Department of Clinical Psychiatry, Nagoya University of Graduate School of Medicine
In the early days of modern psychiatry, the methods for elucidating the pathogenesis of neuropsychiatric disorders were mainly anatomies and neuropathological method based on microscopic observation of the brain. This research has greatly advanced the elucidation of the pathophysiology of neurodegenerative diseases including dementia such as Alzheimer disease. However, the pathogenesis of endogenous psychiatric disorders including schizophrenia or mood disorder has not been declared by neuropathological methods despite energetic research had been made, and it was said “schizophrenia is the graveyard of neuropathologists” with sarcasm at last. But recent advances in histopathological research methods, advances in neuroimaging techniques, and molecular biological research have made it necessary to verify again what is happening in the brain, which is the core of neuropsychiatric function. We are in the age of convincing the results of neuroimaging or molecular psychiatry in brain tissue by neuropathological research from a new perspective in elucidating the pathophysiology of mental disorders such as schizophrenia. For achieve that purpose as well, accumulation of brain tissue as research resources is very important activity, and the success of Japanese Brain bank network system is much expected.
The latest brain science pays much attention on the fact that sensory perception or cognition in the primary sensory cortex depend not only on the bottom‐up information from the sensory organs but also on the top‐down information of the anticipation from the higher brain regions. If the top‐down information of the anticipation dominates the bottom‐up information or if false top‐down information is provided, the sensory perception is perturbed and would result in hallucination. This hypothesis agrees with the pharmacological actions of various psychostimulants ; dopamine releasers enhance the brain activity of the prefrontal cortex and serotonin releasers enhance the information integrity among various cortical regions.
The number of patients with psychiatric disorders, such as major depressive disorder, bipolar disorder and schizophrenia, is increasing at an accelerated rate. However, these fundamental therapies have not necessarily established. This is due to the absence of suitable animal model for individual psychiatric disorders for developing clinical therapies, because the onset and pathophysiological mechanisms of many psychiatric disorders are unknown. Here, we introduce Piccolo, a presynaptic cytomatrix protein, derived from non‐clinical research that focuses on generating animal model for schizophrenia, and outline the significance of postmortem brain analysis in its generation. In the generation of the animal model, the translational approach based on the information from clinical research, especially the postmortem brain analysis, is very important. However, since the information obtained from the analysis is very diverse and enormous, and there are many inconsistencies and difficult to scrutinize them. Therefore, in order to generate animal model associated with several risk factors, it is essential to investigate bidirectional by both the reverse‐translational study based on non‐clinical research and the translational study based on postmortem brain analysis.
In Japan, Japan Brain Bank Net (JBBN) is currently operating by eight major brain banks, and postmortem brain research is expected to be conducted more actively in the future. On the other hand, studies using peripheral tissues that can be collected with relatively low invasiveness are also important for the researches of psychiatric disorders. However, in the studies using peripheral tissues, the significant of findings and the relationship between peripheral and central tissues are always questioned. In this article, we introduce our researches using peripheral blood samples derived from patients with psychiatric diseases. Furthermore, we introduce and discuss comparative studies of peripheral blood and postmortem brain studies. Since the findings obtained in both tissues are not always consistent, both approaches will be necessary to reveal the pathophysiology of psychiatric disorders and develop biomarkers.
In 2014, the genome‐wide association study (GWAS) analysis using a largest sample set of 36,989 subjects with schizophrenia and 113,075 controls specified 108 common genetic variants that altered the risk for onset of schizophrenia and the next generation sequencing (NGS) technologies also identified rare and de novo mutations which were associated with risk of schizophrenia. Despite recent these great advances, the precise molecular mechanisms underlying schizophrenia and other psychiatric diseases have not been clarified. Considering the brain specific genome polymorphism such as transcriptional changes, epigenetic modifications and de novo mutations, using human brain tissue is essential to understand molecular pathophysiology of schizophrenia or bipolar disorders. Since 1997 we have managed the systematic postmortem brain bank on psychiatric diseases specializes in schizophrenia for the first time in Japan in order to understand and cure psychiatric diseases and currently maintains 55 brain tissue resources. Recent several postmortem studies including our ones adopted “genetic neuropathology and provided unique and insights into underlying genetic and molecular mechanisms of schizophrenia. In this article, we show the latest findings of postmortem brain research in psychiatric disease focusing on the results of our genetic neuropathology and co‐research with other institutes using collected postmortem brain samples.
Discrepancies in the efficacy between single‐dose and repeated administrations of oxytocin on autism spectrum disorder (ASD) indicate a time‐course change in efficacy. However, the hypothesis cannot be tested without a repeatable, objective, and quantitative measurement of the core symptoms of ASD. The author’s research group comprehensively examined our single‐site exploratory (n=18, crossover) and multi‐site confirmatory (n=106, parallel‐group) , double‐blind, placebo‐controlled trials of six weeks intranasal oxytocin (48IU/day) in men with ASD. The outcome was statistical representative values of the objectively quantified facial expression intensity during a semi‐structured social interaction in Autism Diagnostic Observation Schedule (ADOS) . The quantitative facial expression analyses on data from two independent clinical trials successfully detect and verify the therapeutic effect of repeated administrations of intranasal oxytocin on autistic feature in facial expressions during social interaction. Furthermore, for the first time, the recent study demonstrated a time‐course change in the efficacy : a deterioration during repetitive administration phase and a preservation during post‐treatment phase. Together with a recent study regarding neural mechanisms of deterioration of oxytocin’s efficacy, the findings are expected to promote further development of optimization of objective, quantitative, and repeatable outcome measure for autistic social deficits and to establish optimized regimen of oxytocin treatment on ASD.
Children with autism spectrum disorder (ASD) are reported to suffer from sleep disorders at a higher rate than children with typical developing (TD) children. Previous study using polysomnography reported that sleep disorders in children with ASD are associated with social disability. Because the depth of sleep is reflected in body movement, quantification of body movement with an accelerometer is also used for evaluation of sleep. On the other hand, no study has focused on the time‐course pattern of nocturnal body movement in children with ASD. We compared the time course of nocturnal body movement in children with ASD with those in typically developing children (TD) using a wearable accelerometer. Seventeen TD children aged 5‐8 years and 17 ASD children participated in this study. As a result, body movement for 2‐3 hours after onset of sleep onset was more frequent in children with ASD. Furthermore, more frequent body movement was associated with low social ability in both children.
In the past years, the scientific literatures have reported dozens of molecular alterations in autism spectrum disorder (ASD) . However, limitations of these studies were the lack of reproducibility, which could be due to the fact that few studies succeeded to account for heterogeneity. Therefore, biological stratification that clarifies biological heterogeneity within ASD will be beneficial in discovering the biological mechanisms of ASD.
The current review paper will overview the previous blood marker research on ASD, and eventually we will discuss the blood marker’s ability to assess the therapeutic effect, given the case of novel candidate therapeutic molecule for ASD, oxytocin.
Difficulty in forming normal social relationships is an important behavioral phenotype for characterizing psychiatric disorders and is often used as a diagnostic criterion. Mice, as well as human, grow by receiving maternal care from their mothers. Numerous studies have reported that maternal separation and social isolation during infancy or juvenile development alter socio‐emotional and cognitive behaviors in mice. By using a newly developed video‐analysis‐based system, we found that adolescent social isolation results in deficient social relationship formation in adulthood, and that the behavior of other mice influences the social‐emotional and social proximity of socially isolated mice. Mice can be an experimental model to elucidate the biological basis of development of social relationships and social behaviors. No potential conflicts of interest were disclosed.