Faculty Bibliography

BACKGROUND:Experimental studies and small clinical trials have suggested that treatment with intranasal oxytocin may reduce social impairment in persons with autism spectrum disorder. Oxytocin has been administered in clinical practice to many children with autism spectrum disorder. METHODS:We conducted a 24-week, placebo-controlled phase 2 trial of intranasal oxytocin therapy in children and adolescents 3 to 17 years of age with autism spectrum disorder. Participants were randomly assigned in a 1:1 ratio, with stratification according to age and verbal fluency, to receive oxytocin or placebo, administered intranasally, with a total target dose of 48 international units daily. The primary outcome was the least-squares mean change from baseline on the Aberrant Behavior Checklist modified Social Withdrawal subscale (ABC-mSW), which includes 13 items (scores range from 0 to 39, with higher scores indicating less social interaction). Secondary outcomes included two additional measures of social function and an abbreviated measure of IQ. RESULTS:Of the 355 children and adolescents who underwent screening, 290 were enrolled. A total of 146 participants were assigned to the oxytocin group and 144 to the placebo group; 139 and 138 participants, respectively, completed both the baseline and at least one postbaseline ABC-mSW assessments and were included in the modified intention-to-treat analyses. The least-squares mean change from baseline in the ABC-mSW score (primary outcome) was -3.7 in the oxytocin group and -3.5 in the placebo group (least-squares mean difference, -0.2; 95% confidence interval, -1.5 to 1.0; P = 0.61). Secondary outcomes generally did not differ between the trial groups. The incidence and severity of adverse events were similar in the two groups. CONCLUSIONS:This placebo-controlled trial of intranasal oxytocin therapy in children and adolescents with autism spectrum disorder showed no significant between-group differences in the least-squares mean change from baseline on measures of social or cognitive functioning over a period of 24 weeks. (Funded by the National Institute of Child Health and Human Development; SOARS-B ClinicalTrials.gov number, NCT01944046.).

BACKGROUND:The prevalence of gestational diabetes mellitus (GDM) has rapidly increased, yet few prior studies have investigated parameters of early brain development in infants born to gestational diabetic mothers. The present study assessed visual evoked potentials (VEPs) in healthy infants born to gestational diabetic mothers and matched controls. METHODS:After exclusions, in this prospective study we examined VEPs in 73 neonates between 37 weeks and 41 weeks gestation at birth (n = 37 infants of gestational diabetic mothers). Stroboscopic flashes were presented through closed eyelids during passive electroencephalography (EEG) recording to derive VEP waveforms during natural sleep. RESULTS:There was a statistically significant moderate correlation between gestational age at birth and P2 latency of the flash VEP where P2 latency significantly decreased with increasing gestational age (Pearson's R(73) = -0.32, p < .01). There was also a significant moderate correlation between postnatal age (hours of life) and P2 latency of the flash VEP where P2 latency significantly decreased with increasing postnatal age (Pearson's R(73) = -0.23, p < .05). When controlling for gestational age at birth, postnatal age, and sex, there was a significant effect of group (GDM-exposed vs. control) on P2 latency of the flash VEP (p < .05). Infants of gestational diabetic mothers had a significantly longer P2 latency (M: 215.29 ± SD: 2.58 ms) than controls (M: 206.41 ± SD: 2.62 ms). CONCLUSION:Our findings suggest P2 flash VEP latency is a potential measure of cortical maturation and marker of immature development in infants of gestational diabetic mothers.

Importance:Research to date has not determined a safe level of alcohol or tobacco use during pregnancy. Electroencephalography (EEG) is a noninvasive measure of cortical function that has previously been used to examine effects of in utero exposures and associations with neurodevelopment. Objective:To examine the association of prenatal exposure to alcohol (PAE) and tobacco smoking (PTE) with brain activity in newborns. Design, Setting, and Participants:This prospective cohort study enrolled mother-newborn dyads from December 2011 through August 2015, with data analyzed from June 2018 through June 2019. Pregnant women were recruited from clinical sites in Cape Town, South Africa, and the Northern Plains region of the US. Participants were a subset of newborns enrolled in the Safe Passage Study. Exclusions included birth at less than 37 or more than 41 weeks' gestation, multiple birth, or maternal use of psychiatric medication during pregnancy. Exposures:PAE and PTE groups were determined by cluster analysis. Main Outcomes and Measures:Analyses of covariance were run on EEG spectral power at 12 scalp locations across the frequency spectrum from 1 to 45 Hz in 3-Hz bins by sleep state. Results:The final sample consisted of 1739 newborns (median [interquartile range] gestational age at birth, 39.29 [1.57] weeks; 886 [50.9%] were female; median [interquartile range] newborn age at assessment, 48.53 [44.96] hours). Newborns whose mothers were in the low continuous (95% CI, -0.379 to -0.031; P < .05; 95% CI, -0.379 to -0.045; P < .05), quit (95% CI, -0.419 to -0.127; P < .001; 95% CI, -0.398 to -0.106; P < .005), and moderate or high continuous (95% CI, -0.430 to -0.124; P < .001; 95% CI, -0.420 to -0.119; P < .005) PAE clusters had increased 4- to 6-Hz and 7- to 9-Hz left-temporal EEG power. Newborns with moderate or high continuous PTE had decreased 19- to 21-Hz (95% CI, 0.034 to 0.327; P < .05) and 22- to 24-Hz (95% CI, 0.022 to 0.316; P < .05) right-central EEG compared with newborns with no PTE. Newborns with moderate or high continuous PTE had significantly decreased 22- to 36-Hz right-central EEG power compared with the quit smoking group (22-24 Hz, 95% CI, 0.001 to 0.579; P < .05; 25-27 Hz, 95% CI, 0.008 to 0.586; P < .05; 28-30 Hz, 95% CI, 0.028 to 0.607; P < .05; 31-33 Hz, 95% CI, 0.038 to 0.617; P < .05; 34-36 Hz, 95% CI, 0.057 to 0.636; P < .05). Conclusions and Relevance:These findings suggest that even low levels of PAE or PTE are associated with changes in offspring brain development.

BACKGROUND:The identification of an early and objective marker of language impairment in autism spectrum disorder (ASD) has the potential to lead to earlier language intervention for affected children. The mismatch negativity (MMN), a passive auditory evoked potential, offers insight into the brain's ability to direct attention to novel sounds. Since exposure to speech is necessary for learning to map meaning onto phonemes, we predicted slower MMN responses to speech sounds would indicate presence of language impairment in ASD. METHODS:We explored the relationship between MMN latency in children ages 5-10 with ASD plus language impairment (ASD + LI), ASD minus language impairment (ASD-LI), and typically developing children (TD) during an auditory oddball experiment presenting speech and pure tone sounds. RESULTS:Contrary to our prediction, children with ASD + LI demonstrated decreased MMN latency in the left hemisphere in response to novel vowel sounds compared to children with ASD-LI and TD controls. Parent responses to the Sensory Experiences Questionnaire revealed that all participating individuals with ASD were hypersensitive to sounds. CONCLUSIONS:Our results lend support to the theory that some children with ASD + LI have increased connectivity in primary sensory cortices at the expense of connectivity to association areas of the brain. This may account for faster speech sound processing despite low language scores in these children. Future studies should focus on individuals with language impairment and hyper-or hyposensitivity to sounds.

The vast individual differences in the developmental origins of risk and resilience pathways combined with sophisticated capabilities of big data science increasingly point to the imperative of large, neurodevelopmental consortia to capture population heterogeneity and key variations in developmental trajectories. At the same time, such large-scale population-based designs involving multiple independent sites also must weigh competing demands. For example, the need for efficient, scalable assessment strategies must be balanced with the need for nuanced, developmentally sensitive phenotyping optimized for linkage to neural mechanisms and specification of common and distinct exposure pathways. Standardized epidemiologic batteries designed for this purpose such as PhenX (consensus measures for Phenotypes and eXposures) and the National Institutes of Health (NIH) Toolbox provide excellent "off the shelf" assessment tools that are well-validated and enable cross-study comparability. However, these standardized toolkits can also constrain ability to leverage advances in neurodevelopmental measurement over time, at times disproportionately advantaging established measures. In addition, individual consortia often expend exhaustive effort "reinventing the wheel," which is inefficient and fails to fully maximize potential synergies with other like initiatives. To address these issues, this paper lays forth an early childhood neurodevelopmental assessment strategy, guided by a set of principles synthesizing developmental and pragmatic considerations generated by the Neurodevelopmental Workgroup of the HEALthy Brain and Child Development (HBCD) Planning Consortium. These principles emphasize characterization of both risk- and resilience-promoting processes. Specific measurement recommendations to HBCD are provided to illustrate application. However, principles are intended as a guiding framework to transcend any particular initiative as a broad neurodevelopmentally informed, early childhood assessment strategy for large-scale consortia science.

OBJECTIVE:To determine normative values for heart rate patterns in healthy fetuses. METHODS:This research is from the Safe Passage Study conducted by the Prenatal Alcohol and SIDS and Stillbirth (PASS) Network. A standardized protocol assessed fetal heart rate (FHR), heart rate variability (HRV), and movement from 1655 fetuses at three-time points during gestation (20-24 weeks, 28-32 weeks, 34-38 weeks gestation). RESULTS:FHR decreased while HRV increased over gestation. At the latter two ages, males had significantly lower FHR than females while there were no sex differences in FHR at 20-24 weeks. When accounting for the fetal state during late gestation (34-28 weeks), we found that males had significantly lower FHR than females in the active fetal state only. CONCLUSION:Results demonstrate significant state, gestational age, and sex-related changes in cardiac activity, somatic activity, and autonomic function as the fetus approaches birth.

Characterization of patterns of alcohol consumption during pregnancy encompasses multiple factors such as magnitude, frequency, and timing of exposure throughout gestation. Traditional statistical models are limited in dealing with multivariate and diverse patterns of exposure as in the context of this analysis. We propose a finite mixture model-based approach to derive clusters of alcohol exposure of participants in the Safe Passage Study (PASS). Daily alcohol consumption data for 11,083 pregnant women have been clustered in 10 different exposed groups. The resulting cluster analysis was able to characterize alcohol consumption in a comprehensive framework capable of taking into account both quantity and timing of exposure as well as the occurrence of binge drinking.

Although electrophysiological (electroencephalography) measures of executive functions (e.g. error monitoring) have been used to predict academic achievement in typically developing children, work investigating a link between error monitoring and academic skills in children with autism spectrum disorder is limited. In this study, we employed traditional electrophysiological and advanced time-frequency methods, combined with principal component analyses, to extract neural activity related to error monitoring and tested their relations to academic achievement in cognitively able kindergarteners with autism spectrum disorder. In total, 35 cognitively able kindergarteners with autism spectrum disorder completed academic assessments and the child-friendly "Zoo Game" Go/No-go task at school entry. The Go/No-go task successfully elicited an error-related negativity and error positivity in children with autism spectrum disorder as young as 5 years at fronto-central and posterior electrode sites, respectively. We also observed increased response-related theta power during errors relative to correct trials at fronto-central sites. Both larger error positivity and theta power significantly predicted concurrent academic achievement after controlling for behavioral performance on the Zoo Game and intelligence quotient. These results suggest that the use of time-frequency electroencephalography analyses, combined with traditional event-related potential measures, may provide new opportunities to investigate neurobiological mechanisms of executive function and academic achievement in young children with autism spectrum disorder.

Research using electroencephalography (EEG) as a measure of brain function and maturation has demonstrated links between cortical activity and cognitive processes during infancy and early childhood. The current study examines whether neonatal EEG is correlated with later atypical socioemotional behaviors or neurocognitive delays. Parental report developmental assessments were administered to families with children ages 24 to 36 months who had previously participated in a neonatal EEG study (N = 129). Significant associations were found between neonatal EEG (higher frequencies in the frontal polar, temporal, and parietal brain regions) and BITSEA ASD risk scores. Infants with lower EEG power in these brain areas were more likely to have higher risk of socioemotional problems. When examining sex differences, significant links were found for males but not for females. These results demonstrate some promising associations between early neural biomarkers and later risk for atypical behaviors, which may shape early neurobehavioral development and could lead to earlier identification and intervention.

High-density electroencephalography (EEG) was used to examine the utility of the P1 event-related potential (ERP) as a marker of visual motion sensitivity to luminance defined low-spatial frequency drifting gratings in 16 children with autism and 16 neurotypical children. Children with autism displayed enhanced sensitivity to large, high-contrast low-spatial frequency stimuli as indexed by significantly shorter P1 response latencies to large vs. small gratings. The current study also found that children with autism had larger amplitude responses to large gratings irrespective of contrast. A linear regression established that P1 adaptive mean amplitude for large, high-contrast sinusoidal gratings significantly predicted hyperresponsiveness item mean scores on the Sensory Experiences Questionnaire for children with autism, but not for neurotypical children. We conclude that children with autism have differences in the mechanisms that underlie low-level visual processing potentially related to altered visual spatial suppression or contrast gain control.