Severity and duration of dysglycemia and brain injury among patients with neonatal encephalopathy.

Background: Evidence is needed to inform thresholds for glycemic management in neonatal encephalopathy (NE). We investigated how severity and duration of dysglycemia relate to brain injury after NE. Methods: A prospective cohort of 108 neonates ≥36 weeks gestational age with NE were enrolled between August 2014 and November 2019 at the Hospital for Sick Children, in Toronto, Canada. Participants underwent continuous glucose monitoring for 72 h, MRI at day 4 of life, and follow-up at 18 months. Receiver operating characteristic curves were used to assess the predictive value of glucose measures (minimum and maximum glucose, sequential 1 mmol/L glucose thresholds) during the first 72 h of life (HOL) for each brain injury pattern (basal ganglia, watershed, focal infarct, posterior-predominant). Linear and logistic regression analyses were used to assess the relationship between abnormal glycemia and 18-month outcomes (Bayley-III composite scores, Child Behavior Checklist [CBCL] T-scores, neuromotor score, cerebral palsy [CP], death), adjusting for brain injury severity. Findings: Of 108 neonates enrolled, 102 (94%) had an MRI. Maximum glucose during the first 48 HOL best predicted basal ganglia (AUC = 0.811) and watershed (AUC = 0.858) injury. Minimum glucose was not predictive of brain injury (AUC <0.509). Ninety-one (89%) infants underwent follow-up assessments at 19.0 ± 1.7 months. A glucose threshold of >10.1 mmol/L during the first 48 HOL was associated with 5.8-point higher CBCL Internalizing Composite T-score (P = 0.029), 0.3-point worse neuromotor score (P = 0.035), 8.6-fold higher odds for CP diagnosis (P = 0.014). While the glucose threshold of >10.1 mmol/L during the first 48 HOL was associated with higher odds of the composite outcome of severe disability or death (OR 3.0, 95% CI 1.0-8.4, P = 0.042), it was not associated with the composite outcome of moderate-to-severe disability or death (OR 0.9, 95% CI 0.4-2.2, P = 0.801). All associations with outcome lost significance after adjusting for brain injury severity. Interpretation: Maximum glucose concentration in the first 48 HOL is predictive of brain injury after NE. Further trials are needed to assess if protocols to control maximum glucose concentrations improve outcomes after NE. Funding: Canadian Institutes for Health Research, National Institutes of Health, and SickKids Foundation.

Seizure Burden and Neurologic Outcomes After Neonatal Encephalopathy.

BACKGROUND AND OBJECTIVES: Seizures are common during neonatal encephalopathy (NE), but the contribution of seizure burden (SB) to outcomes remains controversial. This study aims to examine the relationship between electrographic SB and neurologic outcomes after NE. METHODS: This prospective cohort study recruited newborns ≥36 weeks postmenstrual age around 6 hours of life between August 2014 and November 2019 from a neonatal intensive care unit (NICU). Participants underwent continuous electroencephalography for at least 48 hours, brain MRI within 3-5 days of life, and structured follow-up at 18 months. Electrographic seizures were identified by board-certified neurophysiologists and quantified as total SB and maximum hourly SB. A medication exposure score was calculated based on all antiseizure medications given during NICU admission. Brain MRI injury severity was classified based on basal ganglia and watershed scores. Developmental outcomes were measured using the Bayley Scales of Infant Development, Third Edition. Multivariable regression analyses were performed, adjusting for significant potential confounders. RESULTS: Of 108 enrolled infants, 98 had continuous EEG (cEEG) and MRI data collected, of which 5 were lost to follow-up, and 6 died before age 18 months. All infants with moderate-severe encephalopathy completed therapeutic hypothermia. cEEG-confirmed neonatal seizures occurred in 21 (24%) newborns, with a total SB mean of 12.5 ± 36.4 minutes and a maximum hourly SB mean of 4 ± 10 min/h. After adjusting for MRI brain injury severity and medication exposure, total SB was significantly associated with lower cognitive (-0.21, 95% CI -0.33 to -0.08, p = 0.002) and language (-0.25, 95% CI -0.39 to -0.11, p = 0.001) scores at 18 months. Total SB of 60 minutes was associated with 15-point decline in language scores and 70 minutes for cognitive scores. However, SB was not significantly associated with epilepsy, neuromotor score, or cerebral palsy (p > 0.1). DISCUSSION: Higher SB during NE was independently associated with worse cognitive and language scores at 18 months, even after adjusting for exposure to antiseizure medications and severity of brain injury. These observations support the hypothesis that neonatal seizures occurring during NE independently contribute to long-term outcomes.

Early neonatal heart rate variability patterns in different subtypes of perinatal hypoxic-ischemic brain injury.

BACKGROUND: This study aims to compare the longitudinal changes in heart rate variability (HRV) during therapeutic hypothermia in neonates with different subtypes of hypoxic-ischemic brain injury. METHODS: HRV was computed from 1 hour time-epochs q6 hours for the first 48 hours. Primary outcome was brain-injury pattern on MRI at 4(3-5) days. We fitted linear mixed-effect regression models with HRV metric, brain injury subtype and postnatal age. RESULTS: Among 89 term neonates, 40 neonates had abnormal brain MRI (focal infarct 15 (38%), basal-ganglia predominant 8 (20%), watershed-predominant 5 (13%), and mixed pattern 12 (30%)). There was no significant difference in the HRV metrics between neonates with normal MRI, focal infarcts and basal ganglia pattern. At any given postnatal age, the degree of HRV suppression (HRV measure in the brain-injury subtype group/HRV measure in Normal MRI group) was significant in neonates with watershed pattern (SDNN(0.63, p = 0.08), RMSSD(0.74, p = 0.04)) and mixed pattern injury (SDNN (0.64, p < 0.001), RMSSD (0.75, p = 0.02)). HRV suppression was most profound at the postnatal age of 24-30 h in all brain injury subtypes. CONCLUSION: Neonates with underlying watershed injury with or without basal-ganglia injury demonstrates significant HRV suppression during first 48 hour of hypothermia therapy. IMPACT: Our study suggests that suppression of heart rate variability in neonates during therapeutic hypothermia varies according to the pattern of underlying hypoxic-ischemic brain injury. Neonates with watershed predominant pattern and mixed pattern of brain injury have the most severe suppression of heart rate variability measures. Heart rate variability monitoring may provide early insights into the pattern of hypoxic-ischemic brain injury in neonates undergoing therapeutic hypothermia earlier than routine clinical MRI.

Hyperglycemia associated with acute brain injury in neonatal encephalopathy.

OBJECTIVE: To identify how alterations in glucose levels are associated with regional brain injury in neonatal encephalopathy. METHODS: This was a prospective cohort study of 102 newborns with neonatal encephalopathy, with continuous glucose monitoring for 72 h. 97 (95%) completed 72 h of therapeutic hypothermia. Brain imaging around day 5 of life included diffusion tensor imaging and MR spectroscopy. Regions of interest were placed for both DTI and MR spectroscopy, and tractography of the optic radiation and corticospinal tract were evaluated. Linear regression models related each MR metric with minimum and maximum glucose values during each day of life, adjusting for 5-minute Apgar scores and umbilical artery pH. RESULTS: Higher maximum glucose levels on the first day of life were associated with widespread changes in mean diffusivity in the anterior and posterior white matter, splenium of the corpus callosum, lentiform nucleus, pulvinar nucleus of the thalamus, posterior limb of the internal capsule, and optic radiations, thus including regions traditionally associated with hypoxia-ischemia or hypoglycemia. No associations were found between lower minimum glucose levels and DTI changes in any regions tested, or between glucose levels and MR spectroscopy. CONCLUSIONS: In this cohort of neonatal encephalopathy with therapeutic hypothermia, higher maximal glucose on the first day of life was associated with widespread microstructural changes, but lower minimum glucose levels were not associated with changes in any of the regions tested. Long-term follow-up will determine if imaging findings translate to long-term outcomes.

The Effect of Music and White Noise on Electroencephalographic (EEG) Functional Connectivity in Neonates in the Neonatal Intensive Care Unit.

The purpose of this study is to investigate whether listening to music and white noise affects functional connectivity on scalp electroencephalography (EEG) in neonates in the neonatal intensive care unit.Nine neonates of ≥34 weeks' gestational age, who were already undergoing clinical continuous EEG monitoring in the neonatal intensive care unit, listened to lullaby-like music and white noise for 1 hour each separated by a 2-hour interval of no intervention. EEG segments during periods of music, white noise, and no intervention were band-pass filtered as delta (0.5-4 Hz), theta (4-8 Hz), lower alpha (8-10 Hz), upper alpha (10-13 Hz), beta (13-30 Hz), and gamma (30-45 Hz). Synchronization likelihood was used as a measure of connectivity between any 2 electrodes.In theta, lower alpha, and upper alpha frequency bands, the synchronization likelihood values yielded statistical significance with sound (music, white noise and no intervention) and with edge (between any 2 electrodes) factors. In theta, lower alpha, and upper alpha frequency bands, statistical significance was obtained between music and white noise (t = 3.12, 3.32, and 3.68, respectively; P < .017), and between white noise and no intervention (t = 4.51, 3.09, and 2.95, respectively, P < .017). However, there was no difference between music and no intervention.Although limited by a small sample size and the 1-time only auditory intervention, these preliminary results demonstrate the feasibility of EEG connectivity analyses even at bedside in neonates on continuous EEG monitoring in the neonatal intensive care unit. They also point to the possibility of detecting significant changes in functional connectivity related to the theta and alpha bands using auditory interventions.

Abnormalities in evoked potentials associated with abnormal glycemia and brain injury in neonatal hypoxic-ischemic encephalopathy.

OBJECTIVE: To investigate how functional integrity of ascending sensory pathways measured by visual and somatosensory evoked potentials (VEP & SEP) is associated with abnormal glycemia and brain injury in newborns treated with hypothermia for hypoxic-ischemic encephalopathy (HIE). METHODS: Fifty-four neonates ≥ 36 weeks gestational age with HIE underwent glucose testing, VEPs, SEPs, and magnetic resonance imaging (MRI) the first week of life. Minimum and maximum glucose values recorded prior to evoked potential (EP) testing were compared with VEP and SEP measures using generalized estimating equations. Relationships between VEP and SEP measures and brain injury on MRI were assessed. RESULTS: Maximum glucose is associated with decreased P200 amplitude, and increased odds that N300 peak will be delayed/absent. Minimum glucose is associated with decreased P22 amplitude. Presence of P200 and N300 peaks is associated with decreased odds of brain injury in the visual processing pathway, with delayed/absent N300 peak associated with increased odds of brain injury in posterior white matter. CONCLUSIONS: Deviations from normoglycemia are associated with abnormal EPs, and abnormal VEPs are associated with brain injury on MRI in cooled neonates with HIE. SIGNIFICANCE: Glucose is a modifiable risk factor associated with atypical brain function in neonates with HIE despite hypothermia treatment.

Hyperglycemia and Glucose Variability Are Associated with Worse Brain Function and Seizures in Neonatal Encephalopathy: A Prospective Cohort Study.

OBJECTIVES: To investigate how glucose abnormalities correlate with brain function on amplitude-integrated electroencephalography (aEEG) in infants with neonatal encephalopathy. STUDY DESIGN: Neonates born at full term with encephalopathy were enrolled within 6 hours of birth in a prospective cohort study at a pediatric academic referral hospital. Continuous interstitial glucose monitors and aEEG were placed soon after birth and continued for 3 days. Episodes of hypoglycemia (≤50 mg/dL; ≤2.8 mmol/L) and hyperglycemia (>144 mg/dL; >8.0 mmol/L) were identified. aEEG was classified in 6-hour epochs for 3 domains (background, sleep-wake cycling, electrographic seizures). Generalized estimating equations assessed the relationship of hypo- or hyperglycemia with aEEG findings, adjusting for clinical markers of hypoxia-ischemia (Apgar scores, umbilical artery pH, and base deficit). RESULTS: Forty-five infants (gestational age 39.5 ± 1.4 weeks) were included (24 males). During aEEG monitoring, 16 episodes of hypoglycemia were detected (9 infants, median duration 77.5, maximum 220 minutes) and 18 episodes of hyperglycemia (13 infants, median duration 237.5, maximum 3125 minutes). Epochs of hypoglycemia were not associated with aEEG changes. Compared with epochs of normoglycemia, epochs of hyperglycemia were associated with worse aEEG background scores (B 1.120, 95% CI 0.501-1.738, P < .001), less sleep-wake cycling (B 0.587, 95% CI 0.417-0.757, P < .001) and more electrographic seizures (B 0.433, 95% CI 0.185-0.681, P = .001), after adjusting for hypoxia-ischemia severity. CONCLUSIONS: In neonates with encephalopathy, epochs of hyperglycemia were temporally associated with worse global brain function and seizures, even after we adjusted for hypoxia-ischemia severity. Whether hyperglycemia causes neuronal injury or is simply a marker of severe brain injury requires further study.

Plasma cholesterol levels and brain development in preterm newborns.

BACKGROUND: To assess whether postnatal plasma cholesterol levels are associated with microstructural and macrostructural regional brain development in preterm newborns. METHODS: Sixty preterm newborns (born 24-32 weeks gestational age) were assessed using MRI studies soon after birth and again at term-equivalent age. Blood samples were obtained within 7 days of each MRI scan to analyze for plasma cholesterol and lathosterol (a marker of endogenous cholesterol synthesis) levels. Outcomes were assessed at 3 years using the Bayley Scales of Infant Development, Third Edition. RESULTS: Early plasma lathosterol levels were associated with increased axial and radial diffusivities and increased volume of the subcortical white matter. Early plasma cholesterol levels were associated with increased volume of the cerebellum. Early plasma lathosterol levels were associated with a 2-point decrease in motor scores at 3 years. CONCLUSIONS: Higher early endogenous cholesterol synthesis is associated with worse microstructural measures and larger volumes in the subcortical white matter that may signify regional edema and worse motor outcomes. Higher early cholesterol is associated with improved cerebellar volumes. Further work is needed to better understand how the balance of cholesterol supply and endogenous synthesis impacts preterm brain development, especially if these may be modifiable factors to improve outcomes.

Postnatal polyunsaturated fatty acids associated with larger preterm brain tissue volumes and better outcomes.

BackgroundHuman studies investigating the link between postnatal polyunsaturated fatty acids and preterm brain growth are limited, despite emerging evidence of potential effects on outcomes.MethodsSixty preterm neonates <32 weeks gestational age with magnetic resonance imaging (MRI) scanning at near-birth and near-term age were assessed for brain tissue volumes, including cortical gray matter, white matter, deep gray matter, cerebellum, brainstem, and ventricular cerebrospinal fluid. Red blood cell fatty acid content was evaluated within 1 week of each MRI scan. Neurodevelopmental outcome at 30-36 months corrected age was assessed.ResultsAdjusting for potential confounders, higher near-birth docosahexaenoic acid levels are associated with larger cortical gray matter, deep gray matter, and brainstem volumes and higher near-term levels with larger deep gray matter, cerebellar, and brainstem volumes at near-term age; lower near-birth linoleic acid levels are correlated with larger white matter volume at near-term age. By 30-36 months corrected age, larger cortical and deep gray matter, cerebellar, and brainstem volumes by term age are associated with improved language scores and larger cerebellar and brainstem volumes with improved motor scores.ConclusionSpecific polyunsaturated fatty acid levels have differential and time-dependent associations with brain region growth. Larger brain volumes are associated with improved outcomes at preschool age.

Relational learning and transitive expression in aging and amnesia.

Aging has been associated with a decline in relational memory, which is critically supported by the hippocampus. By adapting the transitivity paradigm (Bunsey and Eichenbaum (1996) Nature 379:255-257), which traditionally has been used in nonhuman animal research, this work examined the extent to which aging is accompanied by deficits in relational learning and flexible expression of relational information. Older adults' performance was additionally contrasted with that of amnesic case DA to understand the critical contributions of the medial temporal lobe, and specifically, the hippocampus, which endures structural and functional changes in healthy aging. Participants were required to select the correct choice item (B versus Y) based on the presented sample item (e.g., A). Pairwise relations must be learned (A->B, B->C, C->D) so that ultimately, the correct relations can be inferred when presented with a novel probe item (A->C?Z?). Participants completed four conditions of transitivity that varied in terms of the degree to which the stimuli and the relations among them were known pre-experimentally. Younger adults, older adults, and DA performed similarly when the condition employed all pre-experimentally known, semantic, relations. Older adults and DA were less accurate than younger adults when all to-be-learned relations were arbitrary. However, accuracy improved for older adults when they could use pre-experimentally known pairwise relations to express understanding of arbitrary relations as indexed through inference judgments. DA could not learn arbitrary relations nor use existing knowledge to support novel inferences. These results suggest that while aging has often been associated with an emerging decline in hippocampal function, prior knowledge can be used to support novel inferences. However, in case DA, significant damage to the hippocampus likely impaired his ability to learn novel relations, while additional damage to ventromedial prefrontal and anterior temporal regions may have resulted in an inability to use prior knowledge to flexibly express indirect relational knowledge.

Maternal Postsecondary Education Associated With Improved Cerebellar Growth After Preterm Birth.

The preterm cerebellum is vulnerable to impaired development impacting long-term outcome. Preterm newborns (<32 weeks) underwent serial magnetic resonance imaging (MRI) scans. The association between parental education and cerebellar volume at each time point was assessed, adjusting for age at scan. In 26 infants, cerebellar volumes at term (P = .001), but not birth (P = .4), were associated with 2-year volumes. For 1 cm(3) smaller cerebellar volume (4% total volume) at term, the cerebellum was 3.18 cm(3) smaller (3% total volume) by 2 years. Maternal postsecondary education was not associated with cerebellar volume at term (P = .16). Maternal postsecondary education was a significant confounder in the relationship between term and 2-year cerebellar volumes (P = .016), with higher education associated with improved volumes by 2 years. Although preterm birth has been found to be associated with smaller cerebellar volumes at term, maternal postsecondary education is associated with improved growth detectable by 2 years.

Can changes in eye movement scanning alter the age-related deficit in recognition memory?

Older adults typically exhibit poorer face recognition compared to younger adults. These recognition differences may be due to underlying age-related changes in eye movement scanning. We examined whether older adults' recognition could be improved by yoking their eye movements to those of younger adults. Participants studied younger and older faces, under free viewing conditions (bases), through a gaze-contingent moving window (own), or a moving window which replayed the eye movements of a base participant (yoked). During the recognition test, participants freely viewed the faces with no viewing restrictions. Own-age recognition biases were observed for older adults in all viewing conditions, suggesting that this effect occurs independently of scanning. Participants in the bases condition had the highest recognition accuracy, and participants in the yoked condition were more accurate than participants in the own condition. Among yoked participants, recognition did not depend on age of the base participant. These results suggest that successful encoding for all participants requires the bottom-up contribution of peripheral information, regardless of the locus of control of the viewer. Although altering the pattern of eye movements did not increase recognition, the amount of sampling of the face during encoding predicted subsequent recognition accuracy for all participants. Increased sampling may confer some advantages for subsequent recognition, particularly for people who have declining memory abilities.