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.