Faculty Bibliography

Advances in neuroimaging and network analyses have lead to discovery of highly connected regions, or hubs, in the connectional architecture of the human brain. Whether these hubs emerge in utero, has yet to be examined. The current study addresses this question and aims to determine the location of neural hubs in human fetuses. Fetal resting-state fMRI data (N = 105) was used to construct connectivity matrices for 197 discrete brain regions. We discovered that within the connectional functional organization of the human fetal brain key hubs are emerging. Consistent with prior reports in infants, visual and motor regions were identified as emerging hub areas, specifically in cerebellar areas. We also found evidence for network hubs in association cortex, including areas remarkably close to the adult fusiform facial and Wernicke areas. Functional significance of hub structure was confirmed by computationally deleting hub versus random nodes and observing that global efficiency decreased significantly more when hubs were removed (p < .001). Taken together, we conclude that both primary and association brain regions demonstrate centrality in network organization before birth. While fetal hubs may be important for facilitating network communication, they may also form potential points of vulnerability in fetal brain development.

Early brain activity is crucial for neurogenesis and the development of brain networks. However, it has been challenging to localize regions in the developing human brain that contribute to spontaneous waves of neuronal activity. Recently, Arichi and colleagues reported that the temporal and heteromodal insular cortices have a central role in propagating these neural instructional signals.

Increased resting-state functional connectivity (rsFC) between the default mode network (DMN) and subgenual anterior cingulate cortex (sgACC) is consistently reported in adults and youth with psychopathologies related to affect dysregulation (e.g. depression, posttraumatic stress disorder). This pattern of increased rsFC is thought to underlie ruminative thought patterns through integration of negative affect (via sgACC) into self-referential operations supported by the DMN. Neurobiological studies in adults show that behavioral activation system (BAS) sensitivity is a potential protective factor against the development of psychopathology, particularly in the context of stress and trauma exposure. However, whether BAS sensitivity is associated with variation in DMN-sgACC stress-vulnerability circuitry in youth, particularly those at risk for affect dysregulation, has not yet been studied. This association was tested in a sample of ninety-eight children and adolescents (ages 6-17) at high sociodemographic risk for psychopathology (i.e., urban, lower income, high frequency of violence and abuse exposure). Participants underwent a six-minute resting-state functional magnetic resonance imaging scan. Using a targeted, small-volume corrected approach, we found that youth with higher BAS sensitivity demonstrated lower DMN-sgACC rsFC, suggesting a potential link between the purported protective effects of BAS sensitivity and stress-vulnerability circuitry. This work suggests that interventions that augment BAS sensitivity, such as behavioral activation therapy, may protect against the development of stress-related psychopathology by modifying a critical rumination circuitry in the brain. Such interventions may be especially important for bolstering resiliency in at-risk urban youth, who are disproportionately burdened by early stress and associated psychopathology.

BACKGROUND:Preclinical data suggest that early life stress has detrimental effects on the brain's dopaminergic system, particularly the mesocorticolimbic pathway. Altered dopamine function is thought to contribute to the development of stress-related pathologies; yet, little is known about the impact of early stress on dopamine systems during childhood and adolescence, when stress-related disorders frequently emerge. Here, we evaluate the impact of early threat exposure (violence, abuse) on functional connectivity of putative dopaminergic midbrain regions, the ventral tegmental area (VTA) and substantia nigra (SN), giving rise to mesocorticolimbic and nigrostriatal pathways, respectively. METHODS:Resting-state functional magnetic resonance imaging scans were completed in 43 trauma-exposed and 43 matched comparison youth (ages 7-17). Functional connectivity of the VTA and SN were compared between groups. RESULTS:The trauma group demonstrated lower functional connectivity between the VTA and hippocampus. No group differences in SN connectivity were observed. Across all participants, there were age-related decreases in connectivity of both VTA and SN with the hippocampus, suggesting that age-related attenuations in VTA-hippocampal circuitry may be exacerbated in trauma-exposed youth. Higher levels of anxiety symptomology were associated with reduced SN-nucleus accumbens connectivity. CONCLUSIONS:Prior research suggests that VTA-hippocampal circuitry is critical for the gating of new information into long-term memory. Lower connectivity in this circuitry suggests a novel mechanism that may serve to adaptively prevent the overwriting of a previously stored trauma memory, but at the same time contribute to the broad range of cognitive and emotional difficulties linked to early stress exposure.

Traumatic experiences early in life predispose animals and humans to later cognitive-behavioral, emotional, and somatic problems. In humans, traumatic experiences are strong predictors of psychiatric illness. A growing body of research has emphasized alterations in neurological structure and function that underscore phenotypic changes following trauma. However, results are mixed and imprecise. We argue that future translation of neurological findings to clinical practice will require: (1) discovery of neurobehavioral associations within a longitudinal context, (2) dissociation of trauma types and of trauma versus chronic stress, and (3) better localization of neural sequelae considerate of the fine resolution of neural circuitry. We provide a brief overview of early brain development and highlight the role of longitudinal research in unearthing brain-behavior relations in youth. We relay an emergent framework in which dissociable trauma types are hypothesized to impact distinct, rationally informed neural systems. In line with this, we discuss the long-standing challenge of separating effects of chronic stress and trauma, as these are often intertwined. We bring to light inconsistencies in localization of neural correlates of trauma, emphasizing results in medial prefrontal regions. We assert that more precise spatial brain localization will help to advance prevailing models of trauma pathways and inform future research.

It has been suggested that neurological problems more frequent in those born preterm are expressed prior to birth, but owing to technical limitations, this has been difficult to test in humans. We applied novel fetal resting-state functional MRI to measure brain function in 32 human fetuses in utero and found that systems-level neural functional connectivity was diminished in fetuses that would subsequently be born preterm. Neural connectivity was reduced in a left-hemisphere pre-language region, and the degree to which connectivity of this left language region extended to right-hemisphere homologs was positively associated with the time elapsed between fMRI assessment and delivery. These results provide the first evidence that altered functional connectivity in the preterm brain is identifiable before birth. They suggest that neurodevelopmental disorders associated with preterm birth may result from neurological insults that begin in utero.

The human brain is highly dynamic, supporting a remarkable range of cognitive abilities that emerge over the course of development. While flexible and dynamic coordination between neural systems is firmly established for children, our understanding of brain functional organization in early life has been built largely on the implicit assumption that functional connectivity (FC) is static. Understanding the nature of dynamic neural interactions during development is a critical issue for cognitive neuroscience, with implications for neurodevelopmental pathologies that involve anomalies in brain connectivity. In this work, FC dynamics of neurocognitive networks in a sample of 146 youth from varied sociodemographic backgrounds were delineated. Independent component analysis, sliding time window correlation, and k-means clustering were applied to resting-state fMRI data. Results revealed six dynamic FC states that re-occur over time and that complement, but significantly extend, measures of static FC. Moreover, the occurrence and amount of time spent in specific FC states are related to the content of self-generated thought during the scan. Additionally, some connections are more variable over time than are others, including those between inferior parietal lobe and precuneus. These regions contribute to multiple networks and likely play a role in adaptive processes in childhood. Age-related increases in temporal variability of FC among neurocognitive networks were also found. Taken together, these findings lay the groundwork for understanding how variation in the developing chronnectome is related to risk for neurodevelopmental disorders. Understanding how brain systems reconfigure with development should provide insight into the ontogeny of complex, flexible cognitive processes. Hum Brain Mapp 38:97-108, 2017. © 2016 Wiley Periodicals, Inc.

The brain is subject to dramatic developmental processes during the prenatal period. Nevertheless, information about the development of functional brain networks during gestation is scarce. Until recently it has not been possible to probe function in the living human fetal brain. Advances in functional MRI have changed the paradigm, making it possible to measure spontaneous activity in the fetal brain and to cross-correlate functional signals to attain information about neural connectional architecture across human gestation. We summarize the earliest MRI studies of fetal neural functional connectivity and highlight unique challenges and limitations inherent in the technique. In addition, we discuss future directions to unlock the potential of fetal brain functional MRI research.

Childhood trauma is a major precipitating factor in psychiatric disease. Emerging data suggest that stress susceptibility is genetically determined, and that risk is mediated by changes in limbic brain circuitry. There is a need to identify markers of disease vulnerability, and it is critical that these markers be investigated in childhood and adolescence, a time when neural networks are particularly malleable and when psychiatric disorders frequently emerge. In this preliminary study, we evaluated whether a common variant in the brain-derived neurotrophic factor (BDNF) gene (Val66Met; rs6265) interacts with childhood trauma to predict limbic gray matter volume in a sample of 55 youth high in sociodemographic risk. We found trauma-by-BDNF interactions in the right subcallosal area and right hippocampus, wherein BDNF-related gray matter changes were evident in youth without histories of trauma. In youth without trauma exposure, lower hippocampal volume was related to higher symptoms of anxiety. These data provide preliminary evidence for a contribution of a common BDNF gene variant to the neural correlates of childhood trauma among high-risk urban youth. Altered limbic structure in early life may lay the foundation for longer term patterns of neural dysfunction, and hold implications for understanding the psychiatric and psychobiological consequences of traumatic stress on the developing brain.