Working Model For The Neural Circuitry Of Anxiety Disorders

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Anxiety disorders are characterized by dysfunction of an interrelated neurochemical and neuroanatomical system. PTSD and PD share many biological and phenomenological similarities that allow them to be considered related. Phobic disorders and GAD are still in early stages of investigation. Although phenomen-ologically they are similar to PTSD and PD, it is premature to include them in a model for human anxiety disorders. PTSD is related more to the deleterious effects of environmental stress, whereas

PD is not as clearly related to stress and may be related more to genetic variability in anxiety. In stress-related anxiety disorders (i.e., PTSD), PTSD symptoms as well as cognitive dysfunction associated with PTSD may be linked to hippocampal dysfunction. A model can be created which incorporates informatiom from animal and clinical research relevant to these disorders, keeping in mind that working models are subject to modification with new information, and that generalizations involving causality should be seen as merely speculative when derived from clinical studies that are by their very nature cross sectional. For a schematic model of the neural circuitry see Fig. 3.

Neural Circuits Anxiety Disorders

Figure 3 A schematic model of the neural circuits involved in the afferent input of fear- and anxiety-inducing stimuli and the processing of the stimuli. The amygdala plays a pivotal role in the assessment of danger and the response. The LC is a critical component in both afferent and efferent systems, mainly through NE release. The amygdala receives input from PAG, LC, thalamus, hippocampus, association cortices, entorhinal cortex, and visceral pathways. Input from mPFC is involved in determining the significance of fear-producing sensory events, the choice and implementation and the type of behavior, and the extinction of conditioned fear responses. States of stress and fear result in a rapid increase in firing of neurons in the LC, with release of NE transmitter in different target sites in the brain. This results in an increase in attention and vigilance, as well as enhancement of memory recall, which can be life saving in threatenting situations. Patients with anxiety disorder, however, develop long-term alterations in the function of this system. The fear response is dependent on previous experience, sensitization, fear conditioning, and extinction of previous fear responses.

Figure 3 A schematic model of the neural circuits involved in the afferent input of fear- and anxiety-inducing stimuli and the processing of the stimuli. The amygdala plays a pivotal role in the assessment of danger and the response. The LC is a critical component in both afferent and efferent systems, mainly through NE release. The amygdala receives input from PAG, LC, thalamus, hippocampus, association cortices, entorhinal cortex, and visceral pathways. Input from mPFC is involved in determining the significance of fear-producing sensory events, the choice and implementation and the type of behavior, and the extinction of conditioned fear responses. States of stress and fear result in a rapid increase in firing of neurons in the LC, with release of NE transmitter in different target sites in the brain. This results in an increase in attention and vigilance, as well as enhancement of memory recall, which can be life saving in threatenting situations. Patients with anxiety disorder, however, develop long-term alterations in the function of this system. The fear response is dependent on previous experience, sensitization, fear conditioning, and extinction of previous fear responses.

A biological model to explain pathological human anxiety should involve both brain stem circuits and cortical and subcortical regions involved in memory and modulation of emotion. The evidence is consistent with chronically increased function of neurochemical systems (CRF and NE) that mediate the fear response in anxiety disorders. Although it is clear that activity at the central portion of the HPA axis is increased, responses at other portions of the HPA axis, including the pituitary and adrenals, and the long-term effects on the hormonal final product (cortisol), are less clear. Increased NE and CRF released in the brain act on specific brain areas, including hippocampus, mPFC, temporal and parietal cortex, and cingulate, that are dysfunctional in human anxiety disorders. Other neurochemical systems, including Bzs, opiates, dopamine, CCK, and NPY, also play a role.

Emotion is a phenomenon uniquely associated with our species. Moving up in terms of species complexity, the most salient change in brain architecture is the massive increase in cortical gray matter, especially frontal cortex. It is therefore not surprising that this frontal lobe plays a role in modulation ofemotionality. The medial portion of prefrontal cortex serves to inhibit more primitive limbic processing and thus has an important role in modulation of human emotion in general and also in fear responsivity and anxiety. Amygdala and LC both play a pivotal role in fear processing and anxiety. Hippocampal dysfunction also plays an important role in the development of symptoms of anxiety. mPFC (areas 24 and 25) and anterior cingulate (area 32) have inhibitory inputs that decrease amygdala responsiveness and have been hypothesized to mediate extinction of fear responding. Activation of this area has been shown to be a normal response to stress or increased emotionality. Dysfunction in this area may mediate increased emotionality and failure of extinction to fear inducing cues in anxiety disorders. Evidence to support this idea includes failure of normal activation in this area with yohimbine-induced provocation of anxiety in both PTSD and PD and failure of activation/decreased blood flow with traumatic cue exposure in PTSD. Again, potentiated release of NE with stressors in PTSD and PD is expected to be associated with a relative decrease in function of neurons in this area.

Studies performed to date are encouraging because many findings from animal studies have been successfully applied to human anxiety disorders. The past decade has seen an exciting expansion of research in the field of fear and anxiety. Future research will need to continue to apply findings from the revolution in neuroscience to further understand fear processing, anxiety, and human anxiety disorders.

See Also the Following Articles

CONVERSION DISORDERS AND SOMATOFORM DISORDERS • DEPRESSION • EMOTION • HOMEOSTATIC MECHANISMS • NEUROPSYCHOLOGICAL ASSESSMENT • PSYCHONEUROENDOCRINOLOGY • STRESS

Suggested Reading

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