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.

Contributions of childhood abuse and neglect to reward neural substrates in adolescence.

BACKGROUND: Childhood adverse experiences may come to bear particularly during adolescence, when neural reward systems are developing rapidly and psychopathology spikes. Despite prior work differentiating threat- (abuse) vs. deprivation- (neglect) related adversity, no research has yet identified their relative nor interactive contributions to reward neural substrates during adolescence. In the present study, we leveraged a diverse sample of adolescents with different childhood adversity profiles to examine neural responses to reward in relation to varying degrees of abuse vs. neglect. METHODS: Adolescents (N = 45; 23 females; mean age = 14.9 years, SD = 1.9) completed a child-friendly monetary incentive delay task during fMRI acquisition. The self-report Childhood Trauma Questionnaire assessed childhood abuse and neglect. Whole brain ANCOVA analyses evaluated reward anticipation (reward vs. no reward expected) and feedback (hitting vs. missing the target with a reward vs. no reward) in relation to abuse and neglect dimensions. RESULTS: Whole-brain analyses revealed that abuse, adjusted for neglect, is associated with greater differences between task conditions (reward vs. no reward, hit vs. miss) in regions associated with threat/emotion regulation (prefrontal and temporal cortices, as well as posterior regions including fusiform and posterior cingulate/precuneus). Additionally, level of neglect modulated neural response associated with abuse in prefrontal and temporoparietal regions, such that youths with high levels of both abuse and neglect showed qualitatively different, more exaggerated neural patterns compared to youths with elevated adversity in only one dimension. CONCLUSIONS: Our findings suggest that early experiences of abuse and neglect have a long developmental reach resulting in reward-related neural alterations in adolescence. Moreover, our results bolster theoretical conceptualizations of adversity along threat and deprivation dimensions and provide evidence that "adding up" adverse life events may not be sufficient to capture the qualitatively different neural profiles produced by differing combinations of types of adversity, which may in turn necessitate different treatment approaches.

Neural mechanisms of reward processing in adolescent irritability.

Irritability is impairing and prevalent across pediatric psychiatric disorders and typical development, yet its neural mechanisms are largely unknown. This study evaluated the relation between adolescent irritability and reward-related brain function as a candidate neural mechanism. Adolescents from intervention-seeking families in the community (N = 52; mean age = 13.80, SD = 1.94) completed a monetary incentive delay task to assess reward anticipation and feedback (reward receipt and omission) during fMRI acquisition. Whole-brain analyses, controlling for age, examined brain activation and striatal and amygdala connectivity in relation to irritability. Irritability was measured using the parent- and youth-reported Affective Reactivity Index. Irritability was associated with altered reward processing-related activation and connectivity in multiple networks during reward anticipation and feedback, including increased striatal activation and altered ventral striatum connectivity with prefrontal areas. Our findings suggest that irritability is associated with altered neural patterns during reward processing and that aberrant prefrontal cortex-mediated top-down control may be related to irritability. These findings inform our understanding of the etiology of youth irritability and the development of mechanism-based 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.