High-Power Imaging
Techniques Take Us 
Inside the Brain

By Leslie Mertz  

The Bruker 12 Tesla MRI System pictured here is one of only tow machines in the country.  It is used to study the brains of transgenic mice and has already led to new discoveries about depression, anxiety disorder, Parkinson's and Alzheimer's disease.

With a generous bank of high-tech equipment, the Brain Imaging Research Division at the WSU School of Medicine is helping clinicians and researchers learn how the human brain works and how those new discoveries might translate into treatment strategies. Already, division researchers have announced findings with the potential to dramatically improve the lives of people with a range of brain disorders.  

The division’s imaging systems, which incorporate a variety of magnetic-resonance-imaging (MRI) scanners and a high-power magnetic-resonance force microscope, allow researchers to detect critical information about the brain’s structure, function and chemistry. Now, the division is preparing for its newest addition, a scanner with an extremely powerful magnet dubbed a “4-Tesla” or “4T” to reflect its strength rating. This scanner can monitor a much wider assortment of neurochemicals, distinguish even slight changes within the brain, and relay those changes in real time.

 “With this new scanner, we hope to be able to predict what medications will be effective in individuals with various brain disorders, and then actually get into the disease process itself: What’s causing someone to be depressed? Is it a specific chemical in the brain? What’s causing a child to have an obsessive-compulsive disorder? Is a specific region of the brain altered? We have good clues using our current 1.5T scanner, but with the 4T scanner, we’ll have the opportunity to nail these things down,” said Gregory Moore, PhD, director of the Brain Imaging Research Division.

The bigger, the better  
He explained, “Simply put, the bigger the magnet, the more precise you’re going to be able to measure things in the brain. The larger the magnet, the higher the spatial resolution, and that gives you the ability to resolve very small structures or to map brain structure, function and chemistry more precisely.”

In addition, the 4T scanner takes pictures much more quickly than the 1.5T. “The gradients, which are the sounds you hear when the MRI is taking pictures, are much faster in the 4T. We will actually be able to take a picture every 20 milliseconds, so we can map regions of the brain that are turning on and off, and see that in real time,” Dr. Moore reported.

One of the scanner’s greatest contributions, he said, will likely be its ability to monitor many more neurochemicals than previous technology could. “With the 1.5T, we are limited at the most to about six different neurochemicals. At 4T, the number of chemicals that we can precisely and accurately measure is in the 20-range,” he said. “These are important things in your brain like glutamate, which is the most abundant amino acid in the brain; lactate and phosphocreatine, which are involved in energy metabolism; and GABA, an important neurotransmitter – there’s a whole list.”  

These researchers form the Brain Imaging Research Division, which serves an intense scientific agenda, operating experiments nearly 24 hours a day, seven days a week.

In the past, the best way to measure this variety of neurochemicals was through a spinal tap. “Besides the invasiveness of the procedure itself, a spinal tap is not actually measuring the chemicals in the brain tissue but in the cerebral spinal fluid that surrounds the brain. The 4T, on the other hand, measures the chemicals in the tissue, and it is completely non-invasive.”

“Striking” discoveries 
Researchers are currently using the division’s state-of-the-art facilities to conduct investigations into a variety of areas. Dr. Moore is particularly excited about a recent study showing that lithium, a drug commonly prescribed for patients with bipolar disorder, increases gray matter volume in the human brain. “If we can prevent neurons from dying or even increase the number or size of neurons in the brain after there has been some neuronal degeneration, we could potentially slow down, halt or even reverse some of the effects of devastating diseases like Parkinson’s and Alzheimer’s,” he remarked.

In a collaboration with Husseini Manji, MD, professor of psychiatry and behavioral neurosciences, Dr. Moore’s research had several stages. Dr. Manji’s studies in cell culture and in the rodent brain showed that lithium heightened levels of a protein known as bcl-2 (b-cell lymphoma protein 2), which is well-known to neuroscience researchers for its ability to rekindle growth in damaged neurons. “People have been looking for ways to increase the levels of this protein, and it turns out that lithium - something that has been around for 50 years - massively upregulates the expression of this protein. This study was the first to find a drug that could increase bcl-2 to such high levels.”

The next step was to determine whether these findings were relevant to the human brain. “This is where the strength of the imaging program really came into play,” he said. “Because our imaging resources span the range of resolution from studies at the molecular and rodent levels to clinical research studies in humans, we were able to return immediately to our clinical research unit and begin a trial of lithium in human subjects with bipolar disorder.”

They monitored 10 patients before medication and again after four weeks of lithium treatment. Instead of measuring bcl-2 levels, which would have required the removal of brain tissue, they used the MRI to scan for N-acetyl aspartate (NAA) that serves as an indirect marker for bcl-2 as well as its related effects on neuronal function and viability. “The results were striking,” Dr. Moore said. “We could see that lithium was increasing that marker in the gray matter of the brain.”

From there, they asked whether it was also increasing the volume of gray matter itself. “We measured that with high-resolution, three-dimensional volumetric MRI and another process called image segmentation, and found that, indeed, gray matter volume increased in the human brain,” he said. Now, he and Dr. Manji plan to conduct an analysis of individual regions of the brain to determine whether lithium can promote neuronal growth in nerve cells that were atrophied as a result of the bipolar disorder.

 “Our finding that total brain gray matter volume had increased has perhaps a broader applicability to neurodegenerative diseases in general, like Alzheimer’s, Parkinson’s and ALS,”  he asserted. That possibility may result in additional studies to find out whether lithium may be useful in the treatment of other neurodegenerative diseases.

Other research  
Beyond the lithium study, Dr. Moore said the Brain Imaging Research Division is involved in about a dozen other research projects by investigators within the division and in many other departments throughout the School of Medicine.

Division researcher Stefan Posse, PhD, assistant professor of psychiatry and behavioral neurosciences, is working on Functional Imaging in Real Time (FIRE), which he developed. “With this technique, you can actually lie in the MRI scanner and tap your fingers, and we can see the motor cortex in your brain activate in real time,” Dr. Moore said. “We can flash lights and see your visual cortex respond. We can have you think thoughts, or we can create conditions using virtual-reality goggles, so that we can actually begin to image cognition and emotion. It’s amazing.”  

In addition, the work is largely responsible for current discussions with a major automotive manufacturer. “The automotive companies know how to keep a driver’s hands on the steering wheel and they know how to keep a driver’s eyes on the road, but they don't know how to keep a driver’s mind on driving,” Dr. Moore explained. The problem with maintaining driver attention is compounded by the addition of novel technology, including in-vehicle cell phones, Internet access and the proposed projection of web pages on windshields. “Auto companies are under a lot of pressure by the federal government and the National Transportation Safety Board to look at these issues.”

With the division equipment, he said, researchers could potentially outfit a person with virtual-reality goggles, project images of driving conditions along with various distractions, then monitor the brain’s reaction. Investigators are also considering adding common medications to the mix. “The psychiatry department is particularly interested in how psychoactive medications affect aging drivers,” said Dr. Moore, pointing out that the average age of American drivers is increasing.  

Another division researcher, Stanley Fricke, PhD, assistant professor psychiatry and behavioral neurosciences, is combining MRI and atomic-force microscopy techniques with the hopes of performing direct, three-dimensional, structure determination of molecules. “That novel technology development project has exciting possibilities for developing a new generation of functional bioinformatics,” Dr. Moore said. Like most other division projects, this research receives funding from the National Institutes of Health.

Diverse uses
Applications for the new 4T scanner are nearly limitless, said Dr. Moore. “Let’s start in the psychiatry department, where researchers and clinicians are investigating depression, bipolar illness, substance abuse, and anxiety. We’ll be able to look at these conditions more precisely, faster and with much higher resolution, and for the first time be able to study directly some unique neurochemicals.” With these advances, the scanner will be able to distinguish whether a medication is working and how it’s working. “Those are things that we can't fundamentally do at 1.5T, because we don’t have enough resolution.”  

Neurosurgeons and neurologists will benefit, too. “Our combination of tools, including functional MRI, magnetic-resonance spectroscopy and structural MRI should be able, for example, to localize more precisely where epileptic seizures are coming from, so the surgeon can pinpoint which area of the brain to remove,” Dr. Moore said. “Additional information makes the medical team much more confident, which we hope would result in better outcomes.”

The new scanner would be a great help in drug treatments, he continued. “Lots of medication trials are underway in the field of neurology, such as treatments for stroke, metabolic diseases in children, multiple sclerosis, Alzheimer’s disease and Parkinson’s. Cancer researchers are also studying drugs for use in chemotherapy for brain tumors. This technology will enable us to follow with much more precision, and much earlier on, the effects of various drugs on brain chemistry and structure.”

With the 4T scanner and other equipment, he said, clinicians can view the immediate effects of neuroprotective or neurotrophic drugs – those that protect nerve cells or encourage their growth – on a patient’s brain and quickly determine whether the treatment is having any effect.  

 “If we’re giving a medication, say, to an individual with Alzheimer’s disease, we would like to know very early on whether these measures in neuronal function or chemistry are changing as a result of that medication. Not only may it take a long time to see a memory improvement or to stop a memory loss in a patient, but those are tricky measures involving a lot of subjectivity,” Dr. Moore noted. “With imaging techniques, you can potentially tell very quickly whether a particular treatment regime is working, and have objective evidence that indicates whether to continue with that particular drug.”

He concluded, “You’d like to know early whether a medication is working, and if it’s not, to try something else so people don’t suffer over a long period of time.”

Where the needs are  
Dr. Moore credits many of the achievements of the five-year-old division to its unique organization conceived by Dr. Thomas Uhde, associate dean for research and graduate programs at the School of Medicine. Usually, he remarked, imaging centers are structured as solitary entities that have little contact with clinicians. “In essence, they have tools in search of a problem. They can do all these measures and look at brain structure, function and chemistry, but they’re in search of problems. What Dr. Uhde did was put an imaging program where the needs were.”

Under the WSU organization, Dr. Moore received a primary faculty appointment in the psychiatry and behavioral neurosciences department and another appointment in the radiology department, which placed him “in the middle of all of these investigators with problems that need solutions.” He described, “We’re talking about physicians and scientists who need critical answers about a disease process or about how a medication works.” He added, “As I get to know those problems, I can actually apply the technology to answer those in helpful ways. That’s a unique approach that we have here. It may seem like a subtle difference, but it’s a real difference, and that’s made our program successful.”

The Brain Imaging Research Division has four sections: the molecular neuroimaging research laboratory, a preclinical neuroimaging research laboratory, a clinical neuroimaging research laboratory, and an image processing laboratory. Each is equipped with highly advanced scanners, high performance computing and other research tools. “We have many, many collaborations throughout the departments in the medical school, and we are giving investigators access to this technology and showing them how to use it to approach a given problem, whether it is at the research, preclinical or clinical level.

 “So far, this approach has been paying off in helping us to get at some of the important questions affecting the human brain.”