MRI contrast agents for functional molecular imaging of brain activity

Functional imaging with MRI contrast agents is an emerging experimental approach that can combine the specificity of cellular neural recording techniques with noninvasive whole-brain coverage. A variety of contrast agents sensitive to aspects of brain activity have recently been introduced. These include new probes for calcium and other metal ions that offer high sensitivity and membrane permeability, as well as imaging agents for high-resolution pH and metabolic mapping in living animals. Genetically encoded MRI contrast agents have also been described. Several of the new probes have been validated in the brain; in vivo use of other agents remains a challenge. This review outlines advantages and disadvantages of specific molecular imaging approaches and discusses current or potential applications in neurobiology.

Introduction

As neuroscientists become increasingly brave in their efforts to study the functioning of neural systems in vivo, there is a growing need for measurement methods that can record comprehensive information about the functioning of living brains. Magnetic resonance imaging (MRI) is a special tool in this regard, because of its relatively high spatial resolution (∼10 μm in high magnetic field scanners) and capacity to scan entire organisms noninvasively. Functional MRI (fMRI) with contrast dependent on cerebral hemodynamics provides an indirect readout of neural activity [1, 2, 3]. Although hemodynamic fMRI has had transformative impact in cognitive science, the techniques lack the specificity and temporal precision of electrophysiology and optical imaging, and have not been widely used in basic neurobiology experiments.

Another way to exploit the unique advantages of MRI for neuroscience is to perform the imaging in conjunction with molecular probes (contrast agents) sensitive to aspects of neuronal physiology [4]. This approach is roughly analogous to performing optical neuroimaging with fluorescent dyes, but is currently far less well-developed. Most MRI contrast agents are paramagnetic chemicals that increase parameters called the T₁ and T₂ relaxation rates of water, as observed in tissue and solution; T₁ or T₂ relaxation enhancements produce image brightening or darkening, respectively. Additional classes of contrast agents work by a chemical exchange-based mechanism called chemical exchange saturation transfer (CEST) [5], or involve imaging nonstandard nuclei like ¹⁹F and ¹³C. The characteristics and physical mechanisms of different types of contrast agent are discussed at length in a number of book chapters and reviews [6, 7, 8, 9, 10, 11], and are summarized in Figure 1. In general, for any agent to be used in functional imaging, either its ability to influence MRI contrast or its spatial distribution must be sensitized to neural activity in some way.

The past few years have seen significant advances in the design of new MRI contrast-based sensors and the introduction of protein contrast agents for brain imaging. These are nascent technologies—few of the efforts have progressed beyond an in vitro or proof-of-concept stage, but in several cases experiments using the new agents in animals can now be performed. The remainder of this review describes contrast agents suitable for functional imaging based on metal ions, pH, metabolic activity, and gene and protein expression. Prospects for future development and application of molecular fMRI methods are discussed.