Neurobehavioral and Clinical Comorbidities in Epilepsy: The Role of White Matter Network Disruption

Epilepsy is a common neurological disorder associated with alterations in cortical and subcortical brain networks. Despite a historical focus on gray matter regions involved in seizure generation and propagation, the role of white matter (WM) network disruption in epilepsy and its comorbidities has sparked recent attention. In this review, we describe patterns of WM alterations observed in focal and generalized epilepsy syndromes and highlight studies linking WM disruption to cognitive and psychiatric comorbidities, drug resistance, and poor surgical outcomes. Both tract-based and connectome-based approaches implicate the importance of extratemporal and temporo-limbic WM disconnection across a range of comorbidities, and an evolving literature reveals the utility of WM patterns for predicting outcomes following epilepsy surgery. We encourage new research employing advanced analytic techniques (e.g., machine learning) that will further shape our understanding of epilepsy as a network disorder and guide individualized treatment decisions. We also address the need for research that examines how neuromodulation and other treatments (e.g., laser ablation) affect WM networks, as well as research that leverages larger and more diverse samples, longitudinal designs, and improved magnetic resonance imaging acquisitions. These steps will be critical to ensuring generalizability of current research and determining the extent to which neuroplasticity within WM networks can influence patient outcomes.