BACKGROUND: White matter (WM) aberrations have been broadly characterized in schizophrenia using standard diffusion tensor imaging (DTI) techniques. The present study aims to distinguish WM alterations in the early course of schizophrenia using advanced diffusion measures of free-water corrected fractional anisotropy (FAt) and free-water fractional volume (FW), in addition to examining their association with neurocognition, social cognition, and clinical measures. We report baseline results from a longitudinal study investigating the effects of cognitive enhancement therapy (CET) on brain structure and function in schizophrenia. METHODS: The sample consisted of 46 early course schizophrenia patients and 20 healthy controls. Diffusion-weighted images were processed using a free-water imaging pipeline, that separately models diffusion of water in tissue (FAt) and the extracellular space (FW). Tract-Based Spatial Statistics was performed on the FAt and FW diffusion tensor maps and average measures from 24 bilateral regions of interest (ROIs) were extracted. We examined WM structural differences between patients and controls and further investigated WM relations to neurocognition, social cognition, and clinical measures specifically in schizophrenia. RESULTS: Patients showed significant FAt reductions in the body of the corpus callosum, posterior thalamic radiation (PTR), cingulate gyrus, anterior corona radiata, corpus callosum, and corona radiata and FW elevations in the posterior corona radiata (PCR), uncinate fasciculus (UNC), and PTR compared to controls. For patients, positive correlations between FAt and working memory were observed in the PCR and fornix & stria terminalis (FXST). Negative associations between FW and attention/vigilance were observed in the UNC. Positive correlations between FAt and theory of mind (ToM) were observed in average whole-brain and FXST. Negative associations between FW and ToM were observed in average whole-brain and PCR. Positive correlations between FW and negative symptom severity were observed in the external capsule. CONCLUSION: Using free-water imaging, we report WM aberrations and FW elevations in the early course of schizophrenia in addition to neural correlates associated with cognition and clinical measures. Future investigations on the longitudinal effects of CET are warranted for a greater understanding of the underlying neural correlates of clinical manifestations in schizophrenia. / 2020-06-14T00:00:00Z