Altered Thalamocortical Functional Connectivity in Tuberous Sclerosis Complex: Insights From Resting‐State fMRI

Background: Tuberous sclerosis complex (TSC) is a genetic disorder commonly associated with drug‐resistant epilepsy. Although epileptogenic tubers (ETs) can be localized in 60% of TSC patients, approximately 40% remain undetectable despite comprehensive multimodal evaluations. The functional network mechanisms underlying seizure generation and propagation in patients with TSC are poorly understood. Methods: Resting‐state fMRI (rs‐fMRI) data from 10 surgically treated patients with TSC (postoperative seizure freedom for ≥ 3 years) and 10 age‐matched healthy controls were analyzed. Functional connectivity (FC) between four thalamic subregions—mediodorsal thalamus (MDT), anterior thalamic nucleus (ANT), centromedian thalamus (CMT), and pulvinar—and ETs, non‐ETs, or normal cortices was assessed. Secondary projection analysis mapped corticothalamic networks associated with ETs. Results: MDT‐ET connectivity was significantly reduced compared with MDT‐non‐ETs ( p = 0.01) and MDT‐normal cortices in controls ( p = 0.03). Secondary analysis identified hyperconnectivity between ET‐associated thalamic clusters and the left middle frontal gyrus ( p GFR < 0.001). No significant differences were observed in other thalamic subregions. Conclusions: The selective reduction in MDT‐ET connectivity highlights disrupted thalamocortical synchronization as a key network mechanism in TSC‐related epilepsy. Enhanced left middle frontal gyrus–thalamic connectivity suggests compensatory cortical engagement within epileptogenic networks. These findings position rs‐fMRI as a critical tool for delineating network‐based biomarkers, advancing precision therapeutic strategies in TSC.