Failure to breathe persists without air hunger or alarm following amygdala seizures
Gail I.S. Harmata, … , John A. Wemmie, Brian J. Dlouhy
Gail I.S. Harmata, … , John A. Wemmie, Brian J. Dlouhy
Published October 3, 2023
Citation Information: JCI Insight. 2023;8(22):e172423. https://doi.org/10.1172/jci.insight.172423.
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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 2

Electrical stimulation of the amygdala evoked persistent post-stimulation apnea, an effect not seen with stimulation outside the amygdala.

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Electrical stimulation of the amygdala evoked persistent post-stimulatio...
(A) Anatomical localization of right amygdala depth electrode contacts (black circles) in the coronal plane of P352. Amygdala nuclei are defined as in Figure 1 (schematic remains the same for B and C). Stimulating contacts R2–R3 (red circles) in P352 resulted in apnea that was almost immediate in onset and lasted the duration of stimulation. After stimulation ended, apneas (black arrows) persisted in total for nearly 60 seconds. Repeated intervals of decreased oxygenation were observed with apneic periods. P352 was able to override stimulation-induced apnea through instructed voluntary breathing, but still exhibited post-stimulation apneas. iEEG signal is shown on top and respiratory trace from nasal pressure transducer shown below (inspiration plotted up; duration of stimulation depicted by shaded gray box; conventions remain the same for B and C). (B) Stimulating contacts L2–L3 in the left amygdala of P384 also resulted in post-stimulation apneas that lasted over 100 seconds in total and a total breathing disruption time of 5 minutes after stimulation ended. (C) Post-stimulation apneas were also observed with stimulation of contacts L1–L2 of the left amygdala in P466. (D) Summary of all stimulation trials (n = 51) for P352, P384, and P466, showing duration of stimulation (hatched gray bars), total apnea time (red bars), and total disrupted breathing time (black dot and line). Stimulation of amygdala sites in A–C led to persistent post-stimulation apneas with every trial at those sites, whereas amygdala stimulation outside these sites led to apnea of various degrees, lasting the duration of stimulation to no effect. Stimulation with the same amplitude (10–15 V) and frequency (50 Hz) outside the amygdala (white matter, WM; hippocampus, Hipp; and orbitofrontal sites) failed to induce any apnea.