in which an individual is exposed to a life-threatening event that causes the development of PTSD symptoms. Stimuli present at the time of trauma exposure often become associated with the traumatic event such that subsequent exposure to one or more of those stimuli triggers fear and anxiety. PTSD patients often develop strategies to avoid trauma-associated contexts or cues and develop multiple symptoms, including cognitive and memory impairments and sleep disturbances.

The advent of neuroimaging tools during the past two decades along with the advancement of preclinical research has provided a platform upon which to begin to examine the neurobiology of PTSD, from predisposing factors leading to its development to developing novel strategies to treat the disorder. This chapter reviews some of the models and experimental approaches used in this domain. The committee must emphasize that a comprehensive review of the literature in this area of research is beyond the scope of this report. Moreover, the committee emphasizes there is not a single experimental model that can or will be able to capture every aspect of this complex disorder, and every experimental model (clinical or preclinical) has its advantages and disadvantages (see review by Brewin and Holmes, 2003). With this perspective in mind, the committee uses many references that rely on one or more experimental models or approaches to examine the neurobiology of PTSD, with an objective to build a wealth of information from different approaches that may lead to a comprehensive understanding of the disorder.

ADAPTIVE AND MALADAPTIVE STRESS RESPONSES

The diagnosis of PTSD requires that a person have “experienced, witnessed, or [been] confronted with an event or events that involved actual or threatened death or serious injury, or a threat to the physical integrity of self or others” and that “the person’s response involved fear, helplessness or horror” (APA, 2000); see Chapter 2 for the complete diagnostic criteria for PTSD. Research suggests that the term stress in relation to disease should be “restricted to conditions where an environmental demand exceeds the natural regulatory capacity of an organism, in particular situations that include unpredictability and uncontrollability” (Koolhaas et al., 2011). Examples of unpredictable and uncontrollable situations include rape, childhood abuse, and military combat (Breslau et al., 1991, 1998; Kessler et al., 1995). Research on PTSD has concentrated on two systems, the sympathetic nervous system and the hypothalamic-pituitary-adrenal (HPA) axis, but there are other neurobiologic systems such as the serotonin system, the opiate system, and sex steroidal systems that have been implicated in pathologic and protective responses to stress (IOM, 2008).

The HPA axis is a neuroendocrine system from which there is successive



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