青少年肥胖中枢机制及针灸治疗的神经影像学及动物模型研究
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摘要
第一部分食物与食欲相关fMRI研究的Meta分析
目的确认大脑功能区对食物刺激反应的一致性,借以探讨中枢对饥饿状态及含不同热量食物反应的调节机制。方法应用SDM体素Meta分析法对正常体重受试者fMRI数据进行分析,分析内容包括：食物与非食物刺激下脑区兴奋性的差异；饥饿状态下的中枢调节；不同热量食物刺激对中枢的影响。结果1.与非食物图片相比,食物图片刺激时具有较强激活的脑区包括：双侧后梭状回,左外侧眶额回及左侧中间岛叶；2.饥饿状态下,影响中枢调节的脑区包括：右侧杏仁核,左外侧眶额回；3.不同热量食物刺激影响的脑区包括：下丘脑及腹侧纹状体。局限性综合上述的结果,脑区激活的一致性仅在中等水平,这意味着实验方法对结果仍存在诸多的影响；此外,其它的脑区仍可能参与食欲及食物刺激的中枢调节。结论降低梭状回,眶额回,杏仁核,下丘脑及腹侧纹状体的兴奋水平可能抑制食欲。
第二部分针灸减肥治疗对肥胖青少年中枢神经系统的影响
目的应用fMRI及DARTEL-VBM分析方法探讨针灸减肥对肥胖青少年中枢神经系统的影响。方法10名单纯性肥胖青少年(男7,女3,14～18岁,右利手,体重指数：29.03±4.81kg/m2)行阶段性针灸减肥治疗,在治疗前、后分别行颅脑高分辨三维T1加权成像及fMRI扫描；同时招募10名年龄和性别相匹配的健康自愿者(右利手,体重指数：25.05±5.02kg/m2)作为对照组。fMRI方案：观察受试者在接受食物图片视觉刺激后的中枢反应,然后用手法针灸左侧足三里(ST36)及右侧丰隆(ST40)的同时,再进行一次同样的fMRI扫描。DARTEL-VBM分析：对比受试者接受阶段性治疗前后大脑灰白质体积差异。数据分析使用基于MATLAB R2009a的SPM8软件.结果1.与非食物图片视觉刺激相比,肥胖儿童接受食物图片视觉刺激后脑干、左侧丘脑、双侧眶额皮质、岛叶皮质、海马及海马旁回、后扣带回、楔前叶、小脑以及枕叶等多个脑区明显激活；2.与针灸前相比,针灸后接受食物图片视觉刺激时,脑干、双侧眶额皮质、岛叶皮质、后扣带回、枕叶及左侧小脑的激活明显受抑制；3. DARTEL-VBM结果：右侧额上回,小脑后叶椎体灰质体积减小,右侧中央前回灰质体积增大；左侧海马旁区梭状回,桥脑及中央前回区白质体积减小；右侧楔前叶白质体积增大；4.治疗前肥胖受试者与体重正常对照组比较,小脑及外侧苍白球灰质体积增大,桥脑及小脑白质体积减小；治疗后肥胖受试者与体重正常对照组比较,外侧苍白球灰质体积显著增大,桥脑白质体积增大,原先位于小脑的灰质及白质差异区未显现。结论针灸减肥疗法不仅能够对中枢产生短时的影响,并有可能导致皮层的重建；正常体重者与肥胖者间可能存在大脑细微结构的差异。
第三部分应用中枢神经影像学及免疫组化的方法研究肥胖模型大鼠
目的应用肥胖动物模型进一步深入研究肥胖发生的中枢机制以及针灸减肥的作用机理。方法利用高脂饲料诱导SD大鼠,构建肥胖模型动物。最终成模11只(雌性6只)。15只大鼠作为正常体重对照组。应用静息态功能磁共振及扩散张量成像手段对鼠脑成像并分析。同时,应用针灸疗法治疗肥胖大鼠,并通过对大鼠腹部脂肪体积测定来确认针灸疗法的作用。研究末期,将大鼠处死并取脑及肝脏组织进行病理及免疫组化的研究。结果1.针灸减肥疗法能有效减低肥胖大鼠的体重,并降低大鼠腹腔内脂肪的比例(P<0.05)；2.大鼠神经影像学的研究发现,肥胖大鼠与正常体重对照组在多个感兴趣区存在功能差异；静息态fMRI结果,肥胖组大鼠双侧海马及右侧中丘脑较活跃,枕叶皮层活跃度较低；而针灸疗法能使大鼠的双侧嗅球,额叶皮层、右侧岛叶及海马活跃增强,而右侧丘脑活跃度减低；3.DTI从另一个角度研究大鼠脑功能差异；肥胖鼠桥脑、嗅球及杏仁核部分DTI参数与对照组存在差异(P<0.05)。桥脑可能存在性别差异；在对影响肥胖发生因素的logistic回归分析中,年龄、纤维束的ADC (apparent diffusion coefficient,表观扩散系数)值及感兴趣区的FA(Fraction Anisotropy,分数各向异性)值与肥胖的发生呈正相关；4.大鼠肝脏病理组织的分析,提示针灸治疗对内脏脂质的分布可能存在影响；脑区免疫组化分析发现,不同脑区的神经递质染色程度不同；肥胖大鼠部分脑区递质染色程度与对照组相异。肥胖组杏仁核及海马较对照组有较高的5-HT染色,在岛叶及桥/小脑对照组5-HT染色更高；瘦素染色程度较低,肥胖组桥小脑区域染色程度较对照组高,对照组在岛叶也存在5-HT染色；神经肽Y在肥胖组的染色程度较对照组高；接受针灸治疗的肥胖大鼠较未接受针灸治疗的肥胖大鼠,各脑区三种神经递质染色程度增强。结论肥胖的发生与神经中枢的功能异常以及解剖、生理基础存在关联；针灸减肥法可能存在分子水平的作用机制。
Part I Meta-analysis of fMRI studies associated with food and appetite
Purpose:To determine the concurrence in the brain regions activated in response to different food and to assess the modulating effects of hunger state and the food's energy content. Materials and Method:Signed differential mapping (SDM) voxel-wise meta-analysis was carried out on fMRI data from healthy normal weight subjects in order to compare the different activated brain regions when food and non-food pictures were shown separately, when subjects were in hunger or full, and when the food contains different energy. Results:1. Compared to non-food picture, bilateral posterior fusiform gyrus, the left lateral orbitofrontal cortex (OFC) and the left middle insuia were activated;2. Hunger modulated the response to food pictures in the right amygdala and left lateral OFC;3. Energy content modulated the response in the hypothalamus and ventral striatum. Limitation According to the results, the concurrence between studies was moderate, meaning other factors might have effects to activation. Regions that were not mentioned in the studies might take a part in the moderation. Conclusions:To reduce neurofunctional activation in posterior fusiform gyrus, OFC, amygdale, hypothalamus and ventral striatum might suppress the desire for food.
Part II Effects of Acupuncture Therapy on Obese Adolescence's Central Nervous System
Purpose:To investigate obese adolescence's brain with acupuncture therapy via fMRI and voxel-based morphometry using Diffeomorphic Anatomic Registration through Exponentiated Lie algebra algorithm (DARTEL) approach. Materials and Method:10subjects with simple obesity (M:7, F:3, Aged14-18, right handed, BMI29.03±4.81kg/m2) underwent periodical acupuncture therapy and were taken high resolution T1W MR Images of the brain before and after the therapy respectively. Another10gender-and age-matched volunteers with normal BMI (right handed, BMI25.05±5.02kg/m2) were enrolled as control group. fMRI methods:Activation regions were caculated by fMRI when food pictures were shown to subjects. fMRI would be performed once more during stimulation of two acupoints (ST36and ST40). DARTEL-VBM analysis:Compare the regional volumetric difference in grey/white matter between before and after the periodic acupuncture therapy. All the analysis was carried out using SPM8software on MATLAB7.8.0.347platform. Results:1. Brainstem, left thalamus, bilateral OFC, insular cortex, hippocampus and parahippocampal gyrus, posterior cingulate gyrus, precuneus lobe, cerebellum, occipital lobe were more activated when food pictures were shown.2. Acupuncture therapy suppressed activation in brainstem, bilateral OFC, insular cortex, posterior cingulate gyrus, occipital lobe and left cerebellum.3. DARTEL results:Partial grey matter decrease was found in cortices of right gyri frontalis superior and pyramis oi cerebellum posterior lobe and that volume increase in gyri centralis anterior between subjects before and after acupuncture therapy. Left fusiform in parahippocampa gyrus, pontine and precentral gyrus were found decrease in volume of white matter. Volume oi white matter in right precuneus turned out to be increased. Obese subjects compared to control group showed volume increase in GM of cerebellum and lateral globus pallidus and volume decrease in WM of pontine and cerebellum. After the therapy, Obese subjects compared to control group showed even larger GM increase in lateral globus palidus and larger pontine WM increase. Previous differences in cerebellum in both GM and WM were not shown. Conclusion:1. Acupuncture therapy might not only have short-term effects on the neural activation but also might influence the process of brain development, leading to reorganization of cortices.2. Microstructural difference might exit in brain because of obesity.
Part III Assessment of Obesity in Modeled Rats with Neuroimages and Immunohistochemical Methods
Purpose:To get further understanding of neural mechanism in obesity and effects of acupuncture therapy by studying obese rats. Materials and Method:Using high fat diets to create obese modeled SD rats.11rats (Female,6) were modeled.15rats with normal weight were set to be control. Rest-fMRI and Diffusion Tensor Imaging were used to image and analyze rats'brain. Meanwhile acupuncture was performed on obese rats to confirm its effect with MR abdominal imaging measuring fat distribution. In the end, rats were sacrificed for its brain and liver needed in immunohistochemical experiments. Results:1. Acupuncture therapy could effectively help obese rats to lose weight as well as reducing proportion of fat within abdomen (P<0.05).2. Neuroimaging in rats suggested functional differences in several regions between rats with normal weight and the obese. Rest-state fMRI showed that bilateral hippocampus and right medial thalamus more active in obese ras than that of control, while occipital cortex was opposite. Acupuncture therapy would enhance the activation of bilateral olfactory bulb, frontal cortex, right insula and hippocampus while deactivating right thalamus.3. DTI showed another perception on the brain function. There seemed different between obese and normal rats in regions of ponstine, olfactory bulb and amygdale (P<0.05). Ponstine might be with sexual difference in structure. Logistic regression about risk factors causing obesity was carried out and found that fraction anisotropy (FA), ADC (apparent diffusion coefficients) of fibers and ages were the risks. They were all positively associated with obesity.4. Pathological exam on rats' liver suggested that acupuncture therapy might be able to change fat distribution within organs. In immunohistochemical experiments, regions of brain were found dyed in different degrees by antibodies of neural transmitters. The difference might exist between obese rats and normal ones. Compared to the control, amygdale and hippocampus were dyed in larger scales in obese rats with5-HT, while in insular lobe, ponstine and cerebellum were opposite. Leptin was not strongly dyed, yet ponstine and cerebellum were in larger scales in obese rats, while insular lobe was found dyed in the normal rats. NPY showed a greater scale in all regions in obese rats. And acupuncture therapy was considered to enhance NPY in all regions of rats' brain. Conclusion:Neural abnormalities and structural difference as well as physiological changes in body were associated with obesity. Acupuncture therapy might have effects on molecular level.
目的确认大脑功能区对食物刺激反应的一致性,借以探讨中枢对饥饿状态及含不同热量食物反应的调节机制。方法应用SDM体素Meta分析法对正常体重受试者fMRI数据进行分析,分析内容包括：食物与非食物刺激下脑区兴奋性的差异；饥饿状态下的中枢调节；不同热量食物刺激对中枢的影响。结果1.与非食物图片相比,食物图片刺激时具有较强激活的脑区包括：双侧后梭状回,左外侧眶额回及左侧中间岛叶；2.饥饿状态下,影响中枢调节的脑区包括：右侧杏仁核,左外侧眶额回；3.不同热量食物刺激影响的脑区包括：下丘脑及腹侧纹状体。局限性综合上述的结果,脑区激活的一致性仅在中等水平,这意味着实验方法对结果仍存在诸多的影响；此外,其它的脑区仍可能参与食欲及食物刺激的中枢调节。结论降低梭状回,眶额回,杏仁核,下丘脑及腹侧纹状体的兴奋水平可能抑制食欲。
第二部分针灸减肥治疗对肥胖青少年中枢神经系统的影响
目的应用fMRI及DARTEL-VBM分析方法探讨针灸减肥对肥胖青少年中枢神经系统的影响。方法10名单纯性肥胖青少年(男7,女3,14～18岁,右利手,体重指数：29.03±4.81kg/m2)行阶段性针灸减肥治疗,在治疗前、后分别行颅脑高分辨三维T1加权成像及fMRI扫描；同时招募10名年龄和性别相匹配的健康自愿者(右利手,体重指数：25.05±5.02kg/m2)作为对照组。fMRI方案：观察受试者在接受食物图片视觉刺激后的中枢反应,然后用手法针灸左侧足三里(ST36)及右侧丰隆(ST40)的同时,再进行一次同样的fMRI扫描。DARTEL-VBM分析：对比受试者接受阶段性治疗前后大脑灰白质体积差异。数据分析使用基于MATLAB R2009a的SPM8软件.结果1.与非食物图片视觉刺激相比,肥胖儿童接受食物图片视觉刺激后脑干、左侧丘脑、双侧眶额皮质、岛叶皮质、海马及海马旁回、后扣带回、楔前叶、小脑以及枕叶等多个脑区明显激活；2.与针灸前相比,针灸后接受食物图片视觉刺激时,脑干、双侧眶额皮质、岛叶皮质、后扣带回、枕叶及左侧小脑的激活明显受抑制；3. DARTEL-VBM结果：右侧额上回,小脑后叶椎体灰质体积减小,右侧中央前回灰质体积增大；左侧海马旁区梭状回,桥脑及中央前回区白质体积减小；右侧楔前叶白质体积增大；4.治疗前肥胖受试者与体重正常对照组比较,小脑及外侧苍白球灰质体积增大,桥脑及小脑白质体积减小；治疗后肥胖受试者与体重正常对照组比较,外侧苍白球灰质体积显著增大,桥脑白质体积增大,原先位于小脑的灰质及白质差异区未显现。结论针灸减肥疗法不仅能够对中枢产生短时的影响,并有可能导致皮层的重建；正常体重者与肥胖者间可能存在大脑细微结构的差异。
第三部分应用中枢神经影像学及免疫组化的方法研究肥胖模型大鼠
目的应用肥胖动物模型进一步深入研究肥胖发生的中枢机制以及针灸减肥的作用机理。方法利用高脂饲料诱导SD大鼠,构建肥胖模型动物。最终成模11只(雌性6只)。15只大鼠作为正常体重对照组。应用静息态功能磁共振及扩散张量成像手段对鼠脑成像并分析。同时,应用针灸疗法治疗肥胖大鼠,并通过对大鼠腹部脂肪体积测定来确认针灸疗法的作用。研究末期,将大鼠处死并取脑及肝脏组织进行病理及免疫组化的研究。结果1.针灸减肥疗法能有效减低肥胖大鼠的体重,并降低大鼠腹腔内脂肪的比例(P<0.05)；2.大鼠神经影像学的研究发现,肥胖大鼠与正常体重对照组在多个感兴趣区存在功能差异；静息态fMRI结果,肥胖组大鼠双侧海马及右侧中丘脑较活跃,枕叶皮层活跃度较低；而针灸疗法能使大鼠的双侧嗅球,额叶皮层、右侧岛叶及海马活跃增强,而右侧丘脑活跃度减低；3.DTI从另一个角度研究大鼠脑功能差异；肥胖鼠桥脑、嗅球及杏仁核部分DTI参数与对照组存在差异(P<0.05)。桥脑可能存在性别差异；在对影响肥胖发生因素的logistic回归分析中,年龄、纤维束的ADC (apparent diffusion coefficient,表观扩散系数)值及感兴趣区的FA(Fraction Anisotropy,分数各向异性)值与肥胖的发生呈正相关；4.大鼠肝脏病理组织的分析,提示针灸治疗对内脏脂质的分布可能存在影响；脑区免疫组化分析发现,不同脑区的神经递质染色程度不同；肥胖大鼠部分脑区递质染色程度与对照组相异。肥胖组杏仁核及海马较对照组有较高的5-HT染色,在岛叶及桥/小脑对照组5-HT染色更高；瘦素染色程度较低,肥胖组桥小脑区域染色程度较对照组高,对照组在岛叶也存在5-HT染色；神经肽Y在肥胖组的染色程度较对照组高；接受针灸治疗的肥胖大鼠较未接受针灸治疗的肥胖大鼠,各脑区三种神经递质染色程度增强。结论肥胖的发生与神经中枢的功能异常以及解剖、生理基础存在关联；针灸减肥法可能存在分子水平的作用机制。
Part I Meta-analysis of fMRI studies associated with food and appetite
Purpose:To determine the concurrence in the brain regions activated in response to different food and to assess the modulating effects of hunger state and the food's energy content. Materials and Method:Signed differential mapping (SDM) voxel-wise meta-analysis was carried out on fMRI data from healthy normal weight subjects in order to compare the different activated brain regions when food and non-food pictures were shown separately, when subjects were in hunger or full, and when the food contains different energy. Results:1. Compared to non-food picture, bilateral posterior fusiform gyrus, the left lateral orbitofrontal cortex (OFC) and the left middle insuia were activated;2. Hunger modulated the response to food pictures in the right amygdala and left lateral OFC;3. Energy content modulated the response in the hypothalamus and ventral striatum. Limitation According to the results, the concurrence between studies was moderate, meaning other factors might have effects to activation. Regions that were not mentioned in the studies might take a part in the moderation. Conclusions:To reduce neurofunctional activation in posterior fusiform gyrus, OFC, amygdale, hypothalamus and ventral striatum might suppress the desire for food.
Part II Effects of Acupuncture Therapy on Obese Adolescence's Central Nervous System
Purpose:To investigate obese adolescence's brain with acupuncture therapy via fMRI and voxel-based morphometry using Diffeomorphic Anatomic Registration through Exponentiated Lie algebra algorithm (DARTEL) approach. Materials and Method:10subjects with simple obesity (M:7, F:3, Aged14-18, right handed, BMI29.03±4.81kg/m2) underwent periodical acupuncture therapy and were taken high resolution T1W MR Images of the brain before and after the therapy respectively. Another10gender-and age-matched volunteers with normal BMI (right handed, BMI25.05±5.02kg/m2) were enrolled as control group. fMRI methods:Activation regions were caculated by fMRI when food pictures were shown to subjects. fMRI would be performed once more during stimulation of two acupoints (ST36and ST40). DARTEL-VBM analysis:Compare the regional volumetric difference in grey/white matter between before and after the periodic acupuncture therapy. All the analysis was carried out using SPM8software on MATLAB7.8.0.347platform. Results:1. Brainstem, left thalamus, bilateral OFC, insular cortex, hippocampus and parahippocampal gyrus, posterior cingulate gyrus, precuneus lobe, cerebellum, occipital lobe were more activated when food pictures were shown.2. Acupuncture therapy suppressed activation in brainstem, bilateral OFC, insular cortex, posterior cingulate gyrus, occipital lobe and left cerebellum.3. DARTEL results:Partial grey matter decrease was found in cortices of right gyri frontalis superior and pyramis oi cerebellum posterior lobe and that volume increase in gyri centralis anterior between subjects before and after acupuncture therapy. Left fusiform in parahippocampa gyrus, pontine and precentral gyrus were found decrease in volume of white matter. Volume oi white matter in right precuneus turned out to be increased. Obese subjects compared to control group showed volume increase in GM of cerebellum and lateral globus pallidus and volume decrease in WM of pontine and cerebellum. After the therapy, Obese subjects compared to control group showed even larger GM increase in lateral globus palidus and larger pontine WM increase. Previous differences in cerebellum in both GM and WM were not shown. Conclusion:1. Acupuncture therapy might not only have short-term effects on the neural activation but also might influence the process of brain development, leading to reorganization of cortices.2. Microstructural difference might exit in brain because of obesity.
Part III Assessment of Obesity in Modeled Rats with Neuroimages and Immunohistochemical Methods
Purpose:To get further understanding of neural mechanism in obesity and effects of acupuncture therapy by studying obese rats. Materials and Method:Using high fat diets to create obese modeled SD rats.11rats (Female,6) were modeled.15rats with normal weight were set to be control. Rest-fMRI and Diffusion Tensor Imaging were used to image and analyze rats'brain. Meanwhile acupuncture was performed on obese rats to confirm its effect with MR abdominal imaging measuring fat distribution. In the end, rats were sacrificed for its brain and liver needed in immunohistochemical experiments. Results:1. Acupuncture therapy could effectively help obese rats to lose weight as well as reducing proportion of fat within abdomen (P<0.05).2. Neuroimaging in rats suggested functional differences in several regions between rats with normal weight and the obese. Rest-state fMRI showed that bilateral hippocampus and right medial thalamus more active in obese ras than that of control, while occipital cortex was opposite. Acupuncture therapy would enhance the activation of bilateral olfactory bulb, frontal cortex, right insula and hippocampus while deactivating right thalamus.3. DTI showed another perception on the brain function. There seemed different between obese and normal rats in regions of ponstine, olfactory bulb and amygdale (P<0.05). Ponstine might be with sexual difference in structure. Logistic regression about risk factors causing obesity was carried out and found that fraction anisotropy (FA), ADC (apparent diffusion coefficients) of fibers and ages were the risks. They were all positively associated with obesity.4. Pathological exam on rats' liver suggested that acupuncture therapy might be able to change fat distribution within organs. In immunohistochemical experiments, regions of brain were found dyed in different degrees by antibodies of neural transmitters. The difference might exist between obese rats and normal ones. Compared to the control, amygdale and hippocampus were dyed in larger scales in obese rats with5-HT, while in insular lobe, ponstine and cerebellum were opposite. Leptin was not strongly dyed, yet ponstine and cerebellum were in larger scales in obese rats, while insular lobe was found dyed in the normal rats. NPY showed a greater scale in all regions in obese rats. And acupuncture therapy was considered to enhance NPY in all regions of rats' brain. Conclusion:Neural abnormalities and structural difference as well as physiological changes in body were associated with obesity. Acupuncture therapy might have effects on molecular level.
引文
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