Free Water Modulation of White Matter Integrity Measures-with Application to Schizophrenia

Fractional anisotropy (FA) is an important parameter derived from diffusion tensor MRI (DTI) [1], and abnormalities in the FA value were found in various brain disorders [2]. A common interpretation for decreases in FA in white matter is change in the myelin, rendering FA a measure of white matter integrity; yet, it is known that FA is not a specific biomarker for myelin, since other possible microstructural abnormalities might cause reductions in FA [3]. For example, it was demonstrated that an isotropic increase change (simultaneous equal change to all eigenvalues) of an initially anisotropic sample not only increases the mean diffusivity (MD), but also decreases FA [4]. Schizophrenia (SZ) is an example of a disorder where abnormal decreases in FA are found in various white matter bundles [5], and these findings associated also with genetics and post-mortem studies demonstrating myelin abnormalities in SZ patients have led to the hypothesis that SZ is a neurological disorder that involves anomalies in the formation or function of myelin sheaths and consequently, white matter functionality [6]. In order to better understand the microstructural origin of the observed decreases in FA in SZ, we have applied the free water elimination framework [4] to separate isotropic and anisotropic components of group-wise abnormalities. The framework fits the diffusion images to a bi-tensor model; one compartment estimates the volume of free water, and the other provides a free water eliminated estimation of tensor quantities such as corrected FA. We tested the effects of these parameters by comparing a group of SZ patients in their first psychotic episode (n=18) with matching controls (n=20), with the goal of improving our understanding of the etiology of the disorder as it is expressed at onset of illness.