The Neural Basis of Functional MRI Responses

功能磁共振成像(FMRI)极大地促进了我们对人脑的了解，特别是它是如何处理感觉刺激的，甚至产生了特定的感知、动作和思想。一个意想不到的转折是，在没有任何任务的情况下研究大脑的自发活动具有很高的价值，这引发了内在大脑网络之间相互作用的观点。就其核心而言，功能磁共振成像代表了血流局部变化的读数，最常见的是神经活动的局部变化。由于血液流动和神经活动的运作原理完全不同，准确地确定它们之间的具体联系一直难以捉摸，而且似乎取决于许多因素。这并不令人惊讶，因为人们如何在一个体素中数百万个神经元之间的特定活动模式与作为局部血流动力学信号测量的单个标量值的缓慢变化之间建立一对一的映射？尽管这个问题令人沮丧，但这个话题非常重要，因为任何关于与局部神经活动或上升神经调节有关的线索，都可能对解释人类的结果产生广泛的影响，包括精神疾病患者。虽然我们的实验室不研究神经血管耦合本身，但我们确实进行了一些实验，为解释血流动力学fMRI信号带来了新的见解。我们正在研究对不同类型信号的尖峰反应中局部神经多样性的本质，以及这如何影响来自相同体素或区域的血流动力学反应。我们还在调查整个大脑的大规模功能核磁共振网络中的活动与在单一位置测量的局部神经活动之间的关系。 在最近发表的一项研究中，我们发现单个体素内的神经元对自然主义电影的反应非常不同，其中只有16%的神经元表面上与血液动力学反应的波动有关。这些特殊的神经元不仅与血管反应相匹配，而且与伽马射程局部场电位(LFP)信号相匹配，表明它们可能参与了介导血管控制的特定局部网络。我们目前正在通过在磁共振扫描仪内使用同时的单单元记录来追求这一研究方向。我们已经开发和购买了许多必要的组件(与MR兼容的电极和微驱动器、合适的射频线圈、前置放大器、电缆和过滤器)来实现这种同时记录。该实验室的一位新的博士后研究员目前正在努力了解使用fMRI测量的活动波动与一系列神经测量结果之间的联系，其中包括单细胞的尖峰。虽然这个项目的主要目的是了解单细胞与全脑fMRI网络的关系，但我们预计这一分析也将为我们提供关于局部神经血管关系的性质的视角。 我们研究fMRI信号基础的第二个区域涉及基底前脑的操作，这是一个广泛投射到大脑皮层的小区域。我们先前表明，可逆性地失活基础前脑导致了自发fMRI活动的全局信号成分的区域性变化(Turchi，Chang等人，2018年)。我们最初的实验是在接受功能磁共振测试的动物身上使这种结构的部分失活。他们认为，基底前脑参与调节整个端脑的自发信号，至少在休息时是这样。通过睁开眼睛和闭上眼睛来衡量，这种效应在觉醒的转换过程中尤其明显。通过协作(刘X等人NAT Commun，2018)，我们还发现人类大脑皮层中的自发信号也可能受到基底前脑输入的驱动。我们现在计划通过将fMRI与直接光遗传刺激基底前脑亚区相结合，在这个方向上走得更远。这一操作将提供至少三种不同的实验机会。首先，局部刺激与fMRI标测相结合，为前脑基底投影的区域标测提供了新的视角。其次，对基底前脑连接的控制可能有助于理解导致功能磁共振功能连接的机制及其与唤醒的关系。第三，选择性刺激基底前脑可能有助于我们理解学习和可塑性的机制。

Functional magnetic resonance imaging (fMRI) has greatly advanced our understanding of the human brain, specifically how it processes sensory stimuli and even gives rise to particular percepts, actions, and thoughts. An unexpected twist has been the high value of studying the brains spontaneous activity in the absence of any task, which has given rise to the perspective of interplay among intrinsic brain networks. At its core, fMRI represents a readout of local changes in blood flow that is most often derived from local changes in neural activity. Since blood flow and neural activity operate by entirely different principles, pinpointing their specific connection has been elusive and seems to depend on a number of factors. This is not surprising surprising, for how can one make a one-to-one mapping between a specific pattern of activity among millions of neurons in a voxel to a slow change of single scalar values measured as the local the hemodynamic signal? Frustrating as the problem is, the topic is of great importance, since any clues about the link to local neural activity or ascending neuromodulation can have wide-reaching consequences for interpreting results in humans, including in psychiatric patients.. While our laboratory does not study neurovascular coupling per se, we do undertake experiments that bring new insights into the interpretation of the hemodynamic fMRI signal. We are studying the nature of local neural diversity of in the spiking responses to different types of signals, and how this bears on the hemodynamic responses from the same voxel or area. We are also investigating the relationship between activity in large-scale functional MRI networks across the brain to local neural activity measured at a single position. In a recently published study, we discovered that neurons from within a single voxel were highly varied in their responses to naturalistic movies, and that only 16% of the neurons measured therein were ostensibly linked with the fluctuations of the hemodynamic response. These special neurons matched not only the vascular response, but also the gamma-range local field potential (LFP) signal, suggesting that they may be involved in a particular local network mediating vascular control. We are currently pursuing this research direction through the use of simultaneous single-unit recordings inside the MR scanner. We have developed and acquired many of the necessary components (MR-compatible electrodes and microdrive, suitable RF coils, preamplifiers, cables, and filters) to achieve such simultaneous recording. A new postdoctoral fellow in the laboratory is currently working to understand the links between the activity fluctuations measured using fMRI and those observed in a host of neural measures, including the spiking of single cells. While the principal aim of this project is to understand the relationship of single cells with brain-wide fMRI networks, we anticipate that this analysis will give us perspectives on the nature of the local neurovascular relationship as well. The second area in which we have investigated the basis of the fMRI signal involves the manipulation of the basal forebrain, a small area that projects broadly to the cerebral cortex. We previously showed that reversibly inactivating the basal forebrain led to regional changes the global signal component of spontaneous fMRI activity (Turchi, Chang, et al.,2018). Our initial experiments inactivated portions of this structure in animals undergoing fMRI testing. They suggested that the basal forebrain is centrally involved in regulating spontaneous signals throughout the telencephalon, at least during rest. This effect is particularly pronounced during transitions of arousal, gauged by eye opening and closure. Through collaboration (Liu X et al. Nat Commun, 2018), we have also found that the spontaneous signals in the human cerebral cortex are likely also driven by basal forebrain input. We now plan to go further in this direction by combining fMRI with direct optogenetic stimulation of basal forebrain subregions. This manipulation will provide at least three different experimental opportunities. First, the local stimulation combined with fMRI mapping affords a new view of regional mapping view of basal forebrain projections. Second, control over basal forebrain connections may help understand mechanisms leading to fMRI functional connectivity and its relationship to arousal. Third, selective stimulation of the basal forebrain may help us to understand mechanisms of learning and plasticity.