Neurodevelopmental disabilities persist in survivors of neonatal hypoxic-ischemic encephalopathy (HIE) despite treatment with therapeutic hypothermia. Cerebrovascular autoregulation, the mechanism that maintains cerebral perfusion during changes in blood pressure, may influence outcomes. Our objective was to describe the relationship between acute autoregulatory vasoreactivity during treatment and neurodevelopmental outcomes at 2 years of age. In a pilot study of 28 neonates with HIE, we measured cerebral autoregulatory vasoreactivity with the hemoglobin volume index (HVx) during therapeutic hypothermia, rewarming, and the first 6 h of normothermia. The HVx, which is derived from near-infrared spectroscopy, was used to identify the individual optimal mean arterial blood pressure (MAPOPT) at which autoregulatory vasoreactivity is greatest. Cognitive and motor neurodevelopmental evaluations were completed in 19 children at 21–32 months of age. MAPOPT, blood pressure in relation to MAPOPT, blood pressure below gestational age + 5 (ga + 5), and regional cerebral oximetry (rSO2) were compared to the neurodevelopmental outcomes. Nineteen children who had HIE and were treated with therapeutic hypothermia performed in the average range on cognitive and motor evaluations at 21–32 months of age, although the mean performance was lower than that of published normative samples. Children with impairments at the 2-year evaluation had higher MAPOPT values, spent more time with blood pressure below MAPOPT, and had greater blood pressure deviation below MAPOPT during rewarming in the neonatal period than those without impairments. Greater blood pressure deviation above MAPOPT during rewarming was associated with less disability and higher cognitive scores. No association was observed between rSO2 or blood pressure below ga + 5 and neurodevelopmental outcomes. In this pilot cohort, motor and cognitive impairments at 21–32 months of age were associated with greater blood pressure deviation below MAPOPT during rewarming following therapeutic hypothermia, but not with rSO2 or blood pressure below ga + 5. This suggests that identifying individual neonates’ MAPOPT is superior to using hemodynamic goals based on gestational age or rSO2 in the acute management of neonatal HIE.

Background/Objectives: The Hammersmith Infant Neurological Examination (HINE) is a standardized neurologic exam for infants between 2 and 24 months. Scores can be compared to optimality cutoffs as one component to support an early diagnosis of cerebral palsy (CP). Some prognosis is also possible for infants diagnosed with CP. We aimed to understand the longitudinal trajectories of HINE scores in infants who were ultimately diagnosed with CP. Methods: Clinical records were reviewed for children who were diagnosed with CP in two high-risk infant follow-up clinics with HINE scores from at least two visits between the corrected ages of 3 months and 2 years. Trajectories were calculated individually and by group for infants in four categories—term neonatal hypoxic ischemic encephalopathy (HIE), term perinatal arterial ischemic stroke (PAIS), premature infants with brain injury, and “Other” (term infants with congenital malformations and/or congenital hydrocephalus). The changes in HINE scores between clinic visits were compared using linear mixed-effect models with a random intercept, pulling data by diagnostic group across visits and accounting for within-child correlations of scores over the follow-up time. Results: The changes in HINE scores for sixty children (twenty-five with prematurity, eighteen with HIE, seven with PAIS, and ten in the other category) were assessed. The linear mixed-effect models indicated that the infants with PAIS had an estimated 10.8-point increase in total HINE scores after 9 months of age compared to earlier assessments (95% CI [2.5, 19.2]. There was no statistically significant improvement in the scores among the infants in the other brain injury groups. The infants with PAIS had an estimated 2.9-point increase in HINE asymmetry scores after 9 months of age compared to prior visits (95% CI [0.7, 5.1]). None of the other diagnostic categories had statistically significant increases in asymmetry scores over time. Conclusions: The children with PAIS with resultant hemiplegia showed increasing HINE scores throughout the first two years of life. In contrast, the HINE scores remained stable for those children with term HIE, prematurity-associated brain injury, and congenital malformations and/or congenital hydrocephalus diagnosed with CP. Tracking individual changes (or stability) in HINE scores can aid diagnosis, inform prognosis, and guide the design of clinical trials targeting neurologic injury.

Background: Cutting-edge neonatal programs diagnose cerebral palsy (CP) or “high risk of CP” using validated neurobehavioral exams in combination with risk history and neuroimaging. In rat models, digital gait analyses are the gold standard adult assessment, but tools in infant rats are limited. Refinement of infant rat neurobehavioral correlates of CP will establish translational behavioral biomarkers to delineate early mechanisms of CP in both humans and rodent models of CP. Objective: To facilitate precision medicine approaches of neurodevelopmental health and integrate basic and clinical research approaches for CP, we developed and piloted a new assay of neonatal rat neurobehavior to mimic human neonate exams. Methods: Our established rat model of CP secondary to chorioamnionitis (CHORIO) that induces bilateral motor impairment reminiscent of spastic CP was used. On postnatal day 10 (P10), 5 min videos were recorded of 26 (6 sham and 20 CHORIO) animals moving freely in a cage were reviewed by an evaluator trained in the human General Movements Assessment (GMA). Non-blinded observation revealed two behaviors that differed between rat pups in each group (time spent rearing; multi-dimensional nose sweeping; and sniffing). Each video was re-coded for these criteria by an evaluator blind to group status. Differences between sham and CP groups were analyzed using a Mann–Whitney U-test or Student’s t-test (p < 0.05 level of significance). Results: Neonatal rats with CP exhibited sensorimotor impairment and decreased spatial exploration. CP rats spent significantly less time rearing (17.85 ± 1.60 s vs. 34.8 ± 2.89 s, p = 0.007) and engaged in multi-dimensional nose sweeping and sniffing (2.2 ± 0.58 episodes vs. 5.5 ± 0.96 episodes, p = 0.03) than sham controls. Conclusions: These pilot findings of harmonized translational and precision biobehavioral assays provide an opportunity for increased expediency of clinical trials at the earliest stages of brain development.

The risk of brain injury following premature birth increases with birth at earlier gestational ages and lower birthweights. The presentation of brain injury and subsequent neurodevelopmental sequelae in this population are extremely heterogeneous, as the injury is due to multifactorial causes; however, increasing amounts of research are elucidating the underlying mechanisms and pathways. This chapter broadly reviews the neurobiology of encephalopathy of prematurity, as well as clinical considerations, associated neurodevelopmental outcomes, and future directions in clinical care and research.