Thinking Inside the Voxel

Mark Does is interested in what’s /really/ going on inside that 1 millimeter cube of MRI space called a “voxel.”* A voxel is like a 3-D pixel in a Magnetic Resonance Imaging (MRI) scan and is the smallest spatial unit an MRI scanner is able to resolve.

“MRI was developed only 30 years ago,” the assistant professor of biomedical engineering at Vanderbilt said. “While it has become a mainstay in clinical radiology, it is rich in capabilities, and we are far from utilizing it to its full potential.”

The MRI imaging modality is very good at distinguishing between different types of soft body tissues, but Does wants to get a closer look at what’s happening to the cells, themselves.

Does has won a National Science Foundation (NSF) CAREER award for his research to develop MRI techniques that can tease out information about bodily tissues at the cellular, sub-voxel level.

His techniques will have immediate application to diagnosis and treatment of multiple sclerosis but ultimately will be applicable to a variety of other tissues, as well.

Multiple sclerosis involves degeneration of the sheath of myelin that insulates the nerve cells and causes the cells to short out and fail to communicate with each other.

“MRI cannot visualize myelin directly, so we are looking at ways to infer its presence,” Does said. “Our immediate objective is simply to measure how much myelin is present, with a longer term goal of distinguishing between healthy myelin and myelin that has broken down.”

Unlocking the secrets of myelin content contained within a single heterogeneous voxel of MRI space is just the beginning. Does’ work will help advance the application of MRI technology to more precisely analyze the cellular level of a wide range of tissues, particularly in the brain, the spinal cord and the heart.

Like most MRI techniques, Does’ approach targets water. “We want to get as complete a picture as we can of how water behaves inside the myelin,”
Does said.

A single voxel imaging nerve and white matter in the brain might contain hundreds or thousands of myelinated axons, which are the connecting components of nerve cells. There is water around these cells as well as water within them. How is one to distinguish the water within ultra-thin myelin from the water everywhere else in the space depicted by the voxel?
Part of the trick lies in manipulating and rearranging the precise “pulse sequences” that make up MRI scans.

Unlike the comparatively straightforward point-and-shoot techniques of X-ray and CT scans, MRI scans are obtained by subjecting bodily tissues to a variety of magnetic and radio energies and discriminating between different tissues based on how they respond to these stimuli.

The large magnet people commonly identify as the “MRI scanner” serves the purpose of creating a magnetic field such that the protons of hydrogen (in water, which pervades the body) aligns with it. You won’t feel it if you’re having an MRI  scan done, but all those hydrogen cells are abandoning their usual random orientation in the body and are lining up north-south with the magnet. Three smaller magnets called gradients then swing into action, each one representing the x, y, and z axes of a three-dimensional graph. These three magnets align so that an area of interest, or slice, can be imaged, because the protons in that area are affected differently from protons outside the slice.

Next the aligned protons are zapped with a radio frequency that is precisely tuned to make hydrogen protons wobble (“precess” is the correct term) at a higher energy level for a short time.

As the stimulated protons relax back to their preferred precession level, they emit energy in the radio frequency range. Protons relax at different rates, depending on the type of tissue they are embedded in and how quickly the surrounding tissue can absorb the released energy.
An MRI receiver picks up the released energy signal, which is transmitted to the computer that plots the relaxation times and other data. This information is then compared with MRI data libraries that have been developed to identify different types of tissue based on these relaxation rates.

As you might imagine, the sequence and precision of these sets of stimuli to the protons must be exquisitely timed and finely tuned in order to achieve the desired precision in the image. If the sequence is altered, different information is gained. Does and his associates are taking advantage of that ultra sensitivity and precision to discern what’s contained within single voxels, based on the relaxation patterns that emerge from different pulse sequences.

“Water in myelin ‘relaxes’ more quickly than the other water in nerve.
We collect a series of images, each at a different time point of this relaxation process,” Does said. “From these we can extract a time course of the relaxation of the combination of all signal within a voxel, which can be mathematically transformed how much signal exists at different relaxation rates.”

In addition to altering the radio frequency pulse sequences to better quantify the amount of myelin at a sub-voxel level, Does is using manganese, a contrast agent readily taken up by calcium channels used to transmit electrical signals through nerve cells. Manganese is a metal ion strongly imaged by MRI equipment.

Does is currently testing his techniques on rats in the Center for Small Animal Imaging, which he directs. The Center is part of the Vanderbilt University Institute of Imaging Science (VUIIS). “This gives us the opportunity to explore the potential of small animal MRI as a research tool,” Does said.