These results suggest that phMRI may potentially prove useful to map DAR function non-invasively in multiple brain regions simultaneously.

Relative to common clinical magnetic field strengths, higher fields benefit functional brain imaging both by providing additional signal for high-resolution applications and by improving the sensitivity of endogenous contrast due to the blood oxygen level dependent (BOLD) mechanism, which has limited detection power at low magnetic fields relative to the use of exogenous contrast agent. This study evaluates the utility of iron oxide contrast agent for gradient echo functional MRI at 9.4 T in rodents using cocaine and methylphenidate as stimuli. Relative to the BOLD method, the use of high iron doses and short echo times provided a roughly twofold global increase in functional sensitivity, while also suppressing large vessel signal and reducing susceptibility artifacts. MRI is widely used to assess brain function in humans and animals due to a powerful combination of capabilities, including high spatiotemporal resolution, volumetric coverage, and the potential for noninvasive, longitudinal studies. Many of the target applications for fMRI in animal models are inherently challenging in terms of sensitivity. For instance, functional signals often are attenuated in disease or recovery states, such as the evolution of neuronal plasticity during recovery from stroke (1-3). Pharmacological stimuli can produce widespread, graded, dosedependent changes in local brain function; low-field blood oxygen level dependent (BOLD) signal is simply inadequate for detecting changes in many brain regions without averaging results from a very large number of animals (4,5).High magnetic field strengths provide numerous advantages for fMRI, as well as challenges (6). Sample polarization increases with magnetic field, providing additional signal that can be traded for higher spatial resolution. Functional changes in the BOLD relaxation rate also increase with field strength (7), making BOLD detection power more competitive with that provided by an exogenous agent (8). Moreover, paramagnetic deoxyhemoglobin shortens blood relaxation times at high field strengths, which should decrease spatially nonspecific signal associated with draining vessels. However, the time scale for relaxation of transverse magnetization using gradient echoes (T 2 *) becomes progressively shorter and more heterogeneous, especially in regions near magnetic susceptibility interfaces that arise at air-tissue and bone-tissue interfaces. Signal dropout and image distortion reduce some of the theoretical advantages of BOLD fMRI at high fields by forcing a choice between increased image artifacts or the reduced sensitivity that accompanies short gradient echo times or spin echo methods.Because of the limitations of BOLD sensitivity, many fMRI applications in animal models have employed exogenous contrast agents (1-3,9 -11), which experimentally have been shown to markedly improve fMRI sensitivity at magnetic field strengths up to 4.7 T (4,5,8,12-14). The use of exogenous agents with very long blood half lives for fMRI has been termed IRON fMRI (5), to denote the increas...

The use of functional magnetic resonance imaging (fMRI) techniques for evaluation of pharmacologic stimuli has great potential for understanding neurotransmitter dynamics for a number of brain disorders, such as drug abuse, schizophrenia, epilepsy, or neurodegeneration. Unfortunately, blood oxygenation level-dependent (BOLD) imaging at common fields strengths, such as 1.5 or 3 T, has very low sensitivity and contrast-to-noise ratios (CNRs). We demonstrate here the utility of using an intravascular superparamagnetic iron oxide contrast agent with a long plasma half-life for evaluation of hemodynamic changes related to dopaminergic stimuli using amphetamine or the cocaine analog 2␤-carbomethoxy-3␤-(4-fluorophenyl)tropane (CFT). We refer to this technique as increased relaxation with iron oxide nanoparticles (IRON). Results obtained here show that even at field strengths as high as 4.7 T, one can obtain increases in CNR by factors of 2-3 over BOLD imaging that lead to greater than an order of magnitude increase in statistical power with greatly increased sensitivity to hemodynamic changes in brain regions difficult to observe using BOLD imaging. Furthermore, use of the intravascular contrast agent allows for a meaningful physiologic parameter to be measured (relative cerebral blood volume (rCBV)), compared to conventional BOLD imaging. J. Magn. THE TECHNIQUE OF FUNCTIONAL MAGNETIC resonance imaging (fMRI) using either relative cerebral blood volume (rCBV) (1), blood oxygenation level-dependent (BOLD) (2,3), or T1-based cerebral blood flow (CBF) techniques (3,4) has led to a revolution in brain mapping. By far the most common application is the BOLD technique. Unfortunately, contrast-to-noise ratios (CNRs) of BOLD are low, especially at field strengths such as 1.5 T (5). In addition, BOLD contrast has no simple relationship to any unique physiologic parameter, although with appropriate calibration and modeling in ideal circumstances, it can be used to infer regional oxygen consumption (6,7). CNRs for flow-based MR measurements based upon T1 changes (3,4,8) are generally even lower than they are for BOLD.Conventional BOLD imaging is often sensitivity limited at field strengths such as 1.5 T. For example, percent signal changes in occipital cortex with photic stimulation protocols are on the order of 2%-3% with a standard gradient echo (GE) EPI acquisition (long TR, moderate TE (30 -50 msec)). Other stimuli of interest, particularly those associated with cognitive tasks, are most often smaller in magnitude and require intersubject averaging. This is obviously inappropriate for clinical studies where one might need data from individual patients. Use of BOLD for mapping of neuronal activation after a pharmacologic challenge has an even greater number of limitations than mapping task activation in conventional fMRI. Generally, pharmacologic stimuli have a longer and uncontrolled time duration, compared to task activation in fMRI (9). Due to the long time course of the pharmacodynamic changes that may take place, BOLD sig...