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Feature Articles : Oct 15, 2010 (Vol. 30, No. 18)

In Vivo Imaging Transfigured by MRI

Researchers Have Their Sights Set on Emerging Tools for Faster and Improved Operations
  • Gail Dutton

Magnetic resonance imaging (MRI) is the tricorder of our time, according to Mark Griswold, Ph.D., associate professor at Case Western Reserve University, referring to the Star Trek medical device that seemingly performs all diagnostic tests with a mere scan. Although it isn’t as advanced as its Star Trek cousin, emerging MRI devices are breaking the barriers in terms of imaging speed and what may be imaged successfully.

Dr. Griswold, who was one of a number of speakers at the Gordon Research Conference on “In Vivo Magnetic Resonance” in Andover, NH, in July, has developed a method that images data 384 times faster than was possible in the mid 1990s, and one of his colleagues has pushed the boundary to 970 times faster than mid ’90s speed, he says. The approach tends to focus tightly on only pixels that contain relevant information and ignores irrelevant pixels. “In many clinical situations, only about 10 percent of an image has relevant data, but the entire image is processed through the same techniques.” 

One approach Dr. Griswold’s lab is investigating uses a library of prior scans to teach the scanner what a typical scan should look like. Afterward, only the portions of an image not recognized on those scans goes to a lossy data-processing channel. The rest of the data is processed by other channels. The goal is to minimize what goes to the lossy channel, thereby dramatically speeding imaging and simultaneously providing higher quality views of the relevant data.

The three broad limitations to speed, he says, are the signal itself, the methodology that encodes data to the image, and power demands. Using conventional encoding, the power needed to achieve a fourfold speed increase would approximate the output of a small nuclear power plant, Dr. Griswold says. To break these accepted speed barriers, he explored compressed sensing, a concept that came from the math world.

The challenge was how to turn this concept into a broadly accepted method to generate clinically relevant data. In the case of angiography, the algorithm was written to image only the aspects of a tissue that changed slowly. Pixels that didn’t change, or that changed quickly, were excluded. “There are tons of processes that applies to.”

Working with Northwestern University, Dr. Griswold is applying his work in fast MRI to arteriovenous malformations to provide a roadmap intended to help physicians locate the malformation. Interventional magnetic resonance is another potential application for fast MRI.

“Ours is sensitive to things that no other modality sees, but there are several areas where characterizing a lesion is still problematic.” For example, in mammograms, traditional diagnostics offer sensitivity of about 90%, while MRI offers sensitivity of 98 to 99%. 

Specificity, however, remains problematic. “If you see something with MRI, you oftentimes still must use pathology to characterize it. A clinician has to have some way of quickly getting a sample from the lesion under MRI guidance.” To that end, researchers are developing ways to use MRI to perform minimally invasive therapies including needle biopsies and using radio frequencies to destroy tumors.

Cardiac imaging is another promising application for fast MRI. For example, using MRI, researchers can watch the beating heart, can ascertain—at a range of hundreds of cells per milliliter—whether the myocytes in the myocardium are dead,  and, one day, may be able to determine the best course of treatment.

“At the physics level, magnetic resonance can measure almost any property of almost any tissue,” Dr. Griswold says. Whether it should be used, however, is often determined by the time available for a given measurement. So, each time MRI can be sped up, MRI becomes more practical for a wider range of studies.

Magnetic Particles

“Pure anatomical imaging is changing to quantitative and functional imaging,” according to Jörn Borgert, Ph.D., senior scientist, Philips Research. Last year in preclinical studies, Dr. Borgert says, Philips became the first to show that magnetic particle imaging (MPI) could produce real-time in vivo images that accurately capture cardiovascular activity.

MPI is becoming especially valuable in diagnosing unknown conditions. It could provide one very focused exam that provides the information more often gained by a battery of tests, such as ultrasounds and cardiac catheterization, without background noise.

“Cardiovascular imaging is not the only field where this can have applications,” says Dr. Borgert, who was not one of the participants in the Gordon Research conference. MPI also may be used in oncology to follow the microvascularization of tumors, and other studies that require extreme sensitivity for cellular imaging, labeling, and tracking.

MPI uses the same magnetic iron oxide material as a contrast material that is used for MRI. The iron-oxide nanoparticles are injected into the bloodstream, Dr. Borgert says. “The method involves direct measurement of the magnetization of the particles.” The result is a 3-D image of the iron oxide that can be 1,000 times more sensitive than MRI, he explains, so operators have the choice of high spatial and temporal resolution or of using less material.

Image acquisition times may be as short as one-fiftieth of a second. That lets researchers look, for example, at the beating heart of a mouse and identify functional changes, Dr. Borgert points out. With a frame rate of 46 volumes per second, smooth video sequences can be generated. The first studies generated a resolution of approximately 1.5 mm along one axis and 3 mm along the other two axes, but the researchers are convinced that with optimized image-acquisition procedures, submillimeter resolution is possible.

A prototype version in preclinical demonstrations for small rodents currently provides 3-D images using a 3 cm imaging bore. A larger 12 cm radius bore is also at the prototype stage, and a 40–60 cm bore version is being developed for human applications. “We need to acquire more knowledge about its clinical value,” Dr. Borgert emphasizes. “We’re approaching those tests step by step.”

“It’s very difficult, technically, to scale-up,” he adds. The key challenge, at this point, centers around magnetic field strength.

Small Molecule Imaging

Ultrahigh field magnetic resonance spectroscopy (MRS) is one of those new techniques that is yielding higher resolution images, higher signal-to-noise ratios, and, sometimes, greater speed.

“Ultrahigh fields for magnetic resonance are being used to target molecules other than water,” explains Jullie Pan, M.D., Ph.D., associate professor of neurosurgery at Yale University. We can now image biochemically important molecules such as lactate, glutamate, and GABA with an imaging resolution that is informative and pertinent to living tissue. Ultrahigh field MRS gives researchers a new slant on what they are looking at, how aggressive a tumor is, whether it’s necrotic or proliferative, et cetera,” she elaborates.

Her lab has had success using ultrahigh field MRS to study brain tumors and epilepsy. “The latter condition works with patients who are mainly MRI-negative but who are clearly suffering from a focal brain disease,” she notes.

“The developments and implementation of ultrahigh field MRS imaging opens a distinctively functional and metabolic avenue to imaging the brain, with resolution comparable to that of a PET scan without the issue of radioactivity, which limits repeatability. There also is long-standing research interest in using MRS imaging to study muscle, liver, prostate, and other cancers.”

In the 1990s, Dr. Pan says, typical field strength for human imaging was 1.5 Tesla. In fact, “whether 1.5 Tesla was the optimum field strength was being debated.” Now, the preferred clinical imaging field strength for the human brain is 3 Tesla. However, at higher field strengths, “the size of the human body is closer to the wavelength of the radiofrequency signal at 7 Tesla,” so the detector technology to optimally generate and detect the signals has had to evolve.

“For even higher magnetic fields such as 9.4 and 11.7 Tesla (which exist for human application), this area of work will continue. It’s a long road.” Nonetheless, while technical difficulties of detectors, homogeneity, and relaxation are major challenges, effective approaches are being developed, opening the way to take advantage of the ultrahigh field’s higher signal-to-noise ratio for imaging of anatomy and biochemistry in human study.

Spin-Lock Contrast

At the A. I. Virtanen Institute, University of Eastern Finland, Olli Gröhn, Ph.D., professor of biomedical NMR, is investigating the application of spin-lock MRI contrast in vivo. “T1p, one of the spin-lock MRI contrasts, is currently used mainly for cartilage MRI. However, spin-lock contrasts seem to be more sensitive to tissue changes associated with cell death than conventional MRI.” 

During the next several years, he believes that applications of spin-lock MRI will expand to more neurological applications and are likely to include imaging for Parkinson disease and stroke as well as monitoring tumor treatment responses, “especially glioma gene therapy,” he predicts. Already, researchers have successfully demonstrated the utility of spin-lock MRI contrast in these applications in clinical settings.

In earlier work, Dr. Gröhn and colleagues found ways to adjust the sensitivity of that technique. While investigating tissue changes associated with hyperacute stroke, he and researchers from the University of Eastern Finland (formerly the University of Kuopio), the University of Minnesota, Kuopio University Hospital in Finland, and Dartmouth Medical School, determined that the sensitivity of spin-lock MRI contrast could be modified by varying the spin-lock preparation blocks.

Traditionally, acute ischemia lesions have been predicted by their diffusion-perfusion mismatch. Dr. Gröhn and his collaborators, however, determined that using longitudinal relaxation time in the rotating frame obtained by on-resonance continuous wave spin-lock MRI “predicts the tissue outcome in the acute phase when therapies based on clot removal and/or neuroprotection are most likely to be beneficial.” 

The limiting factor for the spin-lock MRI contrast technique seems to be the high specific absorption rate (SAR) of energy, which may cause tissue heating. This is a particular concern when tissues within the brain are involved, he points out. That, therefore, is why clinical applications have so far concentrated on monitoring conditions outside the brain.

“Areas outside the brain are easier, as SAR limits are higher,” Dr. Gröhn says. Despite that limitation, he and other researchers have used spin-lock techniques successfully for human brain imaging, allowing researchers to assess slow molecular motions that have an extended range of correlation times.

Molecular Imaging Webinar

For more information on in vivo imaging, check out GEN’s on-demand webinar entitled Applying Molecular Imaging in Drug Discovery and Development. The presentation explores how in vivo molecular imaging using multiple techniques can facilitate identification of novel therapeutics early in the drug discovery and development cycle. Featured speakers include imaging experts from Caliper Life Sciences, Millennium, and Abbott Laboratories. Listen to the archived webinar by visiting: www.genengnews.com/molecularimaging.