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

Abstract

Background: 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.

Methods: 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).

Results: 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.

Conclusion: 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.

Keywords: functional connectivity; graph theory; hippocampus; insula; resting state.

Figure 1

Selected cortical and subcortical regions of interest (ROIs) masks from Harvard-Oxford (HO) atlas. (A) Sagittal (top) and axial (bottom) views of the frontal medial cortex (FMC); (B) sagittal (top) and axial (bottom) views of the subcallosal cortex (SC); (C) coronal (top) and axial (bottom) views of orbitofrontal cortex (OFC); (D) axial view of insulae (Ins); (E) sagittal view of anterior cingulate cortex (ACC); (F) sagittal view of thalamus; (G) sagittal view of hippocampus; (H) coronal view of amygdalae; (I) axial view of putamen; (J) axial view of caudate; and (K) coronal view of brain stem (includes midbrain, pons, and medulla).

Figure 2

Reduced functional connectivity (FC) subnetwork in high risk over lower risk of sudden unexpected death in epilepsy (SUDEP) patients. Subnetwork of reduced FC involving the bilateral brain stem (Bstem), bilateral thalamus (Thal), bilateral putamen (Put), bilateral ACC, and left amygdala (Amyg). L, left; r, right; HS, hippocampal sclerosis; t, t-statistic threshold; M, number of permutations; p value was set at <0.05, family-wise error rate (FWER) corrected. Nodes in white are those which were involved in the significant subnetwork. Red node outline represents search for reduced connectivity (high < low). Visualization using Gephi (https://gephi.org/).

Figure 3

Increased functional connectivity (FC) subnetwork in high risk over lower risk of sudden unexpected death in epilepsy (SUDEP) patients. Subnetwork of enhanced FC in high-risk temporal lobe epilepsy (TLE) patients when compared with low-risk TLE patients. Regions include: bilateral amygdala (L Amyg, R Amyg), right brain stem (R Bstem), right caudate (R Caud), bilateral frontal medial cortex (L FMC, R FMC), bilateral hippocampus (L Hipp, R Hipp), bilateral insula (L Ins, R Ins), bilateral orbitofrontal cortex (L OFC, R OFC), right putamen (R Put), bilateral subcallosal cortex (L SC, R SC), and the left thalamus (L Thal). L, left; R, right; HS, hippocampal sclerosis; t, t-statistic threshold; M, number of permutations; p value was set at <0.05, family-wise error rate (FWER) corrected. White nodes represent ROIs involving significant connections. Blue node outline represents search for increased connectivity (high > low). Visualization using Gephi (https://gephi.org/).