《中国居民营养与慢性病状况报告（2020年）》显示，我国超过一半（50.7%）成人超重和肥胖，日趋严重的肥胖问题已经成为威胁人民生命健康的第三大致死因素。肥胖不仅引起代谢综合征、心血管疾病和癌症的发生，还严重影响大脑认知功能。《“健康中国2030”规划纲要》明确指出降低超重肥胖人口增速，引导合理膳食和促进身心健康。因此，针对肥胖致病和干预机制的研究，对于抗击严峻的肥胖问题、改善和提高人民生命健康水平具有重要的研究价值和临床意义。

不受控制的饮食行为和高热量食物的过量摄入是导致肥胖的主要原因，而在引起异常饮食行为的众多因素中，情绪性进食行为作为一个重要因素，其神经机制尚不明确。缰核（Habenular, Hb）作为调控以反奖赏为基础的关键动机决策和情绪节点，参与编码负性情绪相关的注意偏向和动机行为，且与摄食调节相关能量稳态和享乐系统之间交互，缰核功能结构异常可能诱发负性情绪相关不健康摄食行为，增加肥胖患病和发展恶化风险。减重手术是目前临床治疗重度肥胖唯一长期有效的方式，术后改善的情绪性进食行为与降低的体重密切相关，提示减重手术可能改善了肥胖患者大脑与情绪性进食相关脑区的功能结构。然而，以往肥胖致病和减重手术干预机制研究，大多关注食物奖赏和抑制控制相关饮食行为和大脑功能结构变化，忽视了缰核功能结构变化这一重要因素对于肥胖的影响以及在减重手术干预调节机制中发挥的重要作用。论文假设：缰核功能紊乱影响肥胖状态，可能与摄食调节相关能量稳态/享乐系统脑区间的异常交互有关，而减重手术通过调节这一功能结构连接异常，实现改善饮食行为和有效减重效果。因此，本文开展了以下创新性工作：

研究工作一：减重手术促进缰核灰质体积可塑性恢复的影像学研究。以往研究证实肥胖状态与食物奖赏和抑制控制相关功能脑区灰质体积的改变密切相关，但是其与缰核灰质体积之间的关系尚不清楚。本章通过肥胖与正常体重对照组横向对比、减重手术干预前后（术前、术后1年）纵向追踪的对照实验范式，使用结构磁共振成像和基于体素的形态学测量分析方法，探究肥胖相关的和减重手术诱导的全脑灰质体积变化。研究发现，肥胖组缰核灰质体积显著低于正常体重对照组，而减重术后一年缰核灰质体积显著增加，且达到了与正常对照组无显著差异水平。同时，减重术后增加的缰核灰质体积和降低的体质指数、去抑制进食得分呈现负相关性。研究表明，减重手术诱导肥胖相关的缰核脑区可塑性恢复，且恢复的缰核结构将有助于术后长期饮食行为改善和有效减重。

研究工作二：减重手术改善缰核活动和静息态功能连接的影像学研究。基于上节研究明确的减重手术改善肥胖相关异常缰核结构发现。本章采用相同的对照实验范式、静息态功能磁共振成像，以及基于数据驱动的功能连接密度映射和功能连接分析方法，进一步探究肥胖相关的和减重手术引起的缰核活动和功能连接的异常和变化。研究发现，减重术后1年，1）肥胖组相比于正常对照组降低的丘脑背内侧核、缰核、和额上回/额中回脑区功能连接密度显著增加，而增加的后扣带/楔前叶功能连接密度显著降低。2）肥胖相关增强的缰核与内感受处理（脑岛）、躯体感觉与运动处理（中央前回，罗兰迪克）脑区间功能连接强度在术后显著减弱；而减弱的缰核与摄食调节相关两大系统（下丘脑，丘脑，尾状核）脑区间功能连接强度在术后增强，且上述改善的缰核相关功能连接与术后降低的体质指数、食物成瘾、情绪性进食、以及饥饿水平显著相关。3）手术增加的缰核灰质体积和减弱的缰核和脑岛间功能连接相互影响，共同作用促进术后有效减重。研究表明，减重手术改善了肥胖相关的缰核功能紊乱，可能与增强的饥饿/饱腹相关能量感知、非饥饿状态下的摄食厌恶敏感性、以及与摄食调节相关两大系统脑区间的功能再平衡有关。

研究工作三：减重手术改善缰核与下丘脑和中脑边缘系统结构连接的影像学研究。基于上一章减重手术改善肥胖患者缰核与摄食调节相关两大系统脑区间连接的功能像结果，本章将从结构连接研究角度进一步探究缰核在肥胖致病和减重手术干预中的作用机制。采用相同的对照实验范式，选取与缰核存在解剖学联系且参与摄食调节的两大系统脑区作为感兴趣区域，使用弥散张量成像和概率纤维追踪技术，探究减重手术改变缰核相关脑区的结构连接。研究发现，相比于正常体重组，肥胖组缰核与能量稳态系统下丘脑和包含额上回、杏仁核、眶额回在内享乐系统脑区间结构连接显著减弱，而减重手术显著增强了上述脑区间的结构连接，且达到了与正常对照组无显著差异的水平。相关分析发现，基线状态下，肥胖患者缰核和双侧额上回脑区间结构连接与去抑制性进食呈现负相关性。术后1年，手术增强的缰核和下丘脑脑区间结构连接与降低的汉密尔顿抑郁、外界刺激性进食得分呈现负相关性；增强的缰核和杏仁核脑区间结构连接与降低的情绪性进食得分呈现负相关性；增强的缰核和眶额回脑区间结构连接与降低的体质指数呈现负相关性。研究表明，减重手术改善了缰核和摄食调节相关两大系统脑区间的结构连接异常，术后结构连接的可塑性恢复可能与缰核和两大系统之间的功能再平衡有关。

综上所述，减重手术改善了肥胖造成的缰核相关脑区功能结构异常，术后负性情绪相关不健康摄食行为的改善机制，可能与非饥饿状态下摄食厌恶敏感性增强、与摄食调节相关能量稳态和享乐系统脑区间的功能结构再平衡密切相关，推动实现术后长期饮食行为改善和有效减重。

According to the “Report on the Nutrition and Chronic Diseases Status of Chinese Residents 2020”, the percentage of overweight and obese subjects of Chinese adults was over 50.7%, and the growing obesity epidemic has become the third major death factor threatening people’s life and health. Obesity not only causes metabolic syndrome, cardiovascular disease and cancer, but also negatively affects brain cognitive function, diminishing the quality of life and increasing health care costs. The “Healthy China 2030” initiative, emphasizes reducing the growth rate of the overweight and obese population, guiding reasonable eating behaviors, and promoting physical and mental health. Thus, focusing on the pathogenesis and intervention mechanisms of obesity has clinical significance for combating severe obesity problems and improving population health.

Long-term eating disorder and excessive intake of high-calorie foods play a crucial role in weight gain and obesity. Among the numerous factors inducing eating disorder, emotional eating is one of the primary causes, but the underlying neural mechanisms remain unclear. The habenular (Hb), as a critical node to control antireward-based decision-making and emotions, not only participates in encoding attentional bias and motivational behaviors, but also has functional and structural connectivity (FC/SC) with regions/circuits associated with homeostatic and hedonic regulation. Disrupted interaction between the Hb and homeostatic/hedonic systems might promote emotional related eating disorder and cause obesity. Bariatric surgery, including laparoscopic sleeve gastrectomy (LSG), is currently the most effective treatment for morbid obesity. Improved emotional eating behaviors are associated with weight-loss following surgery, suggesting that bariatric surgery may promote recovery of obesity-associated brain functional and structural abnormalities in regions involved with negative emotion processing. However, previous studies mainly focused on brain functional and structural abnormalities in regions involved with food reward and inhibitory control, few studies investigated Hb-related brain functional and structural changes and how bariatric surgery alters its FC/SC as well as the neural mechanisms in post-surgical weight loss. In the current study, we hypothesized that disrupted Hb connection could be a possible contributor for obesity, which might be associated with the disrupted interactions with regions involved with homeostatic/hedonic regulation, whereas bariatric surgery normalized these FCs/SCs, and would contribute to improved eating behaviors and long-term weight-loss. The primary innovates of this study are listed below:

Firstly, the neuroimaging study on LSG-induced neuroplastic structural recovery in the Hb. Neuroimaging studies showed close associations between obesity and abnormal gray-matter volume (GMV) in brain regions involved with reward and inhibitory control, but little attention has been paid to the Hb and its association with negative emotional-related eating behaviors and body weight in patients with obesity. Therefore, we employed structural MRI and voxel-based morphometry analysis to assess obesity-related and LSG-induced changes in GMV in the Hb in 56 patients with obesity at pre-LSG (PreLSG) and 12-months post-LSG (PostLSG₁₂), and compared them with 78 normal weight (NW) controls. Results showed that: 1) LSG-induced whole brain GMV changes partially overlapped with those between PreLSG and NW, including the Hb. 2) PreLSG relative to NW showed lower Hb GMV, whereas LSG had increased Hb GMV at PostLSG₁₂, which was equivalent to that in NW. 3) Correlation analysis showed that increased Hb GMV was correlated with reduced body mass index (BMI) and disinhibition score following LSG. These findings suggested that LSG may promote neuroplastic structural recovery in the Hb, which might contribute to improved eating behaviors and weight-loss.

Secondly, neuroimaging study on LSG-induced alterations in resting-state activity of Hb and related resting-state FC (RSFC). Since LSG can promote recovery of obesity-related brain structural abnormalities in the Hb, we employed FC density (FCD) mapping and seed-based RSFC to examine obesity-related and LSG-induced alterations in the Hb in patients with obesity at PreLSG and PostLSG₁₂, and in NW controls. Results showed that: 1) PreLSG relative to NW showed decreased FCD in the mediodorsal thalamic nucleus, Hb, superior/middle frontal gyri (SFG/MFG), and increased FCD in the posterior cingulate cortex/precuneus, whereas LSG normalized these FCDs at PostLSG₁₂. 2) PreLSG relative to NW showed greater RSFCs of Hb-insula, Hb-precentral gyrus, Hb-rolandic_oper, and weaker RSFCs of Hb-thalamus, Hb-hypothalamus (Hy), and Hb-caudate, whereas LSG normalized these RSFCs at PostLSG₁₂. These changes in Hb-related RSFCs were associated with reduced BMI, Yale Food Addiction Scale score, emotional eating score, and hunger levels following LSG. 3) Mediation analysis revealed that a bidirectional relationship between Hb GMV and RSFC of Hb-insula contributed to the reduced BMI at PostLSG₁₂. These findings suggested that LSG can promote recovery of obesity-related brain functional abnormalities in the Hb, which might be associated with enhanced sensitivity to hunger/satiety states, enhanced sensitivity to food aversion in non-hunger states, and rebalanced function in brain regions involved with homeostatic/hedonic regulation.

Thirdly, neuroimaging study on LSG-induced improvement in SC of Hb-Hy and Hb-mesolimbic circuitry. Since LSG-induced improvement in RSFCs of Hb-homeostatic/hedonic circuits could serve as a biomarker for the long-term efficacy of LSG in appetite regulation and weight-loss, these SCs of Hb-homeostatic/hedonic circuits after LSG remains unclear. Therefore, we selected regions implicated in homeostatic/hedonic regulation that have anatomical connections with Hb as regions of interest, and used diffusion tensor imaging with probabilistic tractography to calculate SCs between the Hb and these regions of interest in patients with obesity at PreLSG and PostLSG₁₂, and in NW controls. Results showed that: 1) PreLSG relative to NW showed decreased SCs between the Hb and homeostatic/hedonic regions including the Hy, bilateral SFG, left amygdala, and orbitofrontal cortex, whereas LSG increased these SCs at PostLSG₁₂. 2) Correlation analysis showed that: at PreLSG, SC of Hb-bilateral SFG were negatively correlated with disinhibition scores. At PostLSG₁₂, LSG-induced increases in SC of Hb-Hy were correlated with reduced depression and external eating scores; increased SC of Hb-left amygdala was correlated with reduced emotional eating scores; and increases in SC of Hb-left orbitofrontal cortex showed a negative correlation with reduced BMI. These findings suggested that LSG can promote recovery of obesity-related brain structural abnormalities in SCs of Hb-homeostatic/hedonic circuits, which may be associated with functional rebalancing in the Hb.

Overall, LSG can promote recovery of obesity-related brain structural and functional abnormalities in the Hb, which might contribute to the improvement of negative emotional-related eating behaviors and weight-loss. The neural mechanisms underlying improvements in post-surgical eating behaviors may be related to enhanced sensitivity to food aversion in a non-hunger state, and related to rebalanced FCs/SCs between the Hb and regions/circuits involved with homeostatic/hedonic regulation, which would have an impact on the long-term benefits of LSG in appetite regulation and weight-loss.