This R21 application aims to develop and evaluate a novel magnetic resonance imaging (MRI) technique that has considerable potential for detection and mapping of neural activity in the brain with temporal resolution much greater than BOLD (blood oxygen level dependent) imaging or similar approaches that rely on detecting hemodynamic changes. The proposed technique builds on provocative claims by established investigators that MRI methods that are sensitive to the diffusion properties of tissue water (diffusion-weighted MRI, DW-MRI) can detect water shifts and axonal swelling that accompany neural firing, phenomena that are not unexpected and have also been reported by optical imaging, and which occur immediately proximal in space and time to neural electrical activity. However, the origins and robustness of these changes remain controversial and unsubstantiated, and clearly are not easy to detect using conventional DW-MRI. We have pioneered a novel diffusion imaging method that can be selectively sensitized to neural structures of a specific dimension, and which should be much more sensitive to changes in the dimensions of neural cells and water compartments. We therefore propose to explore its use as a method of detecting and mapping brain activity. Conventional DW-MRI methods based on the Pulsed Gradient Spin Echo (PGSE) method reflect the integrated effects of a variety of structural features, including those of relatively large spatial scale, greater than a nerve cell diameter, including nerve cell membranes. We have developed an alternative technique, oscillating gradient spin-echo (OGSE), which is capable of detecting restrictions to diffusion over much smaller spatial scales, which results in a high sensitivity specifically to the effects of changes in cell dimensions. Here we propose to establish whether OGSE imaging can reliably detect immediate diffusion changes induced by neural activity. We will apply optimized OGSE, conventional BOLD and PGSE methods, to image rat brain in vivo before and after administration of a pharmacological agent (PCP) known to elicit robust, slowly varying changes in brain activation, with/or without pre-treatment with an agent that blocks the effect (BINA). These slow-varying activations will allow derivation of quantitative estimates of microstructural changes within the tissue. We will also record BOLD, OGSE and PGSE images at high temporal resolution during forepaw stimulation administered in an event-related design, during normal breathing or while breathing carbogen. By comparing the time courses of these various image series we will be able to verify whether diffusion changes related to activation are detectable, whether they occur faster than vascular changes, and whether the OGSE data at high frequency reveal changes in tissue microstructure (neuronal swelling) that occurs faster and more proximal to the underlying electrical events than other methods. The potential outcome of these studies would be a method for mapping neural activation with high temporal and spatial resolution that could be used in diverse human and animal studies of the functional organization of the brain.
There are widespread applications, in both neuroscience research and clinical neurological and psychiatric practice, for imaging methods that can detect and map brain activity to delineate and understand the functional organization of the brain. Functional MRI is currently the single most powerful method available for obtaining information on brain activation with high spatial resolution, but unfortunately it relies on blood flow changes that have very slow temporal characteristics, so that very little information is obtainable about the timing of neural events at the speed of the underlying electrical activity. The MRI method proposed for development may in principle overcome this shortcoming and allows recordings of brain activity with both high spatial and temporal resolution. The work would also substantiate or refute claims by others about the ability of MRI to assess neural activity with high temporal resolution.