Abstracts

Rationale: Recent work has demonstrated that focal seizures in temporal lobe epilepsy (TLE) are associated with decreased brainstem connectivity that is related to disease severity and neurocognitive performance.^1,2 We hypothesize that over time, recurrent ictal events lead to interictal dysfunction of the brainstem ascending reticular activating system (ARAS), which may contribute to neurocognitive deficits. This is supported by our recent magnetic resonance imaging (MRI) studies of pre-operative patients with TLE, which showed decreased ARAS connectivity.¹ Specifically, TLE patients demonstrated decreased connectivity between three ARAS structures – cuneiform/subcuneiform nuclei (CSC), pedunculopontine nucleus (PPN), and ventral tegmental area (VTA) – and fronto-parietal neocortical regions. In this work, we investigate whether these connectivity disturbances will improve with successful epilepsy surgery. Methods: We evaluated 15 adult TLE patients before and after (> 1 year; mean, 3.4 years) epilepsy surgery, and 15 matched control subjects, and used MRI to measure ARAS functional connectivity, including CSC, PPN, and VTA. Results: TLE patients who achieved seizure freedom after surgery (10 of 15) demonstrated increases in functional connectivity between ARAS structures and fronto-parietal-insular neocortex compared to pre-operative baseline (p<0.05, Kruskal-Wallis). In seizure free post-operative patients, greater increases in CSC, PPN, and VTA functional connectivity were observed in persons who experienced more frequent seizures before surgery (p<0.05, Spearman’s Rho, corrected). Also, greater post-operative increases in PPN connectivity were seen in patients with lower baseline verbal IQ (p<0.05, Spearman’s Rho, uncorrected) or verbal memory (p<0.05, Mann-Whitney U, corrected). Conclusions: Brainstem ARAS functional connectivity disturbances are present in pre-operative TLE patients but may recover after successful epilepsy surgery. Some post-operative connectivity patterns may increase with time after surgery and others may be related to pre-operative seizure frequency. These results are the first to demonstrate connectivity improvements after epilepsy surgery and may lead to the identification of brainstem neuromodulation targets to address aberrant connectivity patterns and neurocognitive sequelae in this devastating disorder.References:1. Englot, D. J. et al. Relating structural and functional brainstem connectivity to disease measures in epilepsy. Neurology ((In Press 2018)).2. Englot, D. J. et al. Functional connectivity disturbances of the ascending reticular activating system in temporal lobe epilepsy. J Neurol Neurosurg Psychiatry 88, 925-932, doi:10.1136/jnnp-2017-315732 (2017). Funding: This work was supported in part by the NIH grants R00 NS097618 (DJE), R01 NS075270 (VLM), T32 EB021937 (HJFG), and T32 GM07347 (HJFG)..