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Subcortical structures, which include the basal ganglia and parts of the limbic system, have key roles in learning, motor control and emotion, but also contribute to higher-order executive functions. Prior studies have reported volumetric alterations in subcortical regions in schizophrenia. Reported results have sometimes been heterogeneous, and few large-scale investigations have been conducted. Moreover, few large-scale studies have assessed asymmetries of subcortical volumes in schizophrenia. Here, as a work completely independent of a study performed by the ENIGMA consortium, we conducted a large-scale multisite study of subcortical volumetric differences between patients with schizophrenia and controls. We also explored the laterality of subcortical regions to identify characteristic similarities and differences between them. T1-weighted images from 1680 healthy individuals and 884 patients with schizophrenia, obtained with 15 imaging protocols at 11 sites, were processed with FreeSurfer. Group differences were calculated for each protocol and meta-analyzed. Compared with controls, patients with schizophrenia demonstrated smaller bilateral hippocampus, amygdala, thalamus and accumbens volumes as well as intracranial volume, but larger bilateral caudate, putamen, pallidum and lateral ventricle volumes. We replicated the rank order of effect sizes for subcortical volumetric changes in schizophrenia reported by the ENIGMA consortium. Further, we revealed leftward asymmetry for thalamus, lateral ventricle, caudate and putamen volumes, and rightward asymmetry for amygdala and hippocampal volumes in both controls and patients with schizophrenia. Also, we demonstrated a schizophrenia-specific leftward asymmetry for pallidum volume. These findings suggest the possibility of aberrant laterality in neural pathways and connectivity patterns related to the pallidum in schizophrenia.

Mismatch negativity (MMN) has gained attention as a biomarker for psychosis and a translational intermediate phenotype in animal models of psychosis, including rodents and non-human primates. MMN has been linked to global functioning (Global Assessment of Functioning [GAF] score) and prognosis (psychosis onset or remission), suggesting that MMN reflects activities beyond auditory processing alone. This review examines the 45-year history of MMN from the perspective of psychiatric researchers and discusses current advances in computational and translational research on MMN, summarizing the current understanding of the MMN generation mechanism. We then address the essential question, "What do we observe through MMN?" Currently, we regard the relationship between global functioning in the real world and MMN as the key to answering this question. As a preliminary investigation, we analyzed the relationship between GAF as an objective variable and MMN, diagnosis, and basic epidemiological factors (age, sex, premorbid intelligence quotient) as explanatory variables (total n = 201, healthy controls: n = 41, patients with psychiatric disorders: n = 160) without assuming diagnostic categories. The relationship between functional outcomes and MMN was confirmed without a case-control design. Finally, we propose that new neurophysiological studies should acknowledge psychophysiological responses such as emotion, intention, and autonomic responses, as well as behavioral differences among participants beyond the dichotomy between healthy controls and patients. Measurements could be conducted in various settings from the participant's perspective. We discuss the potential for research investigating psychosis based on the interaction between individuals and the environment, using MMN as an illustrative model., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Discrepancies in self-rated and observer-rated depression severity may underlie the basis for biological heterogeneity in depressive disorders and be an important predictor of outcomes and indicators to optimize intervention strategies. However, the neural mechanisms underlying this discrepancy have been understudied. This study aimed to examine the brain networks that represent the neural basis of the discrepancy between self-rated and observer-rated depression severity using resting-state functional MRI. To examine the discrepancy between self-rated and observer-rated depression severity, self- and observer-ratings discrepancy (SOD) was defined, and the higher and lower SOD groups were selected from depressed patients as participants showing extreme deviation. Resting-state functional MRI analysis was performed to examine regions with significant differences in functional connectivity in the two groups. The results showed that, in the higher SOD group compared to the lower SOD group, there was increased functional connectivity between the frontal pole and precuneus, both of which are subregions of the default mode network that have been reported to be associated with ruminative and self-referential thinking. These results provide insight into the association of brain circuitry with discrepancies between self- and observer-rated depression severity and may lead to more treatment-oriented diagnostic reclassification in the future., (© The Author(s) 2024. Published by Oxford University Press.)

Previous studies reported decreased glutamate levels in the anterior cingulate cortex (ACC) in non-treatment-resistant schizophrenia and first-episode psychosis. However, ACC glutamatergic changes in subjects at high-risk for psychosis, and the effects of commonly experienced environmental emotional/social stressors on glutamatergic function in adolescents remain unclear. In this study, adolescents recruited from the general population underwent proton magnetic resonance spectroscopy (MRS) of the pregenual ACC using a 3-Tesla scanner. We explored longitudinal data on the association of combined glutamate-glutamine (Glx) levels, measured by MRS, with subclinical psychotic experiences. Moreover, we investigated associations of bullying victimization, a risk factor for subclinical psychotic experiences, and help-seeking intentions, a coping strategy against stressors including bullying victimization, with Glx levels. Finally, path analyses were conducted to explore multivariate associations. For a contrast analysis, gamma-aminobutyric acid plus macromolecule (GABA+) levels were also analyzed. Negative associations were found between Glx levels and subclinical psychotic experiences at both Times 1 (n = 219, mean age 11.5 y) and 2 (n = 211, mean age 13.6 y), as well as for over-time changes (n = 157, mean interval 2.0 y). Moreover, effects of bullying victimization and bullying victimization × help-seeking intention interaction effects on Glx levels were found (n = 156). Specifically, bullying victimization decreased Glx levels, whereas help-seeking intention increased Glx levels only in bullied adolescents. Finally, associations among bullying victimization, help-seeking intention, Glx levels, and subclinical psychotic experiences were revealed. GABA+ analysis revealed no significant results. This is the first adolescent study to reveal longitudinal trajectories of the association between glutamatergic function and subclinical psychotic experiences and to elucidate the effect of commonly experienced environmental emotional/social stressors on glutamatergic function. Our findings may deepen the understanding of how environmental emotional/social stressors induce impaired glutamatergic neurotransmission that could be the underpinning of liability for psychotic experiences in early adolescence., (© 2024. The Author(s).)

The gamma-band auditory steady-state response (ASSR), primarily generated from the auditory cortex, has received substantial attention as a potential brain marker indicating the pathophysiology of schizophrenia. Previous studies have shown reduced gamma-band ASSR in patients with schizophrenia and demonstrated correlations with impaired neurocognition and psychosocial functioning. Recent studies in clinical and healthy populations have suggested that the neural substrates of reduced gamma-band ASSR may be distributed throughout the cortices surrounding the auditory cortex, especially in the right hemisphere. This study aimed to investigate associations between the gamma-band ASSR and white matter alterations in the bundles broadly connecting the right frontal, parietal and occipital cortices to clarify the networks underlying reduced gamma-band ASSR in patients with schizophrenia. We measured the 40 Hz ASSR using electroencephalography and diffusion tensor imaging in 42 patients with schizophrenia and 22 healthy comparison subjects. The results showed that the gamma-band ASSR was positively correlated with fractional anisotropy (an index of white matter integrity) in the regions connecting the right frontal, parietal and occipital cortices in healthy subjects (β = 0.41, corrected p = 0.075, uncorrected p = 0.038) but not in patients with schizophrenia (β = 0.17, corrected p = 0.46, uncorrected p = 0.23). These findings support our hypothesis that the generation of gamma-band ASSR is supported by white matter bundles that broadly connect the cortices and that these relationships may be disrupted in schizophrenia. Our study may help characterize and interpret reduced gamma-band ASSR as a useful brain marker of schizophrenia., (© 2024. The Author(s).)

Differential diagnosis is sometimes difficult in practical psychiatric settings, in terms of using the current diagnostic system based on presenting symptoms and signs. The creation of a novel diagnostic system using objective biomarkers is expected to take place. Neuroimaging studies and others reported that subcortical brain structures are the hubs for various psycho-behavioral functions, while there are so far no neuroimaging data-driven clinical criteria overcoming limitations of the current diagnostic system, which would reflect cognitive/social functioning. Prior to the main analysis, we conducted a large-scale multisite study of subcortical volumetric and lateralization alterations in schizophrenia, bipolar disorder, major depressive disorder, and autism spectrum disorder using T1-weighted images of 5604 subjects (3078 controls and 2526 patients). We demonstrated larger lateral ventricles volume in schizophrenia, bipolar disorder, and major depressive disorder, smaller hippocampus volume in schizophrenia and bipolar disorder, and schizophrenia-specific smaller amygdala, thalamus, and accumbens volumes and larger caudate, putamen, and pallidum volumes. In addition, we observed a leftward alteration of lateralization for pallidum volume specifically in schizophrenia. Moreover, as our main objective, we clustered the 5,604 subjects based on subcortical volumes, and explored whether data-driven clustering results can explain cognitive/social functioning in the subcohorts. We showed a four-biotype classification, namely extremely (Brain Biotype [BB] 1) and moderately smaller limbic regions (BB2), larger basal ganglia (BB3), and normal volumes (BB4), being associated with cognitive/social functioning. Specifically, BB1 and BB2-3 were associated with severe and mild cognitive/social impairment, respectively, while BB4 was characterized by normal cognitive/social functioning. Our results may lead to the future creation of novel biological data-driven psychiatric diagnostic criteria, which may be expected to be useful for prediction or therapeutic selection., (© 2023. The Author(s).)

Adolescence is a critical period for psychological difficulties. Auditory mismatch negativity (MMN) and gamma-band auditory steady-state response (ASSR) are representative electrophysiological indices that mature during adolescence. However, the longitudinal association between MMN/ASSR and psychological difficulties among adolescents remains unclear. We measured MMN amplitude for duration and frequency changes and ASSR twice in a subsample (n = 67, mean age 13.4 and 16.1 years, respectively) from a large-scale population-based cohort. No significant longitudinal changes were observed in any of the electroencephalography indices. Changes in SDQ-TD were significantly associated with changes in duration MMN, but not frequency MMN and ASSR. Furthermore, the subgroup with higher SDQ-TD at follow-up showed a significant duration MMN decrease over time, whereas the subgroup with lower SDQ-TD did not. The results of our population neuroscience study suggest that insufficient changes in electroencephalography indices may have been because of the short follow-up period or non-monotonic change during adolescence, and indicated that the longitudinal association with psychological difficulties was specific to the duration MMN. These findings provide new insights that electrophysiological change may underlie the development of psychosocial difficulties emerging in adolescence., (© The Author(s) 2023. Published by Oxford University Press.)

Patients with schizophrenia can exhibit intelligence decline, which is an important element of cognitive impairment. Previous magnetic resonance imaging (MRI) studies have demonstrated that patients with schizophrenia have altered gray matter structures and functional connectivity associated with intelligence decline defined by a difference between premorbid and current intelligence quotients (IQs). However, it has remained unclear whether white matter microstructures are related to intelligence decline. In the present study, the indices of diffusion tensor imaging (DTI) obtained from 138 patients with schizophrenia and 554 healthy controls were analyzed. The patients were classified into three subgroups based on intelligence decline: deteriorated (94 patients), preserved (42 patients), and compromised IQ (2 patients) groups. Given that the DTI of each subject was acquired using either one of two different MRI scanners, we analyzed DTI indices separately for each scanner group. In the comparison between the deteriorated IQ group and the healthy controls, differences in some DTI indices were noted in three regions of interest irrespective of the MRI scanners, whereas differences in only one region of interest were noted between the preserved IQ group and the healthy controls. However, the comparisons between the deteriorated and preserved IQ groups did not show any reproducible differences. Together with the previous findings, it is thought that gray matter structures and functional connectivity are more promising as markers of intelligence decline in schizophrenia than white matter microstructures., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

According to the operational diagnostic criteria, psychiatric disorders such as schizophrenia (SZ), bipolar disorder (BD), major depressive disorder (MDD), and autism spectrum disorder (ASD) are classified based on symptoms. While its cluster of symptoms defines each of these psychiatric disorders, there is also an overlap in symptoms between the disorders. We hypothesized that there are also similarities and differences in cortical structural neuroimaging features among these psychiatric disorders. T1-weighted magnetic resonance imaging scans were performed for 5,549 subjects recruited from 14 sites. Effect sizes were determined using a linear regression model within each protocol, and these effect sizes were meta-analyzed. The similarity of the differences in cortical thickness and surface area of each disorder group was calculated using cosine similarity, which was calculated from the effect sizes of each cortical regions. The thinnest cortex was found in SZ, followed by BD and MDD. The cosine similarity values between disorders were 0.943 for SZ and BD, 0.959 for SZ and MDD, and 0.943 for BD and MDD, which indicated that a common pattern of cortical thickness alterations was found among SZ, BD, and MDD. Additionally, a generally smaller cortical surface area was found in SZ and MDD than in BD, and the effect was larger in SZ. The cosine similarity values between disorders were 0.945 for SZ and MDD, 0.867 for SZ and ASD, and 0.811 for MDD and ASD, which indicated a common pattern of cortical surface area alterations among SZ, MDD, and ASD. Patterns of alterations in cortical thickness and surface area were revealed in the four major psychiatric disorders. To our knowledge, this is the first report of a cross-disorder analysis conducted on four major psychiatric disorders. Cross-disorder brain imaging research can help to advance our understanding of the pathogenesis of psychiatric disorders and common symptoms., (© 2023. The Author(s).)

Several animal models of schizophrenia and patients with chronic schizophrenia have shown increased spontaneous power of gamma oscillations. However, the most robust alterations of gamma oscillations in patients with schizophrenia are reduced auditory-oscillatory responses. We hypothesized that patients with early-stage schizophrenia would have increased spontaneous power of gamma oscillations and reduced auditory-oscillatory responses. This study included 77 participants, including 27 ultra-high-risk (UHR) individuals, 19 patients with recent-onset schizophrenia (ROS), and 31 healthy controls (HCs). The auditory steady-state response (ASSR) and spontaneous power of gamma oscillations measured as induced power during the ASSR period were calculated using electroencephalography during 40-Hz auditory click-trains. The ASSRs were lower in the UHR and ROS groups than in the HC group, whereas the spontaneous power of gamma oscillations in the UHR and ROS groups did not significantly differ from power in the HC group. Both early-latency (0-100 ms) and late-latency (300-400 ms) ASSRs were significantly reduced and negatively correlated with the spontaneous power of gamma oscillations in the ROS group. In contrast, UHR individuals exhibited reduced late-latency ASSR and a correlation between the unchanged early-latency ASSR and the spontaneous power of gamma oscillations. ASSR was positively correlated with the hallucinatory behavior score in the ROS group. Correlation patterns between the ASSR and spontaneous power of gamma oscillations differed between the UHR and ROS groups, suggesting that the neural dynamics involved in non-stimulus-locked/task modulation change with disease progression and may be disrupted after psychosis onset., (© 2023. The Author(s).)

Although many studies have demonstrated structural brain abnormalities associated with auditory verbal hallucinations (AVH) in schizophrenia, the results remain inconsistent because of the small sample sizes and the reliability of clinical interviews. We compared brain morphometries in 204 participants, including 58 schizophrenia patients with a history of AVH (AVH + ), 29 without a history of AVH (AVH-), and 117 healthy controls (HCs) based on a detailed inspection of medical records. We further divided the AVH+ group into 37 patients with and 21 patients without hallucinations at the time of the MRI scans (AVH++ and AVH+-, respectively) via clinical interviews to explore the morphological differences according to the persistence of AVH. The AVH + group had a smaller surface area in the left caudal middle frontal gyrus (F = 7.28, FDR-corrected p = 0.0008) and precentral gyrus (F = 7.68, FDR-corrected p = 0.0006) compared to the AVH- group. The AVH+ patients had a smaller surface area in the left insula (F = 7.06, FDR-corrected p = 0.001) and a smaller subcortical volume in the bilateral hippocampus (right: F = 13.34, FDR-corrected p = 0.00003; left: F = 6.80, FDR-corrected p = 0.001) compared to the HC group. Of these significantly altered areas, the AVH++ group showed significantly smaller bilateral hippocampal volumes compared to the AVH+- group, and a smaller surface area in the left precentral gyrus and caudal middle frontal gyrus compared to the AVH- group. Our findings highlighted the distinct pattern of structural alteration between the history and presence of AVH in schizophrenia, and the importance of integrating multiple criteria to elucidate the neuroanatomical mechanisms., (© 2022. The Author(s).)

Aim: Subjective quality of life is a clinically relevant outcome that is strongly associated with the severity of clinical symptoms in individuals with ultra-high risk for psychosis and patients with recent-onset psychotic disorder. Our objective was to examine whether longitudinal changes in clinical symptoms are associated with quality of life in ultra-high risk individuals and patients with recent-onset psychotic disorder., Methods: Individuals with ultra-high risk and patients with recent-onset psychosis disorder were recruited in the same clinical settings at baseline and were followed up with more than 6 months and less than 5 years later. We assessed five factors of clinical symptoms using the positive and negative syndrome scale, and quality of life using the World Health Organization quality of life questionnaire-short form. We used multiple regression to examine the relationships between clinical symptoms and quality of life while controlling for diagnosis, follow-up period, age, and sex., Results: Data were collected from 22 individuals with ultra-high risk and 27 patients with recent-onset psychosis disorder. The multiple regression analysis results indicated that the more severe anxiety/depression was at baseline, the poorer the quality of life at follow-up. Further, improvement of anxiety/depression and disorganized thoughts were associated with improvement in quality of life. The difference in diagnosis did not affect the association between clinical symptoms and quality of life., Conclusion: These findings suggest that the improvement of anxiety/depression and disorganized thoughts is important in the early stages of psychosis before it becomes severe, affecting the quality of life., (© 2022 The Authors. Psychiatry and Clinical Neurosciences © 2022 Japanese Society of Psychiatry and Neurology.)

Aim: Information processing is supported by the cortico-cortical transmission of neural oscillations across brain regions. Recent studies have demonstrated that the rhythmic firing of neural populations is not random but is governed by interactions with other frequency bands. Specifically, the amplitude of gamma-band oscillations is associated with the phase of lower frequency oscillations in support of short and long-range communications among networks. This cross-frequency relation is thought to reflect the temporal coordination of neural communication. While schizophrenia patients show abnormal oscillatory responses across multiple frequencies at rest, it is unclear whether the functional relationships among frequency bands are intact. This study aimed to characterize the lower frequency (delta/theta, 1-8 Hz) phase and the amplitude of gamma oscillations in healthy subjects and schizophrenia patients at rest., Methods: Low frequency-phase (delta- and theta- band) angles and gamma-band amplitude relationships were assessed in 142 schizophrenia patients and 128 healthy subjects., Results: Significant low-frequency phase alteration related to high-power gamma was detected across broadly distributed scalp regions in both healthy subjects and patients. In patients, delta phase synchronization related to high-power gamma was significantly decreased at the frontocentral, right middle temporal, and left temporoparietal electrodes but significantly increased at the left parietal electrode., Conclusions: High-power gamma-related delta phase alteration may reflect a core pathophysiologic abnormality in schizophrenia. Data-driven measures of functional relationships among frequency bands may prove useful in the development of novel therapeutics. Future studies are needed to determine whether these alterations are specific to schizophrenia or appear in other neuropsychiatric patient populations., (© 2022 The Authors. Psychiatry and Clinical Neurosciences © 2022 Japanese Society of Psychiatry and Neurology.)

The excellence of the brain is its robustness under various types of noise and its flexibility under various environments. However, how the brain works is still a mystery. The critical brain hypothesis proposes a possible mechanism and states that criticality plays an important role in the healthy brain. Herein, using an electroencephalography dataset obtained from patients with psychotic disorders (PDs), ultra-high risk (UHR) individuals and healthy controls (HCs), and its dynamical network analysis, we show that the brain of HCs remains around a critical state, whereas that of patients with PD falls into more stable states. Meanwhile, the brain of UHR individuals is similar to that of PD in terms of entropy but is analogous to that of HCs in causality patterns. These results not only provide evidence for the criticality of the normal brain but also highlight the practicability of using an analytic biophysical tool to study the dynamical properties of mental diseases., Competing Interests: KIK reports grants from Lily, grants from MSD, grants and personal fees from Astellas, grants and personal fees from Takeda, grants and personal fees from Dainippon-Sumitomo, grants from Novartis, grants from Tanabe-Mitsubishi, grants from Eisai, grants and personal fees from Otsuka, grants from Shionogi, grants from Ono Pharma, personal fees from Fuji-film-Wako, personal fees from Yoshitomi, personal fees from Kyowa, personal fees from Janssen, and personal fees from Meiji Seika Pharma, outside the submitted work during the past 36 months. KA reports grants and personal fees from KKE, grants and personal fees from NEC, grants from Sysmex, personal fees from Novo Nordisk Japan, and grants and personal fees from Toyota Central R&D Labs., outside the submitted work during the past 36 months. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Shi, Kirihara, Tada, Fujioka, Usui, Koshiyama, Araki, Chen, Kasai and Aihara.)

The underlying pathologies of psychiatric disorders, which cause substantial personal and social losses, remain unknown, and their elucidation is an urgent issue. To clarify the core pathological mechanisms underlying psychiatric disorders, in addition to laboratory-based research that incorporates the latest findings, it is necessary to conduct large-sample-size research and verify reproducibility. For this purpose, it is critical to conduct multicenter collaborative research across various fields, such as psychiatry, neuroscience, molecular biology, genomics, neuroimaging, cognitive science, neurophysiology, psychology, and pharmacology. Moreover, collaborative research plays an important role in the development of young researchers. In this respect, the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) consortium and Cognitive Genetics Collaborative Research Organization (COCORO) have played important roles. In this review, we first overview the importance of multicenter collaborative research and our target psychiatric disorders. Then, we introduce research findings on the pathophysiology of psychiatric disorders from neurocognitive, neurophysiological, neuroimaging, genetic, and basic neuroscience perspectives, focusing mainly on the findings obtained by COCORO. It is our hope that multicenter collaborative research will contribute to the elucidation of the pathological basis of psychiatric disorders., (© 2021 The Authors Psychiatry and Clinical Neurosciences published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Psychiatry and Neurology.)

Reproducibility is one of the most important issues for generalizing the results of clinical research; however, low reproducibility in neuroimaging studies is well known. To overcome this problem, the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) consortium, an international neuroimaging consortium, established standard protocols for imaging analysis and employs either meta- and mega-analyses of psychiatric disorders with large sample sizes. The Cognitive Genetics Collaborative Research Organization (COCORO) in Japan promotes neurobiological studies in psychiatry and has successfully replicated and extended works of ENIGMA especially for neuroimaging studies. For example, (a) the ENIGMA consortium showed subcortical regional volume alterations in patients with schizophrenia (n = 2,028) compared to controls (n = 2,540) across 15 cohorts using meta-analysis. COCORO replicated the volumetric changes in patients with schizophrenia (n = 884) compared to controls (n = 1,680) using the ENIGMA imaging analysis protocol and mega-analysis. Furthermore, a schizophrenia-specific leftward asymmetry for the pallidum volume was demonstrated; and (b) the ENIGMA consortium identified white matter microstructural alterations in patients with schizophrenia (n = 1,963) compared to controls (n = 2,359) across 29 cohorts. Using the ENIGMA protocol, a study from COCORO showed similar results in patients with schizophrenia (n = 696) compared to controls (n = 1,506) from 12 sites using mega-analysis. Moreover, the COCORO study found that schizophrenia, bipolar disorder (n = 211) and autism spectrum disorder (n = 126), but not major depressive disorder (n = 398), share similar white matter microstructural alterations, compared to controls. Further replication and harmonization of the ENIGMA consortium and COCORO will contribute to the generalization of their research findings., (© 2020 The Authors. Human Brain Mapping published by Wiley Periodicals, Inc.)

Many studies have tested the relationship between demographic, clinical, and psychobiological measurements and clinical outcomes in ultra-high risk for psychosis (UHR) and first-episode psychosis (FEP). However, no study has investigated the relationship between multi-modal measurements and long-term outcomes for >2 years. Thirty-eight individuals with UHR and 29 patients with FEP were measured using one or more modalities (cognitive battery, electrophysiological response, structural magnetic resonance imaging, and functional near-infrared spectroscopy). We explored the characteristics associated with 13- and 28-month clinical outcomes. In UHR, the cortical surface area in the left orbital part of the inferior frontal gyrus was negatively associated with 13-month disorganized symptoms. In FEP, the cortical surface area in the left insula was positively associated with 28-month global social function. The left inferior frontal gyrus and insula are well-known structural brain characteristics in schizophrenia, and future studies on the pathological mechanism of structural alteration would provide a clearer understanding of the disease., (© 2021. The Author(s).)

Birth order is a crucial environmental factor for child development. For example, later-born children are relatively unlikely to feel secure due to sibling competition or diluted parental resources. The positive effect of being earlier-born on cognitive intelligence is well-established. However, whether birth order is linked to social behavior remains controversial, and the neural correlates of birth order effects in adolescence when social cognition develops remain unknown. Here, we explored the birth order effect on prosociality using a large-scale population-based adolescent cohort. Next, since the amygdala is a key region for sociality and environmental stress, we examined amygdala substrates of the association between birth order and prosociality using a subset neuroimaging cohort. We found enhanced prosociality in later-born adolescents (N = 3160), and observed the mediating role of larger amygdala volume (N = 208) and amygdala-prefrontal functional connectivity with sex-selective effects (N = 183). We found that birth order, a non-genetic environmental factor, affects adolescent social development via different neural substrates. Our findings may indicate the later-born people's adaptive survival strategy in stressful environments., (© 2021. The Author(s).)

Gamma oscillations are physiological phenomena that reflect perception and cognition, and involve parvalbumin-positive γ-aminobutyric acid-ergic interneuron function. The auditory steady-state response (ASSR) is the most robust index for gamma oscillations, and it is impaired in patients with neuropsychiatric disorders such as schizophrenia and autism. Although ASSR reduction is known to vary in terms of frequency and time, the neural mechanisms are poorly understood. We obtained high-density electrocorticography recordings from a wide area of the cortex in 8 patients with refractory epilepsy. In an ASSR paradigm, click sounds were presented at frequencies of 20, 30, 40, 60, 80, 120, and 160 Hz. We performed time-frequency analyses and analyzed intertrial coherence, event-related spectral perturbation, and high-gamma oscillations. We demonstrate that the ASSR is globally distributed among the temporal, parietal, and frontal cortices. The ASSR was composed of time-dependent neural subcircuits differing in frequency tuning. Importantly, the frequency tuning characteristics of the late-latency ASSR varied between the temporal/frontal and parietal cortex, suggestive of differentiation along parallel auditory pathways. This large-scale survey of the cortical ASSR could serve as a foundation for future studies of the ASSR in patients with neuropsychiatric disorders., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

There is clear evidence of intergenerational transmission of life values, cognitive traits, psychiatric disorders, and even aspects of daily decision making. To investigate biological substrates of this phenomenon, the brain has received increasing attention as a measurable biomarker and potential target for intervention. However, no previous study has quantitatively and comprehensively investigated the effects of intergenerational transmission on functional and structural brain networks. Here, by employing an unusually large cohort dataset (N = 84 parent-child dyads; 45 sons, 39 daughters, 81 mothers, and 3 fathers), we show that patterns of functional and structural brain networks are preserved over a generation. We also demonstrate that several demographic factors and behavioral/physiological phenotypes have a relationship with brain similarity. Collectively, our results provide a comprehensive picture of neurobiological substrates of intergenerational transmission and demonstrate the usability of our dataset for investigating the neurobiological substrates of intergenerational transmission., Competing Interests: The authors declare no competing interests., (© 2021 The Author(s).)

Background: Schizophrenia patients have abnormal electroencephalographic (EEG) power over multiple frequency bands, even at rest, though the primary neural generators and spatiotemporal dynamics of these abnormalities are largely unknown. Disturbances in the precise synchronization of oscillations within and across cortical sources may underlie abnormal resting-state EEG activity in schizophrenia patients., Methods: A novel assessment method was applied to identify the independent contributing sources of resting-state EEG and assess the phase discontinuity in schizophrenia patients (N = 148) and healthy subjects (N = 143)., Results: A network of 11 primary contributing sources of scalp EEG was identified in both groups. Schizophrenia patients showed abnormal elevations of EEG power in the temporal region in the theta, beta, and gamma-bands, as well as the posterior cingulate gyrus in the delta, theta, alpha, and beta-bands. The higher theta-band power in the middle temporal gyrus was significantly correlated with verbal memory impairment in patients. The peak frequency of alpha was lower in patients in the cingulate and temporal regions. Furthermore, patients showed a higher rate of alpha phase discontinuity in the temporal region as well as a lower rate of theta phase discontinuity in the temporal and posterior cingulate regions., Conclusions: Abnormal rates of phase discontinuity of alpha- and theta-band, abnormal elevations of EEG power in multiple bands, and a lower peak frequency of alpha were identified in schizophrenia patients at rest. Clarification of the mechanistic substrates of abnormal phase discontinuity may clarify core pathophysiologic abnormalities of schizophrenia and contribute to the development of novel biomarkers for therapeutic interventions., Competing Interests: Declaration of competing interest G.A. Light reported consulting for Astellas Pharma, Inc., Heptares Therapeutics, NeuroSig, Neurocrine, and Novartis., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Aim: Gamma-band auditory steady-state response (ASSR) is a neurophysiologic index that is increasingly used as a translational biomarker in the development of treatments of neuropsychiatric disorders. While gamma-band ASSR is generated by distributed networks of highly interactive temporal and frontal cortical sources, the majority of human gamma-band ASSR studies using electroencephalography (EEG) highlight activity from only a single frontocentral scalp site, Fz, where responses tend to be largest and reductions in schizophrenia patients are most evident. However, no previous study has characterized the relative source contributions to Fz, which is a necessary step to improve the concordance of preclinical and clinical EEG studies., Methods: A novel method to back-project the contributions of independent cortical source components was applied to assess the independent sources and their proportional contributions to Fz as well as source-resolved responses in 432 schizophrenia patients and 294 healthy subjects., Results: Independent contributions of gamma-band ASSR to Fz were detected from orbitofrontal, bilateral superior/middle/inferior temporal, bilateral middle frontal, and posterior cingulate gyri in both groups. In contrast to expectations, the groups showed comparable source contribution weight to gamma-band ASSR at Fz. While gamma-band ASSR reductions at Fz were present in schizophrenia patients consistent with previous studies, no group differences in individual source-level responses to Fz were detected., Conclusion: Small differences in multiple independent sources summate to produce scalp-level differences at Fz. The identification of independent source contributions to a single scalp sensor represents a promising methodology for measuring dissociable and homologous biomarker targets in future translational studies., (© 2021 The Authors Psychiatry and Clinical Neurosciences © 2021 Japanese Society of Psychiatry and Neurology.)

Gamma-band (40-Hz) activity is critical for cortico-cortical transmission and the integration of information across neural networks during sensory and cognitive processing. Patients with schizophrenia show selective reductions in the capacity to support synchronized gamma-band oscillations in response to auditory stimulation presented 40-Hz. Despite widespread application of this 40-Hz auditory steady-state response (ASSR) as a translational electroencephalographic biomarker for therapeutic development for neuropsychiatric disorders, the spatiotemporal dynamics underlying the ASSR have not been fully characterized. In this study, a novel Granger causality analysis was applied to assess the propagation of gamma oscillations in response to 40-Hz steady-state stimulation across cortical sources in schizophrenia patients (n = 426) and healthy comparison subjects (n = 293). Both groups showed multiple ASSR source interactions that were broadly distributed across brain regions. Schizophrenia patients showed distinct, hierarchically sequenced connectivity abnormalities. During the response onset interval, patients exhibited abnormal increased connectivity from the inferior frontal gyrus to the superior temporal gyrus, followed by decreased connectivity from the superior temporal to the middle cingulate gyrus. In the later portion of the ASSR response (300-500 ms), patients showed significantly increased connectivity from the superior temporal to the middle frontal gyrus followed by decreased connectivity from the left superior frontal gyrus to the right superior and middle frontal gyri. These findings highlight both the orchestration of distributed multiple sources in response to simple gamma-frequency stimulation in healthy subjects as well as the patterns of deficits in the generation and maintenance of gamma-band oscillations across the temporo-frontal sources in schizophrenia patients., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Cognitive impairment is a hallmark of schizophrenia and a robust predictor of functional outcomes. Impairments are found in all phases of the illness and are only moderately attenuated by currently approved therapeutics. Neurophysiological indices of sensory discrimination (ie, mismatch negativity (MMN) and P3a amplitudes) and gamma-band auditory steady-state response (ASSR; power and phase locking) are translational biomarkers widely used in the development of novel therapeutics for neuropsychiatric disorders. It is unclear whether laboratory-based EEG measures add explanatory power to well-established models that use only cognitive, clinical, and functional outcome measures. Moreover, it is unclear if measures of sensory discrimination and gamma-band ASSR uniquely contribute to putative causal pathways linking sensory discrimination, neurocognition, negative symptoms, and functional outcomes in schizophrenia. To answer these questions, hierarchical associations among sensory processing, neurocognition, clinical symptoms, and functional outcomes were assessed via structural equation modeling in a large sample of schizophrenia patients (n = 695) and healthy comparison subjects (n = 503). The results showed that the neurophysiologic indices of sensory discrimination and gamma-band ASSR both significantly contribute to and yield unique hierarchical, "bottom-up" effects on neurocognition, symptoms, and functioning. Measures of sensory discrimination showed direct effects on neurocognition and negative symptoms, while gamma-band ASSR had a direct effect on neurocognition in patients. Continued investigation of the neural mechanisms underlying abnormal networks of MMN/P3a and gamma-band ASSR is needed to clarify the pathophysiology of schizophrenia and the development of novel therapeutic interventions., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Mismatch negativity (MMN) and P3a are event-related potential measures of early auditory information processing that are increasingly used as translational biomarkers in the development of treatments for neuropsychiatric disorders. These responses are reduced in schizophrenia patients over the frontocentral scalp electrodes and are associated with important domains of cognitive and psychosocial functioning. While MMN and P3a responses are generated by a dynamic network of cortical sources distributed across the temporal and frontal brain regions, it is not clear how these sources independently contribute to MMN and P3a at the primary frontocentral scalp electrode or to abnormalities observed in schizophrenia. This study aimed to determine the independent source contributions and characterize the magnitude of impairment in source-level MMN and P3a responses in schizophrenia patients., Methods: A novel method was applied to back-project the contributions of 11 independent cortical source components to Fz, the primary scalp sensor that is used in clinical studies, in n = 589 schizophrenia patients and n = 449 healthy comparison subjects., Results: The groups showed comparable individual source contributions underlying both MMN and P3a responses at Fz. Source-level responses revealed an increasing magnitude of impairment in schizophrenia patients from the temporal to more frontal sources., Conclusions: Schizophrenia patients have a normal architecture of source contributions that are accompanied by widespread abnormalities in source resolved mismatch and P3a responses, with more prominent deficits detected from the frontal sources. Quantification of source contributions and source-level responses accelerates clarification of the neural networks underlying MMN reduction at Fz in schizophrenia patients., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Schizophrenia patients show widespread deficits in neurocognitive, clinical, and psychosocial functioning. Mismatch negativity (MMN) and gamma-band auditory steady-state response (ASSR) are robust translational biomarkers associated with schizophrenia and associated with cognitive dysfunction, negative symptom severity, and psychosocial disability. Although these biomarkers are conceptually linked as measures of early auditory information processing, it is unclear whether MMN and gamma-band ASSR account for shared vs. non-shared variance in cognitive, clinical, and psychosocial functioning., Methods: Multiple regression analyses with MMN, gamma-band ASSR, and clinical measures were performed in large cohorts of schizophrenia outpatients (N = 428) and healthy comparison subjects (N = 283)., Results: Reduced MMN (d = 0.67), gamma-band ASSR (d = -0.40), and lower cognitive function were confirmed in schizophrenia patients. Regression analyses revealed that reduced MMN amplitude showed unique associations with lower verbal learning and negative symptoms, reduced gamma-band ASSR showed a unique association with working memory deficits, and both reduced MMN amplitude and reduced gamma-band ASSR showed an association with daily functioning impairment in schizophrenia patients., Conclusion: MMN and ASSR measures are non-redundant and complementary measures of early auditory information processing that are associated with important domains of functioning. Studies are needed to clarify the neural substrates of MMN and gamma-band ASSR to improve our understanding of the pathophysiology of schizophrenia and accelerate their use in the development of novel therapeutic interventions., Competing Interests: Declaration of competing interest G. Light reported consulting for Astellas Pharma, Inc, Heptares Therapeutics, NeuroSig, Neurocrine, and Novartis., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Human social activities are realized by a synergy of neuronal activity over various regions of the brain, which is supported by their connectivity. In the present study, we examined associations between social activities, represented by work hours, and brain connectivity as quantified using diffusion tensor imaging (DTI). In 483 healthy participants, DTI analysis was performed using 3 T magnetic resonance imaging, and work hours were calculated, considering hours of paid employment (the "Work for Pay" category), hours of housework (the "Work at Home" category), and hours of school-related study (the "Student" category). The correlations between each class of work time and DTI indices were analyzed. The mean diffusivity (MD) values of the anterior limb of the internal capsule (ALIC) and the superior fronto-occipital fasciculus (SFO) were negatively correlated with total work hours (ALIC: r = -0.192, p =  2.3 × 10 -5 ; SFO: r = -0.161, p =  3.8 × 10 -4 ). We also found that the MD values of the ALIC and the SFO were correlated with work hours in the Work for Pay category (ALIC: r = -0.211, p =  3.2 × 10 -6 ; SFO: r = -0.163, p =  3.4 × 10 -4 ) but not with those in the Work at Home category or the Student category. These results suggest that social activity is associated with the white matter microstructure of the ALIC and the SFO. The main difference between "Work for Pay" and the other two social activities appears to be the type of motivation-for example, external versus internal. Therefore, the white matter microstructure of the ALIC and SFO may be related to externally motivated social activities., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Synaptic interactions between parvalbumin-positive γ-aminobutyric acid (GABA)-ergic interneurons and pyramidal neurons evoke cortical gamma oscillations, which are known to be abnormal in schizophrenia. These cortical gamma oscillations can be indexed by the gamma-band auditory steady-state response (ASSR), a robust electroencephalographic (EEG) biomarker that is increasingly used to advance the development of novel therapeutics for schizophrenia, and other related brain disorders. Despite promise of ASSR, the neural substrates of ASSR have not yet been characterized. This study investigated the sources underlying ASSR in healthy subjects and schizophrenia patients. In this study, a novel method for noninvasively characterizing source locations was developed and applied to EEG recordings obtained from 293 healthy subjects and 427 schizophrenia patients who underwent ASSR testing. Results revealed a distributed network of temporal and frontal sources in both healthy subjects and schizophrenia patients. In both groups, primary contributing ASSR sources were identified in the right superior temporal cortex and the orbitofrontal cortex. In conjunction with normal activity in these areas, schizophrenia patients showed significantly reduced source dipole density of gamma-band ASSR (ITC > 0.25) in the left superior temporal cortex, orbitofrontal cortex, and left superior frontal cortex. In conclusion, a distributed network of temporal and frontal brain regions supports gamma phase synchronization. We demonstrated that failure to mount a coherent physiologic response to simple 40-Hz stimulation reflects disorganized network function in schizophrenia patients. Future translational studies are needed to more fully understand the neural mechanisms underlying gamma-band ASSR network abnormalities in schizophrenia.

Associations between altered DNA methylation of the serotonin transporter (5-HTT)-encoding gene SLC6A4 and early life adversity, mood and anxiety disorders, and amygdala reactivity have been reported. However, few studies have examined epigenetic alterations of SLC6A4 in schizophrenia (SZ). We examined CpG sites of SLC6A4, whose DNA methylation levels have been reported to be altered in bipolar disorder, using 3 independent cohorts of patients with SZ and age-matched controls. We found significant hypermethylation of a CpG site in SLC6A4 in male patients with SZ in all 3 cohorts. We showed that chronic administration of risperidone did not affect the DNA methylation status at this CpG site using common marmosets, and that in vitro DNA methylation at this CpG site diminished the promoter activity of SLC6A4. We then genotyped the 5-HTT-linked polymorphic region (5-HTTLPR) and investigated the relationship among 5-HTTLPR, DNA methylation, and amygdala volume using brain imaging data. We found that patients harboring low-activity 5-HTTLPR alleles showed hypermethylation and they showed a negative correlation between DNA methylation levels and left amygdala volumes. These results suggest that hypermethylation of the CpG site in SLC6A4 is involved in the pathophysiology of SZ, especially in male patients harboring low-activity 5-HTTLPR alleles., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Patients with schizophrenia show abnormal spontaneous oscillatory activity in scalp-level electroencephalographic (EEG) responses across multiple frequency bands. While oscillations play an essential role in the transmission of information across neural networks, few studies have assessed the frequency-specific dynamics across cortical source networks at rest. Identification of the neural sources and their dynamic interactions may improve our understanding of core pathophysiologic abnormalities associated with the neuropsychiatric disorders. Methods: A novel multivector autoregressive modeling approach for assessing effective connectivity among cortical sources was developed and applied to resting-state EEG recordings obtained from n = 139 schizophrenia patients and n = 126 healthy comparison subjects. Results: Two primary abnormalities in resting-state networks were detected in schizophrenia patients. The first network involved the middle frontal and fusiform gyri and a region near the calcarine sulcus. The second network involved the cingulate gyrus and the Rolandic operculum (a region that includes the auditory cortex). Conclusions: Schizophrenia patients show widespread patterns of hyper-connectivity across a distributed network of the frontal, temporal, and occipital brain regions. Results highlight a novel approach for characterizing alterations in connectivity in the neuropsychiatric patient populations. Further mechanistic characterization of network functioning is needed to clarify the pathophysiology of neuropsychiatric and neurological diseases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Koshiyama, Miyakoshi, Tanaka-Koshiyama, Joshi, Molina, Sprock, Braff and Light.)

Cognitive impairments are pervasive and disabling features of schizophrenia. Targeted cognitive training (TCT) is a "bottom-up" cognitive remediation intervention with efficacy for neurocognitive outcomes in schizophrenia, yet individual responses are variable. Gamma oscillatory measures are leading candidate biomarkers in the development of biologically informed pro-cognitive therapeutics. Forty-two schizophrenia patients were recruited from a long-term residential treatment facility. Participants were randomized to receive either 1 h of cognitive training (TCT, n = 21) or computer games (TAU, n = 21). All participants received standard-of-care treatment; the TCT group additionally completed 30 h of cognitive training. The auditory steady-state response paradigm was used to elicit gamma oscillatory power and synchrony during electroencephalogram recordings. Detailed clinical and cognitive assessments were collected at baseline and after completion of the study. Baseline gamma power predicted cognitive gains after a full course of TCT (MCCB, R 2  = 0.31). A change in gamma power after 1-h TCT exposure predicted improvement in both positive (SAPS, R 2  = 0.40) and negative (SANS, R 2  = 0.30) symptoms. These relationships were not observed in the TAU group (MCCB, SAPS, and SANS, all R 2  < 0.06). The results indicate that the capacity to support gamma oscillations, as well as the plasticity of the underlying ASSR circuitry after acute exposure to 1 h of TCT, reflect neural mechanisms underlying the efficacy of TCT, and may be used to predict individualized treatment outcomes. These findings suggest that gamma oscillatory biomarkers applied within the context of experimental medicine designs can be used to personalize individual treatment options for pro-cognitive interventions in patients with schizophrenia.

Background: Auditory mismatch negativity (MMN) is a translatable event-related potential biomarker, and its reduction in schizophrenia is associated with the severity of clinical symptoms. While MMN recorded at the scalp is generated by a distributed network of temporofrontal neural sources, the primary contributing sources and the dynamic interactions among sources underlying MMN impairments in schizophrenia have not been previously characterized., Methods: A novel data-driven analytic framework was applied to large cohorts of healthy comparison subjects (n = 449) and patients with schizophrenia (n = 589) to identify the independent contributing sources of MMN, characterize the patterns of effective connectivity underlying reduced MMN in patients, and explore the clinical significance of these abnormal source dynamics in schizophrenia., Results: A network of 11 independent contributing sources underlying MMN distributed across temporofrontal cortices was identified. Orderly shifts in peak source activity were detected in a steplike manner, starting at temporal structures and progressing across frontal brain regions. MMN reduction in patients was predominantly associated with reduced contributions from 3 frontal midline sources: orbitofrontal, anterior cingulate, and middle cingulate cortices. Patients showed increased connectivity from temporal to prefrontal regions in conjunction with decreased cross-hemispheric connectivity to prefrontal regions. The decreased connectivity strength of precentral to prefrontal regions in patients with schizophrenia was associated with greater severity of negative symptoms., Conclusions: Alterations in the dynamic interactions among temporofrontal sources underlie MMN abnormalities in schizophrenia. These results advance our understanding of the neural substrates and temporal dynamics of normal and impaired information processing with novel applications for translatable biomarkers of neuropsychiatric disorders., (Copyright © 2020 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

The superior longitudinal fasciculus (SLF) is a white matter structure that has long bidirectional projections among the prefrontal, temporal, occipital, and parietal cortices and extends over a wide area in a human brain. Recently, anatomical details of the SLF have been clarified using a diffusion tensor imaging (DTI) template of subjects from the Human Connectome Project. However, the neurobehavioral functions of the SLF have not been fully elucidated. It is speculated that the SLF contributes to a broad cognitive domain including visuospatial nonverbal cognitive ability and verbal memory ability because of its anatomical location; however, previous findings in imaging studies are inconsistent. Showing the contribution of the SLF to cognitive function may be important for improving our understanding of the functional role of white matter structures in the human brain. This study aimed to identify the relationship between DTI indices of the SLF and the Verbal Comprehension, Perceptual Organization, Working Memory and Processing Speed Indices of the Wechsler Adult Intelligence Scale-Third Edition using regression analysis, accounting for the effects of age, sex and scanner type in 583 healthy volunteers. We showed significant correlations between the fractional anisotropy of the left SLF and the Perceptual Organization Index (β = 0.21, p =  4.5×10 -4 ) and Working Memory Index (β = 0.19, p =  4.0×10 -4 ). These findings may have implications for the rehabilitation of cognitive function in patients with neurological disorders., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Maternal breastfeeding has an impact on motor and emotional development in children of the next generation. Elucidating how breastfeeding during infancy affects brain regional structural development in early adolescence will be helpful for promoting healthy development. However, previous studies that have shown relationships between breastfeeding during infancy and cortical brain regions in adolescence are usually based on maternal retrospective recall of breastfeeding, and the accuracy of the data is unclear. In this study, we investigated the association between breastfeeding duration and brain regional volume in a population-neuroimaging study of early adolescents in Japan (N ​= ​207; 10.5-13.4 years) using voxel-based morphometry, which enabled us to analyze the whole brain. We evaluated breastfeeding duration as indexed by maternal and child health handbook records during infancy. The results showed a significant positive correlation between the duration of breastfeeding and gray matter volume in the dorsal and ventral striatum and the medial orbital gyrus. Post hoc exploratory analyses revealed that the duration of breastfeeding was significantly correlated with emotional behavior. Additionally, the volume in the medial orbital gyrus mediated an association between breastfeeding duration and emotional behavior. This is the first study to evaluate the effect of breastfeeding during infancy on regional brain volumes in early adolescence based on maternal and child health handbook records. Our findings shed light upon the importance of maternal breastfeeding for brain development related to emotional and motivational processing in early adolescence., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

The child-parent relationship is a significant factor in an adolescent's well-being and functional outcomes. Epidemiological evidence indicates that relationships with the father and mother are differentially associated with specific psychobehavioral problems that manifest differentially between boys and girls. Neuroimaging is expected to bridge the gap in understanding such a complicated mapping between the child-parent relationships and adolescents' problems. However, possible differences in the effects of child-father and child-mother relationships on sexual dimorphism in children's brains and psychobehavioral problems have not been examined yet. This study used a dataset of 10- to 13-year-old children (N ​= ​93) to reveal the triad of associations among child-parent relationship, brain, and psychobehavioral problems by separately estimating the respective effects of child-father and child-mother relationships on boys and girls. We first fitted general linear models to identify the effects of paternal and maternal relationships in largely different sets of children's resting-state functional connectivity, which we term paternal and maternal functional brain connectomes (FBCs). We then performed connectome-based predictive modeling (CPM) to predict children's externalizing and internalizing problems from these parental FBCs. The models significantly predicted a range of girls' internalizing problems, whereas the prediction of boys' aggression was also significant using a more liberal uncorrected threshold. A series of control analyses confirmed that CPMs using FBCs associated with peer relationship or family socioeconomic status failed to make significant predictions of psychobehavioral problems. Lastly, a causal discovery method identified causal paths from daughter-mother relationship to maternal FBC, and then to daughter's internalizing problems. These observations indicate sex-dependent mechanisms linking child-parent relationship, brain, and psychobehavioral problems in the development of early adolescence., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: Disruptions in the dopamine system have been observed in psychiatric disorders. Since dopamine is mainly produced in the ventral tegmental area (VTA), elucidating the differences in the VTA neural network across psychiatric disorders would facilitate a greater understanding of the pathophysiological mechanisms underlying these disorders. However, no study has compared VTA-seed-based functional connectivity across psychiatric disorders. Therefore, we conducted a resting-state functional magnetic resonance imaging (rs-fMRI) study to perform a seed-based fMRI analysis, using the VTA as a seed., Methods: We included participants with major depressive disorder (MDD; n = 45), schizophrenia (n = 32), and bipolar disorder (BPD; n = 30), along with healthy control participants (n = 46) who were matched for age, gender, and handedness., Results: The results showed that patients with MDD and BPD had altered VTA-related connectivity in the superior frontal gyrus, frontal pole regions, hippocampus, cerebellum, and posterior cingulate cortex. Some of these differences in connectivity were also found between affective disorders and schizophrenia; however, there were no differences between the schizophrenia and control groups. Connectivity between the VTA and the hippocampus was correlated with positive symptoms in the schizophrenia group. The connectivity was not associated with medication dose, and the results remained significant after controlling for dose., Conclusions: The results suggest that altered brain functional connectivity related to VTA networks could be associated with the distinctive pathophysiologies of psychiatric disorders, especially affective disorders., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Parent-child personality transmission can occur via biological gene-driven processes as well as through environmental factors such as shared environment and parenting style. We recently revealed a negative association between prosociality, a highly valued personality attribute in human society, and anterior cingulate cortex (ACC) γ-aminobutyric acid (GABA) levels in children at the age of 10 years. We thus hypothesized that prosociality would be intergenerationally transmitted, and that transmission would be underwritten by neurometabolic heritability. Here, we collected prosociality data from children aged 10 years and their parents in a large-scale population-based birth cohort study. We also measured ACC GABA+ and glutamate plus glutamine (Glx) levels in a follow-up assessment with a subsample of the participants (aged 11 years) using magnetic resonance spectroscopy. We analyzed the associations among children's and parents' prosociality and GABA+/Glx ratios. We also examined the effect of socioeconomic status (SES) and verbalized parental affection (VPA) on these associations. We found a significant positive parent-child association for prosociality (N ​= ​3026; children's mean age 10.2 years) and GABA+/Glx ratio (N ​= ​99; children's mean age 11.4 years). There was a significant negative association between GABA+/Glx ratio and prosociality in both children (N ​= ​208) and parents (N ​= ​128). Our model accounting for the effects of neurometabolic heritability on prosociality transmission fitted well. Moreover, in this model, a significant positive effect of VPA but not SES on children's prosociality was observed independently of the effect of neurometabolic transmission, while SES but not VPA was significantly associated with parental prosociality. Our results provide novel insights into the neurometabolic substrates of parent-child transmission of social behavior., Competing Interests: Declaration of competing interest All authors declare no conflict of interests., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Schizophrenia patients exhibit cognitive deficits across multiple domains, including verbal memory, working memory, and executive function, which substantially contribute to psychosocial disability. Gamma oscillations are associated with a wide range of cognitive operations, and are important for cortico-cortical transmission and the integration of information across neural networks. While previous reports have shown that schizophrenia patients have selective impairments in the ability to support gamma oscillations in response to 40-Hz auditory stimulation, it is unclear if patients show abnormalities in gamma power at rest, or whether resting-state activity in other frequency bands is associated with cognitive functioning in schizophrenia patients., Methods: Resting-state electroencephalogram (EEG) was assessed over 3 min in 145 healthy comparison subjects and 157 schizophrenia patients. Single-word reading ability was measured via the reading subtest of the Wide Range Achievement Test-3 (WRAT). Auditory attention and working memory were evaluated using Letter-Number Span and Letter-Number Sequencing. Executive function was assessed via perseverative responses on the Wisconsin Card Sorting Test (WCST). Verbal learning performance was measured using the California Verbal Learning Test second edition (CVLT-II)., Results: Schizophrenia patients showed normal levels of delta-band power but abnormally elevated EEG power in theta, alpha, beta, and gamma bands. An exploratory correlation analysis showed a significant negative correlation of gamma-band power and verbal learning performance in schizophrenia patients., Conclusions: Patients with schizophrenia have abnormal resting-state EEG power across multiple frequency bands; gamma-band abnormalities were selectively and negatively associated with impairments in verbal learning. Resting-state gamma-band EEG power may be useful for understanding the pathophysiology of cognitive dysfunction and developing novel therapeutics in schizophrenia patients., (Copyright © 2020 Tanaka-Koshiyama, Koshiyama, Miyakoshi, Joshi, Molina, Sprock, Braff and Light.)

Mismatch negativity (MMN) is a negative deflection of the auditory event-related potential (ERP) elicited by an abrupt change in a sound presented repeatedly. In patients with schizophrenia, MMN is consistently reduced, which makes it a promising biomarker. A non-human primate (NHP) model of MMN based on scalp electroencephalogram (EEG) recordings can provide a useful translational tool, given the high structural homology of the prefrontal and auditory cortices between NHPs, such as macaques, and humans. However, in previous MMN studies, the NHP models used did not allow for comparison with humans because of differences in task settings. Moreover, duration-deviant MMN (dMMN), whose reduction is larger than that in the frequency-deviant MMN (fMMN) in patients with schizophrenia, has never been demonstrated in NHP models. In this study, we determined whether dMMN can be observed in macaque scalp EEG recordings. EEGs were recorded from frontal electrodes (Fz) in two Japanese macaques. Consistent with clinical settings, auditory stimuli consisted of two pure tones, a standard and a deviant tone, in an oddball paradigm. The deviant and standard tones differed in duration (50 and 100 ms for the standard and deviant tones, respectively). A robust dMMN with a latency of around 200 ms, comparable to that in humans, was observed in both monkeys. A comparison with fMMN showed that the dMMN latency was the longer of the two. By bridging the gap between basic and clinical research, our results will contribute to the development of innovative therapeutic strategies for schizophrenia., (Copyright © 2020 Tada, Suda, Kirihara, Koshiyama, Fujioka, Usui, Araki, Kasai and Uka.)

Background: In the early intervention in psychosis, ultra-high risk (UHR) criteria have been used to identify individuals who are prone to develop psychosis. Although the transition rate to psychosis in individuals at UHR is 10% to 30% within several years, some individuals at UHR present with poor prognoses even without transition occurring. Therefore, it is important to identify biomarkers for predicting the prognosis of individuals at UHR, regardless of transition. We investigated whether mismatch negativity (MMN) in response to both duration deviant stimuli (dMMN) and frequency deviant stimuli (fMMN) could predict prognosis, including remission and neurocognitive function in individuals at UHR., Materials and Methods: Individuals at UHR (n = 24) and healthy controls (HC; n = 18) participated in this study. In an auditory oddball paradigm, both dMMN and fMMN were measured at baseline. Remission and neurocognitive function after > 180 days were examined in the UHR group. Remission from UHR was defined as functional and symptomatic improvement using the Global Assessment of Functioning (GAF) score and Scale of Prodromal Symptoms (SOPS) positive subscales. Neurocognitive function was measured using the Brief Assessment of Cognition in Schizophrenia (BACS). We examined differences in MMN amplitude at baseline between those who achieved remission (remitters) and those who did not (non-remitters). Multiple regression analyses were performed to identify predictors for functioning, positive symptoms, and neurocognitive function., Results: Compared with the HC group, the UHR group had a significantly attenuated dMMN amplitude ( p = 0.003). In the UHR group, GAF scores significantly improved during the follow-up period (mean value 47.1 to 55.5, p = 0.004). The dMMN amplitude at baseline was significantly larger in the remitter (n = 6) than in the non-remitter group (n = 18) ( p = 0.039). The total SOPS positive subscale scores and fMMN amplitude at baseline could predict BACS attention subscore at the follow-up point (SOPS positive subscales, p = 0.030; fMMN, p = 0.041)., Conclusion: Our findings indicate that dMMN and fMMN predicted remission and neurocognitive function, respectively, in individuals at UHR, which suggests that there are both promising biomarker candidates for predicting prognosis in individuals at UHR., (Copyright © 2020 Fujioka, Kirihara, Koshiyama, Tada, Nagai, Usui, Morita, Kawakami, Morita, Satomura, Koike, Suga, Araki and Kasai.)

The auditory mismatch negativity (MMN) is a translatable electroencephalographic biomarker automatically evoked in response to unattended sounds that is robustly associated with cognitive and psychosocial disability in patients with schizophrenia. Although recent animal studies have tried to clarify the neural substrates of the MMN, the nature of schizophrenia-related deficits is unknown. In this study, we applied a novel paradigm developed from translational animal model studies to carefully deconstruct the constituent neurophysiological processes underlying MMN generation. Patients with schizophrenia (N = 25) and healthy comparison subjects (HCS; N = 27) underwent MMN testing using both a conventional auditory oddball paradigm and a "many-standards paradigm" that was specifically developed to deconstruct the subcomponent adaptation and deviance detection processes that are presumed to underlie the MMN. Using a conventional oddball paradigm, patients with schizophrenia exhibited large effect size deficits of both duration and frequency MMN, consistent with many previous studies. Furthermore, patients with schizophrenia showed selective impairments in deviance detection but no impairment in adaptation to repeated tones. These findings support the use of the many-standards paradigm for deconstructing the constituent processes underlying the MMN, with implications for the use of these translational measures to accelerate the development of new treatments that target perceptual and cognitive impairments in schizophrenia and related disorders., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

Mismatch negativity (MMN) is a widely used biological marker for schizophrenia research. Previous studies reported that MMN amplitude was reduced in schizophrenia and that reduced MMN amplitude was associated with cognitive impairments and poor functional outcome in schizophrenia. However, the neurobiological mechanisms underlying the reduced MMN amplitude remain unclear. Recent studies suggest that reduced MMN amplitude may reflect altered predictive coding in schizophrenia. In this paper, we reviewed MMN studies that used new paradigms and computational modeling to investigate altered predictive coding in schizophrenia. Studies using the roving oddball paradigm and modified oddball paradigm revealed that the effects of conditional probability were impaired in schizophrenia. Studies using omission paradigms and many-standards paradigms revealed that prediction error, but not adaptation, was impaired in schizophrenia. A study using a local-global paradigm revealed that hierarchical structures were impaired at both local and global levels in schizophrenia. Furthermore, studies using dynamic causal modeling revealed that neural networks with hierarchical structures were impaired in schizophrenia. These findings indicate that altered predictive coding underlies the reduced MMN amplitude in schizophrenia. However, there are several unsolved questions about optimal procedures, association among paradigms, and heterogeneity of schizophrenia. Future studies using several paradigms and computational modeling may solve these questions, and may lead to clarifying the pathophysiology of schizophrenia and to the development of individualized treatments for schizophrenia., (Copyright © 2020 Kirihara, Tada, Koshiyama, Fujioka, Usui, Araki and Kasai.)

Altered gamma oscillations have attracted considerable attention as an index of the excitation/inhibition (E/I) imbalance in schizophrenia and other neuropsychiatric disorders. The auditory steady-state response (ASSR) has been the most robust probe of abnormal gamma oscillatory dynamics in schizophrenia. Here, we review recent ASSR studies in patients with schizophrenia and other neuropsychiatric disorders. Preclinical ASSR research, which has contributed to the elucidation of the underlying pathophysiology of these diseases, is also discussed. The developmental trajectory of the ASSR has been explored and may show signs of the maturation and disruption of E/I balance in adolescence. Animal model studies have shown that synaptic interactions between parvalbumin-positive GABAergic interneurons and pyramidal neurons contribute to the regulation of E/I balance, which is related to the generation of gamma oscillation. Therefore, ASSR alteration may be a significant electrophysiological finding related to the E/I imbalance in neuropsychiatric disorders, which is a cross-disease feature and may reflect clinical staging. Future studies regarding ASSR generation, especially in nonhuman primate models, will advance our understanding of the brain circuit and the molecular mechanisms underlying neuropsychiatric disorders.

Early-maturing girls are relatively likely to experience compromised psychobehavioral outcomes. Some studies have explored the association between puberty and brain morphology in adolescents, while the results were non-specific for females or the method was a region-of-interest analysis. To our knowledge, no large-scale study has comprehensively explored the effects of pubertal timing on whole-brain volumetric development or the neuroanatomical substrates of the association in girls between pubertal timing and psychobehavioral outcomes. We collected structural magnetic resonance imaging (MRI) data of a subsample (N ​= ​203, mean age 11.6 years) from a large-scale population-based birth cohort. Tanner stage, a scale of physical maturation in adolescents, was rated almost simultaneously with MRI scan. The Strengths and Difficulties Questionnaire total difficulties (SDQ-TD) scores were rated by primary parents some duration after MRI scan (mean age 12.1 years). In each sex group, we examined brain regions associated with Tanner stage using whole-brain analysis controlling for chronological age, followed by an exploration of brain regions also associated with the SDQ-TD scores. We also performed mediation analyses. In girls, Tanner stage was significantly negatively correlated with gray matter volumes (GMVs) in the anterior/middle cingulate cortex (ACC/MCC), of which the subgenual ACC (sgACC) showed a negative correlation between GMVs and SDQ-TD scores. Smaller GMVs in the sgACC mediated the association between higher Tanner stages and higher SDQ-TD scores. We found no significant results in boys. Our results from a minimally biased, large-scale sample provide new insights into neuroanatomical correlates of the effect of pubertal timing on developmental psychological difficulties emerging in adolescence., Competing Interests: Declaration of competing interest All authors declare no conflict of interests., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Identifying both the commonalities and differences in brain structures among psychiatric disorders is important for understanding the pathophysiology. Recently, the ENIGMA-Schizophrenia DTI Working Group performed a large-scale meta-analysis and reported widespread white matter microstructural alterations in schizophrenia; however, no similar cross-disorder study has been carried out to date. Here, we conducted mega-analyses comparing white matter microstructural differences between healthy comparison subjects (HCS; N = 1506) and patients with schizophrenia (N = 696), bipolar disorder (N = 211), autism spectrum disorder (N = 126), or major depressive disorder (N = 398; total N = 2937 from 12 sites). In comparison with HCS, we found that schizophrenia, bipolar disorder, and autism spectrum disorder share similar white matter microstructural differences in the body of the corpus callosum; schizophrenia and bipolar disorder featured comparable changes in the limbic system, such as the fornix and cingulum. By comparison, alterations in tracts connecting neocortical areas, such as the uncinate fasciculus, were observed only in schizophrenia. No significant difference was found in major depressive disorder. In a direct comparison between schizophrenia and bipolar disorder, there were no significant differences. Significant differences between schizophrenia/bipolar disorder and major depressive disorder were found in the limbic system, which were similar to the differences in schizophrenia and bipolar disorder relative to HCS. While schizophrenia and bipolar disorder may have similar pathological characteristics, the biological characteristics of major depressive disorder may be close to those of HCS. Our findings provide insights into nosology and encourage further investigations of shared and unique pathophysiology of psychiatric disorders.

Background: Quality of life is severely impaired in patients with depressive disorders. Previous studies have focused on biomarkers predicting depressive symptomatology; however, studies investigating biomarkers predicting quality of life outcomes are limited. Improving quality of life is important because it is related not only to mental health but also to physical health. We need to develop a biomarker related to quality of life as a therapeutic target for patients with depressive disorders. Resting-state electroencephalography (EEG) is easy to record in clinical settings. The index of bandwidth spectral power predicts treatment response in depressive disorders and thus may be a candidate biomarker. However, no longitudinal studies have investigated whether EEG-recorded power could predict quality of life outcomes in patients with depressive disorders., Methods: The resting-state EEG-recorded bandwidth spectral power at baseline and the World Health Organization Quality of Life (QOL)-26 scores at 3-year follow-up were measured in 44 patients with depressive disorders., Results: The high beta band power (20-30 Hz) at baseline significantly predicted QOL at the 3-year follow-up after considering depressive symptoms and medication effects in a longitudinal investigation in patients with depressive disorders (β = 0.38, p = 0.01)., Limitations: We did not have healthy subjects as a comparison group in this study., Conclusions: Our findings suggest that resting-state beta activity has the potential to be a useful biomarker for predicting future quality of life outcomes in patients with depressive disorders., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Aim: Previous studies have reported different brain morphologies in different cognitive subgroups of patients with schizophrenia. We aimed to examine the brain structures and functional connectivity in these cognitive subgroups of schizophrenia., Methods: We compared brain structures among healthy controls and cognitively deteriorated and preserved subgroups of patients with schizophrenia according to the decline in IQ. Connectivity analyses between subcortical regions and other brain areas were performed using resting-state functional magnetic resonance imaging among the groups., Results: Whole brain and total cortical gray matter, right fusiform gyrus, left pars orbitalis gyrus, right pars triangularis, left superior temporal gyrus and left insula volumes, and bilateral cortical thickness were decreased in the deteriorated group compared to the control and preserved groups. Both schizophrenia subgroups had increased left lateral ventricle, right putamen and left pallidum, and decreased bilateral hippocampus, left precentral gyrus, right rostral middle frontal gyrus, and bilateral superior frontal gyrus volumes compared with controls. Hyperconnectivity between the thalamus and a broad range of brain regions was observed in the deteriorated group compared to connectivity in the control group, and this hyperconnectivity was less evident in the preserved group. We also found hyperconnectivity between the accumbens and the superior and middle frontal gyri in the preserved group compared with connectivity in the deteriorated group., Conclusion: These findings provide evidence of prominent structural and functional brain abnormalities in deteriorated patients with schizophrenia, suggesting that cognitive subgroups in schizophrenia might be useful biotypes to elucidate brain pathophysiology for new diagnostic and treatment strategies., (© 2019 The Authors. Psychiatry and Clinical Neurosciences published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Psychiatry and Neurology.)

Mismatch negativity (MMN) reduction is one of the most robust findings among several neurophysiological and neurocognitive measures in patients with schizophrenia. MMN is a promising biomarker for schizophrenia because of the following properties: 1) its relationship with early psychosis, including clinical high-risk (CHR); 2) its relationship with the functional abilities of patients; and 3) its translatability into basic research using animal models. Specifically, the utility of the passive auditory oddball paradigm that does not require subjects to make behavioral responses enables identical physiological activities to be obtained from both experimental animals and patients. This advantage has contributed to clarifying the generating mechanism of MMN in various animal studies. We reviewed clinical reports focused on early psychosis; specifically differential effects of deviance type and relationships to clinical and functional outcome. For the utility of MMN as a tool for translational research, we next reviewed recent MMN studies in rodents and nonhuman primates (NHP) as well as studies using intracranial recordings in humans, a rare opportunity to detect neural signals in vivo in humans. Neural computations of MMN, such as adaptation, deviance detection, and predictive coding, have been recent topics for understanding MMN generating mechanisms. Finally, several significant research questions were provided for future directions. MMN research could contribute to innovative, novel, therapeutic strategies in the future by becoming a bridge between basic and clinical research., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)