Introduction Only a few studies have comprehensively characterized DMN pathology on a structural and functional level, and definite conclusions cannot be drawn due to antipsychotic medication exposure and illness chronicity. The objective of this study was to characterize DMN pathology in medication-naïve first episode psychosis patients (FEP), and determine if DMN structural and functional connectivity (FC) have potential utility as a predictor for subsequent antipsychotic treatment response. Methods Diffusion imaging and resting state FC data from 42 controls and 52 FEP were analyzed. Patients then received 16 weeks of antipsychotic treatment. Using region of interest analyses, we quantified FC of the DMN and structural integrity of the white matter tracts supporting DMN function. We then did linear regressions between DMN structural and FC indices and antipsychotic treatment response. Results We detected reduced DMN fractional anisotropy and axial diffusivity in FEP compared to controls. No DMN FC abnormalities nor correlations between DMN structural and FC were found. Finally, DMN fractional anisotropy and radial diffusivity were associated with response to treatment. Conclusion Our study highlights the critical role of the DMN in the pathophysiology suggesting that axonal damage may already be present in FEP patients. We also demonstrated that DMN pathology is clinically relevant, as greater structural DMN alterations were associated with a less favorable clinical response to antipsychotic medications.

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