Neuroscience Perspectives

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Recent developments in understanding the basic neurobiology of anxiety have allowed theorists to combine a neuroscience and behavioral/learning perspective to understand the role of both nature and nurture in determining the anxiety response. In this conceptualization, both external and internal (i.e., cognitive) environments play important roles in modulating activity in key brain areas that control the processing of environmental signals and the propensity for an anxiety response. This dual contribution is consistent with the equal and important role of both medication and psychotherapeutic approaches to the treatment of the various anxiety disorders.

The amygdala is an almond-shaped brain structure below the cerebral cortex and deep inside the temporal lobes. It serves as a central integrative brain center that coordinates both stimulus processing and anxiety response generation (LeDoux, 1996). This coordination is made possible by a rich set of reciprocal connections to higher cortical cen ters that process and compare multiple sensory and cognitive signals and to lower brain-stem centers that regulate blood pressure, pulse, respiration, digestion, and other arousal-related functions. In animals, lesioning the amygdala prevents acquisition of a conditioned emotional response (so that animals cannot learn the association between, for example, an electric shock and a light signal). Thus, the amygdala is a key brain structure modulating the ability to learn an association between various environmental contexts and danger, anxiety, or apprehension.

Many studies of the anxiety and stress response have implicated key hormones and neurotransmitters. Prominent among these are corticotropin-releasing hormone (CRH), which modulates adrenal cortisol response; norepinephrine, which controls the ratio of signal to noise, thereby alerting the organism to the relevance of certain stimuli; and serotonin, which plays a key "braking" role in controlling sensory input to the amygdala as well as modulating anxiety responsivity. Brain norepinephrine synergizes with CRH in activating arousal of the peripheral sympathetic nervous system and central nervous system, the amygdala plays a key role in orchestrating this response, and these hormones may provide feedback to the amygdala that potentiates the anxiety response.

It is of some interest that the responsivity of a number of these stress hormones has been linked to developmental experience by an elegant series of studies. These studies show that early adverse life experiences appear to set thresholds for activity of these various stress response systems. Separation and loss, hardship, and abuse serve to increase the individual's tendency for hormone/neurotransimitter-related hyperarousal (Coplan et al., 1998). These findings are consistent with studies showing an increased rate of early adverse life experiences, especially separation and loss, in patients with various pathologic anxiety disorders.

There are significant genetic contributions to anxiety (Plomin, DeFries, McClearn, & Rutter, 1997). Twin studies have shown heritability in children for a dimension of fear-fulness called behavioral inhibition, as well as shyness, and in adults for the personality characteristics of neuroticism. Behavioral inhibition before 1 year of age is associated with an increased cortisol and heart rate response (Kagan, 1997) consistent with the setting of lower thresholds for stress response system activation previously noted. However, twin studies also show a significant role for the environment (e.g., a proportion of behaviorally inhibited infants improve by age seven, whereas some noninhibited infants acquire this response at age seven).

In the context of this neurobiologic system that modulates anxiety response, the dual roles of medication and psychotherapy can be readily appreciated. Antidepressant medications (which also have potent anti-anxiety effects) work on neurotransmitter systems in lower brain-stem centers that control input and outflow from the amygdala. More purely anti-anxiety medications (e.g., benzodiazepine tranquilizers) work in the amygdala itself, directly damp-

ening certain inputs and perhaps affecting output. In contrast, psychotherapy probably works at higher cortical centers, which will affect sensory input to the amygdala as well as modifying amygdala processing itself via the reciprocal connections, thereby affecting the proclivity to generate an anxiety response and the likelihood that this response can be extinguished with new experience and learning. The greater effectiveness of combined treatment with both modalities, often observed in studies of anxious patients, can be readily appreciated from this point of view.


Craig, K. J., Brown, K. J., & Baum A. (1995). Environmental factors in the etiology of anxiety. In F. E. Bloom & D. J. Kupfer (Eds.), Psychopharmacology: The fourth generation of progress (pp. 1325-1337). New York: Raven. Coplan, J. D., Trost, R., Owens, M. J., Cooper, T., Gorman, J. M., Nemeroff, C. B., et al. (1998). Cerebrospinal fluid concentrations of somatostatin and biogenic amines in grown primates reared by mothers exposed to manipulated foraging conditions. Archives of General Psychiatry, 55, 473-477. Kagan, J. (1997). Temperament and the reactions to unfamiliarity.

Child Development, 68, 139-143. Kandel, E. R. (1983). From metapsychology to molecular biology: Explorations into the nature of anxiety. American Journal of Psychiatry, 140(10), 1277-1293. LeDoux, J. E. (1996). The emotional brain. New York: Simon and Schuster.

Plomin, R, DeFries, J. C., McClearn, G. E., & Rutter, M. (1997). Behavioral genetics. New York: Freeman.

Peter Roy-Byrne University of Washington, Harborview Medical Center, Seattle, WA

See also: Antidepressant Medications; Cognitive Therapy; Neurotransmitters

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