MRI, novel contrast agent improves measurement of brain’s calcium activity

A new MRI technique developed by researchers from the Massachusetts Institute of Technology (MIT) in Cambridge, may improve the measurement of calcium activity in the brain and perform better than current methods.

The technique, which combines MRI with a manganese-based contract agent, could also help researchers better understand how neurons communicate in the brain, according to a study published online Feb. 22 in Nature Communications.  

In neurons, calcium is a critical signaling molecule which, when imaged in the brain, can reveal how neurons communicate with each other. However, most calcium imaging techniques can only penetrate a few millimeters into the brain.  

“Although optical probes for intracellular calcium imaging have been available for decades, the development of probes for noninvasive detection of intracellular calcium signaling in deep tissue and intact organisms remains a challenge,” wrote researchers led by Ali Barandov, PhD, a senior research scientist at MIT. “To address this problem, we synthesized a manganese-based paramagnetic contrast agent, ManICS1-AM, designed to permeate cells, undergo esterase cleavage, and allow intracellular calcium levels to be monitored by magnetic resonance imaging (MRI).” 

A major obstacle in creating MRI-based calcium sensors has been developing a contrast agent that can get inside brain cells. Last year, the researchers developed an MRI sensor that can measure extracellular calcium concentrations, but they were based on nanoparticles that are too large to enter cells. 

To overcome this issue, the researchers created a new intracellular calcium sensor with the ManICS1-AM contrast agent that can penetrate cell membranes and also contains a calcium-binding arm called a chelator.  

The researchers injected the sensors into the brains of rats, particularly the striatum—a region deep within the brain responsible for planning movement and learning new behaviors. Potassium ions were then used to stimulate electrical activity in neurons of the striatum and the researchers then measured the calcium response within the cells. 

If calcium levels are low, the calcium chelator binds weakly to the manganese atom and shields the manganese from being detected by MRI, according to the researchers. When calcium flows into the cell, the chelator binds to the calcium and releases the manganese, which makes the contrast agent appear brighter on an MRI image. 

When neurons or other brain cells were stimulated, the increase in calcium concentration was detected by the sensors and could be seen on an MRI.  

The researchers hope to use this technique to identify small clusters of neurons involved in specific behaviors or actions, as it can offer more information about the location and timing of neuron activity compared to functional MRI (fMRI).  

“There are amazing things being done with these tools, but we wanted something that would allow ourselves and others to look deeper at cellular-level signaling,” senior author Alan Jasanoff, PhD, a professor of biological engineering at MIT, said in a prepared statement.  

The method could also be used to image the activation of immune cells and, with further modification, may be used to perform diagnostic imaging of the heart and other organs that rely on calcium to function.