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 3

Electrical stimulation of the amygdala induced varying degrees of apnea in all 8 patients with pediatric epilepsy.

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Electrical stimulation of the amygdala induced varying degrees of apnea ...
(A) Focal electrical stimulation was delivered using a bipolar biphasic square waveform, 200-μs pulse width, 50-Hz frequency, and constant voltage (see Methods). (B) Coronal T1-weighted structural MR image showing the left amygdala-depth electrode in subject P381. Artifacts produced by each contact from most medial to lateral are labeled 1 to 8, respectively. (C) Location of electrode contacts superimposed upon an anatomic diagram of P381’s left temporal lobe with amygdala nuclei, hippocampus, and surrounding areas in coronal and axial planes. The dotted magenta line within the axial view represents coronal plane outlined with same dotted line. Amygdala nuclei defined as in Figure 1B. (D) Amygdala stimulation (contacts 1 and 2) in P381 resulted in apnea that was almost immediate in onset and lasted the duration of stimulation. iEEG signal shown on top and respiratory signal from oral/nasal thermistor shown below (inspiration plotted up; duration of stimulation depicted by shaded gray box; duration of apnea shown by horizontal red line; conventions remain the same for E and F). (E) Stimulation of more lateral sites in the amygdala (contacts 2 and 3) in P381 resulted in transient apnea: apnea was almost immediate in onset (<2 s from stimulation onset) but did not last the entire duration of stimulation, and normal breathing resumed despite continued stimulation. (F) Amygdala stimulation elicited apnea or transient apnea in the 7 other pediatric patients. Respiratory traces shown from oral/nasal thermistor or nasal pressure transducer. (G) 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 8 patients and 11 amygdalae. Beneath each bar are the number of sites stimulated (n) and number of trials (m). In total, 159 stimulation trials within 31 different sites induced apnea to varying degrees.