Our laboratory is developing a new generation of functional magnetic resonance imaging (fMRI) methods to study the neural mechanisms of behavior. Our principal focus is on the design and application of new contrast agents that may help define spatiotemporal patterns of neural activity with far better precision and resolution than current techniques allow. Experiments using the new agents will combine the specificity of cellular neuroimaging with the whole brain coverage and noninvasiveness of conventional fMRI. Introduction of these technologies will have far-reaching consequences in neuroscience, because the new imaging methods will be applicable to studies of any neural system in vivo. Our own goal is to use the methods to build explanatory models of neural network function in animals, with current emphasis on brain circuitry involved in instrumental learning behavior.

Contrast agents for “molecular fMRI”

Contrast agents required for functional molecular imaging experiments are roughly analogous to fluorescent dyes used widely in cellular neuroscience. They differ in chemistry—MRI contrast agents are generally paramagnetic, and the structural or electronic changes that allow them to be used as sensors must affect their magnetic properties in some way. We work largely with iron oxide nanoparticles, a potent form of contrast agent whose effects can be regulated through controlled aggregation or the construction of nanoassemblies. We recently created a family of calcium sensors by conjugating iron oxides to calcium sensing proteins, and we are using similar approaches to make sensors for both intra- and extracellular neuronal signaling events. In collaboration with other laboratories at MIT and elsewhere, we are also exploring genetically encodable or small synthetic contrast agents for molecular neuroimaging.

Functional imaging in animals

We use high resolution MRI in animals to test our new contrast agents. In collaboration with David Cory, we built an MRI microscopy system capable of 20-40 µm resolution imaging of small animals like the blowfly Sarcophaga bullata. In this system, we can combine visual stimulation and injection of contrast agents to determine response properties of the agents at the single neuron level. We also use conventional fMRI techniques, in combination with behavioral measures and electrophysiology, to study instrumental learning and plasticity phenomena in rodents. Significant effort is devoted to experiments that address dynamics of distributed brain pathways in awake, behaving animals. Our new sensors will be applied in these studies once effective delivery strategies are established.