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 5

Amygdala stimulation evoked persistent post-stimulation hypoventilation despite hypercapnia.

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Amygdala stimulation evoked persistent post-stimulation hypoventilation ...
(A) Electrode contacts superimposed upon P384’s temporal lobes (see Figure 1A). (B) While the patient was under anesthesia, intubated, and breathing independently, R2–R3 stimulation induced apnea during stimulation (as was observed at bedside). (C) etCO2 increased after apnea followed by rapid increase in respiratory rate (RR), tidal volume (TV), and minute ventilation (VE) to normalize CO2 levels. Dotted line indicates average pre-stimulation values. (D) L2–L3 stimulation induced long-lasting inhibition of independent breathing, causing post-stimulation apneas. Manual breaths and ventilator-dependent breathing were provided without difficulty (green shading) but did not initiate independent breathing. (E) Once independent breathing resumed, baseline RR resumed, but etCO2 remained elevated and TV and VE decreased below baseline. Thus, P384 had persistent hypoventilation despite elevated etCO2 for more than 10 minutes after stimulation. During this time, both etCO2 and TV slowly returned toward baseline. (F) Comparison of respiratory measurements before and after apnea from R2–R3 (dark gray) and L2–L3 (magenta) stimulation. Site L2–L3 resulted in prolonged hypoventilation with elevated etCO2 and lower TV and VE after independent breathing resumed compared with R2–R3. (G) Average ventilatory values before and 50 seconds after breathing resumed from stimulation of R2–R3 (m = 7) and L2–L3 (m = 3). etCO2 was higher but TV was lower for L2–L3 50 seconds after independent breathing resumed, indicating persistent hypoventilation after L2–L3 stimulation. (H and I) Lateral amygdala (R4–R5), adjacent white matter (R5–R6), and hippocampus (H2–H3, H3–H4) stimulation failed to induce apnea or abnormal breathing (H) or changes in RR, TV, or VE (I). (J) Summary of all trials (m = 26) under anesthesia for P384. Only stimulation of L2–L3 led to persistent post-stimulation apneas. Stimulation in nearby white matter and hippocampus with the same parameters (10–15 V; 50 Hz) failed to induce apnea.