Baby Brain Recovery Study

Official title

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

Overview

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

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.

Interventions

• Device Magnetic Resonance Imaging
  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.
• Behavioral Behavioral Assessments
  The behavioral assessments (GMA: General Movements Assessment; HINE: Hammersmith Infant Neurological Examination; Baby Observation of Selective Control AppRaisal (BabyOSCAR); Bayley-4 / Bayley Scales of Infant and Toddler Development 4th ed; Pediatric Evaluation of Disability Inventory -Computer Adaptive Test (PEDI-CAT)) are infant and age-specific and will be administered by trained pediatric occupational and physical therapists.
• Device Non invasive Transcranial Magnetic Stimulation
  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. After this assessment, a brief as

Primary outcome measures

• Change in Cortical excitability measured as presence/absence of motor evoked potentials (MEP) [Time frame: 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) [Time frame: 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 [Time frame: 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 [Time frame: 1 ±1 month]
• Behavioral assessments: General Movements Assessment (GMA) reported on binary (Y/N) scale [Time frame: 3 ±1 months]
• Behavioral assessments: Hammersmith Infant Neurological Examination (HINE) global score [Time frame: 1 ±1 month]
• Behavioral assessments: Hammersmith Infant Neurological Examination (HINE) global score [Time frame: 3-6 months (one visit in this time frame)]
• Behavioral assessments: Hammersmith Infant Neurological Examination (HINE) global score [Time frame: 12±1 months]
• Behavioral assessments: Hammersmith Infant Neurological Examination (HINE) global score [Time frame: 18±1 months]
• Behavioral assessments: Hammersmith Infant Neurological Examination (HINE) global score [Time frame: 24±1 months]

Secondary outcome measures (5)

• Change in blood pressure [Time frame: 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 [Time frame: 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 [Time frame: 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 [Time frame: 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 [Time frame: 1 ±1 month, 3-6 months (one visit in this time frame), 12±1 months, 18±1 months, 24±1 months]

Eligibility criteria

Main 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, periventricular leukomalacia, and hypoxic-ischemic encephalopathy (HIE)
• English-speaking parent/legal guardian (able to provide consent)

Main Exclusion Criteria:

• Other neurologic disorders unrelated to perinatal stroke/brain bleed/HIE
• Metabolic disorders
• Disorders of Cellular Migration and Proliferation
• Acquired Traumatic Brain Injury

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Observational model

Cohort

Study locations

United States · 1 center

• University of Wisconsin School of Medicine and Public Health — Madison

Publications

• Ganesan V, Hogan A, Shack N, Gordon A, Isaacs E, Kirkham FJ. Outcome after ischaemic stroke in childhood. Dev Med Child Neurol. 2000 Jul;42(7):455-61. doi: 10.1017/s0012162200000852. PMID 10972417
• Kirton A, Deveber G. Life after perinatal stroke. Stroke. 2013 Nov;44(11):3265-71. doi: 10.1161/STROKEAHA.113.000739. Epub 2013 Oct 8. No abstract available. PMID 24105698
• Herskind A, Greisen G, Nielsen JB. Early identification and intervention in cerebral palsy. Dev Med Child Neurol. 2015 Jan;57(1):29-36. doi: 10.1111/dmcn.12531. Epub 2014 Jul 9. PMID 25041565
• Novak I, Morgan C, Adde L, Blackman J, Boyd RN, Brunstrom-Hernandez J, Cioni G, Damiano D, Darrah J, Eliasson AC, de Vries LS, Einspieler C, Fahey M, Fehlings D, Ferriero DM, Fetters L, Fiori S, Forssberg H, Gordon AM, Greaves S, Guzzetta A, Hadders-Algra M, Harbourne R, Kakooza-Mwesige A, Karlsson P, Krumlinde-Sundholm L, Latal B, Loughran-Fowlds A, Maitre N, McIntyre S, Noritz G, Pennington L, R PMID 28715518
• Lemon RN. Descending pathways in motor control. Annu Rev Neurosci. 2008;31:195-218. doi: 10.1146/annurev.neuro.31.060407.125547. PMID 18558853
• Cioni G, D'Acunto G, Guzzetta A. Perinatal brain damage in children: neuroplasticity, early intervention, and molecular mechanisms of recovery. Prog Brain Res. 2011;189:139-54. doi: 10.1016/B978-0-444-53884-0.00022-1. PMID 21489387
• Frye RE, Rotenberg A, Ousley M, Pascual-Leone A. Transcranial magnetic stimulation in child neurology: current and future directions. J Child Neurol. 2008 Jan;23(1):79-96. doi: 10.1177/0883073807307972. Epub 2007 Dec 3. PMID 18056688
• Chen CY, Georgieff M, Elison J, Chen M, Stinear J, Mueller B, Rao R, Rudser K, Gillick B. Understanding Brain Reorganization in Infants With Perinatal Stroke Through Neuroexcitability and Neuroimaging. Pediatr Phys Ther. 2017 Apr;29(2):173-178. doi: 10.1097/PEP.0000000000000365. PMID 28350777

Identifiers

NCT: NCT05013736 · 2021-0412 · A536761 · SMPH/PEDIATRICS/PEDIATRICS · Protocol ver 15 · 7R01HD098202-02

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗