-2 months), and 2 visits at each timepoints 2-5 with windows of +- 4 weeks (3-6 months, 12 months, 18 months and 24 months). Visits will consist of Magnetic Resonance Imaging (MRI) assessment during the child's natural sleep, Transcranial Magnetic Stimulation (TMS), and Motor Behavioral Assessments.

Detailed Description
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Perinatal stroke has disabling consequences; 50-75% of individuals will develop life-long motor impairment, and 10-60% will also have cognitive deficits. These deficits lead to challenges in the school and home environments, with decreased likelihood of employment and independence and increased caregiver burden. Additionally, perinatal stroke is one of the primary causes of cerebral palsy (CP), a chronic and disabling neurological condition affecting motor function. The first two years of life constitute a critical period of brain development and heightened neuroplasticity. There is now a consensus that, due to brain plasticity and rapid development, providing an early intervention may result in optimal recovery and lower costs of care. Unfortunately, researchers still have only limited understanding of how the brain develops after perinatal stroke and as a result CP diagnoses are typically not made until two years of age. There is an urgent need for very early diagnosis, prognosis and understanding of mechanisms in order to develop novel early interventions to improve outcomes in perinatal stroke with resultant CP. Integrating study team's experience in studying and caring for this vulnerable infant stroke population, they propose to use non-invasive brain stimulation, neuroimaging, and behavioral assessments to analyze associations between development patterns, especially in the CST, and potential diagnosis of CP. Specific aims of this study are: Aim 1. Map the presence and excitability of corticospinal pathways. Aim 2. Map the structural integrity and connectivity of corticospinal pathways. Aim 3. Compare motor outcomes from clinical behavioral assessments against corticospinal tract excitability and integrity. Aim 4. Identify the association between brain white-matter connectivity and general movements. Aim 5. Identify the association between corticospinal circuitry and general movements. Protocol Amendment approved on 10/22/2021 removes TMS intervention and outcomes, adds a study time point at 0-2 months, and lowers the eligibility age to term. Protocol Amendment approved on 12/21/2021 adds the TMS intervention back.

Official Title
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Perinatal Stroke: Longitudinal Assessment of Infant Brain Organization and Recovery Through Neuroexcitability, Neuroimaging and Motor Development

Conditions
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Perinatal Stroke

Intervention / Treatment
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* Device: Magnetic Resonance Imaging
* Behavioral: Behavioral Assessments
* Device: Non invasive Transcranial Magnetic Stimulation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Infants with corrected gestational age between term age and 24 months of age at study enrollment Radiologically-confirmed acute unilateral or bilateral brain lesions, including perinatal stroke, neonatal hemorrhagic or thrombotic stroke, involving the motor cortex and/or subcortical structures, and intracranial hemorrhage, involving the motor cortex and/or subcortical white matter, or periventricular leukomalacia Diagnosis of hypoxic ischemic encephalopathy English-speaking parent/legal guardian (able to provide consent) Exclusion Criteria: Other neurologic disorders unrelated to perinatal stroke Metabolic disorders Neoplasm Disorders of Cellular Migration and Proliferation Acquired Traumatic Brain Injury Received surgeries that may constrain current spontaneous movements Indwelling metal or incompatible medical devices, or other contraindications for MRI or TMS assessment Apneic episodes and syncope (known heart defects) for the safety of participants in the study Supplemental ventilation Uncontrolled seizure

Ages Eligible for Study
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Minimum Age: 0 Years
Maximum Age: 24 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Infants<br>Pre-term and term born infants with corrected gestational age between term age and 24 months with radiologically-confirmed acute unilateral or bilateral brain lesions, including perinatal stroke, neonatal hemorrhagic or thrombotic stroke, involving the motor cortex and/or subcortical structures, and intracranial hemorrhage, involving the motor cortex and/or subcortical white matter, or periventricular leukomalacia. Parents/legal guardians able to attend study visits at the University of Wisconsin-Madison. | Device: Magnetic Resonance Imaging<br>* 3 Tesla Discovery MR750 MRI scanner (GE Healthcare, Waukesha, WI) will be used to perform structural imaging, diffusion MRI, relaxometry and microstructural imaging. The exact scan length and parameters of each scan type (T1, T2, DWI) will be set for this study to optimize the quality of data and decrease the length of scanning session for each type of scan. All of the imaging methods have been previously implemented at UW-Madison. Each sequence will take approximately 5-10 minutes.<br>* Other names: MRI;Behavioral: Behavioral Assessments<br>* The behavioral assessments (GMA: General Movements Assessment; HINE: Hammersmith Infant Neurological Examination; Bayley-IV, Bayley Scales of Infant and Toddler Development 4th ed) are infant and age-specific and will be administered by trained pediatric occupational and physical therapists.<br>Device: Non invasive Transcranial Magnetic Stimulation<br>* TMS will be used to assess cortical excitability and circuitry (not as a neuromodulation intervention). Single-pulse TMS (Magstim 200², Magstim, UK) with a scalp surface coil will be used to assess how the brain is developing and how connected the tract is, between the brain and a target muscle on the arm. 10-20 TMS stimulation pulses will be delivered at a range of stimulation intensities (50-100%) increasing by 5% maximal stimulator output (MSO) at each stage. In sum, around 150 stimulation pulses per hemisphere are expected for TMS assessment for each infant.<br>* Other names: TMS;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Cortical excitability measured as presence/absence of motor evoked potentials (MEP) | Motor evoked potentials (MEPs) are the electrical signals recorded from the descending motor pathways or from muscles following stimulation of motor pathways within the brain. Responses from TMS pulses will be measured by recording muscle activity, referred to as motor evoked potentials (MEP). | 3-6 months (one visit in this time frame), 12±1 months, 18±1 months, 24±1 months | 
| Change in Cortical excitability measured by intensity of motor threshold (MT) | The MT is the minimum stimulation intensity that will elicit a consistent MEP of a pre-determined amplitude. MT and MEP are the common measures of TMS-induced excitability. Together, these measures provide information about the brain's excitability, associated with synaptic activity. | 3-6 months (one visit in this time frame), 12±1 months, 18±1 months, 24±1 months | 
| Change in Mean Fractional Anisotropy (FA) within the CST | Mean Fractional Anisotropy (FA) within the CST will be used to study structural connectivity. It is a dimensionless index between 0 and 1. (0 equals no anisotropy; greater anisotropy is indicated by higher FA values approaching the maximum of 1). N=10 infants aged 0-2 months (first timepoint) will participate in MRI scans | 1 ±1 month, 3-6 months (one visit in this time frame), 12±1 months, 18±1 months, 24±1 months | 
| Behavioral assessments: General Movements Assessment (GMA) reported on binary (Y/N) scale | The General Movements Assessment is used to identify absent or abnormal general movements. GMA requires 5-10 minutes video taping when infants are placed in spine position for scoring. Absence or abnormal movements will be reported as Y. | 1 ±1 month | 
| Behavioral assessments: General Movements Assessment (GMA) reported on binary (Y/N) scale | The General Movements Assessment is used to identify absent or abnormal general movements. GMA requires 5-10 minutes video taping when infants are placed in spine position for scoring. Absence or abnormal movements will be reported as Y. | 3 ±1 months | 
| Behavioral assessments: Hammersmith Infant Neurological Examination (HINE) score | The HINE includes three sections, the Neurological Examination, the Development of Motor Functions and the State of Behaviour. The first section evaluates cranial nerve, posture, movements, tone and reflexes. These items are not age-dependent. The second section evaluates head control, sitting, voluntary grasping, rolling, crawling and walking. The third section evaluates state of consciousness, emotional state and social orientation. The maximum score for any one item is a score of 3 and the minimum is a score of 0. A subscore can be given for each section and the overall global score can be calculated by summing up all 26 items (range: 0-78), with higher scores indicating better neurological performance. | 1 ±1 month | 
| Behavioral assessments: Hammersmith Infant Neurological Examination (HINE) score | The HINE includes three sections, the Neurological Examination, the Development of Motor Functions and the State of Behaviour. The first section evaluates cranial nerve, posture, movements, tone and reflexes. These items are not age-dependent. The second section evaluates head control, sitting, voluntary grasping, rolling, crawling and walking. The third section evaluates state of consciousness, emotional state and social orientation. The maximum score for any one item is a score of 3 and the minimum is a score of 0. A subscore can be given for each section and the overall global score can be calculated by summing up all 26 items (range: 0-78), with higher scores indicating better neurological performance. | 3-6 months (one visit in this time frame) | 
| Behavioral assessments: Hammersmith Infant Neurological Examination (HINE) score | The HINE includes three sections, the Neurological Examination, the Development of Motor Functions and the State of Behaviour. The first section evaluates cranial nerve, posture, movements, tone and reflexes. These items are not age-dependent. The second section evaluates head control, sitting, voluntary grasping, rolling, crawling and walking. The third section evaluates state of consciousness, emotional state and social orientation. The maximum score for any one item is a score of 3 and the minimum is a score of 0. A subscore can be given for each section and the overall global score can be calculated by summing up all 26 items (range: 0-78), with higher scores indicating better neurological performance. | 12±1 months | 
| Behavioral assessments: Hammersmith Infant Neurological Examination (HINE) score | The HINE includes three sections, the Neurological Examination, the Development of Motor Functions and the State of Behaviour. The first section evaluates cranial nerve, posture, movements, tone and reflexes. These items are not age-dependent. The second section evaluates head control, sitting, voluntary grasping, rolling, crawling and walking. The third section evaluates state of consciousness, emotional state and social orientation. The maximum score for any one item is a score of 3 and the minimum is a score of 0. A subscore can be given for each section and the overall global score can be calculated by summing up all 26 items (range: 0-78), with higher scores indicating better neurological performance. | 18±1 months | 
| Behavioral assessments: Hammersmith Infant Neurological Examination (HINE) score | The HINE includes three sections, the Neurological Examination, the Development of Motor Functions and the State of Behaviour. The first section evaluates cranial nerve, posture, movements, tone and reflexes. These items are not age-dependent. The second section evaluates head control, sitting, voluntary grasping, rolling, crawling and walking. The third section evaluates state of consciousness, emotional state and social orientation. The maximum score for any one item is a score of 3 and the minimum is a score of 0. A subscore can be given for each section and the overall global score can be calculated by summing up all 26 items (range: 0-78), with higher scores indicating better neurological performance. | 24±1 months | 
| Behavioral assessments: Bayley Scales of Infant and Toddler Development Test, 4th edition (Bayley-IV) score | Bayley-IV is a developmental test that measures cognitive, language, motor, and social-emotional domains of infants and young children between 1 and 42 months of age. A higher score generally corresponds with higher function. | 3-6 months (one visit in this time frame) | 
| Behavioral assessments: Bayley Scales of Infant and Toddler Development Test, 4th edition (Bayley-IV) score | Bayley-IV is a developmental test that measures cognitive, language, motor, and social-emotional domains of infants and young children between 1 and 42 months of age. A higher score generally corresponds with higher function. | 12±1 months | 
| Behavioral assessments: Bayley Scales of Infant and Toddler Development Test, 4th edition (Bayley-IV) score | Bayley-IV is a developmental test that measures cognitive, language, motor, and social-emotional domains of infants and young children between 1 and 42 months of age. A higher score generally corresponds with higher function. | 18±1 months | 
| Behavioral assessments: Bayley Scales of Infant and Toddler Development Test, 4th edition (Bayley-IV) score | Bayley-IV is a developmental test that measures cognitive, language, motor, and social-emotional domains of infants and young children between 1 and 42 months of age. A higher score generally corresponds with higher function. | 24±1 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in blood pressure |  | 1 ±1 month, 3-6 months (one visit in this time frame), 12±1 months, 18±1 months, 24±1 months | 
| Change in heart rate |  | 1 ±1 month, 3-6 months (one visit in this time frame), 12±1 months, 18±1 months, 24±1 months | 
| Change in skin integrity reported as presence/absence of skin redness/rash |  | 1 ±1 month, 3-6 months (one visit in this time frame), 12±1 months, 18±1 months, 24±1 months | 
| Change in body temperature |  | 1 ±1 month, 3-6 months (one visit in this time frame), 12±1 months, 18±1 months, 24±1 months | 
| Change in respiration rate | Respiration rate will be measured as breaths/minute. | 1 ±1 month, 3-6 months (one visit in this time frame), 12±1 months, 18±1 months, 24±1 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Magnetic Resonance Imaging (MRI), Brain Reorganization