Electroconvulsive therapy shifting brain dynamics toward more adaptive and integrated states in treatment-resistant depression based on a hidden markov model.

Treatment-resistant depression (TRD) is characterized by persistent symptoms and poor response to conventional therapies, yet its dynamic neural mechanisms and treatment-related changes remain incompletely understood. This study applied a hidden Markov model (HMM) combined with neurotransmitter atlas mapping to investigate whole-brain spatiotemporal dynamics in TRD and their modulation by electroconvulsive therapy (ECT). Resting-state fMRI data were collected from 72 TRD patients (52 completing follow-up) and 63 healthy controls. HMM identified six recurring brain states defined by distinct patterns of functional connectivity and averaged functional activity. At baseline, TRD patients showed reduced occupancy and stability of globally coordinated states and increased engagement of subcortical-dominant states, indicating impaired global stability and disrupted cortical-subcortical balance. After ECT, clinical symptoms improved significantly, accompanied by increased occupancy of states characterized by higher activity within the default mode and frontoparietal networks, as well as a highly integrated whole-brain state. These changes suggest improved overall brain coordination and cortical engagement rather than full normalization of baseline abnormalities. In contrast, subcortical-dominant states persisted after treatment, consistent with trait-like features of TRD. Neurotransmitter mapping showed that treatment-responsive states were associated with serotonergic, dopaminergic, and glutamatergic systems, whereas persistent subcortical states were linked to noradrenergic and cholinergic markers. Overall, these findings suggest that ECT improves symptoms by shifting brain dynamics toward more adaptive and integrated states, rather than fully restoring baseline function. This dynamic perspective provides new insight into the neural mechanisms of TRD and its treatment.