Authors :
Presenting Author: Ariane Rhone, PhD – University of Iowa
Christopher Kovach, PhD – University of Iowa; Sukhbinder Kumar, PhD – University of Iowa; Md Rakibul Mowla, PhD – University of Iowa; George Richerson, MD, PhD – University of Iowa; John Wemmie, MD, PhD – University of Iowa; Brian Dlouhy, MD – University of Iowa
Rationale:
Electrical stimulation of the amygdala and seizures that originate in or spread to amygdala can cause apnea (Dlouhy et al., 2015). Persistent apneas following the end of a seizure (postictal apnea) may contribute to Sudden Unexpected Death in Epilepsy (SUDEP). However, the neural mechanisms contributing to postictal apnea are not well understood. The current study examines the neural basis of apnea that persists beyond the end of stimulation or seizure.
Methods:
A total of 20 subjects (age 3-59; 16 male, 4 female) were studied while undergoing intracranial electroencephalographic (iEEG) seizure monitoring. We used direct electrical stimulation to evaluate respiratory outcomes resulting from stimulation of forebrain sites with hypothesized involvement in control of breathing. Subjects wore respiratory monitoring equipment measuring changes in SpO
2, airflow, and chest wall motion during stimulation mapping. One patient was further studied under anesthesia in the operating room, where detailed ventilatory measures were obtained including tidal volume, respiratory rate, and etCO
2. Machine learning was used to predict the region where apnea and persistent apnea were most likely to occur based on the MNI coordinates of stimulated sites. To evaluate connectivity between the amygdala and brain regions not sampled with iEEG, one patient underwent electrical stimulation plus functional MRI (es-fMRI).
Results:
In 18 subjects, we observed apnea upon electrical stimulation or seizure in amygdala. Stimulation of sites outside amygdala never elicited respiratory changes. In five subjects, apneas persisted beyond the end of stimulation or stimulation-induced seizure. Patients were not aware that their breathing was disrupted, exhibited no air hunger, and showed no signs of distress. In some patients, periods of apnea persisted for over 10 minutes. No changes in event related band power of canonical EEG frequencies were observed during prolonged periods of apnea. Across subjects, machine learning identified a focal region of the amygdala where persistent apnea was most likely to occur. This area was within the previously described amygdala inhibition of respiration (AIR) site (Rhone et al 2020 JCI Insight). Due to the persistence of apnea in the postictal or poststimulation period, we refer to this sub-site as the persistent amygdala inhibition of respiration (pAIR) site. Stimulation of the pAIR site concurrent with functional MRI resulted in BOLD signal changes in the pons, medulla, and insula.
Conclusions:
We found that only five of twenty patients studied developed postictal or post-stimulation apnea, but that those who did demonstrated no awareness of their apneas, even more than 10 minutes after stimulation or seizure end. Stimulation of the focal site which resulted in persistent apnea (the pAIR site) altered BOLD activity in areas implicated in respiratory control and interoceptive processing. These data suggest that some patients with medically intractable epilepsy may be more prone to developing postictal apnea, and that a subregion of the amygdala is likely the locus of this effect. The pAIR site may be a future therapeutic target in the prevention of SUDEP.
Funding:
Funding provided by NIH NINDS K08NS112573