Temporal lobe epilepsy (TLE) is the most common epilepsy in humans undergoing epilepsy surgery. Many of these patients have associated cognitive impairments, particularly in the domain of memory which is an essential, higher cognitive function required for continuity in time, personal history and awareness. The cognitive impairments are no doubt a result of a combination of the brain abnormalities responsible for the disorder, although the mechanisms of this relation remain a mystery. Our laboratory has recently pursued the underlying mechanisms responsible for dynamic cognitive dysfunction in the lithium-pilocarpine model of TLE finding that interictal spikes (IIS), dysfunctions in network oscillation activity (EEG rhythms) and uncoordinated single-neuron firing impact the performance of the animal in a hippocampal- dependent task. We now propose to investigate whether similar mechanisms are at play in humans. These data will ultimately be important for informing therapeutic strategies designed to minimize the cognitive effects of TLE, as well as a better understanding of the pathophysiology of epilepsy on a dynamic level. Three integrated specific aims are proposed. In the first specific aim we will determine the transient effects of IIS on memory, reaction time and related hippocampal oscillations during a hippocampal-dependent memory task in humans. We hypothesize that IIS contribute to memory impairment in patients with TLE through direct impairment of neural processes underlying memory and by disruption of hippocampal oscillations. In the second aim we will investigate the relationships between single unit neural activity and hippocampal oscillations and performance in patients with TLE. Owing to extensive animal work, we hypothesize that deficits in spatial cognition and memory in patients with TLE are due to impaired single unit firing and temporal coding of action potentials. Based on animal data showing impaired coherence in rats with a prior history of seizures, in the third aim we will determine the impact of TLE and related IIS on neuronal network oscillation and cognition, hypothesizing that deficits in working memory in patients with TLE are due to impaired coherence in hippocampal-prefrontal cortex pathways and additional transient coherence disturbances due to IIS. Taken together these three aims will provide considerable insight into the mechanisms of cognitive impairment in TLE. Armed with this information, therapeutic strategies with a scientific basis will be used to treat this devastating comorbidity.

Public Health Relevance

Lay Summary Cognitive impairment as manifested by problems with attention span, learning and memory are a devastating co-morbidity of temporal lobe epilepsy, the most common type of epilepsy. In this study, we will determine the mechanisms of cognitive impairment in epilepsy using patients undergoing evaluation with intracranial electroencephalography electrodes. This information will be invaluable in designing strategies to prevent and treat epilepsy-related cognitive impairment.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Acute Neural Injury and Epilepsy Study Section (ANIE)
Program Officer
Fureman, Brandy E
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Dartmouth College
Schools of Medicine
United States
Zip Code
Horak, Peter C; Meisenhelter, Stephen; Song, Yinchen et al. (2017) Interictal epileptiform discharges impair word recall in multiple brain areas. Epilepsia 58:373-380
Buckley, Ashura W; Holmes, Gregory L (2016) Epilepsy and Autism. Cold Spring Harb Perspect Med 6:a022749
Kleen, Jonathan K; Testorf, Markus E; Roberts, David W et al. (2016) Oscillation Phase Locking and Late ERP Components of Intracranial Hippocampal Recordings Correlate to Patient Performance in a Working Memory Task. Front Hum Neurosci 10:287
Holmes, Gregory L (2016) Effect of Seizures on the Developing Brain and Cognition. Semin Pediatr Neurol 23:120-6
Barry, Jeremy M; Tian, Chengju; Spinella, Anthony et al. (2016) Spatial cognition following early-life seizures in rats: Performance deficits are dependent on task demands. Epilepsy Behav 60:1-6
Mahoney, J Matthew; Titiz, Ali S; Hernan, Amanda E et al. (2016) Short-Range Temporal Interactions in Sleep; Hippocampal Spike Avalanches Support a Large Milieu of Sequential Activity Including Replay. PLoS One 11:e0147708
Holmes, Gregory L (2015) Cognitive impairment in epilepsy: the role of network abnormalities. Epileptic Disord 17:101-16
Flynn, Sean P; Barriere, Sylvain; Barrier, Sylvain et al. (2015) Status Epilepticus Induced Spontaneous Dentate Gyrus Spikes: In Vivo Current Source Density Analysis. PLoS One 10:e0132630
Jobst, Barbara C; Engel Jr, Jerome (2015) Is it time to replace epileptic spikes with fast ripples? Neurology 85:114-5
Savotchenko, Alina; Romanov, Arthur; Isaev, Dmytro et al. (2015) Neuraminidase inhibition primes short-term depression and suppresses long-term potentiation of synaptic transmission in the rat hippocampus. Neural Plast 2015:908190

Showing the most recent 10 out of 28 publications