Widespread white matter microstructural differences in schizophrenia across 4322 individuals: results from the ENIGMA Schizophrenia DTI Working Group

Abstract

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.

Aberrant Middle Prefrontal-Motor Cortex Connectivity Mediates Motor Inhibitory Biomarker in Schizophrenia

“…The corona radiata provides the majority of the ipsilateral fibers connections between frontal and motor cortical areas(67). This white matter structure has shown the largest effect size of white matter microstructural deficits in schizophrenia(68) and is also highly heritable(69). It is not clear why this SICI and white matter relationship was strongly mediated by the connections between ipsilateral prefrontal cortex and motor cortex(Figure 3C).…”

Integration of routine QA data into mega‐analysis may improve quality and sensitivity of multisite diffusion tensor imaging studies

“…Lower integrity of cerebral white matter (WM), quantified as reduced fractional anisotropy (FA) of water diffusion measured from diffusion tensor imaging (DTI), is a consistent finding in schizophrenia (Alba‐Ferrara & de Erausquin ; Ellison‐Wright & Bullmore ; Friedman et al, ; Glahn et al, ; Kelly et al, ; Kochunov & Hong ; Kubicki et al, ; Nazeri et al, ; Perez‐Iglesias et al, ; Phillips, Rogers, Barrett, Glahn, & Kochunov, ; Wright et al, ). FA deficits are hypothesized to be prominent in the associative WM fibers and responsible for neuropsychological deficits association with this disorder (Ellison‐Wright & Bullmore ; Friedman et al, ; Kochunov et al, ; Kubicki et al, ; Nazeri et al, ; Perez‐Iglesias et al, ).…”

“…We assessed the impact of regressing the site‐specific methodological variance and advanced denoising approach by comparing the effect size of schizophrenia on regional FA values to those published by the largest meta‐analytic analysis of regional FA deficits to date ( N = 1,984/2,391 patients/controls, thirty independent cohorts worldwide) performed by ENIGMA (Kelly et al, ). The average effect size for regional FA values in ENIGMA was reported to be Cohen's d =∼.25 (Kelly et al, ). This suggested that a sample of N = 250 patients/250 controls is required to detect such an effect size.…”

“…Therefore, the aim was to study the changes in the agreement in the pattern of regional difference between the SPINS and ENIGMA results. This study was focused on FA and did not explore other diffusion parameters (axial, radial, and mean diffusivities); FA was selected because it is the most commonly studied diffusion‐metric in schizophrenia research, and is the metric most consistently altered between schizophrenia patients and matched controls (Kelly et al, ).…”

Increased densities of white matter neurons as a cross‐disease feature of neuropsychiatric disorders

“…Thus, increased densities of the WM neurons not only indicates the experience of developmental insults, but might also disrupt the development of normal connectivity, which may partly underlie the abnormal functions of the brains associated with an increased densities of WM neurons in patients with neuropsychiatric disorders. An intriguing hypothesis is that the altered connectivities associated with the increase in density of WM neurons might underlie the WM abnormalities detected in diffuse tensor imaging studies of schizophrenia patients . This hypothesis should be verified in future studies.…”