功能性消化不良患者大脑结构和功能异常研究
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摘要
功能性胃肠病，指的是具有复发性或慢性消化道症状，而没有生化和结构异常的一组症状，其在世界范围内有着很高的发病率。功能性胃肠病不仅影响人们的日常生活质量，而且由此产生的医疗费用也是非常高昂的，它已经成为一个严重的社会问题。据一项流行性病学调查研究指出，约有23.5%的中国人患有功能性胃肠病。然而，功能性胃肠病的治疗一直以来是医学界的一个难题，究其原因是其发病机理至今尚不明确。近些年的研究表明，脑-肠轴交互的紊乱在功能性胃肠病的病理生理学中起到了关键作用。
根据罗马III诊断标准，功能性胃肠病可分为功能性消化不良、肠易激综合症以及功能性胸痛等。研究人员利用正电子断层成像技术发现，功能性胃肠病包括功能性消化不良和肠易激综合症患者不仅对胃肠刺激加工中出现异常，而且静息态大脑活动也出现异常。同样，利用磁共振成像技术，研究人员还发现肠易激综合症患者的大脑结构也出现异常。然而，利用磁共振成像技术对功能性消化不良患者大脑活动异常进行研究的报道非常少。和正电子断层成像等相比，磁共振成像具有无创、无放射性等优点，而且成像成本相对较低。此外，利用结构共振成像以及弥散张量成像等可以研究功能性消化不良患者的大脑结构变化。因此，本论文主要采用磁共振成像技术对功能性消化不良患者的中枢异常进行研究，所取得的主要研究结果和创新点如下：
1.功能性消化不良患者大脑白质微结构异常研究。
本研究通过采用弥散张量成像，对功能性消化不良患者大脑白质微结构异常进行了研究。我们采用基于骨架的空间统计分析对功能性消化不良患者和正常被试的弥散张量参数包括各向异性值、平均弥散率、轴向弥散率和径向弥散率进行比较。研究发现，功能性消化不良患者在多处白质纤维存在较高的各向异性值并伴随有较低的平均弥散率和径向弥散率，这些脑区包括双侧前放射冠、胼胝体（体和膝）、外囊、内囊晶状体，右侧丘脑后放射，双侧矢状层和右侧上纵束。弥散张量参数的这种变化模式可能由多种原因导致，而本研究的结果暗示了功能性消化不良患者可能存在大脑结构连接的增强。情绪因素，如焦虑和抑郁，在功能性消化不良的发生和发展中起到了重要作用。为了讨论情绪因素对本文中观察到的白质结构异常的影响，我们进一步讲焦虑和抑郁作为回归因素考虑之后重新进行组间弥散张量参数的比较。结果发现多处白质差异消失，该结果进一步说明了情绪因素在功能性消化不良病理机理中的重要作用。据我们所知，该研究为第一个功能性消化不良患者白质微结构异常的弥散张量影像学研究。
2.功能性消化不良患者半脑间功能连接度异常研究。
本研究采用静息态功能连接度的方法，对功能性消化不良患者半脑间的功能连接进行了研究。研究发现功能性消化不良患者在脑岛、前额叶以及丘脑等脑区均出现了半脑间功能连接度的增强。本研究首次对功能性消化不良患者脑区间功能连接度异常进行了初步的探索性研究，这些发现将有助于我们理解功能性消化不良患者中枢敏感化的神经机制。
3.功能性消化不良患者静息态低频振幅异常研究。
本研究采用功能磁共振成像技术对功能性消化不良患者静息态低频振幅进行了研究。我们的研究发现，功能性消化不良患者脑岛、脑干和小脑分数低频振幅显著增高。紧接着，我们分别选取功能性消化不良患者分数低频振幅增强的脑区作为感兴趣区进行种子点相关的全脑功能连接度分析。结果表明，和正常被试相比，功能性消化不良患者的右侧小脑和多处脑区包括脑干、双侧小脑、旁海马、海马、苍白球、壳核以及丘脑之间的功能连接度显著增强。最后，我们还发现脑岛的分数低频振幅和患者病重显著相关。本研究结果进一步揭示了功能性消化不良患者大脑功能活动异常，并且可能在疾病的发展中起到了重要作用。
4.神经同步性在正常被试中的功能初步研究。
前面的几个研究表明，功能性消化不良患者不仅大脑结构连接可能增强，而且功能连接也出现异常。因此，我们推测患者大脑的神经同步性可能出现了异常，而脑电图是测量神经同步性的一种非常有效的手段。在本研究中，我们首先采用脑电图技术对正常人的神经同步性进行初步探索。我们发现，大脑的神经同步性和人的认知表现是相关的，这进一步说明了其存在的神经生理意义。我们希望在未来的研究中，将磁共振成像和脑电图进行有效的结合，从而能更好的揭示功能性消化不良患者中枢异常尤其是神经同步性异常在疾病的发生和发展中所起的作用。
Functional gastrointestinal disorders (FGIDs) are characterized by chronic or recurrentgastrointestinal symptoms in the absence of in the absence of any organic, systemic, ormetabolic disease that is likely to explain the symptoms. The reported prevalence rate ofFGIDs is high world-wide. FGIDs have become a serious social problem for it itssignificant influence on health-related quality of life as well the high healthcare costs.According to a Chinese-based epidemiology study,23.5%of the community peoplesuffered from FGIDs. However, there has no effective treatment for FGIDs which wasbecause the pathophysiology of the disease still remains incomplete understood. Thereare increasing evidences suggesting that dysfunction of the brain-gut axis (BGA) mightplay a key role in the pathphysiology of the disease.
According to the Rome III criteria, FGIDs can be divided into functional dyspepsia(FD), irritable bowel syndrome (IBS), functional chest pain and et al. Several positronemission tomography (PET) studies have verified that patients with FGIDs showedabnormal brain activity during gastric distension as well as during resting-state.Moreover, brain structural changes in patients with IBS have been found by severalinvestigations using magnetic resonance imaging (MRI). However, studies investigatingbrain activity changes in FD patients with MRI which has the advantage of non-invasiveand non-radioactive over PET were rare. Moreover, whether brain structure is changedin patients with FD is unknown. Therefore, the main aim of the present dissertation wasmainly focused the investigation of brain structural and functional changes in patientswith FD using MRI techniques:
1. White matter microstructural changes in patients with FD.
In this study, we investigated the white matter microstructural changes in FDpatients using diffusion tensor imaging (DTI). We compared multiple DTI measuresincluding fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) andradial diffusivity (RD) with state-of-the-art tract-based spatial statistics (TBSS). Theresults showed that patients with FD had higher FA along with lower MD and RD thanhealthy controls in multiple tracts including the bilateral anterior corona radiata, genuand body of corpus callosum, external capsule, internal capsule (right retrolenticularpart), right posterior thalamic radiation, bilateral sagittal stratum, and right superiorlongitudinal fasciculus. The pattern of DTI measures changes was likely to suggestincreased structural connectivity in patients with FD. Furthermore, psychosocial factors including anxiety and depression explained part of the observed changes of DTImeasures. The result further suggested the import role of psychosocial factors in thepathophysiology of the disease.
2. Interhemispheric functional connectivity abnormalities in patients with FD.
In this study, we investigated interhemispheric functional connectivity changes byusing resting-state functional magnetic resonance imaging (rfMRI). The results revealedthat patients with FD had increased interhemispheric functional connectivity in multiplebrain regions including the insula, anterior cingulate and thalamus. Our findings mighthave provided preliminary evidence of interhemispheric interactions changes in patientswith FD.
3. Fractional amplitude of low-frequency oscillation changes patients with FD.
In this study, we investigated the amplitude of low-frequency (ALFF) changes inpatients with FD using resting-state fMRI. The results revealed that patients with FDhave increased fractional amplitude of low-frequency (fALFF) in multiple brain regionsincluding the insula, brainstem and cerebellum. Furthermore, we applied seed-basedresting-state functional connectivity analysis by using brain regions showing significantbetween-group difference in fALFF as regions of interest (ROIs). We found increasedfunctional connectivity between the right cerebellum and brainstem, bilateralcerebellum, para-/hippocampus, pallidum, putamen and thalamus. Furthermoe, wefound that the insula fALFF was positively correlated with the severity of the disease.
4. The investigation of the role of neural synchronization in healthy subjects usingelectroencephalogram(EEG).
The results of the previous studies have suggested that patients with FD might haveincreased structural and functional connectivity. Therefore, we speculated that theneural synchronization between brain regions might be altered in patients with FD. EEGhas been suggested to be a powerful tool in revealing neural synchronization betweenbrain regions. In the present study, we investigated neural synchronization in healthycontrol using EEG. The results revealed different neural synchronization networks indifferent frequency bands. Furthermore, we also found that the neural synchronizationwas of behavioral significance. In future studies, we would like to combine EEG withfMRI to further revealed neural synchronization abnormalities in the pathogenesis of theFD symptoms.
根据罗马III诊断标准，功能性胃肠病可分为功能性消化不良、肠易激综合症以及功能性胸痛等。研究人员利用正电子断层成像技术发现，功能性胃肠病包括功能性消化不良和肠易激综合症患者不仅对胃肠刺激加工中出现异常，而且静息态大脑活动也出现异常。同样，利用磁共振成像技术，研究人员还发现肠易激综合症患者的大脑结构也出现异常。然而，利用磁共振成像技术对功能性消化不良患者大脑活动异常进行研究的报道非常少。和正电子断层成像等相比，磁共振成像具有无创、无放射性等优点，而且成像成本相对较低。此外，利用结构共振成像以及弥散张量成像等可以研究功能性消化不良患者的大脑结构变化。因此，本论文主要采用磁共振成像技术对功能性消化不良患者的中枢异常进行研究，所取得的主要研究结果和创新点如下：
1.功能性消化不良患者大脑白质微结构异常研究。
本研究通过采用弥散张量成像，对功能性消化不良患者大脑白质微结构异常进行了研究。我们采用基于骨架的空间统计分析对功能性消化不良患者和正常被试的弥散张量参数包括各向异性值、平均弥散率、轴向弥散率和径向弥散率进行比较。研究发现，功能性消化不良患者在多处白质纤维存在较高的各向异性值并伴随有较低的平均弥散率和径向弥散率，这些脑区包括双侧前放射冠、胼胝体（体和膝）、外囊、内囊晶状体，右侧丘脑后放射，双侧矢状层和右侧上纵束。弥散张量参数的这种变化模式可能由多种原因导致，而本研究的结果暗示了功能性消化不良患者可能存在大脑结构连接的增强。情绪因素，如焦虑和抑郁，在功能性消化不良的发生和发展中起到了重要作用。为了讨论情绪因素对本文中观察到的白质结构异常的影响，我们进一步讲焦虑和抑郁作为回归因素考虑之后重新进行组间弥散张量参数的比较。结果发现多处白质差异消失，该结果进一步说明了情绪因素在功能性消化不良病理机理中的重要作用。据我们所知，该研究为第一个功能性消化不良患者白质微结构异常的弥散张量影像学研究。
2.功能性消化不良患者半脑间功能连接度异常研究。
本研究采用静息态功能连接度的方法，对功能性消化不良患者半脑间的功能连接进行了研究。研究发现功能性消化不良患者在脑岛、前额叶以及丘脑等脑区均出现了半脑间功能连接度的增强。本研究首次对功能性消化不良患者脑区间功能连接度异常进行了初步的探索性研究，这些发现将有助于我们理解功能性消化不良患者中枢敏感化的神经机制。
3.功能性消化不良患者静息态低频振幅异常研究。
本研究采用功能磁共振成像技术对功能性消化不良患者静息态低频振幅进行了研究。我们的研究发现，功能性消化不良患者脑岛、脑干和小脑分数低频振幅显著增高。紧接着，我们分别选取功能性消化不良患者分数低频振幅增强的脑区作为感兴趣区进行种子点相关的全脑功能连接度分析。结果表明，和正常被试相比，功能性消化不良患者的右侧小脑和多处脑区包括脑干、双侧小脑、旁海马、海马、苍白球、壳核以及丘脑之间的功能连接度显著增强。最后，我们还发现脑岛的分数低频振幅和患者病重显著相关。本研究结果进一步揭示了功能性消化不良患者大脑功能活动异常，并且可能在疾病的发展中起到了重要作用。
4.神经同步性在正常被试中的功能初步研究。
前面的几个研究表明，功能性消化不良患者不仅大脑结构连接可能增强，而且功能连接也出现异常。因此，我们推测患者大脑的神经同步性可能出现了异常，而脑电图是测量神经同步性的一种非常有效的手段。在本研究中，我们首先采用脑电图技术对正常人的神经同步性进行初步探索。我们发现，大脑的神经同步性和人的认知表现是相关的，这进一步说明了其存在的神经生理意义。我们希望在未来的研究中，将磁共振成像和脑电图进行有效的结合，从而能更好的揭示功能性消化不良患者中枢异常尤其是神经同步性异常在疾病的发生和发展中所起的作用。
Functional gastrointestinal disorders (FGIDs) are characterized by chronic or recurrentgastrointestinal symptoms in the absence of in the absence of any organic, systemic, ormetabolic disease that is likely to explain the symptoms. The reported prevalence rate ofFGIDs is high world-wide. FGIDs have become a serious social problem for it itssignificant influence on health-related quality of life as well the high healthcare costs.According to a Chinese-based epidemiology study,23.5%of the community peoplesuffered from FGIDs. However, there has no effective treatment for FGIDs which wasbecause the pathophysiology of the disease still remains incomplete understood. Thereare increasing evidences suggesting that dysfunction of the brain-gut axis (BGA) mightplay a key role in the pathphysiology of the disease.
According to the Rome III criteria, FGIDs can be divided into functional dyspepsia(FD), irritable bowel syndrome (IBS), functional chest pain and et al. Several positronemission tomography (PET) studies have verified that patients with FGIDs showedabnormal brain activity during gastric distension as well as during resting-state.Moreover, brain structural changes in patients with IBS have been found by severalinvestigations using magnetic resonance imaging (MRI). However, studies investigatingbrain activity changes in FD patients with MRI which has the advantage of non-invasiveand non-radioactive over PET were rare. Moreover, whether brain structure is changedin patients with FD is unknown. Therefore, the main aim of the present dissertation wasmainly focused the investigation of brain structural and functional changes in patientswith FD using MRI techniques:
1. White matter microstructural changes in patients with FD.
In this study, we investigated the white matter microstructural changes in FDpatients using diffusion tensor imaging (DTI). We compared multiple DTI measuresincluding fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) andradial diffusivity (RD) with state-of-the-art tract-based spatial statistics (TBSS). Theresults showed that patients with FD had higher FA along with lower MD and RD thanhealthy controls in multiple tracts including the bilateral anterior corona radiata, genuand body of corpus callosum, external capsule, internal capsule (right retrolenticularpart), right posterior thalamic radiation, bilateral sagittal stratum, and right superiorlongitudinal fasciculus. The pattern of DTI measures changes was likely to suggestincreased structural connectivity in patients with FD. Furthermore, psychosocial factors including anxiety and depression explained part of the observed changes of DTImeasures. The result further suggested the import role of psychosocial factors in thepathophysiology of the disease.
2. Interhemispheric functional connectivity abnormalities in patients with FD.
In this study, we investigated interhemispheric functional connectivity changes byusing resting-state functional magnetic resonance imaging (rfMRI). The results revealedthat patients with FD had increased interhemispheric functional connectivity in multiplebrain regions including the insula, anterior cingulate and thalamus. Our findings mighthave provided preliminary evidence of interhemispheric interactions changes in patientswith FD.
3. Fractional amplitude of low-frequency oscillation changes patients with FD.
In this study, we investigated the amplitude of low-frequency (ALFF) changes inpatients with FD using resting-state fMRI. The results revealed that patients with FDhave increased fractional amplitude of low-frequency (fALFF) in multiple brain regionsincluding the insula, brainstem and cerebellum. Furthermore, we applied seed-basedresting-state functional connectivity analysis by using brain regions showing significantbetween-group difference in fALFF as regions of interest (ROIs). We found increasedfunctional connectivity between the right cerebellum and brainstem, bilateralcerebellum, para-/hippocampus, pallidum, putamen and thalamus. Furthermoe, wefound that the insula fALFF was positively correlated with the severity of the disease.
4. The investigation of the role of neural synchronization in healthy subjects usingelectroencephalogram(EEG).
The results of the previous studies have suggested that patients with FD might haveincreased structural and functional connectivity. Therefore, we speculated that theneural synchronization between brain regions might be altered in patients with FD. EEGhas been suggested to be a powerful tool in revealing neural synchronization betweenbrain regions. In the present study, we investigated neural synchronization in healthycontrol using EEG. The results revealed different neural synchronization networks indifferent frequency bands. Furthermore, we also found that the neural synchronizationwas of behavioral significance. In future studies, we would like to combine EEG withfMRI to further revealed neural synchronization abnormalities in the pathogenesis of theFD symptoms.
引文
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