Neonatal neurobehavioral abnormalities and MRI brain injury in encephalopathic newborns treated with hypothermia

Abstract

Background Neonatal Encephalopathy (NE) is a prominent cause of infant mortality and neurodevelopmental disability. Hypothermia is an effective neuroprotective therapy for newborns with encephalopathy. Post-hypothermia functional-anatomical correlation between neonatal neurobehavioral abnormalities and brain injury findings on MRI in encephalopathic newborns has not been previously described. Aim To evaluate the relationship between neonatal neurobehavioral abnormalities and brain injury on magnetic resonance imaging (MRI) in encephalopathic newborns treated with therapeutic hypothermia. Study Design Neonates with hypoxic ischemic encephalopathy (HIE) referred for therapeutic hypothermia were prospectively enrolled in this observational study. Neurobehavioral functioning was assessed with the NICU Network Neurobehavioral Scale (NNNS) performed at target age 14 days. Brain injury was assessed by MRI at target age 7–10 days. NNNS scores were compared between infants with and without severe MRI injury. Subjects & Outcome Measures Sixty-eight term newborns (62% males) with moderate to severe encephalopathy underwent MRI at median 8 days (range 5–16) and NNNS at median 12 days of life (range 5–20). Fifteen (22%) had severe injury on MRI. Results Overall Total Motor Abnormality Score and individual summary scores for Nonoptimal Reflexes and Asymmetry were higher, while Total NNNS Z-score across cognitive/behavioral domains was lower (reflecting poorer performance) in infants with compared to those without severe MRI injury (p<0.05). Conclusions Neonatal neurobehavioral abnormalities identified by the NNNS are associated with MRI brain injury in encephalopathic newborns post-hypothermia. The NNNS can provide an early functional assessment of structural brain injury in newborns, which may guide rehabilitative therapies in infants after perinatal brain injury.

Comparison of early and late MRI in neonatal hypoxic–ischemic encephalopathy using three assessment methods

“…The two neonates who had normal early MRI but abnormal late MRI had normal signal intensity within the PLIC on both [30][31][32][33]. The good agreement between early and late MRI findings in our study suggests that early MRI might be helpful for managing intensive-care treatment when the hypothermia treatment ends (day 4).…”

Regions of variable DNA methylation in human placenta associated with newborn neurobehavior

“…This is concurrent with other findings using the NNNS assessment, where different NNNS summary scores have been associated with unique and specific epigenetic patterning 10,11,13,41,42 or factors from the prenatal environment. [20][21][22][23][24][25][26][27] Quality of movement and infant attention were associated with methylation of genes involving neurological development and function, including neurotransmitter uptake, dopamine uptake involved in synaptic transmission, and dendritic spine organization. The placenta is an endocrine organ that expresses similar neuropeptides to the human brain, 43 and previous studies have identified associations between methylation of genes that are expressed within the human brain, such as the serotonin receptor HTR2A.…”

“…16 This assessment has established validity in identifying high-risk infants and predicting later life health outcomes. [17][18][19][20][21][22][23][24][25][26][27][28] The cohort examined in this study represents a relatively healthy population, and the maternal environment experienced by these infants is likely similar to the population at large. These results suggest that there is an underlying level of variation in behavioral phenotypes as well as a level of epigenetic variation in the placenta of otherwise healthy infants, and that in some cases the variation in the placenta is related to the variation observed in neurobehavioral outcomes.…”

“…16 The NNNS has established validity in evaluating and predicting cognitive and behavioral outcomes in both healthy infants, 17 preterm infants, [18][19][20] and infants that have been exposed to some degree of in utero adversity. [21][22][23][24][25][26][27][28] Specific newborn characteristics that are quantified within the NNNS assessment, including newborn attention, quality of movement, lethargy, and arousal, have been repeatedly linked to methylation of genes involved in the serotonin response, 13 the development and regulation of the HPA axis, [10][11][12]14,15 and leptin regulation. 29 It is likely that additional genes and pathways, beyond those candidate genes, can be implicated in the development of complex neurobehavioral phenotypes.…”

Neonatal neurobehavior after therapeutic hypothermia for hypoxic ischemic encephalopathy

“…We previously reported the use of the NNNS for quantitatively documenting neurological status in newborns with HIE after therapeutic hypothermia (8). While we observed a significant relationship between NNNS motor abnormalities and severe brain injury by conventional MRI, we seek to extend this work by further examining brain structural-anatomical correlations using more robust quantitative MRI methods.…”