Findings of the studies reviewed in this chapter are con- sistent with dysfunction of an interrelated neurochemi- cal and neuroanatomical system in human anxiety dis- orders. PTSD and panic disorder have several biological and phenomenological similarities that allow them to be considered in relation to each other. Investigation of phobic disorders and generalized anxiety disorder is still in the early stages; although they have some phenome- nological similarities to PTSD and panic disorder, it is premature to include them in a model for human anxi- ety disorders. Obsessive-compulsive disorder is differ- ent in many ways from these other disorders and there- fore has not been reviewed in this chapter. Of the two
anxiety disorders that are the focus of subsequent dis- cussion—PTSD and panic disorder—PTSD is related more to the deleterious effects of environmental stress, whereas panic disorder is not as clearly related to stress and may be related more to genetic variability in anxiety. Therefore, a model can be created that incorporates in- formation 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.
A biological model to explain pathological human anxiety should include both brain stem circuits and cor- tical and subcortical regions involved in memory and modulation of emotion. The evidence reviewed in this chapter is consistent with chronically increased function of neurochemical systems (CRF and norepinephrine) that mediate the stress response in anxiety disorders. Al- TABLE 4–3. Evidence for alterations in other neurotransmitter systems in anxiety disorders
Finding PTSD Panic disorder
Benzodiazepine
Increased symptomatology with benzodiazepine antagonist – ++
Opiate
Naloxone-reversible analgesia +
Increased plasma β-endorphin response to exercise +
Increased endogenous opiates in CSF +
Serotonin
Decreased serotonin reuptake site binding in platelets ++
Decreased serotonin transmitter in platelets –
Blunted prolactin response to buspirone (5-HT1A probe) –
Altered serotonin effect on cAMP in platelets (5-HT1A probe) –
Thyroid
Increased baseline thyroxine +
Increased TSH response to TRH +
Somatostatin
Increased somatostatin levels at baseline in CSF +
Cholecystokinin (CCK)
Increased anxiety symptoms with CCK administration NT ++
Note. –=one or more studies did not support this finding (with no positive studies), or the majority of studies did not support this finding; +=at
least one study supported this finding, with no studies not supporting the finding, or the majority of studies supported the finding; ++=two or more studies supported this finding, with no studies not supporting the finding. cAMP=cyclic adenosine monophosphate; CSF=cerebrospinal fluid; 5-HT1A=serotonin type 1A; NT=not tested (to our knowledge); PTSD=posttraumatic stress disorder; TRH=thyrotropin-releasing hor-
though activity at the central portion of the HPA axis is increased, responses at other portions of the HPA axis, including the pituitary and adrenal, and long-term ef- fects on the hormonal final product, cortisol, do not show increased concentrations of the hormone; instead, levels are normal or low. Increased norepinephrine and CRF released in the brain act on specific brain areas (in- cluding the hippocampus; medial prefrontal, temporal, and parietal cortex; and cingulate) that are dysfunctional in human anxiety disorders. Other neurochemical sys- tems, including benzodiazepines, opiates, dopamine, CCK, and neuropeptide Y, also play a role.
Hippocampal dysfunction may play a role in the pathological symptoms of anxiety. In stress-related anx- iety disorders (i.e., PTSD), symptoms and cognitive dysfunction associated with PTSD may be linked to hippocampal dysfunction. Release of glucocorticoids or other stress-related factors (e.g., stress-induced de- creases in brain-derived neurotrophic factor) may result in hippocampal damage, with lasting deficits in verbal declarative memory dysfunction in PTSD. Although hippocampal volume reduction appears to be specific to stress-related anxiety disorders, patients with panic dis- order have had alterations of parahippocampal gyrus and other portions of extrahippocampal temporal lobe that may underlie declarative memory deficits also seen in panic disorder. Increased cortisol release with stress in both PTSD and panic disorder may result in amnesia and cognitive dysfunction associated with these disor- ders. Excessive release of norepinephrine with stressors in anxiety disorder patients will be predicted to result in decreased function of neurons, which may be related to both cognitive dysfunction and increased anxiety with stress. In addition, given the known role of the hippo- campus in contextual fear, lasting damage to the hip- pocampus may contribute to excessive anxiety and fear
responding in anxiety disorders. Finally, because the hippocampus is involved in integration of individual as- pects of memory at the time of memory retrieval, hip- pocampal dysfunction may lead to memory fragmenta- tion and amnesia in anxiety disorders.
The medial prefrontal cortex also plays a prominent role in anxiety. Moving up in terms of species complex- ity, the most salient change in brain architecture is the massive increase in cortical gray matter, especially fron- tal cortex. It is therefore not surprising that the frontal lobe plays a role in the phenomenon uniquely associated with our species—that is, emotion. The medial portion of the prefrontal cortex seems to have an important role in human emotion and anxiety. The medial prefrontal cortex (subcallosal gyrus [Brodmann area 25] and ante- rior cingulate [Brodmann area 32]) has inhibitory inputs that decrease amygdala responsiveness and has been hy- pothesized to mediate extinction of fear responding. Brodmann area 25 also stimulates the peripheral cortisol and sympathetic response to stress. Activation of this area has been shown to be a normal response to stress or increased emotionality. We have hypothesized that dys- function in this area may mediate increased emotional- ity and failure of extinction to fear-inducing cues in anx- iety disorders. Evidence to support this idea includes failure of normal activation in this area with yohimbine- induced provocation of anxiety in both PTSD and panic disorder and failure of activation/decreased blood flow with traumatic cue exposure in PTSD. Again, potenti- ated release of norepinephrine with stressors in PTSD and panic disorder is expected to be associated with a relative decrease in function of neurons in this area. Findings in anxiety disorder research are consistent, with a long history of literature, mostly from studies of lesions in human subjects, supporting a role for medial prefrontal cortex in emotionality.
Key Clinical Points
• Underlying the symptoms of anxiety disorders are alterations in the function and structure of brain areas involved in stress and memory. These alterations involve neurotransmitters and neural circuits that play a critical role in the stress re- sponse.
• Specific alterations include increased function of neurochemical systems (corti- cotropin-releasing factor and norepinephrine) that mediate the stress response, as well as dysregulation of the hypothalamic-pituitary-adrenal axis.
• The affected neurotransmitters and neurohormones are released in specific brain areas (including the hippocampus; medial prefrontal, temporal, and pari- etal cortex; and cingulate) that are dysfunctional in human anxiety disorders. • Other neurochemical systems, including benzodiazepines, opiates, dopamine,
cholecystokinin, and neuropeptide Y, also play a role in the maintenance of anx- iety symptoms.
• Studies performed to date are encouraging, in that many findings from animal studies have been successfully applied to human anxiety disorders.
• The past decade has seen an exciting expansion of research in human anxiety dis- orders. Future research must continue to apply findings from the revolution in neuroscience to increase understanding of human anxiety disorders.
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