Failure to breathe persists without air hunger or alarm following amygdala seizures
Gail I.S. Harmata, Ariane E. Rhone, Christopher K. Kovach, Sukhbinder Kumar, Md Rakibul Mowla, Rup K. Sainju, Yasunori Nagahama, Hiroyuki Oya, Brian K. Gehlbach, Michael A. Ciliberto, Rashmi N. Mueller, Hiroto Kawasaki, Kyle T.S. Pattinson, Kristina Simonyan, Paul W. Davenport, Matthew A. Howard III, Mitchell Steinschneider, Aubrey C. Chan, George B. Richerson, John A. Wemmie, Brian J. Dlouhy
Gail I.S. Harmata, Ariane E. Rhone, Christopher K. Kovach, Sukhbinder Kumar, Md Rakibul Mowla, Rup K. Sainju, Yasunori Nagahama, Hiroyuki Oya, Brian K. Gehlbach, Michael A. Ciliberto, Rashmi N. Mueller, Hiroto Kawasaki, Kyle T.S. Pattinson, Kristina Simonyan, Paul W. Davenport, Matthew A. Howard III, Mitchell Steinschneider, Aubrey C. Chan, George B. Richerson, John A. Wemmie, Brian J. Dlouhy
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Research Article Neuroscience

Failure to breathe persists without air hunger or alarm following amygdala seizures

Abstract

Postictal apnea is thought to be a major cause of sudden unexpected death in epilepsy (SUDEP). However, the mechanisms underlying postictal apnea are unknown. To understand causes of postictal apnea, we used a multimodal approach to study brain mechanisms of breathing control in 20 patients (ranging from pediatric to adult) undergoing intracranial electroencephalography for intractable epilepsy. Our results indicate that amygdala seizures can cause postictal apnea. Moreover, we identified a distinct region within the amygdala where electrical stimulation was sufficient to reproduce prolonged breathing loss persisting well beyond the end of stimulation. The persistent apnea was resistant to rising CO2 levels, and air hunger failed to occur, suggesting impaired CO2 chemosensitivity. Using es-fMRI, a potentially novel approach combining electrical stimulation with functional MRI, we found that amygdala stimulation altered blood oxygen level–dependent (BOLD) activity in the pons/medulla and ventral insula. Together, these findings suggest that seizure activity in a focal subregion of the amygdala is sufficient to suppress breathing and air hunger for prolonged periods of time in the postictal period, likely via brainstem and insula sites involved in chemosensation and interoception. They further provide insights into SUDEP, may help identify those at greatest risk, and may lead to treatments to prevent SUDEP.

Authors

Gail I.S. Harmata, Ariane E. Rhone, Christopher K. Kovach, Sukhbinder Kumar, Md Rakibul Mowla, Rup K. Sainju, Yasunori Nagahama, Hiroyuki Oya, Brian K. Gehlbach, Michael A. Ciliberto, Rashmi N. Mueller, Hiroto Kawasaki, Kyle T.S. Pattinson, Kristina Simonyan, Paul W. Davenport, Matthew A. Howard III, Mitchell Steinschneider, Aubrey C. Chan, George B. Richerson, John A. Wemmie, Brian J. Dlouhy

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Figure 3

Across-subject analysis localized post-stimulation apnea and postictal apnea to a specific site in the amygdala.

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Across-subject analysis localized post-stimulation apnea and postictal a...
(A) Anterior-posterior, superior-inferior, and oblique views of all stimulated electrode pairs (n = 82 sites) in the temporal lobe and inferior frontal lobe across 18 subjects who had stimulation below seizure threshold (adult: triangles; pediatric: circles) plotted in a common coordinate system (MNI). Electrode contact pairs that produced apnea (red lines) were located in the medial amygdala. Electrode contact pairs that produced transient apnea (dark gray lines) were typically located just lateral or adjacent to this medial region. Electrode contact pairs that failed to induce apnea (light gray lines) were located in the lateral amygdala, areas just outside the amygdala, in hippocampus, Heschl’s gyrus, and orbitofrontal cortex. 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. (B) Anterior-posterior, oblique, and superior-inferior views of all stimulated electrode pairs in the amygdala and hippocampus across the 5 subjects with persistent apnea, plotted in a common coordinate system (MNI). Electrode pairs that induced persistent post-stimulation and postictal apneas are denoted by magenta lines and clustered together mostly spanning the basolateral nucleus and including the cortical and medial nuclei and the medial aspect of the lateral nucleus. Electrode pairs that induced apnea are denoted by red lines, and transient apnea sites are denoted by dark gray lines; sites that did not induce apnea are depicted in light gray. 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 conventions as in Figure 1.