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 which also may be feasible to measure and map in vivo using MRI. Having successfully constructed and tested an experimental system to interrogate organotypic cultured brain cortical slices using diffusion and other forms of MR, we showed that the measured apparent diffusion coefficient (ADC) changed with various environmental 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 directly (or fDMRI--functional diffusion MRI), one working hypothesis was that active water transport processes occurring at many different length scales (i.e., cell streaming, water flow across organelle and cell membranes, etc.) could potentially become 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., resulting in pseudo-diffusion). Previously, we had modified a Rheo-NMR instrument in which well-characterized velocity field distributions could be generated, which resulted in known and predictable amounts of additional "pseudo-diffusion", or apparent changes in diffusivity that were caused by transport processes other than diffusion. The importance of these combined theoretical and experimental studies was 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 from the prior Intravoxel Incoherent Motion (IVIM) concept proposed by Le Bihan et al., which only considers the effect of macroscopic random water motion caused by microcirculatory blood flow as the only contributor 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, probing ever smaller length and time scales to see if some water pools change their signature during excitation. Another area of interest has been 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 it induced changes by monitoring water exchange across membranes non-invasively using NMR. Water transport has been proposed as a good proxy for measuring ion fluxes caused by membrane pumps, to which it is coupled, making water transport a potential reporter or biomarker 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 to exist. 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 neurons or axons that could be excited or depressed by such stimuli. More recently, developed full 3D models of electric field deposition within the brain, obtained from 3D diffusion tensor MRI data. 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 precisely 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 has attempted 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 have 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 or anti-proliferative effects 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 frequency than in TMS--in the 100-300 kHz frequency range and have an amplitude of approximately 1 V/cm or greater. According to our early calculations, these fields would not cause neural stimulation, but could cross 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" oscillating electric fields to brain regions is via electromagnetic induction rather than electrodes placed on the scalp. This idea resulted in us building a device that could be used to assess the effect of electric fields on cell and tissue cultures in a highly controlled manner. Our painstaking work in this area did not suggest a link between applied electric fields and tumor cell death. Clearly more study is required.