Childhood Maltreatment and Amygdala-Mediated Anxiety and Posttraumatic Stress Following Adult Trauma.

Background: Childhood abuse (physical, emotional, and sexual) is associated with aberrant connectivity of the amygdala, a key threat-processing region. Heightened amygdala activity also predicts adult anxiety and posttraumatic stress disorder (PTSD) symptoms, as do experiences of childhood abuse. The current study explored whether amygdala resting-state functional connectivity may explain the relationship between childhood abuse and anxiety and PTSD symptoms following trauma exposure in adults. Methods: Two weeks posttrauma, adult trauma survivors (n = 152, mean age [SD] = 32.61 [10.35] years; women = 57.2%) completed the Childhood Trauma Questionnaire and underwent resting-state functional magnetic resonance imaging. PTSD and anxiety symptoms were assessed 6 months posttrauma. Seed-to-voxel analyses evaluated the association between childhood abuse and amygdala resting-state functional connectivity. A mediation model evaluated the potential mediating role of amygdala connectivity in the relationship between childhood abuse and posttrauma anxiety and PTSD. Results: Childhood abuse was associated with increased amygdala connectivity with the precuneus while covarying for age, gender, childhood neglect, and baseline PTSD symptoms. Amygdala-precuneus resting-state functional connectivity was a significant mediator of the effect of childhood abuse on anxiety symptoms 6 months posttrauma (B = 0.065; 95% CI, 0.013-0.130; SE = 0.030), but not PTSD. A secondary mediation analysis investigating depression as an outcome was not significant. Conclusions: Amygdala-precuneus connectivity may be an underlying neural mechanism by which childhood abuse increases risk for anxiety following adult trauma. Specifically, this heightened connectivity may reflect attentional vigilance for threat or a tendency toward negative self-referential thoughts. Findings suggest that childhood abuse may contribute to longstanding upregulation of attentional vigilance circuits, which makes one vulnerable to anxiety-related symptoms in adulthood.

Experiences of childhood abuse are related to long-term mental health outcomes, but the mechanisms of this relationship have been unclear. In this study of adult trauma survivors, Harb et al. found that experiences of childhood abuse are related to abnormal connectivity patterns of the amygdala, a key region for fear and threat processing, and precuneus. These connectivity patterns were identified as a mechanism through which experiences of child abuse are related to adult anxiety symptoms posttrauma. These findings advance our understanding of the specific downstream impacts of experiencing childhood abuse and can inform targeted assessment and intervention methods, especially in an adult trauma sample.

The Dichotomy of Threat and Deprivation as Subtypes of Childhood Maltreatment: Differential Functional Connectivity Patterns of Threat and Reward Circuits in an Adult Trauma Sample.

BACKGROUND: Childhood maltreatment is associated with reduced activation of the nucleus accumbens, a central region in the reward network, and overactivity in the amygdala, a key region in threat processing. However, the long-lasting impact of these associations in the context of later-life stress is not well understood. The current study explored the association between childhood threat and deprivation and functional connectivity of threat and reward regions in an adult trauma sample. METHODS: Trauma survivors (N = 169; mean age [SD] = 32.2 [10.3] years; female = 55.6%) were recruited from a level I trauma center. Two weeks after injury, participants completed the Childhood Trauma Questionnaire (measuring experiences of threat and deprivation) and underwent resting-state functional magnetic resonance imaging. Seed-to-voxel analyses evaluated the effect of childhood threat and deprivation on amygdala and nucleus accumbens resting-state connectivity. RESULTS: Higher levels of threat were associated with increased connectivity between the right nucleus accumbens with temporal fusiform gyrus/parahippocampal gyrus and the left amygdala and the precuneus (false discovery rate-corrected p < .05). After controlling for posttraumatic symptoms 2 weeks posttrauma and lifetime trauma exposure, only the nucleus accumbens findings survived. There were no significant relationships between experiences of childhood deprivation and amygdala or nucleus accumbens connectivity. CONCLUSIONS: Experiences of threat are associated with increased nucleus accumbens and amygdala connectivity, which may reflect a preparedness to detect salient and visual stimuli. This may also reflect a propensity toward dysregulated reward processing. Overall, these results suggest that childhood threat may be contributing to aberrant neural baseline reward and threat sensitivity later in life in an adult trauma sample.

Differences in parent and youth perceived neighborhood threat on nucleus accumbens-frontoparietal network resting state connectivity and alcohol sipping in children enrolled in the ABCD study.

Purpose: Evidence has shown neighborhood threat (NT) as a social driver of emotional and brain development. Few studies have examined the relationship between NT and neural function. Altered functional connectivity in the nucleus accumbens (NAcc) with the frontoparietal network (FPN) has been implicated in the development of substance use, however, little is known about perceived NT-related brain function or downstream alcohol sipping during early adolescence. This study examined the longitudinal relationship between youth and combined youth/parent perceived NT, resting state functional connectivity (RSFC) of the NAcc-FPN, and alcohol sipping behavior during late childhood and preadolescence. Methods: This study used data (N = 7,744) from baseline to 2-year follow-up (FU) of the Adolescent Brain Cognitive Development Study (ABCD; Release 4.0). Relationships between youth and combined youth/parent perceive NT, alcohol sipping (baseline to two-year FU), and NAcc-FPN (left/right) connectivity, adjusting for demographics, family/peer history of alcohol use, parental monitoring and warmth, externalizing symptoms, and site, were examined in a mediation model via PROCESS in R. Results: Greater youth-reported NT at baseline was significantly associated with lower RSFC between the right (but not left) NAcc-FPN holding covariates constant (R2 = 0.01, B = -0.0019 (unstandardized), F (12, 7,731) = 8.649, p = 0.0087) and increased odds of alcohol sipping at baseline up to the two-year FU (direct effect = 0.0731, 95% CI = 0.0196, 0.1267). RSFC between the right NAcc-FPN did not significantly predict alcohol sipping at the two-year FU (b = -0.0213, SE = 0.42349, p = 0.9599; 95% CI = -0.8086, 0.8512). No significant relationships were observed for combined youth/parent report predicting alcohol sipping or NAcc-FPN connectivity. Conclusion: Findings suggest notable reporting differences in NT. Combined youth/parent report did not reveal significant findings; youth perceived NT was related to increased likelihood of alcohol sipping and lower neural connectivity between the right NAcc-FPN during late childhood and early adolescence. NT context - and source of reporting - may be crucial in examining links with downstream neuronal function and health behaviors. Future research should investigate reward processing and threat as the cohort ages into later adolescence.

Gray space and default mode network-amygdala connectivity.

Introduction: Aspects of the built environment relate to health factors and equity in living conditions, and may contribute to racial, ethnic, or economic health disparities. For example, urbanicity is linked with negative factors including exposure to gray space (e.g., impervious surfaces such as concrete, streets, or rooftops). While there is existing research on access to green space and urbanicity on some mental health and cognitive outcomes, there is limited research on the presence of gray space linked with cognitive functioning in youth. The goal of this study was to investigate the link between gray space and amygdala-default mode network (DMN) connectivity. Methods: This study used data from the ABCD Study. Participants (n = 10,144; age M = 119.11 months, female = 47.62%) underwent resting-state fMRI acquisition at baseline. Impervious surfaces (gray space) were measured via the Child Opportunity Index (COI). To examine the relationship between presence of gray space and -amygdala-DMN (left/right) connectivity, we employed linear mixed effects models. Correlations were run between amygdala-DMN connectivity and internalizing and externalizing symptoms. Finally, post hoc sensitivity analyses were run to assess the impact of race. Results: More gray space, adjusting for age, sex, and neighborhood-level variables, was significantly associated with increased left amygdala-DMN connectivity (p = 0.0001). This association remained significant after sensitivity analyses for race were completed (p = 0.01). No significant correlations were observed between amygdala-DMN and internalizing or externalizing symptoms. Discussion: Findings suggest gray space was linked with increased left amygdala-DMN connectivity, circuits that have been implicated in affective processing, emotion regulation, and psychopathology. Thus gray space may be related to alterations in connectivity that may enhance risk for emotion dysregulation. Future investigation of these relationships is needed, as neuroimaging findings may represent early dysregulation not yet observed in the behavioral analyses at this age (i.e., the present study did not find significant relationships with parent-reported behavioral outcomes). These findings can help to inform future public policy on improving lived and built environments.

Irritability in early to middle childhood: Cross-sectional and longitudinal associations with resting state amygdala and ventral striatum connectivity.

BACKGROUND: Irritability is a common symptom that may affect children's brain development. This study aims to (1) characterize age-dependent and age-independent neural correlates of irritability in a sample of 4-8 year old children, and (2) examine early irritability as a predictor of change in brain connectivity over time. METHODS: Typically developing children, ages 4-8 years, with varying levels of irritability were included. Resting state fMRI and parent-rated irritability (via Child Behavior Checklist; CBCL) were collected at up to three time points, resulting in a cross-sectional sample at baseline (N = 176, M = 6.27, SD = 1.49), and two subsamples consisting of children who were either 4 or 6 years old at baseline that were followed longitudinally for two additional timepoints, one- and two-years post-baseline. That is, a "younger" cohort (age 4 at baseline, n = 34, M age = 4.44, SD = 0.25) and an "older" cohort (age 6 at baseline, n = 29, M age = 6.50, SD = 0.30). Across our exploratory analyses, we examined how irritability related to seed-based intrinsic connectivity via whole-brain connectivity ANCOVAs using the left and right amygdala, and left and right ventral striatum as seed regions. RESULTS: Cross-sectionally, higher levels of irritability were associated with greater amygdala connectivity with the posterior cingulate, controlling for child age. No age-dependent effects were observed in the cross-sectional analyses. Longitudinal analyses in the younger cohort revealed that early higher vs. lower levels of irritability, controlling for later irritability, were associated with decreases in amygdala and ventral striatum connectivity with multiple frontal and parietal regions over time. There were no significant findings in the older cohort. CONCLUSIONS: Findings suggest that irritability is related to altered neural connectivity during rest regardless of age in early to middle childhood and that early childhood irritability may be linked to altered changes in neural connectivity over time. Understanding how childhood irritability interacts with neural processes can inform pathophysiological models of pediatric irritability and the development of targeted mechanistic interventions.

Irritability-related neural responses to frustrative nonreward in adolescents with trauma histories: A preliminary investigation.

Irritability, conceptualized as a lowered frustration response threshold to blocked goal attainment (i.e., frustrative nonreward), is a common, detrimental symptom in adolescence. Yet, neural mechanisms of irritability are not well understood. This preliminary study aims to identify irritability-related neural patterns using a novel frustrative nonreward paradigm. Our study used a diverse sample of N = 31 non-White adolescent participants (mean age 14.53 years, SD = 1.74; 83.87% Hispanic/Latinx) to improve generalizability. During fMRI acquisition, participants performed a child-friendly monetary incentive delay task, modified to provide incorrect, negative feedback on performance. Irritability was associated with alterations in amygdala connectivity with basal ganglia, prefrontal, temporal, and parietal regions, and in activation of prefrontal and posterior cortical structures. Across clusters, youths with greater irritability showed activation/connectivity differences between reward blocked versus received conditions in the opposite direction compared to youths with lowered irritability. Alterations in amygdala-temporoparietal connectivity and lingual gyrus activation demonstrated an altered irritability-related recovery effect from the previous trial. These findings support the central role of frustrative nonreward as a key irritability pathway. Our work is one of the first to document neural correlates of difficult recovery from frustration characteristic of irritability and provides insight into novel treatment targets for irritability in diverse populations.

Reward-related neural correlates of early life stress in school-aged children.

OBJECTIVES: Early life stress likely contributes to dysfunction in neural reward processing systems. However, studies to date have focused almost exclusively on adolescents and adults, measured early life stress retrospectively, and have often failed to control for concurrent levels of stress. The current study examined the contribution of prospectively measured cumulative life stress in preschool-age children on reward-related neural activation and connectivity in school-age children. METHODS: Children (N = 46) and caregivers reported children's exposure to early life stress between birth and preschool age (mean = 4.8 years, SD = 0.80). At follow-up (mean age = 7.52 years, SD = .78), participants performed a child-friendly monetary incentive delay task during functional magnetic resonance imaging. RESULTS: Children with higher levels of cumulative early life stress, controlling for concurrent stressful life events, exhibited aberrant patterns of neural activation and connectivity in reward- and emotion-related regions (e.g., prefrontal cortex, temporal pole, culmen), depending on the presence of a potential reward and whether or not the target was hit or missed. CONCLUSIONS: Findings suggest that stress exposure during early childhood may impact neural reward processing systems earlier in development than has previously been demonstrated. Understanding how early life stress relates to alterations in reward processing could guide earlier, more mechanistic interventions.

Executive functioning moderates neural reward processing in youth.

Although executive functioning has traditionally been studied in "cool" settings removed from emotional contexts, it is highly relevant in "hot" emotionally salient settings such as reward processing. Furthermore, brain structures related to "cool" executive functioning and "hot" reward-related processes develop simultaneously, yet little is known about how executive functioning modulates neural processes related to reward processing during adolescence, a period of time when these systems are still developing. The present study examined how performance on "cool" behavioral executive functioning measures moderates neural reward processing. Youths (N = 43, Mage = 13.74 years, SD = 1.81 years) completed a child-friendly monetary incentive delay task during fMRI acquisition that captures neural responses to reward anticipation and to reward receipt and omission. Performance on inhibitory control and cognitive flexibility measures, captured outside the scanner, was used to predict brain activation and seed-based connectivity (ventral striatum and amygdala). Across analyses, we found that executive functioning moderated youths' neural responses during both reward anticipation and performance feedback, predominantly with respect to amygdala connectivity with prefrontal/frontal and temporal structures, supporting previous theoretical models of brain development during adolescence. Overall, youths with worse executive functioning had more pronounced differences in neural activation and connectivity between task conditions compared with youths with better executive functioning. This study contributes to elucidating the relationship between "cool" and "hot" processes and our findings demonstrate that simple executive functioning skills moderate more complex processes that involve incorporation of numerous skills in an emotionally salient context, such as reward processing.

Neural and behavioral correlates of inhibitory control in youths with varying levels of irritability.

BACKGROUND: Irritability, a relatively lowered threshold for anger, is prevalent in typically and atypically developing youths. Inhibitory control, the ability to suppress behaviors counter to goals, is essential for regulating emotions, including anger. Understanding how irritability relates to behavioral and neural markers of inhibitory control may inform interventions. METHODS: Youths (N=52; mean age=13.78) completed a Flanker task on an iPad to measure behavioral correlates of inhibitory control; a subsample (n=19; mean age=13.21) additionally completed a similar task while undergoing fMRI acquisition to evaluate inhibitory control on a neural level. Irritability was measured using the Affective Reactivity Index. Associations between irritability and inhibitory control were evaluated behaviorally (via Pearson correlations), and neurally (via ANCOVAs with whole-brain activation and amygdala connectivity). RESULTS: fMRI results indicated that higher levels of irritability were associated with aberrant activation (in middle frontal gyrus, amygdala/parahippocampal gyrus, anterior cingulate, lentiform nucleus/striatum) and left amygdala connectivity (with middle temporal gyrus, parahippocampal gyrus, posterior cingulate, fusiform gyrus, and thalamus). Behavioral results were mixed. LIMITATIONS: Longitudinal studies are needed to characterize changes in neural circuitry and delineate whether the brain profiles precede or are a consequence of symptoms. Larger samples powered to examine multiple irritability-related symptom dimensions will be necessary to elucidate shared vs. disorder-specific irritability mechanisms. CONCLUSIONS: Findings suggest that pediatric irritability may be related to neural processes involving inhibitory control. Further, findings underscore the importance of neuroimaging in investigating symptom dimensions such as irritability, as neuroimaging may be more sensitive in detecting underlying abnormalities compared to behavioral data alone.

Social and Non-social Reward: A Preliminary Examination of Clinical Improvement and Neural Reactivity in Adolescents Treated With Behavioral Therapy for Anxiety and Depression.

BACKGROUND: Pediatric anxiety and depression are highly prevalent and debilitating disorders that often co-occur. Neural circuitry of reward processing has been shown to be implicated in both, and there is an emerging evidence base linking treatment response to brain patterns of reward processing. The current study aimed to add to this literature by investigating the association between clinical improvement and social and non-social reward in youth previously treated for anxiety and depression. METHODS: The current study leveraged clinical improvement data from a successful randomized controlled trial testing the efficacy of a transdiagnostic, brief behavioral treatment for youth diagnosed with anxiety or depression. Participants (N = 15) interested in engaging in a neuroimaging follow-up underwent an fMRI scan, during which they completed social (i.e., Face Task) and non-social (i.e., Piñata Task, a youth-friendly monetary incentive delay task) reward tasks. Whole-brain activation and functional connectivity analyses identified neural responses to the tasks separately; a third set of analyses directly compared clinical improvement-related findings to understand the impact of task context on neural reactivity to reward. RESULTS: Activation-based findings were sparse; however, connectivity as a function of degree of treatment response was apparent and robust. Within the context of social reward, significant clusters within frontal and temporal regions driven by happy face contrasts, the social reward stimulus, were observed. This supports connectivity between these regions and both amygdala and ventral striatum seeds as a function of degree of clinical improvement. Connectivity within the context of non-social reward also yielded significant clusters in temporal and parietal regions. Here too, the magnitude and direction of region coupling depended on the degree of clinical improvement and the task conditions. No differences in connectivity by task type as a function of clinical improvement were found. CONCLUSION: Findings serve as preliminary evidence that neural regions found to be related to clinical improvement within the context of social and non-social reward are similar to regions that have been shown to support reward processing in normative samples. Implications for treatment and future work are discussed.