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Neuroscience Institute Journal Club 2016 Articles Seizures Disrupt Memory Network

Seizures Disrupt Memory Network

Epilepsy is a common neurologic condition affecting up to 1 percent of the population. Although epilepsy is defined by its obligatory symptom, the occurrence of spontaneous seizures, it brings with it a host of serious comorbidities that can similarly affect health and quality of life. Cognitive dysfunction is the most prevalent of these comorbidities, but how epileptic activity impairs neural networks involved in cognition is unclear, and no targeted treatments for this dysfunction currently exist.

In our recent work (Gelinas et al., 2016), we investigated how the epileptic activity that occurs between seizures (interictal epileptiform discharges, or IEDs) affects memory consolidation and the underlying neural network mechanisms involved. We focus on the hippocampus and medial prefrontal cortex (mPFC) because the interaction between these two structures has been shown to be important for consolidation of hippocampus-dependent memory. Specifically, high-frequency hippocampal oscillations (ripples) are temporally coupled to lower frequency cortical oscillations (spindles) during non-rapid eye movement (NREM) sleep to facilitate transfer of information from temporary storage in the hippocampus to long-term storage in the cortex.

We used an established animal model of epilepsy, hippocampal kindling, which involves induction of repeated, electrically induced seizures in rats to prime their hippocampi to generate spontaneous IEDs that mimic those seen in patients with temporal lobe epilepsy. We then simultaneously recorded in vivo from the hippocampus and mPFC of these rats during the consolidation period between learning hippocampus-dependent spatial information and retrieving this information 24 hours later. The rate of occurrence of hippocampal IEDs during NREM sleep in the consolidation period was strongly correlated with poor performance on the task, suggesting that IEDs impair consolidation of memory.

To understand how hippocampal IEDs interfered with memory consolidation in our rats, we examined their effects on hippocampal ripples and cortical spindles. We found that in the hippocampus, as the number of IEDs increased, the number of ripples decreased. Furthermore, hippocampal IEDs were able to evoke spindles in the mPFC at a well-defined latency, consistent with the creation of pathological coupling between these structures.

But do these findings translate from an animal model of epilepsy to patients with epilepsy? We looked at electrophysiological recordings from the brains of patients with temporal lobe epilepsy, obtained for the clinical purpose of determining whether they were candidates for epilepsy surgery to control their seizures. Similar to what we observed in epileptic rats, IEDs in the temporal lobe structures of these patients were coupled to spindles predominantly in the frontal cortical regions.

Our results suggest that IEDs could in effect broadcast “nonsense” information to downstream cortical structures, which respond by generating a spindle that would normally function to integrate information into the local cortical network. In this way, integration of pathologic epileptic activity may overwhelm the physiologic mechanisms of memory consolidation and contribute to cognitive impairment. Closed loop systems may allow us to decouple epileptic brain structures from their downstream targets, opening a new avenue for therapeutics of cognitive comorbidity in patients with epilepsy.

—Jennifer N. Gelinas, MD, PhD

Read the paper “Interictal epileptiform discharges induce hippocampal–cortical coupling in temporal lobe epilepsy” in Nature Medicine, published April 25, 2016.