Brain Function

In the brain, there is evidence of structural and functional changes resulting directly from chronic or severe stress. The changes are associated with alterations of the most profound functions of the brain: memory and decision making. They also are associated with symptoms of fear and anxiety, and they might sensitize the brain to substances of abuse and increase the risk of substance-use disorders (Brady and Sinha 2005; Will et al. 1998). The impact of chronic stress on those brain functions is discussed below.

Memory and Cognition

Memory and cognition have been studied extensively in three regions of the brain: the hippocampus, the prefrontal cortex, and the amygdala. The hippocampus, the center of explicit memory, appears be especially vulnerable to chronic stress. Repeated stress, according to animal models, changes the structure of and connections between neurons in the hippocampus devoted to receiving signals from other nerve cells (McEwen 1999b; Sapolsky 2003). When hippocampal neurons are remodeled by glucocorticoids working together with some neurochemicals, they lose their plasticity. Plasticity is vital for encoding memories and learning from them, and its loss leads to impairment of essential cognitive functions of the brain. Cognitive dysfunction is seen in people who use glucocorticoids chronically as treatment for autoimmune or inflammatory disorders, in people who secrete cortisol excessively, and in healthy volunteers given glucocorticoids (Sapolsky 2003).

Plasticity in the hippocampus is thought to depend in part on the production of new nerve cells by proliferation and differentiation of stem cells or progenitor cells in a process known as neurogenesis. In animal models, chronic stress inhibits neurogenesis in the hippocampus and can reduce the number of neurons (Pham et al. 2003). Increases in glucocorticoids, endogenous opioids, and excitatory amino-acid transmitters play a role in this inhibition (Eisch and Harburg 2006; Mirescu and Gould 2006). The inhibition of neurogenesis might also be mediated in part by proinflammatory cytokines (Kempermann and Neumann 2003) that direct neuron stem cells to mature into non-nerve cells in the brain at the expense of generating new nerve cells. That effect can be blocked by anti-inflammatory agents (Monje et al. 2003).

As discussed earlier, the prefrontal cortex integrates such information as whether a sudden noise poses a threat and modulates activity of the HPA axis (McDougall et al. 2004; Radley and Morrison 2005). Repeated stress causes structural remodeling of the neurons in the axis that reduce their ability to receive signals from other neurons. As explicated by McEwen et al. (1999a) in connection with structural remodeling in the hippocampus, changes in the prefrontal cortex are most likely driven by increased concentrations of glucocorticoids and by other neurochemicals in the brain that are increased by repeated exposure to stressors (Radley and Morrison 2005); those changes impair cognitive flexibility (Liston et al. 2006).

The amygdala undergoes structural changes that are the opposite of those seen in the hippocampus and prefrontal cortex. In animal models, the changes are accompanied by an increase in fear conditioning and anxiety-like behaviors (Vyas et al. 2002). That also appears to be the case in humans; veterans with PTSD evaluated with brain-imaging techniques (see Chapter 5) show activation of the amygdala after being exposed to traumatic images (for example, Shin et al. 2004).

Memories formed in association with stressful life events can be indelible and can be triggered, even years later, by cues associated with the original event. The memories can be



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