Juvenile social isolation immediately affects the synaptic activity and firing property of fast-spiking parvalbumin-expressing interneuron subtype in mouse medial prefrontal cortex.

A lack of juvenile social experience causes various behavioral impairments and brain dysfunction, especially in the medial prefrontal cortex (mPFC). Our previous studies revealed that juvenile social isolation for 2 weeks immediately after weaning affects the synaptic inputs and intrinsic excitability of fast-spiking parvalbumin-expressing (FSPV) interneurons as well as a specific type of layer 5 (L5) pyramidal cells, which we termed prominent h-current (PH) cells, in the mPFC. However, since these changes were observed at the adult age of postnatal day 65 (P65), the primary cause of these changes to neurons immediately after juvenile social isolation (postnatal day 35) remains unknown. Here, we investigated the immediate effects of juvenile social isolation on the excitability and synaptic inputs of PH pyramidal cells and FSPV interneurons at P35 using whole-cell patch-clamp recording. We observed that excitatory inputs to FSPV interneurons increased immediately after juvenile social isolation. We also found that juvenile social isolation increases the firing reactivity of a subtype of FSPV interneurons, whereas only a fractional effect was detected in PH pyramidal cells. These findings suggest that juvenile social isolation primarily disturbs the developmental rebuilding of circuits involving FSPV interneurons and eventually affects the circuits involving PH pyramidal cells in adulthood.

Uncinate fasciculus disruption relates to poor recognition of negative facial emotions in Alzheimer's disease: a cross-sectional diffusion tensor imaging study.

BACKGROUND: Recognising facial emotions involves visual and emotional information processing. Patients with dementia, including dementia of Alzheimer's type (DAT), are known to poorly recognise facial emotions, especially negative facial emotions. In this study, we aimed to assess if DAT patients exhibit poor facial emotional recognition, and to identify a neural basis for how poor facial emotional recognition might occur. METHODS: Magnetic resonance imaging and diffusion tensor imaging (DTI) analysis were conducted in 20 DAT patients and 15 cognitive normal (CN) subjects. The uncinate fasciculus (UF), inferior longitudinal fasciculus, and inferior fronto-occipital fasciculus were delineated by deterministic tractography. DTI parameters were calculated for each fibre. Facial emotion recognition was evaluated with the Facial Emotion Selection Test (FEST). The relationships between FEST scores and DTI parameters in each fibre were measured by partial correlation analyses with age, gender, and the Mini-Mental State Examination as covariates. Group-wise comparisons between DAT and CN subjects were performed for each DTI parameter in each fibre. RESULTS: DAT patients showed lower FEST negative emotion scores than CN subjects (P < 0.05). The score of negative emotion subscale was negatively correlated (r = -0.770, P < 0.001) to mean diffusivity of the left UF in DAT patients. There were no relationships between negative emotion subscale and the other fibre tracts. DAT patients showed no differences in the DTI parameters for each fibre compared to CN subjects. CONCLUSIONS: DAT-related prefrontal-limbic network dysfunction is associated with poor recognition of unpleasant emotions; consequently, worse facial recognition of negative emotion is observed in DAT patients.

Neurobiology and treatment of social cognition in schizophrenia: Bridging the bed-bench gap.

Social cognition refers to the psychological processes involved in the perception, encoding, storage, retrieval, and regulation of information about others and ourselves. This process is essential for survival and reproduction in complex social environments. Recent evidence suggests that impairments in social cognition frequently occur in schizophrenia, mainly contributing to poor functional outcomes, including the inability to engage in meaningful work and maintain satisfying interpersonal relationships. With the ambiguous definition of social cognition, the neurobiology underlying impaired social cognition remains unknown, and the effectiveness of currently available intervention strategies in schizophrenia remain limited. Considering the advances and challenges of translational research for schizophrenia, social cognition has been considered a high-priority domain for treatment development. Here, we describe the current state of the framework, clinical concerns, and intervention approaches for social cognition in schizophrenia. Next, we introduce translatable rodent models associated with schizophrenia that allow the evaluation of different components of social behaviors, providing deeper insights into the neural substrates of social cognition in schizophrenia. Our review presents a valuable perspective that indicates the necessity of building bridges between basic and clinical science researchers for the development of novel therapeutic approaches in impaired social cognition in schizophrenia.

Social isolation impairs remyelination in mice through modulation of IL-6.

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.

Microglia-derived neuregulin expression in psychiatric disorders.

Several studies have revealed that neuregulins (NRGs) are involved in brain function and psychiatric disorders. While NRGs have been regarded as neuron- or astrocyte-derived molecules, our research has revealed that microglia also express NRGs, levels of which are markedly increased in activated microglia. Previous studies have indicated that microglia are activated in the brains of individuals with autism spectrum disorder (ASD). Therefore, we investigated microglial NRG mRNA expression in multiple lines of mice considered models of ASD. Intriguingly, microglial NRG expression significantly increased in BTBR and socially-isolated mice, while maternal immune activation (MIA) mice exhibited identical NRG expression to controls. Furthermore, we observed a positive correlation between NRG expression in microglia and peripheral blood mononuclear cells (PBMCs) in mice, suggesting that NRG expression in human PBMCs may mirror microglia-derived NRG expression in the human brain. To translate these findings for application in clinical psychiatry, we measured levels of NRG1 splice-variant expression in clinically available PBMCs of patients with ASD. Levels of NRG1 type III expression in PBMCs were positively correlated with impairments in social interaction in children with ASD (as assessed using the Autistic Diagnostic Interview-Revised test: ADI-R). These findings suggest that immune cell-derived NRGs may be implicated in the pathobiology of psychiatric disorders such as ASD.

Lithium carbonate as a treatment for paliperidone extended-release-induced leukopenia and neutropenia in a patient with schizoaffective disorder; a case report.

BACKGROUND: Antipsychotic drug treatment can potentially lead to adverse events such as leukopenia and neutropenia. Although these events are rare, they represent serious and life-threatening hematological side effects. CASE PRESENTATION: We present a case study of a patient with schizoaffective disorder in a 50-year-old woman. We report a case of paliperidone extended-release (ER)-induced leukopenia and neutropenia in a female patient with schizoaffective disorder. Initiating lithium carbonate treatment and decreasing the dose of valproic acid improved the observed leukopenia and neutropenia. This treatment did not influence psychotic symptoms. CONCLUSION: The combination of paliperidone ER and valproic acid induces increased paliperidone ER plasma levels. Lithium carbonate was successfully used to treat paliperidone ER-induced leukopenia and neutropenia.

Deficits in microRNA-mediated Cxcr4/Cxcl12 signaling in neurodevelopmental deficits in a 22q11 deletion syndrome mouse model.

22q11 deletion syndrome (22q11DS) frequently accompanies psychiatric conditions, some of which are classified as schizophrenia and bipolar disorder in the current diagnostic categorization. However, it remains elusive how the chromosomal microdeletion leads to the mental manifestation at the mechanistic level. Here we show that a 22q11DS mouse model with a deletion of 18 orthologous genes of human 22q11 (Df1/+ mice) has deficits in migration of cortical interneurons and hippocampal dentate precursor cells. Furthermore, Df1/+ mice show functional defects in Chemokine receptor 4/Chemokine ligand 12 (Cxcr4/Cxcl12; Sdf1) signaling, which reportedly underlie interneuron migration. Notably, the defects in interneuron progenitors are rescued by ectopic expression of Dgcr8, one of the genes in 22q11 microdeletion. Furthermore, heterozygous knockout mice for Dgcr8 show similar neurodevelopmental abnormalities as Df1/+ mice. Thus, Dgcr8-mediated regulation of microRNA is likely to underlie Cxcr4/Cxcl12 signaling and associated neurodevelopmental defects. Finally, we observe that expression of CXCL12 is decreased in olfactory neurons from sporadic cases with schizophrenia compared with normal controls. Given the increased risk of 22q11DS in schizophrenia that frequently shows interneuron abnormalities, the overall study suggests that CXCR4/CXCL12 signaling may represent a common downstream mediator in the pathophysiology of schizophrenia and related mental conditions.

[Your Partnership for Psychiatry and Neuroscience in the World -An Integrated Perspective on Mental Illness-].

Human disease structure has constantly changed in close association with the times and society. Nowadays, there are so many"brain and mind problems"against a background of social issues. In developed countries including Japan, mental illnesses have seriously affected the lives and health of patients and their families. It is historically clear that stigma towards mental ill- nesses and a fragile mental health service have led to the existing situation. Therefore, to achieve the development of psychiatry in the future, we need to ruminate over the possibility of prevention, early intervention, and treatment and recovery to reduce stigma towards mental illnesses while regarding them as brain diseases. Based on the point of view that cognitive impairment could largely influence social functioning, and by introducing schizophrenia as a representative cognitive illness, we would like to discuss the remaining problems and future directions of psychiatry.

Expression of activity-regulated transcripts in pyramidal neurons across the cortical visuospatial working memory network in unaffected comparison individuals and individuals with schizophrenia.

Visuospatial working memory (vsWM), which is impaired in schizophrenia (SZ), is mediated by multiple cortical regions including the primary (V1) and association (V2) visual, posterior parietal (PPC) and dorsolateral prefrontal (DLPFC) cortices. In these regions, parvalbumin (PV) or somatostatin (SST) GABA neurons are altered in SZ as reflected in lower levels of activity-regulated transcripts. As PV and SST neurons receive excitatory inputs from neighboring pyramidal neurons, we hypothesized that levels of activity-regulated transcripts are also lower in pyramidal neurons in these regions. Thus, we quantified levels of four activity-regulated, pyramidal neuron-selective transcripts, namely adenylate cyclase-activating polypeptide-1 (ADCYAP1), brain-derived neurotrophic factor (BDNF), neuronal pentraxin-2 (NPTX2) and neuritin-1 (NRN1) mRNAs, in V1, V2, PPC and DLPFC from unaffected comparison and SZ individuals. In SZ, BDNF and NPTX2 mRNA levels were lower across all four regions, whereas ADCYAP1 and NRN1 mRNA levels were lower in V1 and V2. The regional pattern of deficits in BDNF and NPTX2 mRNAs was similar to that in transcripts in PV and SST neurons in SZ. These findings suggest that lower activity of pyramidal neurons expressing BDNF and/or NPTX2 mRNAs might contribute to alterations in PV and SST neurons across the vsWM network in SZ.

Aberrant brain dynamics of large-scale functional networks across schizophrenia and mood disorder.

INTRODUCTION: The dynamics of large-scale networks, which are known as distributed sets of functionally synchronized brain regions and include the visual network (VIN), somatomotor network (SMN), dorsal attention network (DAN), salience network (SAN), limbic network (LIN), frontoparietal network (FPN), and default mode network (DMN), play important roles in emotional and cognitive processes in humans. Although disruptions in these large-scale networks are considered critical for the pathophysiological mechanisms of psychiatric disorders, their role in psychiatric disorders remains unknown. We aimed to elucidate the aberrant dynamics across large-scale networks in patients with schizophrenia (SZ) and mood disorders. METHODS: We performed energy-landscape analysis to investigate the aberrant brain dynamics of seven large-scale networks across 50 healthy controls (HCs), 36 patients with SZ, and 42 patients with major depressive disorder (MDD) recruited at Wakayama Medical University. We identified major patterns of brain activity using energy-landscape analysis and estimated their duration, occurrence, and ease of transition. RESULTS: We identified four major brain activity patterns that were characterized by the activation patterns of the DMN and VIN (state 1, DMN (-) VIN (-); state 2, DMN (+) VIN (+); state 3, DMN (-) VIN (+); and state 4, DMN (+) VIN (-)). The duration of state 1 and the occurrence of states 1 and 2 were shorter in the SZ group than in HCs and the MDD group, and the duration of state 3 was longer in the SZ group. The ease of transition between states 3 and 4 was larger in the SZ group than in the HCs and the MDD group. The ease of transition from state 3 to state 4 was negatively associated with verbal fluency in patients with SZ. The current study showed that the brain dynamics was more disrupted in SZ than in MDD. CONCLUSIONS: Energy-landscape analysis revealed aberrant brain dynamics across large-scale networks between SZ and MDD and their associations with cognitive abilities in SZ, which cannot be captured by conventional functional connectivity analyses. These results provide new insights into the pathophysiological mechanisms underlying SZ and mood disorders.

NARP-related alterations in the excitatory and inhibitory circuitry of socially isolated mice: developmental insights and implications for autism spectrum disorder.

Background: Social isolation during critical periods of development is associated with alterations in behavior and neuronal circuitry. This study aimed to investigate the immediate and developmental effects of social isolation on firing properties, neuronal activity-regulated pentraxin (NARP) and parvalbumin (PV) expression in the prefrontal cortex (PFC), social behavior in juvenile socially isolated mice, and the biological relevance of NARP expression in autism spectrum disorder (ASD). Methods: Mice were subjected to social isolation during postnatal days 21-35 (P21-P35) and were compared with group-housed control mice. Firing properties in the PFC pyramidal neurons were altered in P35 socially isolated mice, which might be associated with alterations in NARP and PV expression. Results: In adulthood, mice that underwent juvenile social isolation exhibited difficulty distinguishing between novel and familiar mice during a social memory task, while maintaining similar levels of social interaction as the control mice. Furthermore, a marked decrease in NARP expression in lymphoblastoid cell lines derived from adolescent humans with ASD as compared to typically developing (TD) humans was found. Conclusion: Our study highlights the role of electrophysiological properties, as well as NARP and PV expression in the PFC in mediating the developmental consequences of social isolation on behavior.

Female sex and age-based advantage of simulated electric field in TMS to the prefrontal cortex in schizophrenia and mood disorders.

This study investigates computational models of electric field strength for transcranial magnetic stimulation (TMS) of the left dorsolateral prefrontal cortex (DLPFC) based on individual MRI data of patients with schizophrenia (SZ), major depressive disorder (MDD), bipolar disorder (BP), and healthy controls (HC). In addition, it explores the association of electric field intensities with age, gender and intracranial volume. The subjects were 23 SZ (12 male, mean age = 45.30), 24 MDD (16 male, mean age = 43.57), 23 BP (16 male, mean age = 39.29), 23 HC (13 male, mean age = 40.91). Based on individual MRI sequences, electric fields were computationally modeled by two independent investigators using SimNIBS ver. 2.1.1. There was no significant difference in electric field strength between the groups (HC vs SZ, HC vs MDD, HC vs BP, SZ vs MDD, SZ vs BP, MDD vs BP). Female subjects showed higher electric field intensities in widespread areas than males, and age was positively significantly associated with electric field strength in the left parahippocampal area as observed. Our results suggest differences in electric field strength of left DLPFC TMS for gender and age. It may open future avenues for individually modeling TMS based on structural MRI data.

Structural connectivity between the hippocampus and cortical/subcortical area relates to cognitive impairment in schizophrenia but not in mood disorders.

Cognitive impairment in schizophrenia and other psychiatric disorders is a challenge to be overcome in order to maintain patients' quality of life and social function. The neurological pathogenesis of cognitive impairment requires further elucidation. In general, the hippocampus interacts between the cortical and subcortical areas for information processing and consolidation and has an important role in memory. We examined the relationship between structural connectivity of the hippocampus and cortical/subcortical areas and cognitive impairment in schizophrenia, major depressive disorder and bipolar disorder. Subjects comprised 21 healthy controls, 19 patients with schizophrenia, 20 patients with bipolar disorder and 18 patients with major depressive disorder. Diffusion-weighted tensor images data were processed using ProbtrackX2 to calculate the structural connectivity between the hippocampus and cortical/subcortical areas. Cognitive function was assessed using the Brief Assessment of Cognition in schizophrenia composite score. Hippocampal structural connectivity index was significantly correlated with composite score in the schizophrenia group but not in the healthy control, major depressive disorder or bipolar disorder groups. There were no statistically significant differences in hippocampal structural connectivity index between the four groups. Structural connectivity between the hippocampus and cortical/subcortical areas is suggested to be a pathophysiological mechanism of comprehensive cognitive impairment in schizophrenia.

Impact of individual factors and personality trait on psychological problems of family members living with staff of a COVID-19 frontline hospital: A cross-sectional self-administered anonymous questionnaire survey.

Aim: This study aims to evaluate the association between individual factors/personality traits and depression and anxiety in family members living with staff working on the frontline of COVID-19 care. Methods: The subjects were family members over the age of 15 years living with staff members of a COVID-19 frontline hospital. Between March 27 and April 11, 2021, 204 self-administered anonymous questionnaires were distributed, and 149 responses were received. Symptoms of depression and anxiety were assessed using the Hospital Anxiety and Depression Scale (HADS). Personality trait was assessed using the Big Five personality traits, and fear of COVID-19 was assessed using the Fear of COVID-19 Scale. We examined associations between HADS depression or anxiety scores with individual background factors, scores of Big Five personality traits, and Fear of COVID-19 Scale. Results: The participants with anxiety had significantly higher scores for neuroticism and for the Fear of COVID-19 Scale. The participants with depression had significantly lower scores for extraversion and higher scores for the Fear of COVID-19 Scale. No individual background factors were significantly associated with HADS depression or anxiety scores. Conclusion: Among family members of staff of a COVID-19 frontline hospital, lower extraversion, higher neuroticism, and fear of COVID-19 were associated with anxiety and depression. This questionnaire survey was conducted before wide-spread rollout of COVID-19 vaccination, so the findings of this study are expected to be applicable to other future novel infectious outbreaks.

Probable progressive supranuclear palsy in a patient with chronic schizophrenia: A case report.

Rare neurodegenerative disorders may be considered in the differential diagnosis of Parkinsonism in patients with schizophrenia who show worsening signs of Parkinsonism under treatment with antipsychotics. To the best of our knowledge, the present study is the first report describing probable progressive supranuclear palsy (PSP) in a patient with chronic schizophrenia. A 64-year-old man presented with hallucinations, delusions and asociality. He had received treatment with both typical and atypical antipsychotics for ~13 years. He began experiencing short-term memory impairment and bradykinesia two years before presentation, and then showed increased dysphagia, upper-limb muscle rigidity, extrapyramidal symptoms, vision loss and photophobia. Psychological manifestations included chronic depression, irritability and, occasionally, euphoria. His gait worsened, leading to repeated falls. Antipsychotics were discontinued, and the patient was almost completely dependent on a wheelchair in daily life. In a neurology consultation, he was diagnosed with probable progressive supranuclear palsy-Richardson's syndrome presenting as vertical supranuclear gaze palsy and prominent postural instability with falls. Brain magnetic resonance imaging (MRI) revealed atrophy of the mesencephalic tegmentum, and 123I-ioflupane single-photon emission computed tomography (SPECT) revealed reduced bilateral striatal reuptake. Overall, PSP should be considered in patients with schizophrenia with worsening Parkinsonism, especially when it is accompanied by supranuclear ophthalmoplegia, pseudobulbar palsy, dysarthria and dystonic stiffness of the neck and upper body. In the present case, the combination of brain MRI and 123I-ioflupane SPECT helped to discriminate PSP from other Parkinsonian syndromes, including drug-induced Parkinsonism, in the differential diagnosis.

Two cases of steroid dementia showing partial recovery during 2-year follow-up.

Background: Steroid dementia has been reported since the 1970s. In the current super-aged society, it increasingly receives attention because of the growing number of elderly people that are medicated with steroids for systemic rheumatic disease. Case Presentation: We report two cases of steroid dementia that were diagnosed as a result of careful observation of clinical symptoms and biological examination, including nuclear medicine tests. Cognitive and daily living functions were partially recovered in both cases after decrease or discontinuance of steroid medication in 2-year follow-up, but their daily living function could not be totally restored to premorbid level. Conclusion: Cognitive dysfunction caused by steroids is suggested by these cases, although definitive diagnosis in these cases is not possible. It was partially reversible over the course of a few years, but some functional loss remains. Cognitive function should be assessed appropriately before, during, and after steroid treatment. Detailed differential diagnosis of neurodegenerative disorders and longitudinal follow-up is required when cognitive dysfunction is observed after initiation of steroid therapy.

Computational modeling of electric fields for prefrontal tDCS across patients with schizophrenia and mood disorders.

This cross-diagnostic study aims to computationally model electric field (efield) for prefrontal transcranial direct current stimulation in mood disorders and schizophrenia. Enrolled were patients with major depressive disorder (n = 23), bipolar disorder (n = 24), schizophrenia (n = 23), and healthy controls (n = 23). The efield was simulated using SimNIBS software (ver.2.1.1). Electrodes were placed at the left and right prefrontal areas and the current intensity was set to 2 mA intensity. Schizophrenia and major depressive disorder groups showed significantly lower 99.5th percentile efield strength than healthy controls. In voxel-wise analysis, patients with schizophrenia showed a significant reduction of simulated efield strength in the bilateral frontal lobe, cerebellum and brain stem compared with healthy controls. Among the patients with schizophrenia, reduction of simulated efield strength was not significantly correlated with psychiatric symptoms or global functioning. The patients with bipolar disorder showed no significant difference in simulated efield strength compared with healthy controls, and there was no significant difference between the clinical groups. Our results suggest attenuated electrophysiological response to transcranial direct current stimulation to the prefrontal cortex in patients with schizophrenia, and to some extent in patients with major depressive disorder.

Expression of actin- and oxidative phosphorylation-related transcripts across the cortical visuospatial working memory network in unaffected comparison and schizophrenia subjects.

Visuospatial working memory (vsWM), which is impaired in schizophrenia (SZ), is mediated by a distributed cortical network. In one node of this network, the dorsolateral prefrontal cortex (DLPFC), altered expression of transcripts for actin assembly and mitochondrial oxidative phosphorylation (OXPHOS) have been reported in SZ. To understand the relationship between these processes, and the extent to which similar alterations are present in other regions of vsWM network in SZ, a subset of actin- (CDC42, BAIAP2, ARPC3, and ARPC4) and OXPHOS-related (ATP5H, COX4I1, COX7B, and NDUFB3) transcripts were quantified in DLPFC by RNA sequencing in 139 SZ and unaffected comparison (UC) subjects, and in DLPFC and three other regions of the cortical vsWM network by qPCR in 20 pairs of SZ and UC subjects. By RNA sequencing, levels of actin- and OXPHOS-related transcripts were significantly altered in SZ, and robustly correlated in both UC and SZ subject groups. By qPCR, cross-regional expression patterns of these transcripts in UC subjects were consistent with greater actin assembly in DLPFC and higher OXPHOS activity in primary visual cortex (V1). In SZ, CDC42 and ARPC4 levels were lower in all regions, BAIAP2 levels higher only in V1, and ARPC3 levels unaltered across regions. All OXPHOS-related transcript levels were lower in SZ, with the disease effect decreasing from posterior to anterior regions. The differential alterations in markers of actin assembly and energy production across regions of the cortical vsWM network in SZ suggest that each region may make specific contributions to vsWM impairments in the illness.