Kathryn L. Humphreys

Prospective association of childhood attention-deficit/hyperactivity disorder (ADHD) and substance use and abuse/dependence: a meta-analytic review.

Given the clinical and public health significance of substance disorders and the need to identify their early risk factors, we examined the association of childhood attention-deficit/hyperactivity disorder (ADHD) with substance use (nicotine, alcohol, marijuana) and abuse/dependence outcomes (nicotine, alcohol, marijuana, cocaine, other). To strengthen a potential causal inference, we meta-analyzed longitudinal studies that prospectively followed children with and without ADHD into adolescence or adulthood. Children with ADHD were significantly more likely to have ever used nicotine and other substances, but not alcohol. Children with ADHD were also more likely to develop disorders of abuse/dependence for nicotine, alcohol, marijuana, cocaine, and other substances (i.e., unspecified). Sex, age, race, publication year, sample source, and version of the Diagnostic and Statistical Manual of Mental Disorders (DSM) used to diagnose ADHD did not significantly moderate the associations with substance outcomes that yielded heterogeneous effect sizes. These findings suggest that children with ADHD are significantly more likely to develop substance use disorders than children without ADHD and that this increased risk is robust to demographic and methodological differences that varied across the studies. Finally, few studies addressed ADHD and comorbid disruptive behavior disorders (DBD), thus preventing a formal meta-analytic review. However, we qualitatively summarize the results of these studies and conclude that comorbid DBD complicates inferences about the specificity of ADHD effects on substance use outcomes.

A Developmental Shift from Positive to Negative Connectivity in Human Amygdala–Prefrontal Circuitry

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.

Early developmental emergence of human amygdala- prefrontal connectivity after maternal deprivation

Significance Early adversity has profound and lasting effects on neurodevelopment and emotional behavior. Under typical environmental conditions, prefrontal cortex connections with the amygdala are immature during childhood and become adult-like during adolescence. Rodent models show that maternal deprivation accelerates this development as an ontogenetic adaptation to adversity. Here, we demonstrate that, as in the rodent, children who experienced early maternal deprivation exhibit early emergence of mature amygdala–prefrontal connectivity. Evidence suggests that the adult-like neural phenotype, which is mediated by cortisol levels, confers some degree of enhanced emotion regulation, as maternally deprived youths with adult-like phenotypes are less anxious than their counterparts with immature phenotypes. Accelerated amygdala–prefrontal development may serve as an ontogenetic adaptation in the human in response to early adversity. Under typical conditions, medial prefrontal cortex (mPFC) connections with the amygdala are immature during childhood and become adult-like during adolescence. Rodent models show that maternal deprivation accelerates this development, prompting examination of human amygdala–mPFC phenotypes following maternal deprivation. Previously institutionalized youths, who experienced early maternal deprivation, exhibited atypical amygdala–mPFC connectivity. Specifically, unlike the immature connectivity (positive amygdala–mPFC coupling) of comparison children, children with a history of early adversity evidenced mature connectivity (negative amygdala–mPFC coupling) and thus, resembled the adolescent phenotype. This connectivity pattern was mediated by the hormone cortisol, suggesting that stress-induced modifications of the hypothalamic–pituitary–adrenal axis shape amygdala–mPFC circuitry. Despite being age-atypical, negative amygdala–mPFC coupling conferred some degree of reduced anxiety, although anxiety was still significantly higher in the previously institutionalized group. These findings suggest that accelerated amygdala–mPFC development is an ontogenetic adaptation in response to early adversity.

The development of human amygdala functional connectivity at rest from 4 to 23 years: A cross-sectional study

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 23years 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, 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 10years) 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.

Stimulant Medication and Substance Use Outcomes: A Meta-analysis

IMPORTANCE Psychostimulant medication is an efficacious treatment for childhood attention-deficit/hyperactivity disorder, yet controversy remains regarding potential iatrogenic effects of stimulant medication, particularly with respect to increasing susceptibility to later substance use disorders. However, stimulant treatment was previously reported to reduce the risk of substance problems. OBJECTIVE To meta-analyze the longitudinal association between treatment with stimulant medication during childhood and later substance outcomes (ie, lifetime substance use and substance abuse or dependence). DATA SOURCES Studies published between January 1980 and February 2012 were identified using review articles, PubMed, and pertinent listservs. STUDY SELECTION Studies with longitudinal designs in which medication treatment preceded the measurement of substance outcomes. DATA EXTRACTION AND SYNTHESIS Odds ratios were extracted or provided by the study authors. Odds ratios were obtained for lifetime use (ever used) and abuse or dependence status for alcohol, cocaine, marijuana, nicotine, and nonspecific drugs for 2565 participants from 15 different studies. MAIN OUTCOMES AND MEASURES Random-effects models estimated the overall association, and potential study moderators were examined. RESULTS Separate random-effects analyses were conducted for each substance outcome, with the number of studies ranging from 3 to 11 for each outcome. Results suggested comparable outcomes between children with and without medication treatment history for any substance use and abuse or dependence outcome across all substance types. CONCLUSIONS These results provide an important update and suggest that treatment of attention-deficit/hyperactivity disorder with stimulant medication neither protects nor increases the risk of later substance use disorders.

Reduced nucleus accumbens reactivity and adolescent depression following early-life stress

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.

Maternal Buffering of Human Amygdala-Prefrontal Circuitry During Childhood but Not During Adolescence

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.

Deviations from the expectable environment in early childhood and emerging psychopathology.

Current frameworks for understanding the link between early adverse childhood experiences and later negative life outcomes, including psychopathology, focus on the mediating negative impact on brain and biological systems in the developing child resulting broadly from stress and trauma. Although this approach is useful, we argue that the framework could be functionally extended by distinguishing the effects of two different types of abnormal input, both deviations from the expectable environment in early childhood. Specifically, we review the consequences of inadequate input (eg, neglect/deprivation) and harmful input (eg, abuse/trauma) on brain and biological development. We then review evidence on the differential links between each type of abnormal input to four selected domains of psychopathology (indiscriminate social behavior, posttraumatic stress disorder, attention-deficit/hyperactivity disorder, and conduct problems), and consider potential mechanisms for inadequate and harmful input to lead to these outcomes. We conclude that the careful consideration of the type of deviation from the expected environment, while acknowledging the practical difficulties in assessing this, is likely to lead to clearer understanding of the mechanism of risk for psychopathology, and that tailored approaches to prevention and intervention may be informed by considering the unique consequences of inadequate and harmful input when experienced in early childhood.

Effects of institutional rearing and foster care on psychopathology at age 12 years in Romania: follow-up of an open, randomised controlled trial

BACKGROUND Early social deprivation can negatively affect domains of functioning. We examined psychopathology at age 12 years in a cohort of Romanian children who had been abandoned at birth and placed into institutional care, then assigned either to be placed in foster care or to care as usual. METHODS We used follow-up data from the Bucharest Early Intervention Project (BEIP), a randomised controlled trial of abandoned children in all six institutions for young children in Bucharest, Romania. In the initial trial, 136 children, enrolled between ages 6-31 months, were randomly assigned to either care as usual or placement in foster care. In this study we followed up these children at age 12 years to assess psychiatric symptoms using the Diagnostic Interview Schedule for Children (4th edition; DISC-IV). We also recruited Romanian children who had never been placed in an institution from paediatric clinics and schools in Bucharest as a comparator group who had never been placed in an institution. The primary outcome measure was symptom counts assessed through DISC-IV scores for three domains of psychopathology: internalising symptoms, externalising symptoms, and attention-deficit hyperactivity disorder (ADHD). We compared mean DISC-IV scores between trial participants and comparators who had never been placed in an institution, and those assigned to care as usual or foster care. Analyses were done by modified intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00747396. FINDINGS We followed up 110 children from the BEIP trial between Jan 27, 2011, and April 11, 2014, and 49 children as comparators who had never been placed in an institution. The 110 children who had ever been placed in an institution had higher symptom counts for internalising disorders (mean 0·93 [SD 1·68] vs 0·45 [0·84], difference 0·48 [95% CI 0·14-0·82]; p=0·0127), externalising disorders (2·31 [2·86] vs 0·65 [1·33], difference 1·66 [1·06-2·25]; p<0·0001), and ADHD (4·00 [5·01] vs 0·71 [1·85], difference 3·29 [95% CI 2·39-4·18]; p<0·0001) than did children who had never been placed in an institution. Compared with 55 children randomly assigned to receive care as usual, the 55 children in the foster-care group had fewer externalising symptoms (mean 2·89 [SD 3·00] for care as usual vs 1·73 [2·61] for foster care, difference 1·16 [95% CI 0·11 to 2·22]; p=0·0255), but symptom counts for internalising disorders (mean 1·00 [1·59] for care as usual vs 0·85 [1·78] for foster care, difference 0·15 [-0·35 to 0·65]; p=0·5681) and ADHD (mean 3·76 [4·61] for care as usual vs 4·24 [5·41] for foster care, difference -0·47 [-2·15 to 1·20; p=0·5790) did not differ. In further analyses, symptom scores substantially differed by stability of foster-care placement. INTERPRETATION Early foster care slightly reduced the risk of psychopathology in children who had been living in institutions, but long-term stability of foster-care placements is an important predictor of psychopathology in early adolescence. FUNDING National Institute of Mental Health and the John D and Catherine T MacArthur Foundation.

Amygdala sensitivity to race is not present in childhood but emerges over adolescence

Neuroimaging research in adults has consistently found that differential perception of race is associated with increased amygdala activity. We hypothesized that such neural biases unlikely reflect innate processes but instead emerge over development. In the current study, we used fMRI to examine the neurodevelopmental trajectory of the amygdala in response to race across childhood and adolescence ranging from 4 to 16 years. Thirty-two youths viewed African American and European American faces during a functional brain scan. Results suggest that differential amygdala response to African American faces does not emerge until adolescence, reflecting the increasing salience of race across development. In addition, greater peer diversity was associated with attenuated amygdala response to African American faces, suggesting that intergroup racial contact may reduce the salience of race.