Normative structural connectome constrains spreading transient brain activity in generalized epilepsy.

Background: Genetic generalized epilepsy is characterized by transient episodes of spontaneous abnormal neural activity in anatomically distributed brain regions that ultimately propagate to wider areas. However, the connectome-based mechanisms shaping these abnormalities remain largely unknown. We aimed to investigate how the normative structural connectome constrains abnormal brain activity spread in genetic generalized epilepsy with generalized tonic-clonic seizure (GGE-GTCS).

Methods: Abnormal transient activity patterns between individuals with GGE-GTCS (n = 97) and healthy controls (n = 141) were estimated from the amplitude of low-frequency fluctuations measured by resting-state functional MRI. The normative structural connectome was derived from diffusion-weighted images acquired in an independent cohort of healthy adults (n = 326). Structural neighborhood analysis was applied to assess the degree of constraints between activity vulnerability and structural connectome. Dominance analysis was used to determine the potential molecular underpinnings of these constraints. Furthermore, a network-based diffusion model was utilized to simulate the spread of pathology and identify potential disease epicenters.

Results: Brain activity abnormalities among patients with GGE-GTCS were primarily located in the temporal, cingulate, prefrontal, and parietal cortices. The collective abnormality of structurally connected neighbors significantly predicted regional activity abnormality, indicating that white matter network architecture constrains aberrant activity patterns. Molecular fingerprints, particularly laminar differentiation and neurotransmitter receptor profiles, constituted key predictors of these connectome-constrained activity abnormalities. Network-based diffusion modeling effectively replicated transient pathological activity spreading patterns, identifying the limbic-temporal, dorsolateral prefrontal, and occipital cortices as putative disease epicenters. These results were robust across different clinical factors and individual patients.

Conclusions: Our findings suggest that the structural connectome shapes the spatial patterning of brain activity abnormalities, advancing our understanding of the network-level mechanisms underlying vulnerability to abnormal brain activity onset and propagation in GGE-GTCS.