精神分裂症幻听患者脑连接研究

发布时间：2018-04-19 10:36

  本文选题：精神分裂症 + 幻听　； 参考：《第四军医大学》2017年博士论文

【摘要】：精神分裂症(SZ)是一种严重的精神疾病,临床上往往表现为症状各异的综合征,涉及感知觉、思维、情感和行为等多方面的障碍以及精神活动与环境的不协调,人群终生发病率约为1%,其患者约占我国住院精神病患者的50%,慢性精神病患者的60%左右。幻听(AVHs)是精神分裂症主要症状之一,也是诊断精神分裂症的重要临床指标,是指在没有相应的外部声音刺激作用于听觉器官的情况下而产生听觉,幻听是听觉对大脑的不服从,精神分裂症患者有幻听症状的占60%-80%。幻听的内容常常威胁病人、命令病人,或谈论病人的思想,评论病人的行为,给病人带来极大的痛苦。特别是在命令性幻听支配下会导致患者爆发出强大的攻击性和破坏性行为,其自伤或伤人暴力行为会危及病人及其家属,甚至危害社会。精神分裂症幻听仍然是病因未明的重性精神病。揭示幻听的神经机制,不但有显著的临床意义,也对研究精神分裂症的病理生理机制有重要意义。近年来,各种神经影像技术开始用于精神分裂症幻听相关的研究并取得了很多突破性的成果,为精神分裂症幻听诊断以及治疗提供了重要的依据,同时也为揭示AVHs产生的机理提供了重要的支撑。通过一系列的研究,幻听产生的神经机制也取得了重要的进展。研究发现,幻听与语音生成和感知相关的脑区结构和功能改变高度相关。相关研究结果已经证明听觉幻觉的形成主要与左中颞回、左颞-顶叶区域和左下额叶有关。最近的研究也进一步表明,AVHs患者在额叶和颞叶皮质区的皮质厚度变薄。基于体素的形态学研究报告,听觉幻觉的严重性与包括初级和次级听觉皮质的颞叶相关。f MRI研究发现,幻听现象与左下额叶皮层和左中颞叶皮层的过度激活有关,meta分析也显示,AVHs与左下额叶和左下顶叶高度相关。然而,精神分裂症是一种具有未知病因和病理生理学的疾病,幻听的发病原因远比局部的脑区异常更为复杂。大量的神经影像学研究认为,认知功能异常不能简单地归因于单一脑区或某几个脑区的结构病变与功能紊乱,认知功能障碍往往是由脑区之间的连接异常引起的。因此,仅限于研究精神分裂症幻听患者表现出的特定脑区异常已经不足以理解幻听的发病机理。研究表明,幻听的产生与大脑语言网络的连接异常高度相关。扩散张量成像(DTI)研究已经发现,连接额叶和颞顶叶语言区域的纤维完整性降低,这项研究也进一步表明,精神分裂症患者听觉幻觉的产生是由大脑皮层语言网络的异常连接引起的。f MRI研究也显示,幻听的出现是大脑额叶和颞叶语言区之间的功能连接异常的结果。额叶和颞叶语言区域之间的功能连接异常在精神分裂症幻听患者句子完成任务、外部语音处理任务和说话声音任务等试验中都被发现。静息态f MRI研究进一步揭示了语言网络的连接异常可能是精神分裂症患者出现持续性幻听的病理基础。基于对大量幻听病例研究的综述也证实,幻听相关病变的脑区基本上都位于大脑语言网络通路上。虽然以前的研究表明幻听的出现与大脑语言网络连通性的改变有关,但是都没有系统研究精神分裂症患者大脑语言区结构连接和功能连接的改变如何导致幻听的产生,这些异常是否有其内在的关系,跟没有进一步研究这些脑区之间的有效连接。大脑有三种连接形式,第一种是结构连接,指不同的脑区在解剖上的连接关系,是功能连接和有效连接的物质基础;第二种是功能连接,反映脑区在动态生理活动中的相互关系,阐明脑区间是否存在功能关系以及其的强弱;第三种是有效连接,描述的是某一脑区是如何对另一脑区进行作用的,阐述脑区之间信息传递的因果模式。我们认为,只有系统研究大脑语言网络的连通性才能真正揭示幻听发生的神经病理机理,对于精神分裂症幻听患者的诊治也有非常重要的意义。本文以核磁共振数据为基础,通过脑连接分析方法,研究幻听的产生与大脑连接异常的关系。在实验一中,我们利用DTI技术研究对比了频繁经历幻听的精神分裂症患者、未曾经历过幻听的患者和健康对照三组被试白质纤维的完整性。结果发现精神分裂症非幻听患者大脑颞叶区域白质FA值异常。而在精神分裂症幻听患者中,颞叶、颞极、额叶、扣带、小脑的脑白质FA值都有降低,异常最大的脑区主要分布在额叶和颞叶的语言区域中。这些脑区最主要的连接是弓状纤维束,也称为弓形束。弓形束的破坏导致从额叶的布罗卡区到颞叶的韦尼克区神经元连接的异常,这些异常会对语言流产生干扰。临床观测发现,幻听的内容通常与患者自己的思想内容密切相关,这也说明了正是患者大脑神经连接的异常,导致语言流不受控制地产生了混乱,引起了幻听的产生。FA值的降低反映了该脑区纤维松散或交叉,纤维的完整性降低。我们的研究结果发现的颞叶和额叶语言区FA值的减少,反映了这些区域纤维束完整性的降低,而纤维束的异常导致语言区域连通性的改变,导致患者大脑语言区域功能障碍从而产生了幻听症状。我们也发现,幻听患者扣带回中的FA值异常。扣带回被视为“情感和认知之间的界面”,并且在精神分裂症、强迫性障碍和重性抑郁症等多种精神疾病如中均发现有损伤,我们的研究结果也与以前的研究相一致。在此项实验中,我们以语言区的LIFG,LMTG和LIPL作为种子点进行了纤维追踪分析,结果显示精神分裂症幻听患者语言区的纤维连接存在很多无序的连接和交叉,也反映了患者大脑语言区纤维完整性减低。在实验一中我们发现在AVHs患者大脑白质纤维结构最大的改变正是位于语言网络中额叶和颞叶之间的重要连接。这些改变很有可能正是幻听产生的根源,并且有助于理解大脑内部生成的信号如何被误认为是从外部生成的语音。我们认为,异常结构连接致使患者不能区分自己大脑内部产生的信号和外部刺激。为了证实这个结论,我们在试验二中对同一批被试在同一时间采集到的功能数据进一步探索幻听患者功能连接的异常。在实验二中,对同一批被试,我们使用独立成分分析的方法,研究了幻听及非幻听精神分裂症患者语言网络的功能连接异常。统计分析显示,与正常对照组相比,两组病人均在语言网络的左侧区域表现出功能连接的降低。同时,幻听患者相对于非幻听组及正常对照组,则在语言网络右侧多个脑区表现出功能连接的增强。本实验发现两组病人均在左侧颞中回、颞上回、额下回功能连接降低,该结果提示,语言网络左侧功能连接的降低可能是精神分裂症患者一个共同的病理改变。该结果与以往关于精神分裂症的研究一致。同时,我们还发现,与非幻听病人及正常对照组相比,幻听病人均表现出功能连接的减弱,相关的脑区包括左侧额下回以及左侧颞中回区域。该结果提示,这些脑区功能连接的异常可能与幻听症状的出现相关。我们在实验一中,已经发现精神分裂症幻听患者在这些脑区的结构连接减弱,本实验的结果与实验一的结果相互印证,这说明幻听的产生正是由于大脑语言区域功能和结构连接产生了异常。在实验三中,我们利用随机动态因果模型(DCM)研究精神分裂症幻听患者与非幻听患者大脑语言网络中的有效连接。在此项静息态f MRI研究中,被试与前面两个实验完全相同。语言处理中三个重要区域LIFG,LMTG和LIPL作为感兴趣区(ROI),提取出这三个ROI的时间序列。对于每个被试,首先构建全连接的DCM模型,然后使用网络发现方案识别最优(获胜)模型。通过单因素ANOVA分析三组之间的统计学差异。结果表明,与非AVHs的患者相比,AVHs患者从LIFG到LMTG的有效连接显着降低。同时,与健康对照相比,AVHs患者从LIPL到LMTG的有效连接显着降低。我们的研究结果发现AVHs患者语言网络中因果交互的模式异常,表明从额叶到颞叶语言区域的连通性降低或中断可能是AVHs病理基础的关键,这些结果也为精神分裂症的“连接异常假说”提供了支撑。我们还发现,与精神分裂症非幻听患者相比,幻听患者从LIFG到LMTG的有效连接显著降低。虽然持续幻听是判定精神分裂症的一个关键症状,但并不是所有的精神分裂症患者都有幻听症状。我们的研究结果也从一个侧面证实,不同的神经损伤导致精神分裂症表现出不同的症状和亚型。在试验一中,我们发现幻听患者额叶与颞叶之间的纤维完整性明显降低,在实验二中,我们发现幻听患者这些脑区。这些结果也为精神分裂症的“连接异常假说”提供了支撑。在三个实验中,我们均发现幻听患者大脑语言区域连接存在异常,表明从语言区域的连通性降低或中断可能是AVHs病理基础的关键。
[Abstract]:Schizophrenia (SZ) is a serious mental illness. Clinical symptoms are often characterized by different symptoms, involving perception, thinking, emotion and behavior, as well as incoordination between mental activity and the environment. The lifetime incidence of the population is about 1%, and the patient accounts for about 50% of the patients in the hospital and the chronic psychosis. About 60%. Auditory hallucination (AVHs) is one of the main symptoms of schizophrenia and an important clinical indicator for the diagnosis of schizophrenia. It means that hearing is produced without the corresponding external sound stimulation in the hearing organ, auditory hallucination is disobedient to the brain, and the schizophrenic patients have auditory hallucinations in 60%-80%. auditory hallucinations. The content often threatens the patient, orders the patient, or talks about the patient's thoughts, reviews the behavior of the patient, and brings great pain to the patient. Especially under the command of auditory hallucination, it will cause the patient to break out powerful aggressive and destructive behavior, and its self injury or the violent behavior will jeopardize the patient and his family, or even harm the society. The auditory hallucination of cleft disease is still a serious psychosis of the unknown etiology. It is of significant significance not only to reveal the nervous mechanism of auditory hallucination, but also to the study of the pathophysiological mechanism of schizophrenia. In recent years, various neuroimaging techniques have been used to study the auditory hallucination of schizophrenia and have made many breakthroughs. It provides an important basis for the diagnosis and treatment of schizophrenia. It also provides important support to reveal the mechanism of AVHs production. Through a series of studies, the neural mechanism of auditory hallucination has also made important progress. The results of the study have shown that the formation of auditory hallucinations is mainly related to the left mesotemporal gyrus, the left temporal parietal region and the left inferior frontal lobe. Recent studies have further demonstrated that the cortical thickness of the frontal and temporal cortex is thinner in AVHs patients. The morphological study based on voxel, the severity of auditory hallucinations and the primary and secondary auditory hallucinations. The temporal lobe related.F MRI study found that auditory hallucinations were associated with excessive activation in the lower left frontal cortex and the left mesial temporal cortex. Meta analysis also showed that AVHs was associated with the lower left frontal lobe and the lower left parietal lobe. However, schizophrenia is a disease with unknown etiology and pathophysiology, and the cause of auditory hallucination is far more than the local brain. A large number of neuroimaging studies suggest that cognitive dysfunction can not be simply attributed to structural disorders and dysfunction in a single brain region or a few brain regions. Cognitive dysfunction is often caused by abnormal connections between the brain regions. Regional abnormalities are not enough to understand the pathogenesis of auditory hallucinations. Studies have shown that auditory hallucinations are associated with abnormal height in the brain's language network. Diffusion tensor imaging (DTI) studies have found that fibrous integrity in the frontal and temporal parietal language areas is reduced, and this study further suggests that the auditory hallucinations of schizophrenia patients are further demonstrated. .f MRI studies, caused by abnormal connections of the cerebral cortex language network, also show that the appearance of auditory hallucinations is the result of abnormal functional connections between the frontal and temporal lobe language areas. The functional connections between the frontal and temporal lobe language regions are abnormal in the sentences of the schizophrenic auditory patients and the external speech processing tasks and the tasks. The resting state f MRI study further revealed that the connection abnormalities of the language network may be the pathological basis for the occurrence of persistent auditory hallucinations in the schizophrenic patients. A review based on a large number of auditory hallucinations also confirms that the brain areas of auditory hallucinations are basically located on the brain's language network pathway. Although previous studies have shown that the appearance of auditory hallucination is related to changes in the connectivity of the brain's language network, there is no systematic study of how the changes in the structural connections and functional connections in the brain of the schizophrenic patients lead to the emergence of auditory hallucinations. The brain has three kinds of connection forms. The first is the structural connection, which refers to the anatomical connection of different brain regions, the material basis for functional connection and effective connection; the second is functional connection, reflects the relationship between the brain regions in the dynamic physiological activities, and explains the existence of functional relations and its strength in the brain region; The three is an effective connection, which describes how a certain brain area acts on another brain region and describes the causal mode of information transfer between the brain regions. We think that only systematic study of the connectivity of the brain's language network can truly reveal the neuropathic mechanism of the hallucination, and the diagnosis and treatment of schizophrenia patients with schizophrenia. On the basis of nuclear magnetic resonance data, this paper studies the relationship between the emergence of auditory hallucination and the abnormal brain connection through the method of brain connective analysis. In experiment one, we used DTI technique to compare the three groups of patients who had experienced auditory hallucinations, those who had never experienced auditory hallucinations and healthy control groups of white matter fibers. The results showed that the FA value of white matter in the temporal lobe region of the non auditory schizophrenic patients was abnormal. In the schizophrenic patients, the temporal lobe, the temporal pole, the frontal lobe, the cingulate band and the cerebellar white matter FA were reduced, the most abnormal brain areas were mainly distributed in the language areas of the frontal and temporal lobes. The most important connection in these brain areas was the bow. Fibrous bundles, also known as arcuate bundles. The destruction of the arcuate bundle leads to abnormal connections between the Broca and the temporal lobe neurons of the frontal lobe, which interfere with the language flow. Clinical observations have found that the content of the auditory hallucination is closely related to the content of the patient's own thought, which also indicates that it is the nerve connection of the patient's brain. The abnormality of the language leads to the confusion of the language flow without the control of the real estate. The decrease of the.FA value of the auditory hallucination reflects the loosening or intersecting of the fibers in the brain and the decrease in the integrity of the fibers. Our results show a decrease in the FA value of the temporal and frontal lobes, reflecting the decrease in the integrity of the fiber bundles in these regions and the abnormality of the fiber bundles. We also found that the FA value in the cingulate gyrus was abnormal. The cingulate gyrus was regarded as "the interface between emotion and cognition", and a variety of mental disorders such as schizophrenia, compulsive disorder, and heavy depressive disorder, such as schizophrenia, were also found. The results of our study were consistent with previous studies. In this experiment, we used LIFG, LMTG, and LIPL as seed points for fiber tracing analysis. The results showed that there were many disordered connections and intersections in the language area of schizophrenic auditory hallucinations, and the patient's brain was also reflected. In experiment one, we found that the largest changes in the white matter fiber structure in the brain of AVHs patients are the important connections between the frontal and temporal lobes in the language network. These changes are likely to be the root of the auditory hallucination, and help to understand how the signals generated within the brain are mistaken for the error. External generated speech. We think that abnormal structural connections cause patients to be unable to distinguish between signals and external stimuli within their own brain. In order to confirm this conclusion, we further explore the functional data of the same batch of subjects at the same time in test 2 to further explore the abnormal functional connection of the auditory hallucinations. In Experiment 2, In the same group, we used an independent component analysis to study the dysfunction of the functional connectivity of the language network of the patients with auditory hallucination and non auditory schizophrenia. Statistical analysis showed that compared with the normal control group, the two groups showed lower functional connectivity in the left area of the language network. At the same time, the auditory hallucinations were compared to non auditory groups. The results showed that the lower left functional connection of the language network may be a common pathological change in the schizophrenic patients. The results suggest that the decrease of the left functional connection in the language network may be a common pathological change in the patients with schizophrenia. The results suggest that the two groups of patients are likely to be a common pathological change in schizophrenia. The previous study of schizophrenia was consistent. At the same time, we also found that, compared with the non auditory hallucination patients and the normal control group, the auditory hallucination patients showed a weakening of the functional connection, and the related brain areas included the left inferior frontal gyrus and the left temporal gyrus. In our experiment, we have found that the structural connections of schizophrenic auditory hallucinations have weakened in these brain regions. The results of this experiment confirm with the results of experiment one. This shows that the auditory hallucination is due to the abnormal function of the brain region and the structural connection. In Experiment 3, we use random dynamic causality modules. DCM study the effective connection in the brain language network of schizophrenic auditory hallucinations and non auditory patients. In this resting state f MRI study, the subjects were exactly the same as the previous two experiments. Three important regions of language processing, LIFG, LMTG and LIPL as the region of interest (ROI), extracted the time series of the three ROI, for each of the subjects, First, a fully connected DCM model was constructed and the network discovery scheme was used to identify the optimal (winning) model. The statistical difference between the three groups was analyzed by a single factor ANOVA. The results showed that the effective connection between the AVHs patients from LIFG to LMTG was significantly lower than that of the non AVHs patients. At the same time, compared with the health control, the AVHs patients were from LIPL to LMTG. Our results show that the pattern abnormality in the causal interaction in the AVHs language network indicates that the reduction or interruption of connectivity from the frontal lobe to the temporal lobe may be the key to the pathological basis of AVHs, and these results also provide support for the "connection anomaly hypothesis" of schizophrenia. The effective connection of auditory hallucinations from LIFG to LMTG decreased significantly compared to non auditory hallucinations. Although persistent auditory hallucinations were a key symptom of schizophrenia, not all schizophrenic patients had hallucinations. Our findings also proved from a side side that different nerve injuries lead to schizophrenia. In trial one, we found that the fibrous integrity between the frontal and temporal lobes of the auditory hallucination patients decreased significantly. In the second experiment, we found the auditory hallucination of these brain regions. These results also supported the "connection abnormality hypothesis" of schizophrenia. In the three experiments, we all found auditory hallucination. Abnormal connectivity of brain brain regions indicates that the decrease or interruption of connectivity from the language area may be the key to the pathological basis of AVHs.

【学位授予单位】：第四军医大学
【学位级别】：博士
【学位授予年份】：2017
【分类号】：R749.3
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本文编号：1772743