Baby Brain Recovery Study

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 assessment of peripheral nerve excitability will be performed. Peripheral stimulation will begin at 40% MSO. Stimulation intensity will be adjusted in increments of 5% until motor responses are evident on the EMG. Once motor responses are identified, 10 pulses will be delivered at the stimulation intensity that produced the response. In sum, around 150 stimulation pulses per hemisphere of brain stimulation and 22-60 pulses of peripheral stimulation are expected for TMS assessment of each infant.

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).

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.

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

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".

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".

Behavioral assessments: Hammersmith Infant Neurological Examination (HINE) global 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. High-risk cutoff scores for cerebral palsy are \<57 at 3 months and \<73 at 6, 9, or 12 months. See Novak et al, 2017 linked in the reference section for context.

Behavioral assessments: Hammersmith Infant Neurological Examination (HINE) global 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. High-risk cutoff scores for cerebral palsy are \<57 at 3 months and \<73 at 6, 9, or 12 months. See Novak et al, 2017 linked in the reference section for context.

Behavioral assessments: Hammersmith Infant Neurological Examination (HINE) global 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. High-risk cutoff scores for cerebral palsy are \<57 at 3 months and \<73 at 6, 9, or 12 months. See Novak et al, 2017 linked in the reference section for context.

Behavioral assessments: Hammersmith Infant Neurological Examination (HINE) global 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. High-risk cutoff scores for cerebral palsy are \<57 at 3 months and \<73 at 6, 9, or 12 months. See Novak et al, 2017 linked in the reference section for context.

Behavioral assessments: Hammersmith Infant Neurological Examination (HINE) global 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. High-risk cutoff scores for cerebral palsy are \<57 at 3 months and \<73 at 6, 9, or 12 months. See Novak et al, 2017 linked in the reference section for context.

Behavioral assessments: Hammersmith Infant Neurological Examination (HINE) Asymmetry Scores

Time frame: data collected at 1 ±1 month, 3-6 months (one visit in this time frame), 12±1 months, 18±1 months, 24±1 months

An asymmetry can also be recorded for each item, with one point maximum allotted per item, with a total score ranging from 0-26. Based on the literature regarding asymmetries, the cutoff score of \>3 asymmetries will be used for recommendation of referral to early intervention service. See article by Fehlings, 2024 for additional context.

Behavioral assessments: Bayley Scales of Infant and Toddler Development Test, 4th edition (Bayley-4) score

Time frame: 3-6 months (one visit in this time frame)

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.

Behavioral assessments: Bayley Scales of Infant and Toddler Development Test, 4th edition (Bayley-4) score

Time frame: 12±1 months

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.

Behavioral assessments: Bayley Scales of Infant and Toddler Development Test, 4th edition (Bayley-IV) score

Time frame: 18±1 months

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.

Behavioral assessments: Bayley Scales of Infant and Toddler Development Test, 4th edition (Bayley-4) score

Time frame: 24±1 months

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.

Baby Observation of Selective Control AppRaisal (Baby OSCAR)

Time frame: 1±1 month

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.

Baby Observation of Selective Control AppRaisal (Baby OSCAR)

Time frame: 3-6 months (one visit in this time frame)

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.

Change in Pediatric Evaluation of Disability Inventory Computer Adaptive Test (PEDI-CAT)

Time frame: 1 ±1 month, 3-6 months (one visit in this time frame), 12±1 months, 18±1 months, 24±1 months

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.

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