The duration of untreated psychosis (DUP) in patients with first-episode schizophrenia (FES) has attracted attention as a determinant of prognosis. We previously reported the DUP in Japan and its relationship with disease outcome. Efforts to shorten the DUP have led to optimal treatment within the critical period. Furthermore, interest in interventions during the prodromal phase, with the intention of preventing the onset of psychosis, has been increasing globally. In 2007, a specialized outpatient clinic (Youth Clinic) and day-care unit (“Il Bosco”) targeting individuals with an at-risk mental state (ARMS) and FES were established at the Toho University Omori Medical Center in Tokyo. These facilities provide a detailed assessment of clinical symptoms using the PRIME ScreenRevised (PS-R) and the Structured Interview for Prodromal Syndromes Japanese version (SIPS-J) . Because ARMS and FES patients exhibit cognitive impairments in a wide variety of domains that are obviously related to the patients’social functioning, cognitive training programs are provided at the Il Bosco facility in addition to psychosocial treatment that takes the younger ages of the patients into account.

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Proton magnetic resonance spectroscopy (1H-MRS) is a non-invasive functional neurological measurement. The N-acetylaspartate (NAA) signal is thought to represent neurons. NAA is located almost exclusively in neurons and its reduction has been considered not only as a marker for neuronal loss but also of the level of neuronal functioning. Brain levels of GABA and NAA were significantly changed in left basal ganglia. These results indicate that dysfunctions of GABAergic neurons exist in early stage of first episode schizophrenia. On the other hand, treatment with atypical antipsychotic drugs did not alter brain GABA levels. We reviewed recent reports using MRI with schizophrenia patients,and we compared those with our previous studies.

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Increasing evidence from cross-sectional and longitudinal magnetic resonance imaging (MRI) studies in first-episode schizophrenia and individuals at risk for developing psychosis (at risk mental state : ARMS) suggests that 1. ARMS subjects who subsequently develop psychosis have baseline brain changes, which could be at least partly predictive of later transition, and that 2. patients with schizophrenia and other psychoses have progressive brain morphologic changes during the transition period as well as initial periods after the onset of florid psychosis. In this article we review recent neuroimaging findings in early psychosis and also refer to remaining issues to be addressed before transferring these neurobioligical research findings to the clinical setting.

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Autism spectrum disorder (ASD) is a neuro-developmental disorder characterized by socio-emotional impairment, but the neural substrate is unknown. One characteristic of ASD is the lack of empathy and emotional engagement with others. Individuals with ASD have difficulty in relating others and recognizing their emotions when other people demonstrate angry, happy or sad feeling. This study aimed at investigating brain activity during perception of facial expression using functional MRI (fMRI) . Thirteen subjects who were diagnosed as ASD according to DSM-IV-TR and 13 age-matched healthy controls were examined. The subjects were watching photographs with happy, sad, angry and neutral facial expression. BOLD signals were obtained during these visual stimuli with GRE-EPI T2* imaging. Region of Interest (ROI) was determined with MarsBar, and comparison was made between the activity in ASD and controls regarding each facial expression with ANOVA. ASD group showed significantly reduced activity in right fusiform gyrus and right mirror neuron system (rMNS) in the frontal cortex. Interaction with facial expression was shown in rMNS. Autism spectrum quotient (AQ) values in ASD subjects were significantly correlated with hypoactivity of rMNs. These results suggest that the disturbance of MNS in the frontal cortex involves in the impairment in perception of facial expression in ASD subjects.

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Arachidonic acid (ARA) and docosahexaenoic acid (DHA) may be related to brain network maturation. ARA has more important role in signal transduction related to neuronal maturation. Supplementation with larger ARA doses added to DHA may therefore mitigate social impairment. In a double-blind, placebo-controlled 16-week trial we administered daily doses of either ARA and DHA (240 mg each) or placebo in 13 participants with autism spectrum disorders (ASD) aged 6 to 28 years old (mean age ± SD=14.6 ± 5.9 years) . The outcome measures were the Social Responsiveness Scale (SRS) and the Aberrant Behavior Checklist-Community (ABC) . Repeated measures analysis of variance revealed that the treatment group significantly improved SRS-measured communication as well as ABC-measured social withdrawal compared to the control group. Plasma levels of transferrin as well as superoxide dismutase showed difference in the change between the two groups. This clinical study suggests that supplementation with larger ARA doses added to DHA improves social impairment in individuals with by upregulating signal transduction or reducing oxidative stress.

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Oxytocin is a neuropeptide that is released into the general circulation from the nerve endings of the posterior pituitary and into the brain from dendrites. The half-life of oxytocin in the brain is longer than that in the blood (about 20 min vs. 2 min, respectively) . Oxytocin is involved in social recognition, pair bonding, and maternal behavior. The transmembrane glycoprotein CD38 regulates oxytocin release, and CD38-knockout mice show insufficient oxytocin release. We have found a single nucleotide polymorphism (SNP) in the exon region of the CD38 gene in a subpopulation of individuals with autism spectrum disorder (ASD) . Oxytocin signaling, including CD38 and oxytocin receptor, is suggested to play an important role in the pathophysiology of ASD, although we did not demonstrate an association between the CD38 gene SNP and ASD. Oxytocin administered using a nasal spray penetrates directly into the brain and not via the general circulation. Four studies have suggested the effectiveness of a single shot of oxytocin in the treatment of ASD. We observed marked improvement in severe irritability shown by two ASD patients using oxytocin nasal spray. The effectiveness of oxytocin in the long-term treatment of patients with ASD should be rigorously investigated in a randomized controlled crossover trial.

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Social affiliation develops through sensory-motor interaction between social agents. We have established a new integrative behavior analysis method to quantitatively evaluate the social behavior and examined the development of social affiliation behavior in two animal models (domestic chick and common marmoset). We found that chick developed the affiliation behavior through a sensitive period and SSRI/SNRI was effective for the chick which did not experience social interaction in the period, but did after the period. This result suggests the possible contribution of our animal model to shed more light on the neural basis of social behavior deficit in developmental disorders and other psychiatric disorders.

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We reviewed on the current status of research on Rett syndrome (RTT) and neurochemical abnormalities in neurotransmitters, neuromodulators and other biological markers in patients with RTT. We have previously investigated the levels of various factors in the blood, plasma, and cerebrospinal fluid of RTT patients, including biogenic amines, lactate, pyruvate, citric acid cycle intermediates, melatonin, substance P, and β-phenylethylamine. Among these factors, an alternation of the levels of monoamines or their metabolites has been repeatedly reported. Other CSF factors such as a reduction of NGF and substance P have been reported, which might explain some clinical features of RTT. We also discussed the possible role of plasma ghrelin in RTT and presented the results of our mouse study of the MECP2-null mutation using ES cells. Finally, we considered the potential for future analyses using our recently developed iPS cell system and discuss the future perspectives for the treatment and management of this developmental disorder.

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We feel strong envy when the advantaged person is self-relevant. We usually sympathize when misfortunes happen to others, but sometimes feel pleasure, Schadenfreude, when envied persons fall from grace. To elucidate the neurocognitive mechanisms of envy and schadenfreude, 2 fMRI studies were performed. Study 1 revealed that when the target person's possession was superior and self-relevant, stronger envy and stronger anterior cingulate cortex (ACC) activation were induced. In study 2, stronger schadenfreude and stronger striatum activation were induced when misfortunes happened to envied persons.

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