Mechanisms for Cognitive Impairment in Epilepsy: Moving Beyond Seizures

Overview

Journal Front Neurol

Specialty Neurology

Date 2022 Jun 1

PMID 35645970

Authors

Mohamed R Khalife

Rod C Scott

Amanda E Hernan

Affiliations

Soon will be listed here.

Abstract

There has been a major emphasis on defining the role of seizures in the causation of cognitive impairments like memory deficits in epilepsy. Here we focus on an alternative hypothesis behind these deficits, emphasizing the mechanisms of information processing underlying healthy cognition characterized as rate, temporal and population coding. We discuss the role of the underlying etiology of epilepsy in altering neural networks thereby leading to both the propensity for seizures and the associated cognitive impairments. In addition, we address potential treatments that can recover the network function in the context of a diseased brain, thereby improving both seizure and cognitive outcomes simultaneously. This review shows the importance of moving beyond seizures and approaching the deficits from a system-level perspective with the guidance of network neuroscience.

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References

Liu X, Muller R, Huang L, Kubie J, Rotenberg A, Rivard B . Seizure-induced changes in place cell physiology: relationship to spatial memory. J Neurosci. 2003; 23(37):11505-15. PMC: 6740937. View

Bettus G, Bartolomei F, Confort-Gouny S, Guedj E, Chauvel P, Cozzone P . Role of resting state functional connectivity MRI in presurgical investigation of mesial temporal lobe epilepsy. J Neurol Neurosurg Psychiatry. 2010; 81(10):1147-54. DOI: 10.1136/jnnp.2009.191460. View

Smeding H, Speelman J, Huizenga H, Schuurman P, Schmand B . Predictors of cognitive and psychosocial outcome after STN DBS in Parkinson's Disease. J Neurol Neurosurg Psychiatry. 2009; 82(7):754-60. DOI: 10.1136/jnnp.2007.140012. View

Lu L, Leutgeb J, Tsao A, Henriksen E, Leutgeb S, Barnes C . Impaired hippocampal rate coding after lesions of the lateral entorhinal cortex. Nat Neurosci. 2013; 16(8):1085-93. DOI: 10.1038/nn.3462. View

Hunt R, Girskis K, Rubenstein J, Alvarez-Buylla A, Baraban S . GABA progenitors grafted into the adult epileptic brain control seizures and abnormal behavior. Nat Neurosci. 2013; 16(6):692-7. PMC: 3665733. DOI: 10.1038/nn.3392. View

Lohnas L, Duncan K, Doyle W, Thesen T, Devinsky O, Davachi L . Time-resolved neural reinstatement and pattern separation during memory decisions in human hippocampus. Proc Natl Acad Sci U S A. 2018; 115(31):E7418-E7427. PMC: 6077719. DOI: 10.1073/pnas.1717088115. View

McGill M, Devinsky O, Kelly C, Milham M, Castellanos F, Quinn B . Default mode network abnormalities in idiopathic generalized epilepsy. Epilepsy Behav. 2012; 23(3):353-9. PMC: 4407647. DOI: 10.1016/j.yebeh.2012.01.013. View

Hunt R, Baraban S . Interneuron Transplantation as a Treatment for Epilepsy. Cold Spring Harb Perspect Med. 2015; 5(12). PMC: 4665034. DOI: 10.1101/cshperspect.a022376. View

Wesnes K, Annas P, Basun H, Edgar C, Blennow K . Performance on a pattern separation task by Alzheimer's patients shows possible links between disrupted dentate gyrus activity and apolipoprotein E ∈4 status and cerebrospinal fluid amyloid-β42 levels. Alzheimers Res Ther. 2014; 6(2):20. PMC: 4054957. DOI: 10.1186/alzrt250. View

10.

Tolhurst D, Movshon J, Dean A . The statistical reliability of signals in single neurons in cat and monkey visual cortex. Vision Res. 1983; 23(8):775-85. DOI: 10.1016/0042-6989(83)90200-6. View

11.

Pouget A, Dayan P, Zemel R . Information processing with population codes. Nat Rev Neurosci. 2001; 1(2):125-32. DOI: 10.1038/35039062. View

12.

van Diessen E, Zweiphenning W, Jansen F, Stam C, Braun K, Otte W . Brain Network Organization in Focal Epilepsy: A Systematic Review and Meta-Analysis. PLoS One. 2014; 9(12):e114606. PMC: 4262431. DOI: 10.1371/journal.pone.0114606. View

13.

Coan A, Appenzeller S, Bonilha L, Li L, Cendes F . Seizure frequency and lateralization affect progression of atrophy in temporal lobe epilepsy. Neurology. 2009; 73(11):834-42. DOI: 10.1212/WNL.0b013e3181b783dd. View

14.

Fries P . A mechanism for cognitive dynamics: neuronal communication through neuronal coherence. Trends Cogn Sci. 2005; 9(10):474-80. DOI: 10.1016/j.tics.2005.08.011. View

15.

Bernhardt B, Worsley K, Besson P, Concha L, Lerch J, Evans A . Mapping limbic network organization in temporal lobe epilepsy using morphometric correlations: insights on the relation between mesiotemporal connectivity and cortical atrophy. Neuroimage. 2008; 42(2):515-24. DOI: 10.1016/j.neuroimage.2008.04.261. View

16.

Hammad M, Schmidt S, Zhang X, Bray R, Frohlich F, Ghashghaei H . Transplantation of GABAergic Interneurons into the Neonatal Primary Visual Cortex Reduces Absence Seizures in Stargazer Mice. Cereb Cortex. 2014; 25(9):2970-9. PMC: 4537440. DOI: 10.1093/cercor/bhu094. View

17.

Sinjab B, Martinian L, Sisodiya S, Thom M . Regional thalamic neuropathology in patients with hippocampal sclerosis and epilepsy: a postmortem study. Epilepsia. 2013; 54(12):2125-33. PMC: 3995016. DOI: 10.1111/epi.12403. View

18.

Anderson J, Carandini M, Ferster D . Orientation tuning of input conductance, excitation, and inhibition in cat primary visual cortex. J Neurophysiol. 2000; 84(2):909-26. DOI: 10.1152/jn.2000.84.2.909. View

19.

Petsche H, Stumpf C, GOGOLAK G . [The significance of the rabbit's septum as a relay station between the midbrain and the hippocampus. I. The control of hippocampus arousal activity by the septum cells]. Electroencephalogr Clin Neurophysiol. 1962; 14:202-11. DOI: 10.1016/0013-4694(62)90030-5. View

20.

Snowball A, Chabrol E, Wykes R, Shekh-Ahmad T, Cornford J, Lieb A . Epilepsy Gene Therapy Using an Engineered Potassium Channel. J Neurosci. 2019; 39(16):3159-3169. PMC: 6468110. DOI: 10.1523/JNEUROSCI.1143-18.2019. View