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 subjects (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.FUNDING National Institute of Neurological Disorders and Stroke — Congress of Neurological Surgeons, National Institute of General Medical Sciences, Roy J. Carver Charitable Trust.
Ariane E. Rhone, Christopher K. Kovach, Gail I.S. Harmata, Alyssa W. Sullivan, Daniel Tranel, Michael A. Ciliberto, Matthew A. Howard, George B. Richerson, Mitchell Steinschneider, John A. Wemmie, Brian J. Dlouhy