What information does laminar fMRI provide about cortical sensorimotor circuits? Validation with electrophysiology and targeted nerve injuries

了解大脑是如何处理信息的，以及它在疾病中是如何受损的，这是科学界面临的巨大挑战之一。信息在由相互连接的大脑区域组成的皮层回路中流动的方式，以及这些回路对信息的处理是大脑功能的基础。然而，我们缺乏有效的方法来无创地研究动物或人类的这种“神经回路”，因为目前的方法要么太粗糙，要么是细粒度的、有创的，但只覆盖了大脑的一小部分。功能性磁共振成像（fMRI）被广泛用于研究大脑功能，它提供了当一个人执行任务时哪个大脑区域是活跃的信息，但它并不能显示信息是如何在大脑中流动的。虽然标准的功能磁共振成像过于粗糙，无法显示皮层回路，但它们可以使用7T高分辨率的功能磁共振成像进行研究。它具有足够高的分辨率来可视化皮层的层（层），这对于理解皮层的活动和连接是必不可少的，因为不同皮层中的神经元在回路中执行不同的功能。例如，信息到达中间层，而深层将输出发送到大脑的其他区域。高分辨率的功能磁共振成像技术开始允许大脑皮层的可视化。然而，功能磁共振成像测量的是血流和代谢，而不是直接测量神经活动，对这些层流fMRI信号与电生理学测量的层流神经活动之间的关系的理解和验证是滞后的。这一信息只能通过使用这两种方法研究动物的层流回路来获得。在这项研究中，我们比较了层流fMRI、静息状态fMRI （rs-fMRI）和大鼠层流电生理记录，以确定层流fMRI提供了关于各层神经计算的哪些信息。Rs-fMRI的原理是，如果两个区域相连，它们的活动就会一起波动。目前的rs-fMRI方法过于粗糙，无法解决信息是如何流动的，但层流rs-fMRI有可能解决这个问题，因为了解哪些皮层是连接的，就有可能确定哪些皮层是发送和接收信息的。我们将首先优化数据采集方法，并表征健康动物体感觉皮层的层流信号。随后，我们将研究皮层回路如何对感觉输入的撤回做出反应，通过脊髓和周围神经的损伤来完成。我们将有选择地破坏将感觉信息从身体传递到大脑的主要脊髓通路（背柱）之一，并将这种部分损伤的反应与切断周围神经导致的感觉输入完全丧失的反应进行比较。为了了解大脑回路重组对感觉剥夺的反应是如何随时间变化的，我们将在损伤后的不同时间，在没有修复的情况下（背柱损伤不能自发修复，神经再生被结扎阻止）进行层流功能磁共振成像和电生理检查。然后，我们将使用神经挤压模型研究在周围神经纤维成功再生的情况下，大脑感觉运动回路如何进一步变化。皮层回路变化的时间将与返回功能的行为测量相关联。我们期望这项研究能够改善（层流）fMRI的解释，并提供关于感觉运动回路的功能活动和连通性的新信息。此外，它将阐明大脑中的可塑性机制，与理解适应性功能恢复、利用活动依赖可塑性的康复策略以及大脑可塑性对周围神经修复后功能恢复的限制高度相关。

Understanding how the brain processes information and how this is impaired in disease is one of the great challenges in science. The way information flows in cortical circuits consisting of interconnected brain areas, and the processing of information by these circuits is fundamental to brain function. However, we lack effective ways to noninvasively study such 'neural circuits' in animals or humans, because current methods are either too coarse, or they are fine-grained and invasive but cover only a small part of the brain. Functional magnetic resonance imaging (fMRI) is widely used to investigate brain function, and it provides information about which brain areas are active when a person performs a task, but it does not show how information flows in the brain. Although standard fMRI is too coarse to show cortical circuits, they can potentially be studied using high-resolution fMRI at 7T. It has sufficiently high resolution to visualize the layers (laminae) of the cortex, which is essential to understand cortical activity and connectivity, because neurons in different cortical layers perform different functions in the circuit. For instance, information arrives in the middle layers, while deep layers send output to other brain areas. High resolution fMRI is starting to allow the visualization of cortical layers. However, fMRI measures blood flow and metabolism, and does not directly measure neural activity, and the understanding and validation of how these laminar fMRI signals relate to laminar neural activity measured with electrophysiology, is lagging behind. This information can only be gained from studying laminar circuits in animals using both methods. In this study, we compare laminar fMRI, resting state fMRI (rs-fMRI) and laminar electrophysiological recordings in rats to determine what information laminar fMRI provides about the neural computations in the layers. Rs-fMRI is based on the principle that if two areas are connected, their activity fluctuates together. Current rs-fMRI methods are too coarse to resolve how information flows, but laminar rs-fMRI can potentially solve this problem, because knowledge of which cortical layers are connected makes it possible to establish those sending and receiving information. We will first optimize the data acquisition methods and characterize the laminar signals in the somatosensory cortex of healthy animals. Subsequently we will investigate how cortical circuits respond to the withdrawal of sensory input, done by making injuries to the spinal cord and peripheral nerve. We will make lesions that selectively interrupt one of the main spinal cord pathways (dorsal columns) carrying sensory information from the body to the brain, and compare the response to this partial injury with the response to complete loss of sensory input caused by cutting the peripheral nerve. To understand how reorganization of brain circuits in response to sensory deprivation changes over time, we will carry out laminar fMRI and electrophysiology at different times after injury, under circumstances where there is no repair (dorsal column injuries do not spontaneously repair, nerve regeneration is prevented by ligation). We will then investigate how brain sensorimotor circuits further change under circumstances where there is successful regeneration of peripheral nerve fibres using a nerve crush model. The timing of changes in cortical circuits will be correlated with behavioral measures of returning function.We expect the study to lead to improved interpretation of (laminar) fMRI, and provide new information about the functional activity and connectivity of sensorimotor circuits. In addition, it will illuminate plastic mechanisms in the brain highly relevant to understanding adaptive functional recovery, rehabilitation strategies utilizing activity-dependent plasticity and the limitations that brain plasticity imposes on functional recovery after peripheral nerve repair.