Amygdala-driven apnea and the chemoreceptive origin of anxiety

Although the amygdala plays an important part in the pathogenesis of anxiety and generation of exteroceptive fear, recent discoveries have challenged the directionality of this brain-behavior relationship with respect to interoceptive fear. Here we highlight several paradoxical findings including: (1) amygdala lesion patients who experience excessive fear and panic following inhalation of carbon dioxide (CO₂), (2) clinically anxious patients who have significantly smaller (rather than larger) amygdalae and a pronounced hypersensitivity toward CO₂, and (3) epilepsy patients who exhibit apnea immediately following stimulation of their amygdala yet have no awareness that their breathing has stopped. The above findings elucidate an entirely novel role for the amygdala in the induction of apnea and inhibition of CO₂-induced fear. Such a role is plausible given the strong inhibitory connections linking the central nucleus of the amygdala with respiratory and chemoreceptive centers in the brainstem. Based on this anatomical arrangement, we propose a model of Apnea-induced Anxiety (AiA) which predicts that recurring episodes of apnea are being unconsciously elicited by amygdala activation, resulting in transient spikes in CO₂ that provoke fear and anxiety, and lead to characteristic patterns of escape and avoidance behavior in patients spanning the spectrum of anxiety. If this new conception of AiA proves to be true, and activation of the amygdala can repeatedly trigger states of apnea outside of one's awareness, then it remains possible that the chronicity of anxiety disorders is being interoceptively driven by a chemoreceptive system struggling to maintain homeostasis in the midst of these breathless states.