创伤后应激障碍的动物模型及其神经生物学机制

创伤后应激障碍是指个体由于经历对生命具有威胁的事件或严重的创伤,导致症状长期持续的精神障碍。研究创伤后应激障碍的主要动物模型为条件性恐惧和应激敏感化模型。研究表明,创伤后应激障碍中长时程留存的恐惧性记忆、高唤醒等症状与大脑杏仁核、内侧前额叶皮层和海马三个脑区及下丘脑-垂体-肾上腺轴负反馈功能增强密切相关。其中杏仁核活动增强是条件性恐惧记忆获得、保持和表达的关键神经基础。内侧前额叶皮层对杏仁核的去抑制及海马向杏仁核传递的威胁性环境信息,促进创伤后应激障碍症状的出现。在经历创伤应激后糖皮质激素受体的上调及多巴胺活动的增强是创伤后应激障碍产生的主要神经基础。对创伤后应激障碍的药物治疗研究证明多巴胺D2受体在改善患者症状中的作用比较重要,但仍需作更深入的探索     

Stress sensitive healthy females show less left amygdala activation in response to withdrawal-related visual stimuli under passive viewing conditions

The amygdalae are key players in the processing of a variety of emotional stimuli. Especially aversive visual stimuli have been reported to attract attention and activate the amygdalae. However, as it has been argued that passively viewing withdrawal-related images could attenuate instead of activate amygdalae neuronal responses, its role under passive viewing conditions remains unclear. Furthermore, because individual sensitivity to stress reactions has been shown to modulate amygdalae processing, the aim of the current event-related fMRI study was to investigate whether individual differences in stress proneness could influence amygdala responses while passively viewing withdrawal and approach-related visual images. We presented 14 healthy female subjects with a random sequence of images of happy 'healthy' baby faces (approach-related) and baby faces disfigured by severe dermatological conditions (withdrawal-related). No instructions were given other than to watch the images attentively. We integrated individual perceived stress (PSS) scores in our analysis. The processing of withdrawal-related pictures resulted in less left amygdala activity in females scoring higher on perceived stress. Our findings suggest that stress-sensitive healthy females are less able to fully attend to withdrawal-related visual material and in essence avoid exposure to such images in an effort to reduce strong psychophysiological responses. Although the relatively small number of participants limits drawing firm conclusions, we suggest that in passive viewing emotional brain imaging paradigms, individual information on stress proneness should be included in the interpretation of amygdala neuronal processes.     

The Biological Findings in Post-Traumatic Stress Disorder: A Review1

In this paper the authors review the literature on biological and treatment studies of post-traumatic stress disorder (PTSD) and present current unifying hypotheses regarding the pathophysiology. The psychophysiological studies stress overarousal, while endocrine studies suggest a decreased Cortisol production in denial and low symptom states with increases in highly symptomatic states. Suggestive evidence is provided that PTSD is associated with permanent changes in brain mechanisms involving the locus coeruleus, amygdala, and the hypothalamo-pituitary-adrenal axis. Drug treatments are promising but not fully satisfactory as yet. Directions for further research are provided.     

Differential effects of inferior temporal cortex lesions upon visual and auditory-evoked potentials in the amygdala of the squirrel monkey (Saimiri sciureus)

Visual-evoked potentials (VEPs) and auditory-evoked potentials (AEPs) were elicited from amygdala nuclei and inferior temporal (IT) cortex in chaired, alert squirrel monkeys to diffuse flash and click stimuli. VEPs were recorded from electrodes placed in basalis lateralis amygdalae (BLA) and basalis medialis amygdalae (BMA) while AEPs could also be obtained from additional electrode sites in basalis accessorius medialis (BAM), centralis amygdalae (CeA), and lateralis amygdalae (LA). The amygdala-evoked potentials resulting from stimulation of the two modalities were similar in terms of component configuration. AEPs recorded from the IT cortex had shorter latencies than the amygdala VEPs that were recorded. Both modalities of stimulation elicited potentials with shorter onset latencies in the amygdala than those recorded from the surface of IT cortex. Bilateral ablation of the IT cortex eliminated VEPs recorded from the BMA but not the BLA amygdala region. AEPs recorded from BMA as well as other amygdala areas were not consistently affected by these IT cortical ablations.     

Integrating Treatment of Posttraumatic Stress Disorder and Substance Use Disorder

Historically, administrators and clinicians have been hesitant to address posttraumatic stress disorder (PTSD) in the treatment of substance use disorders (SUDs). However, research shows that SUD treatment recruitment and outcomes may be adversely affected if co‐occurring PTSD is left untreated. The authors provide guidelines for screening and assessment, treatment services, and workforce and organizational development that are designed to facilitate integrated PTSD–SUD treatment. Case examples illustrate the necessary precautions related to and the potential benefits of integrating treatment of PTSD and SUD.     

Can theories of visual representation help to explain asymmetries in amygdala function?

Emotional processing differs between the left and right hemispheres of the brain, and functional differences have been reported more specifically between the left and right amygdalae, subcortical structures heavily implicated in emotional processing. However, the empirical pattern of amygdalar asymmetries is inconsistent with extant theories of emotional asymmetries. Here we review this discrepancy, and we hypothesize that hemispheric differences in visual object processing help to explain the previously reported functional differences between the left and right amygdalae. The implication that perceptual factors play a large role in determining amygdalar asymmetries may help to explain amygdalar dysfunction in the development and maintenance of posttraumatic stress disorder.     

Incidental retrieval of emotional contexts in post-traumatic stress disorder and depression: an fMRI study

In the present study, we used fMRI to assess patients suffering from post-traumatic stress disorder (PTSD) or depression, and trauma-exposed controls, during an episodic memory retrieval task that included non-trauma-related emotional information. In the study phase of the task neutral pictures were presented in emotional or neutral contexts. Participants were scanned during the test phase, when they were presented with old and new neutral images in a yes/no recognition memory task. fMRI results for the contrast between old and new items revealed activation in a predominantly left-sided network of cortical regions including the left middle temporal, bilateral posterior cingulate, and left prefrontal cortices. Activity common to all three groups when correctly judging pictures encoded in emotional contexts was much more limited. Relative to the control and depressed groups the PTSD group exhibited greater sensitivity to correctly recognised stimuli in the left amygdala/ventral striatum and right occipital cortex, and more specific sensitivity to items encoded in emotional contexts in the right precuneus, left superior frontal gyrus, and bilateral insula. These results are consistent with a substantially intact neural system supporting episodic retrieval in patients suffering from PTSD. Moreover, there was little indication that PTSD is associated with a marked change in the way negatively valenced information, not of personal significance, is processed.     

Cognitive abnormalities in post-traumatic stress disorder

Characteristically arising in response to overwhelmingly terrifying events, post-traumatic stress disorder (PTSD) is a disorder of memory: sufferers seemingly relive their trauma in the form of involuntary recollection. Prominent cognitive abnormalities, especially in memory functioning, have motivated research designed to elucidate the mediating mechanisms that produce PTSD symptoms, especially those involving involuntary recollection. Recent developments suggest a pathophysiological model of PTSD which includes hyporesponsive prefrontal cortical regions and/or a hyper-responsive amygdala. Other work has also identified above-average cognitive ability as a protective factor and below-average hippocampal volume as a vulnerability factor for PTSD among the trauma-exposed. These attempts to elucidate the mediating mechanisms of PTSD have been both cognitive and, more recently, cognitive-neuroscientific in emphasis.     

Amygdala functional connectivity is reduced after the cold pressor task

The amygdala forms a crucial link between central pain and stress systems. Previous research indicates that psychological stress affects amygdala activity, but it is less clear how painful stressors influence subsequent amygdala functional connectivity. In the present study, we used pulsed arterial spin labeling (PASL) to investigate differences in healthy male adults’ resting-state amygdala functional connectivity following a cold pressor versus a control task, with the stressor and control conditions being conducted on different days. During the period of peak cortisol response to acute stress (approximately 15–30 min after stressor onset), participants were asked to rest for 6 min with their eyes closed during a PASL scanning sequence. The cold pressor task led to reduced resting-state functional connectivity between the amygdalae and orbitofrontal cortex (OFC) and ventromedial prefrontal cortex, and this occurred irrespective of cortisol release. The stressor also induced greater inverse connectivity between the left amygdala and dorsal anterior cingulate cortex (ACC), a brain region implicated in the down-regulation of amygdala responsivity. Furthermore, the degree of poststressor left amygdala decoupling with the lateral OFC varied according to self-reported pain intensity during the cold pressor task. These findings indicate that the cold pressor task alters amygdala interactions with prefrontal and ACC regions 15–30 min after the stressor, and that these altered functional connectivity patterns are related to pain perception rather than cortisol feedback.     

Placing the mnemonic model in context: diagnostic, theoretical, and clinical considerations

The mnemonic model of posttraumatic stress disorder (PTSD) proposed by D. C. Rubin, D. Berntsen, and M. K. Bohni presents some provocative and potentially insightful ideas about this mental disorder. D. C. Rubin et al. suggested that PTSD is caused and maintained through a "pathogenic memory" (D. C. Rubin et al., 2008, p. 985) of a negative event rather than by exposure to a traumatic event per se. The present authors examine the mnemonic model in the context of relevant diagnostic, theoretical, and clinical considerations. Specifically, to evaluate the arguments and evidence provided in support of the mnemonic model of PTSD, the present authors focus on 4 issues: (a) problems inherent with comparing a theoretical model (i.e., the mnemonic model) with a diagnostic model (i.e., the DSM-IV-TR model), (b) problems with not comparing the mnemonic model with relevant cognitive and memory models of PTSD, (c) problems with the degree to which the research reviewed provides support for the mnemonic model, and (d) concerns that memory in PTSD is confounded with the basic disorder, rather than causing PTSD. The present authors conclude with suggestions for future theory and research to help differentiate between memory's role in the origins of PTSD and memory's role in the clinical course of the disorder.     

Construct validity of the posttraumatic stress disorder checklist in cancer survivors: analyses based on two samples

The measurement of posttraumatic stress disorder (PTSD) is critically important for the identification and treatment of this disorder. The PTSD Checklist (PCL; F. W. Weathers and J. Ford, 1996) is a self-report measure that is increasingly used. In this study, the authors investigated the factorial validity of the PCL with data from 236 cancer survivors who received a bone marrow or stem cell transplantation. The authors examined the fit of these data with the clinical model of 3 symptom clusters for PTSD, as proposed in the Diagnostic and Statistical Manual of Mental Disorders, and alternative models tested in prior research. By using confirmatory factor analysis the authors found that a 4-first-order-factor model of PTSD provided the best fit. The relations of PTSD symptoms with sociodemographic and medical variables were also explored.     

Conceptually driven pharmacologic approaches to acute trauma

Secondary prevention of posttraumatic stress disorder (PTSD) entails intervening in the aftermath of a traumatic event to forestall the development of PTSD. There has been little psychopharmacologic research in this area. This is surprising, given that PTSD is the mental disorder with the most clearly identified cause and onset. In a translational model of PTSD's pathogenesis presented herein: A traumatic event (unconditioned stimulus) overstimulates endogenous stress hormones (unconditioned response); these mediate an overconsolidation of the event's memory trace; recall of the event in response to reminders (conditioned stimulus); releases further stress hormones (conditioned response); these cause further overconsolidation; and the overconsolidated memory generates PTSD symptoms. Noradrenergic hyperactivity in the basolateral amygdala is hypothesized to mediate this cycle. Preventing pre-synaptic norepinephrine release with alpha2-adrenergic agonists or opioids, or blocking post-synaptic norepinephrine receptors with beta-adrenergic antagonists such as propranolol, reduces hormonally enhanced memories and fear conditioning. Two controlled studies of trauma victims presenting to emergency rooms suggest that posttrauma propranolol reduces subsequent PTSD, as does one naturalistic clinical study of morphine treatment of burned children. Cortisol both enhances memory consolidation and reduces memory retrieval, leading to mixed predictions. Two controlled studies of intensive care unit patients found that cortisol reduced PTSD. One study did not find benzodiazepines effective in preventing PTSD. Selective serotonin reuptake inhibitors, antiepileptics, and alpha2-adrenergic agonists have yet to be tried.     

Brain-imaging studies of posttraumatic stress disorder

Brain-imaging studies of posttraumatic stress disorder (PTSD) have rapidly increased in recent years. Structural studies have identified potential smaller volumes of the hippocampus of traumatized and/or PTSD subjects. Functional activation studies have implicated hyperactive or altered functioning of brain regions, such as the amygdala and the insula, and a failure to engage emotional regulatory structures, such as the medial prefrontal and anterior cingulate cortex. Recent neurochemical investigations have suggested that neuromodulatory systems (eg, gamma-aminobutyric acid, micro-opioid) may underlie these aberrant brain activation patterns. This article reviews the literature on structural, functional, and neurochemical brain-imaging studies of PTSD.     

Posttraumatic stress disorder and retrospectively reported stressor exposure: a longitudinal prediction model

There has been recent concern about the degree to which posttraumatic stress disorder (PTSD) symptomatology influences reports of prior exposure to highly stressful life events. In this longitudinal study of 2,942 male and female Gulf War veterans, the authors documented change in stressor reporting across 2 occasions and the association between change and PTSD symptom severity. A regression-based cross-lagged analysis was used to examine the relationship between PTSD symptom severity and later reported stressor exposure. Shifts in reporting over time were modestly associated with PTSD symptom severity. The cross-lagged analysis revealed a marginal association between Time 1 PTSD symptom severity and Time 2 reported stressor exposure for men and suggested that later reports of stressor exposure are primarily accounted for by earlier reports and less so by earlier PTSD symptomatology.     

PTSD and substance-related problems: the mediating roles of disconstraint and negative emotionality

The authors examined competing hypotheses regarding the role of 2 personality dimensions, disconstraint and negative emotionality, in mediating the relationship between posttraumatic stress disorder (PTSD) severity and substance-related problems. Data were drawn from a large sample of male Vietnam veterans. The best-fitting structural model included significant indirect paths from PTSD to both alcohol- and drug-related outcomes through disconstraint, and a significant indirect path from PTSD to alcohol-related problems through negative emotionality. There were no direct effects of PTSD on either substance-related outcome. These findings indicate distinct pathways to different forms of substance-related problems in PTSD and underscore the role of personality in mediating these relationships.     

Gender differences in the sensitivity to posttraumatic stress disorder: An epidemiological study of urban young adults

The authors examine the relationship between 2 separate but interrelated findings in the epidemiology of posttraumatic stress disorder (PTSD): women's greater PTSD risk following traumatic events and the sensitizing effects of a prior trauma on the PTSD response to a subsequent trauma. Data come from a representative sample of 1,698 young adults from a large U.S. city. Analysis was conducted on the subset exposed to traumatic events. Women's risk for PTSD following assaultive violence was higher than men's. When assaultive violence preceded a later nonassaultive trauma in women, there was an increased risk (relative risk = 4.9) for PTSD, which was not observed in men. The relative risk estimate in women was significantly higher than in men. These findings suggest that assaultive violence elicits women's PTSD response directly and by sensitizing them to the effects of subsequent traumatic events of lesser magnitude.     

Shame,posttraumatic stress disorder,and intimate partner violence perpetration

Drawing from theoretical and empirical literature linking shame to aggression and violence, the authors propose that shame may be an important variable to examine in studies of posttraumatic stress disorder (PTSD) and intimate partner violence (IPV) perpetration. The authors review the literature linking shame, PTSD, and IPV, propose ideas for future research, and suggest that shame and shame regulation may be a useful target of clinical interventions aimed at violence perpetrators.     

Structural and Functional Neuroplasticity in Relation to Traumatic Stress

ABSTRACT— The body's stress response is an essential adaptive and protective mechanism to cope with threatening situations. However, chronic or traumatic stress leads to structural and functional alterations in the traumatized brain. We argue for a building-block effect: Exposure to different types of traumatic events increases the probability of developing posttraumatic stress disorder (PTSD), via incremental enlargement of a fear network. We summarize evidence of brain changes in PTSD, including recent results from research on animal models of stress-related neuroplastic remodeling, with an emphasis on structural and functional changes in the hippocampus, the amygdala, and the medial prefrontal cortex.