Neuronal activity and its role in adiposity and food intake

利用正电子发射扫描和脑核磁共振成像，研究了饥饿和饱腹感的神经解剖学相关性。重要的是，最近对收集的数据的分析表明，左侧背外侧前额叶皮质可能是一个饱腹感中枢，这是大脑中在奖励处理中很重要的一个区域。无论男性还是女性，肥胖患者左侧背侧前额叶皮质神经元的激活程度始终低于瘦人。此外，我们还发现，与匹配的对照组受试者相比，Prader Willi综合征患者在该区域存在失活。 为了研究刺激左侧背外侧前额叶皮质对食物摄入的影响，一项使用经颅直流电刺激(TDC)的随机研究正在进行中。肥胖志愿者被随机分成TDC和Sham治疗组。志愿者将以临床研究单位住院患者的身份接受连续3天的治疗，同时从电脑自动售货机上吃零食。志愿者将继续接受TDCs或Sham治疗4周，以调查这种治疗对减肥的影响。在正在进行的研究中，对TDC的电极位置进行了优化。由于以前的电极放置可能没有提供所需的刺激，我们邀请了完成了初始电极放置的研究的参与者返回到新的电极放置再次参与研究。在那些回来的人中，我们发现那些接受了积极刺激的人总体上摄入的卡路里更少，来自脂肪的卡路里也更少；在研究的住院部分，这些人的体重也下降了更大的百分比。 我们将在我们正在进行的随机研究中确认这些结果，目前正在为该方案进行招募。为了了解TDC如何激活或去激活大脑区域，我们将包括第一次TDC会议之前和之后的功能磁共振成像。 以前研究灰质密度与肥胖的关系的研究没有区分脂肪质量(FM，仅限脂肪组织)和无脂肪质量(FFM)，两者都随着肥胖度的增加而增加。我们发现，去脂体重指数(FFMI)与双侧颞叶内侧和下回的灰质体积(GMV)、双侧腹内侧前额叶皮质延伸至扣带前区、左侧双侧眶额叶皮质延伸至脑岛有关。以身高为指标的脂肪质量(FMI)也与此有类似的重叠关系。体脂百分比仅与左侧颞叶和左侧小脑的GMV减少有关。最重要的是，在同时调整FFM和体脂百分比或FFM和FM的模型中，只有FFM与上述大脑区域有关。这些区域是重要的大脑网络的一部分，负责监控与奖励相关的行为，并参与体内平衡调节。 我们通过研究FFM作为脑血流量(RCBF)的决定因素，对接受全脑PET扫描的个体进行了进一步的分析。我们已经证明，在连接下丘脑和高级脑区的特定中脑区域，FFM与rCBF相关。此外，在这项研究中，实况调查和饥饿分数之间的这些联系有很大的重叠。进一步的分析表明，这些中脑区的rCBF介导了FFM对饥饿评分的影响。我们的结果表明，肥胖增加的大脑区域的差异是由于脱脂而不是脂肪质量的相关增加，并且有一些区域调节FFM和饥饿之间的关联。 在另一项单独的组织学研究中，我们还调查了瘦人和肥胖者纹状体区域的神经细胞和星形胶质细胞密度是否存在差异。在染色和使用体视学计数神经元和星形胶质细胞数量后，我们没有发现瘦人和肥胖者之间的神经元或星形胶质细胞数量有任何差异。然而，肥胖个体在神经元数量上确实有更大的差异。因此，通过脑MRI分析评估的灰质体积的差异可能不是由于这些区域的细胞密度造成的。

Using positron emission scanning and brain MRI, neuroanatomical correlates of hunger and satiety have been investigated. Importantly, recent analyses of this collected data has indicated that the left dorsolateral prefrontal cortex, an area of the brain important in reward processing, may be a satiety center. Neuronal activation in the left dorsolateral prefrontal cortex following a meal is consistently lower in this area in obese versus lean individuals, in both men and women. Furthermore, we have found that patients with Prader Willi Syndrome have deactivation in this region compared to matched control subjects. To investigate the effect of stimulation of the left dorsolateral prefrontal cortex on food intake, a randomized study using trans-cranial direct current stimulation (TDCS) is ongoing. Obese volunteers are randomized to TDCS versus sham therapy. Volunteers will receive treatment 3 days in a row as inpatients on the clinical research unit, while eating ad-libitum from computerized vending machines. Volunteers will continue to receive TDCS or sham for an additional 4 weeks to investigate the effects of this treatment on weight loss. The placement of the electrodes for the TDCS has been optimized during the ongoing study. As the previous placement may not have delivered the needed stimulation, we invited study participants who had completed the study with the initial electrode placement back to participate in the study again with the new electrode placement. In those who returned, we found that those who received the active stimulation consumed fewer overall calories overall and fewer calories from fat; during the inpatient portion of the study these individuals also lost a greater percentage of body weight. We are going confirm these results in our ongoing randomized study, and recruitment is currently ongoing for this protocol. To understand how TDCS activates or deactivates brain regions, we will be including functional MRIs prior to and following the first TDCS session. Previous studies investigating the association of gray matter density with adiposity have not differentiated between fat mass (FM, adipose tissue only) and fat free mass (FFM), and both increase with increasing adiposity. We found that fat free mass indexed to height (FFMI) was associated with reduced gray matter volume (GMV) in the bilateral temporal medial and inferior gyri, the bilateral ventromedial prefrontal cortex extending to the anterior cingulate, and the bilateral orbitofrontal cortex with extension to the insula on the left. Similar overlapping associations were seen with fat mass indexed to height (FMI). Percent body fat was associated only with reduced GMV in left temporal lobe and left cerebellum. Most importantly, in models adjusting for both FFM and percent body fat or FFM and FM, only FFM remained associated with the above brain regions. These regions are part of important brain networks which monitor reward related behavior and are involved in homeostatic regulation. We have followed up this analysis by investigating FFM as a determinant of cerebral blood flow (rCBF) in individuals who had whole brain PET scans. We have demonstrated that FFM is associated with rCBF in specific mid-brain regions which connect the hypothalamus and higher brain regions. Moreover there is substantial overlap between these associations between FFM and hunger scores in this study. Further analyses indicated that the rCBF in these midbrain regions mediated the affect of FFM on hunger scores. Our results indicate that differences in brain regions with increased adiposity are due to the associated increases in fat free rather than fat mass, and that there are regions that mediate the associated between FFM and hunger. In a separate histologic study we also investigated whether neuronal and astrocyte density differed in striatal regions of lean versus obese individuals. After staining and using stereology to count the number of neurons and astrocytes, we did not find any difference in neuronal or astrocyte number between lean and obese individuals. Obese individuals did have greater variance in neuronal number however. Thus, differences in gray matter volume as assessed by analyses of brain MRI may not be due to cellular density in these areas.