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临床神经科学对话。2011年9月; 13（3）：263-278。
doi：10.31887/DCNS.2011.13.2/jsherin
Language: English | Spanish | French
语言：英语|西班牙|法国
Post-traumatic stress disorder: the neurobiological impact of psychological trauma
创伤后应激障碍：心理创伤的神经生物学影响
Trastomo por estrés postraumático: el impacto neurobiológico del trauma psiquico
État de stress post-traumatique: impact neurobiologique du traumatisme psychologique
Abstract 摘要
The classic fight-or-flight response to perceived threat is a reflexive nervous phenomenon thai has obvious survival advantages in evolutionary terms. However, the systems that organize the constellation of reflexive survival behaviors following exposure to perceived threat can under some circumstances become dysregulated in the process. Chronic dysregulation of these systems can lead to functional impairment in certain individuals who become “psychologically traumatized” and suffer from post-traumatic stress disorder (PTSD), A body of data accumulated over several decades has demonstrated neurobiological abnormalities in PTSD patients. Some of these findings offer insight into the pathophysiology of PTSD as well as the biological vulnerability of certain populations to develop PTSD, Several pathological features found in PTSD patients overlap with features found in patients with traumatic brain injury paralleling the shared signs and symptoms of these clinical syndromes.
对感知到的威胁的经典的战或逃反应是一种反射性神经现象，在进化方面具有明显的生存优势。然而，在暴露于感知到的威胁之后，组织反射性生存行为的系统在某些情况下可能在这个过程中变得失调。这些系统的慢性失调可导致某些个体的功能障碍，这些个体变得“心理创伤”并患有创伤后应激障碍（PTSD）。几十年来积累的大量数据已经证明了PTSD患者的神经生物学异常。这些发现中的一些提供了对PTSD的病理生理学以及某些人群发展PTSD的生物脆弱性的深入了解。在PTSD患者中发现的几种病理特征与在创伤性脑损伤患者中发现的特征重叠，这些特征与这些临床综合征的共同体征和症状平行。
关键词：应激，心理创伤，创伤性脑损伤，创伤后应激障碍，生物标志物，精神病理学，病理生理学
Abstract 摘要
La clâsica respuesta de ataque o huida ante la perceptión de una amenaza es un fenómeno nervioso reflejo que, obviamente en términos evolutivos, tiene ventajas para la supervivencia. Sin embargo, los sistemas que organizan la constelación de conductas reflejas de supervivencia que siguen a la exposición a la amenaza percibida en algunas circunstancias pueden constituirse en procesos mal regulados. La mala regulatión crónica de estos sistemas puede llevar a un deterioro funcional en ciertos individuos quienes pueden convertirse en “traumatizados psicológicamente” y presentar un trastorno por estrés postraumático (TEPT), Una gran cantidad de informatión acumulada en varias décadas ha demostrado alteraciones neurobiológicas en los patientes con TEPT, Algunos de estos hallazgos permiten adentrarse en la fisiopatologia asi como en la vulnerabilidad biológica de ciertas poblaciones que van a desarrollar un TEPT Algunas caracteristicas patológicas encontradas en patientes con TEPT se sobreponen con caracteristicas de patientes con daño cerebral traumático, estableciendo un paralelo de signos y sintomas compartidos entre estos sindromes clinicos.
对感知到的威胁做出经典的攻击或逃跑反应是一种反射性神经现象，从进化的角度来看，这种现象显然对生存具有优势。然而，在某些情况下，在暴露于感知到的威胁之后，组织一系列生存反射行为的系统可能是调节不良的过程。 这些系统的慢性失调可导致某些个体的功能障碍，这些个体可能变得"心理创伤"并表现为创伤后应激障碍（PTSD）。几十年来积累的大量信息已显示PTSD患者的神经生物学改变，这些发现中的一些允许深入研究病理生理学以及某些将要发展为PTSD的人群的生物脆弱性。创伤后应激障碍与创伤性脑损伤患者的特征重叠，在这些临床综合征之间建立了相似的体征和症状。
Résumé 总结
La réponse classique de lutte ou de fuite à une menace perçue est un phénomène nerveux réflexe dont les avantages pour la survie sont évidents en termes d'évolution. Cependant, les systèmes organisés en constellation de comportements réflexes de survie après exposition à une menace perçue peuvent se déréguler dans certaines circonstances. Une dysregulation chronique de ces systèmes peut entraîner un déficit fonctionnel chez certains sujets qui deviennent « psychologiquement traumatisés » ef souffrent de l'état de stress posi-traumatique (ESPT), Des données recueillies pendant des dizaines d'années montrent des anomalies neurobiologiques chez les patients souffrant d'ESPT, ce qui permet de mieux comprendre la physiopathologie de l'ESPT ainsi que la vulnérabilité biologique de certaines populations à développer un ESPT, Certaines caractéristiques pathologiques de l'ESPT se superposent à celles trouvées chez des patients atteints de lésion cérébrale traumatique, en parallèle avec les signes et les symptômes partagés par ces deux syndromes.
对感知到的威胁的经典的战斗或逃跑反应是一种反射性神经现象，其生存优势在进化上是显而易见的。然而，在某些情况下，在暴露于感知到的威胁后，组织成一系列反射性生存行为的系统可能会失调。 这些系统的慢性失调可导致一些受试者的功能缺陷，这些受试者变得"心理创伤"并患有创伤后应激障碍（PTSD），几十年来收集的数据显示患有PTSD的患者的神经生物学异常，这使得有可能更好地理解PTSD的病理生理学以及某些人群发展PTSD的生物学脆弱性，创伤后应激障碍的一些病理特征与创伤性脑损伤患者的病理特征重叠，与这两种综合征共有的体征和症状平行。
Overview of psychological trauma, post-traumatic stress disorder, and biological markers
心理创伤、创伤后应激障碍和生物标志物概述
Psychological trauma can result from witnessing an event that is perceived to be life-threatening or to pose the potential of serious bodily injury to self or others. Such experiences, which are often accompanied by intense fear, horror, and helplessness, can lead to the development of, and are required for the diagnosis of, post-traumatic stress disorder (PTSD).1 It was originallythought that PTSD represented a normative response, at the extreme end of a response continuum, the severity of which related primarily to trauma/stressor intensity. However, it has become clear over time that the response of an individual to trauma depends not only on stressor characteristics, but also on factors specific to the individual.2 For the vast majority of the population, the psychological trauma brought about by the experience of profound threat is limited to an acute, transient disturbance. Though transient, such reactions can be quite unpleasant and are typically characterized by phenomena that can be grouped for the most part into three primary domains: (i) reminders of the exposure (including flashbacks, intrusive thoughts, nightmares); (ii) activation (including hyperarousal, insomnia, agitation, irritability, impulsivity and anger); and (iii) deactivation (including numbing, avoidance, withdrawal, confusion, derealization, dissociation, and depression). As these reactions are self-limiting by definition, in general they provoke minimal functional impairment over time. On the other hand, for a significant minority of the population, the psychological trauma brought about by the experience of profound threat leads to a longer-term syndrome that has been defined, validated, and termed PTSD in the clinical literature. PTSD is often accompanied by devastating functional impairment.
心理创伤可能是由于目睹了一个被认为是危及生命的事件，或对自己或他人造成严重身体伤害的可能性。这些经历通常伴随着强烈的恐惧、恐惧和无助，可能导致创伤后应激障碍（PTSD）的发展，也是诊断创伤后应激障碍（PTSD）所必需的。最初人们认为PTSD代表了一种标准反应，处于反应连续体的极端，其严重程度主要与创伤/压力源强度有关。然而，随着时间的推移，人们已经清楚地认识到，一个人对创伤的反应不仅取决于压力源的特征，而且还取决于个人特有的因素。 2 对于绝大多数人来说，由深刻威胁的经历所带来的心理创伤仅限于急性，短暂的干扰。 虽然是短暂的，但这种反应可能是相当不愉快的，并且通常以可以在大多数情况下分为三个主要领域的现象为特征：（包括闪回、侵入性想法、噩梦）;（ii）激活（包括过度觉醒、失眠、激动、易怒、冲动和愤怒）;和（iii）失活（包括麻木、回避、退缩、混乱、现实错乱、解离和抑郁）。由于这些反应根据定义是自限性的，一般而言，随着时间的推移，它们引起的功能损害最小。另一方面，对于相当一部分人来说，深刻的威胁经历所带来的心理创伤会导致一种长期的综合征，这种综合征在临床文献中被定义、证实并称为创伤后应激障碍。创伤后应激障碍往往伴随着毁灭性的功能障碍。
PTSD is characterized by the presence of signs and symptoms in the three primary domains described above for a period extending beyond 1 month (such periods can in some cases occur long after the original, precipitating traumatic exposure). The signs and symptoms of PTSD, therefore, appear to reflect a persistent, abnormal adaptation of neurobiological systems to the stress of witnessed trauma. The neurobiological systems that regulate stress responses include certain endocrine and neurotransmitter pathways as well as a network of brain regions known to regulate fear behavior at both conscious and unconscious levels. Not surprisingly, much research has consequently focused on exploring these systems in more detail as well as attempting to elucidate the pathological changes that occur in patients who develop PTSD. More specifically, there have been and continue to be ongoing efforts to link neurobiological changes identified in patients who suffer from PTSD to the specific clinical features that constitute PTSD, including altered learning/extinction, heightened arousal, and intermittent dissociative behavior as examples relevant to each of the three primary domains. Efforts to identify neurobiological markers for PTSD originally presumed that abnormalities were acquired “downstream” from an exposure, as a consequence of traumatic experience. It could be, however, that certain abnormalities in the patient with PTSD simply represent pre-existing or “upstream” pathology that is functionally dormant until released by trauma exposure and detected thereafter upon investigation. Along these lines, recent interest has focused on factors that seem to modulate outcome variation in neurobiological systems following trauma exposure including genetic susceptibility factors, female gender, prior trauma, early developmental stage at the time of traumatic exposure, and physical injury (including traumatic brain injury - TBI) at the time of psychological trauma; these parameters likely contribute to vulnerability for, versus resilience against, developing PTSD.
PTSD的特征是在上述三个主要领域中存在体征和症状，持续时间超过1个月（在某些情况下，这种时期可能发生在原始的、突发的创伤暴露之后很长时间）。因此，创伤后应激障碍的症状和体征似乎反映了神经生物学系统对目击创伤压力的持续、异常适应。调节应激反应的神经生物学系统包括某些内分泌和神经递质通路，以及已知在意识和无意识水平上调节恐惧行为的大脑区域网络。因此，许多研究都集中在更详细地探索这些系统，并试图阐明PTSD患者发生的病理变化。 更具体地说，已经并将继续努力将患有PTSD的患者中鉴定出的神经生物学变化与构成PTSD的特定临床特征联系起来，包括改变的学习/消退、增强的唤醒和间歇性解离行为，作为与三个主要领域中的每一个相关的示例。鉴定PTSD神经生物学标志物的努力最初假设异常是从暴露的“下游”获得的，作为创伤经历的结果。然而，PTSD患者的某些异常可能只是代表了预先存在的或“上游”病理，这些病理在功能上处于休眠状态，直到被创伤暴露释放，并在随后的调查中被发现。 沿着这些路线，最近的兴趣集中在似乎调节创伤暴露后神经生物学系统结果变化的因素上，包括遗传易感性因素、女性性别、先前的创伤、创伤暴露时的早期发育阶段和身体损伤（包括创伤性脑损伤- TBI）在心理创伤的时候;这些参数很可能导致创伤后应激障碍的脆弱性，而不是对创伤后应激障碍的恢复力。
Although the biological, psychological, and social ramifications of PTSD have been under scientific scrutiny for some time now, and treatment has improved dramatically, much remains unknown about this condition and controversy persists in both the neuroscientific as well as the clinical/treatment literature. In this text, we review the neurobiological impact of psychological trauma from the perspective that genetic, developmental, and experiential factors predispose certain individuals to the development of PTSD. More specifically, we review the current database as pertains to biological markers of PTSD and the possibility that some biological markers may not be acquired but, rather, may in fact predate trauma until functionally “unmasked” by stress. Where relevant, we also make note of similarities between PTSD and TBI, which extend beyond wellknown signs and symptoms (such as irritability and social withdrawal) to include abnormalities in the same neurobiological systems. Lastly, the article includes a short section on basic considerations for future direction. Ideas put forth in this communication are done so in the interest of developing a consistent model for conceptual purposes. It is recognized at the outset that numerous inconsistencies can be found in the literature that highlight the multifactorial and complex nature of this field.
虽然PTSD的生物学、心理学和社会学后果已经受到科学的审查一段时间了，治疗也有了显着的改善，但关于这种情况仍有很多未知之处，神经科学和临床/治疗文献中的争议仍然存在。在本文中，我们从遗传、发展和经验因素使某些个体易患PTSD的角度回顾了心理创伤的神经生物学影响。更具体地说，我们回顾了目前的数据库，涉及到PTSD的生物标志物和可能性，一些生物标志物可能不会被收购，而是，事实上可能早于创伤，直到功能上“揭露”的压力。在相关的地方，我们也注意到创伤后应激障碍和创伤性脑损伤之间的相似之处，这些相似之处超出了众所周知的体征和症状（如易怒和社交退缩），包括相同神经生物系统的异常。 最后，本文包括一个简短的部分，说明未来方向的基本考虑。本文中提出的想法是为了开发一个用于概念目的的一致模型。从一开始就认识到，在文献中可以发现许多不一致之处，突出了这一领域的多因素和复杂性。
The biology of PTSD PTSD的生物学
There are a number of factors that must be considered in contemplating the interplay between adverse environmental stimulation, stress responses/reactions, and pathology. In this section, basic findings are reviewed from endocrinology, neurochemistry, and brain circuitry research conducted on patients with a diagnosis of PTSD (Table I).
在考虑不良环境刺激、应激反应/反应和病理之间的相互作用时，必须考虑许多因素。在本节中，我们回顾了对PTSD患者进行的内分泌学、神经化学和脑回路研究的基本结果（表I）。
Table I 表I
创伤后应激障碍患者的神经生物学特征与已确定的异常和功能影响的总结。CRH，促肾上腺皮质激素释放激素; 5 HT，5-羟色胺; GABA，γ-氨基丁酸; NPY，神经肽Y; ACTH，促肾上腺皮质激素; NE，去甲肾上腺素; CSF，脑脊液
| Feature 特征 | Change 变化 | Effect 效果 |
| A. Neuroendocrine A.神经内 | ||
| Hypothalamic-pituitary-adrenal axis 下丘脑-垂体-肾上腺轴 | Hypocortisolism 皮质醇过少症 | Disinhibits CRH/NE and upregulates response to stress 抑制CRH/NE并上调应激反应 |
| Drives abnormal stress encoding and fear processing 驱动不正常的压力编码和恐惧处理 | ||
| Sustained, increased level of CRH CRH水平持续升高 | Blunts ACTH response to CRH stimulation
减弱ACTH对CRH刺激的反应 | |
| Promotes hippocampal atrophy 促进海马萎缩 | ||
| Hypothalamic-pituitary-thyroid axis 下丘脑垂体甲状腺轴 | Abnormal T3: T4 ratio T3：T4比值异常 | Increases subjective anxiety 增加主观焦虑 |
| B. Neurochemical B。神经化学 | ||
| Catecholamines 儿茶酚胺 | Increased dopamine levels 多巴胺水平升高 | Interferes with fear conditioning by mesolimbic system 通过中脑边缘系统干扰恐惧条件反射 |
| Increased norepinephrine levels/activity 去甲肾上腺素水平/活性增加 | Increases arousal, startle response, encoding of fear memories 增强唤醒，惊吓反应，恐惧记忆编码 | |
| Increases pulse, blood pressure, and response to memories 增加脉搏、血压和对记忆的反应 | ||
| Serotonin 血清素 | Decreased concentrations of 5 HT in:
5 HT浓度降低：
| Disturbs dynamic between amygdala and hippocambus 干扰杏仁核和海马体之间的动力学 |
| Compromises anxiolytic effects 影响抗焦虑作用 | ||
| Increases vigilance, startle, impulsivity, and memory intrusions 增加警惕性、惊吓、冲动和记忆侵入 | ||
| Amino acids 氨基酸 | Decreased GABA activity GABA活性降低 | Compromises anxiolytic effects 影响抗焦虑作用 |
| Increased glutamate 增加谷氨酸 | Fosters derealization and dissociation 造成现实失调和分裂 | |
| peptides 肽 | Decreased plasma NPY concentrations 血浆NPY浓度降低 | Leaves CRH/NE unopposed and upregulates response to stress 使CRH/NE无对抗作用，并上调对应激的反应 |
| Increased CSF b-endorphin levels CSF b-内啡肽水平升高 | Fosters numbing, stress-induced analgesia, and dissociation 促进麻木、应激性镇痛和解离 | |
| C. Neuroanatomic C.神经解剖 | ||
| Hippocampus 海马 | Reduced volume and activity 减少体积和活动 | Alters stress responses and extinction 改变压力反应和灭绝 |
| Amygdala 杏仁核 | Increased activity 增加的活性 | Promotes hypervigilance and impairs discrimination of threat 促进高度警惕，削弱对威胁的辨别力 |
| Cortex | Reduced prefrontal volume | Dysregulates executive functions |
| Reduced anterior cingulate volume | Impairs the extinction of fear responses | |
| Decreased medial prefrontal activation | Unclear |
Endocrine factors 内分泌因素
Core endocrine features of PTSD include abnormal regulation of Cortisol and thyroid hormones, though there is some disagreement about these findings in the literature. Of note, endocrine dysregulation is also found in patients diagnosed with TBI as a result of damage to the pituitary stalk.
PTSD的核心内分泌特征包括皮质醇和甲状腺激素的异常调节，尽管文献中对这些发现存在一些分歧。值得注意的是，内分泌失调也见于诊断为TBI的患者，其原因是垂体柄受损。
The hypothalamic-pituitary-adrenal axis
下丘脑-垂体-肾上腺轴
The hypothalamic-pituitary-adrenal (HPA) axis is the central coordinator of the mammalian neuroendocrine stress response systems, and as such, it has been a major focus of scrutiny in patients with PTSD (Figure 1.) In short, the HPA axis is made up of endocrine hypothalamic components, including the anterior pituitary, as well as an effector organ, the adrenal glands. Upon exposure to stress, neurons in the hypothalamic paraventricular nucleus (PVN) secrete corticotropin-releasing hormone (CRH) from nerve terminals in the median eminence into the hypothalamo-hypophyscal portal circulation, which stimulates the production and release of adrenocorticotropin (ACTH) from the anterior pituitary. ACTH in turn stimulates the release of glucocorticoids from the adrenal cortex. Glucocorticoids modulate metabolism as well as immune and brain function, thereby orchestrating physiological and organismal behavior to manage stressors. At the same time, several brain pathways modulate HPA axis activity. In particular, the hippocampus and prefrontal cortex (PFC) inhibit, whereas the amygdala and aminergic brain stem neurons stimulate, CRH neurons in the PVN. In addition, glucocorticoids exert negative feedback control of the HPA axis by regulating hippocampal and PVN neurons. Sustained glucocorticoid exposure has adverse effects on hippocampal neurons, including reduction in dendritic branching, loss of dendritic spines, and impairment of neurogenesis.3-5
下丘脑-垂体-肾上腺（HPA）轴是哺乳动物神经内分泌应激反应系统的中心协调者，因此，它一直是PTSD患者的主要关注点（图1）。简而言之，HPA轴由下丘脑内分泌成分组成，包括垂体前叶，以及效应器官肾上腺。当暴露于应激时，下丘脑室旁核（PVN）的神经元从正中隆起的神经末梢分泌促肾上腺皮质激素释放激素（CRH）进入下丘脑-垂体门静脉循环，刺激垂体前叶产生和释放促肾上腺皮质激素（ACTH）。ACTH反过来刺激肾上腺皮质释放糖皮质激素。糖皮质激素调节新陈代谢以及免疫和大脑功能，从而协调生理和生物行为来管理压力源。 同时，几个脑通路调节HPA轴活动。特别是，海马和前额皮质（PFC）抑制，而杏仁核和胺能脑干神经元刺激，CRH神经元在PVN。此外，糖皮质激素通过调节海马和PVN神经元对HPA轴施加负反馈控制。持续糖皮质激素暴露对海马神经元有不良影响，包括树突分支减少、树突棘丢失和神经发生受损。 3-5
下丘脑-垂体-肾上腺轴是机体对压力的主要反应系统。下丘脑分泌CRH，其与垂体细胞上的受体结合，垂体细胞产生/释放ACTH，ACTH被转运到肾上腺，肾上腺激素如皮质醇在肾上腺中产生/释放。皮质醇的释放激活交感神经通路并对下丘脑和垂体前叶产生负反馈。这种负反馈系统似乎在创伤后应激障碍患者中受到损害。CRH，促肾上腺皮质激素释放激素;促肾上腺皮质激素，促肾上腺皮质激素
Although stressors as a general rule activate the HPA axis, studies in combat veterans with PTSD demonstrate decreases in Cortisol concentrations, as detected in urine or blood, compared with healthy controls and other com parator groups. This surprising finding, though replicated in PTSD patients from other populations including Holocaust survivors, refugees, and abused persons, is not consistent across all studies.6 It has been suggested that inconsistent findings may result from differences in the severity and timing of psychological trauma, the patterns of signs/symptoms, comorbid conditions, personality, and genetic makeup.7 Studies using low-dose dexamethasone suppression testing suggest that hypocortisolism in PTSD occurs due to increased negative feedback sensitivity of the HPA axis. Sensitized negative feedback inhibition is supported by findings of increased glucocorticoid receptor binding and function in patients with PTSD.6 Further, sustained increases of CRH concentrations have been measured in cerebrospinal fluid (CSF) of patients with PTSD. As such, blunted ACTH responses to CRH stimulation implicate a role for the downregulation of pituitary CRH receptors in patients with PTSD.6 In addition, reduced volume of the hippocampus, the major brain region inhibiting the HPA axis, is a cardinal feature of PTSD.8 Taken as a whole, these neuroendocrine findings in PTSD reflect dysregulation of the HPA axis to stressors.6
虽然压力源作为一般规则激活HPA轴，但对患有PTSD的退伍军人的研究表明，与健康对照组和其他对照组相比，尿液或血液中检测到的皮质醇浓度降低。这一令人惊讶的发现，尽管在其他人群（包括大屠杀幸存者、难民和受虐待者）的PTSD患者中得到了复制，但在所有研究中并不一致。 6 有人认为，不一致的发现可能是由于心理创伤的严重程度和时间、体征/症状的模式、共病状况、个性和遗传构成的差异。 7 使用低剂量地塞米松抑制试验的研究表明，PTSD中皮质醇减少是由于HPA轴负反馈敏感性增加所致。PTSD患者糖皮质激素受体结合和功能增加的研究结果支持敏化负反馈抑制。 6 此外，在PTSD患者的脑脊液（CSF）中测量到CRH浓度的持续增加。因此，促肾上腺皮质激素对促肾上腺皮质激素释放激素刺激的反应减弱暗示了PTSD患者垂体促肾上腺皮质激素释放激素受体下调的作用。 6 此外，抑制HPA轴的主要脑区海马体体积减少是PTSD的主要特征。 8 总体而言，PTSD的这些神经内分泌发现反映了HPA轴对压力源的失调。 6
In the context of the above discussion, prospective studies suggest that low Cortisol levels at the time of exposure to psychological trauma may predict the development of PTSD.9,10 Therefore, hypocortisolism might be a risk factor for maladaptive stress responses and predispose to future PTSD. This hypothesis is supported in principle by the finding that exogenously administered hydrocortisone shortly after exposure to psychological trauma can prevent PTSD.11,12 In addition, it has been shown that simulation of a normal circadian Cortisol rhythm using exogenously introduced hydrocortisone is effective in the treatment of PTSD.13 In sum, it may be that decreased availability of Cortisol, as a result of or in combination with abnormal regulation of the HPA axis, may promote abnormal stress reactivity and perhaps fear processing in general. That said, it should be noted that glucocorticoids interfere with the retrieval of traumatic memories, an effect that may independently prevent or reduce symptoms of PTSD.14
在上述讨论的背景下，前瞻性研究表明，暴露于心理创伤时的低皮质醇水平可能预测PTSD的发展。 9,10 因此，低皮质醇症可能是适应不良压力反应的风险因素，并易患未来的创伤后应激障碍。这一假设原则上得到了以下发现的支持：暴露于心理创伤后不久给予外源性氢化可的松可以预防PTSD。 11,12 此外，已经表明，使用外源引入的氢化可的松模拟正常的昼夜皮质醇节律在治疗PTSD中是有效的。 13 总之，可能是由于HPA轴的异常调节或与HPA轴的异常调节相结合，皮质醇的可用性降低，可能会促进异常的应激反应，也许是一般的恐惧处理。 也就是说，应该注意的是，糖皮质激素会干扰创伤记忆的恢复，这种作用可能会独立地预防或减轻PTSD的症状。 14
The hypothalamic-pituitary-thyroid axis
The hypothalamic-pituitary-thyroid (HPT) axis is involved in regulating metabolic versus anabolic states and other homeostatic functions, which it does by controlling the blood level of thyroid hormones. A possible role for the HPT axis in stress-related syndromes has been suspected for some time because it is known that trauma can trigger thyroid abnormalities. To date, however, there has not been a significant research effort targeting the relationship between the HPT axis and PTSD. Studies have been conducted, however, on Vietnam Veterans with PTSD who were found to have elevated baseline levels of both tri-iodothyronine (T3) and thyroxine (T4). Of note, the level of '13 in these subjects was disproportionately elevated relative to T4, implicating an increase in the peripheral deiodinization process.15,16
下丘脑-垂体-甲状腺轴下丘脑-垂体-甲状腺（HPT）轴参与调节代谢与合成代谢状态和其他稳态功能，它通过控制甲状腺激素的血液水平来实现。HPT轴在应激相关综合征中的可能作用已经被怀疑了一段时间，因为众所周知创伤可以引发甲状腺异常。然而，迄今为止，还没有一个显着的研究工作，针对HPT轴和PTSD之间的关系。然而，已经对患有PTSD的越战老兵进行了研究，发现他们的三碘甲状腺原氨酸（T3）和甲状腺素（T4）的基线水平升高。值得注意的是，这些受试者中的T13水平相对于T4不成比例地升高，暗示外周脱碘过程增加。 15,16
These findings were replicated for the most part in a study of WWII Veterans with more longstanding PTSD diagnoses. In these individuals, isolated T3 levels were elevated whereas T4 levels were normal.17 Taken together, these studies suggest that over time the impact of trauma on T4 levels may abate. The authors suggest that elevated T3 may relate to subjective anxiety in these individuals with PTSD.
这些发现在一项针对二战退伍军人的研究中得到了大部分的重复，这些退伍军人的PTSD诊断时间更长。在这些人中，孤立的T3水平升高，而T4水平正常。 17 总之，这些研究表明，随着时间的推移，创伤对T4水平的影响可能会减弱。作者认为，T3升高可能与这些PTSD患者的主观焦虑有关。
Neurochemical factors 神经化学因素
Core neurochemical features of PTSD include abnormal regulation of catecholamine, serotonin, amino acid, peptide, and opioid neurotransmitters, each of which is found in brain circuits that regulate/integrate stress and fear responses. Of note, catecholamine and serotonin (as well as acetylcholine) dysregulation is also found in patients diagnosed with TBI, presumably as a result of diffuse axonal injury.
PTSD的核心神经化学特征包括对儿茶酚胺、5-羟色胺、氨基酸、肽和阿片类神经递质的异常调节，其中每一种都存在于调节/整合压力和恐惧反应的脑回路中。值得注意的是，在诊断为TBI的患者中也发现了儿茶酚胺和5-羟色胺（以及乙酰胆碱）失调，推测是弥漫性轴突损伤的结果。
The catecholamines 儿茶酚胺
the catecholamine family of neurotransmitters, including dopamine (DA) and norepinephrine (NE), derive from the amino acid tyrosine. Increased urinary excretion of DA and its metabolite has been reported in patients with PTSD. Further, mesolimbic DA has been implicated in fear conditioning. There is evidence in humans that exposure to stressors induces mesolimbic DA release, which in turn could modulate HPA axis responses. Whether or not DA metabolism is altered in PTSD remains unclear, though genetic variations in the DA system have been implicated in moderating risk for PTSD (see below). NE, on the other hand, is one of the principal mediators of autonomic stress responses through both central and peripheral mechanisms. The majority of CNS NE is derived from neurons of the locus ceruleus (LC) that project to various brain regions involved in the stress response, including the prefrontal cortex, amygdala, hippocampus, hypothalamus, periaqueductal grey, and thalamus. In addition, there is evidence for a feed-forward circuit connecting the amygdala and hypothalamus with the LC, in which CRH and NE interact to increase fear conditioning and encoding of emotional memories, enhance arousal and vigilance, and integrate endocrine and autonomic responses to stress. Like other stress pathways, this cascade is inhibited by glucocorticoids,18 which serve as a “brake” for the system. In the periphery, stress-induced sympathetic nervous system activation results in the release of NE and epinephrine from the adrenal medulla, increased release of NE from sympathetic nerve endings, and changes in blood flow to a variety of organs as needed for fight-or-flight behavior. The NE effects arc mediated via postsynaptic α1 β1 , and β2, receptors, whereas another NE-activated receptor, the α2 receptor serves as a presynaptic autoreceptor inhibiting NE release. Because of its multiple roles in regulating arousal and autonomic stress responses, as well as promoting the encoding of emotional memories, NE has been a central focus of many studies investigating the pathophysiology of PTSD.
包括多巴胺（DA）和去甲肾上腺素（NE）在内的神经递质的儿茶酚胺家族衍生自氨基酸酪氨酸。据报道，在PTSD患者中，DA及其代谢产物的尿排泄增加。此外，中脑边缘DA与恐惧条件反射有关。有证据表明，人类暴露于应激诱导中脑边缘DA释放，这反过来又可以调节HPA轴的反应。尽管DA系统的遗传变异与PTSD风险的降低有关（见下文），但PTSD患者的DA代谢是否改变仍不清楚。另一方面，NE是通过中枢和外周机制的自主应激反应的主要介质之一。CNS NE的大部分来源于蓝斑（LC）的神经元，其投射到参与应激反应的各种脑区域，包括前额叶皮质、杏仁核、海马、下丘脑、导水管周围灰质和丘脑。 此外，有证据表明杏仁核和下丘脑与LC之间存在前馈回路，CRH和NE相互作用，增加恐惧条件反射和情绪记忆编码，增强唤醒和警惕，整合内分泌和自主神经对压力的反应。像其他应激途径一样，这种级联反应受到糖皮质激素的抑制， 18 作为系统的“刹车”。在外周，应激诱导的交感神经系统激活导致NE和肾上腺素从肾上腺髓质释放，NE从交感神经末梢的释放增加，以及根据战斗或逃跑行为的需要改变流向各种器官的血流。NE效应通过突触后α 1 、β 1 和β 2 受体介导，而另一种NE激活的受体α 2 受体作为突触前自身受体抑制NE释放。 由于NE在调节唤醒和自主应激反应以及促进情绪记忆编码中的多重作用，NE一直是许多研究PTSD病理生理学的中心焦点。
A cardinal feature of patients with PTSD is sustained hyperactivity of the autonomic sympathetic branch of the autonomic nervous system, as evidenced by elevations in heart rate, blood pressure, skin conductance, and other psychophysiological measures. Accordingly, increased urinary excretion of catecholamines, and their metabolites, has been documented in combat veterans, abused women, and children with PTSD. In addition, patients with PTSD exhibit increased heart rate, blood pressure, and NE responses to traumatic reminders. Decreased platelet α2 receptor binding further suggests NE hyperactivity in PTSD.19,20 Administration of the α2 receptor antagonist yohimbine, which increases NE release, induces flashbacks and increased autonomic responses in patients with PTSD.21 Serial sampling revealed sustained increases in CSF NE concentrations and increased CSF NE responses to psychological stressors in PTSD:22,23 Taken together, there is an abundance of evidence that NF, accounts for certain classic aspects of PTSD symptomatology, including hyperarousal, heightened startle, and increased encoding of fear memories.20
PTSD患者的一个主要特征是自主神经系统的自主交感分支的持续过度活跃，如心率、血压、皮肤电导和其他心理生理学测量的升高所证明的。因此，在退伍军人、受虐待妇女和患有创伤后应激障碍的儿童中，已经记录了儿茶酚胺及其代谢物的尿排泄增加。此外，PTSD患者表现出心率、血压和NE对创伤性提醒的反应增加。血小板α 2 受体结合减少进一步提示PTSD中NE活性亢进。 19,20 给予α 2 受体拮抗剂育亨宾，增加NE的释放，诱导PTSD患者的闪回和增加的自主反应。 21 连续采样揭示了持续增加的CSF NE浓度和增加的CSF NE对PTSD中的心理应激源的反应： 22,23 综合考虑，有大量证据表明NF解释了PTSD病理学的某些经典方面，包括过度觉醒、高度惊吓和增加的恐惧记忆编码。 20
Interestingly, prospective studies have shown that increased heart rate and peripheral epinephrine excretion at the time of exposure to trauma predict subsequent development of PTSD.10 Further, administration of the centrally acting β-adrenergic receptor antagonist propranolol shortly after exposure to psychological trauma has been reported to reduce PTSD symptom severity and reactivity to trauma cues.24 Although propranolol administration in this study did not prevent the development of PTSD, it may have blocked traumatic memory consolidation,25 and therefore may reduce the severity and/or chronicity of PTSD. It is important to note, however, that this finding contradicts those from an earlier study.26 Various antiadrenergic agents have been tested for their therapeutic efficacy in the treatment of PTSD in open-label trials; there is a paucity of controlled trials.20
有趣的是，前瞻性研究表明，暴露于创伤时心率和外周肾上腺素分泌增加可预测随后发生PTSD。此外，据报道，在暴露于心理创伤后不久给予中枢作用的β-肾上腺素能受体拮抗剂普萘洛尔可降低PTSD症状的严重程度和对创伤线索的反应性。 24 虽然在这项研究中普萘洛尔给药不能阻止PTSD的发展，但它可能阻止了创伤记忆的巩固， 25 因此可能降低PTSD的严重程度和/或慢性程度。然而，值得注意的是，这一发现与早期研究的结果相矛盾。 26 各种抗肾上腺素能药物已在开放标签试验中测试了其治疗PTSD的疗效;对照试验很少。 20
Serotonin 血清素
Serotonin (5HT), is a monoamine neurotransmitter synthesized from the amino acid tryptophan. Neurons containing 5HT originate in the dorsal and median raphe nuclei in the brain stem and project to multiple forebrain regions, including the amygdala, bed nucleus of the stria terminalis, hippocampus, hypothalamus, and prefrontal cortex. 5HT has roles in regulating sleep, appetite, sexual behavior, aggression/impulsivity, motor function, analgesia, and neuroendocrine funtion. Not surprisingly, given its connectivity and broad homeostatic role, 5HT has been implicated in the modulation of affective and stress responses, as well as a role in PTSD. Although the mechanisms are not entirely clear, the effects of 5HT on affective and stress responses vary according to stressor intensity, brain region, and receptor type. It is believed that 5HT neurons of the dorsal raphe mediate anxiogenic effects via 5HT2 receptors through projections to the amygdala and hippocampus. In contrast, 5HT neurons from the median raphe are thought to mediate anxiolytic effects, facilitate extinction and suppress encoding of learned associations via 5HT1A receptors. Chronic exposure to stressors induces upregulation of 5HT2 and downregulation of 5HT1A receptors in animal models. Further, 5HT1A knockouts exhibit increased stress responses.
5-羟色胺（5-HT）是一种由色氨酸合成的单胺类神经递质。含有5 HT的神经元起源于脑干中的中缝背核和正中核，并投射到多个前脑区域，包括杏仁核、终纹床核、海马、下丘脑和前额叶皮质。5-HT具有调节睡眠、食欲、性行为、攻击/冲动、运动功能、镇痛和神经内分泌功能的作用。毫不奇怪，鉴于其连接性和广泛的稳态作用，5 HT与情感和应激反应的调节有关，以及在PTSD中的作用。虽然其机制尚不完全清楚，但5-HT对情感和应激反应的影响因应激强度、脑区和受体类型而异。据信中缝背侧的5 HT神经元经由5HT 2 受体通过向杏仁核和海马体的投射来介导致焦虑作用。 相比之下，来自中缝的5HT神经元被认为介导抗焦虑作用，促进消退并通过5HT 1A 受体抑制习得性关联的编码。在动物模型中，慢性暴露于应激源诱导5HT 2 受体上调和5HT 1A 受体下调。此外，5HT 1A 敲除表现出增加的应激反应。
The 5HT system interacts with the CRH and NE systems in coordinating affective and stress responses.19,27 Indirect evidence suggests a role for 5HT in PTSDrelated behaviors including impulsivity, hostility, aggression, depression, and suicidally. In addition, 5HT presumably mediates the therapeutic effects of the selective serotonin reuptake inhibitors (SSRIs). A recent small and controversial study suggests that the street drug 3,4-Methylenedioxymetharnphetamine (also known as .MDMA or “ecstasy”), which alters central serotonin transmission, has therapeutic potential in the treatment of PTSD.28 Other evidence for altered 5 HT neurotransmission in PTSD includes decreased serum concentrations of 5HT, decreased density of platelet 5HT uptake sites, and altered responsiveness to CNS serotonergic challenge in patients diagnosed with PTSD.19,27 However, no differences in CNS 5HT1A receptor binding were detected in patients with PTSD compared with controls using PET imaging.28 Taken together, altered 5HT transmission may contribute to symptoms of PTSD including hypervigilance, increased startle, impulsivity, and intrusive memories, though the exact roles and mechanisms remain uncertain.
5-HT系统与CRH和NE系统相互作用，协调情感和应激反应。 19,27 间接证据表明5-HT在PTSD相关行为中的作用，包括冲动，敌意，侵略，抑郁和自杀。此外，5-HT可能介导选择性5-羟色胺再摄取抑制剂（SSRIs）的治疗作用。最近的一项小型且有争议的研究表明，街头毒品3，4-亚甲二氧基甲基苯丙胺（也称为.MDMA或“摇头丸”）可以改变中枢5-羟色胺的传递，在治疗创伤后应激障碍方面具有治疗潜力。PTSD患者5-HT神经传递改变的其他证据包括血清5-HT浓度降低、血小板5-HT摄取位点密度降低和对CNS多巴胺能刺激的反应性改变。然而，使用PET成像，与对照组相比，在PTSD患者中没有检测到CNS 5 HT 3#受体结合的差异。 28 总之，改变5 HT传输可能有助于PTSD的症状，包括过度警惕，增加惊吓，冲动和侵入性记忆，尽管确切的角色和机制仍然不确定。
Amino acids 氨基酸
γ-Aminobutyric acid (GABA) is the principal inhibitory neurotransmitter in the brain. GABA has profound anxiolytic effects and dampens behavioral and physiological responses to stressors, in part by inhibiting the CRH/NE circuits involved in mediating fear and stress responses. GABA's effects are mediated by GABAA receptors, which are colocalized with benzodiazepine receptors that potentiate the inhibitory effects of GABA on postsynaptic elements. Uncontrollable stress leads to alterations of the GABA/benzodiazepine receptor complex such that patients with PTSD exhibit decreased peripheral benzodiazepine binding sites.29 Further, SPECT and PET imaging studies have revealed decreased binding of radiolabeled benzodiazepine receptor ligands in the cortex, hippocampus, and thalamus of patients with PTSD, suggesting that decreased density or receptor affinity may play a role in PTSD.30-31 However, treatment with benzodiazepines after exposure to psychological trauma does not prevent PTSD.32-33 Further, a recent study suggests that traumatic exposure at times of intoxication actually facilitates the development of PTSD.34 Although perhaps counterintuitive, the authors suggest that the contextual misperceptions which commonly accompany alcohol intoxication may serve to make stressful experiences more difficult to incorporate intellectually, thereby exacerbating fear. Taken together, while there are multiple studies strongly implicating the GABA/bcnzodiazepine receptor system in anxiety disorders, studies in PTSD are relatively sparse and conclusive statements would be premature.19
γ-氨基丁酸（GABA）是脑中主要的抑制性神经递质。GABA具有深刻的抗焦虑作用，并部分通过抑制参与介导恐惧和压力反应的CRH/NE回路来抑制对压力源的行为和生理反应。GABA的作用由GABA A 受体介导，GABA A 受体与苯二氮卓类受体共定位，可增强GABA对突触后元件的抑制作用。不可控制的压力导致GABA/苯二氮卓受体复合物的改变，使得PTSD患者表现出外周苯二氮卓结合位点减少。 29 此外，SPECT和PET成像研究揭示了PTSD患者皮质、海马和丘脑中放射性标记的苯二氮卓类受体配体的结合减少，表明密度或受体亲和力降低可能在PTSD中起作用。 30 - 31 然而，暴露于心理创伤后使用苯二氮卓类药物治疗并不能预防PTSD。此外，最近的一项研究表明，醉酒时的创伤暴露实际上促进了PTSD的发展。#6虽然可能违反直觉，但作者认为，通常伴随酒精中毒的上下文误解可能会使压力体验更难纳入智力，从而加剧恐惧。总之，虽然有多项研究强烈暗示GABA/bcnzodiazepine受体系统在焦虑症，研究创伤后应激障碍是相对稀疏和结论性的声明将是过早的。 19
Glutamate is the primary excitatory neurotransmitter in the brain. Exposure to stressors and the release of, or administration of, glucocorticoids activates glutamate release in the brain. Among a number of receptor subtypes, glutamate binds to N -methyl D -aspartate (NMDA) receptors that are localized throughout the brain. The NMDA receptor system has been implicated in synaptic plasticity, as well as learning and memory, thereby contributing in all likelihood to consolidation of trauma memories in PTSD. The NMDA receptor system is also believed to play a central role in the derealization phenomena and dissocation associated with illicit and medical uses of the anesthetic ketamine. In addition to its role in learning and memory, overexposure of neurons to glutamate is known to be excitotoxic, and may contribute to the loss of neurons and/ or neuronal integrity in the hippocampus and prefrontal cortex of patients with PTSD. Of additional note, elevated glucocorticoids increase the expression and/or sensitivity of NMDA receptors, which may render the brain generally more vulnerable to excitoxic insults at times of stress.
谷氨酸是大脑中主要的兴奋性神经递质。暴露于应激源和糖皮质激素的释放或施用激活大脑中谷氨酸的释放。在许多受体亚型中，谷氨酸结合于位于整个脑中的N -甲基D -天冬氨酸（NMDA）受体。NMDA受体系统与突触可塑性以及学习和记忆有关，因此很可能有助于PTSD中创伤记忆的巩固。NMDA受体系统也被认为在与麻醉剂氯胺酮的非法和医疗用途相关的现实脱节现象和解离中发挥核心作用。除了其在学习和记忆中的作用之外，已知神经元对谷氨酸的过度表达是兴奋性毒性的，并且可能导致患有PTSD的患者的海马和前额皮质中的神经元和/或神经元完整性的丧失。 另外值得注意的是，升高的糖皮质激素增加了NMDA受体的表达和/或敏感性，这可能使大脑在应激时通常更容易受到兴奋性毒性损伤。
Peptides 肽
CRH neurons in the hypothalamic PVN integrate information relevant to stress and thereby serve as a major component of the HPA axis. CRH neurons are also found in widespread circuitry throughout the brain, including the prefrontal and cingulate cortices, central nucleus of the amygdala, the bed nucleus of the stria terminais, hippocampus, nucleus accumbens, periaqueductal gray, and locus coeruleus (LC) as well as both dorsal and median raphe. Direct injection of CRH into the brain of laboratory animals produces physiological stress responses and anxiety-like behavior, including neophobia (fear of new things or experiences), enhanced startle, and facilitated fear conditioning. Anxiety -like behaviors have been specifically linked with increased activity of amygdalar CRH-containing neurons that project to the LC. Of note, glucocorticoids inhibit CRH-induced activation of LC noradrenergic neurons, providing a potential mechanism by which low Cortisol may facilitate sustained central stress and fear responses. The effects of CRH are mediated primarily through two CRH receptor subtypes, CRH2., and CRH2. In animal experiments, both exogenous administration of a CRH1, receptor antagonist, and experimental knockout of the CRH1 receptor, produce attenuated stress responses and reduced anxiety. A recent experiment demonstrated that CRHj receptor blockade impacted not only gastrointestinal measures of chronic stress, but also prevented stress-induced hair loss in rodents.35 Thus, CRH] receptor stimulation may be involved in facilitating stress responses and anxiety. By contrast, CRH7 knockout mice demonstrate stress sensitization and increased anxiety, suggesting a role for CRH2 receptor activation in reducing stress reactivity.3 Given the central effects of CRH, as described in animal models, increased CNS CRH activity may promote certain of the cardinal features of PTSD, such as conditioned fear responses, increased startle reactivity, sensitization to stressor exposure, and hyperarousal. These results suggest that CRH] receptor antagonists and/or CRH, agonists might have important therapeutic potential in the treatment of PTSD.
下丘脑室旁核中的CRH神经元整合与应激相关的信息，从而作为HPA轴的主要组成部分。CRH神经元也广泛存在于整个大脑的回路中，包括前额叶和扣带皮质、杏仁核的中央核、终纹的床核、海马、中脑核、导水管周围灰质和蓝斑（LC）以及中缝背核和中缝背核。将CRH直接注射到实验动物的大脑中会产生生理应激反应和焦虑样行为，包括新恐惧症（对新事物或经历的恐惧），增强惊吓和促进恐惧条件反射。类似焦虑的行为与投射到LC的杏仁核含CRH神经元的活动增加特别相关。 值得注意的是，糖皮质激素抑制CRH诱导的LC去甲肾上腺素能神经元的激活，提供了一种潜在的机制，通过这种机制，低皮质醇可以促进持续的中枢应激和恐惧反应。CRH的作用主要通过两种CRH受体亚型CRH 2 .，CRH 2 。在动物实验中，CRH 1 受体拮抗剂的外源性施用和CRH 1 受体的实验性敲除均产生减弱的应激反应和减少的焦虑。最近的一项实验表明，CRH 1受体阻断不仅影响慢性应激的胃肠道措施，而且还防止啮齿动物中应激诱导的脱发。 35 因此，CRH]受体刺激可能参与促进应激反应和焦虑。相比之下，CRH 7 敲除小鼠表现出应激敏感性和增加的焦虑，表明CRH 2 受体活化在降低应激反应性中的作用。 3 考虑到CRH的中枢效应，正如动物模型中所描述的，CNS CRH活性的增加可能会促进PTSD的某些主要特征，如条件性恐惧反应、惊吓反应性增加、对应激源暴露的敏感化和过度觉醒。这些结果表明，CRH 1受体拮抗剂和/或CRH 1激动剂可能在治疗PTSD中具有重要的治疗潜力。
Neuropeptide Y (NPY) may well be protective against the development of PTSD in that it has anxiolytic and stress-buffering properties. NPY has been shown to inhibit CRH/NE circuits involved in stress and fear responses and to reduce the release of NE from sympathetic neurons. As such, a lack of NPY may promote maladaptive stress responses and contribute to the development of PTSD. Indeed, patients with PTSD have been reported to exhibit decreased plasma NPY concentrations and blunted NPY responses to yohimbine challenge, compared with controls. Together, these findings suggest that decreased NPY activity may contribute to noradrenergic hyperactivity in PTSD.36 Moreover, it has been suggested that NPY may be involved in promoting recovery from, or perhaps resilience to PTSD, given that combat veterans without PTSD have been shown to exhibit elevated NPY levels compared with veterans with PTSD.6
神经肽Y（NPY）具有抗焦虑和缓冲压力的特性，可能对PTSD的发展具有很好的保护作用。NPY已显示出抑制参与应激和恐惧反应的CRH/NE回路，并减少交感神经元释放NE。因此，缺乏NPY可能会促进适应不良的压力反应，并有助于PTSD的发展。事实上，与对照组相比，PTSD患者表现出血浆NPY浓度降低和对育亨宾激发的NPY反应减弱。总之，这些研究结果表明，减少NPY活性可能有助于去甲肾上腺素能亢进的创伤后应激障碍。 36 此外，有人认为，NPY可能参与促进PTSD的恢复，或者可能是对PTSD的恢复，因为与患有PTSD的退伍军人相比，没有PTSD的退伍军人表现出升高的NPY水平。 6
Endogenous opioid peptides including the endorphins and enkephalins act upon the same CNS receptors activated by exogenous opioid molecules such as morphine or heroin. Endogenous opioids exert inhibitory influences on the HPA axis. Naloxone, an opioid receptor antagonist, increases HPA axis activation as evidenced by exaggerated HPA axis response to naloxone. PTSD patients exhibit increased CSF p-endorphin levels, suggesting increased activation of the endogenous opioid system. Alterations in endogenous opioids may be involved in certain PTSD symptoms such as numbing, stress-induced analgesia, and dissociation. Of additional interest, the nonselective opioid receptor antagonist, naltrexone, appears to be effective in treating symptoms of dissociation and flashbacks in traumatized persons.19,37 Further, the administration of morphine has been reported to prevent PTSD.38 Of note, an experiment investigating the hypothesis that PTSD may play an ctiologic role in fostering opioid addiction in an opioiddependent group of subjects rendered negative results.39
内源性阿片肽包括内啡肽和脑啡肽，作用于由外源性阿片分子如吗啡或海洛因激活的相同CNS受体。内源性阿片类物质对HPA轴有抑制作用。纳洛酮是一种阿片受体拮抗剂，可增加HPA轴激活，这一点通过HPA轴对纳洛酮的反应增强得到证明。PTSD患者表现出增加的CSF p-内啡肽水平，表明内源性阿片系统的激活增加。内源性阿片样物质的改变可能参与某些PTSD症状，如麻木，应激诱导的镇痛和解离。另外，非选择性阿片受体拮抗剂纳洛酮似乎能有效治疗创伤患者的解离和闪回症状。 19,37 此外，据报道，吗啡的施用可以预防PTSD。 38 值得注意的是，一项研究PTSD可能在阿片类药物依赖受试者中促进阿片类药物成瘾方面发挥作用的实验得出了负面结果。 39
Brain circuitry 大脑回路
Characteristic changes in brain structure and function have been identified in patients with PTSD using brainimaging methods.40-42 Brain regions that arc altered in patients with PTSD include the hippocampus and amygdala as well as cortical regions including the anterior cingulate, insula, and orbitofrontal region. These areas interconnect to form a neural circuit that mediates, among other functions, adaptation to stress and fear conditioning. Changes in these circuits have been proposed to have a direct link to the development of PTSD.40 Recent work raises the question as to which CNS elements are involved in circuit changes resulting from stress, and suggests a critical role for myelin.43 Similar to PTSD, brain areas most impacted by TBI include inferior frontal and temporal lobes, and it is likely that myelinated circuits are subject to damage broadly as a result of shear forces.
使用脑成像方法已经在PTSD患者中确定了脑结构和功能的特征性变化。 40-42 在PTSD患者中发生改变的大脑区域包括海马体和杏仁核以及皮质区域，包括前扣带回、前额叶和眶额区。这些区域相互连接，形成一个神经回路，调节对压力和恐惧条件反射的适应等功能。这些回路的变化被认为与PTSD的发展有直接联系。 40 最近的研究提出了一个问题，即哪些CNS元素参与了由压力引起的回路变化，并表明髓鞘的关键作用。 43 与创伤后应激障碍类似，受TBI影响最大的大脑区域包括下额叶和颞叶，并且有髓鞘回路很可能因剪切力而受到广泛损伤。
Hippocampus 海马
A hallmark feature of PTSD is reduced hippocampal volume. The hippocampus is implicated in the control of stress responses, declarative memory, and contextual aspects of fear conditioning. Not surprisingly, the hippocampus is one of the most plastic regions in the brain. As mentioned above, prolonged exposure to stress and high levels of glucocorticoids in laboratory animals damages the hippocampus, leading to reduction in dendritic branching, loss of dendritic spines, and impairment of neurogenesis.4 Initial magnetic resonance imaging (M.RI) studies demonstrated smaller hippocampal volumes in Vietnam Veterans with PTSD and patients with abuse-related PTSD compared with controls.44-47 Small hippocampal volumes were associated with the severity of trauma and memory impairments in these studies. These findings were generally replicated in most but not all subsequent work. Studies using proton magnetic resonance spectroscopy further observed reduced levels of N-acctyl aspartate (NAA), a marker of neuronal integrity, in the hippocampus of adult patients with PTSD.40 Of note, NAA reductions were correlated with Cortisol levels.48 Interestingly, reduced hippocampal volume has been observed in depressed women with a history of early life trauma49 but not in children with PTSD.50
PTSD的一个标志性特征是海马体积减小。海马体与压力反应、陈述性记忆和恐惧条件反射的背景方面的控制有关。海马体是大脑中可塑性最强的区域之一，这并不奇怪。如上所述，实验室动物长期暴露于应激和高水平的糖皮质激素会损害海马，导致树突分支减少、树突棘丢失和神经发生受损。 4 最初的磁共振成像（M.RI）研究表明，与对照组相比，患有PTSD的越战老兵和患有滥用相关PTSD的患者的海马体积较小。#1在这些研究中，海马体积小与创伤和记忆障碍的严重程度有关。这些发现在大多数但不是所有的后续工作中普遍重复。 使用质子磁共振波谱的研究进一步观察到患有PTSD的成年患者海马中N-乙酰天冬氨酸（NAA）水平降低，这是神经元完整性的标志物。值得注意的是，NAA的减少与皮质醇水平相关。 48 有趣的是，在有早期生活创伤史的抑郁女性中观察到海马体积减少 49 ，但在PTSD儿童中没有。 50
Hippocampal volume reduction in PTSD may reflect the accumulated toxic effects of repeated exposure to increased glucocorticoid levels or increased glucocorticoid sensitivity, though recent evidence also suggests that decreased hippocampal volumes might be a pre-existing vulnerability factor for developing PTSD.24 Indeed, hippocampal deficits may promote activation of and failure to terminate stress responses, and may also contribute to impaired extinction of conditioned fear as well as deficits in discriminating between safe and unsafe environmental contexts. Studies using functional neuroimaging have further shown that PTSD patients have deficits in hippocampal activation during a verbal declarative memory task.51 Both hippocampal atrophy and functional deficits reverse to a considerable extent after treatment with SSRIs,52 which have been demonstrated to increase neurotrophic factors and neurogenesis in some preclinical studies,5 but not others.53
PTSD患者海马体积减少可能反映了反复暴露于糖皮质激素水平升高或糖皮质激素敏感性升高的累积毒性效应，尽管最近的证据也表明海马体积减少可能是发展PTSD的预先存在的脆弱性因素。事实上，海马缺陷可能会促进应激反应的激活和终止失败，也可能导致条件性恐惧的消退受损以及区分安全和不安全环境的缺陷。使用功能性神经影像学的研究进一步表明，PTSD患者在口头陈述性记忆任务中海马激活有缺陷。 51 用SSRIs治疗后，海马萎缩和功能缺陷在相当大的程度上逆转， 52 在一些临床前研究中已证明增加神经营养因子和神经发生， 5 但不是其他。 53
Amygdala
The amygdala is a limbic structure involved in emotional processing and is critical for the acquisition of fear responses. The functional role of the amygdala in mediating both stress responses and emotional learning implicate its role in the pathophysiology of PTSD. Although there is no clear evidence for structural alterations of the amygdala in PTSD, functional imaging studies have revealed hyper-responsiveness in PTSD during the presentation of stressful scripts, cues, and/or trauma reminders.41 PTSD patients further show increased amygdala responses to general emotional stimuli that are not trauma-associated, such as emotional faces.41 The amygdala also seems to be sensitized to the presentation of subliminally threatening cues in patients with PTSD,54-56 and increased activation of the amygdala has been reported in PTSD patients during fear acquisition in a conditioning experiment.57 Given that increased amygdala reactivity has been linked to genetic traits which moderate risk for PTSD,58,59 increased amygdala reactivity may represent a biological risk factor for developing PTSD.
杏仁核杏仁核是参与情绪处理的边缘系统结构，对获得恐惧反应至关重要。杏仁核在调节应激反应和情绪学习中的功能作用暗示其在PTSD的病理生理学中的作用。虽然没有明确的证据表明PTSD患者杏仁核的结构改变，但功能成像研究显示PTSD患者在呈现压力脚本、线索和/或创伤提醒时具有高反应性。 41 PTSD患者进一步表现出杏仁核对与创伤无关的一般情绪刺激（如情绪化的面孔）的反应增加。#1在PTSD患者中，杏仁核似乎也对阈下威胁线索的呈现敏感，#2在条件反射实验中，PTSD患者在恐惧获得过程中杏仁核的激活增加。 57 鉴于杏仁核反应性的增加与PTSD风险适度的遗传特征有关， 58,59 杏仁核反应性的增加可能代表了PTSD发展的生物风险因素。
Cortex
The medial prefrontal cortex (PFC) comprises the anterior cingulate cortex (ACC), subcallosal cortex, and the medial frontal gyrus. The medial PFC exerts inhibitory control over stress responses and emotional reactivity in part by its connections with the amygdala. It further mediates extinction of conditioned fear through active inhibition of acquired fear responses.41 Patients with PTSD exhibit decreased volumes of the frontal cortex,60 including reduced ACC volumes.61,62 This reduction in ACC volume has been correlated with PTSD symptom severity in some studies. In addition, an abnormal shape of the ACC,63 as well as a decrease of NAA levels in the ACC,64 has been reported for PTSD patients. A recent twin study suggests that, unlike the hippocampus, volume loss in the ACC is secondary to the development of PTSD rather than a pre-existing risk factor.65 Functional imaging studies have found decreased activation of the medial PFC in PTSD patients in response to stimuli, such as trauma scripts,66,67 combat pictures and sounds,68 trauma-unrelated negative narratives,69 fearful faces,70 emotional stroop,71 and others, though there are also discordant findings.41 Reduced activation of the medial PFC was associated with PTSD symptom severity in several studies and successful SSRI treatment has been shown to restore medial prefrontal cortical activation patterns.41 Of note, in the abovementioned conditioning experiment,57 extinction of conditioned fear was associated with decreased activation of the ACC, providing a biological correlate for imprinted traumatic memories in PTSD. Not surprisingly, given the connectivity between the amygdala and medial PFC, interactions in activation patterns between these regions have been reported in PTSD, though the direction of the relationship is inconsistent across studies.41
内侧前额叶皮质（PFC）包括前扣带皮层（ACC）、胼胝体下皮层和内侧额回。内侧前额叶皮层对压力反应和情绪反应的抑制性控制部分是通过它与杏仁核的联系实现的。它还通过主动抑制获得性恐惧反应来介导条件性恐惧的消退。 41 患有PTSD的患者表现出额叶皮质体积减少， 60 包括ACC体积减少。#2在一些研究中，ACC体积的减少与PTSD症状的严重程度相关。此外，对于PTSD患者，已经报道了ACC的异常形状 63 以及ACC中NAA水平的降低 64 。最近的一项双胞胎研究表明，与海马体不同，ACC的体积损失是继发于PTSD的发展，而不是预先存在的风险因素。 功能成像研究发现，PTSD患者在对创伤脚本、战斗画面和声音、与创伤无关的负面叙述、恐惧的面孔、情绪化的斯特鲁普、以及其他刺激做出反应时，内侧PFC的激活减少，尽管也有不一致的发现。 41 在几项研究中，内侧PFC的激活减少与PTSD症状的严重程度相关，成功的SSRI治疗已被证明可以恢复内侧前额叶皮质的激活模式。值得注意的是，在上述条件反射实验中，条件反射恐惧的消退与前扣带回激活的减少有关，这为创伤后应激障碍中的印记创伤记忆提供了生物学相关性。鉴于杏仁核和内侧前额叶皮层之间的联系，PTSD中这些区域之间的激活模式相互作用也就不足为奇了，尽管这种关系的方向在不同的研究中并不一致。 41
The origin of neurobiological abnormalities in PTSD
创伤后应激障碍神经生物学异常的起源
A number of studies have investigated the fundamental question as to whether the neurobiological changes identified in patients with PTSD represent markers of neural risk to develop PTSD upon exposure to extreme stress as opposed to abnormalities acquired through traumatic exposure or, most likely, a combination of both. As an example, low Cortisol levels at the time of a trauma predict subsequent development of PTSD. Thus, low levels of Cortisol might be a pre-existing risk factor that engenders the development of PTSD; low levels of Cortisol could disinhibit CRH/NE circuits and thereby promote unopposed autonomic and neuroendocrine responses to stress, as well as augmented fear conditioning and traumatic memory consolidation. Similarly, the reduced size of the hippocampus in PTSD has remained an unresolved question for many years. There has been considerable debate as to whether this brain region shrinks as a result of trauma exposure, or whether the hippocampus of PTSD patients might be smaller prior to trauma exposure. Studies in twins discordant for trauma exposure have provided a means to address this question, though without complete resolution. Gilbertson and colleagues72 studied 40 pairs of identical twins, including Vietnam Veterans who were exposed to combat trauma and their twins who did not serve in Vietnam, and measured hippocampal volumes in all subjects. As expected, among Vietnam Veterans, the hippocampus was smaller in those diagnosed with PTSD as compared with those without a diagnosis. However, this brain region was abnormally smaller in non-PTSD twins as well, despite the absence of trauma exposure and diagnosis. These findings suggest that a smaller hippocampus could be a pre-existing, potentially genetic, neurodevelopmental, and almost surely multifactorial vulnerability factor that predisposes to the development of PTSD (and perhaps other stress-spectrum disorders). Recent results from the same study group indicate, as above, that gray matter loss in the ACC seems on the contrary to be an acquired feature.65 Studies are needed to identify the timing and/or etiology of other hallmark neurobiological features of PTSD.
一些研究已经调查了一个基本问题，即PTSD患者的神经生物学变化是否代表了暴露于极端压力后发展PTSD的神经风险标志，而不是通过创伤暴露获得的异常，或者最有可能是两者的组合。例如，创伤时皮质醇水平低可预测随后PTSD的发展。因此，低水平的皮质醇可能是导致PTSD发展的预先存在的风险因素;低水平的皮质醇可以解除CRH/NE回路的抑制，从而促进对压力的自主神经和神经内分泌反应，以及增强的恐惧条件反射和创伤记忆巩固。同样，创伤后应激障碍患者海马体的缩小也是一个多年未解决的问题。 关于这个大脑区域是否会因创伤暴露而缩小，或者创伤后应激障碍患者的海马体是否会在创伤暴露前变小，一直存在相当大的争论。对创伤暴露不一致的双胞胎的研究提供了一种解决这个问题的方法，尽管没有完全解决。Gilbertson和同事 72 研究了40对同卵双胞胎，包括暴露于战斗创伤的越战老兵和没有在越南服役的双胞胎，并测量了所有受试者的海马体积。正如预期的那样，在越战老兵中，与那些没有诊断出PTSD的人相比，那些被诊断出PTSD的人的海马较小。然而，尽管没有创伤暴露和诊断，非创伤后应激障碍双胞胎的大脑区域也异常小。 这些发现表明，较小的海马体可能是一个预先存在的，潜在的遗传，神经发育，几乎肯定是多因素的脆弱性因素，易患创伤后应激障碍（也许还有其他应激障碍）。来自同一研究小组的最新结果表明，如上所述，ACC中的灰质损失似乎相反是一种获得性特征。 65 需要研究来确定PTSD的其他标志性神经生物学特征的时间和/或病因。
Risk and resilience for developing PTSD
发展PTSD的风险和弹性
Individuals exposed to an event that either threatens serious injury/death, or is perceived as such, respond in different ways. Most will experience minimal (seconds) to brief (hours) to short-term (days/weeks) abnormalities while a smaller number will suffer from significant psychopathology over longer-term (months) and chronic (lifetime) time frames. In short, not all individuals who face potentially catastrophic trauma go on to develop PTSD. Why some individuals will develop PTSD following trauma, whereas others do not, is of paramount importance. Because the majority of trauma survivors do not go on to develop PTSD, it is crucial going forward to understand vulnerability and resiliency factors. In this section, the role of genetic factors, gender differences, and early developmental stress experiences in moderating risk for developing PTSD in response to psychological trauma are discussed as is the increased risk for developing PTSD in the context of co-occurring physical traumas (including TBI).
暴露于威胁严重伤害/死亡的事件或被认为是严重伤害/死亡的事件的个人，会以不同的方式做出反应。大多数人将经历最小（秒）到短暂（小时）到短期（天/周）的异常，而少数人将在长期（数月）和慢性（终身）时间范围内遭受显着的精神病理学。简而言之，并非所有面临潜在灾难性创伤的人都会发展为PTSD。为什么有些人会在创伤后发展PTSD，而另一些人不会，这是至关重要的。由于大多数创伤幸存者不会继续发展PTSD，因此了解脆弱性和弹性因素至关重要。 在本节中，遗传因素，性别差异和早期发展压力的经验，在缓和风险发展PTSD在心理创伤的作用进行了讨论，因为是在共同发生的身体创伤（包括TBI）的背景下，发展PTSD的风险增加。
Genetic risk factors for PTSD
PTSD的遗传风险因素
Studies on the genetics of PTSD have been hampered by a variety of factors, such as genetic heterogeneity (similar phenotypes develop from different genotypes) and incomplete phenotypic penetrance (a person with genetic risk for PTSD, who is not exposed to trauma, will not develop PTSD). Despite these confounds, there is accumulating evidence that risk for PTSD is heavily influenced by genetic factors. Evidence from family and twin studies has long suggested a heritable contribution to the development of PTSD. In addition, there is evidence for heritable contributions to some of the neurobiological endophenotypes of PTSD as discussed above, such as decreased hippocampal volume72 or exaggerated amygdala reactivity.58 Although it is beyond the scope of this review to comprehensively discuss the genetics of PTSD, it should be noted that there is an emerging literature on genetic variations in those neurobiological systems that drive responses to trauma and, consequently, risk versus resilience to develop PTSD.73
对PTSD遗传学的研究受到各种因素的阻碍，例如遗传异质性（从不同的基因型发展出相似的表型）和不完全的表型遗传（一个有PTSD遗传风险的人，如果没有受到创伤，就不会发展成PTSD）。尽管存在这些困惑，但越来越多的证据表明PTSD的风险受到遗传因素的严重影响。长期以来，来自家庭和双胞胎研究的证据表明，PTSD的发展是遗传性的。此外，有证据表明，PTSD的某些神经生物学内表型具有遗传性，如海马体积减少或杏仁核反应性增强。 58 虽然全面讨论PTSD的遗传学超出了本综述的范围，但应该注意的是，有一个关于神经生物学系统中遗传变异的新兴文献，这些遗传变异驱动对创伤的反应，因此，风险与恢复力发展PTSD。 73
One study has linked a polymorphism in the DA transporter gene to PTSD risk. In this study, PTSD patients were found to have an excess of the SLC6A39 repeat allele. This finding suggests that genetically determined features of DA transmission may contribute to the development of PTSD among trauma survivors.74 Several studies have suggested polymorphisms in the D2 receptor as possible elements of PTSD risk, though results have not been consistent.73 In addition, there is evidence linking a low expression variant of the serotonin transporter to stress responsiveness and risk for developing depression in relation to life stress, particularly in the presence of low social support.59 This finding is intriguing as the same polymorphism is associated with increased amygdala reactivity58 as well as the trait of neuroticism,75 which is another risk factor for PTSD. It must be noted, however, that these findings of genetic risk with regard to the serotonin transporter have recently been questioned.76
一项研究将DA转运蛋白基因的多态性与PTSD风险联系起来。在这项研究中，PTSD患者被发现有过多的SLC6A39重复等位基因。这一发现表明，遗传决定的DA传输功能可能有助于创伤幸存者PTSD的发展。几项研究表明，D 2 受体的多态性是PTSD风险的可能因素，尽管结果并不一致。 73 此外，有证据表明，血清素转运体的低表达变体与压力反应和与生活压力相关的抑郁症风险有关，特别是在社会支持不足的情况下。 59 这一发现很有趣，因为相同的多态性与杏仁核反应性增加 58 以及神经质特征有关， 75 这是PTSD的另一个危险因素。 然而，必须指出的是，这些关于5-羟色胺转运蛋白遗传风险的发现最近受到了质疑。 76
Particularly exciting are findings that a genetic variation of the glucocorticoid receptor cochaperone protein, FKBP5, moderates risk of developing PTSD in relation to childhood abuse.77 This study tested interactions of childhood abuse, adulthood trauma, and genetic polymorphisms in the FKBP5 gene in 900 nonpsychiatric, general internal medicine clinic patients. Childhood abuse and adulthood trauma each predicted PTSD symptoms and FKBP5 polymorphisms significantly interacted with childhood abuse to predict adult PTSD symptoms. The FKBP5 genotype was further linked to enhanced glucocorticoid receptor sensitivity, as reflected by dexamethasone hypersuppression, a hallmark feature of PTSD.77 Most recently, Ressler and colleagues have demonstrated that a female-specific elevation of pituitary adenylate cyclase-activating peptide (PACAP) correlated not only with fear physiology and the diagnosis of PTSD78 but also a specific single nucleotide repeat on an estrogen response element in the same subjects. These findings and this type of work may shed new light not only on the well-known differences in PTSD risk between men and women that are discussed in the next section, but on our mechanistic understanding of PTSD in general.
特别令人兴奋的是，糖皮质激素受体辅伴侣蛋白FKBP 5的遗传变异可以降低与儿童虐待有关的创伤后应激障碍的风险。 77 这项研究测试了900名非精神病，普通内科诊所患者的儿童虐待，成年创伤和FKBP 5基因遗传多态性的相互作用。儿童期虐待和成年期创伤均可预测PTSD症状，FKBP5多态性与儿童期虐待显著交互作用，可预测成年期PTSD症状。FKBP5基因型进一步与糖皮质激素受体敏感性增强有关，如地塞米松过度抑制所反映的，这是PTSD的标志性特征。 最近，Ressler及其同事证明，女性特异性垂体腺苷酸环化酶激活肽（PACAP）的升高不仅与恐惧生理学和PTSD的诊断相关，而且与同一受试者中雌激素反应元件上的特定单核苷酸重复有关。这些发现和此类工作不仅可以为下一节讨论的众所周知的男性和女性之间创伤后应激障碍风险差异提供新的线索，而且可以为我们对创伤后应激障碍的总体机械理解提供新的线索。
Gender differences and risk for PTSD
性别差异与PTSD风险
Women more frequently suffer from PTSD than men for reasons that are not entirely clear. Women and men are, in general, subjected to different types of trauma, though the differences in PTSD frequency (reportedly 2:1) arc unlikely to be explained solely on the basis of exposure type and/or severity alone. In addition to those findings by Ressler described above, a number of gender-related differences in the neurobiological response to trauma have been documented.79 Rodent studies suggest that females generally exhibit greater magnitude and duration of HPA axis responses to stress than males,80 though findings in humans are not entirely consistent.81 Sex differences in neuroendocrine stress responses have been attributed to direct effects of circulating estrogen on CRH neurons.82 Sex steroids also interact with other neurotransmitter systems involved in the stress response, such as the serotonin system.83 Progesterone has been implicated in modulating these systems as well.84 However, gender differences in HPA responses to stress have also been observed independent of acute gonadal steroid effects.85
女性比男性更容易患上PTSD，原因尚不完全清楚。一般来说，女性和男性遭受不同类型的创伤，尽管PTSD频率的差异（据报道为2：1）不太可能仅根据暴露类型和/或严重程度来解释。除了上述Ressler的发现外，还记录了创伤神经生物学反应中的一些与性别有关的差异。 79 啮齿类动物研究表明，雌性动物对压力的HPA轴反应通常比雄性动物表现出更大的幅度和持续时间， 80 尽管人类的研究结果并不完全一致。神经内分泌应激反应的性别差异归因于循环雌激素对CRH神经元的直接影响。 82 性类固醇还与其他参与应激反应的神经递质系统相互作用，如血清素系统。 83 Progestine也参与了这些系统的调节。 #5然而，HPA对压力反应的性别差异也被观察到独立于急性性腺类固醇效应。 85
Factors that might determine gender differences in the stress response include genomic differences (as above) and/or devclopmentally programmed effects of gonadal steroids.81,85,86 Of note, a very recent study of female Veterans demonstrated that pregnancy raises the risk of PTSD above that for nonpregnant females.87 In addition, sex steroids play a role in structural plasticity across the lifespan of several brain regions, including areas involved in stress responsiveness such as the hippocampus and amygdala.86 Functional imaging studies have identified gender differences in the brain's response to fear stimuli.88 Over time our understanding of this constellation of processes may eventually converge to allow for a better description of the basis for gender differences and, specifically, how the consequences of trauma translate into differential risk for PTSD.
可能决定应激反应中性别差异的因素包括基因组差异（如上所述）和/或性腺类固醇的发育程序化效应。值得注意的是，最近一项针对女性退伍军人的研究表明，怀孕会使PTSD的风险高于非怀孕女性。 87 此外，性类固醇在多个大脑区域的生命周期中的结构可塑性中发挥着作用，包括海马体和杏仁核等参与压力反应的区域。功能成像研究已经确定了大脑对恐惧刺激反应的性别差异。#3随着时间的推移，我们对这一系列过程的理解最终可能会趋于一致，从而更好地描述性别差异的基础，特别是创伤的后果如何转化为PTSD的差异风险。
Early developmental factors and PTSD
早期发展因素与PTSD
Previous experience moderates risk for developing PTSD in response to trauma, particularly when exposure to stress occurs early in life. Thus, childhood adversity is associated with increased risk to develop PTSD in response to combat exposure in Vietnam Veterans.51 There is a burgeoning literature documenting that early adverse experience, including prenatal stress and stress throughout childhood, has profound and long-lasting effects on the development of neurobiological systems, thereby “programming” subsequent stress reactivity and vulnerability to develop PTSD.89-91 As an example, children with a history of date violence have recently been shown at risk of developing future PTSD.92 Further, a study of child survivors from the Hurricane Katrina disaster indicates significantly increased risk of PTSD.93 Along these lines, nonhuman primates exposed to a variable foraging demand condition, which causes unpredictable maternal care in the infant, leads to an adult phenotype with sensitization to fear cues, CRH hyperactivity and low Cortisol levels, a pattern of the classic features found in PTSD.94 Consistent with these findings, adult women with childhood trauma histories exhibit sensitization of both neuroendocrine, and autonomic stress responses.95 Studies are needed that identify particular sensitive periods for the effects of early stress, determine parameters for their reversal, and scrutinize the interactions of dispositional factors (genes, gender) with developmental features in determining neurobiological vulnerability to PTSD.
先前的经历可以缓解创伤后应激障碍的风险，特别是在生命早期暴露于压力时。因此，童年逆境与越战退伍军人在战斗暴露中发展PTSD的风险增加有关。有一个新兴的文献记载，早期的不良经历，包括产前压力和整个童年的压力，对神经生物学系统的发展有深远而持久的影响，从而“编程”随后的压力反应性和脆弱性，以发展创伤后应激障碍。#1例如，有约会暴力史的儿童最近被证明有发展未来PTSD的风险。 92 此外，一项对卡特里娜飓风灾难中儿童幸存者的研究表明，PTSD的风险显着增加。 #3沿着这些线索，非人灵长类动物暴露在一个可变的觅食需求条件下，这导致婴儿不可预测的母亲护理，导致成年表型，对恐惧线索敏感，CRH过度活跃和皮质醇水平低，这是创伤后应激障碍的典型特征。#4与这些发现一致，有童年创伤史的成年女性表现出神经内分泌和自主应激反应的敏感性。 95 需要进行研究，以确定早期压力影响的特定敏感期，确定其逆转的参数，并仔细检查性格因素（基因，性别）与发育特征的相互作用，以确定神经生物学对PTSD的脆弱性。
The influence of physical trauma (and TBI) on the development of PTSD
物理创伤（和TBI）对PTSD发展的影响
It has been known for some time that physical injury concomitant with psychological trauma increases risk for the development of PTSD. In studies of Vietnam Veterans,96,97 and more recently in a study of Iraq and Afghanistan Veterans,98 it was found that physical injury increased the risk of PTSD at least twofold. Similarly, a literature review of patients with documented TBI and program evaluation data from surveys of US Marines following blast exposures in Iraq99 demonstrate that TBI presents an increased risk for the development of PTSD. Though differentiating the risk of developing PTSD in patients with TBI is complicated by the subjective and objective abnormalities common to both clinical entities, it is striking that each shares common endocrine, neurochemical, and circuit abnormalities (see above, The biology of PTSD ). As such, it would follow that the existence of both diagnoses in an individual patient might be additive if not multiplicative from a clinical standpoint. For example, in the context of TBI (with frontal lobe damage and behavioral disinhibition) it would be reasonable to expect a very high violence risk profile for a patient suffering from the irritability and anger characteristic of comorbid PTSD. Of additional note, the helplessness that accompanies certain physical injuries (perhaps most notably TBI) is certain to compound issues of limited self-efficacy (and the overall lost sense of agency) that characterize PTSD. The psychological challenges of TBI may thereby introduce an additional chronic risk for the victimization that fosters PTSD in those patients with a tendency to become increasingly dependent over time.
一段时间以来，人们已经知道，伴随心理创伤的身体伤害会增加PTSD发展的风险。在对越战退伍军人的研究中， 96,97 和最近对伊拉克和阿富汗退伍军人的研究中， 98 发现身体伤害会使PTSD的风险增加至少两倍。类似地，对记录有创伤性脑损伤的患者的文献综述和来自美国海军陆战队在伊拉克2号爆炸暴露后的调查的项目评估数据表明，创伤性脑损伤会增加创伤后应激障碍的发展风险。虽然区分创伤性脑损伤患者发生创伤后应激障碍的风险因两种临床实体共同的主观和客观异常而变得复杂，但令人惊讶的是，每种都有共同的内分泌，神经化学和回路异常（见上文，创伤后应激障碍的生物学）。因此，从临床角度来看，个体患者中两种诊断的存在可能是相加的，如果不是相乘的话。 例如，在TBI（额叶损伤和行为抑制解除）的背景下，对于患有PTSD共病的易怒和愤怒特征的患者，预期非常高的暴力风险特征是合理的。另外值得注意的是，伴随着某些身体伤害（也许最明显的是TBI）的无助感肯定会加剧PTSD的自我效能有限（以及整体的主体感丧失）的问题。创伤性脑损伤的心理挑战可能因此引入额外的慢性受害风险，从而在那些随着时间的推移变得越来越依赖的患者中促进创伤后应激障碍。
A basic model of PTSD neurobiology
PTSD神经生物学的基本模型
The biological perturbations observed in patients suffering from PTSD are numerous, and likely reflect an enduring dysregulation of multiple stress-mediating systems that occurs as a result of a psychological “shock.” These pathophysiological perturbations presumably occur in patients with genetic, epigenetic, and experiential predispositions when exposed to certain extreme conditions. Presumably these changes signify an indelible sensory imprint of a maladaptively processed experience that co-opts an imbalanccd degree of emotional importance and thereafter releases (or restrains) behavioral reactions that focus on defending against future trauma via activation (or deactivation) in a losing effort to secure homeostasis.
在患有PTSD的患者中观察到的生物扰动是众多的，并且可能反映了由于心理“休克”而发生的多个压力介导系统的持久失调。这些病理生理学干扰可能发生在具有遗传、表观遗传和经验倾向的患者在暴露于某些极端条件时。据推测，这些变化意味着一种不可磨灭的感觉印记，即一种不适应的加工体验，它吸收了一种不平衡的情感重要性程度，然后释放（或抑制）行为反应，这些反应集中在通过激活（或失活）来防御未来的创伤，从而失去了确保体内平衡的努力。
Considering neurobiological findings in PTSD patients with this overview in mind, a relative lack of baseline Cortisol at the time of a psychological trauma may facilitate overactivation of the central CRH-NE cascade, resulting in enhanced and prolonged stress responses.6,95 This increased stress responsiveness may be further accentuated by inadequate regulatory effects of GABA, serotonin, and NPY. Additionally, altered norpinephrine and stress hormone activity may be critically involved in processes of learning and extinction, both of which are abnormal in PTSD; for example, norepinephrine enhances the encoding of fear memories and glucococorticoids block the retrieval of emotional memories. The constellation of elevated noradrenergic activity and relative hypocortisolism may lead to the enhanced encoding of traumatic memories and the lack of inhibition of memory retrieval both of which presumably trigger re-experiencing phenomena in PTSD.12
考虑到PTSD患者的神经生物学发现，在心理创伤时相对缺乏基线皮质醇可能会促进中枢CRH-NE级联的过度激活，导致应激反应增强和延长。这种增加的应激反应可能会因GABA、5-羟色胺和NPY的调节作用不足而进一步加重。此外，去甲肾上腺素和应激激素活性的改变可能与学习和消退的过程密切相关，这两者在PTSD中都是异常的;例如，去甲肾上腺素增强了恐惧记忆的编码，糖皮质激素阻断了情感记忆的检索。去甲肾上腺素能活动的升高和皮质醇的相对减少可能导致创伤记忆编码的增强和记忆提取抑制的缺乏，这两者可能触发PTSD中的再体验现象。 12
Further, an abnormally functioning hippocampus may account for some of the cognitive symptoms of PTSD, such as declarative memory deficits. In addition, because the hippocampus is critical for context conditioning, an impaired hippocampus may facilitate generalization of learned fear in contexts unrelated to a previous traumatic exposure and impair the ability to discriminate between safe and unsafe stimuli. In combination with exaggerated amygdalar responses seen in patients with PTSD, a limited capacity for discerning threat due to hippocampal and amygdalar dysfunction may promote paranoia, hypervigilance, behavioral activation, exaggerated stress responses, and further acquisition of fear associations. Disrupted prefrontal cortical function may then serve to facilitate PTSD pathology further as a result of deficient suppression of stress responses, fear associations, and extinction.
此外，海马体功能异常可能导致PTSD的一些认知症状，如陈述性记忆缺陷。此外，由于海马体对情境条件反射至关重要，受损的海马体可能会在与先前创伤暴露无关的情境中促进习得性恐惧的泛化，并损害区分安全和不安全刺激的能力。与PTSD患者中观察到的夸张的杏仁核反应相结合，由于海马和杏仁核功能障碍而导致的识别威胁的能力有限可能会促进偏执、过度警觉、行为激活、夸张的应激反应以及进一步获得恐惧联想。前额叶皮质功能的破坏可能会进一步促进创伤后应激障碍的病理，这是由于对压力反应、恐惧联想和灭绝的抑制不足。
Future directions 未来方向
In this article, we have selected findings from a broad range of the PTSD literature to consider the impact of psychological trauma on neurobiological systems. As described, some neurobiological findings in patients with PTSD are controversial and need to be further examined. In addition, there are a number of understudied yet important topics in the field such as factors that impact resiliency and vulnerability. For example, stress-protective neurobiological factors such as activity in oxytocin and NPY-containing circuits could, in principle, be manipulated to promote resilience. In addition, there is a general need to explore further the molecular biology of PTSD; identifying interactions between dispositional factors (genetic and epigenetic) and trauma exposure is critical to understand PTSD risk, gauge illness course, and predict treatment response. The effects of trauma on neurotrophic factors (in the hippocampus), neural plasticity (CNS-wide), circuit remodeling (myelination patterns) and gene expression need to be assessed in detail across illness duration. Though difficult, such studies will necessitate accessing, assaying and following populations at risk for exposure to trauma before any exposure occurs (ideally, predeployment soldiers). Where possible, the distinction between PTSD and TBI must also be better understood. Though the presumed mechanism of injury from psychological trauma as opposed to brain trauma is overtly different, the etiologic abnormalities seem to involve similar neurobiological systems and produce overlapping clinical syndromes.
在这篇文章中，我们从广泛的PTSD文献中选择了研究结果，以考虑心理创伤对神经生物学系统的影响。如前所述，PTSD患者的一些神经生物学研究结果是有争议的，需要进一步研究。此外，该领域还有一些研究不足但很重要的议题，如影响复原力和脆弱性的因素。例如，原则上，可以操纵压力保护神经生物学因素，如催产素和含NPY回路的活动，以促进恢复力。此外，普遍需要进一步探索PTSD的分子生物学;确定性格因素（遗传和表观遗传）和创伤暴露之间的相互作用对于了解PTSD风险，衡量病程和预测治疗反应至关重要。 创伤对神经营养因子（海马）、神经可塑性（CNS范围）、回路重塑（髓鞘形成模式）和基因表达的影响需要在整个病程中详细评估。虽然困难，但这种研究将需要在任何接触发生之前接触、分析和跟踪有遭受创伤风险的人群（最好是部署前的士兵）。在可能的情况下，还必须更好地理解创伤后应激障碍和创伤性脑损伤之间的区别。虽然心理创伤与脑创伤的损伤机制明显不同，但病因异常似乎涉及相似的神经生物学系统，并产生重叠的临床症状。
Acknowledgments 致谢
The authors would like to thank Ms Cynthia CriderVega, Ms Magaly Gomez, and Ms Carmen Alsina for their outstanding administrative assistance.
作者要感谢Cynthia CriderVega女士、Magaly Gomez女士和Carmen Alsina女士出色的行政协助。
Selected abbreviations and acronyms
部分缩略语
| 5 HT | serotonin 血清素 |
| CRH | corticotropin-releasing hormone 皮质激素释放激素 |
| DA | dopamine 多巴胺 |
| GABA | y-aminobutyric acid y-氨基丁酸 |
| HPA | hypothalamic-pituitary-adrenal 下丘脑-垂体-肾上腺 |
| NE | norepinephrine 去甲 |
| NPY | neuropeptide Y 神经肽Y |
| PTSD | post-traumatic stress disorder 创伤后应激障碍 |
REFERENCES 引用
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