【作者】 方雷；

【导师】 马祥兴；

【作者基本信息】 山东大学 ， 影像医学与核医学（专业学位）， 2017， 博士

【摘要】 前言大量研究显示几乎在所有的精神类疾患中都存在着男女脑代谢网络的差异,故脑代谢网络的性别差异正越来越受到神经学家的关注。但是关于男女脑功能网络在某些特定节点及功能连接上存在差异的观点还存在着争议,因此,很有必要去寻找一种更科学有效的方法来探索男女在静息态下的性别差异。神经元的活动能引起葡萄糖利用的增加,这能够被正电子发射断层显像仪(positron emission tomography,PET)可靠地显像,因而PET被视为测量由神经元活动引起的局部脑葡萄糖代谢率改变的有效工具。并且到目前为止,还鲜有以图论来进行静息态下FDG-PET脑代谢网络性别差异研究的报道。因此,本研究的第一部分试图利用静息态 FDG-PET(Resting-state FDG-PET,RS FDG-PET)去锚定健康人群的FDG-PET脑代谢网络的Hub节点及功能连接,进而去显示男女葡萄糖脑代谢网络的性别差异。癌症是一种死亡率高、易伴发抑郁风险、易改变脑功能网络拓扑结构的疾病。一些研究认为肿瘤患者脑网络结构及功能的不平衡或破坏是由化疗所致,另外一些研究则认为抑郁或类似症状常在肿瘤确诊以后发生,严重影响患者的认知功能,造成患者的记忆损伤,并且认为抑郁及相关因素是肿瘤患者脑功能网络拓扑结构优势丧失的重要致病因素。因此,究竟是化疗还是抑郁造成肿瘤患者脑功能网络拓扑结构的改变仍然是一个有争议的问题。并且到目前为止,鲜有关于肿瘤伴抑郁患者(尤其是化疗前的肿瘤伴抑郁患者)脑功能网络拓扑结构的研究。故研究化疗前的肿瘤伴抑郁患者的脑功能网络能够从神经心理学角度为其发病机制提供洞见。在本研究的第二部分,我们试图利用18F-FDG PET研究化疗前肿瘤伴抑郁患者的脑功能网络,期望能够从神经心理学角度为其发病机制提供洞见,为肿瘤并抑郁患者早期心理干预及临床决策提供科学依据。第一部分FDG-PET脑代谢网络属性的性别差异目的利用18F-FDG PET研究静息状态下健康成年人脑葡萄糖代谢网络的性别差异,以期为科研及临床决策提供相关依据。材料及方法利用204例(男104例,女100例)右利手健康成年人静息状态下的FDG-PET数据构建脑代谢网络,并用图论的方法分析其节点及全局参数:类聚系数(Cp),绝对路径长度(Lp)及节点中心性(Cbb)。结果男女两组被试的脑FDG-PET代谢网络均具有小世界属性;同女性相比,男性组有较高的类聚系数(Cp),较长的绝对路径长度(Lp),但两者组间均没有统计学差异;同女性比较,男性的左中央后回、右角回、左侧颞中回颞极的节点中心性显著减少(1000次非参数检验,P<0.05),而在左侧杏仁核、左楔前叶、右侧颞中回颞极、左侧下颞中回的节点中心性则显著增加(1000次非参数检验,P<0.05)。我们的研究结果表明,全脑代谢网络的拓扑结构存在性别差异。结论在实验设计、计算正常对照及试验组的代谢数据及临床决策时,必须将性别当作一个协变量。我们的研究结果或许有助于进一步了解脑活动中的性别差异。第二部分化疗前肿瘤伴抑郁患者脑代谢网络拓扑结构—静息态PET研究目的利用18F-FDG PET研究静息状态下肿瘤伴抑郁患者化疗前脑功能代谢网络的改变,期望为探索其神经心理机制提供新的路径,为早期心理干预及临床决策提供科学依据。材料及方法利用78例癌症伴抑郁患者及相匹配的80例健康对照者的静息状态下的FDG-PET数据构建脑代谢网络。计算两组被试的局部脑葡萄糖代谢率(The regional cerebral glucose metabolism,rCMglc))、贝克量表评分(Beck depression inventory scores,BDIs)、节点及全局参数:类聚系数(Cp),绝对路径长度及节点中心性(Cb),利用图论的方法分析节点及全局参数的组间差异,并对癌症伴抑郁患者的局部葡萄糖代谢率与贝克量表评分做了相关分析。结果肿瘤伴抑郁患者的额叶及颞叶葡萄糖代谢率显著降低(双样本t检验,P<0.05,错误发现率(false discovery rate,FDR)校正,P<0.01)。抑郁与葡萄糖代谢成负相关的脑区主要位于左额下回及左楔叶(r=-0.3278,-0.3216,P<0.05),成正相关的脑区主要位于八个脑区,分别为左侧中央沟盖(r=0.3337,P<0.05)、左岛叶(r=0.3645,P<0.05)、左右海马(r=0.3609,0.3425,P<0.05)、右侧海马旁回(r=0.3338,P<0.05)、左右杏仁核(r=0.3122,0.3263,P<0.05)、左侧颞极:颞中回(r=0.3354,P<0.05)。肿瘤伴抑郁患者具有较低的类聚系数及较长的绝对路径长度。肿瘤伴抑郁患者节点中心性显著降低的脑区主要发现在:额下回的三角区、额中回的眶部,嗅皮层,颞横回,尾状核,双侧海马,右侧海马旁回,杏仁核及前扣带回,节点中心性显著增高的脑区主要位于额中回,岛叶,枕上叶及苍白球(1000次非参数置换检验,P<0.05)。结论肿瘤伴抑郁患者的脑代谢网络虽然仍保存了"小世界"属性,但是拓扑结构的小世界属性有丢失的趋势。低代谢率及贝克量表评分的相关性有助于解释其脑代谢网络的功能丧失及低效。额叶、颞叶及边缘叶全局及局部参数的异常对于理解化疗前肿瘤伴抑郁患者的神经生理机制非常重要。本研究结果或许为探索肿瘤伴抑郁患者的神经生理机制提供了新的路径,这对于减轻其抑郁效应起关键作用。更多还原

【Abstract】 IntroductionSex differences of brain metabolic networks are attracting increasing,well-deserved attention from neuroscientists.A vast variety of studies showed that brain metabolic networks differ between males and females for almost all neuropsychiatric ailments.However,gender differences in some specific nodes and functional connectivities of brain functional networks are still controversial.Therefore,it is necessary to identify more available and scientific methods to explore the gender differences in brain metabolic networks at resting state.Increased synaptic activity can cause elevated glucose use,which can be reliably imaged by positron emission tomography(PET).So regional cerebral glucose metabolism(rCMglc)measured by resting 18F-fluorodeoxyglucose PET(RS 18F-FDG PET)can be viwed as an efficient tool for assessing synaptic function.Furthermore,there is no RS 18F-FDG PET study on gender differences in cerebral metabolic pathways employing graph-based approaches in resting state so far.So at present study(part Ⅰ),we try to use 18F-FDG-PET mapping the brain Hub regions and functional connectome in healthy people and revealing their gender differences of FDG-PET metabolic brain networks.Cancer is a high motality disease accompanied with an increased risk of depression and altered functional brain network topology.Some studies demon-strate functional and structural imbalance or disruption of brain networks frequently occur following chemotherapy in cancer patients.Other studies reveal depression and similar symptoms frequently occur in cancer patients following diagnosis,seriously influence the cognitive function,and cause memory impairment,and suggest depression-related factors may contribute to the less optimal network topology in the metabolic brain network of cancer patients.Therefore,there was still a controversial issure on whether it is depression or chemotherapy that causes the change of brain topological structure in patients with cancer.And so far,few studies have focused on the topological organization of the metabolic brain network in cancer with depression,especially those without chemotherapy.So,investigating the metabolic brain network in pre-chemotherapy cancer with depression could bring new insights into the information regarding the neurophysiological mechanisms.AT present study(part II),we aimed to investigate the metabolic brain network and its relation-ship with depression symptoms using 18F-fluorodeoxyglucose positron emission tomography,and expected that investigating the metabolic brain network in cancer patients could provide a new avenue for exploring the information regarding the neurophysiological mechanisms and providing scientific evidence for early mental intervention and clinical decision-making.Part I Gender Differences of FDG-PET Brain Metabolic NetworksPurposeThis study aimed to investigate gender differences of glucose metabolic network in brains of healthy adult at resting state by using 18F-fluorodeoxy-glucose positron emission tomography,and expected to provide gender-related reference for scientific research and clinical decision making.Materials and MethodsFDG-PET data of 204 right-handed,healthy individuals(100 females and 104 males)were used to construct brain metabolic networks,whose nodal and global parameters(Clustering coefficient(Cp),Characteristic path length(Lp)and Betweenness centrality(Cb)were analyzed by graph theory.ResultsOur results showed that the brain metabolic networks derived from FDG-PET data were with small-world properties in both male and female groups.The male group had higher clustering coefficient compared with females,but longer absolute path length.However,no significant between-group difference of Cpand Lp was found.Compared with females,nodal centrality in males was signify-cantly reduced(Permutation test with 1000 repetitions,P<0.05)in left postcentral gyrus(Postcentral_L),right angular gyrus(Angular_R)and left temporal pole/middle temporal gyrus(Temporal_Pole_Mid_L);and it was increased(Permutation test with 1000 repetitions,P<0.05)in left amyg-dale(Amygdala_L),left precuneus(Precuneus_L),right temporal pole/middle temporal gyrus(Temporal_Pole_Mid_R)and left inferior temporal gyrus(Temporal_Inf_L).Our results revealed gender-related differences of topological structure in whole-brain metabolic networks.ConclusionsGender must be considered as a covariate while designing experiments,accounting for cerebral metabolic data from normal control and experimental patients as well as making clinical decisions.Our results might be beneficial for further grasp of sex differences in cerebral activities.Part Ⅱ Topological Organization of Metabolic BrainNetworks in Pre-Chemotherapy Cancer with Depression:A Resting-State PET Study AbstractPurposeThis study aimed to investigate the alterations of metabolic brain networks in cancer patients with depression symptoms at resting state before chemo-therapy by using 18F-fluorodeoxyglucose positron emission tomography,and ecpected to provide a new way for exploring the neurobiological mechanism and a scientific evidence for early mental intervention and clinical decision-making.Materials and MethodsWe use 18F-fluorodeoxyglucose positron emission tomography data in 78 prechemotherapy cancer patients with depression and 80 matched healthy subjects to construct brain metabolic networks.The regional cerebral glucose metabolism(rCMglc),Beck depression inventory scores(BDIs),nodal and global parameters(Cp,Lp,and Cb)of the metabolic brain network in cancer patients with depression and normal controls(NCs)were computed,their between-group differences were alalyzed by grapy theory,The rCMglc and BDIs in cancer patients with depression were related.ResultsSignificant decreases in metabolism were found in the frontal and temporal gyri in cancer patients compared with healthy subjects(two sample t-test,P<0.05,false discovery rate,FDR,P<0.01).Negative correlations between depression and metabolism were found predominantly in the inferior frontal and cuneus regions(r=-0.3278,-0.3216,P<0.05),whereas positive correlations were observed in eight regions,primarily including the left rolandic operculum(Rolandic_Oper_L,r=0.3337,P<0.05),the left insula(Insula_L,r=0.3645,P<0.05),hippocampus(Hippocampus_L,Hippocampus_R,r=0.3609,0.3425,P<0.05),the right para-hippocampus(ParaHippocampal_R,r=0.3338,P<0.05),amygdale(Amygdala_L,Amygdala_R,r=0.3122,0.3263,P<0.05),Temporal pole:middle temporal gyrus(Temporal_Pole_Mid_R,r=0.3338,P<0.05).Furthermore,a higher clustering efficiency,longer path length were found in cancer patients compared with healthy subjects.Significant decreases in nodal betweenness centralities were found in some brain regions,such as the train-gular part of the inferior frontal gyrus,the orbital part of the middle frontal gyrus,the olfactory cortex,the Heschl gyrus,the caudate nucleus,the bilateral hippo-campus,the right para-hippocampus,the amygdale,and the anterior cingulated,in cancer patients compared with NCs,whereas significant increases in nodal betweenness centralities were found in orther regions mainly including the middle frontal gyrus,insula,superior occipital gyrus,and pallidum(Permutation test with 1000 repetitions,P<0.05).ConclusionAlthough the metabatic brain networks of cancer patients preserved the small-world properties,but the topological architecture was found with partial loss of optimal pattern.The hypo-metabolism and its relationship with BDIs may help explain the dysfunction and inefficiency of the metabolic brain network following the disease.The abnormalities in global and regional parameters were mainly observed in the frontal and temporal lobes as well as the limbic regions,which would be critical to the understanding of the neurobiological mechanism associated with depression symptoms in pre-chemotherapy cancer.The present findings may provide a new avenue for exploring the neurobiological mechanism,which plays a key role in lessening the depression effects in pre-chemotherapy cancer patients.更多还原