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 4

Stimulation-induced apnea was relatively specific to the amygdala and not seen with stimulation of any other forebrain site.

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Stimulation-induced apnea was relatively specific to the amygdala and no...
(A) Plot illustrating durations of stimulation and durations of apnea for each trial, shown by gray and red vertical lines, respectively. All trials of stimulation were at least 5 seconds in duration. Stimulation always induced apnea within 1.9 seconds after onset. Apnea was only observed with stimulation of the amygdala. (B) Location of electrode contacts superimposed upon an anatomic diagram of P381’s left temporal lobe with amygdala nuclei and surrounding areas in coronal plane. Amygdala nuclei defined as in Figure 1B. Stimulation outside and immediately lateral to the amygdala (contacts 5 and 6, pink) failed to elicit apnea. (C) Coronal T1-weighted structural MR image showing the left hippocampus depth electrode in subject P395. Electrode contacts from most medial to lateral are labeled 1–3. Location of electrode contacts superimposed upon an anatomic diagram of the left temporal lobe with hippocampus and surrounding areas in coronal plane. Stimulation of the hippocampus (contacts 2 and 3, pink) failed to elicit apnea. (D) 3D surface-rendered MR image of P395’s left medial hemisphere with superimposed electrode contacts in P395. Stimulation of the cingulate gyrus (pink circles) failed to elicit apnea. (E) 3D surface-rendered MR image of P395’s left convexity with superimposed electrode contacts. Stimulation of the left frontal cortex (pink circles) failed to elicit apnea. (F) Bar graph illustrating the percentage of trials eliciting each of the 3 types of breathing effects (apnea, red; transient apnea, dark gray; no apnea, dot shading) for all patients. Beneath each bar are the number of subjects (N), number of sites stimulated (n), and number of trials (m). Except for 1 electrode pair immediately anterior to the amygdala where stimulation led to transient apnea, stimulation at all other sites and all other trials failed to induce any measurable changes in breathing.