A human amygdala site that inhibits respiration and elicits apnea in pediatric epilepsy.

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 eight pediatric patients with intractable epilepsy undergoing intracranial electroencephalography (iEEG). 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 two 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 eight subjects (3- to 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. TRIAL REGISTRATION: This study was not affiliated with any formal clinical trial. FUNDING: NIH, CNS, Roy J. Carver Charitable Trust.