Extent of Single-Neuron Activity Modulation by Hippocampal Interictal Discharges Predicts Declarative Memory Disruption in Humans

Abstract

Memory deficits are common in epilepsy patients. In these patients, the interictal EEG 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 of 728 neurons were significantly modulated by IEDs, with the strongest modulation in the medial temporal lobe (33 of 416) and in particular the right hippocampus (12 of 58). Putative inhibitory neurons, as identified by their extracellular signature, were more likely to be modulated by IEDs than putative excitatory neurons (19 of 157 vs 31 of 571). Behaviorally, the occurrence of hippocampal IEDs was accompanied by a disruption of recognition of familiar images only if they occurred up to 2 s 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, these data link 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 medial temporal lobe-dependent declarative memory retrieval processes.

Spatiotemporal dynamics between interictal epileptiform discharges and ripples during associative memory processing

“…While IEDs have previously been demonstrated to interfere with sleep-dependent memory consolidation (Gelinas et al, 2016), our work suggests that IEDs also interfere with the physiological processes supporting memory encoding and recall. IEDs likely trigger a prolonged cortical downstate (Gelinas et al, 2016), as supported by a recent study demonstrating IED modulation of inhibitory interneurons in the medial temporal lobe (Reed et al, 2020). The state-dependent decrease in ripple activity after IEDs imply that IEDs are not merely an epiphenomenon of a drowsy or distracted state (Kleen and Kirsch, 2017), but rather trigger decreases in physiological ripples necessary for memory.…”

Single‐neuron correlate of epilepsy‐related cognitive deficits in visual recognition memory in right mesial temporal lobe

“…Although IEDs are generally rare, their occurrence is correlated with impaired memory 42 , 43 , 44 and they transiently entrain neurons within the MTL. 45 It remains an open question whether the selective impairment of MS but not VS cells can be explained by selective entrainment of these neurons by IEDs. Third, memory‐related gamma‐band and other electrophysiological activity is impaired within the SOZ.…”

Temporal Lobe Epilepsy and Alzheimer’s Disease: From Preclinical to Clinical Evidence of a Strong Association

“…Moreover, it was found that IEAs outside a left hemispheric seizure onset zone impacted memory encoding, recall, and retrieval, while those inside the seizure onset zone did not [ 92 ]. Very recently, utilizing single-neuron recordings in patients with medically refractory epilepsy, some authors [ 95 ] demonstrated that hippocampal IEAs transiently changed 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 IEAs predicted the extent of reduction of subjective retrieval confidence. These findings have been observed in patients with refractory seizures by use of depth electrodes.…”