A human amygdala site that inhibits respiration and elicits apnea in pediatric epilepsy
Ariane E. Rhone, … , John A. Wemmie, Brian J. Dlouhy
Ariane E. Rhone, … , John A. Wemmie, Brian J. Dlouhy
Published March 12, 2020
Citation Information: JCI Insight. 2020;5(6):e134852. https://doi.org/10.1172/jci.insight.134852.
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Clinical Research and Public Health Neuroscience

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

Abstract

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.

Authors

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

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Figure 6

Across-subject analysis localized amygdala stimulation-induced apnea to the medial aspect of BL/BM and the ATA/CMN.

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Across-subject analysis localized amygdala stimulation-induced apnea to ...
Anterior-posterior, superior-inferior, and oblique views of all stimulated electrode pairs in the amygdala and hippocampus across subjects plotted in a common coordinate system (MNI). Electrode contact pairs that produced apnea were located in the medial BL/BM and ATA/CMN. Electrode contact pairs that produced transient apnea were typically located just lateral or adjacent to this medial BL/BM region. Electrode contact pairs that failed to induce apnea were located in La, outside the amygdala, or in the hippocampus. Electrode pairs that induced apnea are denoted by dark red lines; those that produced transient apnea are depicted in dark gray lines; sites that did not induce apnea are depicted in light gray. For clarity, electrode sites on the lateral convexity, in the cingulate gyrus, and gyrus rectus are not shown; no sites omitted from this figure demonstrated effects of electrical stimulation on breathing. See Supplemental Table 1 for a list of MNI coordinates and the respiratory effect for each contact pair. Nuclei are color-coded with the same convention as in Figure 1B. Electrode contacts may appear outside of the template brain due to anatomical variation across subjects relative to the MNI coordinate system. All electrode contacts were plotted in the right hemisphere for simplicity, because no differences were observed between right and left amygdala stimulation.