Abstract
INTRODUCTION: Lennox-Gastaut syndrome (LGS) is a severe, childhood-onset epilepsy associated with frequent seizures, cognitive impairment, and high burden of care. Electrical stimulation of the thalamus can be an effective treatment for LGS, but complete seizure control is rarely achieved. Outcomes may be improved by stimulating areas beyond the thalamus, including cortex, but the optimal targets are unknown. METHODS: Brain network maps from 3 group-level studies of LGS were averaged to define the area of peak overlap: combined electroencephalography-functional MRI (EEG-fMRI) of paroxysmal fast activity, [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) of hypometabolism, and structural connectivity associated with efficacy in a previous trial of deep brain stimulation. The resulting “hotspot” was used as a seed in a normative fMRI connectivity analysis to identify connected networks. Two patients underwent bilateral thalamocortical implantations guided by this hotspot. Simultaneous recordings from cortex and thalamus were analyzed for presence and synchrony of epileptiform activity. RESULTS: Peak overlap was in bilateral premotor cortex. Functional connectivity of this hotspot revealed a network of frontoparietal cortex resembling the diffuse abnormalities seen on EEG-fMRI and FDG-PET. Intracranial electrophysiology showed characteristic epileptiform activity of LGS in the cortical hotspot that preceded or co-occurred with similar thalamic activity. CONCLUSIONS: Premotor cortex shows peak involvement in LGS, and functional connectivity of this region resembles the wider epileptic brain network. Thus, it may be an optimal target for neuromodulation therapies, including thalamocortical stimulation. Compared to thalamus-only stimulation, addition of this cortical target may allow more rapid detections and responsive stimulations of seizures, and broader modulation of the brain network underlying LGS to achieve greater seizure control.
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