基于多模态影像下的抑郁症大脑异常
1
2
3
4
Brain abnormalities in depression based on multimodal imaging
1
2
3
4
通讯作者: 胡斌,bh@lzu.edu.cn
修回日期: 2020-05-06 网络出版日期: 2020-06-20
基金资助: |
|
Revised: 2020-05-06 Online: 2020-06-20
Fund supported: |
|
作者简介 About authors
李姗(1997-),女,兰州大学信息科学与工程学院甘肃省可穿戴装备重点实验室硕士生,主要研究方向为大脑形态学分析、情感计算、机器学习等 。
李永超(1995-),女,兰州大学信息科学与工程学院甘肃省可穿戴装备重点实验室硕士生,主要研究方向为功能脑网络分析、抑郁症辅助诊断、机器学习等 。
邹颖(1994-),女,兰州大学信息科学与工程学院甘肃省可穿戴装备重点实验室硕士生,主要研究方向为生物医学图像处理、情感计算与机器学习等 。
杨琳(1998-),女,兰州大学信息科学与工程学院甘肃省可穿戴装备重点实验室本科生,主要研究方向为功能与功能脑网络分析、机器学习等 。
王茵(1998-),女,兰州大学信息科学与工程学院甘肃省可穿戴装备重点实验室本科生,主要研究方向为功能脑网络分析、情感计算、机器学习等 。
姚志军(1977-),男,博士,兰州大学信息科学与工程学院甘肃省可穿戴装备重点实验室教授,博士生导师,主要研究方向为生物医学影像数据处理、普适情感计算、计算机应用技术、人工智能、机器学习等 。
胡斌(1965-),男,博士,兰州大学信息科学与工程学院甘肃省可穿戴装备重点实验室教授、院长,2011年之前,一直担任瑞士苏黎世联邦理工学院客座教授。主要研究方向为普适计算、心理生理计算、数据建模等 E-mail:bh@lzu.edu.cn。
近年来,结构性磁共振成像(sMRI)和功能性磁共振成像(fMRI)被广泛应用于抑郁症研究。从结构形态学、结构网络、功能网络3个角度探索抑郁症患者的大脑异常,了解其发病机制,辅助医生临床诊断、治疗和预后。目前大量研究发现抑郁症患者的海马体、杏仁核出现不同程度的萎缩,脑网络的连接强度、图论属性等均出现显著异常,且出现异常的脑区对应于人的情绪调节、注意力和认知控制等功能,异常的程度与抑郁的严重程度呈现高度相关性。从不同角度对抑郁症的研究现状进行综述,并对未来的研究提出了建议。
关键词:
In recent years,structural magnetic resonance imaging (sMRI) and functional magnetic resonance imaging (fMRI) are widely used in depression research.From the perspectives of morphology,structural network and functional network,the brain abnormalities of depression were explored to understand the pathogenesis,and to assist doctors in clinical diagnosis,treatment and prognosis.A large number of researches have found that the hippocampus and amygdala of depression showed different degrees of atrophy,and the connection strength of brain network and graph theory attributes showed significant abnormal.Moreover,the abnormal brain areas were related to emotional regulation,attention and cognitive control,and the degree of abnormalities were highly correlated with the severity of depression.The research actuality of depression from different perspectives was reviewed,and some suggestions for future research were put forward.
Keywords:
本文引用格式
李姗, 李永超, 邹颖, 杨琳, 王茵, 姚志军, 胡斌.
LI Shan.
1 引言
对抑郁症的诊断目前主要依赖于临床症状,综合严重程度以及症状数量将患者划分为轻度抑郁症、中度抑郁症和重度抑郁症。近年来,随着磁共振影像技术的发展,出现了大量关于抑郁症患者大脑结构以及功能异常的研究,对抑郁症的病理变化及致病机制有了一定的了解[6,7],通过对脑影像进行分析,可以辅助医生做出更准确的诊断、早期预测以及干预;通过分析不同服药阶段的表现来评估药物疗效。磁共振成像主要分为两大类:结构性磁共振成像(structural magnetic resonance imaging, sMRI)和功能性磁共振成像(functional magnetic resonance imaging,fMRI),这些成像方法对人体均无创。抑郁症患者大脑结构形态学的显著变化出现在颞叶、前扣带皮层、眶额叶皮层、海马体、杏仁核、丘脑等区域[8,9],皮层的表面积和厚度都发生了显著变化,且皮下各结构出现了不同程度的萎缩和膨胀,这些结构都与情绪调节以及记忆等功能相关。而在结构网络和功能网络方面,连接的组织效率、连通性都出现了降低,小世界属性丧失,拓扑属性遭到破坏。抑郁症影像学的研究可应用于临床的辅助诊断、药物治疗效果评估、高危人群预测等。本文简述了不同影像的分析方法,并详细探讨了与抑郁症相关的3个重要的功能子网络,结合当前研究现状对未来的研究提出了建议。
2 脑网络构建方法
2.1 结构磁共振成像
形态学分析主要基于皮层厚度、体积、表面积、密度等属性,从解剖学的角度直观反映大脑的变化,其中皮质厚度较难直接测量,因此将其定义为白质表面和软膜表面的最短距离,该方法的有效性已得到验证[10]。除形态学分析之外,大部分研究集中在脑网络分析,使用结构连接或者功能连接构建网络,对抑郁症患者的大脑变化进一步分析,其中每个感兴趣区域(region of interest,ROI)代表一个节点,每个感兴趣区域有其特定的功能,各感兴趣区域之间协同工作。
结构网络基于sMRI进行构建,反映了大脑结构连通性的异常,通常使用脑影像分析工具FreeSurfer 或统计参数图(statistical parametric mapping,SPM)等来计算大脑皮层厚度或灰质体积,根据选定脑区模板进行感兴趣区域的划分。基于每个感兴趣区域的皮层厚度或灰质体积构建结构网络,常用模板有Brodmann(BA)[11]、自动解剖标签(automated anatomical labeling,AAL)[12]、Harvard-Oxford Atlas(HOA)[13]、Brainnetome Atlas-246 [14]等。使用皮尔逊相关性分析来构建各脑区之间的连接,若选择的模板为n个脑区,则形成n×n 的连接矩阵,矩阵的每一行或每一列均表示一个脑区。基于脑网络的拓扑属性分析包括全局或局部属性、模块化、节点属性等,如节点强度表示节点的连接数,聚类系数表示某一节点i的相邻节点之间也互为相邻节点的可能性。其中,中心度用于度量网络中节点的作用与地位,最短路径长度与全局效率衡量了网络的全局传输能力,各项指标既包含大脑整体的完整性,也涉及各功能脑区的变化。
除此之外,弥散张量成像(diffusion tensor imaging,DTI)数据也常被用于构建结构网络,DTI网络通过对全脑纤维束进行追踪,从白质纤维角度评估大脑结构的变化,常用的度量包括平均弥散率(mean diffusivity,MD)和各向异性分数(fractional anisotropy,FA)等指标[15]。
2.2 功能磁共振成像
除了局部一致性(regional homogeneity,ReHo)与低频振幅(amplitude of low frequency fluctuation, ALFF)2个属性,目前对静息态fMRI数据的分析常常基于先验模板或独立成分分析(independent component analysis,ICA)来提取感兴趣区域的血氧合水平依赖(blood oxygenation level dependent, Bold)信号,相比于先验模板提供已经制定好的脑区划分,ICA是一种数据驱动的信号处理方法,不同的研究可能提取出不同数量的独立成分,每个独立成分代表一个脑区。计算每个脑区的平均时间序列,对其进行皮尔逊相关性分析,通过 Fisher’s-z变换将数据转换为正态分布的z值,将计算的相关系数作为网络中边的权值,构建功能连接矩阵,并计算拓扑属性,功能网络的构建过程可借助已有的开源工具来实现,如 GRETNA 等[16,17]。在网络属性的分析方面,功能网络与结构网络相似。
结构网络与功能网络分别从形态和功能两方面反映了抑郁症患者的大脑异常,为了探究结构与功能异常之间的映射关系,使用多个模态的磁共振影像进行联合分析也是研究热点之一。脑网络分析目前被广泛应用,通过选择适当的特征属性,还可对抑郁症进行预测以及辅助诊断。
2.3 抑郁症的主要相关网络
2.3.1 默认模式网络
默认模式网络包括后扣带回皮质(posterior cingulate cortex,PCC)、内侧前额叶皮层(medial prefrontal cortex,mPFC)、楔前叶皮层(precuneus cortex,PCu)以及顶下小叶(inferior parietal lobule, IPL)等脑区。研究发现其与注意力、情绪加工、情景记忆等功能相关,并且随患者年龄的增长发生了显著的变化。
2.3.2 认知控制网络
认知控制网络也被称为中央执行网络(central executive network,CEN)或认知执行网络(cognitive executive network,CEN),主要包括外侧前额叶皮层、后顶叶皮层(posterior parietal cortex,PPC)、前额眼动区(frontal eye fields,FEF)以及部分背内侧前额叶皮层(dorsomedial prefrontal cortex, dmPFC)。
图1
2.3.3 突显网络
3 抑郁症患者的大脑变化
3.1 大脑形态学变化
除了大脑皮层之外,抑郁症患者大脑形态学变化还出现在皮层下结构,发生显著变化的结构包括海马体、杏仁核、丘脑、壳核等,其中体积变化最大的是海马体。海马体和杏仁核在情绪调节[45]、表达[46]、工作记忆[47]等方面起到重要作用。不仅抑郁症患者的海马体发生了显著变化,精神分裂症(schizophrenia)[48]、阿尔兹海默症(Alzheimer’s disease,AD)[49]等精神疾病患者的海马体都发生了显著的变化。笔者研究分析了海马体和杏仁核不同子区的形态学变化,结果显示,双侧海马体的下托和安蒙角(cornu ammonis,CA)1子区,左侧杏仁核的外侧和基底外侧,右侧杏仁核的基底外侧、前区、前皮层都发生了萎缩。在对抑郁症患者的海马体和杏仁核结构表面特征与汉密尔顿抑郁量表(hamilton depression scale,HAMD)评分进行相关分析时,发现二者呈显著正相关,研究者进一步推测,随着抑郁症患者症状的逐渐加重,海马体和杏仁核的萎缩有向其余子区发展的趋势[50]。
虽然不同类型的精神疾病在大脑结构上均会出现变化,但变化的区域以及严重程度存在区别。有研究表明,与轻度认知障碍患者和抑郁症患者相比,阿尔兹海默症患者的海马体表现为整体的严重萎缩,平均减少30.9%,而轻度认知障碍患者的海马体体积减少了17%左右。轻度认知障碍患者的海马头区域有显著的萎缩,抑郁症患者则是在距杏仁核背侧12 mm处的前海马区域显著萎缩[53,54]。在诊断过程中,结合患者临床表现等信息,可避免出现误诊的情况。即使是同一种精神疾病,不同类型也表现出不同的变化,如相比于难治性抑郁症患者,治疗敏感抑郁症患者的结构异常区域更多;部分灰质体积显著减小的区域并未在难治性抑郁症患者中发现[55]。
3.2 结构网络变化
图2
形态学和结构网络的分析从不同角度论证了抑郁症患者的大脑结构已发生明显的损伤,网络拓扑属性被破坏,因此为了进一步研究抑郁症的发病机制,结合静息态fMRI的多模态分析非常有必要,可以从功能网络的角度增加对抑郁症的了解。
3.3 功能网络变化
相对于常见的功能连接,近年来出现了对动态功能连接的分析。笔者将动态功能连接划分为强连接状态和弱连接状态,发现抑郁症患者处于弱连接状态的时间更长且出现功能连接降低的情况,其中部分连接的动态性与抑郁量表显著相关[64]。也有研究发现针对不同的状态,抑郁症患者动态功能连接的连接方式不同,尤其是前额叶网络(prefrontal network,FN)、感觉运动网络(sensorimotor network, SMN)和小脑网络(cerebellum network,CN)[65]。通过对动态网络进行分析,发现与健康对照组相比,抑郁症患者的前扣带皮层的社区分配分布和灵活性存在显著差异,并且抑郁症患者的前扣带皮层与杏仁核、丘脑等之间的连接强度显著降低[66]。
图3
4 临床辅助诊断应用
通过对抑郁症患者的脑影像进行分析,一个重要的应用前景是临床的辅助诊断,抑郁症患者的诊断不仅需要患者积极地配合,还需要医生丰富的诊断经验,如果产生误诊,会严重影响患者的治疗进程,相比患者主观描述的多变性与不完整,磁共振成像能够更客观地反映大脑变化。根据之前的研究,对于首发型与复发型的抑郁症患者来说,不同的治疗方式、不同的服药情况等都会产生截然不同的大脑变化,同时性别、年龄等也是不可忽视的因素。因此计算机辅助诊断系统可以提供一个可靠的建议,帮助医生高效准确地对患者进行诊断,并制定合适的治疗方案。
通过对患者的病理变化进行分析,提取相应的生物标志物,再结合机器学习和神经网络,经过特征选择后,构造合适的预测模型的方法已被大量用于针对精神疾病的预测以及分类研究[71,72,73]。构造模型时,常使用k折交叉验证来评估稳定性,即随机将数据划分为k份,1份作为测试集,其余k-1份作为训练集,k一般选择10或5。也有研究使用留一法,留一法为k折交叉验证的特殊情况,即当k=n (样本总量)时,称为留一法。因为留一法不能考虑分层采样,而且当样本量大时计算开销过大,相比之下十折交叉验证更被广为认可[74];但当样本量过少时,使用留一法更为常见,该方法可以更充分地利用数据,因此应根据实际情况选择验证方法。
结构与功能的指标都被应用于抑郁症分类[77,78],在使用ICA提取20个成分后,通过联合多个功能网络,如默认模式网络和突显网络,计算其赫斯特(Hurst)指数,经过进一步判别分析,线性核SVM对抑郁症患者的识别率达到 90%[79]。除此之外,Rosa等人[80]提出基于高斯图模型和L1范数正则化线性支持向量机的稀疏网络分类模型,该模型通过估计逆协方差矩阵的稀疏模型来估计脑区间的功能连接,并且采用嵌套交叉验证来确保测试集与训练集互不影响。近期有研究团队提出一种基于高阶网络的分类方法,其使用基于滑动窗的动态功能连接,将所有样本的动态功能连接时间序列进行聚类,在提取特征后,也获得了较好的结果[81]。以上研究用于辅助临床诊断,但生活中存在抑郁高风险人群,如孕妇[82]、抑郁症患者子女[83]、留守儿童[84]等,未来也可利用影像学指标对生活中的抑郁高风险人群进行预测。
5 结束语
目前大部分研究是基于基线的研究,即横向研究,其仅限于反映不同类型的抑郁症之间的差异,或抑郁症患者与未患病人群之间的差异。针对抑郁症的纵向研究较少,通过纵向的研究可分析不同治疗方法、不同治疗阶段的治疗效果。同时,大部分工作是基于组水平的研究,不能完全反映个体之间的差异,而在临床治疗中,医生面对的都是独立的患者,症状不一定相同。在未来针对抑郁症的研究中,可以多开展纵向或基于个体的研究,同时结合其他学科的优势,如基因和分子等学科,更加深入地了解抑郁症的发病机制。磁共振成像的分析有助于对抑郁患者进行更准确的靶向治疗,制定更合适的治疗方案以及新药物的研发,降低抑郁症给患者和社会带来的影响。
参考文献
Cognition and depression:current status and future directions
[J]. ,
Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the national comorbidity survey replication
[J]. ,
The prospective long-term course of adult depression in general practice and the community:a systematic literature review
[J]. ,
Can better recognition and treatment of depression reduce suicide rates? A brief review
[J]. ,
Evidence-based health policy-lessons from the global burden of disease study
[J]. ,
The rise and fall of MRI studies in major depressive disorder
[J]. ,
Major depressive disorder and magnetic resonance imaging:a mini-review of recent progress
[J]. ,
Subcortical brain alterations in major depressive disorder:findings from the enigma major depressive disorder working group
[J]. ,
Cortical abnormalities in adults and adolescents with major depression based on brain scans from 20 cohorts worldwide in the enigma major depressive disorder working group
[J]. ,
Validation of freesurfer-estimated brain cortical thickness:comparison with histologic measurements
[J]. ,
Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain
[J]. ,
Advances in functional and structural MR image analysis and implementation as FSL
[J]. ,
The human brainnetome atlas:a new brain atlas based on connectional architecture
[J]. ,
Multimodal imaging reveals a complex pattern of dysfunction in corticolimbic pathways in major depressive disorder
[J]. ,
Aberrant topological organization of the functional brain network associated with prior overt hepatic encephalopathy in cirrhotic patients
[J]. ,
阿尔兹海默症脑网络演化建模
[J]. ,
Brain network evolution modeling based on alzheimer’s disease
[J].
Instability of default mode network connectivity in major depression:a two-sample confirmation study
[J]. ,
Rumination and default mode network subsystems connectivity in first-episode,drug-naive young patients with major depressive disorder
[J]. ,
Altered functional interaction hub between affective network and cognitive control network in patients with major depressive disorder
[J]. ,
Comorbid anxiety increases cognitive control activation in major depressive disorder
[J]. ,
Alteration of spontaneous neuronal activity within the salience network in partially remitted depression
[J]. ,
A treatment-resistant default mode subnetwork in major depression
[J]. ,
The default network and self-generated thought:component processes,dynamic control,and clinical relevance
[J]. ,
Resting-state functional connectivity in major depressive disorder:a review
[J]. ,
Resting-state functional MRI in depression unmasks increased connectivity between networks via the dorsal nexus
[J]. ,
Self-referential processing,rumination,and cortical midline structures in major depression
[J]. ,
Resting state brain network function in major depression-depression symptomatology,antidepressant treatment effects,future research
[J]. ,
Cognitive control network anatomy correlates with neurocognitive behavior:a longitudinal study
[J]. ,
Serotonin transporter polymorphisms,microstructural white matter abnormalities and remission of geriatric depression
[J]. ,
Altered functional connectivity of the dorsolateral prefrontal cortex in first-episode patients with major depressive disorder
[J]. ,
Large-scale network dysfunction in major depressive disorder:a meta-analysis of resting-state functional connectivity
[J]. ,
Functional connectivity in the cognitive control network and the default mode network in late-life depression
[J]. ,
Dorsal anterior cingulate cortex shows fMRI response to internal and external error signals
[J]. ,
Cognitive control and the salience network:an investigation of error processing and effective connectivity
[J]. ,
The salience network is responsible for switching between the default mode network and the central executive network:replication from DCM
[J]. ,
A critical role for the right fronto-insular cortex in switching between central-executive and default-mode networks
[J]. ,
Insular dysfunction within the salience network is associated with severity of symptoms and aberrant inter-network connectivity in major depressive disorder
[J]. ,
Brain-derived neurotrophic factor promoter methylation and cortical thickness in recurrent major depressive disorder
[J]. ,
Paralimbic cortical thickness in first-episode depression:evidence for trait-related differences in mood regulation
[J]. ,
Regional increases of cortical thickness in untreated,first-episode major depressive disorder
[J]. ,
Widespread reductions in gray matter volume in depression
[J]. ,
Cerebral and cerebellar gray matter reduction in first-episode patients with major depressive disorder:a voxel-based morphometry study
[J]. ,
Relationship between cerebellar structure and emotional memory in depression
[J]. ,
Conscious and unconscious emotional learning in the human amygdala
[J]. ,
Impaired recognition of emotion in facial expressions following bilateral damage to the human amygdala
[J]. ,
Inhibition of neurogenesis interferes with hippocampus-dependent memory function
[J]. ,
Hippocampus and amygdala in schizophrenia:assessment of the relationship of neuroanatomy to psychopathology
[J]. ,
Volumetry of amygdala and hippocampus and memory performance in alzheimer’s disease
[J]. ,
Morphological changes in subregions of hippocampus and amygdala in major depressive disorder patients
[J]. ,
Patterns of hippocampal atrophy differ among alzheimer’s disease,amnestic mild cognitive impairment,and late-life depression
[J]. ,
Structural differences in hippocampal subfields among schizophrenia patients,major depressive disorder patients,and healthy subjects
[J]. ,
An MRI study of amygdala in schizophrenia and psychotic bipolar disorder
[J]. ,
Voxel-based morphometry of patients with schizophrenia or bipolar I disorder:a matched control study
[J]. ,
Structural and cognitive deficits in remitting and non-remitting recurrent depression:a voxel-based morphometric study
[J]. ,
Increased cortical-limbic anatomical network connectivity in major depression revealed by diffusion tensor imaging
[J]. ,
Structural alterations of the brain preceded functional alterations in major depressive disorder patients:evidence from multimodal connectivity
[J]. ,
Association of brain network efficiency with aging,depression,and cognition
[J]. ,
Evidence of a dissociation pattern in resting-state default mode network connectivity in first-episode,treatment-naive major depression patients
[J]. ,
Aberrant connectivity within the default mode network in first-episode,treatment-naive major depressive disorder
[J]. ,
Reproducibility of functional brain alterations in major depressive disorder:Evidence from a multisite resting-state functional MRI study with 1 434 individuals
[J]. ,
Rumination network dysfunction in major depression:a brain connectome study
[J]. ,
Changes of functional brain networks in major depressive disorder:a graph theoretical analysis of resting-state fMRI
[J]. ,
Altered dynamic functional connectivity in weakly-connected state in major depressive disorder
[J]. ,
Aberrant dynamic functional network connectivity and graph properties in major depressive disorder
[J]. ,
The dynamic characteristics of the anterior cingulate cortex in resting-state fMRI of patients with depression
[J]. ,
Fronto-parietal and temporal brain dysfunction in depression:a fMRI investigation of auditory mismatch processing
[J]. ,
Large-scale dynamic causal modeling of major depressive disorder based on resting-state functional magnetic resonance imaging
[J]. ,
Relation between structural and functional connectivity in major depressive disorder
[J]. ,
Conjoint and dissociated structural and functional abnormalities in first-episode drug-naive patients with major depressive disorder:a multimodal meta-analysis
[J]. ,
Machine learning in major depression:from classification to treatment outcome prediction
[J]. ,
人工智能在医学影像中的研究与应用
[J]. ,
Research and application of artificial intelligence in medical imaging
[J].
用于轻度认知障碍诊断的群体相似约束功能脑网络建模方法
[J]. ,
Method of functional brain network modeling with group similarity constraint for mild cognitive impairment classification
[J].
Performance evaluation of classification algorithms by k-fold and leave-one-out cross validation
[J]. ,
Multi-centre diagnostic classification of individual structural neuroimaging scans from patients with major depressive disorder
[J]. ,
Classification of different therapeutic responses of major depressive disorder with multivariate pattern analysis method based on structural MR scans
[J]. ,
Machine learning approaches for integrating clinical and imaging features in late-life depression classification and response prediction
[J]. ,
Studying depression using imaging and machine learning methods
[J]. ,
Identifying major depressive disorder using Hurst exponent of resting-state brain networks
[J]. ,
Sparse network-based models for patient classification using fMRI
[J]. ,
Treatment-naive first episode depression classification based on high-order brain functional network
[J]. ,
Frequency and associated factors for anxiety and depression in pregnant women:a hospital-based cross-sectional study
[J]. ,
Maternal postnatal depression and the development of depression in offspring up to 16 years of age
[J]. ,
Depression risk of ‘left-behind children’ in rural China
[J]. ,
Depression increases the risk of hypertension incidence:a meta-analysis of prospective cohort studies
[J]. ,
Depression and cardiac risk:present status and future directions
[J]. ,
The association of age and depression among the elderly:an epidemiologic exploration
[J]. ,
Overweight,obesity,and depression:a systematic review and meta-analysis of longitudinal studies
[J]. ,
Predicting future depression in adolescents using the Short Mood and Feelings Questionnaire:a two-nation study
[J]. ,
Dietary patterns and depression risk:a meta-analysis
[J]. ,
Childhood family environment and sexual abuse as predictors of anxiety and depression in adult women
[J]. ,
Lifetime suicide risk in major depression:sex and age determinants
[J]. ,
/
〈 | 〉 |