Physical-chemical Aspects Of Cell And Tissue Excitability

我们一直在研究可能与神经兴奋及其与测量的MR信号的关系有关的几个生物物理过程。 Uri Nevo，前STBB博士后研究员，现为特拉维夫大学高级讲师，在我们的实验室成功构建并测试了一个实验系统，使用扩散MRI询问器官型培养的脑切片。 这项工作显示了有希望的初步结果，在测量的表观扩散系数（ADC）地图的变化，这些培养的组织受到的环境挑战。从这些研究中出现的一个假设是，在许多不同的长度尺度上发生的活动过程（细胞流动，水流过膜等）。是造成中风中观察到的弥散加权MRI信号降低的部分原因。这一认识促使了一种理论的发展，以解释微观流体流动如何影响测量的弥散加权MRI信号以及可能影响组织中测量的ADC（即，伪扩散）以及实验模型测试系统，一种改进的Rheo-NMR仪器，其中可以产生良好表征的流场分布，其导致可预测的伪扩散量。 这些理论和实验相结合的研究的重要性在于，如果这种微观运动，如流动，水流过膜等，在扩散加权MRI中，这些信息表现为额外的信号损失，那么我们可以使用这些信息来推断细胞功能和活力的不同方面，包括通过对MRI数据的明智分析来推断兴奋性的特征。 该想法代表了相对于Le Bihan等人提出的体素内非相干运动（IVIM）概念的显著进步，IVIM概念仅考虑由微循环水流引起的随机运动的影响，作为对体内观察到的伪扩散的贡献。我们与来自马里兰州大学的生物物理学博士生白瑞良一起继续并扩展这些研究。 我们还参与了经颅磁刺激（TMS）领域的相关研究，以了解感应电场和磁场如何在大脑中分布，以及它们如何选择性地影响不同的神经元群体。 里斯本大学的Pedro米兰达和他的研究小组与STBB合作，使用有限元法（FEM）进行了详细的计算，以预测TMS期间大脑中诱导的电场和电流密度分布。 以前，我们发现组织异质性和电导率的各向异性（即，电导率张量场）显著地导致这些感应场的扭曲，甚至在一些区域中产生先前未预测到的兴奋性或抑制性“热点”。最近，我们一直在开发逼真的有限元模型的皮质褶皱，包含脑回和脑沟，显示这种更复杂的皮质解剖结构可以显着影响组织内的感应电场分布的分布，以及神经细胞的位置和类型，可以兴奋或抑制这种刺激。 我们继续将TMS的宏观FEM模型与CNS中神经兴奋性的微观模型结合起来，以预测TMS中的兴奋位点，甚至是兴奋或抑制的神经元群体。 这些知识对于解决例如TMS治疗临床抑郁症的安全性和有效性基础非常重要-这是我们在90年代初与NINDS和NIMH同事一起帮助开拓的应用。尽管它越来越多地被用于治疗抑郁症和偏头痛，但仍然不知道在治疗性TMS中诱导电磁场在大脑中的作用，特别是它们可能触发或抑制哪些神经群。我们的研究可以为理解TMS的物理学和生理学以及其他临床应用提供基础。 我们最近的研究集中在这些电场和磁场对神经系统细胞的微观影响上，在我们的建模活动中从宏观到微观。 最近，我们也一直在应用这些先进的有限元模型来解释直流激励（DCE）的物理基础，以及在大脑上不同频率的交流电场的其他治疗用途。 该项目的一个分支是最近对应用电场及其在干扰脑癌（特别是多形性胶质母细胞瘤）有丝分裂过程中的治疗用途进行了建模。 这是一个新的活动和实验室，预计将在未来几年增长，可能成为一个单独的项目。

We have been investigating several biophysical processes that may be associated with nerve excitation and their relationship to the measured MR signal. Uri Nevo, a former STBB post-doctoral fellow, and now Senior Lecturer at Tel Aviv University, successfully constructed and tested an experimental system in our lab to interrogate organotypic cultured brain slices using diffusion MRI. This work showed promising preliminary results relating changes in the measured apparent diffusion coefficient (ADC) map to environmental challenges to which these cultured tissues were subjected. One hypothesis that emerged from these studies is that active processes occurring at many different length scales (cell streaming, water flow across membranes, etc.) are responsible for a portion of the reduction in the diffusion weighted MRI signal observed in stroke. This insight prompted the development of a theory to explain how microscopic fluid flows affect the measured diffusion weighted MRI signal and possibly the ADC measured in tissues (i.e., pseudo-diffusion) as well as an experimental model test system, a modified Rheo-NMR instrument, in which well-characterized flow field distributions can be produced that result in a predictable amount of pseudo-diffusion. The importance of these combined theoretical and experimental studies is that if such microscopic motions, like streaming, water flow across membranes, etc., manifest themselves as additional signal loss in diffusion weighted MRI, then we could use this information to infer distinct aspects of cell function and vitality, including features of excitability by a judicious analysis of the MRI data. This idea represents a significant advance over the Intravoxel Incoherent Motion (IVIM) concept proposed by Le Bihan et al, which only considers the effect of random motion caused by microcirculatory water flow as contributing to observed pseudo-diffusion in vivo. We are continuing and expanding these studies with our doctoral student in Biophysics from the University of Maryland, Ruiliang Bai. We have also been involved in companion studies in the area of Transcranial Magnetic Stimulation (TMS) to understand how induced electric and magnetic fields are distributed within the brain and how they could selectively affect different neuronal populations. Pedro Miranda and his research group at the University of Lisbon, in association with STBB, has performed detailed calculations using the finite element method (FEM) to predict the electric field and current density distributions induced in the brain during TMS. Previously, we found that both tissue heterogeneity and anisotropy of the electrical conductivity (i.e., the electrical conductivity tensor field) contribute significantly to distort these induced fields, and even to create excitatory or inhibitory "hot spots" in some regions that were previously not predicted. More recently, we have been developing realistic FEM models of cortical folds, containing gyri and sulci, showing that this more complicated cortical anatomy can significantly affect the distribution of induced electric field distribution within the tissue, and the location and types of nerve cells that could be excited or depressed by such stimuli. We are continuing to marry our macroscopic FEM models of TMS with microscopic models of nerve excitability in the CNS in order to predict the locus of excitation in TMS and even the populations of neurons that are excited or depressed. This knowledge is important to have in addressing, for instance, the safety and basis of efficacy of TMS for the treatment of clinical depression--an application we helped pioneer in the early '90s with our NINDS and NIMH colleagues. Despite its growing use and FDA approval for treating depression and migraines, it is still not known what the action of induced electromagnetic fields is in the brain in therapeutic TMS, and specifically which and what populations of nerves they might trigger or depress. Our research can provide a basis for understanding the physics and physiology of this and other clinical applications of TMS. More recent studies of ours have focused on the microscopic effects of these electric and magnetic fields on cells in the nervous system, moving from the macro to the microscale in our modeling activities. Recently, we have also been applying these advanced FEM models to explain the physical basis for Direct Current Excitation (DCE) as well as other therapeutic uses of AC electric fields at different frequencies on the brain. An offshoot of this project has been the recent modeling of applied electric fields and their therapeutic use in interfering with mitotic processes in brain cancers, particularly Glioblastoma Multiforme. This is a new activity and lab and is expected to grow in subsequent years, possibly becoming a separate project.