Abstracts

Rationale: Spreading depolarization (SD, formerly known as spreading depression) was initially discovered in the context of acute models of seizure, and has recently recognized as occurring associated with spontaneous seizures. Oxygen is a critical component in fueling the ion pumps required for neuron function, and local deficits in oxygenation are known to be able to initiate SD events. We demonstrated that SD frequently occurs associated with the seizures in the tetanus toxin rodent model of temporal lobe epilepsy (Bahari F 2020, www.biorxiv.org/content/10.1101/455519v2). Here we investigate using chronic long term amperometric methods if tissue oxygenation changes lead or follow seizure onset and SD onsets.

Methods: To study tissue oxygenation dynamics during epileptic seizures and co-occurrence SD events, we implemented long-term, continuous tissue oxygenation and biopotential measurements on freely moving rats prepared under the tetanus toxin model of temporal lobe epilepsy (TLE) and applied both the constant potential amperometry (CPA) and a long-term pulse voltammetry (LPV). Ideally these methods yield measures of average tissue oxygen concentration C₀. It is well known that CPA methods suffer from the inability to decouple changes in C₀ from changes in average diffusion constant D_eff. The initial peak in LPV reflects the local C₀ while its tail flat portion is comparable to the mixed CPA measure. We introduce a method to estimate relative changes D_eff from the LPV.

We studied tissue oxygenation dynamics during normal state of vigilance (SOV) transitions, peri-seizure transitions without SD (N=704/412 events), and peri-seizure with SD transitions (N=190/68 events) in (N=9/5) animals using (CPA/LPV) amperometry. Critically these measures were done chronically in during multi-day homecage recordings in freely behaving non-anesthetized animals.

Results: Across all events, we find comparable dynamics from both CPA and the tail portion of LPV. For transitions between non-seizure SOV states, these dynamics are consistent with the peak LPV value, which best measures C₀, because D_eff doesn't change appreciably.

Tissue oxygenation did change of order 5% through seizures and during SD events. But no overt decreases were observed either during the preseizure period, nor ahead of SD onset during seizures. Instead during seizures C₀ typically increased. In contrast, D_eff did decrease as much as 80% during SD events.

Conclusions: We studied tissue oxygenation levels in the tetanus toxin model of temporal lobe epilepsy which expresses spontaneous seizures and frequently seizure-associated spreading depolarization. In these measurements, oxygen dynamics appear to follow seizure and SD onset transitions rather than precede and potentially cause them. Increases in tissue oxygenation during seizures indicate a robust neurovascular response. In addition, during SD oxygen diffusion rates through tissue are significantly decreased, and this leads to significant confounds for use of standard CPA measures.

Funding: Please list any funding that was received in support of this abstract.: Partially funded through NIH R01-EB019804.