Faculty Bibliography

Early life trauma is a risk factor for life-long disorders related to emotional processing, but knowledge underlying its enduring effect is incomplete. This study was motivated by the hypothesis that early life trauma increases amygdala-dependent threat responses via reduction in inhibition by parvalbumin (PV) interneurons and perineuronal nets (PNN) supporting PV cells, thus increasing excitability of the basolateral amygdala (BLA). From postnatal day (PN) 8-12, rat pups of both sexes were reared under normal bedding or under insufficient nest-building materials to induce maternal-to-infant maltreatment trauma (Scarcity-Adversity Model, SAM). At weaning age of PN23, the SAM group exhibited increased threat responses to predator odor. The SAM-induced increase in threat response was recapitulated in normally reared PN22-23 rats that were unilaterally depleted of PNN in the BLA by the enzymes, chondroitinase-ABC plus hyaluronidase at PN19-20. Light and electron microscopic analysis of the BLA revealed that anterior-to-mid levels of SAM group's BLAs exhibited decreased PNN intensity and decreased axo-somatic synapses between PV-to-principal pyramidal-like neurons and PV-to-PV. PV and PNN densities (cells/ mm² ) in the BLA of both control (CON) and SAM groups were still low at PN12 and SAM delayed the ontogenetic rise of PV intensity and PNN density. Moreover, PV cell density in the anterior-to-mid BLA correlated negatively with threat response of CON animals, but not for SAM animals. Thus, reduction of PNN-supported, PV-mediated somatic inhibition of pyramidal cells provides a mechanistic support for the enduring effect of early life maltreatment manifested as increasing innate threat response at weaning.

OBJECTIVE:To report functional outcomes from the multisite Child/Adolescent Anxiety Multimodal Extended Long-term Study (CAMELS), which examined the impact of youth anxiety treatment (cognitive-behavioral therapy [CBT], coping cat; Sertraline, SRT; COMB [CBT + SRT]; pill placebo) on (a) global and (b) domain-specific functioning assessed an average of 3.1 times, 3- to 12-years postrandomization (first assessment = mean 6.5 years postrandomization). METHOD/METHODS:Three-hundred and 19 of 488 families from the Child/Adolescent Anxiety Multimodal Study (CAMS; Walkup et al., 2008) participated. Growth curve modeling examined the impact of treatment condition and acute treatment outcomes (i.e., response, remission) on global functioning, global and domain-specific impairment, and life satisfaction across follow-up visits. Logistic regressions explored the impact of treatment remission and condition on low frequency events (arrests/convictions) and education. RESULTS:Treatment responders and remitters demonstrated better global functioning, decreased overall impairment, and increased life satisfaction at follow-up. Treatment remission, but not response, predicted decreased domain-specific impairment (social relationships, self-care/independence, academic functioning), and maintenance of increased life satisfaction across follow-ups. Participants in the CBT condition, compared with pill placebo, demonstrated improved trajectories pertaining to life satisfaction, overall impairment, and impairment in academic functioning. Randomization to CBT or COMB treatment was associated with increasing employment rates. Trajectories for participants randomized to SRT was not significantly different from placebo. Treatment outcome and condition did not predict legal outcomes, school/work variables, or family life. CONCLUSION/CONCLUSIONS:Positive early intervention outcomes are associated with improved overall functioning, life satisfaction, and functioning within specific domains 6.5 years posttreatment. Treatment type differentially predicted trajectories of functioning. Findings support the positive impact of pediatric anxiety treatment into adolescence and early adulthood. (PsycINFO Database Record

Neurofilament (NFL) proteins have recently been found to play unique roles in synapses. NFL is known to interact with the GluN1 subunit of N-methyl-D-aspartic acid (NMDAR) and be reduced in schizophrenia though functional consequences are unknown. Here we investigated whether the interaction of NFL with GluN1 modulates synaptic transmission and schizophrenia-associated behaviors. The interaction of NFL with GluN1 was assessed by means of molecular, pharmacological, electrophysiological, magnetic resonance spectroscopy (MRS), and schizophrenia-associated behavior analyses. NFL deficits cause an NMDAR hypofunction phenotype including abnormal hippocampal function, as seen in schizophrenia. NFL-/- deletion in mice reduces dendritic spines and GluN1 protein levels, elevates ubiquitin-dependent turnover of GluN1 and hippocampal glutamate measured by MRS, and depresses hippocampal long-term potentiation. NMDAR-related behaviors are also impaired, including pup retrieval, spatial and social memory, prepulse inhibition, night-time activity, and response to NMDAR antagonist, whereas motor deficits are minimal. Importantly, partially lowering NFL in NFL+/- mice to levels seen regionally in schizophrenia, induced similar but milder NMDAR-related synaptic and behavioral deficits. Our findings support an emerging view that central nervous system neurofilament subunits including NFL in the present report, serve distinctive, critical roles in synapses relevant to neuropsychiatric diseases.

Human and animal models suggest that maternal hormonal and physiological adaptations during pregnancy shape maternal brain functioning and behavior crucial for offspring care and survival. Less sensitive maternal behavior, often associated with psychobiological dysregulation and the offspring's behavioral and emotional disorders, has been observed in mothers who have experienced adverse childhood experiences. Strong evidence shows that children who are exposed to domestic violence (DV) are at risk of being abused or becoming abusive in adulthood. Yet little is known about the effect of childhood exposure to DV on the expecting mother, her subsequent caregiving behavior and related effects on her infant. Thus, the present study examined the association of maternal exposure to DV during childhood on prenatal maternal attachment, maternal heart rate reactivity to an infant-crying stimulus and post-natal infant emotional regulation. Thirty-three women with and without exposure to DV during childhood were recruited during the first trimester of pregnancy and followed until 6-month after birth. The Maternal Antenatal Attachment Scale (MAAS) was used to measure prenatal attachment of the mother to her fetus during the second trimester of pregnancy, maternal and fetal heart rate reactivity to an infant-crying stimulus was assessed at the third trimester of pregnancy, and the Infant Behavior Questionnaire-Revised (IBQ-R) was used to assess infant emotional regulation at 6-months. Results showed that pregnant women that were exposed to DV during childhood had a poorer quality of prenatal attachment of mother to fetus, regardless of whether they also experienced DV during adulthood. In addition, maternal exposure to DV during childhood was associated with increased maternal heart rate to infant-crying stimulus and worse infant emotional regulation. These findings highlight the importance of prenatal screening for maternal exposure to DV during childhood as a risk factor for disturbances in the development of maternal attachment, dysfunctional maternal behavior and emotion dysregulation.

Cancer is highly prevalent and one of the leading causes of global morbidity and mortality. Psychological and existential suffering is common in cancer patients, associated with poor psychiatric and medical outcomes. Promising early-phase clinical research (1960s to early 1970s) suggested a therapeutic signal for serotoninergic psychedelics (e.g. psilocybin, LSD) in treating cancer-related psychiatric distress. After several decades of quiescence, research on psychedelic-assisted therapy to treat psychiatric disorders in cancer patients has resumed within the last 2 decades in the US and Europe. This review article is based on a systematic search of clinical trials from 1960-2018 researching the therapeutic use of psychedelic treatment in patients with serious or terminal illnesses and related psychiatric illness. The search found 10 eligible clinical trials, with a total of 445 participants, with the vast majority of the patients having advanced or terminal cancer diagnoses. Six open label trials, published between 1964 and 1980 (n = 341), suggested that psychedelic therapy (mostly with LSD) may improve cancer-related depression, anxiety, and fear of death. Four RCTs trials were published between 2011 and 2016 (n = 104), mostly with psilocybin treatment (n = 92), and demonstrated that psychedelic-assisted treatment can produce rapid, robust, and sustained improvements in cancer-related psychological and existential distress.

A brain-computer-interface (BCI)-based attention training game system has shown promise for treating attention deficit/hyperactivity disorder (ADHD) children with inattentive symptoms. However, little is known about brain network organizational changes underlying behavior improvement following BCI-based training. To cover this gap, we aimed to examine the topological alterations of large-scale brain functional networks induced by the 8-week BCI-based attention intervention in ADHD boys using resting-state functional magnetic resonance imaging method. Compared to the non-intervention (ADHD-NI) group, the intervention group (ADHD-I) showed greater reduction of inattention symptoms accompanied with differential brain network reorganizations after training. Specifically, the ADHD-NI group had increased functional connectivity (FC) within the salience/ventral attention network (SVN) and increased FC between task-positive networks (including the SVN, dorsal attention (DAN), somatomotor, and executive control network) and subcortical regions; in contrast ADHD-I group did not have this pattern. In parallel, ADHD-I group had reduced degree centrality and clustering coefficient as well as increased closeness in task-positive and the default mode networks (prefrontal regions) after the training. More importantly, these reduced local functional processing mainly in the SVN were associated with less inattentive/internalizing problems after 8-week BCI-based intervention across ADHD patients. Our findings suggest that the BCI-based attention training facilitates behavioral improvement in ADHD children by reorganizing brain functional network from more regular to more random configurations, particularly renormalizing salience network processing. Future long-term longitudinal neuroimaging studies are needed to develop the BCI-based intervention approach to promote brain maturation in ADHD.

BACKGROUND:The benefits and safety of medications for attention-deficit hyperactivity disorder (ADHD) remain controversial, and guidelines are inconsistent on which medications are preferred across different age groups. We aimed to estimate the comparative efficacy and tolerability of oral medications for ADHD in children, adolescents, and adults. METHODS:We did a literature search for published and unpublished double-blind randomised controlled trials comparing amphetamines (including lisdexamfetamine), atomoxetine, bupropion, clonidine, guanfacine, methylphenidate, and modafinil with each other or placebo. We systematically contacted study authors and drug manufacturers for additional information. Primary outcomes were efficacy (change in severity of ADHD core symptoms based on teachers' and clinicians' ratings) and tolerability (proportion of patients who dropped out of studies because of side-effects) at timepoints closest to 12 weeks, 26 weeks, and 52 weeks. We estimated summary odds ratios (ORs) and standardised mean differences (SMDs) using pairwise and network meta-analysis with random effects. We assessed the risk of bias of individual studies with the Cochrane risk of bias tool and confidence of estimates with the Grading of Recommendations Assessment, Development, and Evaluation approach for network meta-analyses. This study is registered with PROSPERO, number CRD42014008976. FINDINGS/RESULTS:133 double-blind randomised controlled trials (81 in children and adolescents, 51 in adults, and one in both) were included. The analysis of efficacy closest to 12 weeks was based on 10 068 children and adolescents and 8131 adults; the analysis of tolerability was based on 11 018 children and adolescents and 5362 adults. The confidence of estimates varied from high or moderate (for some comparisons) to low or very low (for most indirect comparisons). For ADHD core symptoms rated by clinicians in children and adolescents closest to 12 weeks, all included drugs were superior to placebo (eg, SMD -1·02, 95% CI -1·19 to -0·85 for amphetamines, -0·78, -0·93 to -0·62 for methylphenidate, -0·56, -0·66 to -0·45 for atomoxetine). By contrast, for available comparisons based on teachers' ratings, only methylphenidate (SMD -0·82, 95% CI -1·16 to -0·48) and modafinil (-0·76, -1·15 to -0·37) were more efficacious than placebo. In adults (clinicians' ratings), amphetamines (SMD -0·79, 95% CI -0·99 to -0·58), methylphenidate (-0·49, -0·64 to -0·35), bupropion (-0·46, -0·85 to -0·07), and atomoxetine (-0·45, -0·58 to -0·32), but not modafinil (0·16, -0·28 to 0·59), were better than placebo. With respect to tolerability, amphetamines were inferior to placebo in both children and adolescents (odds ratio [OR] 2·30, 95% CI 1·36-3·89) and adults (3·26, 1·54-6·92); guanfacine was inferior to placebo in children and adolescents only (2·64, 1·20-5·81); and atomoxetine (2·33, 1·28-4·25), methylphenidate (2·39, 1·40-4·08), and modafinil (4·01, 1·42-11·33) were less well tolerated than placebo in adults only. In head-to-head comparisons, only differences in efficacy (clinicians' ratings) were found, favouring amphetamines over modafinil, atomoxetine, and methylphenidate in both children and adolescents (SMDs -0·46 to -0·24) and adults (-0·94 to -0·29). We did not find sufficient data for the 26-week and 52-week timepoints. INTERPRETATION/CONCLUSIONS:Our findings represent the most comprehensive available evidence base to inform patients, families, clinicians, guideline developers, and policymakers on the choice of ADHD medications across age groups. Taking into account both efficacy and safety, evidence from this meta-analysis supports methylphenidate in children and adolescents, and amphetamines in adults, as preferred first-choice medications for the short-term treatment of ADHD. New research should be funded urgently to assess long-term effects of these drugs. FUNDING/BACKGROUND:Stichting Eunethydis (European Network for Hyperkinetic Disorders), and the UK National Institute for Health Research Oxford Health Biomedical Research Centre.

Recent studies suggest that infants and toddlers evaluate others based on their prosocial and antisocial behaviors and engage in prosocial behaviors themselves. It is unknown to what extent infants' responses in such studies reveal stable individual differences in social and/or moral competence that persist throughout development. The current study (N = 63) demonstrates that infants' performance in sociomoral evaluation and action studies (mean age = 12 months) predicts social and behavioral adjustment at age 4 years. Specifically, a stronger preference for moral actions as an infant was associated with parent reports of fewer callous-unemotional traits, the domain most conceptually related to sociomoral evaluation and action, during preschool. Critically, preschool moral adjustment was uniquely associated with infants' sociomoral responding and not with other more general aspects of infant functioning. When 2 children with an autism spectrum disorder diagnosis were included in the sample, correlations between infant and preschool functioning were more widespread. Taken together, these results provide evidence for developmental continuity in the sociomoral domain and suggest that infants' early behavioral tendencies may be building blocks for subsequent sociomoral development.

BACKGROUND:Children in Sub-Saharan Africa (SSA) comprise half of the total regional population, yet existing mental health services are severely under-equipped to meet their needs. Although effective interventions for the treatment of disruptive behavioral disorders (DBDs) in youth have been tested in high-poverty and high-stress communities in developed countries, and are relevant for widespread dissemination in low- and middle-income countries (LMICs), most of these evidence-based practices (EBPs) have not been utilized in SSA, a region heavily impacted by poverty, diseases including HIV/AIDS, and violence. Thus, this paper presents a protocol for a scale-up longitudinal experimental study that uses a mixed-methods, hybrid type II, effectiveness implementation design to test the effectiveness of an EBP, called Multiple Family Group (MFG) aimed at improving child behavioral challenges in Uganda while concurrently examining the multi-level factors that influence uptake, implementation, sustainment, and youth outcomes. METHODS:The MFG intervention will be implemented and tested via a longitudinal experimental study conducted across 30 public primary schools located in both semi-urban and rural communities. The schools will be randomly assigned to three study conditions (n = 10 per study condition): (1) MFG delivered by trained family peers; (2) MFG delivered by community health workers; or; (3) comparison: usual care comprising mental health care support materials, bolstered with school support materials. A total of 3000 children (ages 8 to 13 years; grades 2 to 7) and their caregivers (N = 3000 dyads); 60 parent peers, and 60 community health workers will be recruited. Each study condition will comprise of 1000 child-caregiver dyads. Data will be collected at baseline, 8 and 16 weeks, and 6-month follow-up. DISCUSSION/CONCLUSIONS:This project is the first to test the effectiveness of the MFG intervention while concurrently examining multi-level factors that influence overall implementation of a family-based intervention provided in schools and aimed at reaching the large child population with mental health service needs in Uganda. Moreover, the study draws upon an EBP that has already been tested for delivery by parent peers and community facilitators, and hence will take advantage of the advancing science behind task-shifting. If successful, the project has great potential to address global child mental health needs. TRIAL REGISTRATION/BACKGROUND:ClinicalTrials.gov, ID: NCT03081195 . Registered on 16 March 2017.