Search

CO 2 inhalation can provoke panic attacks in humans, and the likelihood is increased in patients with panic disorder. Identifying brain sites involved could provide important mechanistic insight into the illness. In mice, the amygdala has been suggested to promote CO 2 responses; however, recent studies in humans with amygdala damage indicate the amygdala is not required for CO 2 -induced fear and panic and might actually oppose these responses. To clarify the role of the amygdala, we produced lesions in mice paralleling the human lesions, and characterized behavioral responses to CO 2 . Compared to sham controls, we found that amygdala-lesioned mice froze less to 10% CO 2 , and unlike shams they also began to jump frenetically. At 20% CO 2 , controls also exhibited jumping, suggesting it is a normal response to more extreme CO 2 concentrations. The effect of amygdala lesions was specific to CO 2 as amygdala-lesioned mice did not jump in response to a predator odor or to an auditory conditioned stimulus. In amygdala-lesioned mice, jumping evoked by 10% CO 2 was eliminated by co-lesioning the dorsal periaqueductal gray, a structure implicated in panic and escape-related behaviors. Together, these observations suggest a dual role for the amygdala in the CO 2 response: promoting CO 2 -induced freezing, and opposing CO 2 -induced jumping, which may help explain the exaggerated CO 2 responses in humans with amygdala lesions., (Published by Elsevier B.V.)

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., Significance Statement: 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., (Copyright © 2015 the authors 0270-6474/15/3510281-09$15.00/0.)