Spatiotemporal alterations of thalamo-cortical effective connectivity in major depressive disorder patients

Background: Thalamic structural and functional abnormalities in major depressive disorder (MDD) are linked to impairments in diverse cognitive and emotional functions via the thalamo-cortical circuit. Given the constraints of temporal and spatial factors on information exchange, investigating frequency-specific effective connectivity (EC) is essential for elucidating the abnormal mechanisms of spatiotemporal information communication in patients with MDD. Method: We employed a large-scale, multicenter resting-state functional magnetic resonance imaging (fMRI) dataset comprising individuals with MDD and matched healthy controls. Frequency-specific EC between the thalamic subregions and cortical/subcortical regions was assessed using spectral Granger causality in four frequency bands: slow-5 (0.01–0.027 Hz), slow-4 (0.027–0.073 Hz), slow-3 (0.073–0.185 Hz), and a classic frequency range (0.01–0.08 Hz). Support vector regression (SVR) models were employed to evaluate the predictive value of altered EC for clinical symptom scores. Results: Individuals with MDD exhibited significant and frequency-dependent abnormalities in thalamocortical and thalamo-subcortical EC, with the most pronounced disruptions observed in the slow-5 band. These abnormalities originate from the specific thalamic subregions and extend to cortical and subcortical regions. Among the frequency bands analyzed, EC alterations in the slow-5 band showed the strongest association with clinical severity and yielded the highest predictive performance in SVR models. Conclusions: Frequency-specific EC disruptions, particularly within the slow-5 band, may reflect fundamental spatiotemporal communication deficits in MDD. These findings highlight the slow-5 thalamocortical and thalamo-subcortical EC as a potential neurobiological marker for diagnosis and a target for treatment strategies in MDD.