title: Breathing Inhibited When Seizures Spread to the Amygdala and upon Amygdala Stimulation.
abstract: Sudden unexpected death in epilepsy (SUDEP) is increasingly recognized as a common and devastating problem. Because impaired breathing is thought to play a critical role in these deaths, we sought to identify forebrain sites underlying seizure-evoked hypoventilation in humans. We took advantage of an extraordinary clinical opportunity to study a research participant with medically intractable epilepsy who had extensive bilateral frontotemporal electrode coverage while breathing was monitored during seizures recorded by intracranial electrodes and mapped by high-resolution brain imaging. We found that central apnea and O2 desaturation occurred when seizures spread to the amygdala. In the same patient, localized electrical stimulation of the amygdala reproduced the apnea and O2 desaturation. Similar effects of amygdala stimulation were observed in two additional subjects, including one without a seizure disorder. The participants were completely unaware of the apnea evoked by stimulation and expressed no dyspnea, despite being awake and vigilant. In contrast, voluntary breath holding of similar duration caused severe dyspnea. These findings suggest a functional connection between the amygdala and medullary respiratory network in humans. Moreover, they suggest that seizure spread to the amygdala may cause loss of spontaneous breathing of which patients are unaware, and thus has potential to contribute to SUDEP.
  
  
  CONCLUSIONS
  Sudden unexpected death in epilepsy (SUDEP) is the most common cause of death in patients with chronic refractory epilepsy. Impaired breathing during and after seizures is common and suspected to play a role in SUDEP. Understanding the cause of this peri-ictal hypoventilation may lead to preventative strategies. In epilepsy patients, we found that seizure invasion of the amygdala co-occurred with apnea and oxygen desaturation, and electrical stimulation of the amygdala reproduced these respiratory findings. Strikingly, the subjects were unaware of the apnea. These findings indicate a functional connection between the amygdala and brainstem respiratory network in humans and suggest that amygdala seizures may cause loss of spontaneous breathing of which patients are unaware-a combination that could be deadly.
authors.affiliation: Departments of Neurosurgery, brian-dlouhy@uiowa.edu.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Dlouhy
authors.affiliation: Internal Medicine.
authors.forename: Brian K
authors.initials: BK
authors.lastname: Gehlbach
authors.affiliation: Psychiatry, Medical Scientist Training Program, Molecular Physiology and Biophysics.
authors.forename: Collin J
authors.initials: CJ
authors.lastname: Kreple
authors.affiliation: Departments of Neurosurgery.
authors.forename: Hiroto
authors.initials: H
authors.lastname: Kawasaki
authors.affiliation: Departments of Neurosurgery.
authors.forename: Hiroyuki
authors.identifier: http://orcid.org/0000-0002-1733-5478
authors.initials: H
authors.lastname: Oya
authors.affiliation: Psychiatry.
authors.forename: Colin
authors.initials: C
authors.lastname: Buzza
authors.affiliation: Neurology, and.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Granner
authors.affiliation: Internal Medicine, Molecular Physiology and Biophysics, Interdisciplinary Graduate Program in Neuroscience, University of Iowa, Iowa City, Iowa 52242, Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, and.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Welsh
authors.affiliation: Departments of Neurosurgery.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Howard
authors.affiliation: Departments of Neurosurgery, Internal Medicine, Psychiatry, Molecular Physiology and Biophysics, Interdisciplinary Graduate Program in Neuroscience, University of Iowa, Iowa City, Iowa 52242, Department of Veterans Affairs Medical Center, Iowa City, Iowa 52242.
authors.forename: John A
authors.initials: JA
authors.lastname: Wemmie
authors.affiliation: Molecular Physiology and Biophysics, Neurology, and Interdisciplinary Graduate Program in Neuroscience, University of Iowa, Iowa City, Iowa 52242, Department of Veterans Affairs Medical Center, Iowa City, Iowa 52242.
authors.forename: George B
authors.identifier: http://orcid.org/0000-0001-5696-1554
authors.initials: GB
authors.lastname: Richerson
mesh_terms: D000679:Amygdala / Q000502:physiology*; D000704:Analysis of Variance; D001049:Apnea / Q000150:complications*; D001931:Brain Mapping; D004558:Electric Stimulation; D004569:Electroencephalography; D004827:Epilepsy / Q000150:complications* / Q000473:pathology*; D005071:Evoked Potentials; D005625:Frontal Lobe / Q000502:physiology / Q000601:surgery; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging; D008297:Male; D010100:Oxygen / Q000378:metabolism*; D012125:Respiratory Center / Q000473:pathology*; D013702:Temporal Lobe / Q000502:physiology / Q000601:surgery
chemical_list: D010100:Oxygen
keywords: SUDEP; amygdala; brainstem; breathing; epilepsy; sudden death