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（BOLD）效应被广泛应用于静息态功能磁共振成像（rs-fMRI），通过相关的BOLD信号波动研究人脑持续神经元活动的功能连接（BOLD-FC）。神经元活动和BOLD信号之间的紧密神经血管耦合构成了绘制脑区域之间神经连接的基础。BOLD-FC在脑部疾病患者中的改变在神经科学和临床应用方面带来了希望，特别是在神经精神疾病中。然而，血液动力学血管的变化，大脑疾病和健康的老龄化要求两个谨慎的解释BOLD-FC与潜在的神经元和代谢活动，因此，校准方法的rs-fMRI。该提案的总体目标是为正在进行的大脑活动的基于静息状态fMRI的BOLD-FC开发一种稳健的校准技术。该提案的动机是脑疾病患者的BOLD-FC受损，例如，颈内动脉狭窄，其中改变的神经血管偶联已被证明对BOLD-FC的影响超出异常神经元活动。该提案基于第一个资助期的结果，即创新的血液动力学-氧合MRI的开发，以及最重要的是，包括神经血管耦合参数的独特BOLD-FC建模。现在，我们计划通过我们的动态BOLD信号模型整合BOLD-FC和血流动力学-氧合MRI，最终将神经元和代谢功能连接与个体的血管血流动力学影响分开。更具体地说，我们计划（i）在对照组和单侧颈动脉狭窄患者中，除了常规rs-fMRI外，还采集一组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受局部神经血管耦合（NVC）损伤和非局部血管混淆的影响，我们计划严格删除系统性非神经元BOLD组件，以隔离局部NVC对BOLD-FC的影响，通过一系列不同的技术。(iii)然后，我们计划系统地探讨“本地”的血管血流动力学过程的影响BOLD-FC的基础上的理论动态BOLD-TC/FC模拟扩展的参数空间和来自逐步血流动力学氧合MRI的约束条件的模型支持的图形解决方案框架。这将允许获得关于受损的本地NVC过程和BOLD-FC之间的潜在因果关系的第一见解。(iv)最后，我们计划通过基于模型的时间分辨、局部清洁的BOLD-TC和非时间分辨的血流动力学-氧合MRI的整合来推导时间分辨的CMRO 2-时间过程-作为代谢BOLD-FC的基础，其中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.