Chromatin accessibility dynamics in a model of human forebrain development.

Forebrain development is characterized by highly synchronized cellular processes, which, if perturbed, can cause disease. To chart the regulatory activity underlying these events, we generated a map of accessible chromatin in human three-dimensional forebrain organoids. To capture corticogenesis, we sampled glial and neuronal lineages from dorsal or ventral forebrain organoids over 20 months in vitro. Active chromatin regions identified in human primary brain tissue were observed in organoids at different developmental stages. We used this resource to map genetic risk for disease and to explore evolutionary conservation. Moreover, we integrated chromatin accessibility with transcriptomics to identify putative enhancer-gene linkages and transcription factors that regulate human corticogenesis. Overall, this platform brings insights into gene-regulatory dynamics at previously inaccessible stages of human forebrain development, including signatures of neuropsychiatric disorders.

Novel aspects of enteric serotonergic signaling in health and brain-gut disease.

Gastrointestinal (GI) comorbidities are common in individuals with mood and behavioral dysfunction. Similarly, patients with GI problems more commonly suffer from co-morbid psychiatric diagnoses. Although the central and enteric nervous systems (CNS and ENS, respectively) have largely been studied separately, there is emerging interest in factors that may contribute to disease states involving both systems. There is strong evidence to suggest that serotonin may be an important contributor to these brain-gut conditions. Serotonin has long been recognized for its critical functions in CNS development and function. The majority of the body's serotonin, however, is produced in the GI tract, where it plays key roles in ENS development and function. Further understanding of the specific impact that enteric serotonin has on brain-gut disease may lay the foundation for the creation of novel therapeutic targets. This review summarizes the current data focusing on the important roles that serotonin plays in ENS development and motility, with a focus on novel aspects of serotonergic signaling in medical conditions in which CNS and ENS co-morbidities are common, including autism spectrum disorders and depression.

Prevalence of co-occurring mental health diagnoses in the autism population: a systematic review and meta-analysis.

BACKGROUND: Co-occurring mental health or psychiatric conditions are common in autism, impairing quality of life. Reported prevalences of co-occurring mental health or psychiatric conditions in people with autism range widely. Improved prevalence estimates and identification of moderators are needed to enhance recognition and care, and to guide future research. METHODS: In this systematic review and meta-analysis, we searched MEDLINE, Embase, PsycINFO, Scopus, Web of Science, and grey literature for publications between Jan 1, 1993, and Feb 1, 2019, in English or French, that reported original research using an observational design on the prevalence of co-occurring mental health conditions in people with autism and reported confirmed clinical diagnoses of the co-occurring conditions and autism using DSM or ICD criteria. For co-occurring mental health conditions reported with at least 15 datapoints (studies), we assessed risk of bias and we determined pooled estimates of prevalence for different co-occurring conditions in autism using random-effects models, and descriptively compared these with prevalence estimates for the general population from the literature (post hoc). We investigated heterogeneity in prevalence estimates using random-effects meta-regression models. This systematic review is registered with PROSPERO, CRD42018103176. FINDINGS: Of 9746 unique studies identified, 432 were selected for full-text review. 100 studies were eligible for inclusion in our qualitative synthesis, of which 96 were included in our meta-analyses. 11 categories of co-occurring conditions were investigated, of which eight conditions were included in the meta-analyses and three were descriptively synthesised (ie, trauma and stressor-related disorders, substance-related and addictive disorders, and gender dysphoria). From our meta-analyses, we found overall pooled prevalence estimates of 28% (95% CI 25-32) for attention-deficit hyperactivity disorder; 20% (17-23) for anxiety disorders; 13% (9-17) for sleep-wake disorders; 12% (10-15) for disruptive, impulse-control, and conduct disorders; 11% (9-13) for depressive disorders; 9% (7-10) for obsessive-compulsive disorder; 5% (3-6) for bipolar disorders; and 4% (3-5) for schizophrenia spectrum disorders. Estimates in clinical sample-based studies were higher than in population-based and registry-based studies, and these estimates were mostly higher than those in the general population (post hoc). Age, gender, intellectual functioning, and country of study were associated with heterogeneity in prevalence estimates, yet remaining heterogeneity not explained was still substantial (all I2 >95%). INTERPRETATION: Co-occurring mental health conditions are more prevalent in the autism population than in the general population. Careful assessment of mental health is an essential component of care for all people on the autism spectrum and should be integrated into clinical practice. FUNDING: Academic Scholars Awards, Department of Psychiatry, University of Toronto; O'Brien Scholars Program, Slaight Family Child and Youth Mental Health Innovation Fund, and The Catherine and Maxwell Meighen Foundation via the Centre for Addiction and Mental Health Foundation.

Fetal Origins of Mental Health: The Developmental Origins of Health and Disease Hypothesis.

The quality of fetal growth and development predicts the risk for a range of noncommunicable, chronic illnesses. These observations form the basis of the "developmental origins of health and disease" hypothesis, which suggests that the intrauterine signals that compromise fetal growth also act to "program" tissue differentiation in a manner that predisposes to later illness. Fetal growth also predicts the risk for later psychopathology. These findings parallel studies showing that antenatal maternal emotional well-being likewise predicts the risk for later psychopathology. Taken together, these findings form the basis for integrative models of fetal neurodevelopment, which propose that antenatal maternal adversity operates through the biological pathways associated with fetal growth to program neurodevelopment. The authors review the literature and find little support for such integrated models. Maternal anxiety, depression, and stress all influence neurodevelopment but show modest, weak, or no associations with known stress mediators (e.g., glucocorticoids) or with fetal growth. Rather, compromised fetal development appears to establish a "meta-plastic" state that increases sensitivity to postnatal influences. There also remain serious concerns that observational studies associating either fetal growth or maternal mental health with neurodevelopmental outcomes fail to account for underlying genetic factors. Finally, while the observed relation between fetal growth and adult health has garnered considerable attention, the clinical relevance of these associations remains to be determined. There are both considerable promise and important challenges for future studies of the fetal origins of mental health.

Fetal programming of neuropsychiatric disorders.

Starting from the Developmental Origins of Health and Disease (DOHaD) hypotheses proposed by David Barker, namely fetal programming, in the past years, there is a growing evidence of the major role played by epigenetic factors during the intrauterine life and the perinatal period. Furthermore, it has been assessed that these factors can affect the health status in infancy and even in adulthood. In this review, we focus our attention on the fetal programming of the brain, analyzing the most recent literature concerning the epigenetic factors that can influence the development of neuropsychiatric disorders such as bipolar disorders, major depressive disorders, and schizophrenia. The perinatal epigenetic factors have been divided in two main groups: maternal factors and fetal factors. The maternal factors include diet, smoking, alcoholism, hypertension, malnutrition, trace elements, stress, diabetes, substance abuse, and exposure to environmental toxicants, while the fetal factors include hypoxia/asphyxia, placental insufficiency, prematurity, low birth weight, drugs administered to the mother or to the baby, and all factors causing intrauterine growth restriction. A better comprehension of the possible mechanisms underlying the pathogenesis of these diseases may help researchers and clinicians develop new diagnostic tools and treatments to offer these patients a tailored medical treatment strategy to improve their quality of life. Birth Defects Research (Part C) 108:207-223, 2016. © 2016 Wiley Periodicals, Inc.

Early-life serotonin dysregulation affects the migration and positioning of cortical interneuron subtypes.

Early-life deficiency of the serotonin transporter (SERT) gives rise to a wide range of psychiatric-relevant phenotypes; however, the molecular and cellular targets of serotonin dyregulation during neural circuit formation remain to be identified. Interestingly, migrating cortical interneurons (INs) derived from the caudal ganglionic eminence (CGE) have been shown to be more responsive to serotonin-mediated signalling compared with INs derived from the medial ganglionic eminence (MGE). Here we investigated the impact of early-life SERT deficiency on the migration and positioning of CGE-derived cortical INs in SERT-ko mice and in mice exposed to the SERT inhibitor fluoxetine during the late embryonic period. Using confocal time-lapse imaging and microarray-based expression analysis we found that genetic and pharmacological SERT deficiency significantly increased the migratory speed of CGE-derived INs and affected transcriptional programmes regulating neuronal migration. Postnatal studies revealed that SERT deficiency altered the cortical laminar distribution of subtypes of CGE-derived INs but not MGE-derived INs. More specifically, we found that the distribution of vasointestinal peptide (VIP)-expressing INs in layer 2/3 was abnormal in both genetic and pharmacological SERT-deficiency models. Collectively, these data indicate that early-life SERT deficiency has an impact on the migration and molecular programmes of CGE-derived INs, thus leading to specific alterations in the positioning of VIP-expressing INs. These data add to the growing evidence that early-life serotonin dysregulation affects cortical microcircuit formation and contributes to the emergence of psychiatric-relevant phenotypes.

Development of cortical interneurons.

Inhibitory local circuit neurons (LCNs), often called interneurons, have vital roles in the development and function of cortical networks. Their inhibitory influences regulate both the excitability of cortical projection neurons on the level of individual cells, and the synchronous activity of projection neuron ensembles that appear to be a neural basis for major aspects of cognitive processing. Dysfunction of LCNs has been associated with neurological and psychiatric diseases, such as epilepsy, schizophrenia, and autism. Here we review progress in understanding LCN fate determination, their nonradial migration to the cortex, their maturation within the cortex, and the contribution of LCN dysfunction to neuropsychiatric disorders.

Prenatal expression patterns of genes associated with neuropsychiatric disorders.

OBJECTIVE: Neurodevelopmental disorders presumably involve events that occur during brain development. The authors hypothesized that neuropsychiatric disorders considered to be developmental in etiology are associated with susceptibility genes that are relatively upregulated during fetal life (i.e., differentially expressed). METHOD: The authors investigated the presence of prenatal expression enrichment of susceptibility genes systematically, as composite gene sets associated with six neuropsychiatric disorders in the microarray-based "BrainCloud" dorsolateral prefrontal cortex transcriptome. RESULTS: Using a fetal/postnatal log2-fold change threshold of 0.5, genes associated with syndromic neurodevelopmental disorders (N=31 genes, p=3.37×10-3), intellectual disability (N=88 genes, p=5.53×10-3), and autism spectrum disorder (N=242 genes, p=3.45×10-4) were relatively enriched in prenatal transcript abundance, compared with the overall transcriptome. Genes associated with schizophrenia by genome-wide association studies were not preferentially fetally expressed (N=106 genes, p=0.46), nor were genes associated with schizophrenia by exome sequencing (N=212 genes, p=0.21), but specific genes within copy-number variant regions associated with schizophrenia were relatively enriched in prenatal transcript abundance, and genes associated with schizophrenia by meta-analysis were functionally enriched for some neurodevelopmental processes. In contrast, genes associated with neurodegenerative disorders were significantly underexpressed during fetal life (N=46 genes, p=1.67×10-3). CONCLUSIONS: The authors found evidence for relative prenatal enrichment of putative susceptibility genes for syndromic neurodevelopmental disorders, intellectual disability, and autism spectrum disorder. Future transcriptome-level association studies should evaluate regions other than the dorsolateral prefrontal cortex, at other time points, and incorporate further RNA sequencing analyses.

General self-efficacy and its relationship to self-reported mental illness and barriers to care: a general population study.

Given the prevalence of mental illness worldwide, it is important to better understand the dynamics of mental health help-seeking behavior to improve access to care. The aim of this study was to investigate if general self-efficacy (GSE) was associated with self-reported mental illness and help-seeking behavior and barriers to care in a randomized population. This study utilized a mailed questionnaire completed by 3,981 persons aged 19-64 years who resided in Western Sweden. GSE was measured and logistic regression models calculated, controlling for various sociodemographic variables. Results showed that 25% of men and 43% of women reported a lifetime prevalence of mental illness that they felt could have benefitted from treatment. Of those, 37% of the men and 27% of the women reported barriers to care. Men and women with low GSE were more likely to suffer from mental illness compared with persons high in GSE, but GSE did not enhance help-seeking behavior or perceived barriers to care. The most prevalent barriers to care for both sexes were beliefs that the illness will pass by itself, doubt whether treatment works, lack of knowledge of where to go and feelings of shame. Overall, GSE scores did not differ among those who experienced various barriers to care with the exception of two barriers only among women.

Quality of life and psychiatric co­morbidity in Indian migraine patients: a headache clinic sample.

BACKGROUND: There is a lack of data from India on the impact of migraine on health-related quality of life (HRQoL) and the extent of psychiatric co-morbidities in migraine. OBJECTIVE: The objectives of the study were to quantify the impairment in HRQoL in migraine patients compared to healthy controls, to compare the prevalence of clinically significant anxiety and depressive symptoms in these groups, and to identify patient and headache characteristics that may predict health-related quality of life. MATERIALS AND METHODS: We interviewed 71 consecutive newly diagnosed migraine patients seen in the headache clinic of a tertiary referral center between September and December 2008. Age- and sex-matched healthy subjects (n = 71) were used as controls. Short Form-36, Migraine Disability Assessment Score, and Hospital Anxiety and Depression Scale were administered. Predictors of HRQoL were identified using regression analysis. RESULTS: Migraineurs were significantly impaired in all subscales of the SF-36 compared to controls, with greatest impairments in role physical, general health, and role emotional subscales. Prevalence of clinically significant anxiety (48%) and depressive (41%) symptoms in patients was higher than in healthy controls. Female gender, headache-related disability, and severity of anxiety predicted worse Physical Component Summary scores, while severity of both anxiety and depressive symptoms predicted worse Mental Component Summary scores. CONCLUSION: HRQoL is significantly reduced in Indian migraine patients compared to healthy controls. Incidence of clinically significant anxiety and depressive symptoms is also much higher in these patients. These findings corroborate well with studies from other parts of the world and suggest that cultural differences do not significantly alter the subjective impact of migraine on quality of life.

Urban adolescents with intellectual disability and challenging behaviour: costs and characteristics during transition to adult services.

Young persons with intellectual disabilities and challenging behaviour in transition usually have complex needs, which may not be served well within existing resources. In this article, we present a survey of all the young people, between 16 and 18 years of age with intellectual disabilities and challenging behaviour identified in one inner London borough. They were in transition to adult services at the time of the study (between 2006 and 2008). The objective was to examine their socio-demographic and clinical characteristics, pattern of service use and associated costs of care. An assessment toolkit was devised to measure the mental and physical health, challenging behaviour and service use of the sample. Instruments within the toolkit included the Strengths and Difficulties Questionnaire, challenging behaviour scale, Client Service Receipt Inventory (CSRI) and socio-demographic data form. Twenty-seven individuals in transition to adult services had challenging behaviour, 23 of whom had mental health diagnoses and 18 of whom had physical diagnoses. Severity of challenging behaviour did not correlate with cost of care. Informal care accounted for the highest proportion of the total cost of care (66%) with education being the second largest contributor at 22%. Evidence on transition outcomes for young people with complex needs and intellectual disabilities and associated costs is lacking. This article illustrates some of the relevant issues in this area. Further research is required to investigate these aspects and guide commissioning of appropriate services.

Reintegration of child soldiers in Burundi: a tracer study.

BACKGROUND: Substantial attention and resources are aimed at the reintegration of child soldiers, yet rigorous evaluations are rare. METHODS: This tracer study was conducted among former child soldiers (N=452) and never-recruited peers (N=191) who participated in an economic support program in Burundi. Socio-economic outcome indicators were measured retrospectively for the period before receiving support (T1; 2005-06); immediately afterwards (T2; 2006-07); and at present (T3; 2010). Participants also rated present functional impairment and mental health indicators. RESULTS: Participants reported improvement on all indicators, especially economic opportunity and social integration. At present no difference existed between both groups on any of the outcome indicators. Socio-economic functioning was negatively related with depression- and, health complaints and positively with intervention satisfaction. CONCLUSION: The present study demonstrates promising reintegration trajectories of former child soldiers after participating in a support program.

Gestational restraint stress and the developing dopaminergic system: an overview.

Prenatal stress exerts a strong impact on fetal brain development in rats impairing adaptation to stressful conditions, subsequent vulnerability to anxiety, altered sexual function, and enhanced propensity to self-administer drugs. Most of these alterations have been attributed to changes in the neurotransmitter dopamine (DA). In humans; dysfunction of dopaminergic system is associated with development of several neurological disorders, such as Parkinson disease, schizophrenia, attention-deficit hyperactivity disorder, and depression. Evidences provided by animal research, as well as retrospective studies in humans, pointed out that exposure to adverse events in early life can alter adult behaviors and neurochemical indicators of midbrain DA activity, suggesting that the development of the DA system is sensitive to disruption by exposure to early stressors. The purpose of this article is to provide a general overview of published studies and our own study related to the effect of prenatal insults on the development of DA metabolism and biology, focusing mainly in articles involving prenatal-restraint stress protocols in rats. We will also attempt to make a correlation between theses alterations and DA-related pathological processes in humans.

MicroRNAs potentiate neural development.

MicroRNAs (miRNAs) are endogenously expressed noncoding RNAs that regulate mRNA expression. In vertebrates, more distinct miRNAs are expressed in the brain than in any other tissue, where they are hypothesized to function in neural development. Recent reports describing the effects of specific miRNAs during development, and studies employing miRNA depletion as neural commitment proceeds in the embryo, support a requisite role for miRNAs in cell-fate decisions and provide clues to their function in other aspects of nervous system development.

In-vivo rodent models for the experimental investigation of prenatal immune activation effects in neurodevelopmental brain disorders.

Based on the epidemiological association between maternal infection during pregnancy and enhanced risk of neurodevelopmental brain disorders in the offspring, a number of in-vivo models have been established in rats and mice in order to study this link on an experimental basis. These models provide indispensable experimental tools to test the hypothesis of causality in human epidemiological associations, and to explore the critical neuroimmunological and developmental factors involved in shaping the vulnerability to infection-induced neurodevelopmental disturbances in humans. Here, we summarize the findings derived from numerous in-vivo models of prenatal infection and/or immune activation in rats and mice, including models of exposure to influenza virus, bacterial endotoxin, viral-like acute phase responses and specific pro-inflammatory cytokines. Furthermore, we discuss the methodological aspects of these models in relation to their practical implementation and their translatability to the human condition. We highlight that these models can successfully examine the influence of the precise timing of maternal immune activation, the role of pro- and anti-inflammatory cytokines, and the contribution of gene-environment interactions in the association between prenatal immune challenge and postnatal brain dysfunctions. Finally, we discuss that in-vivo models of prenatal immune activation offer a unique opportunity to establish and evaluate early preventive interventions aiming to reduce the risk of long-lasting brain dysfunctions following prenatal exposure to infection.