Faculty Bibliography

Magnetic resonance imaging, histological, and gene analysis approaches in living and nonliving human fetuses and in prematurely born neonates have provided insight into the staged processes of prenatal brain development. Increased understanding of micro- and macroscale brain network development before birth has spurred interest in understanding the relevance of prenatal brain development to common neurological diseases. Questions abound as to the sensitivity of the intrauterine brain to environmental programming, to windows of plasticity, and to the prenatal origin of disorders of childhood that involve disruptions in large-scale network connectivity. Much of the available literature on human prenatal neural development comes from cross-sectional or case studies that are not able to resolve the longitudinal consequences of individual variation in brain development before birth. This review will 1) detail specific methodologies for studying the human prenatal brain, 2) summarize large-scale human prenatal neural network development, integrating findings from across a variety of experimental approaches, 3) explore the plasticity of the early developing brain as well as potential sex differences in prenatal susceptibility, and 4) evaluate opportunities to link specific prenatal brain developmental processes to the forms of aberrant neural connectivity that underlie common neurological disorders of childhood.

Since the first neurodevelopmental models that sought to explain the influx of risky behaviors during adolescence were proposed, there have been a number of revisions, variations and criticisms. Despite providing a strong multi-disciplinary heuristic to explain the development of risk behavior, extant models have not yet reliably isolated neural systems that underlie risk behaviors in adolescence. To address this gap, we screened 2017 adolescents from an ongoing longitudinal study that assessed 15-health risk behaviors, targeting 104 adolescents (Age Range: 17-to-21.4), characterized as high-or-average/low risk-taking. Participants completed the Monetary Incentive Delay (MID) fMRI task, examining reward anticipation to "big win" versus "neutral". We examined neural response variation associated with both baseline and longitudinal (multi-wave) risk classifications. Analyses included examination of a priori regions of interest (ROIs); and exploratory non-parametric, whole-brain analyses. Hypothesis-driven ROI analysis revealed no significant differences between high- and average/low-risk profiles using either baseline or multi-wave classification. Results of whole-brain analyses differed according to whether risk assessment was based on baseline or multi-wave data. Despite significant mean-level task activation, these results do not generalize prior neural substrates implicated in reward anticipation and adolescent risk-taking. Further, these data indicate that whole-brain differences may depend on how risk-behavior profiles are defined.

Childhood trauma is associated with many long-term negative outcomes, and is not limited to the individual experiencing the trauma, but extends to subsequent generations. However, mechanisms underlying the association between maternal childhood trauma and child psychopathology are not well understood. Here, we targeted frontal alpha asymmetry (FAA) as a potential underlying factor of the relationship between maternal childhood trauma and child behavioral problems. Electroencephalography (EEG) was recorded from (N = 45) children (Mean age = 57.9 months, SD = 3.13) during an eyes-closed paradigm in order to evaluate FAA. Mothers reported on their childhood trauma experiences using the Childhood Trauma Questionnaire (CTQ), and on their child's behavior using the child behavior checklist (CBCL). We found that maternal childhood trauma significantly predicted child total, internalizing, and externalizing behavior at age 5 years. We also observed a role for FAA such that it acted as a moderator, but not mediator, for behavioral problems. We found that children with relative more right/less left frontal activity were more at risk to develop behavioral problems when their mother had been exposed to trauma in her childhood. These results indicate that child frontal asymmetry may serve as a susceptibility marker for child behavioral problems.

Large-scale functional connectome formation and re-organization is apparent in the second trimester of pregnancy, making it a crucial and vulnerable time window in connectome development. Here we identified which architectural principles of functional connectome organization are initiated prior to birth, and contrast those with topological characteristics observed in the mature adult brain. A sample of 105 pregnant women participated in human fetal resting-state fMRI studies (fetal gestational age between 20 and 40 weeks). Connectome analysis was used to analyze weighted network characteristics of fetal macroscale brain wiring. We identified efficient network attributes, common functional modules and high overlap between the fetal and adult brain network. Our results indicate that key features of the functional connectome are present in the second and third trimesters of pregnancy. Understanding the organizational principles of fetal connectome organization may bring opportunities to develop markers for early detection of alterations of brain function.SIGNIFICANCE STATEMENTThe fetal to neonatal period is well known as a critical stage in brain development. Rapid neurodevelopmental processes establish key functional neural circuits of the human brain. Prenatal risk factors may interfere with early trajectories of connectome formation and thereby shape future health outcomes. Recent advances in MRI have made it possible to examine fetal brain functional connectivity. In this study, we evaluate the network topography of normative functional network development during connectome genesis in utero Understanding the developmental trajectory of brain connectivity provides a basis for understanding how the prenatal period shapes future brain function and disease dysfunction.

This study describes maternal and infant contributions to dyadic affective exchanges during the Still-Face Paradigm (SFP) in an understudied mostly low-income sample. One hundred eleven mothers and their 7-month-old infants were videotaped during the SFP to analyze how a social stressor affects mother-infant positive and negative affective exchanges during interaction. The SFP includes 3 episodes: baseline, maternal still-face, and reunion. Maternal and infant positive and negative affect were scored by masked reliable coders. Data were analyzed using the Actor-Partner Interdependence Model to test the hypotheses that each partner's affectivity during the baseline episode would predict their own affectivity during the reunion episode (actor effects). We also expected that each partner's affectivity during the baseline episode would influence the other partner's affectivity during the reunion episodes (partner effects). After controlling for infant sex and maternal education, results provided evidence for actor effects for maternal and infant positive affect, and for partner effects for maternal baseline positive affect to infant positive affect during the reunion. One significant partner effect was observed for negative affect: Infant negativity during baseline predicted greater maternal negativity during reunion. Findings confirm that both mothers and infants contribute to dyadic affective processes during the SFP but specific findings vary depending on the affective valence in question. Clinical implications and future research are discussed.

Background and aims.- Prevalence of psychiatric disorders differs in males and females, and neurological studies suggest that sex-linked variation in the brain may underlie this dissociation. However, the origin of this difference, and how early in human life sexual dimorphism in brain function emerges is a topic that requires further investigation. Here, we address this gap by assessing brain resting-state functional connectivity (RSFC) between and within brain networks as it relates to fetal sex and gestational age (GA). Methods.- We examined 118 typical human fetuses (70 male; 48 female) between 25.9 and 39.6 weeks GA. Infomap was used to derive 16 separable fetal neural networks distributed across cortical, subcortical, and cerebellar regions. Using enrichment analysis, we identified network pairs revealing distinct patterns of GArelated change in males and females. Results.- Sex-dependent variation of between- and within- network RSFC-GA associations was observed: while females exhibited GA-related variation in connectivity between posterior cingulate and temporal pole regions, and between pre-frontal and cerebellar regions, males demonstrated increased intracerebellar RSFC with advancing age. Conclusions.- Such observations confirm that sex-related differences in functional brain development are present before birth. An important next step in this line of research will be to follow children across early development and discover how sex-related variation in network development relates to future health outcomes

Lead represents a highly prevalent metal toxicant with potential to alter human biology in lasting ways. A population segment that is particularly vulnerable to the negative consequences of lead exposure is the human fetus, as exposure events occurring before birth are linked to varied and long-ranging negative health and behavioral outcomes. An area that has yet to be addressed is the potential that lead exposure during pregnancy alters brain development even before an individual is born. Here, we combine prenatal lead exposure information extracted from newborn bloodspots with the human fetal brain functional MRI data to assess whether neural network connectivity differs between lead-exposed and lead-naïve fetuses. We found that neural connectivity patterns differed in lead-exposed and comparison groups such that fetuses that were not exposed demonstrated stronger age-related increases in cross-hemispheric connectivity, while the lead-exposed group demonstrated stronger age-related increases in posterior cingulate cortex (PCC) to lateral prefrontal cortex (PFC) connectivity. These are the first results to demonstrate metal toxicant-related alterations in human fetal neural connectivity. Remarkably, the findings point to alterations in systems that support higher-order cognitive and regulatory functions. Objectives for future work are to replicate these results in larger samples and to test the possibility that these alterations may account for significant variation in future child cognitive and behavioral outcomes.