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Perinatal Stroke: Brain Reorganization During Infancy

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ClinicalTrials.gov Identifier: NCT05013736
Recruitment Status : Recruiting
First Posted : August 19, 2021
Last Update Posted : August 24, 2022
Sponsor:
Collaborator:
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Information provided by (Responsible Party):
University of Wisconsin, Madison

Brief 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.


Condition or disease Intervention/treatment
Perinatal Stroke Device: Magnetic Resonance Imaging Behavioral: Behavioral Assessments Device: Non invasive Transcranial Magnetic Stimulation

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.

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Study Type : Observational
Estimated Enrollment : 65 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Perinatal Stroke: Longitudinal Assessment of Infant Brain Organization and Recovery Through Neuroexcitability, Neuroimaging and Motor Development
Actual Study Start Date : July 26, 2022
Estimated Primary Completion Date : September 2026
Estimated Study Completion Date : September 2026

Resource links provided by the National Library of Medicine


Group/Cohort Intervention/treatment
Infants
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
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.
Other Name: MRI

Behavioral: Behavioral Assessments
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.

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.
Other Name: TMS




Primary Outcome Measures :
  1. 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 ]

    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).


  2. 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 ]
    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. 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 ]

    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


  4. Behavioral assessments: General Movements Assessment (GMA) reported on binary (Y/N) scale [ Time Frame: 1 ±1 month ]

    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".


  5. Behavioral assessments: General Movements Assessment (GMA) reported on binary (Y/N) scale [ Time Frame: 3 ±1 months ]

    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".


  6. Behavioral assessments: Hammersmith Infant Neurological Examination (HINE) score [ Time Frame: 1 ±1 month ]

    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.


  7. Behavioral assessments: Hammersmith Infant Neurological Examination (HINE) score [ Time Frame: 3-6 months (one visit in this time frame) ]

    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.


  8. Behavioral assessments: Hammersmith Infant Neurological Examination (HINE) score [ Time Frame: 12±1 months ]

    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.


  9. Behavioral assessments: Hammersmith Infant Neurological Examination (HINE) score [ Time Frame: 18±1 months ]

    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.


  10. Behavioral assessments: Hammersmith Infant Neurological Examination (HINE) score [ Time Frame: 24±1 months ]

    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.


  11. Behavioral assessments: Bayley Scales of Infant and Toddler Development Test, 4th edition (Bayley-IV) score [ Time Frame: 3-6 months (one visit in this time frame) ]
    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. Behavioral assessments: Bayley Scales of Infant and Toddler Development Test, 4th edition (Bayley-IV) score [ Time Frame: 12±1 months ]
    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.

  13. Behavioral assessments: Bayley Scales of Infant and Toddler Development Test, 4th edition (Bayley-IV) score [ Time Frame: 18±1 months ]
    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.

  14. Behavioral assessments: Bayley Scales of Infant and Toddler Development Test, 4th edition (Bayley-IV) score [ Time Frame: 24±1 months ]
    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.


Secondary Outcome Measures :
  1. 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 ]
  2. 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 ]
  3. 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 ]
  4. 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 ]
  5. 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 ]
    Respiration rate will be measured as breaths/minute.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   0 Years to 24 Months   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
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 and infants able to attend study visits at the University of Wisconsin-Madison.
Criteria

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
  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05013736


Contacts
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Contact: Bernadette Gillick, PhD, MSPT 608-262-3079 bgillick@wisc.edu

Locations
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United States, Wisconsin
University of Wisconsin School of Medicine and Public Health Recruiting
Madison, Wisconsin, United States, 53705
Sponsors and Collaborators
University of Wisconsin, Madison
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Investigators
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Principal Investigator: Bernadette Gillick, PhD, MSPT University of Wisconsin, Madison
Additional Information:
Publications:

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Responsible Party: University of Wisconsin, Madison
ClinicalTrials.gov Identifier: NCT05013736    
Other Study ID Numbers: 2021-0412
A536761 ( Other Identifier: UW Madison )
SMPH/PEDIATRICS/PEDIATRICS ( Other Identifier: UW Madison )
Protocol ver 3.0 11/17/2021 ( Other Identifier: UW Madison )
7R01HD098202-02 ( U.S. NIH Grant/Contract )
First Posted: August 19, 2021    Key Record Dates
Last Update Posted: August 24, 2022
Last Verified: August 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Individual participant data collected during the trial will be shared after deidentification.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Time Frame: Beginning 3 months after publication of primary outcomes, and ending 5 years after that date
Access Criteria:

Data will be shared with the researchers whose proposed use of the data is for independent verification of study outcomes or to conduct subsequent clinical research. Data sharing will be approved by an independent review committee identified for this purpose.

Proposals should be directed to bgillick@wisc.edu. If approved after review by regulatory counsel, requestors will enter into a formal data sharing agreement. Data will be shared via encrypted single-user file transmission protocol.


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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: Yes
Keywords provided by University of Wisconsin, Madison:
Magnetic Resonance Imaging (MRI)
Brain Reorganization
Additional relevant MeSH terms:
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Stroke
Cerebrovascular Disorders
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Vascular Diseases
Cardiovascular Diseases