Towards calibrated resting-state functional MRI – part 2: Combining advanced hemodynamic-oxygenation MRI with dynamic BOLD signal modelling for individualized intrinsic functional connectivity calibration

血氧水平依赖效应（BOLD）被广泛应用于静息状态功能磁共振成像（rs-fMRI），通过相关BOLD信号波动来研究正在进行的神经元活动（BOLD- fc）的人脑功能连通性。神经元活动和BOLD信号之间的紧密神经血管耦合是绘制脑区域间神经连接的基础。脑部疾病患者BOLD-FC的改变为神经科学和临床应用带来了希望，特别是在神经精神疾病方面。然而，脑部疾病和健康衰老的血流动力学-血管改变需要对BOLD-FC进行谨慎的解释，考虑潜在的神经元和代谢活动，因此，rs-fMRI的校准方法也需要谨慎的解释。本提案的总体目标是开发一种稳健的校准技术，用于静息状态下基于fmri的BOLD-FC正在进行的大脑活动。该提议的动机是脑疾病患者的BOLD-FC受损，例如颈内动脉狭窄，在这些患者中，神经血管偶联改变已被证明对BOLD-FC的影响超出了异常的神经元活动。该提案基于第一个资助期的结果，即创新的血流动力学-氧合MRI的发展，最重要的是-独特的BOLD-FC模型，包括神经血管耦合参数。现在，我们计划通过我们的动态bold信号模型将BOLD-FC和血流动力学-氧合MRI结合起来，最终从个体的血管-血流动力学影响中解开神经元和代谢功能连接。更具体地说，我们计划(i)除了常规的rs-fMRI外，在对照组和单侧颈动脉狭窄患者中获取一套广泛的基于血流动力学-氧合mri的参数作为病变模型。（ii）由于BOLD- fc受到局部神经血管偶联（NVC）损伤和非局部血管混杂的影响，我们计划严格去除全身非神经元BOLD成分，以便通过一系列不同的技术分离局部NVC对BOLD- fc的影响。（iii）然后，我们计划系统地探索“局部”血管血流动力学过程对BOLD-FC的影响，该过程基于扩展参数空间的理论动态BOLD-TC/FC模拟和基于模型支持的图形解决方案框架的逐步血流动力学-氧合MRI的约束。这将有助于首次了解受损的局部NVC过程与BOLD-FC之间的潜在因果关系。（iv）最后，我们计划通过基于模型的时间分辨、局部清洗bold - tc和非时间分辨血流动力学-氧合MRI的整合，推导出时间分辨的cro2时间过程——作为代谢BOLD-FC的基础，后者用于约束模型参数。

The blood oxygenation level dependent (BOLD) effect is widely used in resting state functional magnetic resonance imaging (rs-fMRI) to investigate human brain functional connectivity of ongoing neuronal activity (BOLD-FC) by means of correlated BOLD signal fluctuations. Tight neurovascular coupling between neuronal activity and BOLD signals constitutes the basis for mapping neural connectivity among brain regions. Alterations of BOLD-FC in patients with brain disorders raised hope with respect to both neuroscientific and clinical applications, especially in neuropsychiatric disorders. However, hemodynamic-vascular alterations in brain disorders and healthy aging call for both cautious interpretation of BOLD-FC with respect to underlying neuronal and metabolic activity and, consequently, for calibration approaches of rs-fMRI. The overarching goal of this proposal is to develop a robust calibration technique for resting-state-fMRI-based BOLD-FC of ongoing brain activity. The proposal is motivated by impaired BOLD-FC in patients with brain disorders, e.g., internal carotid artery stenosis, in whom altered neurovascular coupling has been demonstrated to impact on BOLD-FC beyond aberrant neuronal activity. The proposal is based on results of the first funding period, namely the development of innovative hemodynamic-oxygenation MRI and – most importantly – distinct BOLD-FC modelling including neurovascular coupling parameters. Now, we plan to integrate BOLD-FC and hemodynamic-oxygenation MRI by means of our dynamic BOLD-signal model, to finally disentangle neuronal and metabolic functional connectivity from vascular-hemodynamic influences in individual persons. More specifically, we plan (i) to acquire an extensive set of hemodynamic-oxygenation MRI-based parameters in addition to conventional rs-fMRI in controls and unilateral carotid artery stenosis patients as a lesion model. (ii) Because BOLD-FC is influenced by both local neurovascular coupling (NVC) impairments and non-local vascular confounds, we plan to strictly remove systemic non-neuronal BOLD components in order to isolate the influence of local NVC on BOLD-FC by a range of distinct techniques. (iii) We then plan to systematically explore the impact of ‘local’ vascular-hemodynamic processes on BOLD-FC based on both theoretical dynamic BOLD-TC/FC simulations across extended parameter spaces and constraints derived from stepwise hemodynamic-oxygenation MRI in terms of a model-supported graphical solution framework. This will allow for obtaining first insights about potential causal relationships between impaired local NVC processes and BOLD-FC. (iv) Finally, we plan to derive temporally resolved CMRO2-time courses – as basis for metabolic BOLD-FC – by model-based integration of time-resolved, local cleaned BOLD-TCs and non-time-resolved hemodynamic-oxygenation MRI, where the latter serves to constrain the model parameters.