【作者】 赵艺蕾；

【导师】 张敏鸣；

【作者基本信息】 浙江大学 ， 影像医学与核医学， 2009， 博士

【摘要】 研究背景及目的:帕金森病(PD)患者存在着不同程度的感觉加工障碍以及感觉-运动整合的缺陷,这些缺陷体现在PD的早、中和晚期,有人认为其发生机制与认知和行为在较高层次上的连接不协调有关。大量的研究表明,运动的精确性依赖于本体感受器的有效传输与编码,而PD患者的运动障碍被归结为从基底节到运动皮层的功能不全、外周感受输入的异常或它们在中枢神经系统的异常处理干扰了运动程序的输出,其病理生理学基础则被认为是皮层-纹状体环路在某种程度上的中断或额叶多巴胺的缺乏。感觉-运动整合即正确地利用感觉信息来协调运动执行的过程。PD作为最常见的运动障碍疾病,一个重要症状即是在很大程度上依赖外部的感觉信息来辅助他们的运动启动和运动执行过程。例如,当PD运动迟缓者在执行一系列的运动任务时,需不断地依靠外部的视觉、听觉或其它线索,试图改善和提高其运动效率。因此,在PD患者的症状中,感觉-运动整合障碍可能扮演着重要角色。除此之外,一些研究者认为感觉.运动整合的发生是在皮层-皮层下-皮层环路中进行的,包括基底节、运动前区和辅助运动区。躯体感觉诱发电位(SEPs)试验显示出早期PD患者的额叶对感觉刺激的反应性显著降低。迄今为止,正电子发射断层扫描(PET)和功能磁共振成像(fMRI)已经广泛应用于PD的研究。上述研究通过完成相关的任务或观察静息状态下的大脑的激活状况,来探索PD的病理生理学和脑功能的变化。这些研究发现,在执行运动任务时,相对于正常人,PD患者的辅助运动区(SMA)通常激活减弱,而顶叶皮层存在着过度激活现象。此外,大量的证据也显示出PD患者的认知和行为能力的缺陷。据文献报道,他们的认知和行为受损可能与多个系统的功能降低有关。研究脑的运动功能的一个首要问题是人脑如何进行运动计划和感觉反馈。之前的研究已显示出不同的感觉体系处理运动计划是分开进行的,例如:触觉、视觉和听觉。为了恰当地准备和精确地完成一个动作,上述多个感觉体系必须在某种程度上进行信息整合,用以指导和完成运动。对于PD患者而言,在此感觉-运动整合过程中可能存在缺陷,解剖学定位也许在前额叶。感觉-运动整合究竟涉及那些脑区?在这些脑区中正常人和PD患者是否有不同的激活模式?目前国内外均无此相关研究。因此,我们采用了一个多任务设计的脑功能磁共振成像技术来探究以上问题。材料和方法:21名早期PD患者,右利手,其中女11名,男10名,年龄范围43～81岁(平均年龄60.43±9.65岁);实验前均停止服用治疗帕金森病相关药物15小时以上。实验前,进行统一帕金森病等级评定量表,Hoehn and Yahr残疾量表和简易精神量表测试。健康对照组为22名神经学检查正常的右利手者,其中女11名,男11名,年龄范围42～75岁(平均年龄59.23±11.12岁)。任务编码采用组块设计,包括被动触觉刺激、简单右手运动任务和感觉.运动整合任务。图像采集包括高分辨三维容积解剖T1加权像和血氧水平依赖(BOLD)平面回波T2加权像。fMRI数据分析采用SPM2软件,进行第一和第二水平的数据分析。在第一水平数据分析中,采用一般线性模型(general linear model,GLM)得到每个被试各条件下的平均参数激活图,然后将得到的对比数据用来进行第二水平的随机效应分析(random effects analyses)。在组内分析中,采用单样本t-检验来判定每个任务的激活脑区(P<0.001,非校正),每个簇聚块取≥20个体素。在组间分析中,采用两样本t-检验来判定两组被试在每个条件下的不同激活区(P<0.01,非校正)。不同条件下的脑激活区分别叠加在MNI(蒙特利尔神经病学研究所)模板上,并通过Talairach空间转换得到精确坐标定位。结果:执行单纯感觉任务时,正常对照组比早期PD组激活增强的脑区有:两侧初级躯体感觉区,两侧顶后区,左侧辅助运动区,左侧扣带回中部及右侧纹状体外视觉皮层(BA19)。而早期PD组比正常对照组激活增强的脑区有:两侧前额叶及右侧壳核。执行单纯运动任务时,正常对照组比早期PD组激活增强的脑区有:左侧扣带回前部,右侧尾状核及右侧纹状体外视觉皮层(BA18,20)。而早期PD组比正常对照组激活增强的脑区有:右侧前额叶及右侧丘脑。在正常对照组执行感觉-运动整合任务时,有一个广泛的皮层及皮层下神经网络参与,包括:躯体感觉皮层,顶下小叶,额中回,运动前区,纹状体外视觉皮层和两侧小脑半球。而PD患者相应的功能网络主要包括前额叶,运动前区和纹状体外视觉皮层。较之正常对照组,PD患者组在执行感觉到运动整合任务时,纹状体外视觉皮层有显著的激活降低,而两侧前额叶却显示出额外激活。结论:PD患者和正常人参与感觉、运动和感觉-运动整合的神经网络是不同的。纹状体外视觉皮层可能不仅仅处理视觉信息,还是一些多重感觉处理区域,并在感觉、运动和感觉-运动整合过程中担任重要角色。在早期PD患者,由于黑质纹状体和皮层下的多巴胺缺失,可能会导致纹状体外视觉皮层的激活减弱,为了完成感觉和运动的信息整合,需借助两侧前额叶的高级整合中枢来代偿其不足。迄今为止,纹状体外视觉皮层参与感觉-运动整合的现象及PD患者此区域的激活异常还未曾被报道过,我们的研究第一次揭示出以上发现。更多还原

【Abstract】 Introduction:It is long known that sensory and sensory-motor integrations are deficient in patients with Parkinson’s diseases(PD).These deficits are found in early,as well as in moderate and advanced patients,and appear to pertain to a high level linkage between perception and action.A body of studies have identified the accuracy of movements depends to a large extent on the availability of proprioceptive information.Current knowledge attributes movement disorders of Parkinson’s disease to a dysfunction of the basal ganglia-motor cortex circuits,abnormalities in the peripheral afferent inputs or in their central processing may interfere with motor program execution,and its pathophysiological mechanisms have been proposed:disruptions in cortico-striatal circuits or a deficiency in frontal dopamine.Sensorimotor integration,that is,the processing to use sensory information properly for assisting motor program execution. Patients with the most common movement disorders --- Parkinson’s disease --- rely strongly on external sensory information for their motor ability(movement initiation and execution).For example,motor execution of PD patients depends largely on a deficiency in the internal cueing mechanisms used to release successive stages of a movement sequence providing external,visual or auditory,cues,appreciably improves specific features of parkinsonian bradykinesia.Hence,defective sensorimotor integration may have an important role in PD patients’ symptoms.Moreover,some researchers have mentioned a cortico-subcortico-cortical loop about sensorimotor integration that includes the basal ganglia as well as the premotor and supplementary motor areas,and it has been demonstrated that PD patients- especially in the early stages of the disease--- show a severely depressed frontal responsiveness to sensory stimuli as tested via SEPs(sensory evoked potential).By now,some positron emission tomography(PET) and functional magnetic resonance imaging(fMRI) has been extensively used on PD research.These investigations have focused on task-related or resting state brain activity,and found some pathophysilogical and functional changes in PD.For example,the supplementary motor area(SMA) is commonly found hypoactivated,and some other cortical motor regions,like the cerebellum,premotor area(PMA),and parietal cortex are hyperactivated in patients with PD compared to normal controls during performing motor tasks.Also,there is ample evidence that direct and indirect to explain the cognitive and behavioral deficits of PD.As is frequently reported in the literature,patients with PD cognitive and behavioral impairments may be attributed to dysfunction of multiple systems associated with the disease process in Parkinson’s disease that are not necessarily related to motor symptoms.A fundamental question in motor research relates to how motor planning operations and sensory feed-back are implemented in the human brain.Prior studies have shown that there were several sensory systems separate processing of motor planning,for example:haptics, vision,and auditory.In order to prepare and accomplish an action punctually,the information from these systems must somehow be integrated.For PD patients,some deficiency could happen in the sensory-movement integrating process,and the anatomical foci maybe located in prefrontal lobe.Thus,to investigate which regions involved in integration of sensory and movement, whether activity model in these regions are difference between PD and normal controls, we employed a multitask functional magnetic resonance imaging(fMRI) to represent these.Methods and subjects:Twenty-one right-handed patients with at Hoehn and Yahr stage 1 and 2 of Parkinson’s disease(11 female,10 male;age range,43-81 years,mean age 60.43±9.65). Patients were studied only after their medication had been withdrown for at least 15h. They were assessed with the UPDRS(Unified Parkinson’s Disease Rating Scale),the Hoehn and Yahr disability scale and MMSE(Mini-Mental Stated Examination) while off their medications.Twenty-two neurologically normal subjects(11 female,11 male;age range,42-75 years,mean age 59.23±11.12) participated in this study as control,were right-handed and gender matched with patients.The experimental design was block design,which included passive tactile stimulations,right-hand motor tasks,and sensory-movement integrating tasks.Imaging collecting included a high-resolution T1-weighted three-dimensional volume acquisition for anatomical localization and an acquisitions of echoplanar T2*-weighted images with blood oxygenation level-dependent(BOLD) contrast.fMRI data analysis was performed with SPM2 software.Both first- and second-level analyses were performed.In the first-level,data were modelled using a general linear model design.These contrast data were used in the second level for random effects analysis.For the within group analysis,a one-sample t-test model was used to identify the brain activity for each tasks(P <0.001,without correction for multiple comparisons),and spatial extent threshold was cluster size greater than 20 voxels.For intergroup comparisions,a two-sample t-test model(P <0.01,uncorrected) was used to explore the difference between patients and normal controls under each tasks.Locations of activated areas for different conditions were displayed by superimposing them on the Montreal Neurological Institute(MM) template.All coordinates reported were in Talairach space converted from MNI space. Results:As predicted,the results revealed decreased activated in the PD group compared with age-matched controls in somatosensory cortical areas bilaterally,left premotor cortex,thalamus,and the right cerebellum when they performing above three tasks(P < 0.01).Surprisingly and interestingly,significant decreases in activation were observed in the extrastriate visual cortex in the PD group during performing these three tasks, especially during movement task(P < 0.01).In contrast,increasing activities were observed in bilateral frontal lobe in the PD group compared with the aged-matched control group(P < 0.01).Conclusions:There are different neural networks engaged in sensory,movement and sensory-movement integration between PD group and normal controls.The extrastriate visual cortex maybe are multisensory processing regions and play an important role in sensory,movement and sensorimotor integration,nevertheless,in early stage PD, nigrostriatal dopamine depletion and intracortical dopamine deficiency may leads to the decreased activation in extrastriate visual cortex,and to fulfill these integrate processing, the compensation in bilateral prefrontal lobe will be happen.By now,whether the activation in the extrastriate visual cortex in sensorimotor integration is changed in patients with PD has never been reported.Our study is the first time to demonstrate above findings.更多还原