Physical-chemical Aspects Of Cell And Tissue Excitability

细胞和组织兴奋性的物理化学方面

• 批准号: 8941429
• 负责人: PETER J. BASSER
• 金额: $ 10.32万
• 依托单位: EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8941429
• 关键词: Address; Affect; Anatomy; Anisotropy; Area; Biophysical Process; Biophysics; Brain; Brain region; Cell physiology; Cells; Chemicals; Companions; Data; Depressed mood; Development; Diffusion; Diffusion Magnetic Resonance Imaging; Electric Conductivity; Electromagnetic Fields; Elements; Endogenous depression; Environment; Experimental Models; Frequencies; Glioblastoma; Goals; Heterogeneity; Hot Spot; Knowledge; Length; Location; Magnetic Resonance Imaging; Malignant neoplasm of brain; Maps; Maryland; Measurable; Measures; Membrane; Mental Depression; Methods; Microscopic; Migraine; Mitotic; Modeling; Motion; National Institute of Mental Health; National Institute of Neurological Disorders and Stroke; Nerve; Nervous system structure; Neurons; Organism; Peripheral Nervous System; Physics; Physiology; Population; Postdoctoral Fellow; Process; Research; Safety; Signal Transduction; Site; Slice; Source; Stimulus; Stream; Stroke; System; Testing; Theoretical Studies; Therapeutic; Therapeutic Uses; Tissues; Transcranial magnetic stimulation; Universities; Work; base; clinical application; density; doctoral student; electric field; fluid flow; imaging modality; in vivo; insight; instrument; interest; lecturer; magnetic field; non-invasive imaging; research study; theories; tissue culture; water flow

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.

我们一直在研究可能与神经兴奋相关的几种生物物理过程及其与测量的 MR 信号的关系。 Uri Nevo 是前 STBB 博士后研究员，现任特拉维夫大学高级讲师，他在我们的实验室成功构建并测试了一个实验系统，用于使用扩散 MRI 来检查器官型培养脑切片。 这项工作显示了有希望的初步结果，将测量的表观扩散系数（ADC）图的变化与这些培养组织所面临的环境挑战联系起来。这些研究中出现的一个假设是，在许多不同长度尺度上发生的活动过程（细胞流、跨膜水流等）是中风中观察到的扩散加权 MRI 信号减少的部分原因。这一见解促进了一种理论的发展，以解释微观流体流动如何影响测量的扩散加权 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（改进的 Rheo-NMR 仪器） ，其中可以产生特征良好的流场分布，从而产生可预测的伪扩散量。 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、水流跨膜等，在扩散加权 MRI 中表现为额外的信号损失，那么我们可以利用这些信息来推断细胞的不同方面功能和活力，包括通过对 MRI 数据进行明智分析的兴奋性特征。 这个想法代表了 Le Bihan 等人提出的体素内不相干运动 (IVIM) 概念的重大进步，该概念仅考虑微循环水流引起的随机运动的影响，以促进观察到的体内伪扩散。我们正在与马里兰大学生物物理学博士生白瑞亮一起继续并扩大这些研究。 我们还参与了经颅磁刺激 (TMS) 领域的配套研究，以了解感应电场和磁场如何在大脑内分布以及它们如何选择性地影响不同的神经元群体。 里斯本大学的佩德罗·米兰达 (Pedro Miranda) 和他的研究小组与 STBB 合作，使用有限元法 (FEM) 进行了详细计算，以预测 TMS 期间大脑中感应的电场和电流密度分布。 此前，我们发现组织的异质性和电导率的各向异性（即电导率张量场）都会显着扭曲这些感应场，甚至在一些先前未预测到的区域中产生兴奋或抑制“热点” 。最近，我们一直在开发包含脑回和脑沟的皮质褶皱的真实有限元模型，表明这种更复杂的皮质解剖结构可以显着影响组织内感应电场的分布，以及可以影响神经细胞的位置和类型。受到此类刺激而兴奋或沮丧。 我们继续将 TMS 的宏观 FEM 模型与 CNS 神经兴奋性的微观模型结合起来，以预测 TMS 的兴奋位点，甚至是兴奋或抑制的神经元群体。 这些知识对于解决诸如 TMS 治疗临床抑郁症的安全性和有效性基础等问题非常重要——我们在 90 年代初与 NINDS 和 NIMH 同事一起帮助开拓了这一应用。尽管它的使用越来越多，并且 FDA 批准它用于治疗抑郁症和偏头痛，但仍然不知道治疗性 TMS 中感应电磁场在大脑中的作用是什么，特别是它们可能触发或抑制哪些神经群和哪些神经群。我们的研究可以为理解 TMS 的物理和生理学以及其他临床应用提供基础。 我们最近的研究重点是这些电场和磁场对神经系统细胞的微观影响，在我们的建模活动中从宏观转向微观。 最近，我们还应用这些先进的 FEM 模型来解释直流激励 (DCE) 的物理基础以及不同频率的交流电场在大脑中的其他治疗用途。 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建模。 这是一项新的活动和实验室，预计将在接下来的几年中不断发展，并可能成为一个单独的项目。