Interictal Epileptiform Discharges in the Hippocampus as Biomarkers of Memory Dysfunction in Epilepsy and Alzheimer's Disease

Objective

Cognitive impairment is common in patients with epilepsy (PWE) and can severely affect the quality of life. Interictal epileptiform discharges (IEDs) are transient abnormal electrophysiological events happening between seizures, associated with transient cognitive impairment in PWE and observed in patients and rodents with Alzheimer"s disease (AD). IEDs interfere with physiologic oscillations during sleep that are instrumental for memory consolidation, specifically hippocampal sharp-wave ripples (SWRs) and cortical spindles. Recently we demonstrated a negative effect of IEDs on memory consolidation and SWRs in the hippocampal CA1 region in an AD mouse model. Here we characterize the negative impact of IEDs in other hippocampal subfields and in human hippocampal recordings.

Methods

We analyzed the spread of IEDs and their impact on neuronal firing in the hippocampus in two distinct settings. First, we investigated IEDs on 312 hours of human microwire data (Behnke-Fried electrodes) from the hippocampus of surgical PWE with temporal (n=8) and extratemporal (n=7) epilepsy focus. The anatomical locations of the microwires and macroelectrodes were determined via CT-MRI co-registration and hippocampal subfield segmentation (ASHS software). Next, we obtained high-density recordings from the entire dorsal hippocampus (1024 Channel, SiNAPS, Neuronexus) from adult AD transgenic mice (APP/S1, n=5) and analysed the data by hippocampal subfields.

Results

We observed IEDs in the hippocampus of epilepsy patients with temporal and frontal lobe foci and in AD mice, independent of seizure generation or seizure onset zone. SWRs were only detected on electrodes in the CA1 and CA2 regions in all rodents and only in a subset of patients, possibly because of location of the recording electrode outside the CA1/CA2 region. By contrast IEDs were easily detected in human microwire recordings. IEDs showed similar local field potential features and waveforms in both subject groups, and quickly generalized across channels, leading to global suppression of neuronal firing, that could explain the previously observed interruption of physiologic signaling. The high-density rodent recordings demonstrated that the IED spread respected anatomical pathways.

Conclusion

IEDs may be a suitable biomarker for treatment of memory disorders in epilepsy and Alzheimer's Disease by targeted closed-loop stimulation, because of their impact on neuronal firing and feasible detection.