Evidence for white matter abnormalities in schizophrenia

Abstract

Purpose of review-The purpose of this review is to highlight important recent imaging, histological, and genetic findings relevant to white matter abnormalities in schizophrenia. It is cast within the context of research findings conducted over the last 5 years, where we analyze their importance in understanding schizophrenia, as well as discuss future directions for research.Recent findings-White matter abnormalities have long been hypothesized in schizophrenia, although only recently has it become possible to investigate them more closely. This has come about as a result of advances in neuroimaging, including new imaging techniques sensitive to white matter structure, as well as advances in computer science, with new analysis techniques making it possible to evaluate several interconnected brain regions at a time. Postmortem studies, with advances such as fluoroscopy and electron microscopy, have also led to quantifying populations of different brain cells, including myelin-forming oligodendrocytes. Moreover, molecular studies enable examination of immunoreactivity of proteins that are responsible for building myelin sheaths. Additionally, microarray genetic studies allow us to investigate myelin-related genes in schizophrenia. Taken together, these technological advances bring us closer to understanding white matter pathology in schizophrenia.Summary-Advances in new imaging techniques likely account for the renewed interest in investigating white matter abnormalities in schizophrenia, with over 30 new articles published on this topic in the last 12 months, compared with 11 the year before. We review recent imaging, histological, and genetic findings that suggest white matter abnormalities in schizophrenia.

Cingulum bundle white matter in MAG-knockout mice

“…Converging evidence suggests that myelin, and specifically oligodendrocytes, is in some way dysfunctional in schizophrenia [40,49,50].…”

Polymorphisms in SREBF1 and SREBF2, two antipsychotic-activated transcription factors controlling cellular lipogenesis, are associated with schizophrenia in German and Scandinavian samples

“…Since this original report, other studies have shown various signs of oligodendrocyte degeneration and myelin sheath abnormalities in prefrontal cortex in brains from patients with schizophrenia. 29,30 MRI studies using diffusion tensor imaging in vivo have indicated abnormalities in white matter in prefrontal cortex and other brain areas of patients with schizophrenia, indicating the possibility of disturbed maintenance of myelination through oligodendrocytes [31][32][33][34] although not all studies agree. 35,36 Recently, postmortem gene expression profiling has boosted the field by showing that many myelinrelated genes are downregulated in several brain regions of patients with schizophrenia compared with controls [37][38][39][40][41] Furthermore, it is interesting to note that while most of the myelination occurs shortly postnatally, 42 the peak of myelination in the cortical areas and especially in the prefrontal cortex occurs during the adolescence and early adulthood, 43,44 thus coinciding with a critical period for the onset of schizophrenia.…”

A comprehensive assessment of gray and white matter volumes and their relationship to outcome and severity in schizophrenia

“…Although there have been several reports of focal decreases in white matter density (Suzuki et al, 2002;Shapleske et al, 2002;Spaletta et al, 2003;Hulshoff Pol et al, 2004;Davatzikos et al, 2006), regional white matter volumes proper in patients with schizophrenia have not been frequently assessed (Shenton et al, 2001;Kubicki et al, 2005). This is primarily related to difficulties with its parcellation, given a lack of consensual anatomical landmarks or wholebrain partition schemes.…”