Interictale Spikes im Hippocampus als Biomarker für Gedächtnisstörungen für Epilepsie und Alzheimer Demenz

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 necessary for memory consolidation, specifically hippocampal sharp-wave ripples (SPW-Rs) and cortical spindles. Recently we demonstrated a negative effect of IEDs on memory consolidation and hippocampal SWRs in the hippocampal CA1 region in an AD mouse model. Here we aim to characterize the negative impact of IEDs in other hippocampal subfields as well as their clinical relevance.

We compared the spread of IEDs their impact on neuronal firing in the hippocampus in two distinct settings. First, we investigated hippocampal and parahippocampal IEDs in epilepsy patients implanted with combined micro/macrowire intracranial EEG electrodes for surgical resection planning, including patients with temporal (n=8) and extratemporal (n=7) epilepsy focus. Next, we obtained high-density recordings from the entire dorsal hippocampus (1024 Channel, SiNAPS Probes, Neuronexus) from adult AD transgenic mice (APP/S1, n=5).

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 the human microwire recordings. IEDs showed similar local field potential features and waveforms in both subject groups, and quickly generalized across channels, leading to global supression of neuronal firing rates, that could be associated with interruption of physiologic signaling. The high-density rodent recordings demonstrated that the IED spread respected anatomical pathways.

We propose that 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 easy detection.