New Views About the Anatomical and Biochemical Basis of Anxiety

An exciting new line of research proposes that anxiety engages a wide range of neurocircuits. This line of research catapults to prominence two key regulatory centers found in the cerebral hemispheres of the brain the hippocampus and the amygdala. These centers, in turn, are thought to activate the hypothalamic-pituitary-adrenocortical (HPA) axis³ (Goddard & Charney, 1997; Coplan & Lydiard, 1998; Sullivan et al., 1998). Researchers have long established the contribution of the HPA axis to anxiety but have been perplexed by how it is regulated. They are buoyed by new findings about the roles of the hippocampus and the amygdala.

The hippocampus and the amygdala govern memory storage and emotions, respectively, among their other functions. The hippocampus is considered important in verbal memory, especially of time and place for events with strong emotional overtones (McEwen, 1998). The hippocampus and amygdala are major nuclei of the limbic system, a pathway known to underlie emotions. There are anatomical projections between the hippocampus, amygdala, and hypothalalamus (Jacobson & Sapolsky, 1991; Charney & Deutch, 1996; Coplan & Lydiard, 1998).

Studies of emotional processing in rodents (LeDoux, 1996; Rogan & LeDoux, 1996; Davis, 1997) and in humans with brain lesions (Adolphs et al., 1998) have identified the amygdala as critical to fear responses. Sensory information enters the lateral amygdala, from which processed information is passed to the central nucleus, the major output nucleus of the amygdala. The central nucleus projects, in turn, to multiple brain systems involved in the physiologic and behavioral responses to fear. Projections to different regions of the hypothalamus activate the sympathetic nervous system and induce the release of stress hormones, such as CRH.⁴ The production of CRH in the paraventricular nucleus of the hypothalamus activates a cascade leading to release of glucocorticoids from the adrenal cortex. Projections from the central nucleus innervate different parts of the periaqueductal gray matter, which initiates descending analgesic responses (involving the body's endogenous opioids) that can suppress pain in an emergency, and which also activates species-typical defensive responses (e.g., many animals freeze when fearful).

Anxiety differs from fear in that the fear-producing stimulus is either not present or not immediately threatening, but in anticipation of danger, the same arousal, vigilance, physiologic preparedness, and negative affects and cognitions occur. Different types of internal or external factors or triggers act to produce the anxiety symptoms of panic disorder, agoraphobia, post-traumatic stress disorder, specific phobias, and generalized anxiety disorder, and the prominent anxiety that commonly occurs in major depression. It is currently a matter of research to determine whether dysregulation of these fear pathways leads to the symptoms of anxiety disorders. It has now been established, using noninvasive neuroimaging, that the human amygdala is also involved in fear responses. Fearful facial expressions have been shown to activate the amygdala in MRI studies of normal human subjects (Breiter et al., 1996). Functional imaging studies in anxiety disorders, such as PET studies of brain activation in phobias (Rauch et al., 1995), are also beginning to investigate the precise neural circuits involved in the anxiety disorders.

What is especially exciting is that neuroimaging has furnished direct evidence in humans of the damaging effects of glucocorticoids. In people with post-traumatic stress disorder, neuroimaging studies have found a reduction in the size of the hippocampus. The reduced volume appears to reflect the atrophy of dendrites the receptive portion of nerve cells in a select region of the hippocampus. Similarly, animals exposed to chronic psychosocial stress display atrophy in the same hippocampal region (McEwen & Magarinos, 1997). Stress-induced increases in glucocorticoids are thought to be responsible for the atrophy (McEwen, 1998). If the hippocampus is impaired, the individual is thought to be less able to draw on memory to evaluate the nature of the stressor (McEwen, 1998).

Neurotransmitter Alterations

There are many neurotransmitter alterations in anxiety disorders. In keeping with the broader view of anxiety, at least five neurotransmitters are perturbed in anxiety: serotonin, norepinephrine, gamma-aminobutyric acid (GABA), corticotropin-releasing hormone (CRH),⁵ and cholecystokinin (Coplan & Lydiard 1998; Rush et al., 1998). There is such careful orchestration between these neurotransmitters that changes in one neurotransmitter system invariably elicit changes in another, including extensive feedback mechanisms. Serotonin and GABA are inhibitory neurotransmitters that quiet the stress response (Rush et al., 1998). All of these neurotransmitters have become important targets for therapeutic agents either already marketed or in development (as discussed in the section on treatment of anxiety disorders).

Psychological Views of Anxiety

There are several major psychological theories of anxiety: psychoanalytic and psychodynamic theory, behavioral theories, and cognitive theories (Thorn et al., 1999). Psychodynamic theories have focused on symptoms as an expression of underlying conflicts (Rush et al., 1998; Thorn et al., 1999). Although there are no empirical studies to support these psychodynamic theories, they are amenable to scientific study (Kandel, 1999) and some therapists find them useful. For example, ritualistic compulsive behavior can be viewed as a result of a specific defense mechanism that serves to channel psychic energy away from conflicted or forbidden impulses. Phobic behaviors similarly have been viewed as a result of the defense mechanism of displacement. From the psychodynamic perspective, anxiety usually reflects more basic, unresolved conflicts in intimate relationships or expression of anger.

More recent behavioral theories have emphasized the importance of two types of learning: classical conditioning and vicarious or observational learning. These theories have some empirical evidence to support them. In classical conditioning, a neutral stimulus acquires the ability to elicit a fear response after repeated pairings with a frightening (unconditioned) stimulus. In vicarious learning, fearful behavior is acquired by observing others' reactions to fear-inducing stimuli (Thorn et al., 1999). With general anxiety disorder, unpredictable positive and negative reinforcement is seen as leading to anxiety, especially because the person is unsure about whether avoidance behaviors are effective.

Cognitive factors, especially the way people interpret or think about stressful events, play a critical role in the etiology of anxiety (Barlow et al., 1996; Thorn et al., 1999). A decisive factor is the individual's perception, which can intensify or dampen the response. One of the most salient negative cognitions in anxiety is the sense of uncontrollability. It is typified by a state of helplessness due to a perceived inability to predict, control, or obtain desired results (Barlow et al., 1996). Negative cognitions are frequently found in individuals with anxiety (Ingram et al., 1998). Many modern psychological models of anxiety incorporate the role of individual vulnerability, which includes both genetic (Smoller & Tsuang, 1998) and acquired (Coplan et al., 1997) predispositions. There is evidence that women may ruminate more about distressing life events compared with men, suggesting that a cognitive risk factor may predispose them to higher rates of anxiety and depression (Nolen-Hoeksema et al., in press).

Source: Mental Health: A Report of the Surgeon General - Chapter 4

next: Feeling Sick? It Might Be Anxiety NAMI

Footnotes

² Anxiety is one of the few mental disorders for which animal models have been developed. Researchers can reproduce some of the symptoms of human anxiety in animals by introducing different types of stressors, either physical or psychosocial.

³ Hypothalamus and the pituitary gland, and then the cortex, or outer layer, of the adrenal gland. Upon stimulation by the pituitary hormone ACTH, the adrenal cortex releases glucocorticoids into the circulation.

⁴ Also known as coriocotropin-releasing factor.

⁵ CRH may act as a neuromodulator, a neurotransmitter, or a neurohormone, depending on the pathway.