A precise new quantitative brain-scan measurement method

Can quantify the volume of specific brain tissues, a critical measurement of the progression of brain diseases

November 19, 2013

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The image is of the macromolecule tissue volume (MTV) map in a 3D view within a human brain (credit: Aviv Mezer/Stanford University)

An interdisciplinary Stanford team has developed a new method for quantitatively (using numbers) measuring human brain tissue using MRI (which formerly provided mostly qualitative, such as “bright” or “dark,” information).
The team members measured the volume of large molecules (macromolecules) within each cubic millimeter of the brain. Their method may improve how doctors diagnose and treat neurological diseases such as multiple sclerosis.
“We’re moving from qualitative — saying something is off — to measuring how [far] off it is,” said Aviv Mezer, Stanford postdoctoral scholar in psychology. The team’s work, funded by research grants from the National Institutes of Health, appears in the journal Nature Medicine.
He found inspiration in seemingly unrelated basic research from the 1980s. In theory, he read, magnetic resonance could quantitatively discriminate between different types of tissues. But previous quantitative MRI measurements required uncomfortably long scan times. Mezer, whose background is in biophysics, and psychology Professor Brian Wandell unearthed a faster scanning technique, albeit one noted for its lack of consistency.
“Now we’ve found a way to make the fast method reliable,” Mezer said. Mezer and Wandell, working with neuroscientists, radiologists and chemical engineers, calibrated their method with a physical model — a radiological “phantom” — filled with agar gel and cholesterol to mimic brain tissue in MRI scans.
Measuring voxels (3D volumes)
The team used one of Stanford’s own MRI machines, located in the Center for Cognitive and Neurobiological Imaging, or CNI, which Wandell directs.  Their results provided a new way to look at a living brain.
MRI images of the brain are made of many “voxels,” or three-dimensional volume elements. Each voxel represents the signal from a small volume of the brain, much like a pixel represents a small volume of an image. The fraction of each voxel filled with brain tissue (as opposed to water) is called the macromolecular tissue volume, or MTV. Different areas of the brain have different MTVs.
Mezer found that his MRI method produced MTV values in agreement with measurements that, until now, could only come from post-mortem brain specimens. This is a useful first measurement, Mezer said. “The MTV is the most basic entity of the structure. It’s what the tissue is made of.”
Precise MRI brain measurements
“The new method we have developed estimates both the volume of tissue (macromolecules and lipid membrane) and the rate of interaction between water molecules and the tissue surface  (SIR),” Mezer explained to KurzweilAI.
“The MR mapping we propose makes use of a short straightforward clinical sequence supplied by most MR scanners. The calculations are simple and fast enough to be used by any clinical and research MR center. Together, these advantages make it possible to immediately use the methods for scientific and clinical applications by facilitating comparison of data across multiple sites and enabling comparisons between individual participants or patient to a control population or in the same individual over time.
“These fundamental brain-tissue biomarkers can be measured within each brain voxel (roughly 1 cubic millimeter). These measurements are quantitative and thus can be meaningfully compared across sites and within a single individual across time. The quantification of tissue volume and tissue-water interaction will have significant value for those seeking to monitor healthy brain development across the lifespan as well as for clinicians who try to characterize brain pathologies.”
As a test of using these biomarkers, the team applied its method to a group of multiple sclerosis patients. MS attacks a layer of cells called the myelin sheath, which protects neurons the same way insulation protects a wire. Until now, doctors typically used qualitative MRI scans (displaying bright or dark lesions) or behavioral tests to assess the disease’s progression.
Myelin comprises most of the volume of the brain’s “white matter,” the core of the brain. As MS erodes myelin, the MTV of the white matter changes. Just as predicted, Mezer and Wandell found that MS patients’ white matter MTV tissue volumes were significantly lower than those of healthy volunteers.
Mezer and colleagues at Stanford School of Medicine are now following up with the patients to evaluate the effect of MS drug therapies. They’re using MTV values to track individual brain tissue changes over time.
The team’s results were consistent among five MRI machines.
“The qualitative measurement significantly limits the utility of the technique because without units, scientists and clinicians cannot meaningfully compare images obtained at different MR sites or even from the same individual at different points in time,” Mezer added. “Just as we have units to record a child’s height or a patient’s temperature, we need quantitative MR measures to assess brain development or the effect of a drug on neural tissue inflammation.”
Monitoring brain development
Mezer and Wandell will next use MRI measurements to monitor brain development in children, particularly as the children learn to read. Wandell’s previous work mapped the neural connections involved in learning to read. MRI scans can measure how those connections form.
“You can compare whether the circuits are developing within specified limits for typical children,” Wandell said, “or whether there are circuits that are wildly out of spec, and we ought to look into other ways to help the child learn to read.”
Tracking MTV, according to the team, helps doctors better compare patients’ brains to the general population — or to their own history — giving them a chance to act before it’s too late.

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Abstract of Nature Medicine paper
Here, we describe a quantitative neuroimaging method to estimate the macromolecular tissue volume (MTV), a fundamental measure of brain anatomy. By making measurements over a range of field strengths and scan parameters, we tested the key assumptions and the robustness of the method. The measurements confirm that a consistent quantitative estimate of MTV can be obtained across a range of scanners. MTV estimates are sufficiently precise to enable a comparison between data obtained from an individual subject with control population data. We describe two applications. First, we show that MTV estimates can be combined with T1 and diffusion measurements to augment our understanding of the tissue properties. Second, we show that MTV provides a sensitive measure of disease status in individual patients with multiple sclerosis. The MTV maps are obtained using short clinically appropriate scans that can reveal how tissue changes influence behavior and cognition.


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