肥胖者的功能影像與心理生物標記相關性之研究

The correlation between functional neuroimaging and psychobiological markers in obese patients

李承叡(Cheng-Jui Li)

指導教授 ： 翁駿程

中山醫學大學/醫學科技學院/生物醫學科學學系碩士班/碩士(2016年)

摘要

近年來肥胖的問題在社會上越來越受到關注，而且美國每年大約有300,000人死於肥胖相關疾病，並且與吸菸並列第2大可預防的死因。除此之外，世界衛生組織也預測肥胖可能會取代傳統影響健康的因素像是營養不良和傳染病成為影響健康的最大公共健康問題。以前的研究也發現大腦網路的改變會影響肥胖者的飲食行為。因此本研究挑選了對我們影響非常廣泛的疾病”肥胖”作為研究的目標並且透過許多種不同的功能性分析方式對肥胖進行探討，希望能夠找出與肥胖相關的生物標誌並作為未來診斷的依據。
我們收集了20位肥胖患者以及 30位健康受試者，分別接受1.5T MRI (Magnetic resonance imaging) 之靜息態功能性磁振造影 (resting-state functional magnetic resonance imaging, rs-fMRI)和T1 權重造影(T1 weighted imaging, T1WI)。所有的受試者都會接受臨床精神科醫生的診斷並且接受醫院臨床焦慮與憂鬱量表(hospital anxiety and depression scale, HADS)、愛荷華賭局作業(Iowa gambling task, IGT)、干擾指數(interference index)和停止訊號反應時間量表(stop-signal reaction time, SSRT)之評估。功能性分析的部分則進行了功能性連結(functional connectivity, FC)、低頻振福波動(amplitude of low-frequency fluctuations, ALFF)、區域同質性(regional homogeneity, ReHo)、基於體素之統計分析(voxel-based statistical analysis, VBA)、圖論分析(graph theoretical analysis)、基於網路之統計分析(network-based statistical analysis, NBS)、基於體素之形態學分析(voxel-based morphometry, VBM)、以及認知與心理量表分數與影像的相關性分析。
結構分析的部分，肥胖症患者在左側杏仁核呈現灰質體積增加，同時也和BMI呈現顯著的正相關，並且在視丘 (thalamus) 與殼核 (putamen) 呈現灰質體積減少也和HADS和IGT呈現顯著的負相關。肥胖症患者在眶額皮質 (orbitofrontal cortex, OFC) 和視丘的部分呈現顯著的白質體積增加並且與身體質量指數(body mass index, BMI)有顯著的正相關。功能分析的部分，肥胖患者在雙側前扣帶迴皮質 (anterior cingulate cortex, ACC) 功能性連結較高，而在預設模式神經網路 (default mode network, DMN) 的額葉功能性連結較低。肥胖患者在腹內側前額葉 (ventral medial prefrontal cortex, vmPFC) 與後扣帶迴皮質 (posterior cingulate cortex) 的mfALFF訊號呈現下降的趨勢，並且與焦慮量表在vmPFC和OFC呈現顯著負相關，也與憂鬱量表在背內側前額葉 (dorsal medial prefrontal cortex, dmPFC) 和楔前葉 (precuneus) 呈現顯著負相關，同時也和IGT量表在前扣帶迴皮質呈現顯著正相關。除此之外，肥胖患者在背內側前額葉 (dorsal medial prefrontal cortex, dmPFC) 與楔狀葉 (cuneus) 的mReHo訊號呈現下降的趨勢，並且與BMI在dmPFC呈現顯著負相關，也與焦慮量表在vmPFC呈現顯著負相關，同時也和IGT在 vmPFC 呈現顯著負相關。而圖論分析的結果發現肥胖患者大腦網路的局部分隔度呈現顯著的下降並且全球整合度顯著的上升。
研究顯示肥胖和暴飲暴食的人對食物的渴望與成癮的模式非常相似。研究認為成癮是由兩個單獨又相互影響的系統之間失衡的產物，分別為一個與立即性疼痛和快樂相關的杏仁核依賴的衝動系統，和一個與長期結果相關的眼眶額葉依賴的反思系統。而成癮可能是由於這兩個系統的功能失常所造成。許多與成癮相關的研究都指出成癮者會對成癮物質呈現強烈的衝動反應，而且通常與杏仁核有明顯的依賴性。我們的研究顯示肥胖組在低頻震幅的組間分析的部分有明顯的訊號增強且在形態學灰質組間分析的部分也有明顯的體積增加。除此之外，我們還發現杏仁核體積也與身體質量指數有找到明顯的正相關。因此，我們可以推測杏仁核體積的增加可能與過度反應的獎勵機制和衝動有關。而我們在殼核發現的體積減少的情況可能會透過皮質邊緣系統的迴路抑制眼眶額葉皮質，並且同時影響其對不當行為的抑制最後導致肥胖。
我們透過臨床使用的影像分析技術對肥胖進行探討，透過結構、功能、量表相關性和網路的分析技術發現了許多與肥胖相關的心理生物標記，希望未來能夠應用於肥胖相關疾病的診斷與研究上。

關鍵字

肥胖 ； 靜息態功能性磁振造影 ； 功能性連結 ； 圖論分析 ； 基於網路之統計分析 ； 基於體素的型態學測量

並列摘要

There are 300,000 deaths attributed to overweight- and obesity-related diseases in the United States each year, making obesity the second leading cause of preventable death behind tobacco use. Furthermore, the World Health Organization (WHO) predicts that obesity may soon replace more traditional public health concerns such as under-nutrition and infectious diseases as the most significant cause of poor health. Previous studies have discovered alterations in the cerebral networks that regulate ingestive behavior in obese subjects. Kullmann found an altered functional connectivity strength in obese subjects in the default mode network (DMN) and temporal lobe network, which are associated with food regulation. We attempted to identify the obesity-related imaging marker for future diagnosis and research using multimodal fMRI techniques and analysis.
Fifty participants were recruited, including 20 obesity patients and 30 healthy controls. All participants were clinically diagnosed by psychiatrists using the hospital anxiety and depression scale (HADS), Iowa gambling task (IGT), and interference index and stop-signal reaction time (SSRT). All images were acquired using a 1.5 Tesla Phillips MRI system (Ingenia, Phillips, Netherlands). All participants underwent resting-state functional magnetic resonance imaging (rs-fMRI) and T1-weighted imaging. We used a full range of analytical methods and report the complete results for obesity patients. The data analysis included assessments of functional connectivity (FC), the amplitude of low-frequency fluctuations (ALFF), regional homogeneity (ReHo), voxel-based statistical analysis (VBA), graph theoretical analysis (GTA), network-based statistical analysis (NBS), and voxel-based morphometry (VBM). Correlations between the images and clinical inventory scores were also calculated.
In morphometry, obesity patients showed higher gray matter (GM) volumes in the left amygdala, and a positive correlation with body mass index (BMI); lower GM volumes in the right thalamus and putamen, and negative correlations with HADS and IGT; and increased white matter (WM) volumes in the orbitofrontal cortex (OFC) and thalamus, and a positive correlation with BMI. In terms of functional connectivity, the obesity group showed increased functional connectivity in the bilateral anterior cingulate cortex (ACC) and decreased functional connectivity in the DMN. The obesity group exhibited a decreased mfALFF in the ventral medial prefrontal cortex (vmPFC) and precuneus; negative correlations with anxiety in the OFC, insula, vmPFC, dorsal medial prefrontal cortex (dmPFC); positive correlations with depression in the amygdala, vmPFC, and precuneus; and positive correlations with IGT in the ACC, precuneus, and postcentral gyrus. Moreover, the obesity group showed decreased mReHo in the right dmPFC, precuneus, and postcentral gyrus; a negative correlation with BMI in the dmPFC; negative correlations with anxiety in the OFC; and a positive correlation with IGT in the insula and a negative correlation in the vmPFC. In graph theory analysis, the obesity patients showed a significant decrease in local segregation and a significant increase in global integration.
Many studies have indicated that the desire of obese people for food is similar to that observed in addiction models of substance dependence. It is the product of an imbalance between two separate, but interacting, neural systems: 1) an impulsive, amygdala-dependent system for signaling pain or pleasure related to immediate prospects, and 2) a reflective, orbitofrontal-dependent system for signaling the prospects for the future. An imbalance in certain conditions may lead to the dysfunction of these two systems. Many addiction-related studies have shown that addicts display exaggerated autonomic responses toward addictive substances, which has been shown to be dependent on the integrity of the amygdala. The amygdala shows significantly increased functional connectivity and GM volumes based on the results of the between-group mfALFF and VBM analyses. We also calculated the correlation with BMI and found a positive correlation in the amygdala as well. Thus, we speculate that the enlargement of the left amygdala might reflect a sustained hyperactive reaction of the reward system. The putamen is part of the cortico-limbic circuits, and a reduction of its volume will contribute to the reduction of OFC activation, thereby affecting OFC for inappropriate behavior inhibition and, ultimately, the development of obesity.
We used multimodal MRI techniques and analyses to investigate obesity. We found significantly structural and functional differences of several brain regions and networks between the two groups, and the correlation with inventory is discussed. Our results may provide potential structural and functional imaging markers for clinical diagnosis and future research, and they may improve our understanding of the underlying pathophysiology of obesity.

並列關鍵字

obesity ； resting-state functional magnetic resonance imaging (rs-fMRI) ； functional connectivity (FC) ； graph theoretical analysis (GTA) ； network-based statistical analysis (NBS) ； voxel-based morphometry (VBM)

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