Dynamic changes of the structural and functional brain connectome in anorexia nervosa (revision)

神经性厌食症（AN）是一种以严重消瘦为特征的危及生命的进食障碍。在急性AN（acAN）中，脑质量的减少通常在脑扫描中很容易看到，并且几项结构磁共振成像（sMRI）研究（包括我们自己的研究）已经记录了灰质（GM）体积和厚度的大量但可逆的减少。这些过程伴随着剧烈的荷尔蒙和代谢变化，是令人难以置信的动态和无与伦比的精神病学。因此，AN可能是研究大脑可塑性（即结构和功能神经连接（即连接体）的变化）的有价值的模型障碍。这些见解将有助于理解基本的神经机制，并阐明这种神秘的疾病。这些（假）萎缩性变化的生物学机制在AN仍然难以捉摸。例如，目前尚不清楚它们是否可能与白色物质（WM）的变化有关，功能连接体的变化（使用功能性MRI（fMRI）测量的区域大脑信号波动之间的相关性）以及它们如何与已知的认知障碍，临床症状和体重恢复有关。我们试图阐明（1）结构性脑改变的特定模式，特别是WM的完整性和连接性的变化，与acAN使用sMRI，扩散张量成像（DTI）和现代数学和网络理论分析方法的组合。重要的是，通过在体重恢复治疗期间纵向跟踪患者，我们将评估正常化的速度和程度。其次，我们的目标是（2）使用高时间分辨的fMRI序列来表征功能连接体的变化，以研究静态和动态静息状态的连接（即“时间连接体”）。最终，我们的目标是（3）了解AN不同状态下结构和功能脑连接体变化的生物学机制。使用新的髓鞘敏感的MR序列（mcDESPOT，定量T1映射），除了DTI和交叉模态分析，我们将研究GM和WM连接之间的关联，以及局部髓鞘的变化更直接。我们还将研究结构异常或局部fMRI信号模式的变化（例如频率波动的幅度）是否与异常的静态/动态功能连接和不断变化的激素参数相关。现代生物信息学建模技术将揭示激素和连接体特征之间的相互依赖性，并将确定体重增加和认知功能改善的预测因素。使用最先进的神经影像学方法对AN中结构和功能连接体变化的潜在机制进行三角测量，不仅可以告诉我们大脑的基本原理，包括它如何受到能量消耗/补充的影响，而且还可能揭示开发更好的AN治疗方法的新目标。

Anorexia nervosa (AN) is a life-threatening eating disorder characterized by severe emaciation. In acute AN (acAN), reduction of brain mass is often readily visible in brain scans and several structural magnetic resonance imaging (sMRI) studies (including our own) have documented massive but reversible decreases in gray matter (GM) volume and thickness. These processes, which are accompanied by dramatic hormonal and metabolic changes are incredibly dynamic and unparalleled in psychiatry. Therefore, AN may be a valuable model disorder to study the brain's plasticity, i.e. changes in structural and functional neural connections (i.e. the connectome). Insights will contribute to the understanding of basic neural mechanisms and shed light on this enigmatic illness.The biological mechanisms underlying these (pseudo-)atrophic changes in AN remain elusive. For example, it is unclear whether they may be related to changes in white matter (WM), changes in the functional connectome (correlations between regional brain signal fluctuations measured using functional MRI (fMRI)) and how they might be linked to known cognitive impairments, clinical symptoms and weight restoration. We seek to elucidate (1) the specific patterns of structural brain alterations, specifically WM integrity and connectivity changes, associated with acAN using a combination of sMRI, diffusion tensor imaging (DTI) and modern mathematical and network theory analysis approaches. Critically, by following patients longitudinally during weight restoration therapy, we will assess the speed and degree of normalization. Second, we aim (2) to characterize changes in the functional connectome using highly time-resolved fMRI sequences to study static and dynamic resting state connectivity (i.e. the "chronnectome"). Ultimately, we aim (3) to understand the biological mechanisms underlying changes in the structural and functional brain connectome in the different states of AN. Using new myelin-sensitive MR sequences (mcDESPOT, quantitative T1 mapping) in addition to DTI and cross-modal analysis, we will study associations between GM- and WM-connectivity as well as local myelin changes more directly. We will also examine whether structural anomalies or changes of local fMRI signal patterns (e.g. amplitude of frequency fluctuations) are associated with abnormal static/dynamic functional connectivity and the changing hormonal parameters. Modern bioinformatics modelling techniques will reveal interdependencies between hormones and connectome characteristics and will identify predictors of weight gain and improvements in cognitive functioning. Using state of the art neuroimaging methodologies to triangulate the mechanisms underlying changes in the structural and functional connectome in AN will inform us not only about basic principles of the brain including how it is affected by energy depletion/repletion, but also has potential of revealing new targets for the development of better treatments for AN.