Structural variability of the cerebral cortex in schizophrenia and its association with clinical symptoms.

BACKGROUND: Substantial evidence indicates structural abnormalities in the cerebral cortex of patients with schizophrenia (SCZ), although their clinical implications remain unclear. Previous case-control studies have investigated group-level differences in structural abnormalities, although the study design cannot account for interindividual differences. Recent research has focused on the association between the heterogeneity of the cerebral cortex morphometric features and clinical heterogeneity. METHODS: We used neuroimaging data from 420 healthy controls and 695 patients with SCZ from seven studies. Four cerebral cortex measures were obtained: surface area, gray matter volume, thickness, and local gyrification index. We calculated the coefficient of variation (CV) and person-based similarity index (PBSI) scores and performed group comparisons. Associations between the PBSI scores and cognitive functions were evaluated using Spearman's rho test and normative modeling. RESULTS: Patients with SCZ had a greater CV of surface area and cortical thickness than those of healthy controls. All PBSI scores across cortical measures were lower in patients with SCZ than in HCs. In the patient group, the PBSI scores for gray matter volume and all cortical measures taken together positively correlated with the full-scale IQ scores. Patients with deviant PBSI scores for gray matter volume and all cortical measures taken together had lower full-scale IQ scores than those of other patients. CONCLUSIONS: The cerebral cortex in patients with SCZ showed greater regional and global structural variability than that in healthy controls. Patients with deviant similarity of cortical structural profiles exhibited a lower general intelligence than those exhibited by the other patients.

Clinical Characteristics, Support System, and Personality Differences of Cannabis and Stimulant Users in South Korea.

OBJECTIVE: To compare the clinical characteristics, support system, and personality traits of cannabis and stimulant users in South Korea. METHODS: This study was based on electronic medical records. Among a total of 152 subjects who suspected of drug use and who underwent six types of urine-based drug screening tests at the National Center for Mental Health, 104 people who underwent both an interview with a psychiatrist and a psychological test were selected and classified according to the type of substance used. Psychological and personality characteristics were examined through the National Center for Mental Health psychological test battery for addiction. The differences in characteristics between cannabis (n=60) and stimulant (n=18) users were analyzed by an independent t-test for parametric data and chi-square test or Fisher's exact test for nonparametric data, and analysis of covariance for psychological tests. RESULTS: The average age of cannabis users was lower than that of stimulant users and they were more often single. Substance cravings were higher in stimulant users, who more often had a psychiatric history than cannabis users. Moreover, stimulant users had higher clinical scale scores for depression and anxiety. Among the Minnesota Multiphasic Personality Inventory-II clinical scale scores, there was a significant difference in social introversion scores between groups. CONCLUSION: We found differences in demographic, psychological, and personality characteristics between cannabis and stimulant users in South Korea. Considering the recent increase in illegal drug use in South Korea, further follow-up and policy research on drug users are needed.

The PFC-LH-VTA pathway contributes to social deficits in IRSp53-mutant mice.

Dopamine (DA) neurons in the ventral tegmental area (VTA) promote social brain functions by releasing DA onto nucleus accumbens neurons, but it remains unclear how VTA neurons communicate with cortical neurons. Here, we report that the medial prefrontal cortex (mPFC)-lateral hypothalamus (LH)-VTA pathway contributes to social deficits in mice with IRSp53 deletion restricted to cortical excitatory neurons (Emx1-Cre;Irsp53fl/fl mice). LH-projecting mutant mPFC neurons display abnormally increased excitability involving decreased potassium channel gene expression, leading to excessive excitatory synaptic input to LH-GABA neurons. A circuit-specific IRSp53 deletion in LH-projecting mPFC neurons also increases neuronal excitability and induces social deficits. LH-GABA neurons with excessive mPFC excitatory synaptic input show a compensatory decrease in excitability, weakening the inhibitory LHGABA-VTAGABA pathway and subsequently over-activating VTA-GABA neurons and over-inhibiting VTA-DA neurons. Accordingly, optogenetic activation of the LHGABA-VTAGABA pathway improves social deficits in Emx1-Cre;Irsp53fl/fl mice. Therefore, the mPFC-LHGABA-VTAGABA-VTADA pathway contributes to the social deficits in Emx1-Cre;Irsp53fl/fl mice.

Target Discovery Using Deep Learning-Based Molecular Docking and Predicted Protein Structures With AlphaFold for Novel Antipsychotics.

OBJECTIVE: New drugs are needed to treat antipsychotic-resistant schizophrenia, especially those with clozapine-resistant schizophrenia. Atypical antipsychotics have predominantly 5-HT2A and dopaminergic antagonism, but also require investigation of other receptors. METHODS: In this study, the binding affinities between clozapine, olanzapine, and quetiapine with neuropharmacological, immunological, and metabolic receptors were measured using GNINA (Deep Learning Based Molecular Docking) and AlphaFold (Predicted Protein Structures). RESULTS: Through this study, it was determined that these antipsychotics showed high binding affinity to a variety of receptors, such as CB2, 5-HT1BR, NPYR4, and CCR5. Cyclosporin A and everolimus which show high affinities with those receptors could be used for the development of new antipsychotic drugs based on these drugs. CONCLUSION: In the future, the method used in this study will be applied to the development of new antipsychotic drugs, including drug repositioning, and to the discovery of the pathophysiology of schizophrenia.

Early postnatal serotonin modulation prevents adult-stage deficits in Arid1b-deficient mice through synaptic transcriptional reprogramming.

Autism spectrum disorder is characterized by early postnatal symptoms, although little is known about the mechanistic deviations that produce them and whether correcting them has long-lasting preventive effects on adult-stage deficits. ARID1B, a chromatin remodeler implicated in neurodevelopmental disorders, including autism spectrum disorder, exhibits strong embryonic- and early postnatal-stage expression. We report here that Arid1b-happloinsufficient (Arid1b+/-) mice display autistic-like behaviors at juvenile and adult stages accompanied by persistent decreases in excitatory synaptic density and transmission. Chronic treatment of Arid1b+/- mice with fluoxetine, a selective serotonin-reuptake inhibitor, during the first three postnatal weeks prevents synaptic and behavioral deficits in adults. Mechanistically, these rescues accompany transcriptomic changes, including upregulation of FMRP targets and normalization of HDAC4/MEF2A-related transcriptional regulation of the synaptic proteins, SynGAP1 and Arc. These results suggest that chronic modulation of serotonergic receptors during critical early postnatal periods prevents synaptic and behavioral deficits in adult Arid1b+/- mice through transcriptional reprogramming.

Impaired prepulse inhibition in mice with IRSp53 deletion in modulatory neurotransmitter neurons including dopamine, acetylcholine, oxytocin, and serotonin.

Prepulse inhibition (PPI) is a neurophysiological finding that is decreased in schizophrenia patients and has been used in pathophysiology studies of schizophrenia and the development of antipsychotic drugs. PPI is affected by several drugs including amphetamine, ketamine, and nicotinic agents, and it is reported that several brain regions and modulatory neurotransmitters are involved in PPI. Here we showed that mice with IRSp53 deletion in each dopaminergic, cholinergic, oxytocinergic, and serotoninergic modulatory neurons showed a decrease in PPI. Other than PPI, there were no other behavioral changes among IRSp53 deletion mice. Through this study, we could reconfirm that dysfunction of each modulatory neuron such as dopamine, acetylcholine, oxytocin, and serotonin can result in PPI impairment, and it should be considered that PPI could be broadly affected by changes in one of a certain kind of modulatory neurons.

Corrigendum: IRSp53 Deletion in Glutamatergic and GABAergic Neurons and in Male and Female Mice Leads to Distinct Electrophysiological and Behavioral Phenotypes.

[This corrects the article DOI: 10.3389/fncel.2020.00023.].

Characteristics of Patients Presenting to a Psycho-Oncology Outpatient Clinic.

OBJECTIVE: We aimed to determine the overall profile of patients in a psycho-oncology clinic and the differences in their characteristics according to the cancer site. METHODS: The charts of 740 patients aged under 81 years were reviewed. The data from 586 completed questionnaires were subjected to multiple comparison analyses using one-way analysis of variance to examine the demographic and clinical differences according to the cancer site. RESULTS: Most (n=532, 71.9%) patients were referred. Most new patients (n=426, 96.6%) received a psychiatric diagnosis; the most common diagnosis was depressive disorder (n=234, 31.6%). Likewise, depressive disorder accounted for the majority of diagnoses in all groups except for the digestive system cancer group in which sleep-wake disorder was the most prevalent. The female genital cancer group showed a higher level of anxiety symptoms than other groups, except for breast and haematolymphoid cancer groups, and psychological distress than all other groups. CONCLUSION: There appear to be delays in the referral of cancer patients seeking psychiatric help to a psycho-oncology clinic. Along with tailoring approaches by cancer site, thorough evaluation and appropriate management of sleep-wake and anxiety symptoms are important for digestive system and female genital cancer patients, respectively.

Correlates of Psychological Distress in Patients With Cancer at a Psycho-oncology Clinic.

BACKGROUND: Patients with cancer experience significant psychological distress. Most studies investigated individual risk factors for distress in their respective treatment setting, which limit generalizability of results or comparison of relative importance. OBJECTIVE: To investigate the relation between psychological distress in patients referred to a psycho-oncology clinic and its correlates in a comprehensive manner. METHOD: Medical charts of patients who visited the psycho-oncology clinic at a tertiary hospital from May 2019 to May 2020 were reviewed. Demographic, cancer-related, and psychiatric factors; health-related quality of life; and somatic pain were investigated. The Hospital Anxiety and Depression Scale, item 9 on the Patient Health Questionnaire-9, Functional Assessment of Cancer Therapy-General, Present Pain Intensity, and Distress Thermometer were measured at the index visit. Simple and multiple linear regression analyses were performed with the Distress Thermometer score as a dependent variable. RESULTS: A total of 454 patients were included. The univariate analyses showed age and physical, emotional, and functional well-being scores on the Functional Assessment of Cancer Therapy-General were negatively associated with the Distress Thermometer scores, while female genital cancer, advanced disease, recent radiotherapy, the Hospital Anxiety and Depression Scale score, and the Present Pain Intensity score showed a positive relation. After adjusting for all other variables, female genital cancer (P = 0.027), anxiety subscale of the Hospital Anxiety and Depression Scale (P < 0.001), the Present Pain Intensity (P = 0.002), and physical (P < 0.001) and functional (P = 0.019) well-being subscales of the Functional Assessment of Cancer Therapy-General remained significant. CONCLUSIONS: Patients with cancer who visited a psycho-oncology clinic experienced more distress if they had female genital cancer, low health-related quality of life score, severe anxiety, or somatic pain.

Tanc2-mediated mTOR inhibition balances mTORC1/2 signaling in the developing mouse brain and human neurons.

mTOR signaling, involving mTORC1 and mTORC2 complexes, critically regulates neural development and is implicated in various brain disorders. However, we do not fully understand all of the upstream signaling components that can regulate mTOR signaling, especially in neurons. Here, we show a direct, regulated inhibition of mTOR by Tanc2, an adaptor/scaffolding protein with strong neurodevelopmental and psychiatric implications. While Tanc2-null mice show embryonic lethality, Tanc2-haploinsufficient mice survive but display mTORC1/2 hyperactivity accompanying synaptic and behavioral deficits reversed by mTOR-inhibiting rapamycin. Tanc2 interacts with and inhibits mTOR, which is suppressed by mTOR-activating serum or ketamine, a fast-acting antidepressant. Tanc2 and Deptor, also known to inhibit mTORC1/2 minimally affecting neurodevelopment, distinctly inhibit mTOR in early- and late-stage neurons. Lastly, Tanc2 inhibits mTORC1/2 in human neural progenitor cells and neurons. In summary, our findings show that Tanc2 is a mTORC1/2 inhibitor affecting neurodevelopment.

Hyperactive ACC-MDT Pathway Suppresses Prepulse Inhibition in Mice.

Altered prepulse inhibition (PPI) is an endophenotype associated with multiple brain disorders, including schizophrenia. Circuit mechanisms that regulate PPI have been suggested, but none has been demonstrated through direct manipulations. IRSp53 is an abundant excitatory postsynaptic scaffold implicated in schizophrenia, autism spectrum disorders, and attention-deficit/hyperactivity disorder. We found that mice lacking IRSp53 in cortical excitatory neurons display decreased PPI. IRSp53-mutant layer 6 cortical neurons in the anterior cingulate cortex (ACC) displayed decreased excitatory synaptic input but markedly increased neuronal excitability, which was associated with excessive excitatory synaptic input in downstream mediodorsal thalamic (MDT) neurons. Importantly, chemogenetic inhibition of mutant neurons projecting to MDT normalized the decreased PPI and increased excitatory synaptic input onto MDT neurons. In addition, chemogenetic activation of MDT-projecting layer 6 neurons in the ACC decreased PPI in wild-type mice. These results suggest that the hyperactive ACC-MDT pathway suppresses PPI in wild-type and IRSp53-mutant mice.

Shared and distinct white matter abnormalities in schizophrenia and bipolar disorder.

While white matter impairments play an integral part in the pathophysiology of schizophrenia and bipolar disorder, the literature on white matter abnormality differences between the two disorders is insufficient. The University of California Los Angeles Consortium for Neuropsychiatric Phenomic LA5c public dataset, including 47 patients with schizophrenia, 47 with bipolar disorder, and 115 healthy controls, was obtained via OpenNeuro. Whole-brain tractography was performed using Unscented Kalman filter-based two-tensor tractography and White Matter Query Language. Diffusion indices, including fractional anisotropy (FA), axial diffusivity, radial diffusivity (RD), and trace (TR), were used to compare subject groups. Spearman's partial correlation with a covariate of age was used for correlation with clinical variables. Both patient groups exhibited significantly higher RD in the left external capsule and TR in the right extreme capsule. Significantly lower FA in the left external capsule, right thalamo-occipital and thalamo-parietal tracts were found in the schizophrenia group in comparison with bipolar disorder and healthy control groups. Compared with healthy controls, patients with schizophrenia had significantly lower FA in the left-to-right lateral orbitofrontal commissural tract. There were possible associations of the FA and RD of the left external capsule with the anxiety-depression score of the Brief Psychiatric Rating Scale in patients with schizophrenia. The white matter alterations identified in schizophrenia and bipolar disorder may be a neurobiological basis contributing to characterization of the two disorders.

Aberrant Executive Control and Auditory Networks in Recent-Onset Schizophrenia.

PURPOSE: Despite a large number of resting-state functional MRI (rsfMRI) studies in schizophrenia, current evidence on the abnormalities of functional connectivity (FC) of resting-state networks shows high variability, and the findings on recent-onset schizophrenia are insufficient compared to those on chronic schizophrenia. PATIENTS AND METHODS: We performed a rsfMRI in 46 patients with recent-onset schizophrenia and 22 healthy controls. Group independent component brainmap and dual regression were performed for voxel-wise comparisons between the groups. Correlation of the symptom severity, cognitive function, duration of illness, and a total antipsychotics dose with FC was evaluated with Spearman's rho correlation. RESULTS: The patient group had areas with a significantly decreased FC compared to that of the control group in which it existed in the left supplementary motor cortex and supramarginal gyrus (the executive control network) and the right postcentral gyrus (the auditory network). The patient group had a significant correlation of the total antipsychotics dose with the FC of the cluster in the left supplementary motor cortex in the executive control network. CONCLUSION: Patients with recent-onset schizophrenia have decreased FC of the executive control and auditory networks compared to healthy controls.

Haploinsufficiency of Cyfip2 Causes Lithium-Responsive Prefrontal Dysfunction.

OBJECTIVE: Genetic variants of the cytoplasmic FMR1-interacting protein 2 (CYFIP2) encoding an actin-regulatory protein are associated with brain disorders, including intellectual disability and epilepsy. However, specific in vivo neuronal defects and potential treatments for CYFIP2-associated brain disorders remain largely unknown. Here, we characterized Cyfip2 heterozygous (Cyfip2+/- ) mice to understand their neurobehavioral phenotypes and the underlying pathological mechanisms. Furthermore, we examined a potential treatment for such phenotypes of the Cyfip2+/- mice and specified a neuronal function mediating its efficacy. METHODS: We performed behavioral analyses of Cyfip2+/- mice. We combined molecular, ultrastructural, and in vitro and in vivo electrophysiological analyses of Cyfip2+/- prefrontal neurons. We also selectively reduced CYFIP2 in the prefrontal cortex (PFC) of mice with virus injections. RESULTS: Adult Cyfip2+/- mice exhibited lithium-responsive abnormal behaviors. We found increased filamentous actin, enlarged dendritic spines, and enhanced excitatory synaptic transmission and excitability in the adult Cyfip2+/- PFC that was restricted to layer 5 (L5) neurons. Consistently, adult Cyfip2+/- mice showed increased seizure susceptibility and auditory steady-state responses from the cortical electroencephalographic recordings. Among the identified prefrontal defects, lithium selectively normalized the hyperexcitability of Cyfip2+/- L5 neurons. RNA sequencing revealed reduced expression of potassium channel genes in the adult Cyfip2+/- PFC. Virus-mediated reduction of CYFIP2 in the PFC was sufficient to induce L5 hyperexcitability and lithium-responsive abnormal behavior. INTERPRETATION: These results suggest that L5-specific prefrontal dysfunction, especially hyperexcitability, underlies both the pathophysiology and the lithium-mediated amelioration of neurobehavioral phenotypes in adult Cyfip2+/- mice, which can be implicated in CYFIP2-associated brain disorders. ANN NEUROL 2020;88:526-543.

Rapamycin increases the incidence of neuropsychiatric illness in kidney transplant patients through the suppression of neural stem cells.

Rapamycin inhibits protein translation in cells, including neural stem cells (NSCs), by suppressing the mechanistic target of rapamycin (mTOR). This drug has been widely used together with calcineurin inhibitors in transplantation patients to prevent graft rejection. Previous studies have reported an association between mTOR and depression, but few investigations of this have occurred in transplant recipients. We have here tested the psychiatric effects of rapamycin in mice. The animals treated with rapamycin showed decreased locomotion and sugar consumption. In these rapamycin-treated mice also, the granule cells in the dentate gyrus (DG), which actively differentiate and proliferate from NSC, showed decreases in both excitatory and inhibitory synaptic transmission. Furthermore, the SOX2/NeuN ratio in the DG was decreased in mice treated with rapamycin. We further show that kidney transplantation patients who are receiving rapamycin have more psychiatric disorder such as adjustment disorder. Clinical attention is thus needed when administering rapamycin to transplant recipients due to its behavioral effects and its impact on NSC.

WISC-IV Intellectual Profiles in Korean Children and Adolescents with Attention Deficit/Hyperactivity Disorder.

OBJECTIVE: This study aimed to compare the Wechsler Intelligence Scale for Children, Fourth Edition (WISC-IV) profiles of children with attention deficit/hyperactivity disorder (ADHD) and typically-developing children (TC) in Korea. METHODS: The Korean version of the WISC-IV and the Advanced Test of Attention (ATA) were administered to 377 children and adolescents: 224 with ADHD (age 8.2±2.1 years, 182 boys) and 153 TC (age 8.7±2.4 years, 68 boys). Partial correlation and an analysis of covariance were used to investigate the relationship between the scores of the WISC-IV and the ATA. RESULTS: The mean score of the full-scale intelligence quotient was lower in ADHD children than in TC (p<0.001). In analyses controlling for gender and with the full-scale intelligence quotient as a covariate, the working memory index (WMI) (p<0.001) and values of the Digit span subtest (p=0.001) of the WISC-IV were lower in the ADHD group than in TC. The WMI (r=-0.26, p<0.001) and its subtest Arithmetic scores (r=-0.25, p<0.001) were negatively correlated with Commission errors on the auditory ATA. CONCLUSION: Children with ADHD have significantly lower WMI scores, which were clinically correlated with Commission errors on the auditory task of the ATA. Thus, the WMI is an indicator of attention deficit in children with ADHD.

IRSp53 Deletion in Glutamatergic and GABAergic Neurons and in Male and Female Mice Leads to Distinct Electrophysiological and Behavioral Phenotypes.

IRSp53 (also known as BAIAP2) is an abundant excitatory postsynaptic scaffolding protein implicated in autism spectrum disorders (ASD), schizophrenia, and attention-deficit/hyperactivity disorder (ADHD). IRSp53 is expressed in different cell types across different brain regions, although it remains unclear how IRSp53 deletion in different cell types affects brain functions and behaviors in mice. Here, we deleted IRSp53 in excitatory and inhibitory neurons in mice and compared resulting phenotypes in males and females. IRSp53 deletion in excitatory neurons driven by Emx1 leads to strong social deficits and hyperactivity without affecting anxiety-like behavior, whereas IRSp53 deletion in inhibitory neurons driven by Viaat has minimal impacts on these behaviors in male mice. In female mice, excitatory neuronal IRSp53 deletion induces hyperactivity but moderate social deficits. Excitatory neuronal IRSp53 deletion in male mice induces an increased ratio of evoked excitatory and inhibitory synaptic transmission (E/I ratio) in layer V pyramidal neurons in the prelimbic region of the medial prefrontal cortex (mPFC), whereas the same mutation does not alter the E/I ratio in female neurons. These results suggest that IRSp53 deletion in excitatory and inhibitory neurons and in male and female mice has distinct impacts on behaviors and synaptic transmission.

Diagnosing schizophrenia with network analysis and a machine learning method.

OBJECTIVE: Schizophrenia is a chronic and debilitating neuropsychiatric disorder. It has been suggested that impaired brain connectivity underlies the pathophysiology of schizophrenia. Network analysis has thus recently emerged in the field of schizophrenia research. METHODS: We investigated 48 schizophrenia patients and 24 healthy controls using network analysis and a machine learning method. A number of global and nodal network properties were estimated from graphs that were reconstructed using probabilistic brain tractography. These network properties were then compared between groups and used for machine learning to classify schizophrenia patients and healthy controls. RESULTS: In classifying schizophrenia patients and healthy controls via network properties, the support vector machine, random forest, naïve Bayes, and gradient boosting machine learning models showed an encouraging level of performance. The overall connectivity was revealed as the most significant contributing feature to this classification among the global network properties. Among the nodal network properties, although the relative importance of each region of interest was not identical, there were still some patterns. CONCLUSION: In conclusion, the possibility exists to classify schizophrenia patients and healthy controls using network properties, and we have found that there is a provisional pattern of involved brain regions among patients with schizophrenia.

Sexually dimorphic behavior, neuronal activity, and gene expression in Chd8-mutant mice.

Autism spectrum disorders (ASDs) are four times more common in males than in females, but the underlying mechanisms are poorly understood. We characterized sexually dimorphic changes in mice carrying a heterozygous mutation in Chd8 (Chd8+/N2373K) that was first identified in human CHD8 (Asn2373LysfsX2), a strong ASD-risk gene that encodes a chromatin remodeler. Notably, although male mutant mice displayed a range of abnormal behaviors during pup, juvenile, and adult stages, including enhanced mother-seeking ultrasonic vocalization, enhanced attachment to reunited mothers, and isolation-induced self-grooming, their female counterparts do not. This behavioral divergence was associated with sexually dimorphic changes in neuronal activity, synaptic transmission, and transcriptomic profiles. Specifically, female mice displayed suppressed baseline neuronal excitation, enhanced inhibitory synaptic transmission and neuronal firing, and increased expression of genes associated with extracellular vesicles and the extracellular matrix. Our results suggest that a human CHD8 mutation leads to sexually dimorphic changes ranging from transcription to behavior in mice.