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Background: Over the past several decades, more research focuses have been made on the inflammation/immune hypothesis of schizophrenia. Building upon synaptic plasticity hypothesis, inflammation may contribute the underlying pathophysiology of schizophrenia. Yet, pinpointing the specific inflammatory agents responsible for schizophrenia remains a complex challenge, mainly due to medication and metabolic status. Multiple lines of evidence point to a wide-spread genetic association across genome underlying the phenotypic variations of schizophrenia., Method: We collected the latest genome-wide association analysis (GWAS) summary data of schizophrenia, cytokines, and longitudinal change of brain. We utilized the omnigenic model which takes into account all genomic SNPs included in the GWAS of trait, instead of traditional Mendelian randomization (MR) methods. We conducted two round MR to investigate the inflammatory triggers of schizophrenia and the resulting longitudinal changes in the brain., Results: We identified seven inflammation markers linked to schizophrenia onset, which all passed the Bonferroni correction for multiple comparisons (bNGF, GROA(CXCL1), IL-8, M-CSF, MCP-3 (CCL7), TNF- β , CRP). Moreover, CRP were found to significantly influence the linear rate of brain morphology changes, predominantly in the white matter of the cerebrum and cerebellum., Conclusion: With an omnigenic approach, our study sheds light on the immune pathology of schizophrenia. Although these findings need confirmation from future studies employing different methodologies, our work provides substantial evidence that pervasive, low-level neuroinflammation may play a pivotal role in schizophrenia, potentially leading to notable longitudinal changes in brain morphology.

Across the major psychiatric disorders (MPDs), a shared disruption in brain physiology is suspected. Here we investigate the neural variability at rest, a well-established behavior-relevant marker of brain function, and probe its basis in gene expression and neurotransmitter receptor profiles across the MPDs. We recruited 219 healthy controls and 279 patients with schizophrenia, major depressive disorder, or bipolar disorders (manic or depressive state). The standard deviation of blood oxygenation level-dependent signal (SD BOLD ) obtained from resting-state fMRI was used to characterize neural variability. Transdiagnostic disruptions in SD BOLD patterns and their relationships with clinical symptoms and cognitive functions were tested by partial least-squares correlation. Moving beyond the clinical sample, spatial correlations between the observed patterns of SD BOLD disruption and postmortem gene expressions, Neurosynth meta-analytic cognitive functions, and neurotransmitter receptor profiles were estimated. Two transdiagnostic patterns of disrupted SD BOLD were discovered. Pattern 1 is exhibited in all diagnostic groups and is most pronounced in schizophrenia, characterized by higher SD BOLD in the language/auditory networks but lower SD BOLD in the default mode/sensorimotor networks. In comparison, pattern 2 is only exhibited in unipolar and bipolar depression, characterized by higher SD BOLD in the default mode/salience networks but lower SD BOLD in the sensorimotor network. The expression of pattern 1 related to the severity of clinical symptoms and cognitive deficits across MPDs. The two disrupted patterns had distinct spatial correlations with gene expressions (e.g., neuronal projections/cellular processes), meta-analytic cognitive functions (e.g., language/memory), and neurotransmitter receptor expression profiles (e.g., D2/serotonin/opioid receptors). In conclusion, neural variability is a potential transdiagnostic biomarker of MPDs with a substantial amount of its spatial distribution explained by gene expressions and neurotransmitter receptor profiles. The pathophysiology of MPDs can be traced through the measures of neural variability at rest, with varying clinical-cognitive profiles arising from differential spatial patterns of aberrant variability., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Human neuropsychiatric disorders are associated with genetic and environmental factors affecting the brain, which has been subjected to strong evolutionary pressures resulting in an enlarged cerebral cortex and improved cognitive performance. Thus, genes involved in human brain evolution may also play a role in neuropsychiatric disorders. We test whether genes associated with 7 neuropsychiatric phenotypes are enriched in genomic regions that have experienced rapid changes in human evolution (HARs) and importantly, whether HAR status interacts with developmental brain expression to predict associated genes. We used the most recent publicly available GWAS and gene expression data to test for enrichment of HARs, brain expression, and their interaction. These revealed significant interactions between HAR status and whole-brain expression across developmental stages, indicating that the relationship between brain expression and association with schizophrenia and intelligence is stronger among HAR than non-HAR genes. Follow-up regional analyses indicated that predicted HAR-expression interaction effects may vary substantially across regions and developmental stages. Although depression indicated significant enrichment of HAR genes, little support was found for HAR enrichment among bipolar, autism, ADHD, or Alzheimer's associated genes. Our results indicate that intelligence, schizophrenia, and depression-associated genes are enriched for those involved in the evolution of the human brain. These findings highlight promising candidates for follow-up study and considerations for novel drug development, but also caution careful assessment of the translational ability of animal models for studying neuropsychiatric traits in the context of HARs, and the importance of using humanized animal models or human-derived tissues when researching these traits., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Schizophrenia has been characterized as a neurodevelopmental disorder of brain disconnectivity. However, whether disrupted integrity of white matter tracts in schizophrenia can potentially serve as individual discriminative biomarkers remains unclear., Methods: A random forest algorithm was applied to tractography-based diffusion properties obtained from a cohort of 65 patients with first-episode schizophrenia (FES) and 60 healthy individuals to investigate the machine-learning discriminative power of white matter disconnectivity. Recursive feature elimination was used to select the ultimate white matter features in the classification. Relationships between algorithm-predicted probabilities and clinical characteristics were also examined in the FES group., Results: The classifier was trained by 80% of the sample. Patients were distinguished from healthy individuals with an overall accuracy of 71.0% (95% confident interval: 61.1%, 79.6%), a sensitivity of 67.3%, a specificity of 75.0%, and the area under receiver operating characteristic curve (AUC) was 79.3% (χ2 p < 0.001). In validation using the held-up 20% of the sample, patients were distinguished from healthy individuals with an overall accuracy of 76.0% (95% confident interval: 54.9%, 90.6%), a sensitivity of 76.9%, a specificity of 75.0%, and an AUC of 73.1% (χ2 p = 0.012). Diffusion properties of inter-hemispheric fibres, the cerebello-thalamo-cortical circuits and the long association fibres were identified to be the most discriminative in the classification. Higher predicted probability scores were found in younger patients., Conclusions: Our findings suggest that the widespread connectivity disruption observed in FES patients, especially in younger patients, might be considered potential individual discriminating biomarkers., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Testis specific protein, Y-encoded-like 2 (TSPYL2) regulates the expression of genes encoding glutamate receptors. Glutamate pathology is implicated in neurodevelopmental conditions such as autism spectrum disorder, attention deficit hyperactivity disorder (ADHD) and schizophrenia. In line with this, a microduplication incorporating the TSPYL2 locus has been reported in people with ADHD. However, the role of Tspyl2 remains unclear. Therefore here we used a Tspyl2 loss-of-function mouse model to directly examine how this gene impacts upon behavior and brain anatomy. We hypothesized that Tspyl2 knockout (KO) would precipitate a phenotype relevant to neurodevelopmental conditions. In line with this prediction, we found that Tspyl2 KO mice were marginally more active, had significantly impaired prepulse inhibition, and were significantly more 'sensitive' to the dopamine agonist amphetamine. In addition, the lateral ventricles were significantly smaller in KO mice. These findings suggest that disrupting Tspyl2 gene expression leads to behavioral and brain morphological alterations that mirror a number of neurodevelopmental psychiatric traits.

Reduced Gray matter (GM) volume is a core feature of schizophrenia. Mapping genes that is associated with the heritable disease-related phenotypes may be conducive to elucidate the pathogenesis of schizophrenia. This study aims to identify the common genetic variants that underlie the deficits of GM volume in schizophrenia. High-resolution T1 images and whole genome genotyping data were obtained from 74 first-episode treatment-naïve patients with schizophrenia and 51 healthy controls in the Mental Health Centre of the West China Hospital, Sichuan University. All participants were scanned using a 3T MR imaging system and were genotyped using the HumanHap660 Bead Array. Reduced GM volumes in three brain areas including right hOC3v in the collateral sulcus of visual cortex (hOC3vR), left cerebellar vermis lobule 10 (vermisL10) and right cerebellar vermis lobule 10 (vermisR10) were found in patients with schizophrenia [corrected].There was a group by genotype interaction when genotypes from genome-wide scan were subsequently considered in the case-control analyses. SNPs from three genes or chromosomal regions (TBXAS1, PIK3C2G and HS3ST5) were identified to predict the changes of GM volume in hOC3vL, vermisL10 and vermisR10. These results also highlighted the usefulness of endophenotype in exploring the pathogenesis of neuropsychiatric diseases such as schizophrenia although further independent replication studies are needed in the future.

Background: Cerebral morphological abnormalities in schizophrenia may be modulated by treatment, chronicity, and duration of illness. Comparing brain imaging studies of individuals with first-episode schizophrenia and neuroleptic naive (NN-FES) with that of their neuroleptic-treated counterparts (NT-FES) can help to dissect out the effect of these potential confounders., Methods: We used the anatomical likelihood estimation method to compare voxel-based morphometric studies of NN-FES (n = 162 patients) and NT-FES (n = 336 patients) studies. The analysis included a sample size weighting step based on the Liptak-Stouffer method to reflect the greater power of larger studies., Results: Patient samples were matched for age, gender, and duration of illness. An extensive network of gray matter deficits in frontal, temporal, insular, striatal, posterior cingulate, and cerebellar regions was detected in the NN-FES samples as compared with healthy controls. Major deficits were detected in the frontal, superior temporal, insular, and parahippocampal regions for the NT-FES group compared with the NN-FES group. In addition, the NT-FES group showed minor deficits in the caudate, cingulate, and inferior temporal regions compared with the NN-FES group. There were no regions with gray matter volumetric excess in the NT-FES group., Conclusion: Frontal, striato-limbic, and temporal morphological abnormalities are present in the early stage of schizophrenia and are unrelated to the effects of neuroleptic treatment, chronicity, and duration of illness. There may be dynamic effects of treatment on striato-limbic and temporal, but not frontal, regional gray matter volumes of the brain.

Background: MPAs (minor physical anomalies) frequently occur in neurodevelopmental disorders because both face and brain are derived from neuroectoderm in the first trimester. Conventionally, MPAs are measured by evaluation of external appearance. Using MRI can help overcome inherent observer bias, facilitate multi-centre data acquisition, and explore how MPAs relate to brain dysmorphology in the same individual. Optical MPAs exhibit a tightly synchronized trajectory through fetal, postnatal and adult life. As head size enlarges with age, inter-orbital distance increases, and is mostly completed before age 3 years. We hypothesized that optical MPAs might afford a retrospective 'window' to early neurodevelopment; specifically, inter-orbital distance increase may represent a biomarker for early brain dysmaturation in autism., Methods: We recruited 91 children aged 7-16; 36 with an autism spectrum disorder and 55 age- and gender-matched typically developing controls. All children had normal IQ. Inter-orbital distance was measured on T1-weighted MRI scans. This value was entered into a voxel-by-voxel linear regression analysis with grey matter segmented from a bimodal MRI data-set. Age and total brain tissue volume were entered as covariates., Results: Intra-class coefficient for measurement of the inter-orbital distance was 0.95. Inter-orbital distance was significantly increased in the autism group (p = 0.03, 2-tailed). The autism group showed a significant relationship between inter-orbital distance grey matter volume of bilateral amygdalae extending to the unci and inferior temporal poles., Conclusions: Greater inter-orbital distance in the autism group compared with healthy controls is consistent with infant head size expansion in autism. Inter-orbital distance positively correlated with volume of medial temporal lobe structures, suggesting a link to "social brain" dysmorphology in the autism group. We suggest these data support the role of optical MPAs as a "fossil record" of early aberrant neurodevelopment, and potential biomarker for brain dysmaturation in autism.

Background: Anti-psychotic treatment appears to be associated with striatal volume increase, but how early this change occurs is still unknown., Methods: A single prospective cohort of 20 anti-psychotic-naïve patients, newly diagnosed with schizophrenia, underwent magnetic resonance imaging brain scan at baseline. This was repeated following up to 8 weeks of anti-psychotic treatment. Ten patients had repeat scan within only 3 weeks. The choice of anti-psychotic medication was naturalistic, i.e., clinician-led. Well-matched healthy individuals were also scanned to control for non-specific changes over a 3-week period., Results: After 3 weeks of anti-psychotic treatment, significant grey matter volume increase in the right caudate, superior and inferior frontal gyrus, precentral gyrus, and left inferior parietal lobule was noted. However, after 8 weeks of anti-psychotic treatment, volume increase in the right thalamus and bilateral cerebellum was observed. Significant grey matter reduction was detected in the left medial frontal gyrus at both 3- and 8-week intervals., Conclusions: Early increase in striatal volume change occurs as early as 3 weeks after anti-psychotic treatment, whilst thalamic volume increase is apparent later, by 8 weeks of treatment. We speculate that drug-mediated neuroplasticity may provide a biomarker for clinical recovery.

Objectives: Maternal infection during pregnancy increases risk of severe neuropsychiatric disorders, including schizophrenia and autism, in the offspring. The most consistent brain structural abnormality in patients with schizophrenia is enlarged lateral ventricles. However, it is unknown whether the aetiology of ventriculomegaly in schizophrenia involves prenatal infectious processes. The present experiments tested the hypothesis that there is a causal relationship between prenatal immune challenge and emergence of ventricular abnormalities relevant to schizophrenia in adulthood., Method: We used an established mouse model of maternal immune activation (MIA) by the viral mimic PolyI:C administered in early (day 9) or late (day 17) gestation. Automated voxel-based morphometry mapped cerebrospinal fluid across the whole brain of adult offspring and the results were validated by manual region-of-interest tracing of the lateral ventricles. Parallel behavioral testing determined the existence of schizophrenia-related sensorimotor gating abnormalities., Results: PolyI:C-induced immune activation, in early but not late gestation, caused marked enlargement of lateral ventricles in adulthood, without affecting total white and grey matter volumes. This early exposure disrupted sensorimotor gating, in the form of prepulse inhibition. Identical immune challenge in late gestation resulted in significant expansion of 4(th) ventricle volume but did not disrupt sensorimotor gating., Conclusions: Our results provide the first experimental evidence that prenatal immune activation is an environmental risk factor for adult ventricular enlargement relevant to schizophrenia. The data indicate immune-associated environmental insults targeting early foetal development may have more extensive neurodevelopmental impact than identical insults in late prenatal life.

Background: Individuals with an "at-risk mental state" (or "prodromal" symptoms) have a 20-40% chance of developing psychosis; however it is difficult to predict which of them will become ill on the basis of their clinical symptoms alone. We examined whether neurophysiological markers could help to identify those who are particularly vulnerable., Method: 35 cases meeting PACE criteria for the at-risk mental state (ARMS) and 57 controls performed an auditory oddball task whilst their electroencephalogram was recorded. The latency and amplitude of the P300 and N100 waves were compared between groups using linear regression., Results: The P300 amplitude was significantly reduced in the ARMS group [8.6+/-6.4 microvolt] compared to controls [12.7+/-5.8 microvolt] (p<0.01). There were no group differences in P300 latency or in the amplitude and latency of the N100. Of the at-risk subjects that were followed up, seven (21%) developed psychosis., Conclusion: Reduction in the amplitude of the P300 is associated with an increased vulnerability to psychosis. Neurophysiological and other biological markers may be of use to predict clinical outcomes in populations at high risk.

Context: The use of endophenotypes, biological traits that increase the liability to a disorder, represents one strategy to facilitate the detection of susceptibility genes for complex behavioral disorders such as schizophrenia. Establishing that a candidate trait is both heritable and linked genetically to schizophrenia is integral to its validity as an endophenotypic marker. Neurocognitive deficits are among the most promising indicators of increased risk for schizophrenia; however, it is not clear to what extent these deficits are genetically linked to the disorder., Objectives: To quantify the genetic and environmental contributions to the variability of selected neurocognitive measures and to estimate the genetic relationship between these and schizophrenia., Design: Genetic model fitting to monozygotic and dizygotic twin data., Setting: United Kingdom psychiatric research institute., Participants: Two hundred sixty-seven monozygotic and dizygotic twins concordant and discordant for schizophrenia, and healthy monozygotic and dizygotic control twin pairs., Main Outcome Measures: The heritabilities of intelligence, working memory, processing speed, perceptual organization, and verbal comprehension were estimated, and the genetic relationship between each of these and schizophrenia was quantified., Results: Genetic influences contributed substantially to all of the cognitive domains, but intelligence and working memory were the most heritable. A significant correlation was found between intelligence and schizophrenia (r = -0.61; 95% confidence interval, -0.71 to -0.48), with shared genetic variance accounting for 92% of the covariance between the two. Genetic influences also explained most of the covariance between working memory and schizophrenia. Significant but lesser portions of covariance between the other cognitive domains and schizophrenia were also found to be genetically shared. Environmental effects, although separately linked to neurocognition and schizophrenia, did not generally contribute to their covariance., Conclusion: Genomewide searches using factorial designs stratifying for levels of intelligence and working memory will assist in the search for finding quantitative trait loci for schizophrenia.

The normal pattern of cerebral asymmetry may be altered in neurodevelopmental disorders such as autism and schizophrenia. Babies born very preterm have an increased risk of brain damage, and brain abnormalities which persist into adolescence. This study aimed to ascertain whether preterm birth affects the development of fronto-occipital asymmetry. Structural MRI (magnetic resonance imaging) scans from 14 year old individuals born very preterm (n = 61; mean age 14 years 11 months; 29 male) and age-matched full-term controls (n = 49; mean age 14 years 11 months; 31 male) underwent morphometric analysis, using well-validated stereological methods. Measurements of right and left prefrontal, premotor, sensorimotor and occipitoparietal regional volumes were made and asymmetry indices calculated. These factors underwent a reductive factor analysis. There were no significant between-group differences in fronto-occipital asymmetry between the preterm adolescents and their full-term counterparts. It seems unlikely, therefore, that preterm birth per se deviates the development of normal fronto-occipital asymmetry. Neonatal periventricular haemorrhage with ventricular dilatation revealed by ultrasound may be associated with reversal of asymmetry in the sensorimotor area.

Objective: Schizophrenia and psychotic bipolar disorder have a number of overlapping symptoms and risk factors, but it is not yet clear if the disorders are characterized by similar deviations in brain morphometry or whether any such deviations reflect the impact of shared susceptibility genes on brain structure. The authors used region-of-interest morphometry to volumetrically assess brain structures frequently implicated in psychotic illness in families affected with schizophrenia or psychotic bipolar disorder., Method: Magnetic resonance imaging brain scans were obtained from 243 subjects, comprising 42 patients with schizophrenia or schizoaffective disorder, 57 of their unaffected first-degree relatives, 38 patients with psychotic bipolar disorder, 52 of their unaffected first-degree relatives, and 54 healthy comparison subjects. Most of the families affected with schizophrenia and all of the families affected with bipolar disorder were multiply affected with the illness. Volumetric measurements of the cerebrum, lateral ventricles, third ventricle, and hippocampus were completed with stereological methods., Results: Patients with schizophrenia had increased volume of the lateral and third ventricles and reduced hippocampal volume. None of these volumetric abnormalities was present in psychotic bipolar disorder. Unaffected relatives of patients with schizophrenia from multiply affected families had enlarged lateral ventricles but no other volumetric deviations. Unaffected relatives of patients with bipolar disorder showed preservation of ventricular and hippocampal volume., Conclusions: Schizophrenia and psychotic bipolar disorder are characterized by morphometric distinctions in ventricular and hippocampal regions. Lateral ventricular enlargement represents a potential morphometric endophenotype for schizophrenia.

Background: It is unclear whether schizophrenia and psychotic bipolar disorder are associated with similar deviations of brain morphometry., Aims: To assess volumetric abnormalities of grey and white matter throughout the entire brain in individuals with schizophrenia or with bipolar disorder compared with the same control group., Method: Brain scans were obtained by magnetic resonance imaging from 25 people with schizophrenia, 37 with bipolar disorder who had experienced psychotic symptoms and 52 healthy volunteers. Regional deviation in grey and white matter volume was assessed using computational morphometry., Results: Individuals with schizophrenia had distributed grey matter deficit predominantly involving the fronto-temporal neocortex, medial temporal lobe, insula, thalamus and cerebellum, whereas those with bipolar disorder had no significant regions of grey matter abnormality. Both groups had anatomically overlapping white matter deficits in regions normally occupied by major longitudinal and interhemispheric tracts., Conclusions: Schizophrenia and psychotic bipolar disorder are associated with distinct grey matter deficits but anatomically coincident white matter abnormalities.

Context: For more than a century, it has been uncertain whether or not the major diagnostic categories of psychosis--schizophrenia and bipolar disorder--are distinct disease entities with specific genetic causes and neuroanatomical substrates., Objective: To investigate the relationship between genetic risk and structural variation throughout the entire brain in patients and their unaffected relatives sampled from multiply affected families with schizophrenia or bipolar disorder., Design: Analysis of the association between genetic risk and variation in tissue volume on magnetic resonance images., Setting: Psychiatric research center., Participants: Subjects comprised 25 patients with schizophrenia, 36 of their unaffected first-degree relatives, 37 patients with bipolar 1 disorder who experienced psychotic symptoms during illness exacerbation, and 50 of their unaffected first-degree relatives., Main Outcome Measures: We used computational morphometric techniques to map significant associations between a continuous measure of genetic liability for each subject and variation in gray or white matter volume., Results: Genetic risk for schizophrenia was specifically associated with distributed gray matter volume deficits in the bilateral fronto-striato-thalamic and left lateral temporal regions, whereas genetic risk for bipolar disorder was specifically associated with gray matter deficits only in the right anterior cingulate gyrus and ventral striatum. A generic association between genetic risk for both disorders and white matter volume reduction in the left frontal and temporoparietal regions was consistent with left frontotemporal disconnectivity as a genetically controlled brain structural abnormality common to both psychotic disorders., Conclusions: Genetic risks for schizophrenia and bipolar disorder are associated with specific gray matter but generic white matter endophenotypes. Thus, Emil Kraepelin's pivotal distinction was neither wholly right nor wholly wrong: the 2 major psychoses show both distinctive and similar patterns of brain structural abnormality related to variable genetic risk.

Objective: To determine whether patients with schizophrenia have abnormalities in the P300 and P50 waves and to quantify the magnitude of any differences from controls., Method: We conducted a systematic search for articles published between January 1994 and August 2003 that reported P50 or P300 measures in schizophrenic patients and controls. Metaregression analyses were performed using a random effects model. The pooled standardised effect size (PSES) was calculated as the difference between the means of the two groups divided by the common standard deviation., Results: We identified 46 studies suitable for analysis of P300 measures, including 1443 patients and 1251 controls. There were 20 P50 studies including 421 patients and 401 controls. The PSES for the P300 amplitude was 0.85 (95% CI: 0.65 to 1.05; p<0.001), and for the P300 latency was -0.57 (95% CI: -0.75 to -0.38; p<0.001). The PSES of the P50 ratio was -1.56 (95% CI: -2.05 to -1.06; p<0.001). There were no significant differences between patients and controls in P50 latency. Across-study variations in filters, task difficulty, antipsychotic medication and duration of illness did not influence the PSES significantly., Conclusions: This meta-analysis confirms the existence of ERP deficits in schizophrenia. The magnitude of these deficits is similar to the most robust findings reported in neuroimaging and neuropsychology in schizophrenia.

Background: We examined monozygotic twins concordant and discordant for schizophrenia to clarify the role of genetic and environmental factors in determining brain abnormalities., Methods: Magnetic resonance imaging brain scans were obtained from 14 monozygotic twin pairs concordant and 10 monozygotic pairs discordant for schizophrenia, as well as 17 pairs of monozygotic control twins. Twenty-two discordant sibling-pairs and 56 pairs of unrelated control subjects were included to assess the extent of genetic control over these structures., Results: Within-pair similarities for whole brain volume increased as pair members were more closely related genetically (monozygotic twins > siblings > unrelated control subjects). Schizophrenic twins, whether from concordant or discordant pairs, had smaller whole brain volumes than control twins. The probands of discordant pairs showed more abnormalities in hippocampal, third and lateral ventricular volumes than concordant twins., Conclusions: Whole brain volume is under high genetic control and smaller whole brain volume is a reflection of the genetic liability to develop schizophrenia. The variation in hippocampal and ventricular volumes within discordant monozygotic pairs indicates a role for environmental factors in determining these volume abnormalities in schizophrenia. Such factors may also underlie the more extensive morphometric deviations in patients from monozygotic discordant twins than in their counterparts from concordant twins.

Background: Several studies assessing volumetric measurements of regional brain structure in bipolar disorder have been published in recent years, but their results have been inconsistent. Our aim was to complete a meta-analysis of regional morphometry in bipolar disorder as assessed using magnetic resonance imaging (MRI)., Methods: We conducted a systematic literature search of MRI studies of bipolar disorder and identified studies which reported volume measurements in a selected number of regions. Twenty-six studies comprising volumetric measurements on up to 404 independent patients with bipolar disorder were included. A meta-analysis was carried out comparing the volumes of regions in bipolar disorder to comparison subjects using a random effects model., Results: Patients with bipolar disorder had enlargement of the right lateral ventricle, but no other regional volumetric deviations which reached significance. Strong heterogeneity existed for several regions, including the third ventricle, left subgenual prefrontal cortex, bilateral amygdala and thalamus., Conclusions: Regional volume of most structures we studied is preserved in bipolar disorder as a whole, which was significantly associated only with right-sided ventricular enlargement. However the extensive heterogeneity detected indicates the need for further studies to establish if consistent regional brain volume deviation exists in bipolar disorder or in specific clinical subsets of the illness.

Loss of normal fronto-occipital cerebral asymmetry has been reported in patients with schizophrenia and also in their well relatives from multiply affected families, suggesting a relationship with susceptibility genes. We sought to confirm this relationship in a family study of patients with schizophrenia and their unaffected relatives of presumed differing genetic risk. MRI scans were carried out on 25 probands from families multiply affected with the disorder, and 36 of their unaffected relatives, 34 probands from families with no other affected members, 42 of their unaffected relatives, and 76 controls. Volumetric measurements of prefrontal, premotor, sensorimotor and occipitoparietal regions were obtained from which a measure of fronto-occipital torque was derived. There were no significant differences in measurements of fronto-occipital torque between the subject groups. Both schizophrenic probands and their relatives displayed the normal pattern of cerebral asymmetry, with larger right than left frontal regions and a larger left than right occipitoparietal region. Our findings failed to confirm an association between loss of fronto-occipital torque and genetic liability for schizophrenia and also failed to replicate the previously reported association between loss/reversal of fronto-occipital asymmetry and schizophrenia.

Background: Mismatch negativity (MMN) is a measure of cortical activity that occurs in response to a change in auditory stimuli. We investigated whether MMN is a potential marker of genetic vulnerability to schizophrenia by comparing MMN in a group of patients with schizophrenia, their unaffected relatives, and controls., Method: There are 25 schizophrenic patients, 37 of their unaffected first-degree relatives, and 20 unrelated controls that performed the MMN task. Linear regression with robust standard errors, and accounting for correlations within families, was employed to test for differences in MMN amplitude between the groups., Results: Patients had significantly smaller MMN amplitudes compared to both their unaffected relatives and controls at FZ (P<0.01) and at F3 (P=0.01), whereas relatives and controls did not differ at FZ or at F3. No differences were found between any of the groups at F4. Furthermore, we found no strong evidence that the MMN amplitude is a familial trait., Conclusions: Our results confirm that the MMN amplitude is reduced in schizophrenia. However, the MMN does not show a significant familial influence and is normal among the unaffected relatives. We conclude that while the MMN is abnormal in patients with schizophrenia, it is a weak or unreliable marker of vulnerability when applied to subclinical populations, and therefore is unlikely to be an endophenotype for the disorder.

Structural brain abnormalities are consistently reported in schizophrenic subjects but the etiology of these abnormalities remains unclear. We tested the contribution of genetic predisposition and obstetric complications to the structural brain abnormalities found in schizophrenic probands and their relatives. MRI scans were carried out on 35 schizophrenic probands from families multiply affected with the disorder, and 63 of their unaffected relatives, including 10 parents who appeared to transmit genetic risk to their children; as well as 31 schizophrenic probands from families with no other affected members, 33 of their unaffected relatives; and finally 68 controls. Volumetric measurements of whole brain, lateral ventricles, third ventricle, cerebellum, and temporal lobes were completed for each subject. The impact of obstetric complications on brain structure was assessed across the gradient of presumed genetic predisposition. Both groups of schizophrenic probands displayed enlargement of the lateral and third ventricles, and there was a gradient of ventricular enlargement amongst the unaffected relatives in proportion to their likelihood of carrying schizophrenic genes. Ventricular enlargement was largely confined to males in both probands and unaffected relatives. Obstetric complications were associated with ventricular enlargement only in the familial probands. Non-familial probands displayed reduced volume of the temporal lobes bilaterally. In families with several schizophrenic members, ventricular enlargement is a marker for genetic liability, particularly in males. Individuals inheriting the susceptibility to schizophrenia appear particularly prone to develop ventricular enlargement in response to obstetric complications., (Copyright 2002 Wiley-Liss, Inc.)

Background: Convergent evidence has suggested atypical relationships between brain structure and function in major psychiatric disorders, yet how the abnormal patterns coincide and/or differ across different disorders remains largely unknown. Here, we aim to investigate the common and/or unique dynamic structure–function coupling patterns across major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SZ). Methods: We quantified the dynamic structure–function coupling in 452 patients with psychiatric disorders (MDD/BD/SZ = 166/168/118) and 205 unaffected controls at three distinct brain network levels, such as global, meso-, and local levels. We also correlated dynamic structure–function coupling with the topological features of functional networks to examine how the structure–function relationship facilitates brain information communication over time. Results: The dynamic structure–function coupling is preserved for the three disorders at the global network level. Similar abnormalities in the rich-club organization are found in two distinct functional configuration states at the meso-level and are associated with the disease severity of MDD, BD, and SZ. At the local level, shared and unique alterations are observed in the brain regions involving the visual, cognitive control, and default mode networks. In addition, the relationships between structure–function coupling and the topological features of functional networks are altered in a manner indicative of state specificity. Conclusions: These findings suggest both transdiagnostic and illness-specific alterations in the dynamic structure–function relationship of large-scale brain networks across MDD, BD, and SZ, providing new insights and potential biomarkers into the neurodevelopmental basis underlying the behavioral and cognitive deficits observed in these disorders. [ABSTRACT FROM AUTHOR]

The results generated from large psychiatric genomic consortia show us some new vantage points to understand the pathophysiology of psychiatric disorders. We explored the potential of integrating the transcription output of the core gene underlying the commonality of psychiatric disorders with a clustering algorithm to redefine psychiatric disorders. Our results showed that an extended MHC region was associated with the common factor of schizophrenia (SCZ), bipolar disorder (BD), and major depressive disorder (MDD) at the level of genomic significance, with rs7746199 (P = 4.905e-08), a cis-eQTL to the gene ZNF391, pinpointed as a potential causal variant driving the signals in the region. Gene expression pattern of ZNF391 in the brain led to the emergence of 3 biotypes, independent of disorder. The 3 biotypes performed significantly differently in working memory and demonstrated different gray matter volumes in the right inferior frontal orbital gyrus (RIFOG), with a partial causal pathway arising from ZNF391 to RIFOG to working memory. Our study illustrates the potential of a trans-diagnostic, top-down approach in understanding the commonality of psychiatric disorders. [ABSTRACT FROM AUTHOR]

Background: Major depressive disorder (MDD) is a leading cause of disability worldwide and influenced by both environmental and genetic factors. Genetic studies of MDD have focused on common variants and have been constrained by the heterogeneity of clinical symptoms. Methods: We sequenced the exome of 77 cases and 245 controls of Han Chinese ancestry and scanned their brain. Burden tests of rare variants were performed first to explore the association between genes/pathways and MDD. Secondly, parallel Independent Component Analysis was conducted to investigate genetic underpinnings of gray matter volume (GMV) changes of MDD. Results: Two genes (CSMD1 , p = 5.32×10−6; CNTNAP5 , p = 1.32×10−6) and one pathway (Neuroactive Ligand Receptor Interactive, p = 1.29×10−5) achieved significance in burden test. In addition, we identified one pair of imaging-genetic components of significant correlation (r = 0.38, p = 9.92×10−6). The imaging component reflected decreased GMV in cases and correlated with intelligence quotient (IQ). IQ mediated the effects of GMV on MDD. The genetic component enriched in two gene sets, namely Singling by G-protein coupled receptors [false discovery rate (FDR) q = 3.23×10−4) and Alzheimer Disease Up (FDR q = 6.12×10−4). Conclusions: Both rare variants analysis and imaging–genetic analysis found evidence corresponding with the neuroinflammation and synaptic plasticity hypotheses of MDD. The mediation of IQ indicates that genetic component may act on MDD through GMV alteration and cognitive impairment. [ABSTRACT FROM AUTHOR]

Background/Aims: The Remission in Schizophrenia Working Group has defined remission as 'a low-mild symptom intensity level, maintained for a minimum of 6 months, where such symptoms do not affect an individual's behaviour' [Andreasen et al.: Am J Psychiatry 2005;162:441-449]. Since brain morphology relates to symptomatology, treatment and illness progression, MRI may assist in predicting remission. Methods: Thirty-nine patients newly diagnosed with DSM-IV schizophrenia underwent MRI brain scan prior to antipsychotic exposure. The Global Assessment of Functioning (GAF) score was entered into a voxel-based analysis to evaluate its relationship with cerebral grey matter volume from the baseline MRI. We entered age, total intracranial volume and intake GAF score as co-variates. Males and females were analysed separately because gender is a potent determinant of outcome. Results: Males had lower GAF scores than females, both at intake and at 1 year. Males comprised only 40% (12 out of 39) of the early remission group. For females only, early remission was strongly and positively correlated with bilateral lentiform and striatal volumes. For males, there was no such relationship. Conclusion: Larger striato-thalamic volume correlated with early remission in females only. These baseline MRI findings were unlikely to be confounded by antipsychotic treatment and chronicity. These brain morphological markers show gender dimorphism and may assist in the prediction of early remission in newly diagnosed schizophrenia. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Schizophrenia and mania have a number of symptoms and epidemiological characteristics in common, and both respond to dopamine blockade. Family, twin and molecular genetic studies suggest that the reason for these similarities may be that the two conditions share certain susceptibility genes. On the other hand, individuals with schizophrenia have more obvious brain structural and neuropsychological abnormalities than those with bipolar disorder; and pre-schizophrenic children are characterised by cognitive and neuromotor impairments, which are not shared by children who later develop bipolar disorder. Furthermore, the risk-increasing effect of obstetric complications has been demonstrated for schizophrenia but not for bipolar disorder. Perinatal complications such as hypoxia are known to result in smaller volume of the amygdala and hippocampus, which have been frequently reported to be reduced in schizophrenia; familial predisposition to schizophrenia is also associated with decreased volume of these structures. We suggest a model to explain the similarities and differences between the disorders and propose that, on a background of shared genetic predisposition to psychosis, schizophrenia, but not bipolar disorder, is subject to additional genes or early insults, which impair neurodevelopment, especially of the medial temporal lobe. [Copyright &y& Elsevier]