Abstracts

Rationale:
SUDEP is the most common cause of death in refractory epilepsy patients and many cases of SUDEP are thought to be due to fatal postictal apnea. The mechanisms involved in seizure‐induced respiratory arrest (S-IRA) are not known, but evidence suggests the amygdala may be a critical node in the pathway by which seizures spread from the forebrain to the brainstem respiratory network. Depth electrode recordings from the amygdala of epilepsy patients show that prolonged apneas occur when seizures spread into the CeA. Apnea also occurs when the CeA is electrically stimulated in awake patients. Amygdala lesions in DBA/1 mice prevent ventilatory arrest and death without affecting the induction of audiogenic seizures. Here we examined the role of the amygdala in peri‐ictal apnea and SUDEP in Scn1aR1407X/+ mice, a model of Dravet Syndrome (DS).
Method:
Baseline breathing, hypercapnic ventilatory response (HCVR), and hypoxic ventilatory response (HVR) were assessed using whole‐body plethysmography in P26 ± 5 DS mice (n=7) before and after lesioning the CeA. Under surgical anesthesia (1–2% isoflurane), electrolytic lesions were induced in the CeA, after which mice were instrumented with EEG, ECG, and EMG electrodes. After 5 days of recovery, mice were tethered to a preamplifier and placed in a plethysmography chamber. In another set of DS mice, seizures were induced (n=22) by increasing body temperature 0.5°C per minute until the fatal seizure or reach 42.5 C degrees in body temperature using a heat lamp._x000D_ In a separate cohort of DS mice (n=4), the CeA was stimulated under light anesthesia (0.5–1% isoflurane) by injecting current with stereotactically guided monopolar electrodes while measuring breathing using head‐out plethysmography. Electrode placement was verified post hoc using histology. How Amygdala can modify breathing in DS mice was 3D mapped using electrode placement and correlated with Paxinos and Franklin mouse brain atlas coordinates._x000D_ In the third cohort of DS mice (n=12), CeA lesions or sham lesions were made at P21, and mice were video‐monitored for 100 days. A subset of these mice had spontaneous seizures and SUDEP.
Results:
CeA lesions did not affect baseline breathing, HCVR, or HVR, and did not prevent seizures. Apnea and death occurred in control (sham‐lesioned) DS mice following heat‐induced seizures in 54.4% of cases (n=11). In contrast, only 9.1% of DS mice with CeA lesions showed respiratory arrest and death after heat‐induced seizures (n=11; p=0.016)._x000D_ Stimulation of the rostral CeA produced apnea that was dependent on the frequency and amplitude of stimulation, without causing seizures. At 50 Hz and 500 μA, apnea was induced for 1–4 minutes without causing death (n=4) or reversal of anesthetic immobility, suggesting a lack of an arousal response._x000D_ Kaplan‐Meier survival curves showed that mice with CeA lesions had higher survival (64.5%) than sham lesions (28.3%) (p=0.015).
Conclusion:
These data suggest that the CeA can induce apnea but, is not directly involved in baseline respiratory rhythm generation or the ventilatory response to hypercapnia or hypoxia. CeA lesions reduce the risk of apnea during seizures. Therefore, the CeA is a key component of the neural pathway through which seizures spread from the forebrain to respiratory centers in the brainstem to elicit ventilatory arrest after seizures.
Funding:
:NIH/NINDS U01‐NS0904143 SUDEP Research Alliance