White matter structure-function decoupling in juvenile myoclonic epilepsy

Accumulating evidence highlights both structural and functional brain alterations in juvenile myoclonic epilepsy (JME), yet how these structural changes within white matter pathways drive functional disorganization remains largely unknown. Here, we aim to investigate white matter structure-function coupling (SFC) in treatment-naïve, newly diagnosed JME.

Forty-seven patients with JME and 40 demographically matched healthy controls underwent diffusion-weighted imaging (DWI) and resting-state functional magnetic resonance imaging (fMRI). Tract-wise SFC was assessed using a multivariate linear regression, with the amplitude of low-frequency fluctuations as the dependent variable and four microstructural metrics-fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD)-as independent variables. A support vector regression with five-fold cross-validation was employed to establish the associations with clinical severity.

JME patients exhibited widespread white matter microstructural alterations, including increased FA and decreased diffusivity metrics, alongside functional hyperactivity in multiple tracts. Notably, a significant reduction of SFC was observed in the left corticospinal tract (P = 0.008) and left inferior longitudinal fasciculus (P = 0.006). In addition, multimodal models combining structural, functional, and coupling metrics demonstrated superior predictive performance for clinical severity compared to single-modal analyses (P = 0.026).

These findings highlight white matter structure-function decoupling in the early stages of JME, specifically in key pathways relevant to motor and cognitive dysfunctions. Furthermore, the tract-specific SFC investigation offers a useful way for diagnosis, prognosis, and guiding personalized treatment strategies in this complex epilepsy syndrome.