Hippocampal interictal epileptiform activity disrupts cognition in humans

Abstract

Objective: We investigated whether interictal epileptiform discharges (IED) in the human hippocampus are related to impairment of specific memory processes, and which characteristics of hippocampal IED are most associated with memory dysfunction.

Methods: Ten patients had depth electrodes implanted into their hippocampi for preoperative seizure localization. EEG was recorded during 2,070 total trials of a short-term memory task, with memory processing categorized into encoding, maintenance, and retrieval. The influence of hippocampal IED on these processes was analyzed and adjusted to account for individual differences between patients.

Results: Hippocampal IED occurring in the memory retrieval period decreased the likelihood of a correct response when they were contralateral to the seizure focus (p < 0.05) or bilateral (p < 0.001). Bilateral IED during the memory maintenance period had a similar effect (p < 0.01), particularly with spike-wave complexes of longer duration (p < 0.01). IED during encoding had no effect, and reaction time was also unaffected by IED.

Conclusions: Hippocampal IED in humans may disrupt memory maintenance and retrieval, but not encoding. The particular effects of bilateral IED and those contralateral to the seizure focus may relate to neural compensation in the more functional hemisphere. This study provides biological validity to animal models in the study of IED-related transient cognitive impairment. Moreover, it strengthens the argument that IED may contribute to cognitive impairment in epilepsy depending upon when and where they occur.

Figure 1. Examples of depth electrode placement and hippocampal interictal epileptiform discharges

(A) Bilateral depth electrodes visualized by coregistered MRI and CT imaging. From anterior to posterior, contacts are located in the amygdala, hippocampal formation, lateral ventricles, white matter, and occipital cortex. (B) EEG signals illustrate a type 1 IED: repetitive spike-wave complex. From top to bottom, the depth-EEG signals shown are from contacts oriented from anterior to posterior, as illustrated in (A) (i.e., lead 1 is most anterior). (C) Type 2 IED: single spike or spike-wave. (D) Type 3 IED: shown are 2 examples of IED that did not show classical spike or spike-wave morphology. The left panel illustrates aberrant rhythmic activity, while the right panel shows a broad-based high-amplitude sharp wave.

Figure 2. Layout of the Sternberg task

(A) Sternberg trial in which the Test letter is in the previous List sequence. During the intertrial interval (3 seconds), a cross is displayed, followed by the List sequence (2 seconds). A fixation dot is then shown (6 seconds), after which the Test letter is displayed (2 seconds). A correct response in this case would be a left mouse click (“Yes”). (B) A Sternberg trial in which the Test letter is not in the previous List sequence. A correct response in this case would be a right mouse click (“No”). (C) A Lure trial in which the List is always “AAAA” and the Test letter is always “A.” The patient must simply respond with a left mouse click (“Yes”) as soon as the Test letter is shown.

Figure 3. Influence of interictal epileptiform discharges during memory retrieval on accuracy

Predicted odds ratios are shown for the influence of interictal epileptiform discharges that were ipsilateral or contralateral to the seizure focus, or bilateral. Error bars indicate 95% confidence intervals. Contralateral and bilateral spikes during retrieval significantly decreased the likelihood of responding correctly during a trial.

Figure 4. Reaction time in trials with and without interictal epileptiform discharges

The figure shows histograms of the relative frequencies of reaction time in trials without interictal epileptiform discharges (IED) (thick solid blue line) and trials with IED (thick solid red line). The median reaction time was not significantly different between trials without IED (1.085 seconds; solid blue vertical line) and trials with IED (1.100 seconds; dotted red vertical line).