【作者】 何梅；

【导师】 杨宗城；

【作者基本信息】 第三军医大学 ， 外科学， 2008， 博士

【摘要】 随着医学诊疗技术的进步,烧伤救治水平逐年提高,目前我国重症烧伤病人的治愈率已达90%以上。国内外在关注烧伤病人治愈率的同时,更加关注烧伤病人的康复水平,对烧伤病人躯体功能和心理、社会功能的康复提出了更高的要求。抑郁(Depression)是最常见的心境障碍,流行病学调查发现,近年来抑郁症的发病率呈逐年上升的趋势,特别是在遭受重大生活事件的情况下,更易发生;抑郁发生后造成心境低落、兴趣丧失、精神运动性迟滞、悲观绝望,不仅是促使自杀的重要原因,而且也是增加其它生理疾病的发生和发展的诱发因素。烧伤是战时和平时都极易发生的突发性重大事件,烧伤所引起的疼痛、睡眠障碍、反复手术、肢体残障、毁容、人际交往障碍等生理、心理、社会功能的变化导致烧伤后患者抑郁的发病率明显高于正常人群及许多其他疾病患者。目前对烧伤后抑郁情绪障碍的研究主要采用文献回顾和量表法对其发病率和发病特点进行分析,而对导致烧伤后抑郁情绪发病各因素之间的关联性及各因素在抑郁发生中的直接和间接性作用,国内外鲜见系统性研究报道。认知是大脑注意、思维、判断、学习、记忆等的一种综合功能。认知系统随时都在受到外界大量而复杂的信息刺激,然而在同一时间,认知系统对信息的处理能力是有限的,所以,对信息的“注意选择”、“注意转移”及“再认回忆”加工决定认知系统对信息的选择和过滤。认知理论认为抑郁患者由于具有消极认知图式,认知方式上存在逻辑推理上的非理性,在遭遇不良事件时容易形成对未来、对自我、对世界的悲观看法,从而陷入不可自拔的无望、无助等不良情绪。抑郁的认知理论认为认知因素是情绪产生的关键因素,情绪不是由某一诱发事件本身所引起,而是由经历这一事件的个体对事件的解释和评价所引起,认知是情绪反应的重要中介。烧伤并发抑郁患者的认知系统在情绪障碍产生中如何起中介作用,烧伤事件本身对认知过程的改变有无影响,烧伤并发抑郁情绪后患者认知加工是否具有负性偏向,这些负性偏向主要发生在认知过程的哪个阶段,目前在国内外还未见报道。海马是学习记忆能力比较重要的脑区,已有研究认为海马结构受损,动物将会丧失将短时记忆转化为长时记忆的功能,出现学习和记忆能力的下降;同时海马也是应激激素作用的重要靶器官,海马内存在大量对皮质醇敏感的糖皮质激素受体,在正常情况下参与对下丘脑-垂体-肾上腺轴(Hypothalamo Pituitary Adrenal,HPA)的反馈调节,当血液循环中皮质醇浓度过高时,海马就会抑制促肾上腺皮质激素释放因子(Corticotropin Releasing Facter , CRF)的释放,进而使促肾上腺皮质激素(Adrenocorticotropic Hormone,ACTH)和皮质醇的释放减少。在慢性或长期应激作用下,糖皮质激素的负反馈作用失调,下丘脑CRF表达改变,导致海马神经细胞萎缩和死亡。长时程增强效应(Long Term Potentiation LTP)是突触可塑性的重要特点,是形成和巩固学习记忆的基础,海马内NMDA受体被认为是海马神经元长时程增强效应的主要调控者,神经元的长时程增强需要NMDA受体的开放,使大量钙离子通过NMDA受体进入突触后神经元,海马神经元突触可塑性变化可能是引起学习记忆等认知能力障碍的基础。星形胶质细胞在中枢神经系统中数目远远多于神经元细胞,一直以来被认为仅仅是支持和营养神经元,维持神经元正常功能活动的辅助细胞,但近年来研究认为胶质细胞也主动参与了神经元的信号传递,调节突触活动和可塑性。海马神经结构的变化及NMDA受体功能改变是否是烧伤后并发抑郁情绪障碍中认知改变的生理基础,国内外未见系统研究报道。本研究首先通过探讨临床烧伤患者抑郁情绪障碍的发病情况,分析烧伤后不同时期、严重程度、性别、部位、伤前心理状况等情况下抑郁情绪障碍并发率的差异,找出烧伤后抑郁发生的潜在生理、心理、社会危险因素,分析烧伤并发抑郁的直接和间接影响因素,为临床烧伤患者并发抑郁的预测和心理治疗提供初步理论基础依据,构建影响烧伤并发抑郁的因果关系模式;其次,通过烧伤并发抑郁患者对不同阈值刺激下情绪图片材料的注意空间分配偏向、空间转移偏向及再认回忆特点研究,分析烧伤后并发抑郁情绪障碍患者注意选择和固着特点及回忆选择性的负性偏向;同时建立烧伤并发抑郁大鼠模型,采用动物实验观察烧伤后并发抑郁大鼠环境探索、空间记忆和学习、主动回避和被动回避行为,探讨抑郁对烧伤大鼠认知行为的影响;最后通过对烧伤并发抑郁大鼠外周静脉血CRF、ACTH及皮质醇的水平,下丘脑CRF的表达以及海马神经细胞结构及NMDA表达变化进行研究,初步探讨烧伤后抑郁认知和行为改变的病理生理基础。一、方法1.对临床住院期间治疗期和康复期共344名患者进行量表测定,调查烧伤后并发抑郁情绪的发病率,自动负性思维和应对方式,并通过因素分析、回归及路径分析方法,分析烧伤后并发抑郁的发病特点,影响因素及生理-心理-社会因素的回归路径。2.利用认知研究中的点探测范式、线索提示范示,以国际情绪图片系统(IAPS)为研究材料,对临床康复期烧伤后并发抑郁患者、烧伤后无抑郁患者及正常人群进行注意空间选择、注意转移、再认回忆的情绪加工过程进行研究,探讨烧伤并发抑郁患者在认知过程中对不同情绪图片的负性偏向。3.采用慢性不可预见的中度刺激配合孤养,建立30%TBSA深Ⅱ度烧伤并发抑郁大鼠模型,动物经旷场筛选后随机分为正常对照组、单纯抑郁组、单纯烧伤组及烧伤后并发抑郁组。通过糖精摄入、旷场、水迷宫、穿梭箱等行为测试,研究大鼠兴趣、探索行为、空间学习和记忆、主动回避及被动回避行为,探讨烧伤后并发抑郁的认知和行为反应变化规律。4.通过RT-PCR、放射免疫和电镜等技术手段对烧伤后并发抑郁大鼠外周静脉血中CRF、ACTH、皮质醇及下丘脑CRFmRNA的表达变化进行研究;通过电镜对大鼠海马神经元和神经胶质细胞的形态学进行观察;进一步对海马神经元和胶质细胞结构、N-甲基-D-天冬氨酸(N-methyl-D-aspartate,NMDA)的变化进行研究,初步探讨烧伤后并发抑郁情绪障碍认知和行为改变的生理基础。二、结果1.烧伤后抑郁情绪障碍的发病率高达65.4 %,其中重度抑郁占9.6%,中度抑郁占26.7%,轻度抑郁占29.1%;女性比男性发病率高;康复期比治疗期发病率高;有手足、面部及生殖器烧伤的患者比无特殊部位烧伤的发病率高;伤前性格内向的人比性格外向的人发病率高。2.无论是从反应时还是正确率来看,烧伤后并发抑郁情绪对情绪图片刺激的注意选择存在负性偏向,主要表现为对负性情绪图片存在过度警觉,关注敏感,这种对负性刺激的注意选择性在认知过程的早期便出现;烧伤后不并发抑郁情绪组对负性情绪图片的注意选择偏向也具有显著差异。3.烧伤后并发抑郁情绪对负性刺激有明显的注意转移加工偏向,在对负性刺激的加工过程中注意不易转移,还会干扰对靶刺激的正确判断;烧伤后不并发抑郁情绪组无注意转移的负性偏向。4.烧伤后并发抑郁情绪对负性刺激过分关注,并在大脑内长期存留,当再次出现时,表现出对正性刺激的忽略,对负性刺激的提取增高,回忆增强;烧伤后不并发抑郁情绪组无明显的负性回忆倾向。5.烧伤后并发抑郁大鼠兴趣减弱、行动迟缓、惰性增强、好奇心降低、空间学习记忆能力降低,主动躲避危险的能力降低。6.烧伤并发抑郁情绪大鼠外周血液中CRF、ACTH、皮质醇含量均明显高于正常对照组,下丘脑CRF表达明显上调,表明下丘脑-垂体-肾上腺轴在烧伤并发抑郁的发病中有重要作用。7.烧伤后并发抑郁大鼠海马神经元树突表达减少,平均光密度和累积光密度降低,主要是在CA3区及齿状回有明显改变,而在CA1区无显著差异;星形胶质细胞主要是在CA3区和齿状回有明显减少;NMDA主要在齿状回有明显减少,在CA1和CA3区变化均无显著差异;电镜观察海马神经元和胶质细胞有轻度线粒体髓鞘样、肿胀、空泡化改变。三、结论1.烧伤后抑郁情绪障碍发生率高,存在明显的性别、病情阶段、严重程度、有无手、面部、生殖器烧伤的差异;同时还受到负性自动思维、应对方式、人际交往、伤前心理、社会支持等因素的显著影响。2.烧伤后抑郁情绪障碍对负性情绪图片具有明显的认知偏向性,负性自动思维明显,对负性刺激敏感,固着,不易遗忘是烧伤后产生抑郁情绪障碍的重要认知因素。3.烧伤后并发抑郁大鼠兴趣减弱、行为迟缓、惰性增强、好奇心降低、空间学习记忆能力降低,躲避危险的学习能力降低,出现明显的类临床抑郁病人症状。4.下丘脑-垂体-肾上腺轴在烧伤并发抑郁中具有重要作用,表现为烧伤并发抑郁大鼠血液中CRF、ACTH、皮质醇应激激素含量明显升高,下丘脑CRFmRNA高表达是烧伤后抑郁的中枢机制之一。5.海马可能在烧伤后并发抑郁情绪障碍发生中具有重要作用,海马神经元和胶质细胞的形态、结构改变及NMDA受体的改变是造成的大鼠学习记忆障碍的重要原因。更多还原

【Abstract】 Depression is one of the most frequent emotional disorder. Epidemiologic studies found that the morbidity rised up year by year, especially after major life events occurred. Depression is associated with low spirit, lack of interests, hysteresis of psychomotor and hopeless which leads to suicide or susceptibility of other desease. Burn patients are extremely likely to develop mental disorders, particularly depression, due to long periods of therapy, sleep disorder, pain, disfigurement of face, functional disability, interpersonal disorders, and social adaptation deficiency, Although the cure rate of severe burn patients has been increasing, the pattern of psychological therapy and counseling for burn patients is still under investigation.Studies on depression after burns are mainly focused on the epidemic status, developmental characteristics and influential factors. However, the interaction of influential factors is seldom studied.Cognition is a composite function of attention, thought, analyses, study, memory and information transfer. When multiple and complicated information stimulate the cognitive system, they can not be accepted in the same time. Therefore, the selection of information, transference of attention and remember of cognitive process are very important. Theories about cognitive disorder associated with depression propose that automatic thoughts and preferential processing of negative material play an important role in the onset, maintenance, and recurrence of depressive episodes. There is no report on cognitive processing disorder associated with depression after burns.Hippocampus is one of the most important encephalic regions for cognition and memory. Hippocampus contains many glucocorticoid receptors which are susceptive to cortisol. In normal condition, hippocampus participates in the feedback regulation of hypothalamic-pituitary-adrenal by inhibiting the release of corticotrophin -releasing factor and then decreasing the adrenocorticotropic hormone and cortisol release when the density of cortisol is too high, While under chronic or long-term stress, the disorder of feedback regulation leads to hippocampus neurone atrophy which aggravates the cognitive disorder.We presume that hippocampus and HPA play a role physiologically in cognitive processing disorder associated with depression after burns. There is still no such report.This study contains three parts. First, through studying the morbidity status, character and influential factors to analyze the potential physiological, psychological, social dangerous factors. Second, through studying the attention spatial distribution, attention shift and recognition to emotional pictures, we analyze the cognitive biases of depression after burns.And through glucide fluid intake, open-field, water maze,suttle box experiments to observe the cognitive and behavior changes of depression rats after burn model. At last, through studying the exchange of CRF, ACTH and Cortisol in blood , the hippocampus structure damage,express of CRFmRNA in hypothalamus of the depression after burn rats to analyze the neuromechanism of depression after burns.The results of this study are as follows:1. The morbidity of depression after burns is 65.4%, among which 9.6% is serious, 26.7% is midrange, 29.1% is light. The morbidity of female is higher than male, and that in rehabilitation period is higher than in therapeutic period, and that in the patients with special area burns such as hands and face is higher than in the patients without special area burn, et al.2. No matter from the reaction time and the accurate rates, the patients of depression after burns has cognitive bias in the spatial distribution of attention.They have over alert tendency to the negative pictures,even in the early cognitive stage. This bias has also been found in the burn patients without depression.3. Negative cognitive processing bias is also found in the attention shift stage.It shows that depression patients after burns are not easily to shift their attention from the negative pictures and the accurate rate to the target is lower. There is no such bias in the burn patients without depression and the control groups.4. The negative cognitive processing bias of recognition stage is found in burn patients with depression.They neglect more positive pictures intentionally and recognize more negative pictures correctly. There is no such bias in the burn patients without depression and the control groups.5. The behaviour of the depression after burn rats significantly changed, such as lack of interesting, slow in the action, spatial study and memory ability decrease.6. The espress of CRFmRNA in hypothalamus of the depression after burns are significantly higher than the other groups.7. The level of CRF, ACTH and Cortisol in the depression after burn rats’blood are higher than the rats without depression.8. The structure and function of neurons and glia in the hippocampus of depression after burn rats changes, especially in CA3 and dentate gyrus.While the express of NMDA decrease in dentate gyrus significantly.Conclution:1. The morbidity of depression after burns is very high. There exist significant differences in sexuality, stage of disease and special parts of burn.It is also influenced significantly by the automatic thoughts, coping style, communication ability,psycho status before burn,social support,et al.2. The patients of depression after burns have significantly cognitive bias to negative pictures.This negative bias of cognitive may be the important factor of depression after burns.3. We establish depression after burn model with 30%TBSA second degree burn combine chronic mild stress successfully.The depression after burn rats show similar cognitive and behaviour change of the depression after burn patients.4.Hippocampus plays very important role in depression after burns. It can interfere the cognition and behavior ability directly through neuron and glia plastic and also can change that through regulating HPA.更多还原