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)
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
Nair, Swayamprabha; Morse, Richard P; Mott, Stephen H et al. (2014) Transitory effect of spike and spike-and-wave discharges on EEG power in children. Brain Dev 36:505-9
Burroughs, Scott A; Morse, Richard P; Mott, Steven H et al. (2014) Brain connectivity in West syndrome. Seizure 23:576-9
Titiz, A S; Mahoney, J M; Testorf, M E et al. (2014) Cognitive impairment in temporal lobe epilepsy: role of online and offline processing of single cell information. Hippocampus 24:1129-45
Noam, Yoav; Raol, Yogendra H; Holmes, Gregory L (2013) Searching for new targets for treatment of pediatric epilepsy. Epilepsy Behav 26:253-60
Holmes, Gregory L (2013) EEG abnormalities as a biomarker for cognitive comorbidities in pharmacoresistant epilepsy. Epilepsia 54 Suppl 2:60-2
Bender, Alex C; Natola, Heather; Ndong, Christian et al. (2013) Focal Scn1a knockdown induces cognitive impairment without seizures. Neurobiol Dis 54:297-307
Bender, Alex C; Morse, Richard P; Scott, Rod C et al. (2012) SCN1A mutations in Dravet syndrome: impact of interneuron dysfunction on neural networks and cognitive outcome. Epilepsy Behav 23:177-86