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.

我们一直在研究几种可能与神经激发及其与测量MR信号的关系有关的生物物理过程。 前STBB博士后研究员，现在是特拉维夫大学的高级讲师Uri Nevo，成功地构建并测试了我们实验室中的实验系统，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，该结果将测得的明显扩散系数（ADC）图与对这些培养的​​组织所面临的环境挑战的变化有关。从这些研究中出现的一个假设是，在许多不同的长度尺度（细胞流，跨膜的水流等）下发生的主动过程是导致在中风中观察到的扩散加权MRI信号的一部分。这种洞察力促使理论的发展解释了微观流体流如何影响测得的扩散加权MRI信号，以及在组织中测量的ADC（即伪扩散）以及实验模型测试系统，以及一种修改的Rheo-NMR仪器，在哪种良好的流动场分布中可以产生可预测的prodiff ins prodiff of progine deflecte deflecto defive deflece。 这些合并的理论和实验研究的重要性是，如果这种微观运动，例如流媒体，跨膜的水流等，将自己表现为扩散加权MRI中的额外信号损失，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数据的出色分析进行兴奋性的特征。 这一想法代表了Le Bihan等人提出的玻璃体内不相干运动（IVIM）概念的重大进展，该概念仅考虑了由微循环水流引起的随机运动的影响，这导致了观察到的伪扩散在体内。我们正在与马里兰州大学鲁里安格·拜大学（Ruiliang Bai）大学的生物物理学博士生一起继续研究和扩展这些研究。 我们还参与了经颅磁刺激区域（TMS）领域的伴侣研究，以了解诱导的电场和磁场如何分布在大脑中，以及它们如何有选择地影响不同的神经元种群。 佩德罗·米兰达（Pedro Miranda）和他在里斯本大学的研究小组与STBB联合使用，使用有限元方法（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）在某些以前没有预测的地区中某些地区的兴奋性或抑制性“热点”都显着造成了扭曲这些诱导的场，甚至产生了兴奋性或抑制性的“热点”。最近，我们一直在开发含有回旋和硫磺的皮质褶皱模型的现实性FEM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诱导的电场分布的分布，以及可能受到这种刺激的神经细胞的位置和类型。 我们将继续将TMS的宏观FEM模型与中枢神经系统中神经兴奋性的微观模型结合在一起，以预测TMS中的激发源，甚至是激发或抑郁的神经元种群。 这种知识对于解决TMS治疗临床抑郁症的功效的安全性和基础很重要 - 我们在90年代初与我们的Ninds和NIMH同事一起帮助了一项应用。尽管它使用日益增长的用途和FDA批准用于治疗抑郁症和偏头痛，但仍不知道诱导电磁场在治疗性TMS中的大脑中的作用是什么，特别是它们可能触发或抑制的哪些以及哪些以及哪些神经群体。我们的研究可以为理解TMS和其他临床应用的物理学和生理学提供基础。 对我们的研究的最新研究集中在这些电场和磁场对神经系统细胞的显微镜作用，从宏到我们的建模活动中的微观效果。 最近，我们还一直在应用这些先进的FEM模型来解释直接电流激发（DCE）的物理基础，以及在大脑上不同频率下AC电场的其他治疗用途。 该项目的分支是对应用电场的最新建模及其在干扰脑癌中有丝分裂过程的治疗用途，尤其是多形胶质母细胞瘤。 这是一项新的活动和实验室，预计将在随后的几年中增长，可能成为一个单独的项目。