A new MRI sensor can image the activity deep in the brain

Calcium is an essential signaling molecule for most cells, especially for neurons. Calcium imaging in brain cells can reveal how neurons communicate with each other. However, current imaging techniques can only penetrate a few millimeters into the brain.

MIT researchers have developed a new way of imaging calcium activity from magnetic resonance imaging (MRI) and allowing them to observe much deeper in the brain. With the help of this technique, they can follow signaling processes in living animal neurons, allowing them to link neuronal activity to specific behaviors.

"This article describes the first MRI detection of intracellular calcium signaling, directly badogous to powerful optical approaches widely used in neuroscience, but now allows for such in vivo measurements in deep tissue," says Alan Jasanoff, professor at MIT. Biological Engineering, Brain Sciences and Cognitive Science, and Nuclear Science and Engineering, and Associate Member of the McGovern Brain Research Institute of MIT.

Jasanoff is the lead author of the paper, which appears in the February 22 issue of Nature Communications. MIT postdocs, Ali Barandov and Benjamin Bartelle, are the main authors of the newspaper. Catherine Williamson, MIT senior, Emily Loucks, a recent MIT graduate, and Stephen Amber Noyes, professor emeritus of chemistry, are also the authors of the study.

Enter the cells

At rest, the neurons have a very low calcium level. However, when they trigger an electrical impulse, calcium enters the cell. In recent decades, scientists have developed ways to image this activity by labeling calcium with fluorescent molecules. This can be done in cells grown in a lab box or in the brain of live animals, but this type of microscopic imaging can only penetrate a few tenths of a millimeter into the tissue, limiting most studies on the surface of the brain.

"These tools can do incredible things, but we wanted something that would allow us and others to deepen the signaling at the cellular level," Jasanoff said.

To achieve this, the MIT team has turned to MRI, a non-invasive technique that detects magnetic interactions between an injected contrast agent and water molecules at the same time. 39, inside the cells.

Many scientists have been working on MRI-based calcium sensors, but the major hurdle has been the development of a contrast agent that can penetrate inside brain cells. Last year, Jasanoff's laboratory developed an MRI sensor capable of measuring extracellular calcium concentrations, but relying on nanoparticles too large to penetrate cells.

To create their new intracellular calcium sensors, the researchers used building blocks that could cross the cell membrane. The contrast agent contains manganese, a metal that interacts weakly with magnetic fields, bound to an organic compound that can penetrate cell membranes. This complex also contains an arm binding calcium called chelator.

Once inside the cell, if the calcium levels are low, the calcium chelator binds weakly to the manganese atom, thus protecting the manganese from MRI detection. When calcium enters the cell, the chelator binds to the calcium and releases the manganese, making the contrast agent brighter in an MRI image.

"When neurons, or other brain cells called glial cells, are stimulated, their calcium concentration is often increased tenfold, and our sensor can detect these changes," explains Jasanoff.

Precise measurements

Researchers tested their sensor in the rat by injecting it into the striatum, a region of the brain involved in motion planning and learning new behaviors. They then used potbadium ions to stimulate electrical activity in the striatal neurons and were able to measure the calcium response of these cells.

Jasanoff hopes to use this technique to identify small clusters of neurons involved in specific behaviors or actions. As this method directly measures the signaling within cells, it can provide much more precise information on the localization and synchronization of neuron activity than traditional functional MRI (fMRI), which measures the flow blood in the brain.

"This could be useful for understanding how different brain structures work together to treat stimuli or coordinate behaviors," he says.

In addition, this technique could be used to image calcium as it fulfills many other roles, such as facilitating the activation of immune cells. With additional modifications, it could also one day be used to perform diagnostic imaging of the brain or other organs whose functions depend on calcium, such as the heart.

Provided by
Mbadachusetts Institute of Technology