The Deep Breath Before the Plunge: Ictal Apnea and the Amygdala

A Human Amygdala Site That Inhibits Respiration and Elicits Apnea in Pediatric Epilepsy Rhone AE, Kovach CK, Harmata GIS, et al. JCI Insight. 2020;5(6):e134852. doi:10.1172/jci.insight. 134852 Background: Seizure-induced inhibition of respiration plays a critical role in sudden unexpected death in epilepsy (SUDEP). However, the mechanisms underlying seizure-induced central apnea in pediatric epilepsy are unknown. Methods: We studied 8 pediatric patients with intractable epilepsy undergoing intracranial electroencephalography. We recorded respiration during seizures and during electrical stimulation mapping of 174 forebrain sites. A machine learning algorithm was used to delineate brain regions that inhibit respiration. Results: In 2 patients, apnea coincided with seizure spread to the amygdala. Supporting a role for the amygdala in breathing inhibition in children, electrically stimulating the amygdala produced apnea in all 8 patients (3-17 years old). These effects did not depend on epilepsy type and were relatively specific to the amygdala, as no other site affected breathing. Remarkably, patients were unaware that they had stopped breathing, and none reported dyspnea or arousal, findings critical for SUDEP. Finally, a machine learning algorithm based on 45 stimulation sites and 210 stimulation trials identified a focal subregion in the human amygdala that consistently produced apnea. This site, which we refer to as the amygdala inhibition of respiration (AIR) site, includes the medial subregion of the basal nuclei, cortical and medial nuclei, amygdala transition areas, and intercalated neurons. Conclusions: A focal site in the amygdala inhibits respiration and induces apnea (AIR site) when electrically stimulated and during seizures in children with epilepsy. This site may prove valuable for determining those at greatest risk for SUDEP and as a therapeutic target. Seizure-Related Apneas Have an Inconsistent Linkage to Amygdala Seizure Spread Park K, Kanth K, Bajwa S, et al. Epilepsia. 2020;61(6):1253-1260. Objective: Sudden unexpected death in epilepsy (SUDEP) is a frequent cause of death in epilepsy. Respiratory dysfunction is implicated as a critical factor in SUDEP pathophysiology. Human studies have shown that electrical stimulation of the amygdala resulted in apnea, indicating that the amygdala has a role in respiration control. Unilateral amygdala stimulation resulted in immediate onset of respiratory dysfunction occurring only during nose breathing. In small numbers of patients, some but not all spontaneous seizures resulted in apnea occurring shortly after seizure spread to the amygdala. With this study, we aimed to determine whether seizure onset or spread to the amygdala was necessary and sufficient to cause apnea. Methods: We investigated the temporal relationship between apnea/hypopnea (AH) onset and initial seizure involvement within the amygdala in patients with implanted depth electrodes. Results: Data from 17 patients (11 female) with 47 seizures were analyzed. With 7 seizures (3 patients), AH preceded amygdala seizure involvement by 2 to 55 seconds. There was no AH with 4 seizures (3 patients) that involved the amygdala. With 8 seizures (4 patients), AH occurred within 2 seconds following amygdala seizure onset. With 28 seizures, AH started >2 seconds after amygdala seizure onset (range: 3-158 seconds). Following seizure onset, there was a significant difference between AH onset time and amygdala seizure onset (P < .001). The mean ± standard deviation AH onset was 27.8 ± 41.06 seconds, and the mean time to amygdala involvement was 8.83 ± 20.19 seconds. Significance: There is a wide range of AH onset times relative to amygdala seizure involvement. With some seizures, amygdala seizure involvement occurs without AH. With other seizures, AH precedes amygdala seizures, suggesting that, with spontaneous seizures, involvement of the amygdala may not be crucial to induction of AH with all seizures. Other pathophysiology impacting brain stem respiratory networks may be of greater relevance to seizure-triggered apneas.