One of the most influential theories has conceived unexpected panic attack (PA) as a primal defensive reaction
to threat within the internal milieu of the body. This theory is based on findings suggesting the involvement of
dysfunctional respiratory regulation and/or abnormally sensitive central neural network of carbon dioxide (CO2)/hydrogen
ion (H+) chemoreception in PA. Thus, unexpected PA may be related to phylogenetically older brain structures, including
the brainstem areas, which process basic functions related to the organism’s internal milieu. The brainstem represents a
crucial area for homeostatic regulation, including chemoreception and cardio-respiratory control. In addition, the midbrain
dorsal periaqueductal gray may be involved in the unconditioned defense reactions to proximal threats, including internal
physical stimuli. Our aim was to specifically consider the potential involvement of the brainstem in panic disorder (PD)
by a comprehensive review of the available neuroimaging studies. Available data are limited and potentially affected by
several limitations. However, preliminary evidence of a role of the brainstem in PD can be found and, secondly, the
brainstem serotonergic system seems to be involved in panic modulation with indications of both altered serotonergic
receptors and 5-HT transporter bindings. In conclusion, our review suggests that the brainstem may be involved in
psychopathology of PD and supports the relevant role of subcortical serotonergic system in panic pathogenesis.
Keywords: Anxiety disorders, brain imaging, brainstem, panic disorder, provocation studies, serotonergic receptors.
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