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The COVID-19 pandemic is an ongoing stressor that has resulted in the exacerbation of mental health problems worldwide. However, longitudinal studies that identify preexisting behavioral and neurobiological factors associated with mental health outcomes during the pandemic are lacking. Here, we examined associations between prepandemic coping strategy engagement and frontolimbic circuitry with internalizing symptoms during the pandemic. In 85 adults (71.8% female; age 18-30 years), we assessed prototypically adaptive coping strategies (Connor-Davidson Resilience Scale), resting-state functional magnetic resonance imaging functional connectivity (FC) of frontolimbic circuitry, and depression and anxiety symptoms (Beck Depression Inventory, Screen for Child Anxiety-Related Emotional Disorders-Adult, respectively). We conducted general linear models to test preregistered hypotheses that (1) lower coping engagement prepandemic and (2) weaker frontolimbic FC prepandemic would predict elevated symptoms during the pandemic; and (3) coping would interact with FC to predict symptoms during the pandemic. Depression and anxiety symptoms worsened during the pandemic (ps.001). Prepandemic adaptive coping engagement and frontolimbic FC were not associated with depression or anxiety symptoms during the pandemic (uncorrected ps.05). Coping interacted with insula-rostral anterior cingulate cortex (ACC) FC (p = .003, pFDR = .014) and with insula-ventral ACC FC (p.001, pFDR.001) to predict depression symptoms, but these findings did not survive FDR correction after removal of outliers. Findings from our preregistered study suggest that specific prepandemic factors, particularly adaptive coping and frontolimbic circuitry, are not robustly associated with emotional responses to the pandemic. Additional studies that identify preexisting neurobehavioral factors implicated in mental health outcomes during global health crises are needed. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Exposure to socioeconomic disadvantages (SED) can have negative impacts on mental health, yet SED are a multifaceted construct and the precise processes by which SED confer deleterious effects are less clear. Using a large and diverse sample of preadolescents (ages 9–10 years at baseline, n = 4038, 49% female) from the Adolescent Brain Cognitive Development Study, we examined associations among SED at both household (i.e., income–needs and material hardship) and neighborhood (i.e., area deprivation and neighborhood unsafety) levels, frontoamygdala resting-state functional connectivity, and internalizing symptoms at baseline and 1-year follow-up. SED were positively associated with internalizing symptoms at baseline and indirectly predicted symptoms 1 year later through elevated symptoms at baseline. At the household level, youth in households characterized by higher disadvantage (i.e., lower income-to-needs ratio) exhibited more strongly negative frontoamygdala coupling, particularly between the bilateral amygdala and medial OFC (mOFC) regions within the frontoparietal network. Although more strongly positive amygdala–mOFC coupling was associated with higher levels of internalizing symptoms at baseline and 1-year follow-up, it did not mediate the association between income-to-needs ratio and internalizing symptoms. However, at the neighborhood level, amygdala–mOFC functional coupling moderated the effect of neighborhood deprivation on internalizing symptoms. Specifically, higher neighborhood deprivation was associated with higher internalizing symptoms for youth with more strongly positive connectivity, but not for youth with more strongly negative connectivity, suggesting a potential buffering effect. Findings highlight the importance of capturing multilevel socioecological contexts in which youth develop to identify youth who are most likely to benefit from early interventions.

The Adolescent Brain Cognitive Development (ABCD) Study® is a 10-year longitudinal study of children recruited at ages 9 and 10. A battery of neuroimaging tasks are administered biennially to track neurodevelopment and identify individual differences in brain function. This study reports activation patterns from functional MRI (fMRI) tasks completed at baseline, which were designed to measure cognitive impulse control with a stop signal task (SST; N = 5,547), reward anticipation and receipt with a monetary incentive delay (MID) task (N = 6,657) and working memory and emotion reactivity with an emotional N-back (EN-back) task (N = 6,009). Further, we report the spatial reproducibility of activation patterns by assessing between-group vertex/voxelwise correlations of blood oxygen level-dependent (BOLD) activation. Analyses reveal robust brain activations that are consistent with the published literature, vary across fMRI tasks/contrasts and slightly correlate with individual behavioral performance on the tasks. These results establish the preadolescent brain function baseline, guide interpretation of cross-sectional analyses and will enable the investigation of longitudinal changes during adolescent development. This paper reports activation patterns for fMRI tasks assessing response inhibition, working memory and reward processing obtained at baseline in the longitudinal ABCD Study, providing a reference for research into adolescent brain development.

Nearly all families in the United States were exposed to varying degrees of stress related to the COVID-19 pandemic during the spring of 2020. Building on previous research documenting the pernicious effects of stress on youth mental health, we aimed to test the effects of exposure to COVID-19-related stress on youth symptomatology. Further, in light of evidence suggesting that parents play an important role in buffering children from environmental stress, we assessed how specific parental behaviors (i.e., parental emotion socialization, maintenance of home routines, and availability to discuss the pandemic with child) contributed to effective parental buffering of the impact of pandemic-related stress on children's symptomatology. Conversely, we tested whether parental anxiety-related symptomatology and parenting stress exacerbated the effect of children's exposure to pandemic-related stress on children's symptomatology. Results suggest that parents who engaged in relatively higher levels of emotion coaching of children's negative emotions and who maintained more stable home routines during the pandemic were more effectively able to buffer the effects of pandemic-related stress on children's symptomatology. Parents who reported higher levels of parenting stress and anxiety-related symptomatology were less likely to effectively buffer stress. Though interpretation of the findings is limited due to sole reliance on parental report and the cross-sectional study design due to the constraints of collecting data during a global pandemic, findings underscore the importance of assessing family-level factors when considering the impact of stressors on children's symptomatology and highlight the need to support parents during global events that place families under significant stress.

Background Findings on structural brain volume associated with pediatric posttraumatic stress disorder (PTSD) have been variable, and it is unclear whether any structural differences are specific to pediatric PTSD in comparison with adult PTSD or other co-occurring pediatric psychiatric conditions. Methods We tested volumetric brain differences between pediatric groups with and without PTSD in a region-of-interest meta-analysis. We conducted meta-regressions to test the effects of age and sex on heterogeneous study findings. To assess specificity, we compared pediatric PTSD with the following: adult PTSD, pediatric trauma exposure without PTSD, pediatric depression, and pediatric anxiety. Results In 15 studies examined, pediatric PTSD was associated with smaller total gray matter and cerebral, temporal lobe (total, right, and left), total cerebellar vermis, and hippocampal (total, right, and left) volumes, compared to peers without PTSD. In the pediatric PTSD group, but not the comparison group, we found a trend toward smaller total, right, and left amygdalar volumes. In an external comparison, smaller hippocampal volume was not significantly different between adult and pediatric PTSD groups. Qualitative comparisons with a pediatric trauma exposure without PTSD group, a pediatric depression group, and a pediatric anxiety group revealed differences that may be unique to pediatric PTSD, and others that may be convergent with these related clinical conditions in youth. Conclusions Pediatric PTSD is associated with structural differences that parallel those associated with adult PTSD. Furthermore, pediatric PTSD appears to be distinct from other related pediatric conditions at the structural level. Future studies employing longitudinal, dimensional, and multimodal neuroimaging approaches will further elucidate the nature of neurobiological differences in pediatric PTSD.

The Adolescent Brain Cognitive Development (ABCD) Study of 11,880 youth incorporates a comprehensive range of measures assessing predictors and outcomes related to mental health across childhood and adolescence in participating youth, as well as information about family mental health history. We have previously described the logic and content of the mental health assessment battery at Baseline and 1-year follow-up. Here, we describe changes to that battery and issues and clarifications that have emerged, as well as additions to the mental health battery at the 2-, 3-, 4-, and 5-year follow-ups. We capitalize on the recent release of longitudinal data for caregiver and youth report of mental health data to evaluate trajectories of dimensions of psychopathology as a function of demographic factors. For both caregiver and self-reported mental health symptoms, males showed age-related decreases in internalizing and externalizing symptoms, while females showed an increase in internalizing symptoms with age. Multiple indicators of socioeconomic status (caregiver education, family income, financial adversity, neighborhood poverty) accounted for unique variance in both caregiver and youth-reported externalizing and internalizing symptoms. These data highlight the importance of examining developmental trajectories of mental health as a function of key factors such as sex and socioeconomic environment.

In 2020, individuals of all ages engaged in demonstrations condemning police brutality and supporting the Black Lives Matter (BLM) movement. Research that used parent reports and trends commented on in popular media suggested that adolescents under 18 had become increasingly involved in this movement. In the first large-scale quantitative survey of adolescents’ exposure to BLM demonstrations, 4,970 youth (mean age = 12.88 y) across the United States highlighted that they were highly engaged, particularly with media, and experienced positive emotions when exposed to the BLM movement. In addition to reporting strong engagement and positive emotions related to BLM demonstrations, Black adolescents in particular reported higher negative emotions when engaging with different types of media and more exposure to violence during in-person BLM demonstrations. Appreciating youth civic engagement, while also providing support for processing complex experiences and feelings, is important for the health and welfare of young people and society.

The endocannabinoid system is an important regulator of emotional responses such as fear, and a number of studies have implicated endocannabinoid signaling in anxiety. The fatty acid amide hydrolase (FAAH) C385A polymorphism, which is associated with enhanced endocannabinoid signaling in the brain, has been identified across species as a potential protective factor from anxiety. In particular, adults with the variant FAAH 385A allele have greater fronto-amygdala connectivity and lower anxiety symptoms. Whether broader network-level differences in connectivity exist, and when during development this neural phenotype emerges, remains unknown and represents an important next step in understanding how the FAAH C385A polymorphism impacts neurodevelopment and risk for anxiety disorders. Here, we leveraged data from 3,109 participants in the nationwide Adolescent Brain Cognitive Development Study℠ (10.04 ± 0.62 years old; 44.23% female, 55.77% male) and a cross-validated, data-driven approach to examine associations between genetic variation and large-scale resting-state brain networks. Our findings revealed a distributed brain network, comprising functional connections that were both significantly greater (95% CI for p values = [

Gastrointestinal and mental disorders are highly comorbid, and animal models have shown that both can be caused by early adversity (e.g., parental deprivation). Interactions between the brain and bacteria that live within the gastrointestinal system (the microbiome) underlie adversity–gastrointestinal–anxiety interactions, but these links have not been investigated during human development. In this study, we utilized data from a population of 344 youth (3–18 years old) who were raised with their biological parents or were exposed to early adverse caregiving experiences (i.e., institutional or foster care followed by international adoption) to explore adversity–gastrointestinal–anxiety associations. In Study 1, we demonstrated that previous adverse care experiences were associated with increased incidence of gastrointestinal symptoms in youth. Gastrointestinal symptoms were also associated with concurrent and future anxiety (measured across 5 years), and those gastrointestinal symptoms mediated the adversity–anxiety association at Time 1. In a subsample of children who provided both stool samples and functional magnetic resonance imaging of the brain (Study 2, which was a “proof-of-principle”), adversity was associated with changes in diversity (both alpha and beta) of microbial communities, and bacteria levels (adversity-associated and adversity-independent) were correlated with prefrontal cortex activation to emotional faces. Implications of these data for supporting youth mental health are discussed.

Early institutional rearing is associated with increased risk for subsequent peer relationship difficulties, but the underlying mechanisms have not been identified. Friendship characteristics, social behaviors with peers, normed assessments of social problems, and social cue use were assessed in 142 children (mean age = 10.06, SD = 2.02; range 7–13 years), of whom 67 were previously institutionalized (PI), and 75 were raised by their biological families. Anxiety and attention-deficit/hyperactivity disorder (ADHD) symptoms, often elevated among PI children, were examined as potential mediators of PI status and baseline social functioning and longitudinal follow-ups (2 and 4 years later). Twenty-seven percent of PI children fell above the Child Behavior Checklist Social Problems cutoff. An examination of specific social behaviors with peers indicated that PI and comparison children did not differ in empathic concern or peer social approach, though parents were more likely to endorse aggression/overarousal as a reason that PI children might struggle with friendships. Comparison children outperformed PI children in computerized testing of social cue use learning. Finally, across these measures, social difficulties exhibited in the PI group were mediated by ADHD symptoms with predicted social problems assessed 4 years later. These findings show that, when PI children struggle with friendships, mechanisms involving attention and behavior regulation are likely contributors.

Childhood experiences play a profound role in conferring risk and resilience for brain and behavioral development. However, how different facets of the environment shape neurodevelopment remains largely unknown. Here we sought to decompose heterogeneous relationships between environmental factors and brain structure in 989 school-aged children from the Adolescent Brain Cognitive Development Study. We applied a cross-modal integration and clustering approach called ‘Similarity Network Fusion’, which combined two brain morphometrics (i.e., cortical thickness and myelin-surrogate markers), and key environmental factors (i.e., trauma exposure, neighborhood safety, school environment, and family environment) to identify homogeneous subtypes. Depending on the subtyping resolution, results identified two or five subgroups, each characterized by distinct brain structure-environment profiles. Notably, more supportive caregiving and school environments were associated with increased myelination, whereas less supportive caregiving, higher family conflict and psychopathology, and higher perceived neighborhood safety were observed with increased cortical thickness. These subtypes were highly reproducible and predicted externalizing symptoms and overall mental health problems. Our findings support the theory that distinct environmental exposures differentially influence neurodevelopment. Delineating more precise associations between risk factors, protective factors, and brain development may inform approaches to enhance risk identification and optimize interventions targeting specific experiences.

Author(s): Herting, Megan M; Uban, Kristina A; Gonzalez, Marybel Robledo; Baker, Fiona C; Kan, Eric C; Thompson, Wesley K; Granger, Douglas A; Albaugh, Matthew D; Anokhin, Andrey P; Bagot, Kara S; Banich, Marie T; Barch, Deanna M; Baskin-Sommers, Arielle; Breslin, Florence J; Casey, BJ; Chaarani, Bader; Chang, Linda; Clark, Duncan B; Cloak, Christine C; Constable, R Todd; Cottler, Linda B; Dagher, Rada K; Dapretto, Mirella; Dick, Anthony S; Dosenbach, Nico; Dowling, Gayathri J; Dumas, Julie A; Edwards, Sarah; Ernst, Thomas; Fair, Damien A; Feldstein-Ewing, Sarah W; Freedman, Edward G; Fuemmeler, Bernard F; Garavan, Hugh; Gee, Dylan G; Giedd, Jay N; Glaser, Paul EA; Goldstone, Aimee; Gray, Kevin M; Hawes, Samuel W; Heath, Andrew C; Heitzeg, Mary M; Hewitt, John K; Heyser, Charles J; Hoffman, Elizabeth A; Huber, Rebekah S; Huestis, Marilyn A; Hyde, Luke W; Infante, M Alejandra; Ivanova, Masha Y; Jacobus, Joanna; Jernigan, Terry L; Karcher, Nicole R; Laird, Angela R; LeBlanc, Kimberly H; Lisdahl, Krista; Luciana, Monica; Luna, Beatriz; Maes, Hermine H; Marshall, Andrew T; Mason, Michael J; McGlade, Erin C; Morris, Amanda S; Nagel, Bonnie J; Neigh, Gretchen N; Palmer, Clare E; Paulus, Martin P; Potter, Alexandra S; Puttler, Leon I; Rajapakse, Nishadi; Rapuano, Kristina; Reeves, Gloria; Renshaw, Perry F; Schirda, Claudiu; Sher, Kenneth J; Sheth, Chandni; Shilling, Paul D; Squeglia, Lindsay M; Sutherland, Matthew T; Tapert, Susan F; Tomko, Rachel L; Yurgelun-Todd, Deborah; Wade, Natasha E; Weiss, Susan RB; Zucker, Robert A | Abstract: AimTo examine individual variability between perceived physical features and hormones of pubertal maturation in 9-10-year-old children as a function of sociodemographic characteristics.MethodsCross-sectional metrics of puberty were utilized from the baseline assessment of the Adolescent Brain Cognitive Development (ABCD) Study-a multi-site sample of 9-10 year-olds (n = 11,875)-and included perceived physical features via the pubertal development scale (PDS) and child salivary hormone levels (dehydroepiandrosterone and testosterone in all, and estradiol in females). Multi-level models examined the relationships among sociodemographic measures, physical features, and hormone levels. A group factor analysis (GFA) was implemented to extract latent variables of pubertal maturation that integrated both measures of perceived physical features and hormone levels.ResultsPDS summary scores indicated more males (70%) than females (31%) were prepubertal. Perceived physical features and hormone levels were significantly associated with child's weight status and income, such that more mature scores were observed among children that were overweight/obese or from households with low-income. Results from the GFA identified two latent factors that described individual differences in pubertal maturation among both females and males, with factor 1 driven by higher hormone levels, and factor 2 driven by perceived physical maturation. The correspondence between latent factor 1 scores (hormones) and latent factor 2 scores (perceived physical maturation) revealed synchronous and asynchronous relationships between hormones and concomitant physical features in this large young adolescent sample.ConclusionsSociodemographic measures were associated with both objective hormone and self-report physical measures of pubertal maturation in a large, diverse sample of 9-10 year-olds. The latent variables of pubertal maturation described a complex interplay between perceived physical changes and hormone levels that hallmark sexual maturation, which future studies can examine in relation to trajectories of brain maturation, risk/resilience to substance use, and other mental health outcomes.

Cognitive-behavioral therapy (CBT), a first-line treatment for pediatric anxiety disorders, is based on principles of threat learning and extinction. However, CBT does not work sufficiently for up to 40% of clinically anxious youth. The neural and behavioral correlates of conditioned inhibition might provide promising targets for attempts to improve CBT response. During conditioned inhibition, threat and safety cues appear together, forming a safety compound. Here, we test whether this safety compound elicits a reduced fear response compared to pairing the threat cue with a novel cue (novel compound). The current pilot study compares behavioral, physiological, and neural correlates of conditioned inhibition between children with (n = 17, Mage = 13.09, SDage = 3.05) and without (n = 18, Mage = 14.49, SDage = 2.38) anxiety disorders. Behavioral and physiological measures did not differ between children with and without anxiety disorders during fear acquisition. During testing, children with anxiety disorders showed overall higher skin conductance response and expected to hear the aversive sound following the novel compound more often than children without anxiety disorders. Children with anxiety disorders showed more activity in the right ventromedial prefrontal cortex (vmPFC) to the safety versus novel compound. Children without anxiety disorders showed the opposite pattern – more right vmPFC activity to the novel versus safety compound (F(1,31) = 5.40, p = 0.03). No group differences manifested within the amygdala, dorsal anterior cingulate cortex, or hippocampus. These pilot findings suggest a feasible approach for examining conditioned inhibition in pediatric anxiety disorders. If replicated in larger samples, findings may implicate perturbed conditioned inhibition in pediatric anxiety disorders and provide targets for CBT.

A substantial body of research demonstrates that experiences of trauma are associated with disruptions in learning processes. Specifically, research shows altered nonassociative and associative learning in individuals who report traumatic experiences. The combination of trauma and altered learning also confers risk for negative health and mental health outcomes. One subtype of trauma that receives less attention in terms of its association with learning processes is exposure to violence (ETV)-witnessing violence, hearing gunfire, and/or being the victim of violence. Preliminary evidence shows that ETV is related to disruptions in nonassociative and associative learning processes, but these studies did not use direct and objective measures of learning. Additionally, research documents a robust relationship between ETV and violent behavior, but there has been no work examining whether it is the combination of elevated levels of ETV and learning patterns that poses a risk for engagement in violent behavior. In the present study, 164 participants completed two auditory basic learning tasks, one measuring nonassociative learning (habituation) and another measuring associative learning acquisition (classical conditioning), while skin conductance was recorded. Results indicate that individuals with higher ETV display a decreased likelihood of physiological habituation, but ETV is unrelated to associative learning acquisition. Further, the combination of higher ETV and nonhabituation predicts a greater number of violent crimes. These findings suggest that, for those with higher ETV, variations in capability for nonassociative learning may confer risk for violent behavior. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

While graph theoretical modeling has dramatically advanced our understanding of complex brain systems, the feasibility of aggregating connectomic data in large imaging consortia remains unclear. Here, using a battery of cognitive, emotional and resting fMRI paradigms, we investigated the generalizability of functional connectomic measures across sites and sessions. Our results revealed overall fair to excellent reliability for a majority of measures during both rest and tasks, in particular for those quantifying connectivity strength, network segregation and network integration. Processing schemes such as node definition and global signal regression (GSR) significantly affected resulting reliability, with higher reliability detected for the Power atlas (vs. AAL atlas) and data without GSR. While network diagnostics for default-mode and sensori-motor systems were consistently reliable independently of paradigm, those for higher-order cognitive systems were reliable predominantly when challenged by task. In addition, based on our present sample and after accounting for observed reliability, satisfactory statistical power can be achieved in multisite research with sample size of approximately 250 when the effect size is moderate or larger. Our findings provide empirical evidence for the generalizability of brain functional graphs in large consortia, and encourage the aggregation of connectomic measures using multisite and multisession data.

Early caregiving adversity is associated with increased risk for social difficulties. The ventral striatum and associated corticostriatal circuitry, which have demonstrated vulnerability to early exposures to adversity, are implicated in many aspects of social behavior, including social play, aggression, and valuation of social stimuli across development. Here, we used resting-state functional magnetic resonance imaging to assess the degree to which early caregiving adversity was associated with altered coritocostriatal resting connectivity in previously institutionalized youth (n = 41) relative to youth who were raised with their biological families from birth (n = 47), and the degree to which this connectivity was associated with parent-reported social problems. Using a seed-based approach, we observed increased positive coupling between the ventral striatum and anterior regions of medial prefrontal cortex (mPFC) in previously institutionalized youth. Stronger ventral striatum–mPFC coupling was associated with parent reports of social problems. A moderated-mediation analysis showed that ventral striatal–mPFC connectivity mediated group differences in social problems, and more so with increasing age. These findings show that early institutional care is associated with differences in resting-state connectivity between the ventral striatum and the mPFC, and this connectivity seems to play an increasingly important role in social behaviors as youth enter adolescence.

Several studies have shown that young children who have experienced early caregiving adversity (e.g. previously institutionalization (PI)) exhibit flattened diurnal cortisol slopes; however, less is known about how these patterns might differ between children and adolescents, since the transition between childhood and adolescence is a time of purported plasticity in the hypothalamic-pituitary-adrenal (HPA) axis. PI youth experience a massive improvement in caregiving environment once adopted into families; therefore we anticipated that a developmental increase in HPA axis plasticity during adolescence might additionally allow for an enhanced enrichment effect by the adoptive family. In a cross-sectional sample of 197 youths (PI and Comparison; 4–15 years old) we observed age-related group differences in diurnal slope. First replicating previous findings, PI children exhibited flattened diurnal slope. This group difference, however, was not observed in adolescents. Moderation analyses showed that pubertal development, increased time with family, and early adoption contributed to the steeper diurnal cortisol slope in PI adolescents. These findings add support to existing theories positing that the transition between middle childhood and adolescence may mark an additional sensitive period for diurnal cortisol patterning, allowing PI youth to benefit from the enriched environment provided by adoptive parents during this period of development. Keywords: Childhood, Adolescence, Stress, Enrichment, Early adversity

Decades of research have shown long-term effects of early caregiving adversity (ECA) on stress physiology and limbic brain volume (e.g. amygdala, hippocampus). Although these systems undergo significant maturational change during childhood and adolescence, and reciprocally influence each other, the effects of ECA on these developmental processes is not well understood. In the current study, we used an accelerated longitudinal design to assess the development of stress physiology, amygdala, and hippocampal volume following early institutional care. Previously Institutionalized (PI; N = 93) and comparison (COMP; N = 161) youth (ages 4-20 years old) completed 1-3 waves of data collection, each spaced approximately 2 years apart, for diurnal cortisol (N = 239, providing a total of 380 diurnal datasets), structural MRI (N = 156, providing a total of 306 scans) and parent-reported internalizing symptoms (N = 133, providing a total of 227 time points). We observed a developmental shift in morning cortisol in the PI group, with blunted levels in childhood and heightened levels in late adolescence. PI history was associated with reduced hippocampal volume and reduced growth rate of the amygdala, resulting in smaller volumes by adolescence. Results also suggested feed-forward brain-to-hormone mechanisms; amygdala and hippocampal volumes were prospectively associated with morning cortisol levels two years later. Finally, amygdala and hippocampal volumes were independently associated with internalizing scores. These results indicate that adversity-related physiological and neural phenotypes are not stationary during development but instead exhibit dynamic and interdependent changes from early childhood to early adulthood.

Given the importance of early prevention and intervention strategies for children exposed to trauma, detection of early risk factors for exposure to traumatic events in childhood is critical. The present study examined associations between three known prenatal risk factors that characterize environmental instability in utero-prenatal substance exposure, prenatal violence victimization, and unintended pregnancy-and child exposure to interparental violence and other adverse experiences in a sample of 198 mother-child dyads (M child age = 44.48 months) referred to a hospital clinic for treatment following exposure to trauma. Prenatal substance and violence exposure were associated with child trauma exposure, and prenatal violence victimization was also associated with maternal severity ratings of traumatic exposures. Unintended pregnancy was not associated with child trauma exposure or severity. These findings expand our understanding of prenatal risk factors for trauma exposure in childhood and, specifically, highlight prenatal substance exposure and violence victimization as risk factors for subsequent exposure to trauma in early childhood. Results suggest that prenatal prevention and intervention programs should target reducing maternal substance use and in-utero exposure to violence.Dada la importancia de las estrategias de prevención e intervención tempranas para niños expuestos al trauma, el detectar los tempranos factores de riesgo en el caso de estar expuesto a eventos traumáticos en la niñez es crítico. El presente estudio examinó las asociaciones entre tres conocidos factores de riesgo prenatales que caracterizan la inestabilidad ambiental en el útero -el haber estado expuesto a sustancias prenatalmente, la victimización de la violencia prenatal, y el embarazo no intencional -y el que el niño esté expuesto a la violencia entre progenitores (IPV) y otras experiencias adversas en un grupo muestra de 198 díadas madre-niño (edad promedio del niño = 44.48 meses) que habían sido referidas a una clínica hospital para el tratamiento que seguía al haber estado expuestos al trauma. El haber estado expuesto a sustancia y violencia prenatal se asoció con el hecho de que el niño había estado expuesto a trauma, y la victimización de la violencia prenatal también se asoció con la severidad maternal de clasificación de la exposición traumática. El embarazo no intencional no se asoció con la exposición del niño al trauma o la severidad. Estos resultados amplían nuestra comprensión de los factores de riesgo prenatales en cuanto al haber estado expuesto al trauma en la niñez y, específicamente, subrayan el haber estado expuesto a sustancias prenatalmente y la victimización de la violencia como subsecuentes factores de riesgo para estar expuesto al trauma en la temprana niñez. Los resultados sugieren que los programas de prevención e intervención prenatales deber enfocarse en reducir el uso de sustancias por parte de la madre y el estar expuesto dentro del útero a la violencia.Vu l'importance des stratégies de prévention précoce et d'intervention pour les enfants exposés au trauma, la détection de facteurs de risque précoce pour l'exposition à des événements traumatiques s'avère critique. Cette étude a examiné les liens entre trois facteurs de risque prénatals connus qui caractérisent l'instabilité environnementale in utero - l'exposition prénatale à des substances toxiques, la victimisation liée à la violence prénatale, et la grossesse involontaire - ainsi que l'exposition à la violence conjugale et d'autres expériences adverses chez un échantillon de 198 dyades mère-enfant (moyenne d’âge de l'enfant = 44,48 mois) envoyées consulter en clinique hospitalière pour un traitement suivant une exposition à un trauma. L'exposition à la toxicomanie et l'exposition à la violence étaient liées à l'exposition de l'enfant au trauma et la victimisation liée à la violence prénatale était également liée à la sévérité des scores maternels d'expositions traumatiques. La grossesse involontaire n’était pas liée à l'exposition au trauma de l'enfant ou à la sévérité. Ces résultats élargissent notre compréhension des facteurs prénatals d'exposition au trauma dans l'enfance et mettent en lumière plus spécifiquement l'exposition à la toxicomanie prénatale et la victimisation liée à la violence en tant que facteurs de risque d'exposition ultérieure au trauma durant la petite enfance. Les résultats suggèrent que la prévention prénatale et les programmes d'intervention devraient cibler la réduction d'utilisation toxicomane maternelle et l'exposition à la violence in-utero.Zusammenhänge zwischen pränataler Drogen- bzw. Gewaltexposition, ungewollter Schwangerschaft und Traumatisierung in der Kindheit in einem klinischen Setting Angesichts der Bedeutung früher Präventions- und Interventionsstrategien bei traumatisierten Kindern, ist die Aufdeckung potenzieller Risikofaktoren für Traumatisierung entscheidend. Die vorliegende Studie überprüft Zusammenhänge zwischen drei bekannten, eine Umgebungsinstabilität in utero charakterisierenden, pränatalen Risikofaktoren (pränatale Drogen- bzw. Gewaltexposition und ungewollte Schwangerschaft) und kindlicher Belastung durch zwischenelterliche Gewalt (interparental violence; IPV) sowie anderen widrigen Erfahrungen. Die Stichprobe bestand aus 198 Mutter-Kind Dyaden (mittleres Alter der Kinder = 44.48 Monate), die sich aufgrund traumatischer Erfahrungen in Behandlung begeben haben. Pränatale Drogen- bzw. Gewaltexposition wiesen Zusammenhänge zu kindlicher Traumatisierung auf. Des Weiteren wies pränatale Gewaltexposition auch einen Zusammenhang zu den mütterlichen Ratings der Traumaschwere auf. Ungewollte Schwangerschaft war nicht mit kindlicher Traumatisierung oder Traumaschwere assoziiert. Diese Ergebnisse ermöglichen es uns, pränatale Risikofaktoren für kindliche Traumatisierung besser zu verstehen. Insbesondere werden pränatale Drogen- und Gewaltexposition als Risikofaktoren für eine darauffolgende Traumatisierung in der frühen Kindheit hervorgehoben. Die Ergebnisse legen nahe, dass pränatale Präventions- und Interventionsprogramme darauf abzielen sollten, mütterlichen Drogenkonsum und Gewalterfahrungen in utero zu minimieren.胎児期の薬物暴露・胎児期の暴力虐待・予期せぬ妊娠と、臨床現場における小児期のトラウマ暴露の関連 トラウマに曝された子どもへの早期予防と介入の方法の重要性を考えると、小児期にトラウマとなる出来事に暴露される初期の危険因子を検出することは必須である。本研究は、トラウマに曝され治療のために病院の外来に紹介された198 組の母子 (子どもの平均年齢 44.48 ヶ月) において、胎内の環境不安定性を特徴づける３つの既知の出生前リスク因子−胎児期の薬物暴露、胎児期の暴力虐待、予期せぬ妊娠―と、パートナー間の暴力 (IPV) やその他の逆境体験に子どもが曝されること、との関連性を検討した。胎児期の薬物と暴力への暴露は、子どものトラウマ暴露と関連し、胎児期の暴力虐待は母親のトラウマ暴露の深刻さの評価とも関連した。予期せぬ妊娠は子どものトラウマ暴露や深刻さに関連していなかった。これらの結果から小児期のトラウマ暴露に関連する胎児期のリスク因子への我々の理解が広まり、特に胎児期の薬物暴露と暴力虐待は早期小児期のトラウマ暴露に引き続くリスク因子であると強調する。出生前の予防と介入プログラムは、母親の薬物使用と胎児期に暴力に晒されることを減らすことをターゲットにすべきであると、この結果から提案する。.產前物質使用丶產前暴力受害丶意外懷孕和兒童創傷在臨床環境中的關係 鑑於經歷過創傷的兒童早期預防和干預策略的重要性, 檢測兒童受創事件的早期風險因素至關重要。本研究在受創傷後轉診到醫院診所接受治療的 198 個母親-兒童二元組樣本中 (平均兒童年齡 = 44.48 個月), 探討三種已知的產前風險因素 - 產前使用物質丶產前暴力受害丶及意外懷孕 - 做成的不穩定環境與兒童經歷過父母間暴力 (IPV) 和其他不良經歷的關聯。母親產前物質使用和暴力經歷與兒童創傷有關, 產前暴力受害也與母親創傷的評分相關。意外懷孕與兒童創傷或嚴重程度無關。這些研究結果擴展了我們對兒童創傷的產前風險因素的理解, 特別強調產前物質使用和暴力受害, 是隨後兒童早期創傷的風險因素。結果表明, 產前預防和干預計劃的目標, 應該是減少母體物質使用和產前暴力經歷。.العلاقة بين التعرض للمواد المخدرة قبل الولادة، وإيذاء العنف قبل الولادة، والحمل غير المقصود، والتعرض للصدمات النفسية في مرحلة الطفولة في سياق إكلينيكي بالنظر إلى أهمية استراتيجيات الوقاية والتدخل المبكرة للأطفال المعرضين للصدمات النفسية، فإن الكشف عن عوامل الخطر المبكرة للتعرض للأحداث الصادمة في مرحلة الطفولة أمر بالغ الأهمية. تناولت هذه الدراسة الارتباطات بين ثلاثة عوامل خطر معروفة قبل الولادة تميز عدم الاستقرار البيئي في التعرض للمواد داخل الرحم قبل الولادة، والإيذاء أثناء الولادة، والحمل غير المقصود - وتعرض الأطفال للعنف بين الوالدين وغيره من التجارب السلبية في عينة من 198 من ثنائيات الأم والطفل (متوسط عمر الطفل = 44.48 شهراً) الذين تم إحالتهم إلى عيادة لتلقي العلاج بعد التعرض للصدمات. وترتبط المواد السابقة للولادة والتعرض للعنف بالتعرض لصدمات الأطفال، كما يرتبط الإيذاء الناجم عن العنف قبل الولادة بتقديرات الأم بشدة الصدمات. ولا يرتبط الحمل غير المقصود بالتعرض لصدمات الأطفال أو شدتها. وتوسع هذه النتائج فهمنا لعوامل الخطر قبل الولادة للتعرض للصدمات في مرحلة الطفولة، وعلى وجه التحديد، تسليط الضوء على التعرض لمواد ما قبل الولادة والإيذاء الناجم عن العنف كعوامل خطر للتعرض اللاحق للصدمات في مرحلة الطفولة المبكرة. وتشير النتائج إلى أن برامج الوقاية والتدخل قبل الولادة ينبغي أن تستهدف الحد من تعاطي المواد أثناء الحمل والتعرض للعنف داخل الرحم.

Background The human brain remains highly plastic for a protracted developmental period. Thus, although early caregiving adversities that alter amygdala development can result in enduring emotion regulation difficulties, these trajectories should respond to subsequent enriched caregiving. Exposure to high-quality parenting can regulate (i.e., decrease) children’s amygdala reactivity, a process that, over the long term, is hypothesized to enhance emotion regulation. We tested the hypothesis that even following adversity, the parent–child relationship would be associated with decreases in amygdala reactivity to parent cues, which would in turn predict lower future anxiety. Methods Participants were 102 children (6–10 years of age) and adolescents (11–17 years of age), for whom data were collected at one or two time points and who either had experienced institutional care before adoption (n = 45) or had lived always with their biological parents (comparison; n = 57). We examined how amygdala reactivity to visual cues of the parent at time 1 predicted longitudinal change (from time 1 to time 2) in parent-reported child anxiety across 3 years. Results At time 1, on average, amygdala reactivity decrements to parent cues were not seen in children who had received institutional care but were seen in children in the comparison group. However, some children who previously experienced institutional care did show decreased amygdala reactivity to parent cues (∼40%), which was associated with greater child-reported feelings of security with their parent. Amygdala decreases at time 1 were followed by steeper anxiety reductions from time 1 to time 2 (i.e., 3 years). Conclusions These data provide a neurobiological mechanism by which the parent–child relationship can increase resilience, even in children at significant risk for anxiety symptoms.

Anxiety and sleep function change dynamically across development, and sleep dysfunction has emerged as a correlate and predictor of anxiety in pediatric clinical samples. Despite this, previous research has not investigated how associations between qualitative and quantitative measures of sleep function change with anxiety across development, specifically from childhood to adolescence. The present study used actigraphy collection to examine whether associations between quantitative and qualitative sleep function and anxiety differed as a function of developmental stage in a community pediatric sample (8–17 years old; N = 92). Age moderated the association between anxiety and sleep quantity, but not sleep quality. Contrary to hypotheses, higher anxiety was related to increased sleep for children, but not adolescents. Results suggest age-related changes in the association between sleep function and anxiety across development, with implications for targeting sleep-related interventions for youth with anxiety.

Importance Incidental findings (IFs) are unexpected abnormalities discovered during imaging and can range from normal anatomic variants to findings requiring urgent medical intervention. In the case of brain magnetic resonance imaging (MRI), reliable data about the prevalence and significance of IFs in the general population are limited, making it difficult to anticipate, communicate, and manage these findings. Objectives To determine the overall prevalence of IFs in brain MRI in the nonclinical pediatric population as well as the rates of specific findings and findings for which clinical referral is recommended. Design, setting, and participants This cohort study was based on the April 2019 release of baseline data from 11 810 children aged 9 to 10 years who were enrolled and completed baseline neuroimaging in the Adolescent Brain Cognitive Development (ABCD) study, the largest US population-based longitudinal observational study of brain development and child health, between September 1, 2016, and November 15, 2018. Participants were enrolled at 21 sites across the US designed to mirror the demographic characteristics of the US population. Baseline structural MRIs were centrally reviewed for IFs by board-certified neuroradiologists and findings were described and categorized (category 1, no abnormal findings; 2, no referral recommended; 3; consider referral; and 4, consider immediate referral). Children were enrolled through a broad school-based recruitment process in which all children of eligible age at selected schools were invited to participate. Exclusion criteria were severe sensory, intellectual, medical, or neurologic disorders that would preclude or interfere with study participation. During the enrollment process, demographic data were monitored to ensure that the study met targets for sex, socioeconomic, ethnic, and racial diversity. Data were analyzed from March 15, 2018, to November 20, 2020. Main outcomes and measures Percentage of children with IFs in each category and prevalence of specific IFs. Results A total of 11 679 children (52.1% boys, mean [SD] age, 9.9 [0.62] years) had interpretable baseline structural MRI results. Of these, 2464 participants (21.1%) had IFs, including 2013 children (17.2%) assigned to category 2, 431 (3.7%) assigned to category 3, and 20 (0.2%) assigned to category 4. Overall rates of IFs did not differ significantly between singleton and twin gestations or between monozygotic and dizygotic twins, but heritability analysis showed heritability for the presence or absence of IFs (h2 = 0.260; 95% CI, 0.135-0.387). Conclusions and relevance Incidental findings in brain MRI and findings with potential clinical significance are both common in the general pediatric population. By assessing IFs and concurrent developmental and health measures and following these findings over the longitudinal study course, the ABCD study has the potential to determine the significance of many common IFs.

Early institutional care can be profoundly stressful for the human infant, and, as such, can lead to significant alterations in brain development. In animal models, similar variants of early adversity have been shown to modify amygdala-hippocampal-prefrontal cortex development and associated aversive learning. The current study examined this rearing aberration in human development. Eighty-nine children and adolescents who were either previously institutionalized (PI youth; N = 46; 33 females and 13 males; age range, 7-16 years) or were raised by their biological parents from birth (N = 43; 22 females and 21 males; age range, 7-16 years) completed an aversive-learning paradigm while undergoing functional neuroimaging, wherein visual cues were paired with either an aversive sound (CS+) or no sound (CS-). For the PI youth, better aversive learning was associated with higher concurrent trait anxiety. Both groups showed robust learning and amygdala activation for CS+ versus CS- trials. However, PI youth also exhibited broader recruitment of several regions and increased hippocampal connectivity with prefrontal cortex. Stronger connectivity between the hippocampus and ventromedial PFC predicted significant improvements in future anxiety (measured 2 years later), and this was particularly true within the PI group. These results suggest that for humans as well as for other species, early adversity alters the neurobiology of aversive learning by engaging a broader prefrontal-subcortical circuit than same-aged peers. These differences are interpreted as ontogenetic adaptations and potential sources of resilience.Prior institutionalization is a significant form of early adversity. While nonhuman animal research suggests that early adversity alters aversive learning and associated neurocircuitry, no prior work has examined this in humans. Here, we show that youth who experienced prior institutionalization, but not comparison youth, recruit the hippocampus during aversive learning. Among youth who experienced prior institutionalization, individual differences in aversive learning were associated with worse current anxiety. However, connectivity between the hippocampus and prefrontal cortex prospectively predicted significant improvements in anxiety 2 years following scanning for previously institutionalized youth. Among youth who experienced prior institutionalization, age-atypical engagement of a distributed set of brain regions during aversive learning may serve a protective function.

Anxiety disorders peak in incidence during adolescence, a developmental window that is marked by dynamic changes in gene expression, endocannabinoid signaling, and frontolimbic circuitry. We tested whether genetic alterations in endocannabinoid signaling related to a common polymorphism in fatty acid amide hydrolase (FAAH), which alters endocannabinoid anandamide (AEA) levels, would impact the development of frontolimbic circuitry implicated in anxiety disorders. In a pediatric imaging sample of over 1,000 3- to 21-y-olds, we show effects of the FAAH genotype specific to frontolimbic connectivity that emerge by ∼12 y of age and are paralleled by changes in anxiety-related behavior. Using a knock-in mouse model of the FAAH polymorphism that controls for genetic and environmental backgrounds, we confirm phenotypic differences in frontoamygdala circuitry and anxiety-related behavior by postnatal day 45 (P45), when AEA levels begin to decrease, and also, at P75 but not before. These results, which converge across species and level of analysis, highlight the importance of underlying developmental neurobiology in the emergence of genetic effects on brain circuitry and function. Moreover, the results have important implications for the identification of risk for disease and precise targeting of treatments to the biological state of the developing brain as a function of developmental changes in gene expression and neural circuit maturation.

Decision making in the context of risk is a complex and dynamic process that changes across development. Here, we assessed the influence of sensitivity to negative feedback (e.g., loss) and learning on age-related changes in risky decision making, both of which show unique developmental trajectories. In the present study, we examined risky decision making in 216 individuals, ranging in age from 3-26 years, using the balloon emotional learning task (BELT), a computerized task in which participants pump up a series of virtual balloons to earn points, but risk balloon explosion on each trial, which results in no points. It is important to note that there were 3 balloon conditions, signified by different balloon colors, ranging from quick- to slow-to-explode, and participants could learn the color-condition pairings through task experience. Overall, we found age-related increases in pumps made and points earned. However, in the quick-to-explode condition, there was a nonlinear adolescent peak for points earned. Follow-up analyses indicated that this adolescent phenotype occurred at the developmental intersection of linear age-related increases in learning and decreases in sensitivity to negative feedback. Adolescence was marked by intermediate values on both these processes. These findings show that a combination of linearly changing processes can result in nonlinear changes in risky decision making, the adolescent-specific nature of which is associated with developmental improvements in learning and reduced sensitivity to negative feedback.

One of the most important social identities that children learn to define themselves and others by is sex, becoming a salient social category by early childhood. Although older children begin to show greater flexibility in their gendered behaviors and attitudes, gender rigidity intensifies again around the time of puberty. In the current study, we assessed behavioral and neural biases to sex across a wide age group. Ninety-three youth (ages 7–17 years) provided behavioral rating of same- and opposite-sex attitudes, and 52 youth (ages 4–18 years) underwent an fMRI scan as they matched the emotion of same- and opposite-sex faces. We demonstrate significant age-related behavioral biases of sex that are mediated by differential amygdala response to opposite-sex relative to same-sex faces in children, an effect that completely attenuates by the teenage years. Moreover, we find a second peak in amygdala sensitivity to opposite-sex faces around the time of puberty. Thus, the amygdala codes for developmentally dependent and motivationally relevant social identification across development.

Incentives play a crucial role in guiding behavior throughout our lives, but perhaps no more so than during the early years of life. The ventral striatum is a critical piece of an incentive-based learning circuit, sharing robust anatomical connections with subcortical (e.g., amygdala, hippocampus) and cortical structures (e.g., medial prefrontal cortex (mPFC), insula) that collectively support incentive valuation and learning. Resting-state functional connectivity (rsFC) is a powerful method that provides insight into the development of the functional architecture of these connections involved in incentive-based learning. We employed a seed-based correlation approach to investigate ventral striatal rsFC in a cross-sectional sample of typically developing individuals between the ages of 4.5 and 23-years old (n=66). Ventral striatal rsFC with the mPFC showed regionally specific linear age-related changes in connectivity that were associated with age-related increases in circulating testosterone levels. Further, ventral striatal connectivity with the posterior hippocampus and posterior insula demonstrated quadratic age-related changes characterized by negative connectivity in adolescence. Finally, across this age range, the ventral striatum demonstrated positive coupling with the amygdala beginning during childhood and remaining consistently positive across age. In sum, our findings suggest that normative ventral striatal rsFC development is dynamic and characterized by early establishment of connectivity with medial prefrontal and limbic structures supporting incentive-based learning, as well as substantial functional reorganization with later developing regions during transitions into and out of adolescence.

Resting-state functional connectivity (FC) fMRI (rs-fcMRI) offers an appealing approach to mapping the brain's intrinsic functional organization. Blood oxygen level dependent (BOLD) and arterial spin labeling (ASL) are the two main rs-fcMRI approaches to assess alterations in brain networks associated with individual differences, behavior and psychopathology. While the BOLD signal is stronger with a higher temporal resolution, ASL provides quantitative, direct measures of the physiology and metabolism of specific networks. This study systematically investigated the similarity and reliability of resting brain networks (RBNs) in BOLD and ASL. A 2 × 2 × 2 factorial design was employed where each subject underwent repeated BOLD and ASL rs-fcMRI scans on two occasions on two MRI scanners respectively. Both independent and joint FC analyses revealed common RBNs in ASL and BOLD rs-fcMRI with a moderate to high level of spatial overlap, verified by Dice Similarity Coefficients. Test-retest analyses indicated more reliable spatial network patterns in BOLD (average modal Intraclass Correlation Coefficients: 0.905 ± 0.033 between-sessions; 0.885 ± 0.052 between-scanners) than ASL (0.545 ± 0.048; 0.575 ± 0.059). Nevertheless, ASL provided highly reproducible (0.955 ± 0.021; 0.970 ± 0.011) network-specific CBF measurements. Moreover, we observed positive correlations between regional CBF and FC in core areas of all RBNs indicating a relationship between network connectivity and its baseline metabolism. Taken together, the combination of ASL and BOLD rs-fcMRI provides a powerful tool for characterizing the spatiotemporal and quantitative properties of RBNs. These findings pave the way for future BOLD and ASL rs-fcMRI studies in clinical populations that are carried out across time and scanners.

Multisite neuroimaging studies can facilitate the investigation of brain-related changes in many contexts, including patient groups that are relatively rare in the general population. Though multisite studies have characterized the reliability of brain activation during working memory and motor functional magnetic resonance imaging tasks, emotion processing tasks, pertinent to many clinical populations, remain less explored. A traveling participants study was conducted with eight healthy volunteers scanned twice on consecutive days at each of the eight North American Longitudinal Prodrome Study sites. Tests derived from generalizability theory showed excellent reliability in the amygdala ( Eρ2 = 0.82), inferior frontal gyrus (IFG; Eρ2 = 0.83), anterior cingulate cortex (ACC; Eρ2 = 0.76), insula ( Eρ2 = 0.85), and fusiform gyrus ( Eρ2 = 0.91) for maximum activation and fair to excellent reliability in the amygdala ( Eρ2 = 0.44), IFG ( Eρ2 = 0.48), ACC ( Eρ2 = 0.55), insula ( Eρ2 = 0.42), and fusiform gyrus ( Eρ2 = 0.83) for mean activation across sites and test days. For the amygdala, habituation ( Eρ2 = 0.71) was more stable than mean activation. In a second investigation, data from 111 healthy individuals across sites were aggregated in a voxelwise, quantitative meta-analysis. When compared with a mixed effects model controlling for site, both approaches identified robust activation in regions consistent with expected results based on prior single-site research. Overall, regions central to emotion processing showed strong reliability in the traveling participants study and robust activation in the aggregation study. These results support the reliability of blood oxygen level-dependent signal in emotion processing areas across different sites and scanners and may inform future efforts to increase efficiency and enhance knowledge of rare conditions in the population through multisite neuroimaging paradigms.

Multi-site neuroimaging studies offer an efficient means to study brain functioning in large samples of individuals with rare conditions; however, they present new challenges given that aggregating data across sites introduces additional variability into measures of interest. Assessing the reliability of brain activation across study sites and comparing statistical methods for pooling functional data are critical to ensuring the validity of aggregating data across sites. The current study used two samples of healthy individuals to assess the feasibility and reliability of aggregating multi-site functional magnetic resonance imaging (fMRI) data from a Sternberg-style verbal working memory task. Participants were recruited as part of the North American Prodrome Longitudinal Study (NAPLS), which comprises eight fMRI scanning sites across the United States and Canada. In the first study sample (n= 8), one participant from each home site traveled to each of the sites and was scanned while completing the task on two consecutive days. Reliability was examined using generalizability theory. Results indicated that blood oxygen level-dependent (BOLD) signal was reproducible across sites and was highly reliable, or generalizable, across scanning sites and testing days for core working memory ROIs (generalizability ICCs. = 0.81 for left dorsolateral prefrontal cortex, 0.95 for left superior parietal cortex). In the second study sample (n= 154), two statistical methods for aggregating fMRI data across sites for all healthy individuals recruited as control participants in the NAPLS study were compared. Control participants were scanned on one occasion at the site from which they were recruited. Results from the image-based meta-analysis (IBMA) method and mixed effects model with site covariance method both showed robust activation in expected regions (i.e. dorsolateral prefrontal cortex, anterior cingulate cortex, supplementary motor cortex, superior parietal cortex, inferior temporal cortex, cerebellum, thalamus, basal ganglia). Quantification of the similarity of group maps from these methods confirmed a very high (96%) degree of spatial overlap in results. Thus, brain activation during working memory function was reliable across the NAPLS sites and both the IBMA and mixed effects model with site covariance methods appear to be valid approaches for aggregating data across sites. These findings indicate that multi-site functional neuroimaging can offer a reliable means to increase power and generalizability of results when investigating brain function in rare populations and support the multi-site investigation of working memory function in the NAPLS study, in particular. © 2014 Elsevier Inc.

Functional connectivity (FC) between the amygdala and the ventromedial prefrontal cortex underlies socioemotional functioning, a core domain of impairment in autism spectrum disorder (ASD). Although frontoamygdala circuitry undergoes dynamic changes throughout development, little is known about age-related changes in frontoamygdala networks in ASD. Here we characterize frontoamygdala resting-state FC in a cross-sectional sample (ages 7–25) of 58 typically developing (TD) individuals and 53 individuals with ASD. Contrary to hypotheses, individuals with ASD did not show different age-related patterns of frontoamygdala FC compared with TD individuals. However, overall group differences in frontoamygdala FC were observed. Specifically, relative to TD individuals, individuals with ASD showed weaker frontoamygdala FC between the right basolateral (BL) amygdala and the rostral anterior cingulate cortex (rACC). These findings extend prior work to a broader developmental range in ASD, and indicate ASD-related differences in frontoamygdala FC that may underlie core socioemotional impairments in children and adolescents with ASD. Keywords: Autism spectrum disorder (ASD), Amygdala, Development, Resting-state functional connectivity, Adolescence, Prefrontal cortex

Background Significant disruption in caregiving is associated with increased internalizing symptoms, most notably heightened separation anxiety symptoms during childhood. It is also associated with altered functional development of the amygdala, a neurobiological correlate of anxious behavior. However, much less is known about how functional alterations of amygdala predict individual differences in anxiety. Here, we probed amygdala function following institutional caregiving using very subtle social-affective stimuli (trustworthy and untrustworthy faces), which typically result in large differences in amygdala signal, and change in separation anxiety behaviors over a 2-year period. We hypothesized that the degree of differentiation of amygdala signal to trustworthy versus untrustworthy face stimuli would predict separation anxiety symptoms. Methods Seventy-four youths mean (SD) age = 9.7 years (2.64) with and without previous institutional care, who were all living in families at the time of testing, participated in an fMRI task designed to examine differential amygdala response to trustworthy versus untrustworthy faces. Parents reported on their children's separation anxiety symptoms at the time of scan and again 2 years later. Results Previous institutional care was associated with diminished amygdala signal differences and behavioral differences to the contrast of untrustworthy and trustworthy faces. Diminished differentiation of these stimuli types predicted more severe separation anxiety symptoms 2 years later. Older age at adoption was associated with diminished differentiation of amygdala responses. Conclusions A history of institutional care is associated with reduced differential amygdala responses to social-affective cues of trustworthiness that are typically exhibited by comparison samples. Individual differences in the degree of amygdala differential responding to these cues predict the severity of separation anxiety symptoms over a 2-year period. These findings provide a biological mechanism to explain the associations between early caregiving adversity and individual differences in internalizing symptomology during development, thereby contributing to individualized predictions of future clinical outcomes.

Although the functional architecture of the brain is indexed by resting-state connectivity networks, little is currently known about the mechanisms through which these networks assemble into stable mature patterns. The current study posits and tests the long-term phasic molding hypothesis that resting-state networks are gradually shaped by recurring stimulus-elicited connectivity across development by examining how both stimulus-elicited and resting-state functional connections of the human brain emerge over development at the systems level. Using a sequential design following 4- to 18-year-olds over a 2 year period, we examined the predictive associations between stimulus-elicited and resting-state connectivity in amygdala-cortical circuitry as an exemplar case (given this network's protracted development across these ages). Age-related changes in amygdala functional connectivity converged on the same regions of medial prefrontal cortex (mPFC) and inferior frontal gyrus when elicited by emotional stimuli and when measured at rest. Consistent with the long-term phasic molding hypothesis, prospective analyses for both connections showed that the magnitude of an individual's stimulus-elicited connectivity unidirectionally predicted resting-state functional connectivity 2 years later. For the amygdala-mPFC connection, only stimulus-elicited connectivity during childhood and the transition to adolescence shaped future resting-state connectivity, consistent with a sensitive period ending with adolescence for the amygdala-mPFC circuit. Together, these findings suggest that resting-state functional architecture may arise from phasic patterns of functional connectivity elicited by environmental stimuli over the course of development on the order of years.SIGNIFICANCE STATEMENTA fundamental issue in understanding the ontogeny of brain function is how resting-state (intrinsic) functional networks emerge and relate to stimulus-elicited functional connectivity. Here, we posit and test the long-term phasic molding hypothesis that resting-state network development is influenced by recurring stimulus-elicited connectivity through prospective examination of the developing human amygdala-cortical functional connections. Our results provide critical insight into how early environmental events sculpt functional network architecture across development and highlight childhood as a potential developmental period of heightened malleability for the amygdala-medial prefrontal cortex circuit. These findings have implications for how both positive and adverse experiences influence the developing brain and motivate future investigations of whether this molding mechanism reflects a general phenomenon of brain development.

Emotion processing deficits are prominent in schizophrenia and exist prior to the onset of overt psychosis. However, developmental trajectories of neural circuitry subserving emotion regulation and the role that they may play in illness onset have not yet been examined in patients at risk for psychosis. The present study employed a cross-sectional analysis to examine age-related functional activation in amygdala and prefrontal cortex, as well as functional connectivity between these regions, in adolescents at clinical high risk (CHR) for psychosis relative to typically developing adolescents. Participants (n=34) performed an emotion processing fMRI task, including emotion labeling, emotion matching, and non-emotional control conditions. Regression analyses were used to predict activation in the amygdala and ventrolateral prefrontal cortex (vlPFC) based on age, group, sex, and the interaction of age by group. CHR adolescents exhibited altered age-related variation in amygdala and vlPFC activation, relative to controls. Controls displayed decreased amygdala and increased vlPFC activation with age, while patients exhibited the opposite pattern (increased amygdala and decreased vlPFC activation), suggesting a failure of prefrontal cortex to regulate amygdala reactivity. Moreover, a psychophysiological interaction analysis revealed decreased amygdala-prefrontal functional connectivity among CHR adolescents, consistent with disrupted brain connectivity as a vulnerability factor in schizophrenia. These results suggest that the at-risk syndrome is marked by abnormal development and functional connectivity of neural systems subserving emotion regulation. Longitudinal data are needed to confirm aberrant developmental trajectories intra-individually and to examine whether these abnormalities are predictive of conversion to psychosis, and of later deficits in socioemotional functioning.

Resting-state functional magnetic resonance imaging (fMRI) has provided a novel approach for examining interhemispheric interaction, demonstrating a high degree of functional connectivity between homotopic regions in opposite hemispheres. However, heterotopic resting-state functional connectivity (RSFC) remains relatively uncharacterized. In the present study, we examine non-homotopic regions, characterizing heterotopic RSFC and comparing it to intrahemispheric RSFC, to examine the impact of hemispheric separation on the integration and segregation of processing in the brain. Resting-state fMRI scans were acquired from 59 healthy participants to examine inter-regional correlations in spontaneous low frequency fluctuations in BOLD signal. Using a probabilistic atlas, we correlated probability-weighted time series from 112 regions (56 per hemisphere) distributed throughout the entire cerebrum. We compared RSFC for pairings of non-homologous regions located in different hemispheres (heterotopic connectivity) to RSFC for the same pairings when located within hemisphere (intrahemispheric connectivity). For positive connections, connectivity strength was greater within each hemisphere, consistent with integrated intrahemispheric processing. However, for negative connections, RSFC strength was greater between the hemispheres, consistent with segregated interhemispheric processing. These patterns were particularly notable for connections involving frontal and heteromodal regions. The distribution of positive and negative connectivity was nearly identical within and between the hemispheres, though we demonstrated detailed regional variation in distribution. We discuss implications for leading models of interhemispheric interaction. The future application of our analyses may provide important insight into impaired interhemispheric processing in clinical and aging populations.

Anxiety is linked to compromised interactions between the amygdala and the dorsal and ventral medial prefrontal cortex (mPFC). While numerous task-based neuroimaging studies show that anxiety levels predict amygdala-mPFC connectivity and response magnitude, here we tested the hypothesis that anxiety would predict functional connectivity between these brain regions even during rest. Resting-state functional magnetic resonance imaging scans and self-reported measures of anxiety were acquired from healthy subjects. At rest, individuals with high anxiety were characterized by negatively correlated amygdala-ventral mPFC functional connectivity, while low anxious subjects showed positively correlated activity. Further, high anxious subjects showed amygdala-dorsal mPFC activity that was uncorrelated, while low anxious subjects showed negatively correlated activity. These data show that amygdala-mPFC connectivity at rest indexes normal individual differences in anxiety.

Major depressive disorder (MDD) begins frequently in adolescence and is associated with severe outcomes, but the developmental neurobiology of MDD is not well understood. Research in adults has implicated fronto-limbic neural networks in the pathophysiology of MDD, particularly in relation to the subgenual anterior cingulate cortex (ACC). Developmental changes in brain networks during adolescence highlight the need to examine MDD-related circuitry in teens separately from adults. Using resting state functional magnetic resonance imaging (fMRI), this study examined functional connectivity in adolescents with MDD (n = 12) and healthy adolescents (n = 14). Seed-based connectivity analysis revealed that adolescents with MDD have decreased functional connectivity in a subgenual ACC-based neural network that includes the supragenual ACC (BA 32), the right medial frontal cortex (BA 10), the left inferior (BA 47) and superior frontal cortex (BA 22), superior temporal gyrus (BA 22), and the insular cortex (BA 13). These preliminary data suggest that MDD in adolescence is associated with abnormal connectivity within neural circuits that mediate emotion processing. Future research in larger, un-medicated samples will be necessary to confirm this finding. We conclude that hypothesis-driven, seed-based analyses of resting state fMRI data hold promise for advancing our current understanding of abnormal development of neural circuitry in adolescents with MDD.

Human cerebral development is remarkably protracted. Although microstructural processes of neuronal maturation remain accessible only to morphometric post-mortem studies, neuroimaging tools permit the examination of macrostructural aspects of brain development. The analysis of resting-state functional connectivity (FC) offers novel possibilities for the investigation of cerebral development. Using seed-based FC methods, we examined the development of 5 functionally distinct cingulate-based intrinsic connectivity networks (ICNs) in children (n = 14, 10.6 +/- 1.5 years), adolescents (n = 12, 15.4 +/- 1.2) and young adults (n=14, 22.4 +/- 1.2). Children demonstrated a more diffuse pattern of correlation with voxels proximal to the seed region of interest (ROI) ("local FC"), whereas adults exhibited more focal patterns of FC, as well as a greater number of significantly correlated voxels at long distances from the seed ROI. Adolescents exhibited intermediate patterns of FC. Consistent with evidence for different maturational time courses, ICNs associated with social and emotional functions exhibited the greatest developmental effects. Our findings demonstrate the utility of FC for the study of developing functional organization. Moreover, given that ICNs are thought to have an anatomical basis in neuronal connectivity, measures of FC may provide a quantitative index of brain maturation in healthy subjects and those with neurodevelopmental disorders.

Mature amygdala-prefrontal circuitry regulates affect in adulthood but shows protracted development. In altricial and semialtricial species, caregivers provide potent affect regulation when mature neurocircuitry is absent. The present investigation examined a potential mechanism through which caregivers provide regulatory influences in childhood. Children, but not adolescents, showed evidence of maternal buffering, such that maternal stimuli suppressed amygdala reactivity. In the absence of maternal stimuli, children exhibited immature amygdala-prefrontal connectivity. However, in the presence of maternal stimuli, children’s connectivity was more mature, resembling adolescents’ connectivity. Children showed improved affect-related regulation in the presence of their mothers. Individual differences emerged, with greater maternal influence on amygdala-prefrontal circuitry associated with stronger mother-child relationships and maternal modulation of behavioral regulation. These findings suggest a neural mechanism through which caregivers modulate children’s regulatory behavior by inducing more mature connectivity and buffering against heightened reactivity. Maternal buffering in childhood, but not adolescence, suggests that childhood may be a sensitive period for amygdala-prefrontal development.

Functional connections (FC) between the amygdala and cortical and subcortical regions underlie a range of affective and cognitive processes. Despite the central role amygdala networks have in these functions, the normative developmental emergence of FC between the amygdala and the rest of the brain is still largely undefined. This study employed amygdala subregion maps and resting-state functional magnetic resonance imaging to characterize the typical development of human amygdala FC from age 4 to 23 years old (n = 58). Amygdala FC with subcortical and limbic regions was largely stable across this developmental period. However, three cortical regions exhibited age-dependent changes in FC: amygdala FC with the medial prefrontal cortex (mPFC) increased with age, while amygdala FC with a region including the insula and superior temporal sulcus decreased with age, and amygdala FC with a region encompassing the parahippocampal gyrus and posterior cingulate also decreased with age. The transition from childhood to adolescence (around age 10 years) marked an important change-point in the nature of amygdala-cortical FC. We distinguished unique developmental patterns of coupling for three amygdala subregions and found particularly robust convergence of FC for all subregions with the mPFC. These findings suggest that there are extensive changes in amygdala-cortical functional connectivity that emerge between childhood and adolescence.

Recent human imaging and animal studies highlight the importance of frontoamygdala circuitry in the regulation of emotional behavior and its disruption in anxiety-related disorders. Although tracing studies have suggested changes in amygdala–cortical connectivity through the adolescent period in rodents, less is known about the reciprocal connections within this circuitry across human development, when these circuits are being fine-tuned and substantial changes in emotional control are observed. The present study examined developmental changes in amygdala–prefrontal circuitry across the ages of 4–22 years using task-based functional magnetic resonance imaging. Results suggest positive amygdala–prefrontal connectivity in early childhood that switches to negative functional connectivity during the transition to adolescence. Amygdala–medial prefrontal cortex functional connectivity was significantly positive (greater than zero) among participants younger than 10 years, whereas functional connectivity was significantly negative (less than zero) among participants 10 years and older, over and above the effect of amygdala reactivity. The developmental switch in functional connectivity was paralleled by a steady decline in amygdala reactivity. Moreover, the valence switch might explain age-related improvement in task performance and a developmentally normative decline in anxiety. Initial positive connectivity followed by a valence shift to negative connectivity provides a neurobiological basis for regulatory development and may present novel insight into a more general process of developing regulatory connections.

Depression is a common outcome for those having experienced early-life stress (ELS). For those individuals, depression typically increases during adolescence and appears to endure into adulthood, suggesting alterations in the development of brain systems involved in depression. Developmentally, the nucleus accumbens (NAcc), a limbic structure associated with reward learning and motivation, typically undergoes dramatic functional change during adolescence; therefore, age-related changes in NAcc function may underlie increases in depression in adolescence following ELS. The current study examined the effects of ELS in 38 previously institutionalized children and adolescents in comparison to a group of 31 youths without a history of ELS. Consistent with previous research, the findings showed that depression was higher in adolescents than children with a history of ELS. Additionally, functional magnetic resonance imaging results showed atypical NAcc development, where the ELS group did not show a typical increase in NAcc reactivity during adolescence. Consequently, the ELS group showed NAcc hypoactivation during adolescence, and lower NAcc reactivity was correlated with higher depression scores. The results have important implications for understanding how ELS may influence increases in depression via neural development during the transition to adolescence and highlight the importance of identifying at-risk individuals in childhood, a potential critical period for depression-targeted intervention.

Background The recent upsurge in interest about pediatric bipolar disorder (BD) has spurred the need for greater understanding of its neurobiology. Structural and functional magnetic resonance imaging studies have implicated fronto-temporal dysfunction in pediatric BD. However, recent data suggest that task-dependent neural changes account for a small fraction of the brain's energy consumption. We now report the first use of task-independent spontaneous resting state functional connectivity (RSFC) to study the neural underpinnings of pediatric BD. Methods We acquired task-independent RSFC blood oxygen level-dependent functional magnetic resonance imaging scans while participants were at rest and also a high-resolution anatomical image (both at three Tesla) in BD and control youths ( n = 15 of each). We focused, on the basis of prior research, on the left dorsolateral prefrontal cortex (DLPFC), amygdala, and accumbens. Image processing and group-level analyses followed that of prior work. Results Our primary analysis showed that pediatric BD participants had significantly greater negative RSFC between the left DLPFC and the right superior temporal gyrus versus control subjects. Secondary analyses using partial correlation showed that BD and control youths had opposite phase relationships between spontaneous RSFC fluctuations in the left DLPFC and right superior temporal gyrus. Conclusions Our data indicate that pediatric BD is characterized by altered task-independent functional connectivity in a fronto-temporal circuit that is also implicated in working memory and learning. Further study is warranted to determine the effects of age, gender, development, and treatment on this circuit in pediatric BD.

Electrophysiological studies have long demonstrated a high degree of correlated activity between the left and right hemispheres, however little is known about regional variation in this interhemispheric coordination. Whereas cognitive models and neuroanatomical evidence suggest differences in coordination across primary sensory-motor cortices versus higher-order association areas, these have not been characterized. Here, we used resting-state functional magnetic resonance imaging data acquired from 62 healthy volunteers to examine interregional correlation in spontaneous low-frequency hemodynamic fluctuations. Using a probabilistic atlas, we correlated probability-weighted time series from 112 regions comprising the entire cerebrum. We then examined regional variation in correlated activity between homotopic regions, contrasting primary sensory-motor cortices, unimodal association areas, and heteromodal association areas. Consistent with previous studies, robustly correlated spontaneous activity was noted between all homotopic regions, which was significantly higher than that between nonhomotopic (heterotopic and intrahemispheric) regions. We further demonstrated substantial regional variation in homotopic interhemispheric correlations that was highly consistent across subjects. Specifically, there was a gradient of interhemispheric correlation, with highest correlations across primary sensory-motor cortices (0.758, SD = 0.152), significantly lower correlations across unimodal association areas (0.597, SD = 0.230) and still lower correlations across heteromodal association areas (0.517, SD = 0.226). These results demonstrate functional differences in interhemispheric coordination related to the brain's hierarchical subdivisions. Synchrony across primary cortices may reflect networks engaged in bilateral sensory integration and motor coordination, whereas lower coordination across heteromodal association areas is consistent with functional lateralization of these regions. This novel method of examining interhemispheric coordination may yield insights regarding diverse disease processes as well as healthy development.