Acute stress shifts the brain into a state that fosters rapid defense mechanisms. Stress-related neuromodulators are thought to trigger this change by altering properties of large-scale neural populations throughout the brain. We investigated this brain-state shift in humans. During exposure to a fear-related acute stressor, responsiveness and interconnectivity within a network including cortical (frontoinsular, dorsal anterior cingulate, inferotemporal, and temporoparietal) and subcortical (amygdala, thalamus, hypothalamus, and midbrain) regions increased as a function of stress response magnitudes. β-adrenergic receptor blockade, but not cortisol synthesis inhibition, diminished this increase. Thus, our findings reveal that noradrenergic activation during acute stress results in prolonged coupling within a distributed network that integrates information exchange between regions involved in autonomic-neuroendocrine control and vigilant attentional reorienting.

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Background Early childhood anxiety has been linked to an increased risk for developing mood and anxiety disorders. Little, however, is known about its effect on the brain during early childhood – a period when anxiety-related traits begin to be reliably identifiable. Even less is known about the neurodevelopmental origins of individual differences in childhood anxiety. Methods We combined structural and functional magnetic resonance imaging (fMRI) with neuropsychological assessment of anxiety based on daily life experiences to investigate the effects of anxiety on the brain in seventy-six young children. We then used machine learning algorithms with balanced cross-validation to examine brain-based predictors of individual differences in childhood anxiety. Results Even in children as young as ages 7–9, high childhood anxiety is associated with enlarged amygdala volume and this enlargement is localized specifically to the basolateral amygdala. High childhood anxiety is also associated with increased connectivity between the amygdala and distributed brain systems involved in attention, emotion perception and regulation, and these effects are most prominent effect in basolateral amygdala. Critically, machine learning algorithms revealed that levels of childhood anxiety could be reliably predicted by amygdala morphometry and intrinsic functional connectivity, with the left basolateral amygdala emerging again as the strongest predictor. Conclusions Individual differences in anxiety can be reliably detected with high predictive value in amygdala-centric emotion circuits at a surprisingly young age. Our study provides important new insights into the neurodevelopmental origins of anxiety, and has significant implications for the development of predictive biomarkers to identify children at-risk for anxiety disorders.

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The importance of the hippocampal system for rapid learning and memory is well recognized, but its contributions to a cardinal feature of children's cognitive development – the transition from procedure-based to memory-based problem solving strategies – are unknown. Here we show that the hippocampal system is pivotal to this strategic transition. Longitudinal fMRI in children, ages 7 to 9, revealed that the transition from use of counting to memory-based retrieval parallels increased hippocampal and decreased prefrontal-parietal engagement during arithmetic problem solving. Critically, longitudinal improvements in retrieval strategy use were predicted by increased hippocampal-neocortical functional connectivity. Beyond childhood, retrieval strategy use continued to improve through adolescence into adulthood, and was associated with decreased activation but more stable inter-problem representations in the hippocampus. Our findings provide novel insights into the dynamic role of the hippocampus in the maturation of memory-based problem solving, and establish a critical link between hippocampal-neocortical reorganization and children's cognitive development.

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The human brain undergoes protracted development, with dramatic changes in expression and regulation of emotion from childhood to adulthood. The amygdala is a brain structure that plays a pivotal role in emotion-related functions. Investigating developmental characteristics of the amygdala and associated functional circuits in children is important for understanding how emotion processing matures in the developing brain. The basolateral amygdala (BLA) and centromedial amygdala (CMA) are two major amygdalar nuclei that contribute to distinct functions via their unique pattern of interactions with cortical and subcortical regions. Almost nothing is currently known about the maturation of functional circuits associated with these amygdala nuclei in the developing brain. Using intrinsic connectivity analysis of functional magnetic resonance imaging data, we investigated developmental changes in functional connectivity of the BLA and CMA in twenty-four 7-to 9-y-old typically developing children compared with twenty-four 19-to 22-y-old healthy adults. Children showed significantly weaker intrinsic functional connectivity of the amygdala with subcortical, paralimbic, and limbic structures, polymodal association, and ventromedial prefrontal cortex. Importantly, target networks associated with the BLA and CMA exhibited greater overlap and weaker dissociation in children. In line with this finding, children showed greater intraamygdala connectivity between the BLA and CMA. Critically, these developmental differences were reproducibly identified in a second independent cohort of adults and children. Taken together, our findings point toward weak integration and segregation of amygdala circuits in young children. These immature patterns of amygdala connectivity have important implications for understanding typical and atypical development of emotion-related brain circuitry. F rom childhood to adulthood, the development of functional brain networks underlies the maturation of increasingly nuanced cognitive and affective abilities (1, 2). In particular, human capabilities for a wide range of affective functions change dramatically from childhood to adulthood, suggesting remarkable maturation of the brain's affective systems. The amygdala lies at the core of brain's affective processing systems (3, 4) and multiple lines of research in human adults have implicated amygdala-centered networks in emotion (5-7). The amygdalar complex encompasses multiple anatomical subregions with distinct connectivity profiles that support distinct affective functions (3,8). However, almost nothing is known about how networks associated with the amygdala mature with development. Knowledge of how major amygdalar circuits mature in children is important not only for gaining insights into typical development of affective functions, but also for understanding the ontogeny of affective dysfunction in disorders such as anxiety and depression (9, 10).The basolateral amygdala (BLA) and centromedial amygdala (CMA) are two major groups of amygdalar nuclei t...

Acute psychological stress can trigger normal and abnormal motivated behaviors such as reward seeking, habitual behavior, and drug craving. Animal research suggests that such effects may result from actions of catecholamines and glucocorticoids that converge in brain regions that regulate motivated behaviors and incentive processing. At present, however, little is known about the acute effects of stress on these circuits in humans. During functional magnetic resonance imaging (fMRI), twenty-seven healthy young women performed a modified version of the monetary incentive delay (MID) task, which is known to robustly engage ventral striatal and medial prefrontal regions. To induce psychological stress, strongly aversive movie clips (versus neutral movie clips) were shown with the instruction to imagine being an eyewitness. Physiological (cortisol levels, heart rate frequency, and heart rate variability) and subjective measurements confirmed successful induction of moderate levels of acute psychological stress. Brain imaging data revealed that stress induction resulted in a significant decrease in reward-related responses in the medial prefrontal cortex (PFC) without affecting ventral striatal responses. Our results thus show that acute psychological stress induces regionally specific changes in functioning of incentive processing circuits. This regional specificity is in line with animal data showing inverted U-shaped relations between levels of stress-related neuromodulators and functioning of the PFC, a structure that is believed to be critical for coordinating behavior in accordance with higher order internal goals. Our findings thus suggest that stress-related increases in habitual and reward-seeking behaviors may be triggered primarily by an impairment of such PFC-dependent cognitive control mechanisms.