ReviewNeurobiology of posttraumatic stress disorder
Introduction
Once a diagnosis shrouded in controversy, posttraumatic stress disorder (PTSD) is now not only generally accepted as a valid diagnostic entity but also is accumulating a significant database of neurobiological research. The neurobiology of PTSD bears striking similarities to that of major depression; however, there are differences that underscore the uniqueness of PTSD as a stress-induced syndrome distinct from depression. Like depression studies, PTSD studies have focused upon the two biological systems with the richest traditions in stress-related research: the hypothalamic–pituitary–adrenal (HPA) axis and the catecholamine/sympathetic nervous system. Both depression and PTSD are associated with hyperactivity in these two systems; however, PTSD bears the noteworthy distinction of being associated with normal to low cortisol levels (hypocortisolaemia) despite hypersecretion of corticotropin-releasing factor (CRF).
Recent advances in PTSD research have extended these findings on several fronts. First, the function of the HPA axis is being more closely scrutinized in an effort to elucidate the underlying pathophysiology that might explain the frequently reported hypocortisolemia in patients with PTSD. Second, animal models are increasingly being used to incorporate novel stress protocols (such as predator exposure) and biological studies (such as hippocampal receptor assays) that would be impractical in humans. Third, the almost exclusive study of combat veterans in PTSD research is giving way to the study of other patient groups suffering from non-combat traumas such as rape or child abuse. In fact, some of the first research in children with PTSD is just now being reported. Fourth, other biological systems including the immune system, the endogenous opiates, and the serotonin system are beginning to receive attention from PTSD researchers. Finally, functional brain imaging is providing our first glimpse into the dysfunction of specific neuroanatomical loci during stimulus processing and symptomatic exacerbation in patients with PTSD. During imaging, symptomatic states can be manifested by intrusive memories of the trauma or by evidence of physiological arousal such as increased heart rate and sweating. PTSD symptoms can be provoked during an imaging session by exposure to a trauma-related cue (e.g. recordings of combat sounds) or by guided mental imagery (e.g. imagining the trauma). As these data continue to accumulate, the role of pharmacological interventions for treating PTSD — including the forthcoming CRF receptor antagonists — can be refined, allowing significant treatment advances in the near future.
As early as the American Civil War, physicians were documenting the finding that persistent psychological distress often follows exposure to war-related trauma. It was soon realized that other traumatic experiences such as natural disasters or serious accidents could produce similar long-lasting psychological symptoms. Previously known by a variety of combat-related colloquialisms such as shell shock, war neurosis, and battle fatigue, it was not until the introduction of the third edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-III) in 1980 that PTSD was included among the recognized psychiatric disorders.
PTSD is characterized in the DSM-III by a phenomenological triad incorporating the symptoms of re-experiencing, avoidance, and hyperarousal. The re-experiencing symptoms of PTSD include nightmares, intrusive memories and flashbacks of the trauma. The avoidance symptoms include amnesia for the trauma or a reluctance to discuss or think about the trauma. Finally, the hyperarousal symptoms include an exaggerated startle response, fitful sleep and poor concentration. Despite this comprehensive description, the inclusion of PTSD in the DSM-III produced considerable controversy in the field, largely on phenomenological grounds. Some contended that the disorder overlapped so greatly with other anxiety and mood disorders that it was superfluous to psychiatric nosology [1]. There were even implications that political pressures unduly contributed to its inclusion in the DSM-III 2, 3. In addition, others debated whether PTSD belonged among the anxiety disorders, the mood disorders, or a unique class of stress response disorders [4].
Some researchers now contend that the neurobiological uniqueness of PTSD validates it as a distinct diagnostic entity 1, 5. This is indeed ironic when we recognize that the earliest attempts at developing an etiology-based psychiatric nosology were abandoned in the DSM-III — the same edition that first included PTSD — due to the inherent difficulty of demonstrating the underlying biology of psychiatric illnesses. Although a comprehensive neurobiology of PTSD remains to be definitively elucidated, the argument that its unique neurobiology validates its nosological classification may be a harbinger to a day when psychiatric diagnostic schemes again rely more upon the pathophysiology of an illness.
The bulk of PTSD neurobiological research has focused upon the HPA axis and the catecholamine/sympathetic nervous system, with Vietnam combat veterans comprising the largest contingent of research participants. However, PTSD research is now expanding in several domains. First, recent studies incorporate non-combat related PTSD (e.g. victims of rape, child abuse, natural disasters or terrorism). Second, inquiry has extended into other stress-responsive neurobiological systems. Third, new investigative tools such as functional brain imaging are being increasingly utilized. Fourth, several researchers are conducting laboratory animal studies to remedy the long-recognized deficiency of animal models for PTSD [6]. Finally, novel lines of research are investigating the contribution of childhood trauma to the diathesis for adulthood PTSD 7, 8, 9, 10.
In this review, we offer an update of the major contributions to the literature on the neurobiology of PTSD that have appeared in the past year. This article will survey new research into the neurocognition and functional neuroanatomy of PTSD, the neuroendocrinology of PTSD, neurotransmitter studies of PTSD, and finally the immunological sequelae of PTSD. Previous reviews of PTSD neurobiology can be consulted for a more comprehensive review of research published prior to 1999 1, 6, 11, 12, 13••, 14.
Section snippets
Neurocognition and functional neuroanatomy
Many of the hallmark symptoms of PTSD (e.g. nightmares, flashbacks, amnesia for the traumatic event, dissociative episodes, exaggerated startle response) represent, at least in part, disturbances in neurocognitive processing. In particular, sensory input and memory processing appear to be awry in PTSD. Not only are pharmacological probes being used to investigate psychiatric illness at the cellular level, but new tools are also becoming available to investigate brain function in psychiatric
Hypothalamic–pituitary–adrenal axis
The classic HPA axis response to stress is hierarchically organized, with increases in hypothalamic CRF secretion that in turn increase the release from the pituitary of adrenocorticotropin hormone (ACTH), and ultimately increase the adrenocortical release of cortisol. Patients with major depression exhibit, as a group, both CRF hypersecretion and hypercortisolemia. Furthermore, negative feedback within the HPA axis has been shown to be dysfunctional in depression (e.g. see 26, 27).
The HPA axis
Norepinephrine
Norepinephrine (NE) is by far the most thoroughly studied classical neurotransmitter involved in the biological response to traumatic stress. Since World War II, psychophysiological research has demonstrated physical responses to stress suggestive of increased sympathetic tone such as tachycardia, hypertension, diaphoresis, and dizziness. These physiological measures are accompanied by evidence of NE hypersecretion. For example, numerous studies have reported increased urinary concentrations of
Psychoneuroimmunology
It has long been assumed that stress has a deleterious impact on the function of the immune system; however, research results have been inconsistent. Investigations of the association between stress and immunological disturbance include measures of both cellular and humoral immunity [48]. Cellular immunity refers to the infection-fighting capacity of immune cells such as lymphocytes, neutrophils, macrophages, and natural killer cells. Measures of cellular immunity include the absolute numbers
Conclusions
The vast literature regarding the neurobiology of stress and depression has provided a template for PTSD research. Therefore, it is understandable that the bulk of neurobiological research to date has focused upon the NE and HPA axis stress response systems. Although research to date provides an unsatisfyingly incomplete picture, there is increasing evidence that the neurobiology of PTSD is truly distinct from other mental disorders. It remains unclear, however, which of the neurobiological
Acknowledgements
Supported by the National Institute of Mental Health Emory Conte Center for the Neuroscience of Mental Disorders (MH-58922). DJ Newport is the recipient of the American Psychiatric Association/Lilly Psychiatric Research Fellowship.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
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