A human amygdala site that inhibits respiration and elicits apnea in pediatric epilepsy
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
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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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 5

Stimulation-induced effects on breathing varied by contact location in the amygdala.

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Stimulation-induced effects on breathing varied by contact location in t...
(A) Coronal T1-weighted structural MR image showing the left amygdala-depth electrode in subject P395. Electrode contacts from most medial to lateral are labeled 1 to 8, respectively. (B) The location of electrode contacts superimposed upon anatomic diagrams of P395’s left temporal lobe with amygdala nuclei, hippocampus, and surrounding areas in coronal, axial and sagittal planes. The dotted magenta line within the axial and sagittal view represents coronal plane outlined with the same dotted line. The red line in the axial and coronal view represents the sagittal plane outlined with the same red line. Amygdala nuclei defined as in Figure 1B. (C) Stimulation of bipolar contacts 1–8 from medial to lateral within the amygdala nuclei elicited different effects on breathing. Apnea was observed with stimulation of the basal nuclei (BL/BM) and only transient apnea was observed with stimulation of the lateral amygdala. No apnea was observed with ATA stimulation. Oxygen desaturation corresponded with the length of apnea and transient apnea at each site. (D) Bar graph depicting across-subject respiratory effects in the 3 grouped amygdala nuclei for which stimulation elicited effects on breathing. Within the BL/BM, 79% of stimulated electrode contact pairs were characterized by apnea, and 11% were characterized by transient apnea. Fewer sites in the ATA/CMN showed breathing disruption (40% apnea, 20% transient apnea). Transient apnea (57% of sites) or no apnea occurred with electrical stimulation of the La. Omnibus Fisher’s exact test showed significant association between the 3 nuclei and the 3 respiratory outcomes (P = 0.00137). Post hoc planned comparisons showed significant association between sites in BL/BM and apnea (BL/BM versus other areas, and apnea versus other respiratory outcome, Fisher’s exact test, P = 0.0011). Oxygen desaturation nadir occurred after amygdala stimulation because oxygen saturation was measured with a pulse oximeter on the extremities resulting in a 15- to 20-second delay.