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Summer 2003, Vol. I, No. 3

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NTRODUCTION

Once a diagnosis shrouded in controversy, post-traumatic stress disorder (PTSD) is now not only generally accepted as a valid diagnostic entity butalso is accumulating a significant database of neu-robiological research. The neurobiology of PTSDbears striking similarities to that of major depres-sion; however, there are differences that underscorethe uniqueness of PTSD as a stress-induced syn-drome distinct from depression. Like depressionstudies, PTSD studies have focused upon the twobiological systems with the richest traditions instress-related research: the hypothalamic-pituitary-adrenal (HPA) axis and the catecholamine/sympa-thetic nervous system. Both depression and PTSDare associated with hyperactivity in these two sys-tems; however, PTSD bears the noteworthy dis-tinction of being associated with normal to low cortisol levels (hypocortisolaemia) despite hyper-secretion of corticotropin-releasing factor (CRF).Recent advances in PTSD research haveextended these findings on several fronts. First, thefunction of the HPA axis is being more closely scrutinized in an effort to elucidate the underlyingpathophysiology that might explain the frequently reported hypocortisolemia in patients with PTSD.Second, animal models are increasingly being usedto incorporate novel stress protocols (such as pred-ator exposure) and biological studies (such as hip-pocampal receptor assays) that would be impracti-cal in humans. Third, the almost exclusive study of combat veterans in PTSD research is giving way tothe study of other patient groups suffering fromnon-combat traumas such as rape or child abuse. Infact, some of the first research in children withPTSD is just now being reported. Fourth, otherbiological systems including the immune system,the endogenous opiates, and the serotonin systemare beginning to receive attention from PTSDresearchers. Finally, functional brain imaging isproviding our first glimpse into the dysfunction of specific neuroanatomical loci during stimulus pro-cessing and symptomatic exacerbation in patients with PTSD. During imaging, symptomatic statescan be manifested by intrusive memories of thetrauma or by evidence of physiological arousal suchas increased heart rate and sweating. PTSD symp-toms can be provoked during an imaging sessionby exposure to a trauma-related cue (e.g. recordingsof combat sounds) or by guided mental imagery (e.g. imagining the trauma). As these data continueto accumulate, the role of pharmacological inter-ventions for treating PTSD—including the forth-coming CRF receptor antagonists—can be refined,allowing significant treatment advances in the nearfuture. As early as the American Civil War, physicians were documenting the finding that persistent psy-chological distress often follows exposure to war-

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Neurobiology of PosttraumaticStress Disorder

D. Jeffrey NewportCharles B. Nemeroff

Recent advances on the neurobiology of posttraumatic stress disorder include: the utilization of func-tional brain imaging; the incorporation of cross-system research including neuroendocrine (hypothala-mic-pituitary-adrenal and hypothalamic-pituitary-thyroid axes), neurochemical (corticotropin-releasingfactor, norepinephrine, serotonin, endogenous opiates), and neuroimmunological (humoral and cellularimmunity) systems; the expansion beyond exclusive study of combat veterans to include posttraumaticstress disorder patients suffering from noncombat traumas; and the development of animal models of traumatic stress.

(Reprinted with permission from Current Opinion in Neurobiology 2000; 10:211–218)

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THE JOURNAL OF LIFELONG LEARNING IN PSYCHIATRY

related trauma. It was soon realized that other trau-matic experiences such as natural disasters or seri-ous accidents could produce similar long-lastingpsychological symptoms. Previously known by avariety of combat-related colloquialisms such asshell shock, war neurosis, and battle fatigue, it wasnot until the introduction of the third edition of the Diagnostic and Statistical Manual of MentalDisorders (DSM-III) in 1980 that PTSD wasincluded among the recognized psychiatric disor-ders.PTSD is characterized in the DSM-III by a phe-nomenological triad incorporating the symptomsof re-experiencing, avoidance, and hyperarousal.The re-experiencing symptoms of PTSD includenightmares, intrusive memories and flashbacks of the trauma. The avoidance symptoms includeamnesia for the trauma or a reluctance to discuss orthink about the trauma. Finally, the hyperarousalsymptoms include an exaggerated startle response,fitful sleep and poor concentration. Despite thiscomprehensive description, the inclusion of PTSDin the DSM-III produced considerable controversy in the field, largely on phenomenological grounds.Some contended that the disorder overlapped sogreatly with other anxiety and mood disorders thatit was superfluous to psychiatric nosology (1).There were even implications that political pres-sures unduly contributed to its inclusion in theDSM-III (2, 3). In addition, others debated whether PTSD belonged among the anxiety disor-ders, the mood disorders, or a unique class of stressresponse disorders (4).Some researchers now contend that the neurobi-ological uniqueness of PTSD validates it as a dis-tinct diagnostic entity (1, 5). This is indeed ironic when we recognize that the earliest attempts atdeveloping an etiology-based psychiatric nosology were abandoned in the DSM-III—the same edi-tion that first included PTSD—due to the inherentdifficulty of demonstrating the underlying biology of psychiatric illnesses. Although a comprehensiveneurobiology of PTSD remains to be definitively elucidated, the argument that its unique neurobi-ology validates its nosological classification may bea harbinger to a day when psychiatric diagnosticschemes again rely more upon the pathophysiology of an illness.The bulk of PTSD neurobiological research hasfocused upon the HPA axis and the cate-cholamine/sympathetic nervous system, withVietnam combat veterans comprising the largestcontingent of research participants. However,PTSD research is now expanding in severaldomains. First, recent studies incorporate non-combat related PTSD (e.g. victims of rape, childabuse, natural disasters or terrorism). Second,inquiry has extended into other stress-responsiveneurobiological systems. Third, new investigativetools such as functional brain imaging are beingincreasingly utilized. Fourth, several researchers areconducting laboratory animal studies to remedy the long-recognized deficiency of animal modelsfor PTSD (6). Finally, novel lines of research areinvestigating the contribution of childhood traumato the diathesis for adulthood PTSD (7–10).In this review, we offer an update of the majorcontributions to the literature on the neurobiology of PTSD that have appeared in the past year. Thisarticle will survey new research into the neurocog-nition and functional neuroanatomy of PTSD, theneuroendocrinology of PTSD, neurotransmitterstudies of PTSD, and finally the immunologicalsequelae of PTSD. Previous reviews of PTSD neu-robiology can be consulted for a more comprehen-sive review of research published prior to 1999 (1,6, 11–14).

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EUROCOGNITION AND FUNCTIONALNEUROANATOMY

Many of the hallmark symptoms of PTSD (e.g.nightmares, flashbacks, amnesia for the traumaticevent, dissociative episodes, exaggerated startleresponse) represent, at least in part, disturbances inneurocognitive processing. In particular, sensory input and memory processing appear to be awry inPTSD. Not only are pharmacological probes beingused to investigate psychiatric illness at the cellularlevel, but new tools are also becoming available toinvestigate brain function in psychiatric disorders.Some of the methods used to investigate neurocog-nitive processing in patients with PTSD includeneuropsychological testing, sensory evoked poten-tials, electroencephalography, polysomnography,and various modalities for functional brain imag-ing, including single photon emission computedtomography (SPECT), positron emission tomogra-phy (PET), and functional magnetic resonanceimaging (fMRI).Because the clinical course of anxiety disorderslike PTSD is marked by periods of symptom qui-escence punctuated by acute episodes of symptomexacerbation, it is important that functional brainimaging studies be conducted both in the restingcondition and in the symptomatic state.Consequently, imaging studies of patients withPTSD utilize symptom provocation protocols thattake one of two forms: trauma stimulus exposure,and guided mental imagery. The most often usedtrauma stimulus exposure in PTSD research is theplaying of combat sounds to war veterans with

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PTSD. In guided mental imagery, PTSD patientslisten to scripts of both neutral (e.g. a beach sunset)and traumatic events. These events may be fictionalor may be based upon real events in the patient’slife. After listening to the script, the patient isinstructed to imagine the events described in thescript while the brain imaging is being conducted.Both trauma stimulus exposure and mentalimagery of trauma reliably produce both subjectivereports and objective physiological measures of anxiety in patients with PTSD.Disturbances in sensory processing are believedto play a prominent role in the hyperarousal symp-toms of PTSD such as the exaggerated startleresponse. Evoked potentials (also known as event-related potentials) have provided the most impor-tant tool to date in the study of sensory processingin PTSD. Previous PTSD studies have reportedabnormalities in the P300 component of theevoked potential (so called because it is the majorpositive deflection that occurs at around 300 msafter the stimulus onset), which measures atten-tion-dependent conscious processing of target anddistractor events. These P300 disturbances may infact reflect attentional deficits, which have alsobeen measured by neuropsychological paradigmssuch as the Stroop test (15) and digit-recognitiontasks (16). Two studies in 1999 applied the use of evoked potentials to the study of PTSD sensory processing. One study reported that women withsexual-assault-related PTSD displayed abnormali-ties in evoked potential mismatch-negativity at theP50 time point when compared with controls (17).In the mismatch negativity protocol, the subject ispresented with two auditory stimuli. The first is afrequently repeated “standard” sound. The secondis an infrequently repeated “deviant” or “oddball”sound that differs in frequency from the standardsound. The electrical activity in the brain provokedby the two sounds produces distinct waveformsthat are measured during an evoked potential ses-sion. The difference in the amplitude of the wave-forms evoked by the two sounds is known as themismatch negativity. We have known for sometime that patients with PTSD exhibit an exagger-ated mismatch at the P300 time point. However,the fact that patients with PTSD demonstrate anexaggerated mismatch as early as 50 milliseconds(i.e. P50) after the stimulus exposure (when thesound has not yet reached conscious awareness)indicates that abnormalities in sensory processingoccur independently of the attentional deficits pre-viously measured at the P300 time component. A second recent study reported that the P1 (i.e. thefirst positive deflection) component of an auditory evoked potential exhibited reduced sensory gatingboth in women with rape-related PTSD and inmen with combat-related PTSD (18). Sensory gat-ing deficits of the P1 auditory evoked potentialsuggest that patients with PTSD have difficulty fil-tering incoming auditory stimuli. Future researchusing fMRI may allow for the identification of theneuroanatomical loci associated with these distur-bances in sensory processing.Memory processing is also disturbed in PTSD.Memory is often conceptually organized intoexplicit and implicit components. Explicit memory comprises verbal recall and a storage buffer knownas working memory. Implicit memory consists of embedded knowledge evident during the perform-ance of learned tasks. The neuroanatomical loci of memory processing include both subcortical struc-tures (e.g. the hippocampus and amygdala) andcortical regions (e.g. the prefrontal, anterior cingu-late, and orbitofrontal cortices).The hippocampus is involved in the verbal recallaspect of explicit memory. Although one recentstudy detected no difference in hippocampal vol-ume in children with abuse-related PTSD (19),right-sided hippocampal atrophy in adult PTSDpatients associated with measurable deficits in ver-bal recall has been reported (20). Stress-related hip-pocampal atrophy appears to be a consequence of increased exposure to excitatory amino acids andglucocorticoids. An earlier report noted increasedright parahippocampal activation in a PET study of Vietnam veterans with PTSD when presented with traumatic stimuli. One 1999 PET study reported decreased right hippocampal activationduring script-driven guided mental imagery of traumatic experiences in women with childhoodabuse-related PTSD when compared to sexually abused women without PTSD (21).The amygdala plays a key role in consolidatingthe emotional significance of events. Thus, thisregion has played a crucial role in our understand-ing of conditioned fear processing, a process that isimportant in the pathophysiology of PTSD. Infact, laboratory animal studies have clearly demon-strated that the central nucleus of the amygdala isone of the critical neuroanatomical loci in thedevelopment of the fear-potentiated startle (one of the hyperarousal symptoms of PTSD). In a SPECTstudy comparing Vietnam combat veterans withPTSD to combat veterans without PTSD and tononcombatant controls, only the PTSD groupexhibited left amygdala activation in response toexposure to combat sounds (22).Of the cerebrocortical regions, the prefrontalcortex appears to play a seminal role in the work-ing memory component of explicit memory andmay play a counter-regulatory role in the stress

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