【作者】 尹训涛；

【导师】 刘树伟； Alan C.Evans；

【作者基本信息】 山东大学 ， 人体解剖与组织胚胎学， 2012， 博士

【摘要】 注意是指对客观环境或主观意识的某一方面进行准备与选择的过程,是认知科学的中心主题。因为人脑只能同时处理有限的信息量,因而在日常生活中必须适当的对信息进行选择处理。随着神经心理学和神经影像学等研究技术的不断进步,注意的研究可以导致教育和认知训练等方面的革新。此外,许多神经精神疾病,如注意缺陷多动障碍、精神分裂症等,往往伴随注意能力的缺陷,因此,对注意的神经基础的研究也有助于揭示相关疾病的发病机制。注意包含不同的维度和特征。以往大量疾病和功能成像研究表明注意网络可分为警觉、定向和执行控制三个子网络,各有特定的解剖区域和生化机制。警觉是指维持一个灵敏状态以接受信息的传入,定向是指从传入的感觉中选择信息,执行控制是指解决反应中的冲突。然而,由于注意理论上的不一致以及脑成像模态的多样化,使得目前对注意功能的脑结构和功能基础仍然存在许多争论,这极大地阻碍了认知科学的发展。本研究借助于功能磁共振成像、弥散张量成像和结构磁共振成像等多模态脑成像方法,系统全面的研究注意功能的神经基础。研究结果表明注意的子网络与任务状态下的脑功能连接、白质各向异性和皮质厚度等指标均存在显著联系。本研究因而有助于我们从多种角度深入认识注意的神经机制。第一部分：任务状态下的脑功能连接影响注意的执行控制目的：执行控制功能是注意功能的一部分,是涉及行为调节、语言、记忆和情绪等高级的认知过程。本研究探讨执行控制过程中正常人大脑前扣带回与其它脑区之间的功能连接状况,及功能连接与注意网络测试行为学表现之间的关系。材料与方法：20例17～20岁的健康男性志愿者进行3.0T功能磁共振扫描,采用注意网络测试作为实验范式,注意网络测试能在单一的任务实验中提供警觉、定向和执行控制三种注意子网络功能的行为学数据。利用SPM进行数据预处理,分析执行控制网络激活的脑区,并计算前扣带回与背外侧额前皮质之间的功能连接,然后与注意网络测试的行为学得分做相关分析。结果：受试者的平均反应准确率达到95.4%,表明注意网络测试易于理解且数据可信。他们的执行控制和平均反应时间之间存在显著相关(r=0.58；P<0.01),警觉、定向和执行控制三个网络得分无相关性。执行控制网络激活的区域主要包括：前扣带回、额中回、额上回、丘脑等。在执行控制过程中,背侧前扣带回与两侧的背外侧额前皮质之间存在显著的功能连接,但只有左侧的背侧前扣带回与左侧的背外侧额前皮质之间的功能连接系数与执行控制的行为学得分存在显著负相关(r=-0.627；P<0.01),控制年龄、平均反应时间和准确率作为协变量。全脑功能连接分析也发现其他注意相关的区域与背侧前扣带回存在显著的功能连接,特别是左侧,主要包括两侧的缘上回、辅助运动区、岛叶和皮层下核。结论：注意的警觉、定向和执行控制三个子网络的行为学得分互不相关,表明它们三个是独立的网络系统。背侧前扣带回与背外侧额前皮质之间存在功能连接,并对注意的执行控制功能存在有利的影响,这有助于我们理解注意功能中相关脑区的功能整合作用。第二部分：注意三个子网络与后顶叶灰、白质的关系目的：神经心理学和功能影像学研究发现人脑后顶叶是行使注意功能的关键脑区。一般来讲,后顶叶涉及三个明确的认知功能：空间感知、视觉运动转换和视空间注意。警觉、定向和执行控制包含了后顶叶的这些功能,并且将不同的注意组分整合为一个完整的系统。注意的解剖结构基础,尤其是后顶叶的功能目前仍存有争论,这一方面说明注意功能的复杂性,另一方面也说明后顶叶各个分区参与了不同的注意亚功能网络。本研究即借助弥散张量成像和结构磁共振成像方法,调查后顶叶各个亚区皮质与皮质下的白质特性与注意功能的关系。材料与方法：我们收集了36位(男性22名)健康青少年的的磁共振和弥散张量成像数据。受试者男女之间的年龄和受教育程度无显著差异。本次试验使用注意网络测试的效率得分来检测注意的警觉、定向和执行控制表现。利用蒙特利尔神经病研究所脑成像中心的流程软件提取和配准皮质表面图像,使用牛津大学的FSL处理弥散张量数据。之后利用白动解剖标签模板把每侧的后顶叶分割为五个部分：顶上小叶、顶下小叶、缘上回、角回和楔前叶。计算出每个分区的皮质厚度、表面积和白质参数,并与行为学数据做相关分析。我们还使用基于纤维束的空间统计方法进行体素为基础的白质相关分析。最后,我们对相关的白质区域做概率纤维追踪,以明确其纤维联系。结果：注意的行为学表现和后顶叶皮质以及皮下结构的联系表现在多个水平：首先,我们发现右侧顶下小叶的皮质厚度、白质完整性与定向表现有关。概率纤维追踪揭示连接双侧顶下小叶的白质的完整性介导了注意的定向功能；其次,执行控制得分与右侧缘上回的白质参数存在明显相关；最后,基于纤维束的空间统计发现警觉功能与连接右侧丘脑和辅助运动区的白质区域的各向异性存在显著关联。结论：本研究首次利用多模态成像揭示了后顶叶各个分区的灰、白质特征与注意的三个子网络存在关联。这使我们对后顶叶参与视空间注意的神经机制有了更完整的认识。第三部分：白质各向异性侧化及其与注意功能的关系目的：人脑半球间存在着结构和功能的不对称性。相对于结构磁共振成像,弥散张量成像技术可以获得更多纤维微结构信息,因而被广泛用于白质侧化性研究。然而以往图像分析方法存在着诸多局限性,并且白质侧化与认知功能的关系目前仍然知之甚少。因此本研究的主要目的是利用弥散张量成像分析人脑白质的侧化,并研究其与注意功能的关系。材料与方法：我们招募15-19岁健康青少年志愿者59例(男31例,女28例),利用注意网络测试评价其警觉、定向和执行控制能力,并获取他们的脑弥散张量图像。利用FSL软件对图像进行预处理,采用基于纤维束的空间统计方法来研究白质区域侧化,所有受试者经过对称处理后的白质骨架图做左右翻转并与原图像相减,得到骨架侧化差异图。使用FSL随机化程序进行非参数的单样本t检验来分析骨架的侧化性。最后统计检验侧化和注意功能(警觉、定向和执行控制)的关系。结果：许多白质区域存在着明显的侧化,包括左侧化(左>右)的前扣带束、皮质脊髓束和大脑脚,右侧化的内囊、上纵束和后辐射冠,以及同时存在左右侧化的胼胝体和前辐射冠。进一步的研究发现额下区前辐射冠的左侧化与执行控制能力显著负相关；群组概率纤维追踪证实相关的纤维束来自下额枕束。下额枕束连接腹侧注意系统的关键脑区——下额叶和颞枕叶,该区白质损伤与精神分裂症和脑创伤后的执行能力下降有密切关联。我们的研究同时发现警觉和定向功能与白质各向异性侧化没有显著关联。结论：我们首次采用基于纤维束的空间统计方法来研究白质侧化,并分析了其与注意各个组分的关系。研究揭示人脑半球白质存在大量的侧化现象,其中额下区前辐射冠的左侧化降低注意的执行控制能力。我们推测认为人脑白质左右对称性有利于高级认知活动的完成,尤其是该认知功能涉及两个大脑半球时。更多还原

【Abstract】 Attention is a central theme in cognitive science. It refers to both the preparedness for and selection of certain aspects of our physical environment or some ideas in our mind. Because of the limited capacity of the brain to handle information, the appropriate selection of information for processing becomes especially critical in our daily life. With more research tools in neuropsychological and neuroimaging studies becoming available, our understanding of attention is likely to yield innovations in education and cognitive training. Furthermore, the dysfunction of attention has been implicated in a number of neurological and psychiatric disorders, such as deficit/hyperactivity disorder and schizophrenia. Therefore, the studies for the neural basis of attention may bring new insights into the abnormal mechanisms of these diseases.Attention has various dimensions and characteristics. The previous lesion and functional neuroimaging studies have indicated that there were three key subsystems of attention, i.e. alerting, orienting, and executive control. These components of attention network have been shown to differ in their functional anatomy and neurochemical pathways. Briefly, alerting is defined as achieving and maintaining a state of high sensitivity; orienting refers to the selection of sensory information; and executive control is involved with the processing of cognitively incongruent stimuli or conflict. However, the brain functional and anatomical substrates of attention function are still highly debated, mainly due to the inconsistency among the attention models and the variations in the utilized imaging modalities. Therefore, it has become important to distinguish the roles of distinct brain cortical and subcortical regions on attention function. In this thesis, we utilized multi-modal imaging techniques, including task-related functional magnetic resonance imaging (fMRI), magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI), to investigate the neural substrates of attention. The findings revealed that the three components of attention were associated with the functional connectivity, cortical thickness and white matter (WM) integrity in distinct brain regions. In conclusion, current research would provide a better understanding for the neural substrates of attention.Part1:Effects of Functional Connectivity on Executive Control of AttentionObjective:Executive control of attention refers to the higher order cognitive processes involved in the self-regulation of behavior, cognition such as memory, language, emotion and motivation. The current study aims to explore the functional connectivity between anterior cingulate cortex (ACC) and other brain regions, such as the dorsolateral prefrontal cortex (DLPFC), during the manipulation of attentional network test (ANT) and its relationship with the behavioral performance.Materials and Methods:The fMRI was used in twenty healthy male subjects of17to20years, with ANT as the paradigm. ANT could isolate three different attention components: alerting, orienting and executive control. Data were preprocessed by SPM. Correlation analysis was conducted between ACC-DLPFC functional connectivity and behavioral scores of ANT.Results:On average, the accuracy of ANT performance was very high (95.4%), indicating that the participants understood the instruction and were able to response reliably. The correlation between executive control effect and overall mean RT was significant (r=0.58; P<0.01). We found no significant correlations between any two items of the three components of attention. Several regions were activated by executive control, i.e., ACC, middle frontal gyrus, superior frontal gyrus, and thalamus. Significant functional connectivity between the dorsal ACC (dACC) with bilateral DLPFC was found. Furthermore, event-related functional connectivity coefficients between left dACC and left DLPFC were negatively associated with the behavioral scores of executive control (r=-0.627; P<0.01), controlled for age, mean reaction time and correct rate. Whole-brain analysis also revealed other attention-related regions, including bilateral supramarginal gurus, supplementary motor area, insula and subcortical nuclei that show functional connectivity with seed regions (especially the left dACC). Conclusion:The behavioral results prove that the alerting, orienting and executive control is independent to each other. Our findings provide new evidence that ACC and DLPFC are functionally connected and such functional connectivity would exhibit an advantageous influence on executive control function of attention, thereby contributing to our understanding of the integrated role of these brain regions in attentional network. Part2:Anatomical Substrates of the Attention Components: Focus on the Posterior Parietal LobeObjective:Both neuropsychological and functional neuroimaging studies have identified that the posterior parietal lobe (PPL) is critical for the attention function. Generally, it is proposed that human PPL is involved in three distinguishing cognitive functions:spatial perception, vision-for-action and visuospatial attention. The taxonomy of alerting, orienting and executive control attention encompasses those parietal functions and integrates different attention components into one complete system. Controversy over the anatomical substrates of attention has highlighted the heterogeneity of this core cognitive operation and emphasized the complicated roles of distinct parietal subregions. Therfore, this part aims to investigate the unique role of distinct parietal cortical subregions and their underlying WM on attention by means of MRI and DTI.Materials and Methods:In this study, we collected both MRI and DTI data in36(22males) normal young participants. The males and females did not differ in mean age (18.4±0.9vs.17.9±0.9years) and education years (8.6±1.2vs.8.5±1.0years). Then we evaluated their attention performance using ANT. The MR images were first processed with the CIVET MRI analysis pipeline (version1.1.9) developed at Montreal Neurological Institute (MNI) to automatically extract and co-register the cortical surfaces for each subject. The DTI data was processed using FSL (University of Oxford, UK). Cortical thickness, surface area and DTI parameters were extracted from predefined PPL subregions using the automated anatomical labelling (AAL) template and correlated with behavioral performance. The AAL template segmented the PPL in each hemisphere into five partitions:superior parietal lobule, inferior parietal lobule, supramarginal gyrus, angular gyrus and precuneus. Tract-based spatial statistics (TBSS) was used for the voxel-wise statistical analysis. At last we performed Probabilistic diffusion tractography (PDT) to identify the WM pathways.Results:Results indicated structure-behavior relationships on multiple levels. First, a link between the cortical thickness and WM integrity of the right inferior parietal regions and orienting performance was observed. Specifically, PDT demonstrated that the integrity of WM connectivity between the bilateral inferior parietal lobules mediated the orienting performance. Second, the scores of executive control were significantly associated with the WM diffusion metrics of the right supramarginal gyrus. Finally, TBSS analysis revealed that alerting performance was significant correlated with the fractional anisotropy of local WM connecting the right thalamus and supplementary motor area. Conclusion:The most significant novelty is the validation of the distinct roles of PPL subregions on the three sub-networks of attention. These findings could yield a more complete understanding of the nature of the PPL contribution to visuospatial attention. Part3:The Asymmetries of White Matter and Their Influences on AttentionObjective:Human brain hemispheres differ in their anatomy and function. Compared with structural MRI measures of WM volume or density, DTI provides more information about WM tissue microstructure and organization. WM asymmetries of the human brain have been well documented using DTI. However, the relationship between WM asymmetry pattern and cognitive performance is poorly understood because of the limitations of the applied techniques. So the main purpose of this study is to assess the effects of DTI asymmetries on individual differences in attention performances.Materials and Methods:A total of59healthy young subjects (31males) aged15～19years were included in the study. A version of the ANT was adapted as the cognitive task. DTI was performed for each of the subject and the DTI data was processed using FSL. We then used TBSS to test the asymmetries of fiber tracts. To implement the inter-hemispheric comparison of fibers, the4D DTI symmetric skeleton dataset was left-right flipped, and the voxel-wise difference map between the original and flipped images was created. The nonparametric1-sample t-test for the difference map was performed by Randomise program in the FSL, to determine the WM skeleton regions showing significant asymmetries. Finally we tested the correlations between WM integrity/asymmetries and three distinct components of attention, namely alerting, orienting, and executive control.Results:We revealed a number of WM anisotropy asymmetries, including leftward asymmetry of cingulum, corticospinal tract and cerebral peduncle, rightward asymmetry of internal capsule, superior longitudinal fasciculus and posterior corona radiata, as well as heterogeneous asymmetries in anterior corpus callosum and anterior corona radiata (ACR). Moreover, specific correlation was found between asymmetric pattern of inferior frontal ACR and executive control performance. Further tractography from correlated regions generated sagittal fiber paths, which exactly overlapped with inferior fronto-occipital fasciculus (IFOF). The reductions of WM integrity in IFOF are associated with deficits of executive function in patients with first-episode psychosis or chronic trauma. Additionally, current study also proposed that there were no significant relationships of WM anisotropy asymmetries to alerting and orienting functions.Conclusion:We used TBSS to investigate WM integrity asymmetries and for the first time to evaluate their relationships to distinct components of attention. There are a number of differences in WM integrity between human brain hemispheres. Specially, the anisotropy asymmetry in inferior frontal ACR plays a crucial role in executive control function. We speculate that WM anisotropy symmetry might be crucial for specific cognitive functions, especially the implement of which employs both hemispheres.更多还原