Default Mode Network, Disorganization, and Treatment-Resistant Schizophrenia

Background and Hypothesis Disorganized thinking is a prominent feature of schizophrenia that becomes persistent in the presence of treatment resistance. Disruption of the default mode network (DMN), which regulates self-referential thinking, is now a well-established feature of schizophrenia. However, we do not know if DMN disruption affects disorganization and contributes to treatment-resistant schizophrenia (TRS). Study Design This study investigated the DMN in 48 TRS, 76 non-TRS, and 64 healthy controls (HC) using a spatiotemporal approach with resting-state functional magnetic resonance imaging. We recovered DMN as an integrated network using multivariate group independent component analysis and estimated its loading coefficient (reflecting spatial prominence) and Shannon Entropy (reflecting temporal variability). Additionally, voxel-level analyses were conducted to examine network homogeneity and entropy within the DMN. We explored the relationship between DMN measures and disorganization using regression analysis. Results TRS had higher spatial loading on population-level DMN pattern, but lower entropy compared to HC. Non-TRS patients showed intermediate DMN alterations, not significantly differing from either TRS or HC. No voxel-level differences were noted between TRS and non-TRS, emphasizing the continuum between the two groups. DMN's loading coefficient was higher in patients with more severe disorganization. Conclusions TRS may represent the most severe end of a spectrum of spatiotemporal DMN dysfunction in schizophrenia. While excessive spatial contribution of the DMN (high loading coefficient) is specifically associated with disorganization, both excessive spatial contribution and exaggerated temporal stability of DMN are features of schizophrenia that become more pronounced with refractoriness to first-line treatments.