MRI contrast agents for functional molecular imaging of brain activity
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.
Section snippets
Indicators for Ca2+ and other metal ions
Calcium ions are an important target for neuroimaging agents because neuronal calcium fluxes are dramatic and directly related to synaptic activity. Recent two-photon fluorescence imaging studies have demonstrated the power of calcium measurements to characterize neuronal population behavior in exposed regions of the brain [12, 13]. MRI indicators for calcium can facilitate calcium imaging of deep tissue structures. Several relaxation-based contrast agents for calcium-dependent MRI have been
pH Indicators
The extracellular medium becomes slightly acidified during neural activity [27]. Although these changes (in the range from pH 7.2 to 7.4) are not restricted to individual neurons, they could be monitored by pH-sensitive probes and used for functional fMRI. Both relaxation and CEST-based MRI contrast agents work by mechanisms that involve water or proton exchange (Figure 1a–c), which are inherently pH dependent and therefore easily compatible with pH sensing. In fact, a diverse set of pH
Probes for metabolic activity
Changes in metabolic activity are closely coupled to neural signaling, and MRI contrast agents sensitive to cellular respiration may be used for functional imaging. Given evidence that metabolic processes including the consumption of oxygen are locally regulated on a much faster timescale than changes in hemodynamics [33], direct monitoring of these variables could provide more precise information about brain function than hemodynamic fMRI techniques can. The best-known oxygen sensitive
Genetically controlled contrast agents
The discovery of green fluorescent protein (GFP) and the development of genetically encoded fluorescent indicators like cameleons [39] and synaptophluorins [40] are continuing to revolutionize the modern practice of neuroscience. Unlike fluorescent proteins, genetically encodable contrast agents (most of them paramagnetic metalloproteins) are plentiful in nature, but it is only in the past few years that any of these have been exploited as ectopically expressed markers for imaging. The iron
Conclusions
A number MRI contrast agents with potential utility for functional imaging have been discussed. Table 1 summarizes advantages and disadvantages of many of the approaches. Although some of the contrast agents have been applied in animals, only Mn2+ dependent labeling has so far been used for functional imaging of neural activity. For basic neuroscience studies, none of the new techniques is currently a surrogate for hemodynamic fMRI or invasive neural recording methods. Major progress has been
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
The author wishes to acknowledge support from the NIH (EB5723), the McKnight Endowment Fund for Neuroscience, and the Raymond and Beverly Sackler Foundation.
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