Toward a Structural and Functional Basis for Changes in Brain Signal Variability with Age (Emmy Noether Group 6th year extension application)

自从生命神经动力学（Emmy Noether）小组成立以来，我们在测量、理解和操纵认知和衰老背景下的大脑信号变异性方面取得了巨大的进展。对于我们最初的Emmy Noether研究目标，我们发现：(1)脑结构与衰老过程中表达的脑信号变异性水平呈正相关，但在横断面和纵向数据中表现出明显的空间分化；(2)功能连接与脑信号在区域水平上的变异性紧密正相关，表明脑区域内表达的信号变异性可能是由突触输入而非“局部噪声”来源引起的。这种功能连通性和局部信号变异性的结合也反映了整个成人生命周期的大范围认知，在横截面和纵向数据中都存在关联；(3)多巴胺继续为理解衰老和认知背景下的脑信号变异性提供丰富的神经化学基础。值得注意的是，我们发现能够更好地调节工作记忆负荷下大脑信号变异性的老年人能够更好地增加功能网络整合，反应更快，表达更高的基线多巴胺水平。然而，毫无疑问，COVID-19大流行推迟了我在最初的艾米·诺特提案中概述的几个研究目标的进展。特别是，我们已经推迟了解决我们的主要原始目标，即检查年轻人和老年人在不确定性下信号变异性的灵活调制。这一研究目标将成为我们第6年艾美诺特集团扩展的唯一焦点。使用两个独特的实验范式（一个数据集在大流行前已经收集），当参与者接受脑电图和功能磁共振成像时，参数化地操纵不确定性，我们试图解决老年人是否不太能够：(a)在不确定性下，通过从有节奏的神经状态转变为更嘈杂的神经状态来调节他们的“状态空间”；(b)将他们的大脑状态限制在与任务相关的状态（即提示）。我们还将估计fMRI和基于脑电图的神经变异性估计中与不确定性相关的变化在人体内耦合的程度，以及这种耦合如何因年龄和表现而不同。这项工作需要综合多学科（如寿命认知神经科学、数学、统计学）、多方法（如多模态成像、计算建模）的方法。

Since the inception of the Lifespan Neural Dynamics (Emmy Noether) Group, we have made tremendous ground in measuring, understanding, and manipulating brain signal variability in the context of cognition and aging. Regarding our original Emmy Noether research targets, we have found that: (1) brain structure is a positive yet modest correlate of the level of brain signal variability expressed during aging, yet shows marked spatial differentiation when examining cross-sectional vs. longitudinal data; (2) functional connectivity is tightly and positively coupled with brain signal variability at the regional level, suggesting that signal variability expressed within brain regions is likely due to synaptic input rather than “local noise” sources. This combination of functional connectivity and local signal variability also reflects broad-scale cognition across the adult lifespan, associations that hold at cross-section and in longitudinal data; (3) dopamine continues to provide a fruitful neurochemical basis for understanding brain signal variability in the context of aging and cognition. Notably, we find that older adults who can better modulate brain signal variability under working memory load are better able to increase functional network integration, can respond faster, and express higher baseline dopamine levels. Without question however, the COVID-19 pandemic has delayed progress on several research goals outlined in my original Emmy Noether proposal. In particular, we have been delayed in addressing our primary original objective of examining the flexible modulation of signal variability under uncertainty in younger and older adults. This research objective would serve as the singular focus within our 6th year Emmy Noether Group extension. Using two unique experimental paradigms (one dataset already collected pre-pandemic) that parametrically manipulate uncertainty while participants undergo EEG and fMRI, we seek to address whether older adults are less able to: (a) modulate their "state space" by shifting from a rhythmic to a noisier neural regime under uncertainty; (b) constrain their brain states to those that are task relevant (i.e., cued). We will also estimate the extent to which uncertainty-related shifts in fMRI and EEG-based estimates of neural variability are coupled within-person, and how this coupling differs by age and performance. This work requires a comprehensive multidisciplinary (e.g., lifespan cognitive neuroscience, mathematics, statistics), multi-method (e.g., multimodal imaging; computational modelling) approach.