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The etiology of autism spectrum disorder (ASD) is complex, and its pathobiology is characterized by enhanced inflammatory activities; however, the precise pathobiology and underlying causes of ASD remain unclear. This study was performed to identify inflammatory indicators useful for diagnosing ASD. The mRNA expression of cytokines, including tumor necrosis factor-α (TNF-α), was measured in cultured M1 and M2 macrophages from patients with ASD (n = 29) and typically developed (TD) individuals (n = 30). Additionally, TNF-α expression in the monocytes of patients with ASD (n = 7), showing aberrations in TNF-α expression in M1/M2 macrophages and TD individuals (n = 6), was measured. TNF-α expression in M1 macrophages and the TNF-α expression ratio in M1/M2 macrophages were markedly higher in patients with ASD than in TD individuals; however, this increase was not observed in M2 macrophages (M1: sensitivity = 34.5%, specificity = 96.7%, area under the curve = 0.74, positive likelihood ratio = 10.34; ratio of M1/M2: sensitivity = 55.2%, specificity = 96.7%, area under the curve = 0.79, positive likelihood ratio = 16.55). Additionally, TNF-α expression in monocytes did not significantly differ between patients with ASD and TD individuals. In conclusion, further studies on TNF-α expression in cultured macrophages may improve the understanding of ASD pathobiology. LAY SUMMARY: TNF-α expression in differentiated M1 macrophages and TNF-α expression ratio in differentiated M1/M2 macrophages were markedly higher in patients with ASD than in TD individuals, while no difference in TNF-α expression was found in pre-differentiation cells such as monocytes. These measurements allow elucidation of the novel pathobiology of ASD and can contribute to biomarker implementation for the diagnosis of adult high-functioning ASD.

Attention-deficit/hyperactivity disorder (ADHD) is characterized by age-inappropriate and impairing levels of inattention, hyperactivity, or impulsivity, or a combination of these characteristics. It is estimated to affect around 4% of adults worldwide. In the past few decades, prescriptions for ADHD drugs (psychostimulants and non-psychostimulants) have increased significantly. However, the efficacy and safety of adult ADHD medications remains controversial. Guanfacine extended-release (GXR) is a non-psychostimulant ADHD drug that is a selective α2A-adrenergic receptor agonist, first approved for treatment of adult ADHD in Japan in June 2019. Our aim was to provide an overview of GXR pharmacology and review the studies on efficacy and safety that have been conducted in adults with ADHD. The beneficial actions of guanfacine are thought to be attributed to the strengthening of prefrontal cortical network connections, which regulate attention, emotion, and behavior via the activity at post-synaptic α2A receptors. Current evidence of GXR efficacy and safety suggests that GXR is an effective monotherapy treatment option for adults with ADHD.

Childhood maltreatment is defined as experiencing of physical, emotional and sexual abuse and neglect in childhood. Maltreatment in childhood leads to substantial psychosocial problems later in life in the general population. Individuals with autism spectrum disorder (ASD) have a higher risk of experiencing stressful and traumatic events, such as maltreatment, during childhood. Although childhood maltreatment reportedly leads to psychosocial problems in adults with ASD, the biological associations between childhood experiences and brain function in this population remain understudied. Here, we evaluated the relationships between childhood experiences and event-related potential (ERP) components during the auditory odd-ball task in adults with ASD (N = 21) and typically developed (TD) individuals (N = 22). We found that the higher the severity of sexual abuse, the larger the amplitude of P300 at Fz, Cz, C3, and C4 in individuals with ASD. Conversely, the severity of child maltreatment was associated with P300 latency at Cz and C3 in TD individuals. Moreover, full IQ was significantly associated with the MMN amplitude at Fz, Cz, C3, and C4 in TD individuals. These findings provide the first evidence that ERPs could be used to study the impacts childhood experiences on the brain of individuals with ASD and that childhood sexual abuse has salient impacts on brain function in this population.

BackgroundMania usually occurs secondary to organic etiologies such as head trauma within a short time of the primary condition’s onset; however, there have been a few cases reported in the literature of long time spans before the manifestation of mania. The orbitofrontal cortex has been reported to be associated with manic states in bipolar disorder and with mania-inducing lesions. Head trauma commonly disrupts various cognitive functions, including attention and information processing. Traumatic brain injury patients have been shown to have greater posterior cingulate cortex and precuneus functional connectivity to the rest of the default mode network. We describe a case of secondary mania after head trauma 24 years ago with low blood flow in the orbitofrontal cortex, high blood flow in the posterior cingulate cortex, and impaired cognitive functioning, including impaired attention and lowered processing speed.Case presentationWe describe a 30-year-old Japanese man with secondary mania and a medical history of head trauma 24 years ago. After head trauma at 6 years of age, the patient first showed apathy as a sign of frontal lobe impairment. After recovering, he experienced no psychiatric problems during adolescence, although he did show disinhibited behavior. At the onset of mania, low blood flow in the OFC and high blood flow in the PCC were observed as well as impaired cognitive function, including inattention and lowered processing speed. Abnormal cerebral blood flow was less prominent and cognitive dysfunction was partially recovered following recovery from mania, but his processing speed remained low.ConclusionsAlthough functional recovery from head trauma in childhood is better than that in adulthood, the brain may remain vulnerable for a long time. The risk of psychotic symptoms such as mania should be considered, even if sufficient superficial brain functional recovery is shown.

Background School refusal behavior (SRB), which is the refusal to attend or remain in school, has been associated with emotional, psychological, and other behavioral problems, as well as a lower health-related quality of life (HRQOL). However, the effects of self-esteem and a psychiatric diagnosis in students with SRB on HRQOL are not yet known. Understanding these relationships could help to develop more effective therapeutic interventions. Methods A total of 175 young people (aged 8-18 years old) who visited our medical centers and outpatient clinics participated in the study. This comprised the SRB group (n = 70) and an age- and sex-matched control group (n = 105). Information about any psychiatric diagnosis was collected from medical records, HRQOL was measured using the J-KIDSCREEN-52, SRB was assessed using the School Refusal Assessment Scale-Revised for Japanese Attendance at School, self-esteem was measured using the Rosenberg Self-Esteem Scale, children's mental health status was measured using the Strengths and Difficulties Questionnaire, and social support was measured using the Oslo 3-item Social Support Scale. We performed between-group comparisons and multiple regression analysis. Results The SRB had a significantly lower HRQOL than the control group in several of the KIDSCREEN-52 dimensions. In the SRB group, 35.7% had chronic disease and 35.7% of their parents had health problems and were receiving treatment. The multiple regression analysis revealed that, within the SRB group, a psychiatric diagnosis was associated with a lower HRQOL. However, this was not the case for a diagnosis of autistic spectrum disorder. Self-esteem positively affected HRQOL in six dimensions of the KIDSCREEN-52 within the SRB group. Conclusion Our results could inform the development of support strategies for young people with SRB. Namely, support that enhances self-esteem could be used to increase HRQOL in young people with SRB. Furthermore, the presence of psychiatric disorders should be assessed as early as possible.

Social isolation during the juvenile critical window is detrimental to proper functioning of the prefrontal cortex (PFC) and establishment of appropriate adult social behaviors. However, the specific circuits that undergo social experience-dependent maturation to regulate social behavior are poorly understood. We identify a specific activation pattern of parvalbumin-positive interneurons (PVIs) in dorsal-medial PFC (dmPFC) prior to an active bout, or a bout initiated by the focal mouse, but not during a passive bout when mice are explored by a stimulus mouse. Optogenetic and chemogenetic manipulation reveals that brief dmPFC-PVI activation triggers an active social approach to promote sociability. Juvenile social isolation decouples dmPFC-PVI activation from subsequent active social approach by freezing the functional maturation process of dmPFC-PVIs during the juvenile-to-adult transition. Chemogenetic activation of dmPFC-PVI activity in the adult animal mitigates juvenile isolation-induced social deficits. Therefore, social experience-dependent maturation of dmPFC-PVI is linked to long-term impacts on social behavior., Isolation during critical periods of development prevents development of normal social behaviours in mice, and this is thought to involve the prefrontal cortex. Here, the authors identify an activation pattern in parvalbumin-positive interneurons in the dorsal medial prefrontal cortex that when activated promotes sociability behaviours in mice.

Accumulating evidence indicates that social stress in the juvenile period affects hypothalamic-pituitary-adrenal (HPA) axis activity in adulthood. The biological mechanisms underlying this phenomenon remain unclear. We aimed to elucidate them by comparing adult mice that had experienced social isolation from postnatal day 21-35 (juvenile social isolation (JSI) group) with those reared normally (control group). JSI group mice showed an attenuated HPA response to acute swim stress, while the control group had a normal response to this stress. Activity levels of the paraventricular nucleus in both groups were comparable, as shown by c-Fos immunoreactivities and mRNA expression of c-Fos, Corticotropin-releasing factor (CRF), Glucocorticoid receptor, and Mineralocorticoid receptor. We found greater vascular coverage by tanycytic endfeet in the median eminence of the JSI group mice than in that of the control group mice under basal condition and after acute swim stress. Moreover, CRF content after acute swim stress was greater in the median eminence of the JSI group mice than in that of the control group mice. The attenuated HPA response to acute swim stress was specific to JSI group mice, but not to control group mice. Although a direct link awaits further experiments, tanycyte morphological changes in the median eminence could be related to the HPA response.

The mechanisms by which common risk variants of small effect interact to contribute to complex genetic disorders remain unclear. Here, we apply a genetic approach, using isogenic human induced pluripotent stem cells (hiPSCs), to evaluate the effects of schizophrenia-associated common variants predicted to function as brain expression quantitative trait loci (SZ-eQTLs). By integrating CRISPR-mediated gene editing, activation and repression technologies to study one putative SZ-eQTL (FURIN rs4702) and four top-ranked SZ-eQTL genes (FURIN, SNAP91, TSNARE1, CLCN3), our platform resolves pre- and post-synaptic neuronal deficits, recapitulates genotype-dependent gene expression differences, and identifies convergence downstream of SZ-eQTL gene perturbations. Our observations highlight the cell-type-specific effects of common variants and demonstrate a synergistic effect between SZ-eQTL genes that converges on synaptic function. We propose that the links between rare and common variants implicated in psychiatric disease risk constitute a potentially generalizable phenomenon occurring more widely in complex genetic disorders.

Microglia are a heterogeneous population whose identity and function are dictated by signals from their microenvironment. Kana et al. show CSF-1 signaling is critical for cerebellar microglial transcriptional identity and homeostasis, and that altering the CSF-1–CSF-1R axis leads to motor and behavioral defects., Microglia, the brain resident macrophages, critically shape forebrain neuronal circuits. However, their precise function in the cerebellum is unknown. Here we show that human and mouse cerebellar microglia express a unique molecular program distinct from forebrain microglia. Cerebellar microglial identity was driven by the CSF-1R ligand CSF-1, independently of the alternate CSF-1R ligand, IL-34. Accordingly, CSF-1 depletion from Nestin+ cells led to severe depletion and transcriptional alterations of cerebellar microglia, while microglia in the forebrain remained intact. Strikingly, CSF-1 deficiency and alteration of cerebellar microglia were associated with reduced Purkinje cells, altered neuronal function, and defects in motor learning and social novelty interactions. These findings reveal a novel CSF-1–CSF-1R signaling-mediated mechanism that contributes to motor function and social behavior.

Background The etiology of autism spectrum disorder (ASD) is complex. Its pathobiology is characterized by enhanced inflammatory activities; however, the exact ASD pathobiology remains unclear. Some cases of ASD are difficult to diagnose using existing psychological assessments because the careful exclusion of other psychiatric disorders is challenging. To distinguish between the appropriate targets for interventions and research, the demand for identifying efficient diagnostic biomarkers is increasing. This study aimed to find an inflammatory indicator beneficial for the diagnosis of ASD.Methods Cytokine mRNA expression, including tumor necrosis factor-α (TNF-α), was measured in the differentiated M1 and M2 macrophages of ASD patients (n = 29) and typically developed (TD) individuals (n = 30). TNF-α expression was also measured in the monocytes of ASD patients (n = 7) and TD individuals (n = 6).Results TNF-α expression in M1 macrophages and TNF-α expression ratio of M1/M2 macrophages were markedly higher in ASD patients than in TD subjects; however, this difference was not observed in M2 macrophages (M1: p < 0.01; ratio of M1/M2: p < 0.0001; M2: p > 0.05), suggesting that this indicator could be a useful tool for diagnosing ASD (M1: sensitivity = 34.5%, specificity = 96.7%, area under the curve (AUC) = 0.74, positive likelihood ratio (PLR) = 10.34; ratio of M1/M2: sensitivity = 55.2%, specificity = 96.7%, AUC = 0.79, PLR = 16.55). However, there was no significant difference in the TNF-α expression in monocytes between ASD and TD individuals (p > 0.05).Conclusion These findings suggest that TNF-α expression in differentiated macrophages represents a novel adjunctive tool for the diagnosis of ASD.

One of the risk factors for schizophrenia is maternal infection. We have previously shown that Polyriboinosinic-polyribocytidylic acid (poly I:C) induced maternal immune activation in mice caused histological changes in the hippocampal CA1 area of offspring during the developmental period and impaired sensorimotor gating in offspring during adulthood, resulting in behavioral changes. However, it remains unclear how maternal immune activation functionally impacts the hippocampal neuronal activity of offspring. We studied the effect of prenatal poly I:C treatment on synaptic transmission of hippocampal CA1 pyramidal cells in postnatal and adult offspring. Treatment with poly I:C diminished excitatory and enhanced inhibitory (GABAergic) synaptic transmission on pyramidal cells in adult offspring. During the early developmental period, we still observed that treatment with poly I:C decreased excitatory synaptic transmission and potentially increased GABAergic synaptic transmission, which was uncovered under a condition of high extracellular potassium-activated neurons. In conclusion, we demonstrate that maternal immune activation decreased excitatory and increased inhibitory synaptic transmission on hippocampal pyramidal cells from an early developmental period to adulthood, which could result in net inhibition in conjunction with poor functional organization and integration of hippocampal circuits.

During brain development, the design of primary neural networks is primarily determined by environmental stimuli after their formation. In particular, the juvenile period is critical, during which neuronal circuits that consist of both excitatory and inhibitory neurons are remodeled by experience. Social isolation during the juvenile period profoundly affects brain development and contributes to the development of psychiatric disorders. We previously reported that 2 weeks of social isolation after weaning reduced excitatory synaptic inputs and intrinsic excitability in a subtype of layer 5 pyramidal cells, which we defined as prominent h-current (PH) cells, in the medial prefrontal cortex (mPFC) in mice. However, it remains unclear how juvenile social isolation affects inhibitory neuronal circuits that consist of pyramidal cells and interneurons. We found that 2 weeks of social isolation after weaning increased inhibitory synaptic inputs exclusively onto PH cells with a concomitant deterioration of action potential properties. Although social isolation did not alter the inhibitory synaptic release mechanisms or the number of inhibitory functional synapses on PH cells, we found that it increased the intrinsic excitability of fast-spiking (FS) interneurons with less excitatory synaptic inputs and more h-current. Our findings indicate that juvenile social isolation enhances the activity of inhibitory neuronal circuits in the mPFC.

The frontal cortex, especially the anterior cingulate cortex area (ACA), is essential for exerting cognitive control after errors, but the mechanisms that enable modulation of attention to improve performance after errors are poorly understood. Here we demonstrate that during a mouse visual attention task, ACA neurons projecting to the visual cortex (VIS; ACAVIS neurons) are recruited selectively by recent errors. Optogenetic manipulations of this pathway collectively support the model that rhythmic modulation of ACAVIS neurons in anticipation of visual stimuli is crucial for adjusting performance following errors. 30-Hz optogenetic stimulation of ACAVIS neurons in anesthetized mice recapitulates the increased gamma and reduced theta VIS oscillatory changes that are associated with endogenous post-error performance during behavior and subsequently increased visually evoked spiking, a hallmark feature of visual attention. This frontal sensory neural circuit links error monitoring with implementing adjustments of attention to guide behavioral adaptation, pointing to a circuit-based mechanism for promoting cognitive control.

Juvenile social isolation reduces sociability in adulthood, but the underlying neural circuit mechanisms are poorly understood. We found that, in male mice, 2 weeks of social isolation immediately following weaning leads to a failure to activate medial prefrontal cortex neurons projecting to the posterior paraventricular thalamus (mPFC→pPVT) during social exposure in adulthood. Chemogenetic or optogenetic suppression of mPFC→pPVT activity in adulthood was sufficient to induce sociability deficits without affecting anxiety-related behaviors or preference toward rewarding food. Juvenile isolation led to both reduced excitability of mPFC→pPVT neurons and increased inhibitory input drive from low-threshold-spiking somatostatin interneurons in adulthood, suggesting a circuit mechanism underlying sociability deficits. Chemogenetic or optogenetic stimulation of mPFC→pPVT neurons in adulthood could rescue the sociability deficits caused by juvenile isolation. Our study identifies a pair of specific medial prefrontal cortex excitatory and inhibitory neuron populations required for sociability that are profoundly affected by juvenile social experience. Yamamuro et al. show that juvenile social isolation disrupts prefrontal neurons projecting to the paraventricular thalamus and associated prefrontal somatostatin interneurons, and thereby impairs sociability in adulthood.

Background School refusal behavior (SRB), which is the refusal to attend or remain in school, has been associated with emotional, psychological, and other behavioral problems, as well as a lower health-related quality of life (HRQOL). However, the effects of self-esteem and a psychiatric diagnosis in students with SRB on HRQOL are not yet known. Understanding these relationships could help to develop more effective therapeutic interventions. Methods A total of 175 young people (aged 8–18 years old) who visited our medical centers and outpatient clinics participated in the study. This comprised the SRB group (n = 70) and an age- and sex-matched control group (n = 105). Information about any psychiatric diagnosis was collected from medical records, HRQOL was measured using the J-KIDSCREEN-52, SRB was assessed using the School Refusal Assessment Scale-Revised for Japanese Attendance at School, self-esteem was measured using the Rosenberg Self-Esteem Scale, children’s mental health status was measured using the Strengths and Difficulties Questionnaire, and social support was measured using the Oslo 3-item Social Support Scale. We performed between-group comparisons and multiple regression analysis. Results The SRB had a significantly lower HRQOL than the control group in several of the KIDSCREEN-52 dimensions. In the SRB group, 35.7% had chronic disease and 35.7% of their parents had health problems and were receiving treatment. The multiple regression analysis revealed that, within the SRB group, a psychiatric diagnosis was associated with a lower HRQOL. However, this was not the case for a diagnosis of autistic spectrum disorder. Self-esteem positively affected HRQOL in six dimensions of the KIDSCREEN-52 within the SRB group. Conclusion Our results could inform the development of support strategies for young people with SRB. Namely, support that enhances self-esteem could be used to increase HRQOL in young people with SRB. Furthermore, the presence of psychiatric disorders should be assessed as early as possible.

Head trauma is a well-established epidemiological risk factor for Alzheimer's disease, but a study of early detection of its pathology has not yet been performed in human patients in vivo. To address this issue, we performed 11 C-labelled Pittsburgh compound B-positron emission tomography on a right-handed 30-year-old man with cognitive deterioration after repetitive head trauma during karate matches. Structural magnetic resonance imaging was also performed on this patient. The same positron emission tomography analysis was performed on elderly healthy controls (15 men, mean age: 70.7 ± 6.2 years). To analyze grey matter volume, structural magnetic resonance imaging was performed on age-matched healthy controls (15 men, mean age: 28.5 ± 3.6 years). The cognitive deterioration in our patient was fixed and partially improved in the 10 years after the repetitive head trauma. However, Pittsburgh compound B-non-displaceable binding potential was significantly elevated in the patient. Volume reduction was shown in the medial temporal region, cerebellum, and the basal frontal cortex, while amyloid-β increase was shown in the bilateral prefrontal cortex. This is the first study to show an early degenerative process due to head trauma in the prefrontal cortex, where structural damage is not yet visible. Early recognition of the degenerative pathology due to repetitive head trauma by amyloid and possibly tau imaging would help clinicians determine how to treat those with early symptoms.

Purpose Antipsychotic drug treatment can potentially lead to adverse events such as extrapyramidal symptoms (EPSs). If these events persist, they lower patient quality of life. The purpose of this report is to present our experience with such a case, as an example to encourage further study. Patients and methods The patient was a 64-year-old male who had been diagnosed with schizophrenia that had been treated with oral antipsychotics for over 40 years. Due to lack of compliance, he was treated with the long-acting injectable antipsychotic, paliperidone palmitate, but developed persistent EPSs after 6 months. He was subsequently treated and monitored in our inpatient facility. Results Antipsychotic treatment was stopped. After 6 weeks, the patient's psychosis had worsened, but his EPSs remained unchanged. Levodopa treatment was then started (up to 400 mg/d), which improved his EPSs, so he was restarted on oral antipsychotic therapy (aripiprazole, 6-18 mg/d). His psychotic symptoms improved over 2 months. The improvements in both psychosis and EPSs remained stable. Dopamine transporter scans revealed moderate dopamine transporter loss in the striatum, and computed tomography revealed no sign of brain abnormalities, suggesting that the patient was susceptible to dopamine reductions. Conclusion Paliperidone palmitate can induce EPSs, even if injected only a few times. Although the characteristics of the drug are potential causes, the patient's predisposition to dopamine perturbations can also influence the outcome. Therefore, adequate awareness is required before injection.

Background Schizophrenia (SZ) and bipolar disorder (BD) are characterized by different clinical symptoms, and have previously been considered as categorically separate. However, several lines of evidence controversially suggest that these two disorders may run on a continuum. While it is therefore important to evaluate the subtle differences between SZ and BD, few studies have investigated the difference of brain functioning between the two by focusing on the common symptoms of cognitive functioning and impulsivity, rather than positive/negative and mood symptoms. Recent developments in near-infrared spectroscopy (NIRS) technology have enabled noninvasive assessment of brain function in people with psychiatric disorders. Methods Near-infrared spectroscopy (NIRS) using 24-channels was conducted during the verbal fluency task (VFT) and Stroop color-word task (SCWT) in 38 patients diagnosed with SZ, 34 patients with BD, and 26 age- and sex-matched healthy controls. Results Oxyhemoglobin changes in the prefrontal cortex (PFC) were significantly lower particularly in the SZ compared to control group during the VFT. On the other hand, these were significantly lower particularly in the BD and SZ group to control group during the SCWT. Regression analysis showed that hemodynamic changes were significantly correlated with verbal memory and impulsivity in both disorders. Conclusion These findings suggest that different hemodynamic responses in the prefrontal cortex might reflect cognitive functioning and impulsivity, providing a greater insight into SZ and BD pathophysiology.

Attention deficit is commonly observed in several psychiatric conditions. In particular, patients with attention deficit hyperactivity disorder exhibit not only attention deficit, but also intra-individual variability in response times (IIV-RT) during the performance of cognitive tasks related to attention span and sustained attention. Although obsessive compulsive disorder (OCD) is commonly observed across childhood, little is known about abnormalities in IIV-RT during the auditory odd-ball task, and how these changes relate to event-related potentials (ERPs) components. In the present study, we compared the ERPs of 15 adolescent and pediatric patients with OCD with 15 healthy age, sex, and IQ-matched controls. We found that tau of IIV-TR was not significantly different between the OCD group and controls, whereas the OCD group exhibited lower mu and sigma compared to controls. Furthermore, we revealed that P300 amplitude was significantly attenuated in the OCD group at Fz, C3, and C4, compared with controls. The present study thereby provided the first evidence that individuals with pediatric or adolescent OCD exhibit lower variability in reaction time in IIV-RT during an auditory odd-ball task than controls. These results suggest that there are no impairments in attention span and sustained attention in pediatric and adolescent patients with OCD.

Aim Recent developments in near-infrared spectroscopy (NIRS) have enabled non-invasive clarification of brain functions in psychiatric disorders. In pediatric attention-deficit hyperactivity disorder (ADHD), reduced prefrontal hemodynamic responses have been observed with NIRS repeatedly. However, there are few studies of adult ADHD by multi-channel NIRS. Therefore, in this study, we used multi-channel NIRS to examine the characteristics of prefrontal hemodynamic responses during the Stroop Color-Word Task (SCWT) in adult ADHD patients and in age- and sex-matched control subjects. Methods Twelve treatment-naive adults with ADHD and 12 age- and sex-matched healthy control subjects participated in the present study after giving consent. We used 24-channel NIRS to measure the oxygenated hemoglobin (oxy-Hb) changes at the frontal lobes of participants during the SCWT. We compared the oxy-Hb changes between adults with ADHD and control subjects by t-tests with Bonferroni correction. Results During the SCWT, the oxy-Hb changes observed in the ADHD group were significantly smaller than those in the control group in channels 11, 16, 18, 21, 22, 23, and 24, corresponding to the prefrontal cortex. At channels 16, 21, 23, and 24 of the ADHD group, there were negative correlations between the symptomatic severity and the oxy-Hb changes. Conclusion The present study suggests that adults with ADHD have reduced prefrontal hemodynamic response as measured by NIRS.

Schizophrenia is a major psychiatric disorder, but the molecular mechanisms leading to its initiation or progression remain unclear. To elucidate the pathophysiology of schizophrenia, we used an in vitro neuronal cell culture model involving human induced pluripotent stem cells (hiPSCs) derived from a monozygotic-twin discordant schizophrenia pair. The cultured neurons differentiated from hiPSCs were composed of a mixture of glutamatergic excitatory neurons and gamma aminobutyric acid (GABA)ergic inhibitory neurons. In the electrophysiological analysis, a different pattern of spontaneous neuronal activity was observed under the condition without any stimulants. The frequency of spontaneous excitatory post-synaptic currents (sEPSCs) was significantly higher in the hiPSC-derived neurons of the patient with schizophrenia than in the control sibling at day-in-vitro 30. However, the synaptic formation was not different between the patient with schizophrenia and the control sibling during the same culture period. To explain underlying mechanisms of higher excitability of presynaptic cells, we focused on the potassium-chloride co-transporter KCC2, which contributes to excitatory-to-inhibitory GABA polarity switch in developing neurons. We also revealed the altered expression pattern of KCC2 in hiPSC-derived neurons from the patient with schizophrenia, which could contribute to understanding the pathology of schizophrenia in the developing nervous system.

Aims Antipsychotics are effective for treating schizophrenia, but atypical antipsychotics can cause several adverse side effects including weight gain, hyperprolactinemia, and extrapyramidal symptoms. Moreover, weight gain increases the risk of metabolic diseases. Methods We treated a case of olanzapine-induced weight gain in a 41-year-old man with schizophrenia by switching his medication from olanzapine to asenapine. Results The weight gain improved after switching the medication, from 80.3 to 75.0 kg, a weight loss of 6.6%, and there was no significant worsening of psychological symptoms or other adverse effects. Conclusions Asenapine might be effective for treating patients with schizophrenia who experience olanzapine-induced weight gain.

Aims Both attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are frequently accompanied by serious aggression that requires psychiatric treatment. However, little is known about the experiences psychiatrists have had using pharmacotherapy to treat aggression in patients who have both ASD and ADHD (ASD/ADHD). The purpose of this study was to examine the experiences of Japanese child and adolescent psychiatrists in prescribing medication for aggression in patients with ASD/ADHD. Methods A prospective questionnaire was mailed to 2,001 psychiatrists affiliated with the Japanese Society for Child and Adolescent Psychiatry. Multivariate logistic regression analysis was used to identify factors predicting the outcome of pharmacotherapeutic treatment of aggression in pediatric and adolescent patients with ASD/ADHD. Results Of 2,001 psychiatrists, 571 (28.5%) completed the full questionnaire (final sample). Of these, 488 (85.4%) prescribed psychotropic medication in treating pediatric and adolescent patients with ASD/ADHD, 299 (61.3%) of them doing so to treat aggression. Prescribers’ duration of practice (odds ratio [OR]: 1.055; P = 0.038) and patient symptoms of residual impulsivity (OR, 2.479; P = 0.039) increased the odds of prescribing psychotropic medications to treat aggression in these patients. The respondents reported a similar effect for patients with ADHD/ASD compared with those with ADHD only in treating aggression. Conclusions Japanese psychiatrists tended to prescribe psychotropic medication for aggression in pediatric and adolescent patients with ASD/ADHD. Future studies examining aggression in pediatric and adolescent patients with ASD/ADHD should aim to accumulate evidence for the use of psychotropic medications, which could help clinicians make better decisions.

Juvenile social experience is crucial for the functional development of forebrain regions, especially the prefrontal cortex (PFC). We previously reported that social isolation for 2 weeks after weaning induces prefrontal cortex dysfunction and hypomyelination. However, the effect of social isolation on physiological properties of PFC neuronal circuit remained unknown. Since hypomyelination due to isolation is prominent in deep-layer of medial PFC (mPFC), we focused on 2 types of Layer-5 pyramidal cells in the mPFC: prominent h-current (PH) cells and nonprominent h-current (non-PH) cells. We found that a 2-week social isolation after weaning leads to a specific deterioration in action potential properties and reduction in excitatory synaptic inputs in PH cells. The effects of social isolation on PH cells, which involve reduction in functional glutamatergic synapses and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/N-methyl-d-aspartate charge ratio, are specific to the 2 weeks after weaning and to the mPFC. We conclude that juvenile social experience plays crucial roles in the functional development in a subtype of Layer-5 pyramidal cells in the mPFC. Since these neurons project to subcortical structures, a deficit in social experience during the critical period may result in immature neural circuitry between mPFC and subcortical targets.

Background Functional neuroimaging studies suggest that prefrontal cortex dysfunction is present in people with autism spectrum disorder (ASD). Near-infrared spectroscopy is a noninvasive optical tool for examining oxygenation and hemodynamic changes in the cerebral cortex by measuring changes in oxygenated hemoglobin. Methods Twelve drug-naïve male participants, aged 7–15 years and diagnosed with ASD according to DSM-5 criteria, and 12 age- and intelligence quotient (IQ)-matched healthy control males participated in the present study after giving informed consent. Relative concentrations of oxyhemoglobin were measured with frontal probes every 0.1 s during the Stroop color-word task, using 24-channel near-infrared spectroscopy. Results Oxyhemoglobin changes during the Stroop color-word task in the ASD group were significantly smaller than those in the control group at channels 12 and 13, located over the dorsolateral prefrontal cortex (FDR-corrected P: 0.0021–0.0063). Conclusion The results suggest that male children with ASD have reduced prefrontal hemodynamic responses, measured with near-infrared spectroscopy.

Background Patients with attention deficit/hyperactivity disorder (ADHD) often experience comorbid conditions, such as autism spectrum disorder (ASD) and Tourette syndrome (TS). Although pharmacotherapies are effective for treating ADHD, they are likely to elicit a variety of adverse effects. It is, thus, important to select an effective and well-tolerated pharmacotherapeutic treatment for patients with ADHD/ASD comorbid with TS. Case presentation We report the case of a 10-year-old boy with ADHD/ASD comorbid with TS who was treated with guanfacine (GUAN). He experienced several side effects of atomoxetine (ATX) and methylphenidate (MPH) before being treated with GUAN. In the presented case, symptoms of ADHD as well as tic symptoms were improved by treatment with GUAN. Conclusion GUAN might be effective and well tolerated in the treatment of patients with ADHD/ASD comorbid with TS who experience side effects of ATX and MPH.

Diagnostic and treatment guidelines for childhood attention deficit/hyperactivity disorder (ADHD) were first released in Japan in 2003. Since then, there has been numerous changes in how ADHD is treated, such as the approval of slow-release methylphenidate and atomoxetine for use from childhood to adulthood. Demand regarding adult ADHD has also risen, as the symptoms of ADHD can persist into adulthood, and due to problems with high prevalence rates and comorbidities. Moreover, the DSM-5 recognized the coexistence of ADHD and autis- tic spectrum disorder (ASD), which further raised the level of concern. Yet at present, treat- ment guidelines have not been established for ASD with ADHD symptoms, so it is hoped such guidelines will be created quickly. This article provides a brief summary of recent findings on pharmacological therapy for ASD with ADHD symptoms.

Aim Increasing clinical evidence points to impulsivity as a symptom of obsessive–compulsive disorder (OCD). However, little is known about its persistence over time. Methods In this study, we evaluated the performance of 12 pediatric patients with OCD on the Stroop color–word task, which assesses impulsivity, and compared this with age- and sex-matched controls. In parallel, we measured changes in hemodynamic responses during the task, using near-infrared spectroscopy. As patients in the OCD group were naive to treatment, we compared results before and after 3-year medication with serotonin reuptake inhibitors. Results We report that, compared with controls, the OCD group had significantly poorer performance and less activation in the prefrontal cortex during the Stroop color–word task. Surprisingly, while serotonin-reuptake-inhibitors treatment reduced OCD symptomology, it did not improve the diminished hemodynamic responses or task performance of these patients. Conclusion Our findings suggest that a persistent deficit exists in the inhibitory control of pediatric patients with OCD; they also provide insight into the pathophysiology of OCD.

Recent studies have revealed that social experience affects myelination. These findings have important implications for disorders that feature abnormal myelination, such as multiple sclerosis (MS), as previous studies have shown that psychosocial stress exacerbates the pathobiology of MS. However, most studies have focused on psychosocial stress during the demyelination phase of MS and have not investigated the effects of social experience on remyelination. Thus, the current study sought to determine whether social experience can alter remyelination after myelin depletion. Myelin in the mouse medial prefrontal cortex was depleted with cuprizone, and the effects of subsequent social isolation on remyelination were evaluated. Remyelination was severely impaired in socially isolated mice. Social isolation also increased IL-6 levels in the medial prefrontal cortex, and administration of an IL-6 inhibitor (ND50 = 0.01-0.03 μg for 0.25 ng/ml IL-6) ameliorated remyelination impairments. Consistent with this result, IL-6 administration (ED50 = 0.02-0.06 ng/ml) disturbed remyelination. In addition, neuron-oligodendrocyte coculture experiments showed that IL-6 treatment (ED50 ≤ 0.02 ng/ml) markedly impeded myelination, which was recovered with IL-6 inhibitor administration (ND50 = 0.01-0.03 μg for 0.25 ng/ml IL-6). This study provides the first direct evidence, to our knowledge, that social experience influences remyelination via modulation of IL-6 expression. These findings indicate that psychosocial stress may disturb remyelination through regulation of IL-6 expression in patients with such demyelinating diseases that involve remyelination as MS.-Makinodan, M., Ikawa, D., Miyamoto, Y., Yamauchi, J., Yamamuro, K., Yamashita, Y., Toritsuka, M., Kimoto, S., Okumura, K., Yamauchi, T., Fukami, S., Yoshino, H., Wanaka, A., Kishimoto, T. Social isolation impairs remyelination in mice through modulation of IL-6.

Background: Attention deficit/hyperactivity disorder (ADHD) symptoms can continue through adolescence and adulthood, including difficulty in staying focused, paying attention, and controlling behavior, as well as hyperactivity. While children and adolescents with ADHD have functional impairments at multiple dimensions, there are no objective biological indicators to assess the severity of ADHD. Event-related potentials (ERPs) are widely used as a noninvasive method for evaluating sensory and cognitive processes involved in attention tasks. Previous studies have shown that P300 amplitude or latency, a main component in ERPs, is altered in patients with ADHD. However, little is known about the relationship between P300 and the severity of ADHD symptoms. Method: We sought to measure both P300 amplitude and latency in ERPs during auditory oddball tasks in 44 patients with ADHD (mean age ± SD 10.28 ± 3.43 years) and 15 age- and gender-matched normally developing children (11.40 ± 3.02 years). In ADHD patients, we also assessed symptom severity using the ADHD rating scale-IV-Japanese version. Result: In ADHD groups, P300 amplitude and latency were attenuated and prolonged compared to controls at the frontocentral, centroparietal, and parietal positions. Furthermore, levels of P300 latency at these positions are positively correlated with the inattention subscale scores measured by the ADHD rating scale-IV-Japanese version. Conclusions: The present study revealed that the degree of P300 latency might reflect the severity of ADHD symptoms with children and adolescents, suggesting that ERPs are a useful technique to evaluate the severity of ADHD symptoms.

Adults diagnosed with Autism spectrum disorder (ASD) are at high risk of experiencing suicidality compared with other clinical groups. Recently, near-infrared spectroscopy (NIRS) studies have investigated the association between frontotemporal functional abnormalities and suicidality in patients with mood disorders. However, whether these prefrontal hemodynamic responses are associated with suicide vulnerability in individuals with ASD remains unclear. Here, we used 24-channel NIRS to examine the characteristics of prefrontal hemodynamic responses during a verbal fluency task in 20 adults with ASD and in age-, sex-, and intelligence quotient-matched healthy controls. In addition, we used Spearman's correlation analysis to identify the relationship between the time-course of prefrontal hemodynamic activation and the current suicide risk in patients with ASD. We found no significant differences between the verbal fluency task-induced prefrontal hemodynamic responses in the ASD vs. control group. However, we found a significant positive correlation between the current suicide risk score and the time-course of prefrontal hemodynamic activation in the ASD group. Thus, the 24-channel NIRS system appears to be useful in assessing suicide risk in individuals with ASD.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired social interaction, poor communication skills, and repetitive/restrictive behaviors. Recent studies have indicated that early rehabilitative intervention can alleviate the symptoms of individuals with ASD. However, it remains unknown whether rehabilitative intervention can restore brain structures such as myelin, which generally shows abnormalities in individuals with ASD. Therefore, in the present study, we used a mouse model of ASD (BTBR mice) that demonstrated asocial behaviors and hypomyelination in the medial prefrontal cortex (mPFC) to investigate whether interaction with social peers (C57BL/6J mice) has an effect on myelination. We found that housing with C57BL/6J mice after weaning through adulthood increased the myelin thickness in mPFC, but not in the motor cortex, of BTBR mice. There was no effect of cross-rearing with C57BL/6J mice on axon diameter in mPFC of BTBR mice. This finding suggests that early rehabilitative intervention may alleviate myelin abnormalities in mPFC as well as clinical symptoms in individuals with ASD.

Social isolation is an important factor in the development of psychiatric disorders. It is necessary to develop an effective psychological treatment, such as cognitive rehabilitation, for children who have already suffered from social isolation, such as neglect and social rejection. We used socially isolated mice to validate whether elaborate re-socialization after juvenile social isolation can restore hypomyelination in the medial prefrontal cortex (mPFC) and the attendant functions manifested in socially isolated mice. While mice who underwent re-socialization with socially isolated mice after juvenile social isolation (Re-IS mice) demonstrated less mPFC activity during exposure to a strange mouse, as well as thinner myelin in the mPFC than controls, mice who underwent re-socialization with socially housed mice after juvenile social isolation (Re-SH mice) caught up with the controls in terms of most mPFC functions, as well as myelination. Moreover, social interaction of Re-IS mice was reduced as compared to controls, but Re-SH mice showed an amount of social interaction comparable to that of controls. These results suggest that the mode of re-socialization after juvenile social isolation has significant effects on myelination in the mPFC and the attendant functions in mice, indicating the importance of appropriate psychosocial intervention after social isolation.

Yoshinori Kayashima,1,2,* Kazuhiko Yamamuro,1,* Manabu Makinodan,1 Yoko Nakanishi,1 Akio Wanaka,2 Toshifumi Kishimoto1 1Department of Psychiatry, 2Department of Anatomy and Neuroscience, Nara Medical University School of Medicine, Kashihara, Japan *These authors contributed equally to this work Abstract: A number of studies have indicated that relaxing and pleasant melodies are useful for the treatment of patients with psychiatric disorders, including schizophrenia, depression, and dementia. However, few studies have investigated what constitutive elements of the music had an effect on brain activity. As Canon chord progression is one of critical elements for pleasant melodies, we sought to examine the effects of Canon chord progression and pitch-shifted Canon chord progression on brain activity using performance on the auditory oddball task during event-related potentials (ERPs) in 30 healthy subjects. Unexpectedly, we found no differences in ERP components between subjects listening to Canon chord progression (n=15) or pitch-shifted Canon chord progression (n=15). Next, we divided participants into two groups: those who found the melody pleasant (n=17) and those who did not (n=13), for both Canon chord progression and pitch-shifted Canon chord progression. The average of P300 amplitude was higher at Fz in subjects found the music pleasant versus those finding it unpleasant. Moreover, subjects who found it pleasant exhibited higher motivation scores than those who felt it was unpleasant, whereas listening to Canon chord progression did not matter. These findings suggest that the effects of Canon chord progression on brain activity and motivation depend on subjective feelings, not the chord progression per se. Keywords: music, Canon chord progression, motivation, event-related potential, subjective feelings&nbsp

Aim Atomoxetine, approved in Japan for the treatment of pediatric attention-deficit/hyperactivity disorder (ADHD) in April 2009, is a nonstimulant that is thought to act presynaptically via the inhibition of norepinephrine reuptake. Near-infrared spectroscopy is a non-invasive optical tool that can be used to study oxygenation and hemodynamic changes in the cerebral cortex. The present study examined the effects of a clinical dose of atomoxetine on changes in prefrontal hemodynamic activity in children with ADHD, as measured by near-infrared spectroscopy using the Stroop Color–Word Task. Methods Ten children with ADHD participated in the present study. We used 24-channel near-infrared spectroscopy to measure the relative concentrations of oxyhemoglobin in the frontal lobes of participants in the drug-naive condition and those who had received atomoxetine for 8 weeks. Measurements were conducted every 0.1 s during the Stroop Color–Word Task. We used the ADHD Rating Scale-IV-Japanese version (Home Version) to evaluate ADHD symptoms. Results We found a significant decrease in ADHD Rating Scale-IV-Japanese version scores, from 30.7 to 22.6 (P = 0.003). During the Stroop Color–Word Task, we found significantly higher levels of oxyhemoglobin changes in the prefrontal cortex of participants in the atomoxetine condition compared with those in the drug-naive condition. Conclusions This increase in oxyhemoglobin changes might indicate an intensified prefrontal hemodynamic response induced by atomoxetine. Near-infrared spectroscopy is a sensitive tool for measuring the pharmacological effects of atomoxetine in children with ADHD.