Cardiorespiratory Response to Hypercapnia Across Epileptogenesis in the Kainic Acid Model

Rational: Central apnea accompanied by cardiac abnormalities emerge to be the key contributor for Sudden unexpected death in epilepsy (SUDEP). Particularly dysregulation of central CO chemoreception (CCR), the system detecting changes in PCO2 levels, is postulated to play a role in SUDEP, accompanied by autonomic anomalies. CCR can be quantified with ventilatory response to hypercapnic challenge and has not been previously studied during the epileptogenesis of a chronic model of temporal lobe epilepsy, in which SUDEP may be observed. Methods: Therefore, we aim to investigate the cardiorespiratory responses to acute hypercapnia through epileptogenesis in the kainic acid (KA) model. We used Sprague-Dawley KA rats injected with KA intrahippocampal to obtain severe spontaneous seizures after 4 months. We analyzed the cardiorespiratory response before injection and continued monthly for 6 months post injection. Photoplethysmography method was used to measure interictal ventilatory frequency (fB), heart rate (HR) and oxygen saturation (PO2) before, during and after 1hr, 10%CO challenge through 6 months. Electroencephalography was used to follow the epileptogenesis and determine the severity of epilepsy. Results: The results showed a stable PO2 at approximately 100%. However, the fB response to 10% CO2 was significantly attenuated with severity of epilepsy at the fourth, fifth and sixth months compared to baseline (p<0.0001, p<0.0001 and p<0.001 respectively, 2-way ANOVA, Fisher's LSD test). Moreover, the HR response to 10%CO2 was significantly increased with severity of epilepsy for the first, third and fourth months compared to baseline (p<0.05, p<0.0001 and p<0.0001 respectively, 2-way ANOVA, Fisher's LSD test) and was ablated at the fifth and sixth months. Conclusion: Overall, these results indicate that in chronic KA model, epileptic rats display impaired cardiorespiratory response to hypercapnia that evolves with the severity of epilepsy. These findings model and help to understand the high-risk breathing disturbances that are observed among SUDEP cases and facilitate future studies to investigate where in the brainstem these dysfunctions originate.