Imaging the functional anatomy of fascicles in the mammalian vagus nerve with neural tracers, electrophysiology and Electrical Impedance Tomography.

在过去的二十年里，神经系统的电刺激已经从学术研究活动发展成为主流医疗用途。植入大脑的刺激器现在用于治疗运动障碍和帕金森氏病;电刺激颈部迷走神经已成功地用于减少癫痫发作的频率。身体中的神经可大致分为供应四肢中的肌肉和感觉的神经-“躯体神经”，以及当神经供应身体器官如心脏、肺和肝脏时的“自主”神经系统。目前，人们对将电刺激的概念扩展到治疗与自主神经系统相关的疾病（例如糖尿病或类风湿性关节炎）产生了极大的兴趣。一个方便的自主目标是颈部的迷走神经，因为它很容易接近，一个小的植入芯片可以用来控制胸部和腹部的十几个不同的供应器官。目前，刺激器技术只能激活或抑制它所连接的整个神经。对于像迷走神经这样的神经来说，这是不幸的，因为可能会刺激其他器官。一个例子是，当癫痫患者接受迷走神经刺激时，他们会变得嘶哑，因为声带的神经被无意中刺激。神经被组织成内部束，称为“束”。对于躯体神经系统来说，神经束的组织结构已经得到了很好的研究，但对于迷走神经和其他自主神经来说，它几乎是完全未知的。为了将来能够选择性地刺激迷走神经内的器官，必须了解这些神经束在神经内的排列方式以及它们的功能。例如，不知道颈部迷走神经内的任何一个分支是否供应单个器官，或者这些分支是否混合在一起。如果它们混合在一起，那么就不可能用颈部的刺激器刺激单个器官。本项目的目的是研究人类颈部迷走神经中的神经束的功能和解剖。解剖学将使用专门的染料（神经示踪剂）进行研究，这些染料可以应用于神经，然后沿着神经向上移动，以便在显微镜下检查时可以明显地看到它们与大脑的连接。第二，解剖学连接将通过一种方法进行研究，其中从颈部到其末端器官的整个迷走神经将被切成精细切片，在显微镜下检查，并且计算机将用于跟踪神经内的所有神经束在其整个过程中。这种方法将首次确定颈部迷走神经中的哪些神经束与哪些终末器官相连。它们的电功能可以使用可以插入神经的小尖峰电极的精细阵列或一种新方法来研究，快速神经电阻抗断层扫描（EIT）。它能够在神经放电中产生神经束的图像，并且是这四种技术中唯一适合人类使用的技术。它需要通过手术在迷走神经周围放置柔性橡胶套。这对于暴露颈部迷走神经以插入迷走神经刺激器的癫痫患者来说是符合伦理和实用的。研究将首先在麻醉动物中使用所有四种方法进行。这一发现将用于使用快速神经EIT在人类受试者中进行的最终研究。这项工作的成果将是，第一次，在整个过程中迷走神经的解剖和功能的地图集。这将为未来的努力提供一个独特的平台，其中迷走神经将被刺激以治疗疾病，并且刺激选定的器官以避免副作用将是有益的。

Over the past two decades, electrical stimulation of the nervous system has progressed from an academic research exercise into mainstream medical use. Implanted stimulators in the brain are now used to treat movement disorders and Parkinson's disease; electrical stimulation of the vagus nerve in the neck has been successfully used in reducing the frequency of epileptic seizures. Nerves in the body may be broadly divided into those that supply muscles and sensation in the limbs - "somatic nerves", and the "autonomic" nervous system when nerves supply bodily organs such as the heart, lungs and liver. There is currently great interest in extending the concept of electrical stimulation to treating diseases related to the autonomic nervous system such as diabetes mellitus or rheumatoid arthritis. A convenient autonomic target is the vagus nerve in the neck because it is easily accessible and a small implanted chip could be used to control about a dozen different supplied organs in the chest and abdomen. At the moment, stimulator technology is only available which would activate or suppress the entire nerve to which it is attached. For a nerve like the vagus nerve, this is unfortunate, as organs other than that intended may be stimulated. An example of this is that when patients with epilepsy have vagus nerve stimulation, they become hoarse, because nerves to the vocal cords are inadvertently stimulated.Nerves are organised into internal bundles, termed "fascicles". The organisation of fascicles is well studied for the somatic nervous system but it is almost completely unknown for the vagus and other autonomic nerves. In order to be able to stimulate an organ selectively within the vagus nerve in the future, it is essential to understand how these fascicles are arranged within the nerve, and what their function is. For example, it is not known if any one fascicle within the vagus nerve in the neck supplies an individual organ, or whether these are all mixed together. If they are mixed together, then it will not be possible to stimulate an individual organ with a stimulator in the neck.The purpose of this project will be to investigate the function and anatomy of the fascicles in the vagus nerve in the neck in humans. The anatomy will be studied with specialised dyes (neural tracers) which can be applied to a nerve and then travel up the nerve so that their connection all the way up to the brain is evident on inspection with a microscope. Secondly, the anatomical connection will be studied with a method in which the entire vagus nerve from the neck to its end organ will be cut into fine slices, inspected under a microscope, and a computer will be used to track all the fascicles within the nerve over its entire course. This approach will, for the first time, identify which fascicles in the cervical vagus nerve in the neck are connected to which end organs. Their electrical function may be studied using a fine array of small spike electrodes which can be inserted into the nerve or a new method, fast neural electrical impedance tomography (EIT). It enables production of images of fascicles in the nerve firing and is the only of these four techniques suitable for human use. It requires surgical placement of a flexible rubber cuff around the vagus nerve. This is ethical and practical in patients with epilepsy in whom the vagus nerve in the neck is exposed for insertion of a vagus nerve stimulator.Studies will be initially undertaken in anaesthetised animals with all four methods. The findings from this will be used to inform a final study in human subjects using fast neural EIT. The output of this work will be, for the first time, an atlas of the anatomy and function of the vagus nerve throughout its course. This will provide a unique platform for efforts in the future where the vagus nerve will be stimulated to treat diseases and it will be beneficial to stimulate selected organs in order to avoid side effects.