Faculty Bibliography

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.

Depression, anxiety, and posttraumatic stress disorder are linked to altered limbic morphology, dysregulated neuroendocrine function, and heightened amygdala responses to salient social cues. Oxytocin appears to be a potent modulator of amygdala reactivity and neuroendocrine responses to psychosocial stress. Given these stress regulatory effects, there is increasing interest in understanding the role of oxytocin in vulnerability to stress-related clinical disorders. The present study examines the impact of a common functional variant within the oxytocin receptor (OXTR) gene (rs2254298) on structure and function of the amygdala in a high-risk sample of urban, low-income, minority youth with a high incidence of early life stress (ELS). Compared to G/G homozygotes, youth carrying the OXTR A-allele showed increased amygdala volume, reduced behavioral performance, and heightened amygdala response during two functional magnetic resonance imaging (fMRI) tasks that involved viewing socially-relevant face stimuli. Higher amygdala response was related to ELS in A-allele carriers but not G/G homozygotes. These findings underscore a series of relations among a common oxytocin system gene variant, ELS exposure, and structure and function of the amygdala in early life. Heightened amygdala response to salient social cues in OXTR A-allele carriers may elevate risk for emotional psychopathology by increasing amygdala involvement in disambiguating environmental cues, particularly for individuals with ELS.

Early life trauma exposure represents a potent risk factor for the development of mental illnesses such as anxiety, depression and post-traumatic stress disorder. Moreover, deleterious consequences of trauma are exacerbated in youth living in impoverished, urban environments. A priori probability maps were used to examine resting-state functional connectivity (FC) of the amygdala in 21 trauma-exposed, and 21 age- and sex-matched urban children and adolescents (youth) without histories of trauma. Intrinsic FC analyses focused on amygdala-medial prefrontal circuitry, a key emotion regulatory pathway in the brain. We discovered reduced negative amygdala-subgenual cingulate connectivity in trauma-exposed youth. Differences between groups were also identified in anterior insula and dorsal anterior cingulate to amygdala connectivity. Overall, results suggest a model in which urban-dwelling trauma-exposed youth lack negative prefrontal to amygdala connectivity that may be critical for regulation of emotional responses. Functional changes in amygdala circuitry might reflect the biological embedding of stress reactivity in early life and mediate enhanced vulnerability to stress-related psychopathology.

OBJECTIVE:Behavioral inhibition (BI) is an early developing trait associated with cautiousness and development of clinical depression and anxiety. Little is known about the neural basis of BI and its predictive importance concerning risk for internalizing disorders. We looked at functional connectivity of the default-mode network (DMN) and salience network (SN), given their respective roles in self-relational and threat processing, in the risk for internalizing disorders, with an emphasis on determining the functional significance of these networks for BI. METHOD/METHODS:We used functional magnetic resonance imaging to scan, during the resting state, children and adolescents 8 to 17 years of age who were either at high familial risk (HR; n = 16) or low familial risk (LR; n = 18) for developing clinical depression and/or anxiety. Whole-brain DMN and SN functional connectivity were estimated for each participant and compared across groups. We also compared the LR and HR groups on levels of BI and anxiety, and incorporated these data into follow-up neurobehavioral correlation analyses. RESULTS:The HR group, relative to the LR group, showed significantly decreased DMN connectivity with the ventral striatum and bilateral sensorimotor cortices. Within the HR group, trait BI increased as DMN connectivity with the ventral striatum and sensorimotor cortex decreased. The HR and LR groups did not differ with respect to SN connectivity. CONCLUSION/CONCLUSIONS:Our findings show, in the risk for internalizing disorders, a negative functional relation between brain regions supporting self-relational processes and reward prediction. These findings represent a potential neural substrate for behavioral inhibition in the risk for clinical depression and anxiety.

Early-life trauma is one of the strongest risk factors for later emotional psychopathology. Although research in adults highlights that childhood trauma predicts deficits in emotion regulation that persist decades later, it is unknown whether neural and behavioral changes that may precipitate illness are evident during formative, developmental years. This study examined whether automatic regulation of emotional conflict is perturbed in a high-risk urban sample of trauma-exposed children and adolescents. A total of 14 trauma-exposed and 16 age-, sex-, and IQ-matched comparison youth underwent functional MRI while performing an emotional conflict task that involved categorizing facial affect while ignoring an overlying emotion word. Engagement of the conflict regulation system was evaluated at neural and behavioral levels. Results showed that trauma-exposed youth failed to dampen dorsolateral prefrontal cortex activity and engage amygdala-pregenual cingulate inhibitory circuitry during the regulation of emotional conflict, and were less able to regulate emotional conflict. In addition, trauma-exposed youth showed greater conflict-related amygdala reactivity that was associated with diminished levels of trait reward sensitivity. These data point to a trauma-related deficit in automatic regulation of emotional processing, and increase in sensitivity to emotional conflict in neural systems implicated in threat detection. Aberrant amygdala response to emotional conflict was related to diminished reward sensitivity that is emerging as a critical stress-susceptibility trait that may contribute to the emergence of mental illness during adolescence. These results suggest that deficits in conflict regulation for emotional material may underlie heightened risk for psychopathology in individuals that endure early-life trauma.