The profile of brain structural abnormalities in schizophrenia is still not fully understood, despite decades of research using brain scans. To validate a prospective meta-analysis approach to analyzing multicenter neuroimaging data, we analyzed brain MRI scans from 2028 schizophrenia patients and 2540 healthy controls, assessed with standardized methods at 15 centers worldwide. We identified subcortical brain volumes that differentiated patients from controls, and ranked them according to their effect sizes. Compared with healthy controls, patients with schizophrenia had smaller hippocampus (Cohen's d=-0.46), amygdala (d=-0.31), thalamus (d=-0.31), accumbens (d=-0.25) and intracranial volumes (d=-0.12), as well as larger pallidum (d=0.21) and lateral ventricle volumes (d=0.37). Putamen and pallidum volume augmentations were positively associated with duration of illness and hippocampal deficits scaled with the proportion of unmedicated patients. Worldwide cooperative analyses of brain imaging data support a profile of subcortical abnormalities in schizophrenia, which is consistent with that based on traditional meta-analytic approaches. This first ENIGMA Schizophrenia Working Group study validates that collaborative data analyses can readily be used across brain phenotypes and disorders and encourages analysis and data sharing efforts to further our understanding of severe mental illness.

http://enigma.ini.usc.edu/wp-content/uploads/2015/07/ENIGMA-Schizophrenia-Molecular-Psychiatry-van-Erp-T-2015.pdf

Subcortical brain volume abnormalities in 2028 individuals with schizophrenia and 2540 healthy controls via the ENIGMA consortium

Schizophrenia is a complex mental disorder with disorganized communication among large-scale brain networks, as demonstrated by impaired resting-state functional connectivity (rsFC). Individual rsFC studies, however, vary greatly in their methods and findings. We searched for consistent patterns of network dysfunction in schizophrenia by using a coordinate-based meta-analysis. Fifty-six seed-based voxel-wise rsFC datasets from 52 publications (2115 patients and 2297 healthy controls) were included in this meta-analysis. Then, coordinates of seed regions of interest (ROI) and between-group effects were extracted and coded. Seed ROIs were categorized into seed networks by their location within an a priori template. Multilevel kernel density analysis was used to identify brain networks in which schizophrenia was linked to hyper-connectivity or hypo-connectivity with each a priori network. Our results showed that schizophrenia was characterized by hypo-connectivity within the default network (DN, self-related thought), affective network (AN, emotion processing), ventral attention network (VAN, processing of salience), thalamus network (TN, gating information) and somatosensory network (SS, involved in sensory and auditory perception). Additionally, hypo-connectivity between the VAN and TN, VAN and DN, VAN and frontoparietal network (FN, external goal-directed regulation), FN and TN, and FN and DN were found in schizophrenia. Finally, the only instance of hyper-connectivity in schizophrenia was observed between the AN and VAN. Our meta-analysis motivates an empirical foundation for a disconnected large-scale brain networks model of schizophrenia in which the salience processing network (VAN) plays the core role, and its imbalanced communication with other functional networks may underlie the core difficulty of patients to differentiate self-representation (inner world) and environmental salience processing (outside world).

/pdf/dysfunction-of-large-scale-brain-networks-in-schizophrenia-a-1nejqdhz21.pdf

Dysfunction of Large-Scale Brain Networks in Schizophrenia: A Meta-analysis of Resting-State Functional Connectivity

Cognition and resting-state functional connectivity in schizophrenia

Meta-analysis of cognitive performance in drug-naïve patients with schizophrenia

The brain’s default mode network (DMN) is highly heritable and is compromised in a variety of psychiatric disorders However, genetic control over the DMN in schizophrenia (SZ) and psychotic bipolar disorder (PBP) is largely unknown Study subjects (n = 1,305) underwent a resting-state functional MRI scan and were analyzed by a two-stage approach The initial analysis used independent component analysis (ICA) in 324 healthy controls, 296 SZ probands, 300 PBP probands, 179 unaffected first-degree relatives of SZ probands (SZREL), and 206 unaffected first-degree relatives of PBP probands to identify DMNs and to test their biomarker and/or endophenotype status A subset of controls and probands (n = 549) then was subjected to a parallel ICA (para-ICA) to identify imaging–genetic relationships ICA identified three DMNs Hypo-connectivity was observed in both patient groups in all DMNs Similar patterns observed in SZREL were restricted to only one network DMN connectivity also correlated with several symptom measures Para-ICA identified five sub-DMNs that were significantly associated with five different genetic networks Several top-ranking SNPs across these networks belonged to previously identified, well-known psychosis/mood disorder genes Global enrichment analyses revealed processes including NMDA-related long-term potentiation, PKA, immune response signaling, axon guidance, and synaptogenesis that significantly influenced DMN modulation in psychoses In summary, we observed both unique and shared impairments in functional connectivity across the SZ and PBP cohorts; these impairments were selectively familial only for SZREL Genes regulating specific neurodevelopment/transmission processes primarily mediated DMN disconnectivity The study thus identifies biological pathways related to a widely researched quantitative trait that might suggest novel, targeted drug treatments for these diseases

https://www.pnas.org/content/pnas/111/19/E2066.full.pdf

Multivariate analysis reveals genetic associations of the resting default mode network in psychotic bipolar disorder and schizophrenia

BackgroundGiven the important role of the default mode network (DMN) in cognitive function and the well-known neurocognitive deficit in schizophrenia, it is intriguing to examine systematically the relationship between neurocognitive dysfunction and aberrant intrinsic activities, and also functional connectivity, of the DMN in patients with schizophrenia.MethodFirst-episode, treatment-naive patients with schizophrenia (FES) (n = 115) and healthy controls (n = 113) underwent resting-state functional magnetic resonance imaging (fMRI) scans and neurocognitive tests. Intrinsic neural activities evaluated by using the fragment amplitude of low-frequency fluctuations (fALFF) and the resting-state functional connectivity assessed by seed-based correlational analysis were compared between patients and controls. Aberrant intrinsic activities and DMN connectivity in patients were then correlated to neurocognitive performance and clinical symptoms.ResultsCompared to controls, patients with FES showed decreased fALFF in the bilateral medial prefrontal cortex (MPFC) and the orbitofrontal cortex (OFC), and increased fALFF in the bilateral putamen. Increased functional connectivity with the DMN was observed in the left insula and bilateral dorsolateral PFC (DLPFC) in patients with FES. In patients, aberrant fALFF in the bilateral OFC were correlated with cognitive processing speed; fALFF in the left OFC and right putamen were correlated with the clinical factors excited/activation and disorganization; and increased DMN functional connectivity in the left insula was correlated with the clinical factors positive, excited/activation, disorganization and neurocognitive deficit in the domain of sustained attention.ConclusionsThese associations between neurocognitive dysfunction and aberrant intrinsic activities, and also functional connectivity, of the DMN in patients with schizophrenia may provide important insights into the neural mechanism of the disease.

https://www.cambridge.org/core/services/aop-cambridge-core/content/view/A8E46C94384493441B971A8450F61DF2/S0033291712001638a.pdf/div-class-title-aberrant-intrinsic-brain-activity-and-cognitive-deficit-in-first-episode-treatment-naive-patients-with-schizophrenia-div.pdf

Aberrant intrinsic brain activity and cognitive deficit in first-episode treatment-naive patients with schizophrenia

Background. Brain structure appears to alter after antipsychotic administration, but it is unknown whether these alterations are associated with improvement of psychopathology in patients with schizophrenia. In this study, the authors explore this relationship. Method. Altogether, 66 first-episode, drug-naive patients with schizophrenia and 23 well-matched healthy controls underwent brain magnetic resonance imaging scans at baseline. All 23 healthy controls and 42 of the patients were rescanned after 6 weeks follow-up. The patients received regular antipsychotic treatment during the 6-week period and their psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS) at baseline and 6 weeks. The difference in PANSS scores between baseline and 6 weeks was expressed as a ratio of the scores at baseline - ' PANSS reduction ratio '. A modified tensor-based morphometry procedure was applied to analyse longitudinal images. Correlations between regional volume changes, PANSS reduction ratio and antipsychotic drug dosages were explored. Results. Compared with healthy controls, there was a significant increase in grey-matter volume of the right putamen in patients after 6 weeks treatment. This volume change was positively correlated with a positive PANSS reduction score but not related to drug dosages. Conclusions. Putaminal volume increased after 6 weeks antipsychotic treatment in first-episode schizophrenia. The increased volume was closely correlated with improved psychopathology, suggesting the putamen might be a biomarker to predict the treatment response in schizophrenia.

/pdf/volume-increases-in-putamen-associated-with-positive-symptom-e7obmahzv6.pdf

Z. He

Papers

Aberrant intrinsic brain activity and cognitive deficit in first-episode treatment-naive patients with schizophrenia

Volume increases in putamen associated with positive symptom reduction in previously drug-naive schizophrenia after 6 weeks antipsychotic treatment.