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The regional distribution of white matter (WM) abnormalities in schizophrenia remains poorly understood, and reported disease effects on the brain vary widely between studies. In an effort to identify commonalities across studies, we perform what we believe is the first ever large-scale coordinated study of WM microstructural differences in schizophrenia. Our analysis consisted of 2359 healthy controls and 1963 schizophrenia patients from 29 independent international studies; we harmonized the processing and statistical analyses of diffusion tensor imaging (DTI) data across sites and meta-analyzed effects across studies. Significant reductions in fractional anisotropy (FA) in schizophrenia patients were widespread, and detected in 20 of 25 regions of interest within a WM skeleton representing all major WM fasciculi. Effect sizes varied by region, peaking at (d=0.42) for the entire WM skeleton, driven more by peripheral areas as opposed to the core WM where regions of interest were defined. The anterior corona radiata (d=0.40) and corpus callosum (d=0.39), specifically its body (d=0.39) and genu (d=0.37), showed greatest effects. Significant decreases, to lesser degrees, were observed in almost all regions analyzed. Larger effect sizes were observed for FA than diffusivity measures; significantly higher mean and radial diffusivity was observed for schizophrenia patients compared with controls. No significant effects of age at onset of schizophrenia or medication dosage were detected. As the largest coordinated analysis of WM differences in a psychiatric disorder to date, the present study provides a robust profile of widespread WM abnormalities in schizophrenia patients worldwide. Interactive three-dimensional visualization of the results is available at www.enigma-viewer.org.

A progressive post-onset decrease in gray matter volume 1.5 years after first hospitalization in schizophrenia has been shown in superior temporal gyrus (STG). However, it is still controversial whether progressive volume reduction occurs in chronic schizophrenia in the STG and amygdala-hippocampal complex (AHC), structures found to be abnormal in chronic schizophrenia. These structures were measured at two time points in 16 chronic schizophrenia patients and 20 normal comparison subjects using manual tracing with high spatial resolution magnetic resonance imaging (MRI). Average interscan interval was 3.1 years for schizophrenia patients and 1.4 years for healthy comparison subjects. Cross-sectional comparisons showed smaller relative volumes in schizophrenia compared with controls in posterior STG and AHC. An ANCOVA with interscan interval as a covariate showed there was no statistically significant progression of volume reduction in either the STG or AHC in the schizophrenia group compared with normal subjects. In the schizophrenia group, volume change in the left anterior AHC significantly correlated with PANSS negative symptoms. These data, and separately reported first episode data from our laboratory, suggest marked progression at the initial stage of schizophrenia, but less in chronic schizophrenia. [ABSTRACT FROM AUTHOR]

Orbitofrontal Cortex (OFC) structural abnormality in schizophrenia has not been well characterized, probably due to marked anatomical variability and lack of consistent definitions. We previously reported OFC sulcogyral pattern alteration and its associations with social disturbance in schizophrenia, but OFC volume associations with psychopathology and cognition have not been investigated. We compared chronically treated schizophrenia patients with healthy control (HC) subjects, using a novel, reliable parcellation of OFC subregions and their association with cognition, especially the Iowa Gambling Task (IGT), and with schizophrenic psychopathology including thought disorder. Twenty-four patients with schizophrenia and 25 age-matched HC subjects underwent MRI. OFC Regions of Interest (ROI) were manually delineated according to anatomical boundaries: Gyrus Rectus (GR); Middle Orbital Gyrus (MiOG); and Lateral Orbital Gyrus (LOG). The OFC sulcogyral pattern was also classified. Additionally, MiOG probability maps were created and compared between groups in a voxel-wise manner. Both groups underwent cognitive evaluations using the IGT, Wisconsin Card Sorting Test, and Trail Making Test (TMT). An 11% bilaterally smaller MiOG volume was observed in schizophrenia, compared with HC (F(1,47) = 17.4, P = 0.0001). GR and LOG did not differ, although GR showed a rightward asymmetry in both groups (F(1,47) = 19.2, P < 0.0001). The smaller MiOG volume was independent of the OFC sulcogyral pattern, which differed in schizophrenia and HC (chi2 = 12.49, P = 0.002). A comparison of MiOG probability maps suggested that the anterior heteromodal region was more affected in the schizophrenia group than the posterior paralimbic region. In the schizophrenia group, a smaller left MiOG was strongly associated with worse 'positive formal thought disorder' (r = -0.638, P = 0.001), and a smaller right MiOG with a longer duration of the illness (r = -0.618, P = 0.002). While schizophrenics showed poorer performance than HC in the IGT, performance was not correlated with OFC volume. However, within the HC group, the larger the right hemisphere MiOG volume, the better the performance in the IGT (r = 0.541, P = 0.005), and the larger the left hemisphere volume, the faster the switching attention performance for the TMT, Trails B (r = -0.608, P = 0.003). The present study, applying a new anatomical parcellation method, demonstrated a subregion-specific OFC grey matter volume deficit in patients with schizophrenia, which was independent of OFC sulcogyral pattern. This volume deficit was associated with a longer duration of illness and greater formal thought disorder. In HC the finding of a quantitative association between OFC volume and IGT performance constitutes, to our knowledge, the first report of this association. [ABSTRACT FROM AUTHOR]

Objective: Magnetic resonance imaging (MRI) studies of schizophrenia reveal temporal lobe structural brain abnormalities in the superior temporal gyrus and the amygdala-hippocampal complex. However, the middle and inferior temporal gyri have received little investigation, especially in first-episode schizophrenia.Method: High-spatial-resolution MRI was used to measure gray matter volume in the inferior, middle, and superior temporal gyri in 20 patients with first-episode schizophrenia, 20 patients with first-episode affective psychosis, and 23 healthy comparison subjects.Results: Gray matter volume in the middle temporal gyrus was smaller bilaterally in patients with first-episode schizophrenia than in comparison subjects and in patients with first-episode affective psychosis. Posterior gray matter volume in the inferior temporal gyrus was smaller bilaterally in both patient groups than in comparison subjects. Among the superior, middle, and inferior temporal gyri, the left posterior superior temporal gyrus gray matter in the schizophrenia group had the smallest volume, the greatest percentage difference, and the largest effect size in comparisons with healthy comparison subjects and with affective psychosis patients.Conclusions: Smaller gray matter volumes in the left and right middle temporal gyri and left posterior superior temporal gyrus were present in schizophrenia but not in affective psychosis at first hospitalization. In contrast, smaller bilateral posterior inferior temporal gyrus gray matter volume is present in both schizophrenia and affective psychosis at first hospitalization. These findings suggest that smaller gray matter volumes in the dorsal temporal lobe (superior and middle temporal gyri) may be specific to schizophrenia, whereas smaller posterior inferior temporal gyrus gray matter volumes may be related to pathology common to both schizophrenia and affective psychosis. [ABSTRACT FROM AUTHOR]

Background: Previous voxelwise Diffusion Tensor Imaging (DTI) investigations of white matter in first-episode schizophrenia (FESZ) have been limited to the analysis of Fractional Anisotropy (FA) and mean diffusivity (MD), with their findings inconsistent in terms of the anatomical locations and extent of abnormalities. This study examines white matter abnormalities in FESZ, compared with healthy controls, using a tract-based spatial statistics (TBSS) approach applied to multiple measures of tract integrity, and correlates these findings with symptom severity.Methods: Seventeen first-episode patients with schizophrenia and seventeen age- and gender-matched healthy controls (HC) participated in this imaging study where FA, MD, and axial and radial diffusivities were compared between the two groups using TBSS.Results: First-episode patients with schizophrenia showed lower FA values in the genu and body of corpus callosum, the internal capsule, the external capsule, the fornix, the superior, inferior fronto-occipital fasciculus, the cingulum, and the uncinate fasciculus compared with HC. Increased MD and radial diffusivity were shown in virtually all white matter regions. There was no significant difference, however, observed for axial diffusivity between the two groups. Pearson correlation analysis showed that the FA values of the right inferior fronto-occipital fasciculus were positively correlated with positive symptoms, negative symptoms, and total correct items of the Wisconsin Card Sorting Test. FA values of right external capsule also showed significant positive correlation with category completed scores of the WCST.Conclusions: These data suggest extensive, possibly myelin related white matter disruptions in FESZ. [ABSTRACT FROM AUTHOR]

Schizophrenia has a heritability of 60-80% 1 , much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Objective: The cerebellum serves a wide range of functions and is suggested to be composed of discrete regions dedicated to unique functions. We recently developed a new parcellation of the dentate nuclei (DN), the major output nuclei of the cerebellum, which optimally divides the structure into 3 functional territories that contribute uniquely to default-mode, motor-salience, and visual processing networks as indexed by resting-state functional connectivity (RsFc). Here we test for the first time whether RsFc differences in the DN, precede the onset of psychosis in individuals at risk of developing schizophrenia., Methods: We used the magnetic resonance imaging (MRI) dataset from the Shanghai At Risk for Psychosis study that included subjects at high risk to develop schizophrenia (N = 144), with longitudinal follow-up to determine which subjects developed a psychotic episode within 1 year of their functional magnetic resonance imaging (fMRI) scan (converters N = 23). Analysis used the 3 functional parcels (default-mode, salience-motor, and visual territory) from the DN as seed regions of interest for whole-brain RsFc analysis., Results: RsFc analysis revealed abnormalities at baseline in high-risk individuals who developed psychosis, compared to high-risk individuals who did not develop psychosis. The nature of the observed abnormalities was found to be anatomically specific such that abnormal RsFc was localized predominantly in cerebral cortical networks that matched the 3 functional territories of the DN that were evaluated., Conclusions: We show for the first time that abnormal RsFc of the DN may precede the onset of psychosis. This new evidence highlights the role of the cerebellum as a potential target for psychosis prediction and prevention., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: To assess cortical thickness (CT) and surface area (SA) of frontal, temporal, and parietal brain regions in a large clinical high risk for psychosis (CHR) sample, and to identify cortical brain abnormalities in CHR who convert to psychosis and in the whole CHR sample, compared with the healthy controls (HC)., Methods: Magnetic resonance imaging, clinical, and cognitive data were acquired at baseline in 92 HC, 130 non-converters, and 22 converters (conversion assessed at 1-year follow-up). CT and SA at baseline were calculated for frontal, temporal, and parietal subregions. Correlations between regions showing group differences and clinical scores and age were also obtained., Results: CT but not SA was significantly reduced in CHR compared with HC. Two patterns of findings emerged: (1) In converters, CT was significantly reduced relative to non-converters and controls in the banks of superior temporal sulcus, Heschl's gyrus, and pars triangularis and (2) CT in the inferior parietal and supramarginal gyrus, and at trend level in the pars opercularis, fusiform, and middle temporal gyri was significantly reduced in all high-risk individuals compared with HC. Additionally, reduced CT correlated significantly with older age in HC and in non-converters but not in converters., Conclusions: These results show for the first time that fronto-temporo-parietal abnormalities characterized all CHR, that is, both converters and non-converters, relative to HC, while CT abnormalities in converters relative to CHR-NC and HC were found in core auditory and language processing regions., (© 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.)

Auditory P300 oddball and novel components index working memory operations and salience processing, respectively, and are regarded as biomarkers of neurocognitive changes in both chronic and first-episode schizophrenia. Much less is known about whether P300 abnormalities exist in individuals at clinical high risk for psychosis (CHR) and if they are predictors of both transition to psychosis and remission from symptoms. One hundred and four CHR and 69 healthy control individuals (HC) completed P300 oddball paradigm, and 131 CHR and 69 HC subjects completed P300 novel paradigm. All CHR subjects were followed up for one year and stratified into CHR converters (CHRC) and non-converters (CHR-NC), with CHR-NC further stratified into remitted and non-remitted subgroups. Between-group comparisons of P300 oddball and novel amplitude and latency were performed among CHRC, CHR-NC and HC, as well as among CHRC, non-remitted CHR, remitted CHR and HC. CHR converters had lower fronto-central P300 novel amplitude as well as marginally lower P300 oddball amplitude relative to HC. When CHR non-converters were stratified into remitted and non-remitted subgroups, P300 novel amplitude in remitted CHR subjects was comparable to HC, and it was higher than that in CHR subjects who converted to psychosis or who did not remit. Thus, reduced P300 novel amplitude indexing impaired salience processing marked both conversion to psychosis and remission from psychotic symptoms., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The emergence of prodromal symptoms of schizophrenia and their evolution into overt psychosis may stem from an aberrant functional reorganization of the brain during adolescence. To examine whether abnormalities in connectome organization precede psychosis onset, we performed a functional connectome analysis in a large cohort of medication-naive youth at risk for psychosis from the Shanghai At Risk for Psychosis (SHARP) study. The SHARP program is a longitudinal study of adolescents and young adults at Clinical High Risk (CHR) for psychosis, conducted at the Shanghai Mental Health Center in collaboration with neuroimaging laboratories at Harvard and MIT. Our study involved a total of 251 subjects, including 158 CHRs and 93 age-, sex-, and education-matched healthy controls. During 1-year follow-up, 23 CHRs developed psychosis. CHRs who would go on to develop psychosis were found to show abnormal modular connectome organization at baseline, while CHR non-converters did not. In all CHRs, abnormal modular connectome organization at baseline was associated with a threefold conversion rate. A region-specific analysis showed that brain regions implicated in early-course schizophrenia, including superior temporal gyrus and anterior cingulate cortex, were most abnormal in terms of modular assignment. Our results show that functional changes in brain network organization precede the onset of psychosis and may drive psychosis development in at-risk youth.

We investigated brain wiring in chronic schizophrenia and healthy controls in frontostriatal circuits using diffusion magnetic resonance imaging tractography in a novel way. We extracted diffusion streamlines in 27 chronic schizophrenia and 26 healthy controls connecting 4 frontal subregions to the striatum. We labeled the projection zone striatal surface voxels into 2 subtypes: dominant-input from a single cortical subregion, and, functionally integrative, with mixed-input from diverse cortical subregions. We showed: 1) a group difference for total striatal surface voxel number (P = .045) driven by fewer mixed-input voxels in the left (P  = .007), but not right, hemisphere; 2) a group by hemisphere interaction for the ratio quotient between voxel subtypes (P  = .04) with a left (P  = .006), but not right, hemisphere increase in schizophrenia, also reflecting fewer mixed-input voxels; and 3) fewer mixed-input voxel counts in schizophrenia (P  = .045) driven by differences in left hemisphere limbic (P  = .007) and associative (P  = .01), but not sensorimotor, striatum. These results demonstrate a less integrative pattern of frontostriatal structural connectivity in chronic schizophrenia. A diminished integrative pattern yields a less complex input pattern to the striatum from the cortex with less circuit integration at the level of the striatum. Further, as brain wiring occurs during early development, aberrant brain wiring could serve as a developmental biomarker for schizophrenia., (Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center 2020.)

The N1, P2, and P3 event-related potentials (ERPs) are impaired in first-episode schizophrenia (FESz). Reduced pitch-deviant mismatch negativity (MMN) is present in chronic schizophrenia but not FESz. We examined effect sizes of, and correlations between, N1, P2, P3, and MMN in 106 FESz and 114 matched psychiatrically well controls to determine which ERPs maximally differentiated groups, and whether late sensory/perceptual deficits (N1, P2) affected preattentive memory (MMN) and conscious attention (P3). Furthermore, we compared hallucinators and nonhallucinators within FESz. Participants completed 1 of 3 oddball tasks, silently counting target tones among standard tones. Sixty-seven FESz and 72 matched participants also completed pitch-deviant MMN testing. Measures were z -scored from task appropriate controls before merging samples. Mean z -scores for N1, P2, and P3 were significantly abnormal in FESz, while pitch-deviant MMN was not. N1 showed the largest deficit ( z = 0.53), and only N1 was smaller in hallucinators (n = 71) than nonhallucinators (n = 27). Among all participants, early sensory processing (N1, P2) correlated with later cognitive processing (P3), and P2 and P3 also correlated with automatic preattentive memory (pitch-deviant MMN). In well individuals, N1 was associated with MMN. These data are consistent with bottom-up sensory/perceptual processes affecting more cognitive processes. However, N1 and MMN were not associated in FESz, suggesting different auditory cortex physiology underlie these ERPs, which is differentially affected in FESz. Larger P2 and P3 with greater estimated premorbid intellect in patients indicate a possible neuroprotective effect of intellect in FESz.

Background . Abnormalities of mismatch negativity (MMN), an event-related potential, indexing preattentive mechanisms, are consistently reported in schizophrenia (SZ). MMN abnormalities elicited to different deviant types have been recently shown to distinguish among patients according to length of their illness as well as inpatient versus outpatient status, and to be modulated by premorbid IQ. The objective of this study was to evaluate the MMN elicited by both frequency and duration deviant stimuli in patients with early schizophrenia (EP) recruited from an outpatient clinic in Boston, Massachusetts. Methods . Twenty-two healthy controls (HC) and 22 age-, handedness-, and gender-matched EP were tested using a frequency and duration MMN paradigm. Clinical data were also collected. Results . Frequency MMN amplitude but not duration MMN was significantly reduced in EP relative to HC subjects ( P = .015). Conclusions . These results indicate that in this sample of early psychosis outpatient group, reductions in frequency MMN but not in duration MMN index clinical status. The relationship between age at first hospitalization and MMN frequency and duration amplitude and latency indicates that neurodevelopmental stage, auditory function, and clinical status are tightly linked.

We hypothesized that neuropsychological disturbance in schizophrenia (SZ) may reflect faulty interactions of executive attention and episodic memory, emanating, in part, from reduced prefrontal cortex (PFC) gray matter volume. Participants with SZ (n = 84) and age-matched (n = 77) controls completed both the Wisconsin Card Sorting Test (WCST) and the Wechsler Memory Scale-Third Edition (WMS-III), used, respectively, as measures of executive attention and episodic memory. A subset of SZ (n = 27) and control (n = 17) groups also had available 3-T magnetic resonance imaging (MRI) studies of the PFC. For SZ, but not control groups, neuropsychological results indicated that executive attention interacted significantly with episodic memory, with failures of executive attention, as reflected by increased WCST perseverative errors, directly linked to poor performance on the WMS-III measure of delayed visual recall of action scenes. MRI results indicated reduced left PFC gray matter volume for SZ group, which in turn correlated significantly with their deficits in visual memory but not in executive attention. Results showed that 61% of the variance in neuropsychological performance in the SZ group was attributed to gray matter volume of left inferior prefrontal gyrus gray matter volume. PFC-mediated failure of executive attention-episodic memory interactions may represent an important mechanism in neuropsychological disturbance in SZ.

Existing evidence suggests that patients with schizophrenia may have a deficit in processing facial expressions. However, the neural basis of this processing deficit remains unclear. A total of 20 men diagnosed with chronic schizophrenia and 13 age- and sex-matched controls participated in the study. We investigated visual N170 and P3a components evoked in response to fearful, happy, and sad faces during an emotion discrimination task. Compared with control subjects, patients showed significantly smaller N170 amplitudes bilaterally ( P = .04). We found no significant main effect of emotion of the presented faces (fearful, happy, or sad) on N170 amplitude. Patients showed significantly smaller P3a amplitudes in response to fearful ( P = .01) and happy ( P = .02) faces, but no significant between-group differences were observed for sad faces ( P = .22). Moreover, we found no significant P3a modulation effect in response to emotional faces in patients with schizophrenia. Our results suggest that altered P3a modulations to emotional faces may be associated with emotion recognition deficits in patients with schizophrenia.

We investigated whether the gray matter volume of primary auditory cortex (Heschl's gyrus [HG]) was associated with abnormal patterns of auditory γ activity in schizophrenia, namely impaired γ synchronization in the 40-Hz auditory steady-state response (ASSR) and increased spontaneous broadband γ power. (The γ data were previously reported in Hirano et al, JAMA Psychiatry , 2015;72:813-821). Participants were 24 healthy controls (HC) and 23 individuals with chronic schizophrenia (SZ). The ASSR was obtained from the electroencephalogram to click train stimulation at 20, 30, and 40 Hz rates. Dipole source localization of the ASSR was used to provide a spatial filter of auditory cortex activity, from which ASSR evoked power and phase locking factor (PLF), and induced γ power were computed. HG gray matter volume was derived from structural magnetic resonance imaging at 3 T with manually traced regions of interest. As expected, HG gray matter volume was reduced in SZ compared with HC. In SZ, left hemisphere ASSR PLF and induced γ power during the 40-Hz stimulation condition were positively and negatively correlated with left HG gray matter volume, respectively. These results provide evidence that cortical gray matter structure, possibly resulting from reduced synaptic connectivity at the microcircuit level, is related to impaired γ synchronization and increased spontaneous γ activity in schizophrenia.