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Front Neurol. 2017 Oct 16;8:544. doi: 10.3389/fneur.2017.00544. eCollection 2017.

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

Allen LA1,2,3, Harper RM3,4,5, Kumar R3,5,6,7,8, Guye M9, Ogren JA3,4, Lhatoo SD3,10, Lemieux L1,2, Scott CA1,3, Vos SB2,3,11, Rani S3,10, Diehl B1,2,3.

Author information

1
Institute of Neurology, University College London, London, United Kingdom.
2
Epilepsy Society, Chalfont St. Peter, United Kingdom.
3
The Center for SUDEP Research, National Institute of Neurological Disorders and Stroke, Bethesda, MD, United States.
4
Department of Neurobiology, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States.
5
UCLA Brain Research Institute, Los Angeles, CA, United States.
6
Department of Anaesthesiology, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States.
7
Department of Radiological Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States.
8
Department of Bioengineering, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States.
9
Aix Marseille University, CNRS, CRMBM UMR 7339, Marseille, France.
10
Epilepsy Centre, Neurological Institute, University Hospitals Case Medical Centre, Cleveland, OH, United States.
11
Translational Imaging Group, University College London, London, United Kingdom.

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

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