Transport Processes and Nervous System Function

Eunice Kennedy Shriver National Institute Of Child Health & Human Development

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Abstract

We have been investigating several biophysical mechanisms possibly associated with neuronal excitation for which it may be feasible measure and map using MRI. Having successfully constructed and tested an experimental system to interrogate organotypic cultured brain cortical slices using diffusion MRI, we showed promising results, relating changes in the measured apparent diffusion coefficient (ADC) with various environmental changes and challenges to which these cultured tissues were subjected. These included oxygen and glucose deprivation, osmotic pressure challenges, temperature changes, etc. While this work did not support the use of conventional diffusion MRI data to detect neuronal excitation, one working hypothesis that emerged from these studies was that active water transport processes occurring at many different length scales (cell streaming, water flow across organelle and cell membranes, etc.) could potentially be the basis of a new biophysically based fMRI methods. This insight prompted the development of a theory to explain how microscopic fluid flows affect the measured diffusion weighted MRI (DWI) signal and possibly the ADC measured in tissues (i.e., pseudo-diffusion). Previously, we had modified Rheo-NMR instrument in which well-characterized velocity field distributions could be generated, which resulted in known and predictable amounts of addition "pseudo-diffusion", or apparent changes in diffusivity that are caused by transport processes other than diffusion. The importance of these combined theoretical and experimental studies is that if such microscopic motions, like cell streaming, water flow across membranes, water exudation from vessels, etc., manifest themselves as additional signal loss in DWIs, then we could use this knowledge to infer distinct aspects of cell function and vitality by judiciously analyzing MRI data at different length and timescales, and from different water pools. This approach represents a significant departure and advance over the prior Intravoxel Incoherent Motion (IVIM) concept proposed by Le Bihan et al., which only considers the effect of random water motion caused by microcirculatory blood flow as contributing to observed increased pseudo-diffusion in vivo. We then continued to expand and amplify these studies with former Visiting Fellow Ruiliang Bai, who investigated possible relationships between neuronal excitation and different MRI contrasts, such as diffusion, and T1 and T2. Dr. Bai showed that while DMRI was sensitive to changes caused by stroke and epilepsy-like biological perturbations, neuronal firing associated with normal neuronal activity could not be detected. We continue to explore aspects of this exciting new area of research, probing ever smaller length and time scales to see if some water pools change their signature during excitation. Another area of interest has been in improving our measurement of relaxation/diffusion/exchange processes in living tissue, particularly taking advantage of advanced data compression techniques (such as compressed sensing) to obtain 1D and 2D relaxation spectra suitable for in vitro and in vivo studies. Subsequently, we have moved this research into a new direction of following basal cell metabolism and its pathological changes by monitoring water exchange across membranes non-invasively using NMR. Water transport is a good indicator ion fluxes, to which it is coupled, making water a good reporter of cellular activity. We have also been involved in complementary studies to understand how induced electric and magnetic fields are distributed within the brain and how they could selectively affect different neuronal populations. We performed detailed calculations using the finite element method (FEM) to predict the electric field and current density distributions induced in the brain during Transcranial Magnetic Stimulation (TMS). Previously, we found that both tissue heterogeneity and anisotropy of the electrical conductivity (i.e., the electrical conductivity tensor field) distort these induced fields, and even create excitatory or inhibitory "hot spots" in some brain regions that were previously not known or predicted. More recently, we developed realistic FEM models of cortical gyri and sulci, showing that this more complicated cortical anatomy can also significantly affect the induced electric field distribution within the tissue, and the location and types of nerve cells that could be excited or depressed by such stimuli. More recently, we have been developing full 3D models of electric field deposition within the brain, obtained from 3D diffusion tensor MRI data. We are continuing to marry our macroscopic FEM models of TMS with microscopic models of neuronal 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 then colleagues Mark George (NIMH) and later Eric Wassermann (NINDS). Despite its growing use and subsequent FDA approval for treating persistent clinical depression and migraines, it is still not known what mechanism of action induced electromagnetic fields have in the brain in this important therapeutic TMS application, and specifically which and what populations of neurons or axons might be triggered or depressed when TMS is applied. Our research attempts to provide a biophysical basis and bridge for understanding the physiology of this and other clinical applications of TMS to help in part better assess its safety and efficacy. 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. Moreover, we have not limited ourselves to TMS. We also applied 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. A surprising offshoot of this earlier TMS research has been the recent study of the possible anti-mitotic effect of applied electric fields and their potential therapeutic use in treating brain cancers, particularly Glioblastoma Multiforme (GBM). The electric fields used in this application are higher than in TMS--in the 100-300 kHz frequency range and have an amplitude of approximately 1 V/cm or greater. According to our calculations, these fields will not cause neural stimulation, but can enter cells across cell membranes and may be large enough to interfere with mitotic spindle formation, required for cell division, or interfere with cell membrane "pinching", which occurs just before two daughter cells are formed from one parent cell. We proposed that an efficient alternative means to deliver these "low frequency" electric fields to brain regions is via electromagnetic induction rather than electrodes placed on the scalp. This idea resulted in a patent application for devices that could be used to assess the effect of electric fields on tissue as well as therapeutic devices for treating various brain cancers. Although in a preliminary stage of development, our group continues to work on advancing this technology by developing novel means to deliver such induced fields to in vitro cell and tissue cultures. We believe that in addition to its possible clinical applications, it may provide us with a means to perturb normally developing cells to help better understand biophysical forces and flows at work during different phases of the cell cycle.