Anxiety Disorders ____________________________________________________________________________
Alterations in Brain Transmitter Chemicals Neurotransmitters allow communication between brain regions. Alterations in neurotransmitter systems implicated in anxiety disorder pathogenesis include the monoamines serotonin (5-hydroxytryptamine or 5-HT), norepinephrine, and dopamine. Aberrant limbic signaling is associated with decreased inhibitory signaling by gamma-amino-butyric acid (GABA) or increased excitatory neurotransmission by gluta- mate. Many other neurotransmitter systems participate in the modulation of fear and anxiety, including the neuropeptide substances P, N, and Y; corticotropin-releasing factor (CRF); and endocannabinoids. Abnormalities in these systems are associated with structural and functional alterations in specific brain areas, such as the amygdala, prefrontal cortex, locus coeruleus, and hippocampus, and represent the therapeutic targets of drug therapy [70]. Gene products that regulate monoamine signaling may be criti- cal in facilitating antidepressant effect. Monoaminergic regula- tors include transmitter receptors; vesicular monoamine trans- porter, which packages monoamines into vesicles; oxytocin and vasopressin; transmitter-specific reuptake transporters, such as the serotonin transporter, norepinephrine transporter, and dopamine transporter; monoamine oxidase, which degrades monoamines; and catecholamine- O -methyltransferase, which degrades norepinephrine and dopamine [67]. However, the cause of anxiety disorders is not simply a deficiency of one neurotransmitter or excess of another. The networks governed by these transmitters are extensively inter-related, with multiple feedback mechanisms and complex receptor structures. This complexity contributes to unpredictable and sometimes para- doxical medication responses [70]. GENERALIZED ANXIETY DISORDER Neuronal circuits implicated in GAD are distinct from panic disorder, likely involving much greater frontal and prefrontal lobe than amygdala involvement. GAD is characterized by abnormalities in frontal and limbic structures and in the connectivity between these regions. The most frequently implicated frontal regions are the prefrontal cortex and the anterior cingulate cortex; in the limbic region, the amygdala and possibly the hippocampus are involved. Structural abnor- malities and decreased structural and functional connectivity between frontal and limbic regions have repeatedly been docu- mented in GAD [71; 72]. Functional neuroimaging suggests that GAD is characterized by inefficient biologic mechanisms associated with emotion regulation. Worry induction increases prefrontal cortex activation and decreases amygdala activity in patients with GAD and non-anxious controls, but unlike non- anxious subjects, patients with GAD are unable to normalize this neural activity afterward. The results from studies using tasks that require conflict monitoring and emotion regulation support a model of GAD characterized by hypoactivation in the prefrontal cortex and anterior cingulate cortex indicative of deficient “top-down” emotional control [73].
Altered limbic and prefrontal cortex functioning characterize anxiety disorders, with amygdala hyper-responsivity to threat- ening stimuli and impaired ventromedial prefrontal contex inhibitory control over limbic-generated, anxiety-inducing signals, associated with aberrant communication and func- tional connectivity between the amygdala and the prefrontal cortex [67]. Narrowing brain region contribution, amygdala and insula hyperactivation contribute to anxiety disorders triggered by specific stimuli (e.g., panic disorder, specific phobia). The insula integrates sensory, emotional, and cognitive information through extensive connections between the lateral prefrontal cortex, ventromedial prefrontal cortex, orbitofrontal cortex, cingulate, amygdala, bed nucleus of the stria terminalis, and ventral striatum. Changes in the level of insula activation influence anxiety level [66]. Amygdala-medial prefrontal cortex functional connectivity shows a developmental trajectory, and early temperamental risk for anxiety is associated with disruption of these circuits. Aberrant amygdala-prefrontal cortex connectivity is found in patients with adult-onset anxiety disorders who showed child- hood temperament risk factors but did not develop early-onset anxiety. This suggests aberrant connectivity is a lingering biomarker of risk [68]. Familial and Environmental Contribution Persons with anxiety and mood disorders show a shared genetic predisposition, with specific manifestation the product of genetic and environmental interactions. A developmental dynamic pattern of genetic influence on individual differences in anxiety and depression symptoms is apparent. Genetic influence on psychopathology changes over the lifespan, with different developmental stages associated with a unique pattern of risk factors [67]. Significant early-life stress (e.g., maternal deprivation) may degrade prefrontal cortex functional connectivity with sub- cortical panic-generating circuits, elevating risks of anxiety disorders and other psychopathology. Many significant early- life stress events (e.g., child abuse, neglect, parental loss from death or abandonment) are receiving heightened attention as contributing factors to anxiety disorders and trauma pathology, as in PTSD. Previous childhood or adult trauma is considered a predisposing/contributing factor to panic disorder and SEPAD as well as major depressive disorder and PTSD that may be primary or comorbid with other anxiety disorders [69]. Aver- sive experiences can lead to complex behavioral adaptations, including increased levels of anxiety and fear generalization.
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