Faculty Bibliography

AIM: This proof-of-concept study examined if early trauma influences features of schizophrenia, consistent with hypothalamic-pituitary-adrenal (HPA) axis activation. METHODS: Early trauma and current perceived stress were assessed in 28 treated schizophrenia cases, along with salivary cortisol, brain volumes, cognition and symptoms. RESULTS: Early trauma predicted more positive (r = .66, P = .005) and dysthymia symptoms (r -.65, P = .007), but less negative symptoms (r = -.56, P = .023), as well as reduced whole brain volumes (r = .50, P = .040) and increased amygdala to whole brain volume ratios (r = .56, P = .018). Larger volume reductions accompanied cortisol levels: evening values predicted smaller whole brain and hippocampal volumes whereas afternoon levels only significantly predicted smaller brain volumes in women. Sex differences were demonstrated between early trauma and cognition, with better cognition in traumatized women than other women and no male effects. Current perceived stress was related to dysthymia (especially in women) and diminished sense of purpose and social drive (especially in men). CONCLUSIONS: These results suggest that early trauma and current stress impact features of schizophrenia, consistent with stress sensitization and increased dopamine activity for treatment refractory positive symptoms, as well as the cascade of increased morning cortisol, reduced brain volumes, and depressive and deficit symptoms. Conversely, cognitive deficits and negative symptoms may arise from a distinct diathesis. The sex differences accord with the literature on human HPA function and stress responses. Early trauma may be a stressor in the aetiopathophysiology of schizophrenia, particularly for cases with treatment refractory positive symptoms, and may guide future treatment development.

Depression is one of the most prevalent mental health challenges in low- and middle-income countries. However, the mechanisms of parental depression on children's development are understudied in these countries. This study examined the prevalence of parental depression, contextual predictors of parental depression, and the associations between parental depression, parenting and children's development in one of the Sub-Saharan African countries-Uganda. Three hundred and three Ugandan parents of young children were recruited and interviewed. Results indicated that about 28 % of parents were depressed. Contextual factors such as low educational attainment, food insecurity, low social support, and high number of children were associated with parental depression. Structural equation modeling also indicated that Ugandan parents' depression was associated with less optimal parenting, and higher problem behavior, lower social competence, and poorer physical health and school functioning in children. Results provide several cross cultural consistency evidence in associations among parental depression, parenting, and child development.

BACKGROUND: Moderators of differential psychotherapy outcome for posttraumatic stress disorder (PTSD) are rare, yet have crucial clinical importance. We tested the moderating effects of trauma type for three psychotherapies in 110 unmedicated patients with chronic DSM-IV PTSD. METHODS: Patients were randomized to 14 weeks of prolonged exposure (PE, N = 38), interpersonal psychotherapy (IPT, N = 40), or relaxation therapy (RT, N = 32). The Clinician-Administered PTSD Scale (CAPS) was the primary outcome measure. Moderator candidates were trauma type: interpersonal, sexual, physical. We fit a regression model for week 14 CAPS as a function of treatment (a three-level factor), an indicator of trauma type presence/absence, and their interactions, controlling for baseline CAPS, and evaluated potential confounds. RESULTS: Thirty-nine (35%) patients reported sexual, 68 (62%) physical, and 102 (93%) interpersonal trauma. Baseline CAPS scores did not differ by presence/absence of trauma types. Sexual trauma as PTSD criterion A significantly moderated treatment effect: whereas all therapies had similar efficacy among nonsexually-traumatized patients, IPT had greater efficacy among sexually traumatized patients (efficacy difference with and without sexual trauma: IPT vs. PE and IPT vs. RT P's < .05), specifically in PTSD symptom clusters B and D (P's < .05). CONCLUSIONS: Few studies have assessed effects of varying trauma types on effects of differing psychotherapies. In this exploratory study, sexual trauma moderated PTSD outcomes of three therapies: IPT showed greater benefit for sexually traumatized patients than PE or RT. The IPT focuses on affect to help patients determine trust in their current environments may particularly benefit patients who have suffered sexual assault.

Objective/UNASSIGNED:To identify factors associated with early initiation and achievement of therapeutic hypothermia (TH) in newborns with hypoxic-ischemic encephalopathy (HIE). Methods/UNASSIGNED:Retrospective cohort study of newborns who received TH according to National Institute of Child Health and Human Development (NICHD) criteria in two academic level 3 Neonatal Intensive Care Units (NICU) between 2009 and 2013. All infants were transported by a neonatal transport team (NNTT). Multivariate linear regression including who initiated cooling and degree of resuscitation in the model was performed. Results/UNASSIGNED:Two hundred and seven infants were included. Waiting for advice from a tertiary care NICU was independently associated with a 50 minute delay in the median time of initiation of TH. The need for extensive resuscitation (cardiopulmonary resuscitation [CPR] or epinephrine) was independently associated with a reduction of 43 minutes in the median time to reach target core temperature. Log-transformed time to initiation of TH was associated with time to reach target core temperature (P<0.001). A doubling of time to initiation of TH corresponds to a 24% (95% CI 18% to 30%) increase in median time to reach target core temperature. Conclusions/UNASSIGNED:Initiating passive cooling at the referring centre, before transfer, is critical to faster achievement of target core temperature in asphyxiated infants. Greater outreach education and development of clinical care pathways are needed to improve optimal delivery of TH to enhance outcome.

Restless legs syndrome (RLS) is a relatively common neurological disorder in childhood, although it is usually overlooked due to the atypical presentation in children and associated comorbid conditions that may affect its clinical presentation. Here, we aimed to perform, for the first time, a systematic review of studies reporting the association between RLS in children and adolescents (<18 y) and somatic or neuropsychiatric conditions. We searched for peer-reviewed studies in PubMed, Ovid (including PsycINFO, Ovid MEDLINE(R), and Embase), Web of Knowledge (Web of Science, Biological abstracts, BIOSIS, FSTA) through November 2015, with no language restrictions. We found 42 pertinent studies. Based on the retrieved studies, we discuss the association between RLS and a number of conditions, including growing pains, kidney disease, migraine, diabetes, epilepsy, rheumatologic disorders, cardiovascular disease, liver and gastrointestinal disorders, and neuropsychiatric disorders (e.g., attention deficit hyperactivity disorder (ADHD), depression, and conduct disorder). Our systematic review provides empirical evidence supporting the notion that RLS in children is comorbid with a number of somatic and neuropsychiatric conditions. We posit that the awareness on comorbid diseases/disorders is pivotal to improve the diagnosis and management of RLS and might suggest fruitful avenues to elucidate the pathophysiology of RLS in children.

PURPOSE/BACKGROUND: Deficits in N-methyl-D-aspartate receptor (NMDAR) function contribute to symptoms and cognitive dysfunction in schizophrenia and are associated with impaired generation of event-related potential measures including auditory mismatch negativity. Parallel studies of the NMDAR agonist d-serine have suggested that sensitivity of these measures to glutamate-based interventions is related to symptomatic and cognitive response. Bitopertin is a selective inhibitor of glycine transport. This study investigates effects of bitopertin on NMDAR-related event-related potential deficits in schizophrenia. METHODS/PROCEDURES: Patients with schizophrenia/schizoaffective disorder were treated with bitopertin (10 mg, n = 29), in a double-blind, parallel group investigation. Auditory mismatch negativity served as primary outcome measures. Secondary measures included clinical symptoms and neurocognitive performance. FINDINGS/RESULTS: No significant changes were seen with bitopertin for neurophysiological, clinical, or neurocognitive assessments. IMPLICATIONS/CONCLUSIONS: These findings represent the first assessment of the effect of bitopertin on neurophysiological biomarkers. Bitopertin did not significantly affect either symptoms or NMDAR-related biomarkers at the dose tested (10 mg). Mismatch negativity showed high test-retest reliability, supporting its use as a target engagement measure.

OBJECTIVES: This study examined whether children with distinct brain disorders show different profiles of strengths and weaknesses in executive functions, and differ from children without brain disorder. METHODS: Participants were children with traumatic brain injury (N=82; 8-13 years of age), arterial ischemic stroke (N=36; 6-16 years of age), and brain tumor (N=74; 9-18 years of age), each with a corresponding matched comparison group consisting of children with orthopedic injury (N=61), asthma (N=15), and classmates without medical illness (N=68), respectively. Shifting, inhibition, and working memory were assessed, respectively, using three Test of Everyday Attention: Children's Version (TEA-Ch) subtests: Creature Counting, Walk-Don't-Walk, and Code Transmission. Comparison groups did not differ in TEA-Ch performance and were merged into a single control group. Profile analysis was used to examine group differences in TEA-Ch subtest scaled scores after controlling for maternal education and age. RESULTS: As a whole, children with brain disorder performed more poorly than controls on measures of executive function. Relative to controls, the three brain injury groups showed significantly different profiles of executive functions. Importantly, post hoc tests revealed that performance on TEA-Ch subtests differed among the brain disorder groups. CONCLUSIONS: Results suggest that different childhood brain disorders result in distinct patterns of executive function deficits that differ from children without brain disorder. Implications for clinical practice and future research are discussed. (JINS, 2017, 23, 529-538).

We examined global and local visual processing in autism spectrum disorder (ASD) via a match-to-sample task using Kanizsa illusory contours (KIC). School-aged children with ASD (n = 28) and age-matched typically developing controls (n = 22; 7-13 years) performed a sequential match-to-sample between a solid shape (sample) and two illusory alternatives. We tracked eye gaze and behavioral performance in two task conditions: one with and one without local interference from background noise elements. While analyses revealed lower accuracy and longer reaction time in ASD in the condition with local interference only, eye tracking robustly captured ASD-related global atypicalities across both conditions. Specifically, relative to controls, children with ASD showed decreased fixations to KIC centers, indicating reduced global perception. Notably, they did not differ from controls in regard to fixations to local elements or touch response location. These results indicate impaired global perception in the absence of heightened local processing in ASD. They also underscore the utility of eye-tracking measures as objective indices of global/local visual processing strategies in ASD. Autism Res 2017. (c) 2017 International Society for Autism Research, Wiley Periodicals, Inc.

Development passes through sensitive periods, during which plasticity allows for genetic and environmental factors to exert indelible influence on the maturation of the organism. In the context of central nervous system (CNS) development, such sensitive periods shape the formation of neuro-circuits that mediate, regulate, and control behavior. This general mechanism allows for development to be guided by both the genetic blueprint, as well as the environmental context. While allowing for adaptation, such sensitive periods are also windows of vulnerability during which external and internal factors can confer risk to brain disorders by derailing adaptive developmental programs. Our group has been particularly interested in developmental periods that are sensitive to serotonin (5-HT) signaling, and impact behavior and cognition relevant to psychiatry. Specifically, we review a 5-HT-sensitive period that impacts fronto-limbic system development, resulting in cognitive, anxiety, and depression-related behaviors. We discuss preclinical data to establish biological plausibility and mechanistic insights. We also summarize epidemiological findings that underscore the potential public health implications resulting from the current practice of prescribing 5-HT reuptake inhibiting antidepressants during pregnancy. These medications enter the fetal circulation, likely perturb 5-HT signaling in the brain, and may be affecting circuit maturation in ways that parallel our findings in the developing rodent brain. More research is needed to better disambiguate the dual effects of maternal symptoms on fetal and child development from the effects of 5-HT reuptake inhibitors on clinical outcomes in the offspring. Birth Defects Research 109:924-932, 2017. © 2017 Wiley Periodicals, Inc.