Detailed Investigation of Human Epilepsy: Growing Human Neuron Cell Bodies to Regular Lattice Structures on Controllable Silicon Chips

这项研究旨在增进理解，并开始解释大脑中神经元所经历的同步效应。该研究特别关注癫痫期间发生的异常同步性，传统的想法是所有神经元同时放电。然而，大约有40种不同类型的癫痫，每一种都有独特的脑电图特征。因此，我们假设神经元经历非常不同的同步途径，这反过来意味着同步途径依赖于癫痫类型。这可能是由于网络中的神经元彼此物理连接的方式，即网络的结构和神经元的相对放电。因此，通过识别导致这种异常同步的神经元的网络结构和时间行为，人们将深入了解癫痫发作的基本电路以及癫痫发作类型之间的差异。Murray在爱丁堡大学IMNS的研究小组已经开发出一种平台技术，可以迫使细胞沿着使用无机材料在半导体衬底上定义的线生长。这项技术已被用于干细胞、大鼠神经元和神经胶质细胞的建模。他们有兴趣将这项技术扩展到其他结构的细胞模式和不同的细胞类型。奥克兰大学的Unsworth小组对偶联神经元晶格中的同步效应很感兴趣，特别强调人类癫痫中发生的异常同步。他们的工作采用了著名的黑本耦合振荡器模型来研究神经元同步。从理论上讲，这些研究证明了同步确实依赖于神经网络的结构，并获得了神经学基金会戈达德奖。此外，在未发表的工作中，Unsworth研究了人工神经网络晶格模型和混沌神经网络晶格模型来描述癫痫。这些模型也从理论上证实了同步是依赖于架构的。此外，他们还揭示了同步是如何在许多时间和空间尺度上存在的（即不同的神经元组独立地打开和关闭其他神经元组），而不是像通常认为的那样，所有神经元都同时放电。他们感兴趣的是开发新的计算机模型，其中的推理直接来自于人类神经元生长成规则晶格排列的体外实验。通过这种拟议的伙伴关系，这两个群体的需求都将得到满足。这项合作计划首先利用和扩展爱丁堡小组开发的平台技术来培养神经元，不仅沿着线条，而且还将神经元的细胞体定位为规则的晶格结构，并通过多电极阵列（MEAs）单独控制它们。其次，拟培养一种新的细胞类型；芯片上的人类神经元因此加强了其现有的专利申请。以这种方式扩展平台技术，将有助于奥克兰小组对生长成规则晶格的人类神经元的体外行为进行调查，并开发新的精确的人类癫痫模型。因此，这项研究的目的是开始将爱丁堡开发的技术用于未来对培养的真实神经元模式中癫痫信号模式的详细探索。这次访问的主要目的是将细胞模式技术转移到Unsworth的实验室，从而启动一项雄心勃勃的长期合作研究计划。

This research aims to increase understanding and to begin to explain the synchronisation effects that neurons undergo in the brain. In particular, the research is interested in the abnormal synchrony that occurs during epilepsy where conventional thinking is that the neurons all fire simultaneously. However, there are approximately 40 different types of epilepsy, each with a distinctive EEG signature . As such, we hypothesise that the neurons undergo very different routes to synchronisation which in turn implies that the synchronisation pathway is seizure-type dependent. This could be due to the way in which the neurons in the network are connected physically to one another, known as the architecture of the network and the relative firings of the neurons. Thus, by identifying the network architectures and temporal behavior of the neurons responsible for such abnormal synchrony, one would gain an insight into the fundamental circuitry involved in seizure and the differences between seizure types. Murray's group at the University of Edinburgh's IMNS have developed a platform technology which forces cells to grow along lines that are defined on a semi-conductor substrate using inorganic materials. The technique has been used to pattern stem cells, rat neurons and glia. They are interested in expanding the technique both to pattern cells in other configurations and also to different cell types.Unsworth's group at the University of Auckland are interested in the synchronisation effects that occur in lattices of coupled neurons with particular emphasis on the abnormal synchrony that occurs in human epilepsy. Their work adapted the well-known Kuromoto coupled oscillator model to allow for the study of neuronal synchronisation. Such work demonstrated, theoretically, that the synchronisation was indeed dependent on the architecture of the network and was awarded the Neurological Foundations Goddard Prize. In addition, in unpublished work, Unsworth has investigated Artificial Neural Network lattice models and Chaotic Neural Network lattice models to describe epilepsy. These models have also confirmed theoretically that synchronisation is architecture dependent. Moreover, they have revealed how the synchrony exists on many temporal and spatial scales (i.e where different groups of neurons switch on and off independently to other groups of neurons) rather than all firing simultaneously as is commonly thought. They are interested to develop new computer models where the inference is derived directly from in vitro experiment with human neurons grown to regular lattice arrangements.Through this proposed partnership, both groups needs will be addressed. This collaboration intends to firstly exploit and expand the platform technology developed by the Edinburgh group to grow neurons, not only along lines, but also to localise the cell bodies of the neurons to regular lattice structures and individually control them by Multi-Electrode Arrays (MEAs). Secondly, it intends to culture a new cell type; the human neuron on chip thus strengthening its existing filed patent. Expanding the platform technology in such a way, will facilitate the Auckland group, to undertake investigations into the in vitro behaviour of human neurons grown to regular lattices and to develop new precise models of human epilepsy.Thus, this fellowship aims to begin to bring to bear techniques developed in Edinburgh on future detailed explorations of epileptic signalling patterns in patterns of cultured, real neurons. The primary aim of the visit is to transfer cell-patterning technology to Unsworth's lab and thus launch an ambitious, long-term collaborative research programme.