1. A major focus is quantitative characterization of biophysical and neurophysiologic events that contribute to the blood oxygenation level dependent (BOLD) functional MRI contrast. The focus here is to use multi-modal approaches (e.g., electrophysiological and optical techniques along with NMR methods) in rodent brain to probe the variety of events over a range of spatial and temporal scales to fully characterize the stimulation-induced dynamics of the fMRI signal. This approach applied to rat brain at 7T has provided a quantitative understanding about the energetic basis of the BOLD signal at steady-state. The current focus is to extend these types of quantitative studies towards characterizing the dynamic BOLD signal. (see Kida et al (2000; 2001), Hyder et al (2001; 2002), Shulman et al (2002), and Smith et al (2002) as examples of this research direction).

2. A longstanding strength of the laboratory has been development of animal models for functional MRI studies at high magnetic field. The highest spatial resolutions ever reached in vivo with BOLD imaging (e.g., 0.0015 uL) were obtained on the 7T horizontal-bore animal system at the Yale MRRC. We have recently acquired new horizontal-bore animal systems (9.4T and 11.7T). To date, three sensory models have been developed for neurophysiologic studies of the rodent brain (i.e., forepaw, whisker, olfaction) and the current interest is to extend the BOLD spatial resolution to study neuronal architecture in mouse brain. While the forepaw and whisker models have been utilized by the MRI community as models for functional MRI studies, the olfactory bulb model is being used to acquire neurobiological basis of olfaction and behavior. (see Yang et al (1996), Kida et al (2002), and Xu et al (2000; 2003) as examples of this research direction).

3. A major focus of the research at the Yale MRRC is the development of 13C NMR methods to probe metabolism of natural substrates (e.g., 13C-labeled glucose) in order to determine cellular energetics and function. A fundamental requirement for quantitative characterization of the BOLD signal is to measure oxygen consumption of glutamatergic neurons (i.e., glutamate is the major excitatory neurotransmitter in mammalian cerebral cortex). The current interest is to extend the 13C NMR spatial resolution to voxels smaller than a few uL (using chemical shift imaging methods at high speeds) so that the energetic basis of the BOLD signal at steady-state is reliable at higher spatial resolution. More recent 1H NMR sdevelopments have focused on direct measurements of tissue temperature and pH. (see Hyder et al (1999; 2003) and Trübel et al (2003) as examples of this research direction).