Dysfunctional Brain Networking among Autonomic Regulatory Structures in Temporal Lobe Epilepsy Patients at High Risk of Sudden Unexpected Death in Epilepsy

Luke A. Allen, Ronald M. Harper, Rajesh Kumar, Maxime Guye, Jennifer A Ogren, Samden D. Lhatoo, Louis Lemieux, Catherine A. Scott, Sjoerd B. Vos, Sandhya Rani, Beate Diehl

Sudden unexpected death in epilepsy (SUDEP) is common among young people with epilepsy. Individuals who are at high risk of SUDEP exhibit regional brain structural and functional connectivity (FC) alterations compared with low-risk patients. However, less is known about network-based FC differences among critical cortical and subcortical autonomic regulatory brain structures in temporal lobe epilepsy (TLE) patients at high risk of SUDEP. 32 TLE patients were risk-stratified according to the following clinical criteria: age of epilepsy onset, duration of epilepsy, frequency of generalized tonic-clonic seizures, and presence of nocturnal seizures, resulting in 14 high-risk and 18 low-risk cases. Resting-state functional magnetic resonance imaging (rs-fMRI) signal time courses were extracted from 11 bilateral cortical and subcortical brain regions involved in autonomic and other regulatory processes. After computing all pairwise correlations, FC matrices were analyzed using the network-based statistic. FC strength among the 11 brain regions was compared between the high- and low-risk patients. Increases and decreases in FC were sought, using high-risk > low-risk and low-risk > high-risk contrasts (with covariates age, gender, lateralization of epilepsy, and presence of hippocampal sclerosis). High-risk TLE patients showed a subnetwork with significantly reduced FC (t = 2.5, p = 0.029) involving the thalamus, brain stem, anterior cingulate, putamen and amygdala, and a second subnetwork with significantly elevated FC (t = 2.1, p = 0.031), which extended to medial/orbital frontal cortex, insula, hippocampus, amygdala, subcallosal cortex, brain stem, thalamus, caudate, and putamen. TLE patients at high risk of SUDEP showed widespread FC differences between key autonomic regulatory brain regions compared to those at low risk. The altered FC revealed here may help to shed light on the functional correlates of autonomic disturbances in epilepsy and mechanisms involved in SUDEP. Furthermore, these findings represent possible objective biomarkers which could help to identify high-risk patients and enhance SUDEP risk stratification via the use of non-invasive neuroimaging, which would require validation in larger cohorts, with extension to patients with other epilepsies and subjects who succumb to SUDEP.