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J Neurosci. 2019 Nov 21. pii: 1380-19. doi: 10.1523/JNEUROSCI.1380-19.2019. [Epub ahead of print]

Extent of single-neuron activity modulation by hippocampal interictal discharges predicts declarative memory disruption in humans.

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Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA 90048.
Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, CA 90048.
Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA 90048
Center for Neural Science and Medicine, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048.
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena CA, 91125.


Memory deficits are common in epilepsy patients. In these patients, the interictal electroencephalography commonly shows interictal epileptiform discharges (IEDs). While IEDs are associated with transient cognitive impairments, it remains poorly understood why this is. We investigated the effects of human (male and female) hippocampal IEDs on single-neuron activity during a memory task in patients with medically-refractory epilepsy undergoing depth electrode monitoring. We quantified the effects of hippocampal IEDs on single-neuron activity and the impact of this modulation on subjectively declared memory strength. Across all recorded neurons, the activity of 50/728 neurons were significantly modulated by IEDs, with the strongest modulation in the MTL (33/416) and in particular the right hippocampus (12/58). Putative inhibitory neurons, as identified by their extracellular signature, where more likely to be modulated by IEDs than putative excitatory neurons (19/157 vs. 31/571). Behaviorally, the occurrence of hippocampal IEDs was accompanied by a disruption of recognition of familiar images only if they occurred up to 2s before stimulus onset. In contrast, IEDs did not impair encoding or recognition of novel images, indicating high temporal and task specificity of the effects of IEDs. The degree of modulation of individual neurons by an IED correlated with the declared confidence of a retrieval trial, with higher firing rates indicative of reduced confidence. Together, this data links the transient modulation of individual neurons by IEDs to specific declarative memory deficits in specific cell types, thereby revealing a mechanism by which IEDs disrupt MTL-dependent declarative memory retrieval processes.SIGNIFICANCE STATEMENTInterictal epileptiform discharges (IEDs) are thought to be a cause of memory deficits in chronic epilepsy patients, but the underlying mechanisms are not understood. Utilizing single-neuron recordings in epilepsy patients, we found that hippocampal IEDs transiently change firing of hippocampal neurons and disrupted selectively the retrieval, but not encoding, of declarative memories. The extent of the modulation of the individual firing of hippocampal neurons by an IED predicted the extent of reduction of subjective retrieval confidence. Together, this data reveal a specific kind of transient cognitive impairment caused by IEDs and link this impairment to the modulation of the activity of individual neurons. Understanding the mechanisms by which IEDs impact memory is critical for understanding memory impairments in epilepsy patients.

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