Baby Brain Recovery Study

Perinatal Stroke Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05013736
• Other study ID #: 2021-0412
• Secondary ID: A536761SMPH/PEDI
• Status: Recruiting
• Start date: July 26, 2022
• Est. completion date: September 2026

Study information

• Verified date: January 2024
• Source: University of Wisconsin, Madison
• Contact: Bernadette Gillick, PhD, MSPT
• Phone: 608-262-3079
• Email: bgillick[@]wisc.edu
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 65
• Est. completion date: September 2026
• Est. primary completion date: September 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 0 Years to 24 Months

Eligibility

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

Related Conditions & MeSH terms

• Perinatal Stroke
• Stroke

Intervention

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. In sum, around 150 stimulation pulses per hemisphere are expected for TMS assessment for each infant.

Locations

Country	Name	City	State
United States	University of Wisconsin School of Medicine and Public Health	Madison	Wisconsin

Sponsors (2)

Lead Sponsor	Collaborator
University of Wisconsin, Madison	Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Country where clinical trial is conducted

United States, 

References & Publications (21)

Adde L, Rygg M, Lossius K, Oberg GK, Stoen R. General movement assessment: predicting cerebral palsy in clinical practise. Early Hum Dev. 2007 Jan;83(1):13-8. doi: 10.1016/j.earlhumdev.2006.03.005. Epub 2006 May 2. — View Citation

Allen CH, Kluger BM, Buard I. Safety of Transcranial Magnetic Stimulation in Children: A Systematic Review of the Literature. Pediatr Neurol. 2017 Mar;68:3-17. doi: 10.1016/j.pediatrneurol.2016.12.009. Epub 2017 Jan 4. — View Citation

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. — View Citation

Chen CY, Rich TL, Cassidy JM, Gillick BT. Corticospinal Excitability in Children with Congenital Hemiparesis. Brain Sci. 2016 Oct 20;6(4):49. doi: 10.3390/brainsci6040049. — View Citation

Chen CY, Tafone S, Lo W, Heathcock JC. Perinatal stroke causes abnormal trajectory and laterality in reaching during early infancy. Res Dev Disabil. 2015 Mar;38:301-8. doi: 10.1016/j.ridd.2014.11.014. Epub 2015 Jan 9. — View Citation

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. — View Citation

Dean DC 3rd, Dirks H, O'Muircheartaigh J, Walker L, Jerskey BA, Lehman K, Han M, Waskiewicz N, Deoni SC. Pediatric neuroimaging using magnetic resonance imaging during non-sedated sleep. Pediatr Radiol. 2014 Jan;44(1):64-72. doi: 10.1007/s00247-013-2752-8. Epub 2013 Aug 6. — View Citation

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. — View Citation

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. — View Citation

Gillick BT, Gordon AM, Feyma T, Krach LE, Carmel J, Rich TL, Bleyenheuft Y, Friel K. Non-Invasive Brain Stimulation in Children With Unilateral Cerebral Palsy: A Protocol and Risk Mitigation Guide. Front Pediatr. 2018 Mar 16;6:56. doi: 10.3389/fped.2018.00056. eCollection 2018. — View Citation

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. — View Citation

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. — View Citation

Kowalski JL, Nemanich ST, Nawshin T, Chen M, Peyton C, Zorn E, Hickey M, Rao R, Georgieff M, Rudser K, Gillick BT. Motor Evoked Potentials as Potential Biomarkers of Early Atypical Corticospinal Tract Development in Infants with Perinatal Stroke. J Clin Med. 2019 Aug 13;8(8):1208. doi: 10.3390/jcm8081208. — View Citation

Lemon RN. Descending pathways in motor control. Annu Rev Neurosci. 2008;31:195-218. doi: 10.1146/annurev.neuro.31.060407.125547. — View Citation

Nemanich ST, Chen CY, Chen M, Zorn E, Mueller B, Peyton C, Elison JT, Stinear J, Rao R, Georgieff M, Menk J, Rudser K, Gillick B. Safety and Feasibility of Transcranial Magnetic Stimulation as an Exploratory Assessment of Corticospinal Connectivity in Infants After Perinatal Brain Injury: An Observational Study. Phys Ther. 2019 Jun 1;99(6):689-700. doi: 10.1093/ptj/pzz028. — View Citation

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, Romeo DM, Shepherd R, Spittle AJ, Thornton M, Valentine J, Walker K, White R, Badawi N. Early, Accurate Diagnosis and Early Intervention in Cerebral Palsy: Advances in Diagnosis and Treatment. JAMA Pediatr. 2017 Sep 1;171(9):897-907. doi: 10.1001/jamapediatrics.2017.1689. Erratum In: JAMA Pediatr. 2017 Sep 1;171(9):919. — View Citation

Peyton C, Yang E, Msall ME, Adde L, Stoen R, Fjortoft T, Bos AF, Einspieler C, Zhou Y, Schreiber MD, Marks JD, Drobyshevsky A. White Matter Injury and General Movements in High-Risk Preterm Infants. AJNR Am J Neuroradiol. 2017 Jan;38(1):162-169. doi: 10.3174/ajnr.A4955. Epub 2016 Oct 27. — View Citation

Romeo DM, Ricci D, Brogna C, Mercuri E. Use of the Hammersmith Infant Neurological Examination in infants with cerebral palsy: a critical review of the literature. Dev Med Child Neurol. 2016 Mar;58(3):240-5. doi: 10.1111/dmcn.12876. Epub 2015 Aug 25. — View Citation

Roze E, Harris PA, Ball G, Elorza LZ, Braga RM, Allsop JM, Merchant N, Porter E, Arichi T, Edwards AD, Rutherford MA, Cowan FM, Counsell SJ. Tractography of the corticospinal tracts in infants with focal perinatal injury: comparison with normal controls and to motor development. Neuroradiology. 2012 May;54(5):507-16. doi: 10.1007/s00234-011-0969-5. Epub 2011 Oct 18. — View Citation

van der Aa NE, Northington FJ, Stone BS, Groenendaal F, Benders MJ, Porro G, Yoshida S, Mori S, de Vries LS, Zhang J. Quantification of white matter injury following neonatal stroke with serial DTI. Pediatr Res. 2013 Jun;73(6):756-62. doi: 10.1038/pr.2013.45. Epub 2013 Mar 11. — View Citation

Yu YT, Hsieh WS, Hsu CH, Chen LC, Lee WT, Chiu NC, Wu YC, Jeng SF. A psychometric study of the Bayley Scales of Infant and Toddler Development - 3rd Edition for term and preterm Taiwanese infants. Res Dev Disabil. 2013 Nov;34(11):3875-83. doi: 10.1016/j.ridd.2013.07.006. Epub 2013 Sep 9. — View Citation

* Note: There are 21 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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)
Primary	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
Primary	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
Primary	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
Primary	Behavioral assessments: Bayley Scales of Infant and Toddler Development Test, 4th edition (Bayley-4) score	Bayley-4 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)
Primary	Behavioral assessments: Bayley Scales of Infant and Toddler Development Test, 4th edition (Bayley-4) score	Bayley-4 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
Primary	Behavioral assessments: Bayley Scales of Infant and Toddler Development Test, 4th edition (Bayley-IV) score	Bayley-4 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
Primary	Behavioral assessments: Bayley Scales of Infant and Toddler Development Test, 4th edition (Bayley-4) score	Bayley-4 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
Primary	Baby Observation of Selective Control AppRaisal (Baby OSCAR)	Baby OSCAR assessments are scored from video recordings of infant movement. Each limb is scored separately, with scores ranging 0-7 per lower limb, and 0-9 per upper limb for a total score of 0-32. Higher scores indicate better selective motor control.	1±1 month
Primary	Baby Observation of Selective Control AppRaisal (Baby OSCAR)	Baby OSCAR assessments are scored from video recordings of infant movement. Each limb is scored separately, with scores ranging 0-7 per lower limb, and 0-9 per upper limb for a total score of 0-32. Higher scores indicate better selective motor control.	3-6 months (one visit in this time frame)
Primary	Change in Pediatric Evaluation of Disability Inventory Computer Adaptive Test (PEDI-CAT)	Patient/caregiver-reported outcome measure of functional abilities and performance in children with disabilities. Scores are displayed instantly after completion of an assessment. A Detailed Score Report and a Summary Score Report are available. Normative scores are provided as age percentiles and T scores are based on a child's chronological age and intended for use by clinicians so that they may interpret a particular child's functioning relative to others of the same age. Scaled scores provide a way to look at a child's current functional skills and progress in these skills over time. Scaled scores are especially helpful in documenting improvements in functional skills for children not expected to exhibit or regain normative levels of functioning.	1 ±1 month, 3-6 months (one visit in this time frame), 12±1 months, 18±1 months, 24±1 months
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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

External Links

•   Link to ClinicalTrials.gov record of the pilot study which lead to current study