Search

Objective: To test the hypothesis that death with physiological parallels to human cases of sudden unexpected death in epilepsy (SUDEP) can be induced in seizing rats by ictal activation of oxygen‐conserving reflexes (OCRs). Methods: Urethane‐anesthetized female Long‐Evans rats were implanted with electrodes for electrocardiography (ECG), electrocorticography (ECoG), and respiratory thermocouple; venous and arterial cannulas; and a laryngoscope guide and cannula or nasal cannula for activation of the laryngeal chemoreflex (LCR) or mammalian diving reflex (MDR), respectively. Kainic acid injection, either systemic or into the ventral hippocampus, induced prolonged acute seizures. Results: Reflex challenges during seizures caused sudden death in 18 of 20 rats—all MDR rats (10) and all but two LCR rats (8) failed to recover from ictal activation of OCRs and died within minutes of the reflexes. By comparison, 4 of 4 control (ie, nonseizing) rats recovered from 64 induced diving reflexes (16 per rat), and 4 of 4 controls recovered from 64 induced chemoreflexes (16 per rat). Multiple measures were consistent with reports of human SUDEP. Terminal central apnea preceded terminal asystole in all cases. Heart and respiratory rate fluctuations that paralleled those seen in human SUDEP occurred during OCR‐induced sudden death, and mean arterial pressure (MAP) was predictive of death, showing a 17 or 15 mm Hg drop (MDR and LCR, respectively) in the 20 s window centered on the time of brain death. OCR activation was never fatal in nonseizing rats. Significance: These results present a method of inducing sudden death in two seizure models that show pathophysiology consistent with that observed in human cases of SUDEP. This proposed mechanism directly informs previous findings by our group and others in the field; provides a repeatable, inducible animal model for the study of sudden death; and offers a potential explanation for observations made in cases of human SUDEP. [ABSTRACT FROM AUTHOR]

• Oxygen-conserving reflex (OCR) activation in rats after carotid body (CB) denervation reliably induces sudden death. • Oxygen-conserving reflex in rat models of epilepsy induces death, but electrical CB stimulation prevents death. • Oxygen-conserving reflex-mediated death shares multiple physiological parallels with human SUDEP. • Oxygen-conserving reflex activation in non-seizing rats with intact CB never leads to sudden death. • The CB plays a vital role in restoring respiratory drive following OCR activation. To investigate carotid body (CB) mechanisms related to sudden death during seizure. Ictal activation of oxygen-conserving reflexes (OCRs) can trigger fatal cardiorespiratory collapse in seizing rats, which presents like human sudden unexpected death in epilepsy (SUDEP). The CB is strongly implicated in OCR pathways; we hypothesize that modulating CB activity will provide insight into these mechanisms of death. Long-Evans rats were anesthetized with urethane. Recordings included: electrocorticography, electrocardiography, respiration via nasal thermocouple, and blood pressure (BP). The mammalian diving reflex (MDR) was activated by cold water delivered through a nasal cannula. Reflex and stimulation trials were repeated up to 16 times (4 pre-intervention, 12 post-intervention) or until death. In some animals, one or both carotid bodies were denervated. In some animals, the CB was electrically stimulated, both with and without MDR. Seizures were induced with kainic acid (KA). Animals without seizure and with no CB modulation survived all reflexes. Non-seizing animals with CB denervation survived 7.1 ± 5.4 reflexes before death, and only 1 of 7 survived past the 12-trial threshold. Electrical CB stimulation without seizure and without reflex caused significant tachypnea and hypotension. Electrical CB stimulation with seizure and without reflex required higher amplitudes to replicate the physiological responses seen outside seizure. Seizing animals without CB intervention survived 3.2 ± 3.6 trials (per-reflex survival rate 42.0% ± 44.4%), and 0 of 7 survived past the 12-trial threshold. Seizing animals with electrical CB stimulation survived 10.5 ± 4.7 ictal trials (per-reflex survival rate 86.3% ± 35.0%), and 6 of 8 survived past the 12-trial threshold. These results suggest that, during seizure, the ability of the CB to stimulate a restart of respiration is impaired. The CB and its afferents may be relevant to fatal ictal apnea and SUDEP in humans, and CB stimulation may be a relevant intervention technique in these deaths. [ABSTRACT FROM AUTHOR]

Abstract: Several variations of microelectrode arrays are used to record and stimulate intracortical neuronal activity. Bypassing the immune response to maintain a stable recording interface remains a challenge. Companies and researchers are continuously altering the material compositions and geometries of the arrays in order to discover a combination that allows for a chronic and stable electrode–tissue interface. From this interface, they wish to obtain consistent quality recordings and a stable, low impedance pathway for charge injection over extended periods of time. Despite numerous efforts, no microelectrode array design has managed to evade the host immune response and remain fully functional. This study is an initial effort comparing several microelectrode arrays with fundamentally different configurations for use in an implantable epilepsy prosthesis. Specifically, NeuroNexus (Michigan) probes, Cyberkinetics (Utah) Silicon and Iridium Oxide arrays, ceramic-based thin-film microelectrode arrays (Drexel), and Tucker-Davis Technologies (TDT) microwire arrays are evaluated over a 31-day period in an animal model. Microelectrodes are compared in implanted rats through impedance, charge capacity, signal-to-noise ratio, recording stability, and elicited immune response. Results suggest significant variability within and between microelectrode types with no clear superior array. Some applications for the microelectrode arrays are suggested based on data collected throughout the longitudinal study. Additionally, specific limitations of assaying biological phenomena and comparing fundamentally different microelectrode arrays in a highly variable system are discussed with suggestions on how to improve the reliability of observed results and steps needed to develop a more standardized microelectrode design. [Copyright &y& Elsevier]