The prefrontal cortex, pathological anxiety, and anxiety disorders.

Anxiety is experienced in response to threats that are distal or uncertain, involving changes in one's subjective state, autonomic responses, and behavior. Defensive and physiologic responses to threats that involve the amygdala and brainstem are conserved across species. While anxiety responses typically serve an adaptive purpose, when excessive, unregulated, and generalized, they can become maladaptive, leading to distress and avoidance of potentially threatening situations. In primates, anxiety can be regulated by the prefrontal cortex (PFC), which has expanded in evolution. This prefrontal expansion is thought to underlie primates' increased capacity to engage high-level regulatory strategies aimed at coping with and modifying the experience of anxiety. The specialized primate lateral, medial, and orbital PFC sectors are connected with association and limbic cortices, the latter of which are connected with the amygdala and brainstem autonomic structures that underlie emotional and physiological arousal. PFC pathways that interface with distinct inhibitory systems within the cortex, the amygdala, or the thalamus can regulate responses by modulating neuronal output. Within the PFC, pathways connecting cortical regions are poised to reduce noise and enhance signals for cognitive operations that regulate anxiety processing and autonomic drive. Specialized PFC pathways to the inhibitory thalamic reticular nucleus suggest a mechanism to allow passage of relevant signals from thalamus to cortex, and in the amygdala to modulate the output to autonomic structures. Disruption of specific nodes within the PFC that interface with inhibitory systems can affect the negative bias, failure to regulate autonomic arousal, and avoidance that characterize anxiety disorders.