____________________________________________________________________________ Anxiety Disorders
PANIC DISORDER Core Pathophysiology
In patients with panic disorder/agoraphobia, fear conditioning has shown enhanced activation of the bilateral dorsal inferior frontal gyrus. Simple conditioning, safety signal processing, and anxiety sensitivity correlate with the extent of midbrain acti- vation. These findings suggest alterations in “top-down” and “bottom-up” processes during fear conditioning, interpreted within a neural framework of defensive reactions that mediate threat through distal (forebrain) versus proximal (midbrain) brain structures. This network may play a key role in panic disorder pathogenesis [83]. Genetic polymorphism (variation) may influence panic disorder with agoraphobia treatment response. Serotonin transporter gene promoter polymorphism (5-HTTLPR) is conclusively linked to emotion regulation and related patterns of brain connectivity. During functional MRI imaging, the patient subgroup that showed inhibitory anterior cingulate cortex-amygdala coupling during fear conditioning predomi- nantly possessed the L/L genotype of 5-HTTLPR polymor- phism. This activation of inhibitory function, the normal function in non-anxious persons, suggests an intermediate connectivity phenotype that modulates response to exposure- based CBT [84]. Expanding on these results, patients with panic disorder/ago- raphobia and the low-expression allele of 5-HTTLPR showed more favorable exposure therapy response than patients with other 5-HTTLPR genotypes. This genetic contribution to exposure therapy outcome implicates the serotonergic system as a response mediator to exposure treatments [85]. Balance System Abnormalities Patients with panic disorder/agoraphobia have shown subclini- cal abnormalities in balance system function that seemed to influence agoraphobia severity and contribute to dizziness and disorientation symptoms in complex sensory environ- ments (e.g., shopping malls, traffic, crowds). These patients also display greater balance control reliance on non-vestibular, proprioceptive, visually dependent cues and greater balance system reactivity to peripheral visual stimulation. These pos- sibly link to a more active visual alarm system involving visual, vestibular, and limbic areas. Patients with panic disorder/ agoraphobia also show high sensitivity to light or brightness stimuli with photophobic behavior and abnormal retinal and pupillary reflex responses possibly linked to serotonergic and/ or dopaminergic dysfunction. This overall amplified sensitivity to environmental stimuli suggests that agoraphobia involves activation of complex systems beyond panic attack fear and behavioral avoidance, including emotional responses to desta- bilizing/distressing environmental stimuli and operant-learn- ing avoidance of experiences that provoke this distress [86].
Genetic, developmental, hormonal, and environmental factors interact to impair the ventromedial prefrontal cortex’s ability to inhibit panic impulses generated by limbic regions. This underlies the pathogenesis of the initial onset of unexpected panic attacks. This pathology is further compounded by recur- rent panic attacks with repeated activation of panic-generating subcortical sites, leading to recruitment and plasticity within extended amygdala fear-hippocampus-cortical circuits. This in turn facilitates the development of situational and anticipated panic attacks and agoraphobia. Imaging studies have demon- strated ventromedial prefrontal cortex structural abnormalities in patients with panic disorder, reflecting the loss of inhibitory control over panic-generating sites. CBT enhances medial prefrontal cortex activity in subjects with anxiety disorders, which may explain its efficacy in treating panic disorder [69]. Other Pathophysiologic Models In addition to ventromedial prefrontal cortex inhibition, other alterations in brain function have been suggested in panic dis- order. Involvement of the central nuclei of the amygdala and activation of other fear centers in the thalamus, hypothalamus, and hippocampus may dysregulate respiratory control in the brainstem [74; 75]. Additionally, it has been proposed that genetic risk variants partly drive fear network activity [76]. Exaggerated hypothalamic-pituitary-adrenal axis reactivity to environmental stimuli may be involved in panic disorder etiology [77; 78]. In patients with panic disorder, CBT significantly reduces left interior frontal gyrus region activation, and reduced activity is correlated with reduced agoraphobic symptoms [79]. This reduced activation appears to be a specific substrate of CBT effects in patients with panic disorder/agoraphobia without comorbid depressive disorders [80]. Functional magnetic reso- nance imaging (MRI) shows that pre-treatment activation of the bilateral insula and left dorsolateral prefrontal cortex during threat processing is associated with rapid response to CBT [81]. AGORAPHOBIA Patients with panic disorder and agoraphobia who are antici- pating agoraphobia-specific stimuli have shown stronger region- specific activations in the bilateral ventral striatum and left insula versus controls. Patients processed these stimuli more intensively based on individual salience, and this activation is stronger than found in patients with panic disorder alone. Ventral striatum and insula hyperactivation when anticipating agoraphobia-specific situations may be a key neurofunction modulator in agoraphobia [82].
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