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.

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.

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.

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.

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.

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.

Developmental dysregulation of excitatory-to-inhibitory GABA-polarity switch may underlie schizophrenia pathology: A monozygotic-twin discordant case analysis in human iPS cell-derived neurons.

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.

Tumor necrosis factor-α expression aberration of M1/M2 macrophages in adult high-functioning autism spectrum disorder.

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.

Suicide prevention in Japan: Government and community measures, and high-risk interventions.

Suicide is one of the most critical issues worldwide. In Japan, more than 30 000 people died by suicide every year between 1998 and 2011, and the Japanese government, local governments, and various other agencies have been working on suicide prevention programs to reduce the suicide rate. While the number of suicides is still high (more than 20 000 per year), many specialists are striving to further reduce the number of suicides in Japan. The Japanese government has played a central role in suicide prevention through the enactment of several laws, and in recent years, suicide prevention has shifted from government to community-specific measures. This review discusses the suicide prevention measures that have been taken so far: (1) policy strategies for suicide prevention by the Japanese government, (2) community suicide prevention, and (3) strategic studies for suicide prevention. Finally, as shown in the ACTION-J study, we conclude that cooperation among related organizations in the community, not just one institution, is important for future suicide prevention, especially youth suicide prevention.

Retrospective analysis of heroin detoxification with buprenorphine in a psychiatric hospital in Japan.

AIM: We assessed the efficacy of buprenorphine replacement taper therapy in a psychiatric hospital in Japan. METHODS: Based on the medical records, a retrospective analysis was performed to evaluate the outcomes of buprenorphine replacement taper therapy in 106 subjects with heroin dependence. RESULTS: We found that replacement and taper therapy with buprenorphine could significantly reduce withdrawal symptoms during detoxification. In addition, the completion rate of detoxification was significantly improved and the length of hospital stay was significantly reduced relative to those who received conventional treatment without buprenorphine. However, the readmission rate increased after the introduction of detoxication therapy with buprenorphine. CONCLUSION: The present findings suggest not only the efficacy and safety of buprenorphine replacement and taper therapy, but also the requirement for maintenance therapy for individuals with heroin dependence.

Maternal Immune Activation Affects Hippocampal Excitatory and Inhibitory Synaptic Transmission in Offspring From an Early Developmental Period to Adulthood.

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.

Delayed prefrontal hemodynamic response associated with suicide risk in autism spectrum disorder.

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.

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.

Anti-inflammatory Effect of Ghrelin in Lymphoblastoid Cell Lines From Children With Autism Spectrum Disorder.

The gut hormone ghrelin has been implicated in a variety of functional roles in the central nervous system through the brain-gut axis, one of which is an anti-inflammatory effect. An aberrant brain-gut axis producing immune dysfunction has been implicated in the pathobiology of autism spectrum disorder (ASD), and elevated expression of inflammatory markers has been shown in blood and brain tissue from subjects with ASD. We hypothesized that ghrelin may mitigate this effect. Lymphoblastoid cell lines from typically developed children (TD-C) (N = 20) and children with ASD (ASD-C) (N = 20) were cultured with PBS or human ghrelin (0.01 µM) for 24 h, and mRNA expression levels of the inflammation-related molecules interleukin-1ß (IL-1ß), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and nuclear factor kappa B (NF-κB) were measured to examine the effects of ghrelin as an anti-inflammatory agent. Expression levels of TNF-α and NF-κB mRNA, but not IL-1ß or IL-6, were significantly elevated in ASD-C compared to TD-C. Ghrelin showed a tendency to reduce the expression of TNF-α and NF-κB, but this was not statistically significant. Considering the heterogenous pathobiology of ASD, we examined the effects of ghrelin on TD-C and ASD-C with expression levels of TNF-α and NF-κB in the highest and lowest quartiles. We found that ghrelin markedly reduced mRNA expression of TNF-α and NF-κB s in ASD-C with highest-quartile expression, but there were no effects in ASD-C with lowest-quartile expression, TD-C with highest quartile expression, or TD-C with lowest quartile expression. Together, these findings suggest that ghrelin has potential as a novel therapeutic agent for ASD with inflammation and/or immune dysfunction.

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.

Dosage-related nature of escitalopram treatment-emergent mania/hypomania: a case series.

OBJECTIVE: Several studies have documented that treatment with various antidepressant agents can result in mood switching during major depressive episodes. Escitalopram, one of the newer selective serotonin reuptake inhibitors (SSRIs), is considered preferable due to its relatively high efficacy and acceptability. Although a few cases of escitalopram treatment-emergent mania have been reported, it remains unknown whether this effect is dose-related. METHOD: In the present report, we discuss three cases of treatment-emergent mania/hypomania in patients receiving escitalopram for major depressive episodes. No patients had a family or personal history of bipolar disorder. RESULTS: In all three cases, manic or hypomanic symptoms emerged within 1 month right after the dosage of escitalopram was increased to 20 mg/day. Moreover, manic episodes subsided as the dosage of escitalopram was reduced. Mood switching was not observed after the cessation of escitalopram treatment. CONCLUSION: Our case series indicates that escitalopram may induce treatment-emergent mania/hypomania in a dose-related manner. Treatment at lower doses and with careful upward titration might be favorable in certain patients with bipolar depression and major depressive disorder in order to minimize the risk of mood switching.

Altered gene expression in lymphoblastoid cell lines after subculture.

Lymphoblastoid cell lines (LCLs) are nearly immortalized B lymphocytes that are used as long-lasting supply of human cells for studies on gene expression analyses. However, studies on the stability of the cellular features of LCLs are scarce. To address this issue, we measured gene expression in LCLs with different passage numbers and observed that gene expression substantially changed within 10 passages. In particular, the expression of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a well-known housekeeping gene, varied considerably during subculture; thus, the use GAPDH as an internal control may be unsuitable. In conclusion, this study highlights the need for exercising caution during determination of gene expression in LCLs.

Distinct patterns of blood oxygenation in the prefrontal cortex in clinical phenotypes of schizophrenia and bipolar disorder.

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.