How far can mice carry autism research?

In the face of growing controversy about the utility of genetic mouse models of human disease, Rothwell et al. report on a shared mechanism by which two different neuroligin-3 mutations, associated with autism spectrum disorders in humans, produce an enhancement in motor learning. The open question is how much we can learn about human ills from such models.

A bone to pick with compulsive behavior.

Mice with mutations in the Hoxb8 gene exhibit compulsive grooming behavior. Chen et al. (2010) now report that this behavior stems from Hoxb8 deficiency in microglia, a type of immune cell in the brain derived from bone marrow. These findings provide intriguing connections between immune dysfunction and neuropsychiatric disorders.

Problems with Using Polygenic Scores to Select Embryos.

Companies have recently begun to sell a new service to patients considering in vitro fertilization: embryo selection based on polygenic scores (ESPS). These scores represent individualized predictions of health and other outcomes derived from genomewide association studies in adults to partially predict these outcomes. This article includes a discussion of many factors that lower the predictive power of polygenic scores in the context of embryo selection and quantifies these effects for a variety of clinical and nonclinical traits. Also discussed are potential unintended consequences of ESPS (including selecting for adverse traits, altering population demographics, exacerbating inequalities in society, and devaluing certain traits). Recommendations for the responsible communication about ESPS by practitioners are provided, and a call for a society-wide conversation about this technology is made. (Funded by the National Institute on Aging and others.).

Study Protocol: Global Research Initiative on the Neurophysiology of Schizophrenia (GRINS) project.

BACKGROUND: Objective and quantifiable markers are crucial for developing novel therapeutics for mental disorders by 1) stratifying clinically similar patients with different underlying neurobiological deficits and 2) objectively tracking disease trajectory and treatment response. Schizophrenia is often confounded with other psychiatric disorders, especially bipolar disorder, if based on cross-sectional symptoms. Awake and sleep EEG have shown promise in identifying neurophysiological differences as biomarkers for schizophrenia. However, most previous studies, while useful, were conducted in European and American populations, had small sample sizes, and utilized varying analytic methods, limiting comprehensive analyses or generalizability to diverse human populations. Furthermore, the extent to which wake and sleep neurophysiology metrics correlate with each other and with symptom severity or cognitive impairment remains unresolved. Moreover, how these neurophysiological markers compare across psychiatric conditions is not well characterized. The utility of biomarkers in clinical trials and practice would be significantly advanced by well-powered transdiagnostic studies. The Global Research Initiative on the Neurophysiology of Schizophrenia (GRINS) project aims to address these questions through a large, multi-center cohort study involving East Asian populations. To promote transparency and reproducibility, we describe the protocol for the GRINS project. METHODS: The research procedure consists of an initial screening interview followed by three subsequent sessions: an introductory interview, an evaluation visit, and an overnight neurophysiological recording session. Data from multiple domains, including demographic and clinical characteristics, behavioral performance (cognitive tasks, motor sequence tasks), and neurophysiological metrics (both awake and sleep electroencephalography), are collected by research groups specialized in each domain. CONCLUSION: Pilot results from the GRINS project demonstrate the feasibility of this study protocol and highlight the importance of such research, as well as its potential to study a broader range of patients with psychiatric conditions. Through GRINS, we are generating a valuable dataset across multiple domains to identify neurophysiological markers of schizophrenia individually and in combination. By applying this protocol to related mental disorders often confounded with each other, we can gather information that offers insight into the neurophysiological characteristics and underlying mechanisms of these severe conditions, informing objective diagnosis, stratification for clinical research, and ultimately, the development of better-targeted treatment matching in the clinic.

The Hierarchical Taxonomy of Psychopathology (HiTOP) in psychiatric practice and research.

The Hierarchical Taxonomy of Psychopathology (HiTOP) has emerged out of the quantitative approach to psychiatric nosology. This approach identifies psychopathology constructs based on patterns of co-variation among signs and symptoms. The initial HiTOP model, which was published in 2017, is based on a large literature that spans decades of research. HiTOP is a living model that undergoes revision as new data become available. Here we discuss advantages and practical considerations of using this system in psychiatric practice and research. We especially highlight limitations of HiTOP and ongoing efforts to address them. We describe differences and similarities between HiTOP and existing diagnostic systems. Next, we review the types of evidence that informed development of HiTOP, including populations in which it has been studied and data on its validity. The paper also describes how HiTOP can facilitate research on genetic and environmental causes of psychopathology as well as the search for neurobiologic mechanisms and novel treatments. Furthermore, we consider implications for public health programs and prevention of mental disorders. We also review data on clinical utility and illustrate clinical application of HiTOP. Importantly, the model is based on measures and practices that are already used widely in clinical settings. HiTOP offers a way to organize and formalize these techniques. This model already can contribute to progress in psychiatry and complement traditional nosologies. Moreover, HiTOP seeks to facilitate research on linkages between phenotypes and biological processes, which may enable construction of a system that encompasses both biomarkers and precise clinical description.

Psychiatric Disorders: Grounded in Human Biology but Not Natural Kinds.

The third edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-III) and its descriptive psychiatry-based intellectual antecedents imagined psychiatric disorders as discontinuous categories, presumably natural kinds, that would be empirically validated based on future scientific studies. Validation would emerge from a predicted convergence of clinical descriptions (symptom clusters that could be shown to be stable over the lifespan), laboratory results, and family studies. That future science is now arriving, but rather than validating the categorical DSM approach, large-scale genetics along with modern neurobiology and epidemiology have emphatically undercut it. Clinical description, laboratory studies, and family (now genetic) studies do not converge at all on distinct categories. Rather, modern studies are consistent with psychiatric disorders as heterogeneous quantitative deviations from health. The characteristics of these disorders have proven to be discoverable rather than invented and thus are grounded in nature. However, scientific results demonstrate that psychiatric disorders cannot reasonably be understood as discrete categories-and certainly not as natural kinds.

DSM-5 and RDoC: progress in psychiatry research?

Neuroscience studies into psychiatric disorders generally rely on disease definitions that are based on the influential Diagnostic and Statistical Manual of Mental Disorders (DSM), the fifth edition of which (DSM-5) was released earlier this year. Designed as a purely diagnostic tool, the DSM considers different disorders as distinct entities. However, boundaries between disorders are often not as strict as the DSM suggests. To provide an alternative framework for research into psychiatric disorders, the US National Institute of Mental Health (NIMH) has recently introduced its Research Domain Criteria (RDoC) project. In the RDoC, five 'domains' each reflect a brain system in which functioning is impaired, to different degrees, in different psychiatric conditions. Nature Reviews Neuroscience asked six leading investigators for their thoughts on how DSM-5 and the RDoC will influence neuroscience research into psychiatric disorders.

Genetic research in autism spectrum disorders.

PURPOSE OF REVIEW: The recent explosion of genetic findings in autism spectrum disorder (ASD) research has improved knowledge of the disorder's underlying biology and etiologic architecture. This review introduces concepts and results from recent genetic studies and discusses the manner in which those findings can influence the trajectory of ASD research. RECENT FINDINGS: Large consortium studies have associated ASDs with many types of genetic risk factors, including common polygenic risk, de novo single nucleotide variants, copy number variants, and rare inherited variants. In aggregate, these results confirm the heterogeneity and complexity of ASDs. The rare variant findings in particular point to genes and pathways that begin to bridge the gap between behavior and biology. SUMMARY: Genetic studies have the potential to identify the biological underpinnings of ASDs and other neuropsychiatric disorders. The data they generate are already being used to examine disease pathways and pathogenesis. The results also speak to ASD heterogeneity and, in the future, may be used to stratify research studies and treatment trials.

A glimmer of light for neuropsychiatric disorders.

Understanding the pathogenesis of neuropsychiatric disorders is a substantial challenge for neurobiologists. It has long been hoped that identifying alleles that confer increased risk of such disorders would provide clues for neurobiological investigation. But this quest has been stymied by a lack of validated biological markers for characterizing and distinguishing the different disorders and by the genetic complexity underpinning these diseases. Now, modern genomic technologies have begun to facilitate the discovery of relevant genes.

Might stimulant drugs support moral agency in ADHD children?

Stimulants have been shown to be safe and effective for reduction of the symptoms of attention deficit hyperactivity disorder. Despite much debate, however, there has been little empirical evidence as to whether stimulants affect authenticity and moral agency in children. Singh presents evidence that stimulants do not undercut children's' sense of self and increase their experience of agency. These findings are consistent with laboratory evidence that stimulant drugs in therapeutic doses improve cognitive control over thought and behavior.

Shifting the trajectory of therapeutic development for neurological and psychiatric disorders.

Clinical trials for central nervous system disorders often enroll patients with unrecognized heterogeneous diseases, leading to costly trials that have high failure rates. Here, we discuss the potential of emerging technologies and datasets to elucidate disease mechanisms and identify biomarkers to improve patient stratification and monitoring of disease progression in clinical trials for neuropsychiatric disorders. Greater efforts must be centered on rigorously standardizing data collection and sharing of methods, datasets, and analytical tools across sectors. To address health care disparities in clinical trials, diversity of genetic ancestries and environmental exposures of research participants and associated biological samples must be prioritized.

Cohort profile: SUPER-Finland - the Finnish study for hereditary mechanisms of psychotic disorders.

PURPOSE: SUPER-Finland is a large Finnish collection of psychosis cases. This cohort also represents the Finnish contribution to the Stanley Global Neuropsychiatric Genetics Initiative, which seeks to diversify genetic sample collection to include Asian, Latin American and African populations in addition to known population isolates, such as Finland. PARTICIPANTS: 10 474 individuals aged 18 years or older were recruited throughout the country. The subjects have been genotyped with a genome-wide genotyping chip and exome sequenced. A subset of 897 individuals selected from known population sub-isolates were selected for whole-genome sequencing. Recruitment was done between November 2015 and December 2018. FINDINGS TO DATE: 5757 (55.2%) had a diagnosis of schizophrenia, 944 (9.1%) schizoaffective disorder, 1612 (15.5%) type I or type II bipolar disorder, 532 (5.1 %) psychotic depression, 1047 (10.0%) other psychosis and for 530 (5.1%) self-reported psychosis at recruitment could not be confirmed from register data. Mean duration of schizophrenia was 22.0 years at the time of the recruitment. By the end of the year 2018, 204 of the recruited individuals had died. The most common cause of death was cardiovascular disease (n=61) followed by neoplasms (n=40). Ten subjects had psychiatric morbidity as the primary cause of death. FUTURE PLANS: Compare the effects of common variants, rare variants and copy number variations (CNVs) on severity of psychotic illness. In addition, we aim to track longitudinal course of illness based on nation-wide register data to estimate how phenotypic and genetic differences alter it.