Connectivity-enhanced diffusion analysis reveals white matter density disruptions in first episode and chronic schizophrenia.

Reduced fractional anisotropy (FA) is a well-established correlate of schizophrenia, but it remains unclear whether these tensor-based differences are the result of axon damage and/or organizational changes and whether the changes are progressive in the adult course of illness. Diffusion MRI data were collected in 81 schizophrenia patients (54 first episode and 27 chronic) and 64 controls. Analysis of FA was combined with "fixel-based" analysis, the latter of which leverages connectivity and crossing-fiber information to assess both fiber bundle density and organizational complexity (i.e., presence and magnitude of off-axis diffusion signal). Compared with controls, patients with schizophrenia displayed clusters of significantly lower FA in the bilateral frontal lobes, right dorsal centrum semiovale, and the left anterior limb of the internal capsule. All FA-based group differences overlapped substantially with regions containing complex fiber architecture. FA within these clusters was positively correlated with principal axis fiber density, but inversely correlated with both secondary/tertiary axis fiber density and voxel-wise fiber complexity. Crossing fiber complexity had the strongest (inverse) association with FA (r = -0.82). When crossing fiber structure was modeled in the MRtrix fixel-based analysis pipeline, patients exhibited significantly lower fiber density compared to controls in the dorsal and posterior corpus callosum (central, postcentral, and forceps major). Findings of lower FA in patients with schizophrenia likely reflect two inversely related signals: reduced density of principal axis fiber tracts and increased off-axis diffusion sources. Whereas the former confirms at least some regions where myelin and or/axon count are lower in schizophrenia, the latter indicates that the FA signal from principal axis fiber coherence is broadly contaminated by macrostructural complexity, and therefore does not necessarily reflect microstructural group differences. These results underline the need to move beyond tensor-based models in favor of acquisition and analysis techniques that can help disambiguate different sources of white matter disruptions associated with schizophrenia

Assessing neural tuning for object perception in schizophrenia and bipolar disorder with multivariate pattern analysis of fMRI data.

IntroductionDeficits in visual perception are well-established in schizophrenia and are linked to abnormal activity in the lateral occipital complex (LOC). Related deficits may exist in bipolar disorder. LOC contains neurons tuned to object features. It is unknown whether neural tuning in LOC or other visual areas is abnormal in patients, contributing to abnormal perception during visual tasks. This study used multivariate pattern analysis (MVPA) to investigate perceptual tuning for objects in schizophrenia and bipolar disorder.MethodsFifty schizophrenia participants, 51 bipolar disorder participants, and 47 matched healthy controls completed five functional magnetic resonance imaging (fMRI) runs of a perceptual task in which they viewed pictures of four different objects and an outdoor scene. We performed classification analyses designed to assess the distinctiveness of activity corresponding to perception of each stimulus in LOC (a functionally localized region of interest). We also performed similar classification analyses throughout the brain using a searchlight technique. We compared classification accuracy and patterns of classification errors across groups.ResultsStimulus classification accuracy was significantly above chance in all groups in LOC and throughout visual cortex. Classification errors were mostly within-category confusions (e.g., misclassifying one chair as another chair). There were no group differences in classification accuracy or patterns of confusion.ConclusionsThe results show for the first time MVPA can be used successfully to classify individual perceptual stimuli in schizophrenia and bipolar disorder. However, the results do not provide evidence of abnormal neural tuning in schizophrenia and bipolar disorder

Neural Substrates of Visual Masking by Object Substitution in Schizophrenia

Abstract: Despite a well-known behavioral finding of visual backward masking impairment in schizophrenia, its underlying neural mechanism remains obscure. This study examined neural correlates of a distinct type of visual backward masking, object substitution masking (OSM), in schizophrenia. Twenty schizophrenia patients and 26 healthy controls completed a 4-Dot OSM task and three functional localizer tasks for the lateral occipital (LO), human motion-sensitive (hMT1), and retinotopic areas in the scanner. In 4-dot masking, subjects detected a target that was followed by a mask consisting of 4 dots that surrounded a target. Stimulus-onset asynchrony (SOA) between target and mask was varied to examine the modulation of masking: (1) within three visual processing areas regions of interest (ROI) (i.e., ROI analysis) and (2) in brain regions outside the three visual processing areas (i.e., whole brain analysis). In the ROI analyses, LO and retinotopic areas showed increased peak amplitude when SOA become longer in both patients and controls. There was also an effect of ROI in that both groups showed higher activation in LO and hMT1 compared with the retinotopic areas. The whole brain analyses revealed a significantly activated area for longer SOAs vs. a short SOA in the occipital cortex in controls only, but the group contrast was not significant. Overall, this study did not find strong evidence for neural abnormalities of OSM in schizophrenia, suggesting that neural substrates of OSM in schizophrenia are not as compromised as those involved in the more common masking methods that rely on disruption of object formation. Hum Brain Mapp 35:4654-4662, 2014. V C 2014 Wiley Periodicals, Inc

Healthy adolescent performance on the MATRICS Consensus Cognitive Battery (MCCB): Developmental data from two samples of volunteers

The MATRICS Consensus Cognitive Battery (MCCB) fills a significant need for a standardized battery of cognitive tests to use in clinical trials for schizophrenia in adults aged 20-59. A need remains, however, to develop norms for younger individuals, who also show elevated risks for schizophrenia. Toward this end, we assessed performance in healthy adolescents. Baseline MCCB, reading and IQ data were obtained from healthy controls (ages 12-19) participating in two concurrent NIMH-funded studies: North American Prodromal Longitudinal Study phase 2 (NAPLS-2; n=126) and Boston Center for Intervention Development and Applied Research (CIDAR; n=13). All MCCB tests were administered except the Managing Emotions subtest from the Mayer-Salovey-Caruso Emotional Intelligence Test. Data were collected from 8 sites across North America. MCCB scores were presented in four 2-year age cohorts as T-scores for each test and cognitive domain, and analyzed for effects of age and sex. Due to IQ differences between age-grouped subsamples, IQ served as a covariate in analyses. Overall and sex-based raw scores for individual MCCB tests are presented for each age-based cohort. Adolescents generally showed improvement with age in most MCCB cognitive domains, with the clearest linear trends in Speed of Processing, Attention/Vigilance, and Working Memory. These control data show that healthy adolescence is a dynamic period for cognitive development that is marked by substantial improvement in MCCB performance through the 12-19 age range. They also provide healthy comparison raw scores to facilitate clinical evaluations of adolescents, including those at risk for developing psychiatric disorders such as schizophrenia-related conditions

Mapping genomic loci implicates genes and synaptic biology in schizophrenia

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