Surface area in the insula was associated with 28-month functional outcome in first-episode psychosis.

Many studies have tested the relationship between demographic, clinical, and psychobiological measurements and clinical outcomes in ultra-high risk for psychosis (UHR) and first-episode psychosis (FEP). However, no study has investigated the relationship between multi-modal measurements and long-term outcomes for >2 years. Thirty-eight individuals with UHR and 29 patients with FEP were measured using one or more modalities (cognitive battery, electrophysiological response, structural magnetic resonance imaging, and functional near-infrared spectroscopy). We explored the characteristics associated with 13- and 28-month clinical outcomes. In UHR, the cortical surface area in the left orbital part of the inferior frontal gyrus was negatively associated with 13-month disorganized symptoms. In FEP, the cortical surface area in the left insula was positively associated with 28-month global social function. The left inferior frontal gyrus and insula are well-known structural brain characteristics in schizophrenia, and future studies on the pathological mechanism of structural alteration would provide a clearer understanding of the disease.

Machine-learning classification using neuroimaging data in schizophrenia, autism, ultra-high risk and first-episode psychosis.

Neuropsychiatric disorders are diagnosed based on behavioral criteria, which makes the diagnosis challenging. Objective biomarkers such as neuroimaging are needed, and when coupled with machine learning, can assist the diagnostic decision and increase its reliability. Sixty-four schizophrenia, 36 autism spectrum disorder (ASD), and 106 typically developing individuals were analyzed. FreeSurfer was used to obtain the data from the participant's brain scans. Six classifiers were utilized to classify the subjects. Subsequently, 26 ultra-high risk for psychosis (UHR) and 17 first-episode psychosis (FEP) subjects were run through the trained classifiers. Lastly, the classifiers' output of the patient groups was correlated with their clinical severity. All six classifiers performed relatively well to distinguish the subject groups, especially support vector machine (SVM) and Logistic regression (LR). Cortical thickness and subcortical volume feature groups were most useful for the classification. LR and SVM were highly consistent with clinical indices of ASD. When UHR and FEP groups were run with the trained classifiers, majority of the cases were classified as schizophrenia, none as ASD. Overall, SVM and LR were the best performing classifiers. Cortical thickness and subcortical volume were most useful for the classification, compared to surface area. LR, SVM, and DT's output were clinically informative. The trained classifiers were able to help predict the diagnostic category of both UHR and FEP Individuals.

Promoter Activity-Based Case-Control Association Study on SLC6A4 Highlighting Hypermethylation and Altered Amygdala Volume in Male Patients With Schizophrenia.

Associations between altered DNA methylation of the serotonin transporter (5-HTT)-encoding gene SLC6A4 and early life adversity, mood and anxiety disorders, and amygdala reactivity have been reported. However, few studies have examined epigenetic alterations of SLC6A4 in schizophrenia (SZ). We examined CpG sites of SLC6A4, whose DNA methylation levels have been reported to be altered in bipolar disorder, using 3 independent cohorts of patients with SZ and age-matched controls. We found significant hypermethylation of a CpG site in SLC6A4 in male patients with SZ in all 3 cohorts. We showed that chronic administration of risperidone did not affect the DNA methylation status at this CpG site using common marmosets, and that in vitro DNA methylation at this CpG site diminished the promoter activity of SLC6A4. We then genotyped the 5-HTT-linked polymorphic region (5-HTTLPR) and investigated the relationship among 5-HTTLPR, DNA methylation, and amygdala volume using brain imaging data. We found that patients harboring low-activity 5-HTTLPR alleles showed hypermethylation and they showed a negative correlation between DNA methylation levels and left amygdala volumes. These results suggest that hypermethylation of the CpG site in SLC6A4 is involved in the pathophysiology of SZ, especially in male patients harboring low-activity 5-HTTLPR alleles.

Paternal age contribution to brain white matter aberrations in autism spectrum disorder.

AIM: Although advanced parental age holds an increased risk for autism spectrum disorder (ASD), its role as a potential risk factor for an atypical white matter development underlying the pathophysiology of ASD has not yet been investigated. The current study was aimed to detect white matter disparities in ASD, and further investigate the relationship of paternal and maternal age at birth with such disparities. METHODS: Thirty-nine adult males with high-functioning ASD and 37 typically developing (TD) males were analyzed in the study. The FMRIB Software Library and tract-based spatial statistics were utilized to process and analyze the diffusion tensor imaging data. RESULTS: Subjects with ASD exhibited significantly higher mean diffusivity (MD) and radial diffusivity (RD) in white matter fibers, including the association (inferior fronto-occipital fasciculus, right inferior longitudinal fasciculus, superior longitudinal fasciculi, uncinate fasciculus, and cingulum), commissural (forceps minor), and projection tracts (anterior thalamic radiation and right corticospinal tract) compared to TD subjects (Padjusted < 0.05). No differences were seen in either fractional anisotropy or axial diffusivity. Linear regression analyses assessing the relationship between parental ages and the white matter aberrations revealed a positive correlation between paternal age (PA), but not maternal age, and both MD and RD in the affected fibers (Padjusted < 0.05). Multiple regression showed that only PA was a predictor of both MD and RD. CONCLUSION: Our findings suggest that PA contributes to the white matter disparities seen in individuals with ASD compared to TD subjects.

Aberrant attentive and inattentive brain activity to auditory negative words, and its relation to persecutory delusion in patients with schizophrenia.

BACKGROUND AND PURPOSE: Previous research has suggested that deficits in emotion recognition are involved in the pathogenesis of persecutory delusion in schizophrenia. Although disruption in auditory and language processing is crucial in the pathophysiology of schizophrenia, the neural basis for the deficits in emotion recognition of auditorily presented language stimuli and its relation to persecutory delusion have not yet been clarified. PATIENTS AND METHODS: The current functional magnetic resonance imaging study used a dichotic listening task for 15 patients with schizophrenia and 23 healthy controls matched for age, sex, parental socioeconomic background, handedness, dexterous ear, and intelligence quotient. The participants completed a word recognition task on the attended side in which a word with emotionally valenced content (negative/neutral) was presented to one ear and a different neutral word was presented to the other ear. Participants selectively attended to either ear. RESULTS: The whole brain analysis detected the aberrant neural activity in the right inferior frontal gyrus in the patients with schizophrenia compared to that in the controls (P<0.05, false discovery rate-corrected). Brain activity in the right pars triangularis of the inferior frontal gyrus was significantly reduced when negatively valenced words were presented to the right ear, whereas the activity of the same region was significantly enhanced when these words were presented to the left ear, irrespective of the attended ear, in the participants with schizophrenia compared to the controls. Furthermore, this diminished brain response to auditorily presented negatively valenced words significantly correlated with severe positive symptoms (r=-0.67, P=0.006) and delusional behavior (r=-0.62, P=0.014) in the patients with schizophrenia. CONCLUSION: The present results indicate that the significantly impaired brain activity in response to auditorily presented negatively valenced words in the right pars triangularis of the inferior frontal gyrus is associated with the pathogenesis of positive symptoms such as persecutory delusion.

Neuroanatomical Correlates of Advanced Paternal and Maternal Age at Birth in Autism Spectrum Disorder.

Although advanced paternal and maternal age at birth (PA/MA) increases the risk of autism spectrum disorder (ASD), the underlying neurobiological mechanisms are not fully understood. To explore the neuroanatomical correlates of advanced PA/MA, the current study conducted brain morphometric analyses in 39 high-functioning adult males with ASD and 39 age-, intellectual level-, and parental socioeconomic background-matched, typically developed (TD) males. Whole-brain analysis revealed that the regional gray matter volume (GMV) in bilateral posterior cingulate cortex (PCC) and precuneus (PCU) were significantly smaller in the individuals with ASD than in TD subjects (false discovery rate-corrected P = 0.014). Additional analyses of the constituents of GMV reduction in these brain regions revealed that the cortical thickness of the right ventral PCC was significantly thinner (P = 0.014) and the surface area of bilateral PCU was significantly smaller (left: P = 0.001; right: P = 0.049) in the adults with ASD, compared with TD subjects. Although the analyses were exploratory, the thinner cortical thickness of right ventral PCC was significantly correlated with older PA in the ASD individuals (P = 0.028). The current findings shed new light on the neurobiological mechanisms underlying the link between advanced PA and ASD.

A randomized controlled trial of comprehensive early intervention care in patients with first-episode psychosis in Japan: 1.5-year outcomes from the J-CAP study.

The first episode of psychosis represents a critical period wherein comprehensive early intervention in psychosis (EIP) may alter the course of illness. However, evidence from randomized controlled trials that have examined the impact of comprehensive EIP care on clinical and functional recovery assessed by independent blinded raters is limited. The objective of this study was to conduct a single-blinded multicenter trial comparing comprehensive EIP care and standard care in young patients with first-episode psychosis (FEP) in Japan (J-CAP Study). A total of 77 participants with FEP (aged 15-35 years) were randomized to receive standard care or specialized comprehensive EIP care and were followed up for 1.5 years (trial no.: UMIN000005092). Function (measured with the Global Assessment of Functioning) and clinical remission (defined by internationally standardized criteria proposed by the Remission in Schizophrenia Working Group) were evaluated by independent raters who were blinded to group assignment. Dropout rate and other secondary outcomes were also examined. The specialized EIP care group had a higher clinical remission rate (odds ratio, 6.3; 95% confidence interval, 1.0-37.9) and lower treatment dropout rate (odds ratio, 0.038; 95% confidence interval, 0.002-0.923) than the standard care group, even after adjusting for baseline characteristics. Functional improvement in the specialized EIP care group was slightly higher than that in the standard care group, but this difference was not statistically significant (p = 0.195). From the results, we conclude that comprehensive EIP care may provide advantages over standard care in patients with FEP.

Oxytocin receptor gene variations predict neural and behavioral response to oxytocin in autism.

Oxytocin appears beneficial for autism spectrum disorder (ASD), and more than 20 single-nucleotide polymorphisms (SNPs) in oxytocin receptor (OXTR) are relevant to ASD. However, neither biological functions of OXTR SNPs in ASD nor critical OXTR SNPs that determine oxytocin's effects on ASD remains known. Here, using a machine-learning algorithm that was designed to evaluate collective effects of multiple SNPs and automatically identify most informative SNPs, we examined relationships between 27 representative OXTR SNPs and six types of behavioral/neural response to oxytocin in ASD individuals. The oxytocin effects were extracted from our previous placebo-controlled within-participant clinical trial administering single-dose intranasal oxytocin to 38 high-functioning adult Japanese ASD males. Consequently, we identified six different SNP sets that could accurately predict the six different oxytocin efficacies, and confirmed the robustness of these SNP selections against variations of the datasets and analysis parameters. Moreover, major alleles of several prominent OXTR SNPs-including rs53576 and rs2254298-were found to have dissociable effects on the oxytocin efficacies. These findings suggest biological functions of the OXTR SNP variants on autistic oxytocin responses, and implied that clinical oxytocin efficacy may be genetically predicted before its actual administration, which would contribute to establishment of future precision medicines for ASD.

Neural basis for inferring false beliefs and social emotions in others among individuals with schizophrenia and those at ultra-high risk for psychosis.

Inferring beliefs and social emotions of others has different neural substrates and possibly different roles in the pathophysiology of different clinical phases of schizophrenia. The current study investigated the neural basis for inferring others' beliefs and social emotions, as individual concepts, in 17 subjects at ultra-high risk for psychosis (UHR), 16 patients with schizophrenia and 20 healthy controls. Brain activity significantly differed from normal in both the left superior temporal sulcus (STS) and the inferior frontal gyrus (IFG) in the schizophrenia group while inferring others' beliefs, whereas those of UHR group were in the middle of those in the schizophrenia and healthy-control groups. Brain activity during inferring others' social emotions significantly differed in both the left STS and right IFG among individuals at UHR; however, there was no significant difference in the schizophrenia group. In contrast, brain activity differed in the left IFG of those in both the schizophrenia and UHR groups while inferring social emotion. Regarding the difference in direction of the abnormality, both the UHR and schizophrenia groups were characterized by hyper-STS and hypo-IFG activations when inferring others' beliefs and emotions. These findings might reflect different aspects of the same pathophysiological process at different clinical phases of psychosis.

Association between impaired brain activity and volume at the sub-region of Broca's area in ultra-high risk and first-episode schizophrenia: A multi-modal neuroimaging study.

Recent studies have suggested that functional abnormalities in Broca's area, which is important in language production (speech and thoughts before speech), play an important role in the pathophysiology of schizophrenia. While multi-modal approaches have proved useful in revealing the specific pathophysiology of psychosis, the association of functional abnormalities with gray matter volume (GMV) here in subjects with an ultra-high risk (UHR) of schizophrenia, those with first-episode schizophrenia (FES), and healthy controls has yet to be clarified. Therefore, the relationship between cortical activity measured using functional near-infrared spectroscopy (fNIRS) during a verbal fluency task, and GMV in the Broca's area assessed using a manual tracing in magnetic resonance imaging (MRI), which considers individual structural variation, was examined for 57 subjects (23 UHR/18 FES/16 controls). The UHR and FES group showed significantly reduced brain activity compared to control group in the left pars triangularis (PT) (P=.036, .003, respectively). Furthermore in the FES group, the reduced brain activity significantly positively correlated with the volume in the left PT (B=0.29, P=.027), while significant negative association was evident for all subjects (B=-0.18, P=.010). This correlation remained significant after adjusting for antipsychotics dosage, and voxel-wise analysis could not detect any significant correlation between impaired cortical activity and volume. The significant relationship between neural activity and GMV in the left PT may reflect a specific pathophysiology related to the onset of schizophrenia.

Association between rostral prefrontal cortical activity and functional outcome in first-episode psychosis: a longitudinal functional near-infrared spectroscopy study.

BACKGROUND: Few biomarkers can be used easily and noninvasively to measure clinical condition and future outcome in patients with first-episode psychosis (FEP). To develop such biomarker using multichannel functional near-infrared spectroscopy (fNIRS), cortical function in the prefrontal cortex was longitudinally measured during a verbal fluency task. METHODS: Sixty-nine fNIRS measurements and 77 clinical assessments were obtained from 31 patients with FEP at baseline, 6-month, and 12-month follow-ups. Sixty measurements were obtained from 30 healthy controls matched for age, sex, and premorbid IQ. We initially tested signal changes for 12 months, and then investigated the relationship between fNIRS signals and clinical assessments. RESULTS: Signal changes from baseline to 12-month follow-up were not evident in any group. Patients with FEP had significant positive correlation coefficients between 6-month fNIRS signals and the 12-month Global Assessment of Functioning (GAF) score in the left middle frontal gyrus (FDR-corrected p=.0016-.0052, r=.65-.59). fNIRS signals at the 12-month follow-up were associated with 12-month GAF score in the bilateral superior and middle frontal gyri (FDR-corrected p=.00085-.018, r=.72-.55), and with the difference between baseline and 12-month GAF scores in the right superior frontal gyrus (FDR-corrected p=.000067-.00012, r=.80-.78). These associations were significant even after controlling for demographic variables. No association between baseline fNIRS signals and later GAF scores was found. DISCUSSION: fNIRS measurement can potentially be used as a biomarker to aid sequential assessment of neuro-clinical conditions through the early stage of psychosis.

Oxytocin improves behavioural and neural deficits in inferring others' social emotions in autism.

Recent studies have suggested oxytocin's therapeutic effects on deficits in social communication and interaction in autism spectrum disorder through improvement of emotion recognition with direct emotional cues, such as facial expression and voice prosody. Although difficulty in understanding of others' social emotions and beliefs under conditions without direct emotional cues also plays an important role in autism spectrum disorder, no study has examined the potential effect of oxytocin on this difficulty. Here, we sequentially conducted both a case-control study and a clinical trial to investigate the potential effects of oxytocin on this difficulty at behavioural and neural levels measured using functional magnetic resonance imaging during a psychological task. This task was modified from the Sally-Anne Task, a well-known first-order false belief task. The task was optimized for investigation of the abilities to infer another person's social emotions and beliefs distinctively so as to test the hypothesis that oxytocin improves deficit in inferring others' social emotions rather than beliefs, under conditions without direct emotional cues. In the case-control study, 17 males with autism spectrum disorder showed significant behavioural deficits in inferring others' social emotions (P = 0.018) but not in inferring others' beliefs (P = 0.064) compared with 17 typically developing demographically-matched male participants. They also showed significantly less activity in the right anterior insula and posterior superior temporal sulcus during inferring others' social emotions, and in the dorsomedial prefrontal cortex during inferring others' beliefs compared with the typically developing participants (P < 0.001 and cluster size > 10 voxels). Then, to investigate potential effects of oxytocin on these behavioural and neural deficits, we conducted a double-blind placebo-controlled crossover within-subject trial for single-dose intranasal administration of 24 IU oxytocin in an independent group of 20 males with autism spectrum disorder. Behaviourally, oxytocin significantly increased the correct rate in inferring others' social emotions (P = 0.043, one-tail). At the neural level, the peptide significantly enhanced the originally-diminished brain activity in the right anterior insula during inferring others' social emotions (P = 0.004), but not in the dorsomedial prefrontal cortex during inferring others' beliefs (P = 0.858). The present findings suggest that oxytocin enhances the ability to understand others' social emotions that have also required second-order false belief rather than first-order false beliefs under conditions without direct emotional cues in autism spectrum disorder at both the behaviour and neural levels.

An fMRI study of visual lexical decision in patients with schizophrenia and clinical high-risk individuals.

Disturbances in semantic and phonological aspects of language processing are indicated in patients with schizophrenia, and in high-risk individuals for schizophrenia. To uncover neural correlates of the disturbances, a previous functional magnetic resonance imaging (fMRI) study using a visual lexical decision task in block design reported less leftward lateralization in the inferior frontal cortices, in patients with schizophrenia and individuals with high genetic risk for psychosis compared with normal control subjects. However, to our knowledge, no previous study has investigated contrasts between word and non-word processing that allow dissociation between semantic and phonological processing using event-related design visual lexical decision fMRI tasks in subjects with ultra-high-risk for psychosis (UHR) and patients with schizophrenia. In the current study, 20 patients with schizophrenia, 11 UHR, and 20 demographically matched controls underwent lexical decision fMRI tasks. Compared with controls, both schizophrenia and UHR groups showed significantly decreased activity in response to non-words compared with words in the inferior frontal regions. Additionally, decreased leftward lateralization in the non-word compared with word activity contrast was found in subjects with UHR compared with controls, which was not evident in patients with schizophrenia. The present findings suggest neural correlates of difficulty in phonological aspects of language processing during non-word processing in contrast to word, which at least partially commonly underlies the pathophysiology of schizophrenia and UHR. Together with a previous study in genetic high-risk subjects, the current results also suggest that reduced functional lateralization in the language-related frontal cortex may be a vulnerability marker for schizophrenia. Furthermore, the current result may suggest that the genetic basis of psychosis is presumed to be related to the evolution of the language capacity characteristic of humans.

Network structure underlying resolution of conflicting non-verbal and verbal social information.

Social judgments often require resolution of incongruity in communication contents. Although previous studies revealed that such conflict resolution recruits brain regions including the medial prefrontal cortex (mPFC) and posterior inferior frontal gyrus (pIFG), functional relationships and networks among these regions remain unclear. In this functional magnetic resonance imaging study, we investigated the functional dissociation and networks by measuring human brain activity during resolving incongruity between verbal and non-verbal emotional contents. First, we found that the conflict resolutions biased by the non-verbal contents activated the posterior dorsal mPFC (post-dmPFC), bilateral anterior insula (AI) and right dorsal pIFG, whereas the resolutions biased by the verbal contents activated the bilateral ventral pIFG. In contrast, the anterior dmPFC (ant-dmPFC), bilateral superior temporal sulcus and fusiform gyrus were commonly involved in both of the resolutions. Second, we found that the post-dmPFC and right ventral pIFG were hub regions in networks underlying the non-verbal- and verbal-content-biased resolutions, respectively. Finally, we revealed that these resolution-type-specific networks were bridged by the ant-dmPFC, which was recruited for the conflict resolutions earlier than the two hub regions. These findings suggest that, in social conflict resolutions, the ant-dmPFC selectively recruits one of the resolution-type-specific networks through its interaction with resolution-type-specific hub regions.

Reduced frontal glutamate + glutamine and N-acetylaspartate levels in patients with chronic schizophrenia but not in those at clinical high risk for psychosis or with first-episode schizophrenia.

Changes in brain pathology as schizophrenia progresses have been repeatedly suggested by previous studies. Meta-analyses of previous proton magnetic resonance spectroscopy ((1)H MRS) studies at each clinical stage of schizophrenia indicate that the abnormalities of N-acetylaspartate (NAA) and glutamatergic metabolites change progressively. However, to our knowledge, no single study has addressed the possible differences in (1)H MRS abnormalities in subjects at 3 different stages of disease, including those at ultrahigh risk for psychosis (UHR), with first-episode schizophrenia (FES), and with chronic schizophrenia (ChSz). In the current study, 24 patients with UHR, 19 FES, 25 ChSz, and their demographically matched 3 independent control groups (n = 26/19/28 for the UHR, FES, and ChSz control groups, respectively) underwent (1)H MRS in a 3-Tesla scanner to examine metabolites in medial prefrontal cortex. The analysis revealed significant decreases in the medial prefrontal NAA and glutamate + glutamine (Glx) levels, specifically in the ChSz group as indexed by a significant interaction between stage (UHR/FES/ChSz) and clinical status (patients/controls) (P = .008). Furthermore, the specificity of NAA and Glx reductions compared with the other metabolites in the patients with ChSz was also supported by a significant interaction between the clinical status and types of metabolites that only occurred at the ChSz stage (P = .001 for NAA, P = .004 for Glx). The present study demonstrates significant differences in (1)H MRS abnormalities at different stages of schizophrenia, which potentially correspond to changes in glutamatergic neurotransmission, plasticity, and/or excitotoxicity and regional neuronal integrity with relevance for the progression of schizophrenia.

Genetic influences on prefrontal activation during a verbal fluency task in adults: a twin study based on multichannel near-infrared spectroscopy.

Near-infrared spectroscopy (NIRS) studies have reported that prefrontal hemodynamic dysfunction during executive function tasks may be a promising biomarker of psychiatric disorders, because its portability and noninvasiveness allow easy measurements in clinical settings. Here, we investigated the degree to which prefrontal NIRS signals are genetically determined. Using a 52-channel NIRS system, we monitored the oxy-hemoglobin (oxy-Hb) signal changes in 38 adult pairs of right-handed monozygotic (MZ) twins and 13 pairs of same-sex right-handed dizygotic (DZ) twins during a letter version of the verbal fluency task. Heritability was estimated based on a classical twin paradigm using structured equation modeling. Significant genetic influences were estimated in the right dorsolateral prefrontal cortex and left frontal pole. The degrees of heritability were 66% and 75% in the variances, respectively. This implies that the prefrontal hemodynamic dysfunction observed during an executive function task measured by NIRS may be an efficient endophenotype for large-scale imaging genetic studies in psychiatric disorders.

Mitigation of sociocommunicational deficits of autism through oxytocin-induced recovery of medial prefrontal activity: a randomized trial.

IMPORTANCE: Sociocommunicational deficits make it difficult for individuals with autism spectrum disorders (ASD) to understand communication content with conflicting verbal and nonverbal information. Despite growing prospects for oxytocin as a therapeutic agent for ASD, no direct neurobiological evidence exists for oxytocin's beneficial effects on this core symptom of ASD. This is slowing clinical application of the neuropeptide. OBJECTIVE: To directly examine whether oxytocin has beneficial effects on the sociocommunicational deficits of ASD using both behavioral and neural measures. DESIGN, SETTING, AND PARTICIPANTS: At the University of Tokyo Hospital, we conducted a randomized, double-blind, placebo-controlled, within-subject-crossover, single-site experimental trial in which intranasal oxytocin and placebo were administered. A total of 40 highly functioning men with ASD participated and were randomized in the trial. INTERVENTIONS: Single-dose intranasal administration of oxytocin (24 IU) and placebo. MAIN OUTCOMES AND MEASURES: Using functional magnetic resonance imaging, we examined effects of oxytocin on behavioral neural responses of the participants to a social psychological task. In our previous case-control study using the same psychological task, when making decisions about social information with conflicting verbal and nonverbal contents, participants with ASD made judgments based on nonverbal contents less frequently with longer time and could not induce enough activation in the medial prefrontal cortex. Therefore, our main outcomes and measures were the frequency of the nonverbal information-based judgments (NVJs), the response time for NVJs, and brain activity of the medial prefrontal cortex during NVJs. RESULTS: Intranasal oxytocin enabled the participants to make NVJs more frequently (P = .03) with shorter response time (P = .02). During the mitigated behavior, oxytocin increased the originally diminished brain activity in the medial prefrontal cortex (P < .001). Moreover, oxytocin enhanced functional coordination in the area (P < .001), and the magnitude of these neural effects was predictive of the behavioral effects (P ≤ .01). CONCLUSIONS AND RELEVANCE: These findings provide the first neurobiological evidence for oxytocin's beneficial effects on sociocommunicational deficits of ASD and give us the initial account for neurobiological mechanisms underlying any beneficial effects of the neuropeptide. TRIAL REGISTRATION: umin.ac.jp/ctr Identifier: UMIN000002241 and UMIN000004393.

Altered metabolites in the plasma of autism spectrum disorder: a capillary electrophoresis time-of-flight mass spectroscopy study.

Clinical diagnosis and severity of autism spectrum disorders (ASD) are determined by trained clinicians based on clinical evaluations of observed behaviors. As such, this approach is inevitably dependent on the expertise and subjective assessment of those administering the clinical evaluations. There is a need to identify objective biological markers associated with diagnosis or clinical severity of the disorder. To identify novel candidate metabolites as potential biomarkers for ASD, the current study applied capillary electrophoresis time-of-flight mass spectroscopy (CE-TOFMS) for high-throughput profiling of metabolite levels in the plasma of 25 psychotropic-naïve adult males with high-functioning ASD and 28 age-matched typically-developed control subjects. Ten ASD participants and ten age-matched controls were assigned in the first exploration set, while 15 ASD participants and 18 controls were included in the second replication set. By CE-TOFMS analysis, a total of 143 metabolites were detected in the plasma of the first set. Of these, 17 metabolites showed significantly different relative areas between the ASD participants and the controls (p<0.05). Of the 17 metabolites, we consistently found that the ASD participants had significantly high plasma levels of arginine (p = 0.024) and taurine (p = 0.018), and significantly low levels of 5-oxoproline (p<0.001) and lactic acid (p = 0.031) compared with the controls in the second sample set. Further confirmatory analysis using quantification of absolute metabolite concentrations supported the robustness of high arginine (p = 0.001) and low lactic acid (p = 0.003) in the combined sample (n = 53). The present study identified deviated plasma metabolite levels associated with oxidative stress and mitochondrial dysfunction in individuals with ASD.

A multimodal approach to investigate biomarkers for psychosis in a clinical setting: the integrative neuroimaging studies in schizophrenia targeting for early intervention and prevention (IN-STEP) project.

Longitudinal clinical investigations and biological measurements have determined not only progressive brain volumetric and functional changes especially around the onset of psychosis but also the abnormality of developmental pathways based on gene-environment interaction model. However, these studies have contributed little to clinical decisions on their diagnosis and therapeutic choices because of subtle differences between patients and healthy controls. A multi-modal approach may resolve this limitation and is favorable to explore the pathophysiology of psychosis. The integrative neuroimaging studies for schizophrenia targeting early intervention and prevention (IN-STEP) is a research project aimed at exploring the pathophysiological features of the onset of psychosis and investigating possible predictive biomarkers for the clinical treatment of psychosis. Since 2008, we have adopted blood sampling, neurocognitive batteries, neurophysiological assessment, structural imaging, and functional imaging longitudinally for help-seeking ultra-high-risk (UHR) individuals and patients with first-episode psychosis (FEP). Here, we intend to introduce the IN-STEP research study protocol and present preliminary clinical findings. Thirty-seven UHR individuals and 30 patients with FEP participated in this study. Six months later, there was no difference in objective and subjective scores between the groups, which suggests that young people having symptoms and functional deficits should be cared for regardless of their history of psychosis according to their clinical stages. The rate of transition to psychosis was 7.1%, 8.0%, and 35.3% (at 6, 12, and 24months, respectively). Through this research project, we expect to clarify the pathophysiological features around the onset of psychosis and improve the prognosis of psychosis through clinical application.