Hippocampal interictal spikes disrupt cognition in rats

Abstract

Objective-Cognitive impairment is common in epilepsy, particularly in memory function. Interictal spikes are thought to disrupt cognition, but it is difficult to delineate their contribution from general impairments in memory produced by etiology and seizures. We investigated the transient impact of focal interictal spikes on the hippocampus, a structure crucial for learning and memory and yet highly prone to interictal spikes in temporal lobe epilepsy.Methods-Bilateral hippocampal depth electrodes were implanted into fourteen Sprague-Dawley rats, followed by intrahippocampal pilocarpine or saline infusion unilaterally. Rats that developed chronic spikes were trained in a hippocampal-dependent operant behavior task, delayed-match-tosample. Depth EEG was recorded during 5,562 trials among five rats, and within-subject analyses evaluated the impact of hippocampal spikes on short-term memory operations.Results-Hippocampal spikes that occurred during memory retrieval strongly impaired performance (p<0.001). However, spikes that occurred during memory encoding or memory maintenance did not affect performance in those trials. Hippocampal spikes also affected response latency, adding approximately 0.48 seconds to the time taken to respond (p<0.001).Interpretation-We found that focal interictal spike-related interference in cognition extends to structures in the limbic system, which required intrahippocampal recordings. Hippocampal spikes seem most harmful if they occur when hippocampal function is critical, extending human studies showing that cortical spikes are most disruptive during active cortical functioning. The cumulative effects of spikes could therefore impact general cognitive functioning. These results strengthen the argument that suppression of interictal spikes may improve memory and cognitive performance in patients with epilepsy.

“Untangling” Alzheimer's Disease and Epilepsy

“…interictal spikes impair fundamental neurobiological phenomena associated with memory formation and consolidation (12,13). These studies and others provided support for the idea that even brief episodes of epileptiform activity (e.g., interictal spikes) can impair memory.…”

Hippocampal interictal epileptiform activity disrupts cognition in humans

“…One study 13 showed a 6% decline in working memory performance related to mesial temporal IED. However, as demonstrated in previous studies of cortical IED, 9,10 the degree of cognitive impact could have been underestimated since the authors did not consider 1) the precise timing of the IED within the memory task trials and 2) the specific components involved in memory processing.Using a rodent model of TLE, 14 we recently found that hippocampal IED were related to considerable decrements in short-term memory retrieval but not memory encoding or maintenance. Therefore, the cognitive impact of IED in the hippocampus may be substantially more important than previously documented.…”

“…Using a rodent model of TLE, 14 we recently found that hippocampal IED were related to considerable decrements in short-term memory retrieval but not memory encoding or maintenance. Therefore, the cognitive impact of IED in the hippocampus may be substantially more important than previously documented.…”

“…Interrater reliability was greater than 95%. Based on our previous rodent study, 14 3 stages of short-term memory processing were inferred in the task a priori: encoding (time window from 2 seconds before to 2 seconds after the List presentation onset), maintenance (the subsequent 4-second window), and retrieval (4-second window immediately prior to the patient's response). IED were classified according to whether or not they fell within these epochs during the Sternberg trials (e.g., retrieval IED were those that occurred within the 4-second window preceding the patient's response).…”

“…DISCUSSION We show that hippocampal IED may be associated with greater decrements in memory performance than previously reported, 13 depending on their timing and location. We also provide the first clinical translation of IED-associated transient cognitive impairment findings across species, from a rodent model 14 to patients with epilepsy.…”