Mechanisms, response heterogeneity and dosing from MRI-derived electric field models in tDCS augmented cognitive training: a secondary data analysis of the ACT study

摘要 迫切需要有效的干预措施来补救与年龄相关的认知衰退，并改变 走向阿尔茨海默氏症的轨迹。NIA阿尔茨海默病倡议资助第三阶段增强 老年人认知训练(ACT)试验旨在证明经颅直流电刺激 (Tdcs)配合认知训练可以实现这一目标。这项研究提出了一项最先进的研究 对ACT试验数据的二次数据分析将通过1)阐明潜在的作用机制来促进这一目标 使用CT对tDCS治疗的响应，2)通过确定以下内容来解决tDCS增强CT中响应的异质性 输送到大脑的电流剂量的个体差异如何与个体大脑相互作用 解剖特点；3)通过评估方法，完善TDC与CT配对的介入策略 对于精确的交付，有针对性的剂量特性，以促进tdcs扩大的结果。Tdcs干预 DATE，包括ACT，采用固定剂量方法，即单一刺激强度(例如，2 mA)和一组 头皮上的电极位置(例如，F3/F4)适用于所有参与者/患者。然而，我们最近的工作已经 证明了神经解剖学中与年龄相关的变化以及头部/大脑结构中的个体变异性 (例如，头骨厚度)显著影响大脑中感应电流的分布和强度 来自tdcs。该项目将使用特定于人的磁共振成像得出的电流的有限元计算模型 特性(电流强度和流向)和提高精度和方向的新方法 精确量化老年人当前分娩的异质性的衍生模型的准确性。我们会 利用这些个性化的精确模型和最先进的支持向量机学习方法 确定电流特征与tdcs和CT治疗反应的关系。我们会 利用神经解剖学和固定电流交付的固有异质性，不仅提供对 哪些剂量参数与治疗反应有关，但也与大脑区域特定信息有关 促进在未来的试验中有针对性地提供刺激。此外，目前的研究还将开拓新的方法 用于计算tdcs输送的精确配药参数，以潜在地优化治疗反应。 AS确定与老年人TDC和CT反应相关的临床和人口学特征 成年人。利用强大而全面的行为和多模式神经成像数据集进行ACT 先进的计算方法，拟议的研究将为机制提供关键信息， 治疗反应的异质性和治疗年龄的精确剂量方法的途径- 相关的认知衰退和改变老年人患阿尔茨海默病的轨迹。

ABSTRACT There is a pressing need for effective interventions to remediate age-related cognitive decline and alter the trajectory toward Alzheimer’s disease. The NIA Alzheimer’s Disease Initiative funded Phase III Augmenting Cognitive Training in Older Adults (ACT) trial aimed to demonstrate that transcranial direct current stimulation (tDCS) paired with cognitive training could achieve this goal. The present study proposes a state of the art secondary data analysis of ACT trial data that will further this aim by 1) elucidate mechanism of action underlying response to tDCS treatment with CT, 2) address heterogeneity of response in tDCS augmented CT by determining how individual variation in the dose of electrical current delivered to the brain interacts with individual brain anatomical characteristics; and 3) refine the intervention strategy of tDCS paired with CT by evaluating methods for precision delivery targeted dosing characteristics to facilitate tDCS augmented outcomes. tDCS intervention to date, including ACT, apply a fixed dosing approach whereby a single stimulation intensity (e.g., 2mA) and set of electrode positions on the scalp (e.g., F3/F4) is applied to all participants/patients. However, our recent work has demonstrated that age-related changes in neuroanatomy as well as individual variability in head/brain structures (e.g., skull thickness) significantly impacts the distribution and intensity of electrical current induced in the brain from tDCS. This project will use person-specific MRI-derived finite element computational models of electric current characteristics (current intensity and direction of current flow) and new methods for enhancing the precision and accuracy of derived models to precisely quantify the heterogeneity of current delivery in older adults. We will leverage these individualized precision models with state-of-the-art support vector machine learning methods to determine the relationship between current characteristics and treatment response to tDCS and CT. We will leverage the inherent heterogeneity of neuroanatomy and fixed current delivery to provide insight in the not only which dosing parameters were associated with treatment response, but also brain region specific information to facilitate targeted delivery of stimulation in future trials. Further still, the current study will also pioneer new methods for calculation of precision dosing parameters for tDCS delivery to potentially optimize treatment response, as well as identify clinical and demographic characteristics that are associated with response to tDCS and CT in older adults. Leveraging a robust and comprehensive behavioral and multimodal neuroimaging data set for ACT with advanced computational methods, the proposed study will provide critical information for mechanism, heterogeneity of treatment response and a pathway to refined precision dosing approaches for remediating age- related cognitive decline and altering the trajectory of older adults toward Alzheimer’s disease.