The purpose of the research proposed in this application is to investigate the extent to which the brain apparent diffusion coefficient (ADC) changes due to neuronal activation both in an animal model. Thus the work will contribute to understanding of the neuronal microenvironment during neuronal activity and potentially provide a new tool for noninvasive localization and possible quantitation of brain activity. Evidence from invasive, optical (infra-red) imaging of the surface of the brain during task activation indicates that there is the expected vascular response located primarily in the pial artioles and the draining veins in the region of neuronal activation. This is the source of the blood-oxygenation-level dependent (BOLD) changes that underlie the bulk of functional magnetic resonance imaging (fMRI). There also appears to be a direct, cellular response that has been shown to be related to glial and/or neuronal swelling due to changes in the intra/extra-cellular solute balance as a consequence of increased metabolic and membrane activity. The cellular response appears to be much more directly related to the actual region of neuronal activity than the vascular response. Preliminary data in human subjects supports the idea that the cellular swelling should also result in a change of the local tissue ADC that could be observed with MR imaging. There are major challenges to utilizing this ADC contrast such as the low contrast-to-noise ratio of the effect and motion artifacts from diffusion gradients. Early results in humans have shown a mixture of diffusion effects, some at the area of BOLD activation and others that seem unrelated. Due to the difficulties of controlling human motions and/or performing human drug interventions to modulate the effect it is proposed here to proceed to establish the effect in an animal model where motion can be controlled and interventions performed.
The aims of this research are: (1) establish the spatial extent of the ADC change compared to BOLD fMRI in a rat forepaw electrical stimulation model using a 7 Tesla small animal MR imaging system with very strong (400roT/m) gradients; (2) determine whether there are residual BOLD effects in the ADC signal by blocking vascular response in the pial arterioles using an infusion of a drug such as theophylline or caffeine to block vascular adenosine receptors and nitric oxide synthase inhibitors to block nitric oxide signaling.
