Revealing Changes in Linear and Nonlinear Functional Connectivity After Psilocybin and Escitalopram Treatment in Patients with Depression

Major Depressive Disorder (MDD) is typically characterized by altered linear functional connectivity (FC) across large-scale brain networks. Yet, it is unclear whether similar alterations are observed when nonlinear FC is examined. This study investigated how antidepressant treatment (i.e., psilocybin and escitalopram) modulates both linear FC and nonlinear FC in individuals with MDD. Here, we focused specifically on five key canonical brain networks: the Default Mode Network (DMN), Frontoparietal Network (FPN), Salience Network (SAL), Dorsal Attention Network (DAN), and Ventral Attention Network (VAN). Across both treatments, using resting-state fMRI data, we first compared changes in linear and nonlinear FC between responders and non-responders. Responders exhibited increased linear FC within the VAN and greater nonlinear FC within the DMN and VAN than non-responders. We also observed more between-network linear FC for DMN-DAN and nonlinear FC for DMN-VAN in responders than non-responders. Next, we compared treatments and observed that Psilocybin responders showed greater connectivity between FPN-VAN (linear FC), DMN-VAN (nonlinear FC), and SAL-VAN (nonlinear FC) integration than Escitalopram responders, reflecting enhanced coordination and integration between higher-order networks. Conversely, Escitalopram responders exhibited reduced within-network linear FC within the DMN and SAL and between the DMN and VAN, consistent with a dampening of self-referential and salience processing and altered attentional control. These findings highlight potentially distinct mechanisms of action for psilocybin and escitalopram. Incorporating both linear and nonlinear FC analyses provided a novel characterization of these effects, emphasizing the role of these different interactions in antidepressant response. Future studies should investigate the long-term stability of these network changes and their relationship to clinical outcomes.