The cognitive response to threat involves placing the threatening object in space and time. Specific cortical brain areas are involved in these functions; for example, parietal cortex is involved in determining where an object is located in space; posterior portions of the cingulate have connections to parietal cortex, hippocampus, and adjacent cortex (important in visuospatial processing); prefrontal cortex is also involved in memory and cognition and with parietal cortex has important dual reciprocal connections with all the subcortical areas; and the dorsolateral prefrontal cortex has a range of functions, including declarative and working memory as well as planning of action, whereas the parietal cortex plays an important role in spatial memory. The medial prefrontal cortex (mPFC) and parietal cortex probably work in concert in the alerting and planning aspects of the stress response that is critical for survival. mPFC, including anterior cingulate (Brodmann area 32) and subcallosal gyrus (areas 24 and 25), is involved in selection of responses for action and emotion. This area and other medial portions of the prefrontal cortex, including orbito-frontal cortex, modulate emotional and physiological responses to stress, specifically in the effectiveness of the individual's behavior (e.g., the capacity to inhibit and change behavior in the face of threat) and are discussed in more detail later. Lesions of the mPFC increase resistance to extinction of fear-conditioned responses. The reciprocal interactions between subcortical limbic structures and orbitofrontal cortex may point to interaction in learning and unlearning of the significance of fear-producing sensory events and the choice and implementation of behaviors important for survival. Lesions in the prefrontal cortex cause profound changes in affect, mood, and social behavior.

mPFC areas (areas 24, 25, and 32) modulate emotional responsiveness through inhibition of amygdala function. It has projections to the amygdala, which are involved in the suppression of amygdala responsiveness to fearful cues. Dysfunction of these areas can be responsible for the failure of extinction to fearful cues, which is an important part of the anxiety response. Area 25 also has direct projections to brain stem and is involved in regulation of peripheral responses to stress, including heart rate, blood pressure, and cortisol response. Lesions of this area in animals result in impairments in mounting the peripheral glucocorticoid and sympathetic response to stress. Human subjects with lesions of medial prefrontal cortical areas (e.g., the famous case of Phineas Gage) have deficits in interpretation of emotional situations that are accompanied by impairments in social relat-edness. Other case studies of humans with brain lesions have implicated mPFC in "emotion" and socially appropriate interactions. Auditory association areas (temporal lobe) have also been implicated in animal studies as mediating extinction to fear responding.

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