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

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. 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. 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. 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.