Microstate Analysis of Continuous Infant EEG: Tutorial and Reliability.

Microstate analysis of resting-state EEG is a unique data-driven method for identifying patterns of scalp potential topographies, or microstates, that reflect stable but transient periods of synchronized neural activity evolving dynamically over time. During infancy - a critical period of rapid brain development and plasticity - microstate analysis offers a unique opportunity for characterizing the spatial and temporal dynamics of brain activity. However, whether measurements derived from this approach (e.g., temporal properties, transition probabilities, neural sources) show strong psychometric properties (i.e., reliability) during infancy is unknown and key information for advancing our understanding of how microstates are shaped by early life experiences and whether they relate to individual differences in infant abilities. A lack of methodological resources for performing microstate analysis of infant EEG has further hindered adoption of this cutting-edge approach by infant researchers. As a result, in the current study, we systematically addressed these knowledge gaps and report that most microstate-based measurements of brain organization and functioning except for transition probabilities were stable with four minutes of video-watching resting-state data and highly internally consistent with just one minute. In addition to these results, we provide a step-by-step tutorial, accompanying website, and open-access data for performing microstate analysis using a free, user-friendly software called Cartool. Taken together, the current study supports the reliability and feasibility of using EEG microstate analysis to study infant brain development and increases the accessibility of this approach for the field of developmental neuroscience.

Exploring the Association Between EEG Microstates During Resting-State and Error-Related Activity in Young Children.

The error-related negativity (ERN) is a negative deflection in the electroencephalography (EEG) waveform at frontal-central scalp sites that occurs after error commission. The relationship between the ERN and broader patterns of brain activity measured across the entire scalp that support error processing during early childhood is unclear. We examined the relationship between the ERN and EEG microstates - whole-brain patterns of dynamically evolving scalp potential topographies that reflect periods of synchronized neural activity - during both a go/no-go task and resting-state in 90, 4-8-year-old children. The mean amplitude of the ERN was quantified during the -64 to 108 millisecond (ms) period of time relative to error commission, which was determined by data-driven microstate segmentation of error-related activity. We found that greater magnitude of the ERN associated with greater global explained variance (GEV; i.e., the percentage of total variance in the data explained by a given microstate) of an error-related microstate observed during the same -64 to 108 ms period (i.e., error-related microstate 3), and to greater anxiety risk as measured by parent-reported behavioral inhibition. During resting-state, six data-driven microstates were identified. Both greater magnitude of the ERN and greater GEV values of error-related microstate 3 associated with greater GEV values of resting-state microstate 4, which showed a frontal-central scalp topography. Source localization results revealed overlap between the underlying neural generators of error-related microstate 3 and resting-state microstate 4 and canonical brain networks (e.g., ventral attention) known to support the higher-order cognitive processes involved in error processing. Taken together, our results clarify how individual differences in error-related and intrinsic brain activity are related and enhance our understanding of developing brain network function and organization supporting error processing during early childhood.

Electrical brain activations in young children during a probabilistic reward-learning task are associated with behavioral strategy.

Both adults and children learn through feedback which events and choices in the environment are associated with higher probability of reward. This probability reward-learning ability is thought to be supported by the development of fronto-striatal reward circuits. Recent developmental studies have applied computational models of reward learning to investigate such learning in children. However, there has been limited development of task tools capable of measuring the cascade of neural reward-learning processes in children. Using a child-version of a probabilistic reward-learning task while recording event-related-potential (ERP) measures of electrical brain activity, this study examined key processes of reward learning in preadolescents (n=30), namely: (1) reward-feedback sensitivity, as measured by the early reward-related frontal ERP positivity, (2) rapid attentional shifting of processing toward favored visual stimuli, as measured by the N2pc component, and (3) longer-latency attention-related responses to reward feedback as a function of behavior strategies (i.e., Win-Stay-Lose-Shift), as measured by the central-parietal P300. Consistent with our prior work in adults, the behavioral findings indicate that preadolescents could learn stimulus-reward outcome associations, but at varying levels of performance. Neurally, poor preadolescent learners (those with slower learning rates) showed greater reward-related positivity amplitudes relative to good learners, suggesting greater reward sensitivity. We also found attention shifting towards to-be-chosen stimuli, as evidenced by the N2pc, but not to more highly rewarded stimuli. Lastly, we found an effect of behavioral learning strategies (i.e., Win-Stay-Lose-Shift) on the feedback-locked P300 over the parietal cortex. These findings provide novel insights into the key neural processes underlying reinforcement learning in preadolescents.

Associations between pre-pandemic authoritative parenting, pandemic stressors, and children's depression and anxiety at the initial stage of the COVID-19 pandemic.

Large-scale changes due to the Novel Coronavirus (COVID-19) pandemic negatively affected children's mental health. Prior research suggests that children's mental health problems during the pandemic may have been concurrently attenuated by an authoritative parenting style and exacerbated by family stress. However, there is a gap in the literature investigating these mechanisms and whether pre-pandemic authoritative parenting had a lasting positive influence on children's mental health while they were exposed to pandemic-related family stressors. The current study begins to fill this gap by investigating these unique relationships in a sample of 106 4-8 year old children (51% female). Before the pandemic, caregivers completed questionnaires on their parenting style and their children's depression and anxiety symptoms. Shortly after the onset of COVID-19's stay-at-home mandate, parents answered questionnaires about their children's depression and anxiety symptoms and pandemic-related family stressors. Child depression and anxiety symptom severity increased. Higher levels of pandemic-related family stress were associated with increases only in child anxiety scores. Further, greater endorsement of a pre-pandemic authoritative parenting style was associated with smaller changes only in child depression scores. Study findings elucidate unique and complex associations between young children's anxiety and depression symptoms severity and pre-pandemic parenting and pandemic-related family stressors.

Exploring the association between EEG microstates during resting-state and error-related activity in young children.

The error-related negativity (ERN) is a negative deflection in the electroencephalography (EEG) waveform at frontal-central scalp sites that occurs after error commission. The relationship between the ERN and broader patterns of brain activity measured across the entire scalp that support error processing during early childhood is unclear. We examined the relationship between the ERN and EEG microstates - whole-brain patterns of dynamically evolving scalp potential topographies that reflect periods of synchronized neural activity - during both a go/no-go task and resting-state in 90, 4-8-year-old children. The mean amplitude of the ERN was quantified during the - 64 to 108 millisecond (ms) period of time relative to error commission, which was determined by data-driven microstate segmentation of error-related activity. We found that greater magnitude of the ERN associated with greater global explained variance (GEV; i.e., the percentage of total variance in the data explained by a given microstate) of an error-related microstate observed during the same - 64 to 108 ms period (i.e., error-related microstate 3), and to greater parent-report-measured anxiety risk. During resting-state, six data-driven microstates were identified. Both greater magnitude of the ERN and greater GEV values of error-related microstate 3 associated with greater GEV values of resting-state microstate 4, which showed a frontal-central scalp topography. Source localization results revealed overlap between the underlying neural generators of error-related microstate 3 and resting-state microstate 4 and canonical brain networks (e.g., ventral attention) known to support the higher-order cognitive processes involved in error processing. Taken together, our results clarify how individual differences in error-related and intrinsic brain activity are related and enhance our understanding of developing brain network function and organization supporting error processing during early childhood.

Toxicant exposure and the developing brain: A systematic review of the structural and functional MRI literature.

Youth worldwide are regularly exposed to pollutants and chemicals (i.e., toxicants) that may interfere with healthy brain development, and a surge in MRI research has begun to characterize the neurobiological consequences of these exposures. Here, a systematic review following PRISMA guidelines was conducted on developmental MRI studies of toxicants with known or suspected neurobiological impact. Associations were reviewed for 9 toxicant classes, including metals, air pollution, and flame retardants. Of 1264 identified studies, 46 met inclusion criteria. Qualitative synthesis revealed that most studies: (1) investigated air pollutants or metals, (2) assessed exposures prenatally, (3) assessed the brain in late middle childhood, (4) took place in North America or Western Europe, (5) drew samples from existing cohort studies, and (6) have been published since 2017. Given substantial heterogeneity in MRI measures, toxicant measures, and age groups assessed, more research is needed on all toxicants reviewed here. Future studies should also include larger samples, employ personal exposure monitoring, study independent samples in diverse world regions, and assess toxicant mixtures.

Reduced cortical surface area globally and in reward-related cortex is associated with elevated depressive symptoms in preschoolers.

BACKGROUND: Elevated depressive symptoms in early childhood strongly predict depression onset in youth. Nevertheless, little is known about the neural correlates of these symptoms, information that is key for understanding the early development of depression. As a result, the present study conducted a novel investigation of the association between cortical structure and depressive symptoms in preschoolers. METHODS: Forty-six preschool age children (Mage = 5.90, SD = 0.75), some (N = 15) at high risk for depression, participated in the study. Data included parent-report of child depressive symptoms and measures of child whole brain and regional cortical structure acquired via 3T MRI. RESULTS: After adjustment for maternal depression, socio-economic status, child age, child sex, and intracranial volume, reduced total cortical surface area and reduced surface area of the lateral orbitofrontal cortex were associated with elevated depressive symptoms. Cortical thickness was not associated with depressive symptoms. LIMITATIONS: The present data are cross-sectional, limiting any causal interpretations. CONCLUSIONS: Results suggest that reduced cortical surface area, rather than thickness, is a neural correlate of depressive symptoms in preschoolers. Findings highlight the importance of surface area in reward processing regions (i.e., lateral orbitofrontal cortex) in particular. The present results provide novel insight into early emerging associations between brain structure and features of depression in young children and underscore early childhood as an important developmental period for understanding depression.

Spatiotemporal dynamics of EEG microstates in four- to eight-year-old children: Age- and sex-related effects.

The ultrafast spatiotemporal dynamics of large-scale neural networks can be examined using resting-state electroencephalography (EEG) microstates, representing transient periods of synchronized neural activity that evolve dynamically over time. In adults, four canonical microstates have been shown to explain most topographic variance in resting-state EEG. Their temporal structures are age-, sex- and state-dependent, and are susceptible to pathological brain states. However, no studies have assessed the spatial and temporal properties of EEG microstates exclusively during early childhood, a critical period of rapid brain development. Here we sought to investigate EEG microstates recorded with high-density EEG in a large sample of 103, 4-8-year-old children. Using data-driven k-means cluster analysis, we show that the four canonical microstates reported in adult populations already exist in early childhood. Using multiple linear regressions, we demonstrate that the temporal dynamics of two microstates are associated with age and sex. Source localization suggests that attention- and cognitive control-related networks govern the topographies of the age- and sex-dependent microstates. These novel findings provide unique insights into functional brain development in children captured with EEG microstates.

Stress-induced cortisol response is associated with right amygdala volume in early childhood.

Rodent research suggests that dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and the resulting cortisol stress response can alter the structure of the hippocampus and amygdala. Because early-life changes in brain structure can produce later functional impairment and potentially increase risk for psychiatric disorder, it is critical to understand the relationship between the cortisol stress response and brain structure in early childhood. However, no study to date has characterized the concurrent association between cortisol stress response and hippocampal and amygdala volume in young children. In the present study, 42 young children (M age  = 5.97, SD = 0.76), completed a frustration task and cortisol response to stress was measured. Children also underwent magnetic resonance imaging (MRI), providing structural scans from which their hippocampal and amygdala volumes were extracted. Greater cortisol stress response was associated with reduced right amygdala volume, controlling for whole brain volume, age, sex, and number of cortisol samples. There were no significant associations between cortisol stress response and bilateral hippocampus or left amygdala volumes. The association between right amygdala volume and cortisol stress response raises the non-mutually exclusive possibilities that the function of the HPA axis may shape amygdala structure and/or that amygdala structure may shape HPA axis function. As both cortisol stress response and amygdala volume have been associated with risk for psychopathology, it is possible that the relationship between cortisol stress response and amygdala volume is part of a broader pathway contributing to psychiatric risk.

Editorial: Shedding Light on the Early Neurobiological Roots of Infant Temperament and Risk for Anxiety.

Temperament refers to early-appearing variations in emotional reactivity and regulation that show moderate stability across time and settings. The association of some features of early temperament with later emerging childhood psychiatric disorders has been well established. For example, a temperamental predisposition toward experiencing increased negative affect in the presence of novelty during early childhood has been linked to later anxiety disorders.1 Accumulating research directed at understanding the mechanistic links between temperament and psychopathology indicates that, at least for most disorders, the 2 constructs cannot be viewed as simply different points along a shared continuum. That is, temperament as a risk factor for psychopathology has been suggested to depend on a number of other internal as well as external factors,2 and these factors likely exert their influence at least in part by shaping the early course of brain development.3 However, until recently, the associations between very early features of temperament and brain development have remained relatively understudied owing to the practical and technical challenges of using neuroimaging techniques such as functional magnetic resonance imaging during this highly sensitive developmental period. Nevertheless, with advances in each of these areas, early functional magnetic resonance imaging evidence is beginning to provide an exciting new window into these relationships.

Amygdala Functional Connectivity Is Associated With Emotion Regulation and Amygdala Reactivity in 4- to 6-Year-Olds.

OBJECTIVE: Emotion dysregulation has been suggested to be a potent risk factor for multiple psychiatric conditions. Altered amygdala-prefrontal cortex (PFC) connectivity has been consistently linked to emotion dysregulation. Recent data indicate that amygdala-PFC functional connectivity undergoes a prolonged period of development, with amygdala reactivity during early childhood potentially shaping this unfolding process. Little is known about the relationships between amygdala-PFC functional connectivity, amygdala reactivity, and emotion regulation during early childhood. This information is likely critical for understanding early emotion dysregulation as a transdiagnostic risk factor for psychopathology. The current study examined the relationships between amygdala functional connectivity, amygdala reactivity, and emotion regulation in preschoolers. METHOD: A total of 66 medication-naive 4- to 6-year-olds participated in a study where resting-state functional magnetic resonance imaging (rs-fMRI) and parent-reported child emotion regulation ability data were collected. fMRI data collected during a face viewing task was also available for 24 children. RESULTS: Right amygdala-medial PFC (mPFC) functional connectivity was positively associated with child emotion regulation ability and negatively associated with child negative affect and right amygdala reactivity to facial expressions of emotion. Right amygdala-mPFC functional connectivity also statistically mediated the relationship between heightened right amygdala reactivity and elevated child negative affect. CONCLUSION: Study findings suggest that amygdala-mPFC functional connectivity during early childhood, and its relationships with amygdala reactivity and emotion regulation during this highly sensitive developmental period, may play an important role in early emotional development. These results inform the neurodevelopmental biology of emotion regulation and its potential relationship with risk for psychopathology.

Cortical thinning in preschoolers with maladaptive guilt.

Maladaptive guilt is a central symptom of preschool-onset depression associated with severe psychopathology in adolescence and adulthood. Although studies have found that maladaptive guilt is associated with structural alterations in the anterior insula (AI) and dorsomedial prefrontal cortex (dmPFC) in middle childhood and adolescence, no study has examined structural neural correlates of maladaptive guilt in preschool, when this symptom first emerges. This study examined a pooled sample of 3-to 6-year-old children (N = 76; 40.8% female) from two studies, both which used the same type of magnetic resonance imaging scanner and conducted diagnostic interviews for depression that included clinician ratings of whether children met criteria for maladaptive guilt. Preschoolers with maladaptive guilt displayed significantly thinner dmPFC than children without this symptom. Neither children's depressive severity nor their vegetative or other emotional symptoms of depression were associated with dmPFC thickness, suggesting that dmPFC thinning is specific to maladaptive guilt. Neither AI gray matter volume or thickness nor dmPFC gray matter volume differed between children with and without maladaptive guilt. This study is the first to identify a structural biomarker for a specific depressive symptom in preschool. Findings may inform neurobiological models of the development of depression and aid in detection of this symptom.

Social origins of self-regulated attention during infancy and their disruption in autism spectrum disorder: Implications for early intervention.

To understand the complex relationships between autism spectrum disorder (ASD) and other frequently comorbid conditions, a growing number of studies have investigated the emergence of ASD during infancy. This research has suggested that symptoms of ASD and highly related comorbid conditions emerge from complex interactions between neurodevelopmental vulnerabilities and early environments, indicating that developing treatments to prevent ASD is highly challenging. However, it also suggests that attenuating the negative effects of ASD on future development once identified is possible. The present paper builds on this by conceptualizing developmental delays in nonsocial skills as the potential product of altered caregiver-infant interactions following the emergence of ASD during infancy. And, following emerging findings from caregiver-infant dyadic head-mounted eye-tracking (D-ET) research, it also suggests that a multiple pathway model of joint attention can provide mechanistic insights into how ASD alters the ability of caregiver and infant to create a context for infant learning. The potential for this view to inform early intervention is further discussed and illustrated through D-ET data collected prior to and following a brief, parent-mediated intervention for infant ASD. While promising, further research informing how a multiple pathway model of joint attention can inform ASD early intervention is needed.

Continuity and stability of preschool depression from childhood through adolescence and following the onset of puberty.

BACKGROUND: A growing body of research now supports the validity, clinical significance, and long-term negative impact of depression occurring during the preschool period. However, the prospective continuity of depressive symptoms and risk for major depressive disorder (MDD) from childhood through adolescence for preschoolers experiencing this highly impairing disorder remains unexplored. Such information is likely to be critical for understanding the developmental continuity of preschool depression and whether it continues to be a salient risk factor for an MDD diagnosis following the transition into adolescence and the onset of biological changes associated with it (i.e., puberty). METHODS: Subjects were participants in the Preschool Depression Study conducted at the Early Emotional Development Program at Washington University School of Medicine in St. Louis. Subjects and their parents completed baseline assessments that included comprehensive measures of psychopathology and development at baseline and up to 9 follow-up assessments between 2003 and 2017. N = 279 subjects had diagnostic and clinical data available for the preschool period and the early pubertal and/or later pubertal periods and were included in the analyses. There were N = 275 subjects assessed during the early pubertal period and N = 184 subjects assessed during the later pubertal period. RESULTS: Preschool depression was a highly salient predictor of prepubertal and mid-to-post pubertal MDD. Across all modeled time points children with a history of preschool depression continued to demonstrate elevated levels of depressive symptoms from childhood through adolescence, suggesting a heightened trajectory of depressive symptoms relative to their same age peers. CONCLUSION: Findings from the current study suggest that children with a history of preschool depression follow a trajectory of depression severity elevated relative to their same age peers from childhood through adolescence but with a similar shape over time. They also support the homotypic continuity of preschool depression into adolescence and the onset of puberty.

The Lifespan Human Connectome Project in Development: A large-scale study of brain connectivity development in 5-21 year olds.

Recent technological and analytical progress in brain imaging has enabled the examination of brain organization and connectivity at unprecedented levels of detail. The Human Connectome Project in Development (HCP-D) is exploiting these tools to chart developmental changes in brain connectivity. When complete, the HCP-D will comprise approximately ∼1750 open access datasets from 1300 + healthy human participants, ages 5-21 years, acquired at four sites across the USA. The participants are from diverse geographical, ethnic, and socioeconomic backgrounds. While most participants are tested once, others take part in a three-wave longitudinal component focused on the pubertal period (ages 9-17 years). Brain imaging sessions are acquired on a 3 T Siemens Prisma platform and include structural, functional (resting state and task-based), diffusion, and perfusion imaging, physiological monitoring, and a battery of cognitive tasks and self-reports. For minors, parents additionally complete a battery of instruments to characterize cognitive and emotional development, and environmental variables relevant to development. Participants provide biological samples of blood, saliva, and hair, enabling assays of pubertal hormones, health markers, and banked DNA samples. This paper outlines the overarching aims of the project, the approach taken to acquire maximally informative data while minimizing participant burden, preliminary analyses, and discussion of the intended uses and limitations of the dataset.

Amygdala Reward Reactivity Mediates the Association Between Preschool Stress Response and Depression Severity.

BACKGROUND: Research in adolescents and adults has suggested that altered neural processing of reward following early life adversity is a highly promising depressive intermediate phenotype. However, very little is known about how stress response, neural processing of reward, and depression are related in very young children. The present study examined the concurrent associations between cortisol response following a stressor, functional brain activity to reward, and depression severity in children 4 to 6 years old. METHODS: Medication-naïve children 4 to 6 years old (N = 52) participated in a study using functional magnetic resonance imaging to assess neural reactivity to reward, including gain, loss, and neutral outcomes. Parent-reported child depression severity and child cortisol response following stress were also measured. RESULTS: Greater caudate and medial prefrontal cortex reactivity to gain outcomes and increased amygdala reactivity to salient (i.e., both gain and loss) outcomes were observed. Higher total cortisol output following a stressor was associated with increased depression severity and reduced amygdala reactivity to salient outcomes. Amygdala reactivity was also inversely associated with depression severity and was found to mediate the relationship between cortisol output and depression severity. CONCLUSIONS: Results suggest that altered neural processing of reward is already related to increased cortisol output and depression severity in preschoolers. These results also demonstrate an important role for amygdala function as a mediator of this relationship at a very early age. Our results further underscore early childhood as an important developmental period for understanding the neurobiological correlates of early stress and increased risk for depression.

Amygdala reactivity to sad faces in preschool children: An early neural marker of persistent negative affect.

BACKGROUND: Elevated negative affect is a highly salient risk factor for later internalizing disorders. Very little is known about the early neurobiological correlates of negative affect and whether they associate with developmental changes in negative emotion. Such information may prove critical for identifying children deviating from normative developmental trajectories of negative affect and at increased risk for later internalizing disorders. The current study examined the relationship between amygdala activity and negative affect measured concurrently and approximately 12 months later in preschool-age children. METHOD: Amygdala activity was assessed using functional magnetic resonance imaging in 31 medication-naive preschool age children. Negative affect was measured using parent report both at the time of scan and 12 months later. RESULTS: Negative affect at baseline was positively correlated with right amygdala activity to sad faces, right amygdala activity to happy faces, and left amygdala activity to happy faces. Right amygdala activity to sad faces also positively predicted parent-reported negative affect 12 months later even when negative affect reported at baseline was controlled. CONCLUSIONS: The current findings provide preliminary evidence for amygdala activity as a potential biomarker of persistent negative affect during early childhood and suggest future work examining the origins and long-term implications of this relationship is necessary.

Stimulus-Driven Attention, Threat Bias, and Sad Bias in Youth with a History of an Anxiety Disorder or Depression.

Attention biases towards threatening and sad stimuli are associated with pediatric anxiety and depression, respectively. The basic cognitive mechanisms associated with attention biases in youth, however, remain unclear. Here, we tested the hypothesis that threat bias (selective attention for threatening versus neutral stimuli) but not sad bias relies on stimulus-driven attention. We collected measures of stimulus-driven attention, threat bias, sad bias, and current clinical symptoms in youth with a history of an anxiety disorder and/or depression (ANX/DEP; n = 40) as well as healthy controls (HC; n = 33). Stimulus-driven attention was measured with a non-emotional spatial orienting task, while threat bias and sad bias were measured at a short time interval (150 ms) with a spatial orienting task using emotional faces and at a longer time interval (500 ms) using a dot-probe task. In ANX/DEP but not HC, early attention bias towards threat was negatively correlated with later attention bias to threat, suggesting that early threat vigilance was associated with later threat avoidance. Across all subjects, stimulus-driven orienting was not correlated with early threat bias but was negatively correlated with later threat bias, indicating that rapid stimulus-driven orienting is linked to later threat avoidance. No parallel relationships were detected for sad bias. Current symptoms of depression but not anxiety were related to decreased stimulus-driven attention. Together, these results are consistent with the hypothesis that threat bias but not sad bias relies on stimulus-driven attention. These results inform the design of attention bias modification programs that aim to reverse threat biases and reduce symptoms associated with pediatric anxiety and depression.

Amygdala functional connectivity, HPA axis genetic variation, and life stress in children and relations to anxiety and emotion regulation.

Internalizing pathology is related to alterations in amygdala resting state functional connectivity, potentially implicating altered emotional reactivity and/or emotion regulation in the etiological pathway. Importantly, there is accumulating evidence that stress exposure and genetic vulnerability impact amygdala structure/function and risk for internalizing pathology. The present study examined whether early life stress and genetic profile scores (10 single nucleotide polymorphisms within 4 hypothalamic-pituitary-adrenal axis genes: CRHR1, NR3C2, NR3C1, and FKBP5) predicted individual differences in amygdala functional connectivity in school-age children (9- to 14-year-olds; N = 120). Whole-brain regression analyses indicated that increasing genetic "risk" predicted alterations in amygdala connectivity to the caudate and postcentral gyrus. Experience of more stressful and traumatic life events predicted weakened amygdala-anterior cingulate cortex connectivity. Genetic "risk" and stress exposure interacted to predict weakened connectivity between the amygdala and the inferior and middle frontal gyri, caudate, and parahippocampal gyrus in those children with the greatest genetic and environmental risk load. Furthermore, amygdala connectivity longitudinally predicted anxiety symptoms and emotion regulation skills at a later follow-up. Amygdala connectivity mediated effects of life stress on anxiety and of genetic variants on emotion regulation. The current results suggest that considering the unique and interacting effects of biological vulnerability and environmental risk factors may be key to understanding the development of altered amygdala functional connectivity, a potential factor in the risk trajectory for internalizing pathology.

HPA axis genetic variation, pubertal status, and sex interact to predict amygdala and hippocampus responses to negative emotional faces in school-age children.

Accumulating evidence suggests a role for stress exposure, particularly during early life, and for variation in genes involved in stress response pathways in neural responsivity to emotional stimuli. Understanding how individual differences in these factors predict differences in emotional responsivity may be important for understanding both normative emotional development and for understanding the mechanisms underlying internalizing disorders, like anxiety and depression, that have often been related to increased amygdala and hippocampus responses to negatively valenced emotional stimuli. The present study examined whether stress exposure and genetic profile scores (10 single nucleotide polymorphisms within four hypothalamic-pituitary-adrenal axis genes: CRHR1, NR3C2, NR3C1, and FKBP5) predict individual differences in amygdala and hippocampus responses to fearful vs. neutral faces in school-age children (7-12 year olds; N = 107). Experience of more stressful and traumatic life events predicted greater left amygdala responses to negative emotional stimuli. Genetic profile scores interacted with sex and pubertal status to predict amygdala and hippocampus responses. Specifically, genetic profile scores were a stronger predictor of amygdala and hippocampus responses among pubertal vs. prepubertal children where they positively predicted responses to fearful faces among pubertal girls and positively predicted responses to neutral faces among pubertal boys. The current results suggest that genetic and environmental stress-related factors may be important in normative individual differences in responsivity to negative emotional stimuli, a potential mechanism underlying internalizing disorders. Further, sex and pubertal development may be key moderators of the effects of stress-system genetic variation on amygdala and hippocampus responsivity, potentially relating to sex differences in stress-related psychopathology.