Faculty Bibliography

Perceived social support (PSS) has been related to physical and mental well-being in typically developing individuals, but systematic characterizations of PSS in autism spectrum disorder (ASD) are limited. We compared self-report ratings of the multidimensional scale of PSS (MSPSS) among age- and IQ-matched groups of adults (18-58 years) with cognitively high-functioning ASD (N = 41), or attention-deficit/hyperactivity disorder (ADHD; N = 69), and neurotypical controls (NC; N = 69). Accompanying group comparisons, we used machine learning random forest (RF) analyses to explore predictors among a range of psychopathological and socio-emotional variables. Relative to both ADHD and NC, adults with ASD showed lower MSPSS ratings, specifically for the friends subscale (MSPSS-f). Across ASD and ADHD, interindividual differences in autism severity, affective empathy, symptoms of anxiety related to social interactions, hyperactivity/impulsivity, and somatization best predicted MSPSS-f. These relationships did not differ between clinical groups. While group comparisons demonstrated greater impairment in individuals with ASD, analyzing individuals' characteristics revealed cross-diagnoses similarities in regard to their MSPSS-f relationships. This is consistent with the Research Domain Criteria framework, supporting a trans-diagnostic approach as on the path toward "precision medicine." Autism Res 2017. (c) 2017 International Society for Autism Research, Wiley Periodicals, Inc.

Young infant rat pups learn to approach cues associated with pain rather than learning amygdala-dependent fear. This approach response is considered caregiver-seeking and ecologically relevant within the context of attachment. With maturation, increases in the stress hormone corticosterone permit amygdala-dependent fear, which is crucial for survival during independent living. During the developmental transition from attachment to fear learning, maternal presence suppresses corticosterone elevation to block amygdala-dependent fear learning and re-engage the attachment circuitry. Early life trauma disrupts this developmental sequence by triggering a precocious increase of corticosterone, which permits amygdala-dependent threat responses. In this review, we explore the importance of the stress hormone corticosterone in infants' transition from complete dependence on the caregiver to independence, with consideration for environmental influences on threat response ontogeny and mechanistic importance of social buffering of the stress response.

OBJECTIVE: The Child and Adolescent Mental Health Studies (CAMS) program is housed in a Liberal Arts undergraduate college of a large research university. Psychiatrists, clinical psychologists, and social workers at the university's medical center teach the courses. The purpose of this study is to evaluate the extent to which CAMS encourages graduates of the program to pursue a career in child and adolescent mental health (CAMH). METHODS: In 2015-2016, graduates of the CAMS program were invited to participate in a mixed methods study. In addition to statistical analyses, qualitative thematic analyses were performed to interpret free-text responses. RESULTS: Forty-five percent (314/702) of invited graduates completed the online survey. Interviews were conducted with 11% (34/314) of participants by study staff over the phone. Quantitative results suggested that 81% (149/185) of participants enrolled in educational programs after graduation due to an interest in CAMH. A significantly higher proportion of the total sample (t = 3.661, p < .001) reported that they changed their career goals while undergraduate students compared to those who did so after graduation. Results of qualitative interviews with 34 participants uncovered five key themes unique to CAMS that may explain the program's influence on graduates' career choices and career development: practitioners-as-instructors, instructor mentorship, novel course content, experiential learning opportunities, and career training and skills. CONCLUSIONS: Quantitative and qualitative results indicated that teaching college undergraduate students about CAMH encourages them to set career goals within the field. These findings suggest the utility of implementing similar programs at other undergraduate colleges.

BACKGROUND: Neuroimaging studies have shown structural alterations in several brain regions in children and adults with attention deficit hyperactivity disorder (ADHD). Through the formation of the international ENIGMA ADHD Working Group, we aimed to address weaknesses of previous imaging studies and meta-analyses, namely inadequate sample size and methodological heterogeneity. We aimed to investigate whether there are structural differences in children and adults with ADHD compared with those without this diagnosis. METHODS: In this cross-sectional mega-analysis, we used the data from the international ENIGMA Working Group collaboration, which in the present analysis was frozen at Feb 8, 2015. Individual sites analysed structural T1-weighted MRI brain scans with harmonised protocols of individuals with ADHD compared with those who do not have this diagnosis. Our primary outcome was to assess case-control differences in subcortical structures and intracranial volume through pooling of all individual data from all cohorts in this collaboration. For this analysis, p values were significant at the false discovery rate corrected threshold of p=0.0156. FINDINGS: Our sample comprised 1713 participants with ADHD and 1529 controls from 23 sites with a median age of 14 years (range 4-63 years). The volumes of the accumbens (Cohen's d=-0.15), amygdala (d=-0.19), caudate (d=-0.11), hippocampus (d=-0.11), putamen (d=-0.14), and intracranial volume (d=-0.10) were smaller in individuals with ADHD compared with controls in the mega-analysis. There was no difference in volume size in the pallidum (p=0.95) and thalamus (p=0.39) between people with ADHD and controls. Exploratory lifespan modelling suggested a delay of maturation and a delay of degeneration, as effect sizes were highest in most subgroups of children (<15 years) versus adults (>21 years): in the accumbens (Cohen's d=-0.19 vs -0.10), amygdala (d=-0.18 vs -0.14), caudate (d=-0.13 vs -0.07), hippocampus (d=-0.12 vs -0.06), putamen (d=-0.18 vs -0.08), and intracranial volume (d=-0.14 vs 0.01). There was no difference between children and adults for the pallidum (p=0.79) or thalamus (p=0.89). Case-control differences in adults were non-significant (all p>0.03). Psychostimulant medication use (all p>0.15) or symptom scores (all p>0.02) did not influence results, nor did the presence of comorbid psychiatric disorders (all p>0.5). INTERPRETATION: With the largest dataset to date, we add new knowledge about bilateral amygdala, accumbens, and hippocampus reductions in ADHD. We extend the brain maturation delay theory for ADHD to include subcortical structures and refute medication effects on brain volume suggested by earlier meta-analyses. Lifespan analyses suggest that, in the absence of well powered longitudinal studies, the ENIGMA cross-sectional sample across six decades of ages provides a means to generate hypotheses about lifespan trajectories in brain phenotypes. FUNDING: National Institutes of Health.

The central nervous system is functionally organized as a dynamic network of interacting neural circuits that underlies observable behaviors. At higher resolution, these behaviors, or phenotypes, are defined by the activity of a specific set of biomolecules within those circuits. Identification of molecules that govern psychiatric phenotypes is a major challenge. The only organic molecular entities objectively associated with psychiatric phenotypes in humans are drugs that induce psychiatric phenotypes and drugs used for treatment of specific psychiatric conditions. Here, we identified candidate biomolecules contributing to the organic basis for psychosis by deriving an in vivo biomolecule-tissue signature for the atypical pharmacologic action of the antipsychotic drug clozapine. Our novel in silico approach identifies the ensemble of potential drug targets based on the drug's chemical structure and the region-specific gene expression profile of each target in the central nervous system. We subtracted the signature of the action of clozapine from that of a typical antipsychotic, chlorpromazine. Our results implicate dopamine D4 receptors in the pineal gland and muscarinic acetylcholine M1 (CHRM1) and M3 (CHRM3) receptors in the prefrontal cortex (PFC) as significant and unique to clozapine, whereas serotonin receptors 5-HT2A in the PFC and 5-HT2C in the caudate nucleus were common significant sites of action for both drugs. Our results suggest that D4 and CHRM1 receptor activity in specific tissues may represent underappreciated drug targets to advance the pharmacologic treatment of schizophrenia. These findings may enhance our understanding of the organic basis of psychiatric disorders and help developing effective therapies.

Brain enlargement has been observed in children with autism spectrum disorder (ASD), but the timing of this phenomenon, and the relationship between ASD and the appearance of behavioural symptoms, are unknown. Retrospective head circumference and longitudinal brain volume studies of two-year olds followed up at four years of age have provided evidence that increased brain volume may emerge early in development. Studies of infants at high familial risk of autism can provide insight into the early development of autism and have shown that characteristic social deficits in ASD emerge during the latter part of the first and in the second year of life. These observations suggest that prospective brain-imaging studies of infants at high familial risk of ASD might identify early postnatal changes in brain volume that occur before an ASD diagnosis. In this prospective neuroimaging study of 106 infants at high familial risk of ASD and 42 low-risk infants, we show that hyperexpansion of the cortical surface area between 6 and 12 months of age precedes brain volume overgrowth observed between 12 and 24 months in 15 high-risk infants who were diagnosed with autism at 24 months. Brain volume overgrowth was linked to the emergence and severity of autistic social deficits. A deep-learning algorithm that primarily uses surface area information from magnetic resonance imaging of the brain of 6-12-month-old individuals predicted the diagnosis of autism in individual high-risk children at 24 months (with a positive predictive value of 81% and a sensitivity of 88%). These findings demonstrate that early brain changes occur during the period in which autistic behaviours are first emerging.

Although DSM-5 stipulates that symptoms of attention-deficit hyperactivity disorder (ADHD) are the same for adults as children, clinical observations suggest that adults have more diverse deficits than children in higher-level executive functioning and emotional control. Previous psychometric analyses to evaluate these observations have been limited in ways addressed in the current study, which analyzes the structure of an expanded set of adult ADHD symptoms in three pooled US samples: a national household sample, a sample of health plan members, and a sample of adults referred for evaluation at an adult ADHD clinic. Exploratory factor analysis found four factors representing executive dysfunction/inattention (including, but not limited to, all the DSM-5 inattentive symptoms, with non-DSM symptoms having factor loadings comparable to those of DSM symptoms), hyperactivity, impulsivity, and emotional dyscontrol. Empirically-derived multivariate symptom profiles were broadly consistent with the DSM-5 inattentive-only, hyperactive/impulsive-only, and combined presentations, but with inattention including executive dysfunction/inattention and hyperactivity-only limited to hyperactivity without high symptoms of impulsivity. These results show that executive dysfunction is as central as DSM-5 symptoms to adult ADHD, while emotional dyscontrol is more distinct but nonetheless part of the combined presentation of adult ADHD.

The updating of a memory is triggered whenever it is reactivated and a mismatch from what is expected (i.e., prediction error) is detected, a process that can be unraveled through the memory's sensitivity to protein synthesis inhibitors (i.e., reconsolidation). As noted in previous studies, in Pavlovian threat/aversive conditioning in adult rats, prediction error detection and its associated protein synthesis-dependent reconsolidation can be triggered by reactivating the memory with the conditioned stimulus (CS), but without the unconditioned stimulus (US), or by presenting a CS-US pairing with a different CS-US interval than during the initial learning. Whether similar mechanisms underlie memory updating in the young is not known. Using similar paradigms with rapamycin (an mTORC1 inhibitor), we show that preweaning rats (PN18-20) do form a long-term memory of the CS-US interval, and detect a 10-sec versus 30-sec temporal prediction error. However, the resulting updating/reconsolidation processes become adult-like after adolescence (PN30-40). Our results thus show that while temporal prediction error detection exists in preweaning rats, specific infant-type mechanisms are at play for associative learning and memory.