Abstracts

Rationale: Many forms of epilepsy are associated with aberrant neuronal connections, but the relationship between such pathological connectivity and the physiological changes underlying a predisposition to seizures is not clear. We sought to investigate the cortical excitability profile of a developmental form of epilepsy that serves as a model for circuit epileptogenesis due to its well-characterized anatomy and known structural and functional connectivity abnormalities. Methods: We employed transcranial magnetic stimulation (TMS) with simultaneous scalp EEG recording to study cortical physiology in eight patients with epilepsy from periventricular nodular heterotopia (PNH) and matched healthy controls. We used connectivity imaging findings to guide TMS in these groups and compared the evoked responses to single-pulse stimulation from different cortical regions. Results: Heterotopia patients with active epilepsy demonstrated an augmented late cortical response (between 225 and 700 msec following single-pulse stimulation) that was significantly greater than that of matched controls. This abnormality was specific to cortical regions that had demonstrated connectivity to subcortical heterotopic gray matter. Topographic mapping of these late response differences showed distributed cortical networks that were not limited to the local stimulation site. Conclusions: Our findings indicate that patients with epilepsy in the setting of gray matter heterotopia have altered cortical physiology consistent with hyperexcitability, and this abnormality is specifically linked to the presence of aberrant connectivity. These results confirm the utility of TMS-EEG as a biomarker in epilepsy, expand our understanding of circuit mechanisms of epileptogenesis, provide support for the neurophysiologic significance of resting-state fMRI connectivity, and have implications for therapeutic neuromodulation in epileptic conditions associated with deep lesions.