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The brain, with its tangled bundles of neurons and strangely named regions, has been called the most complex structure in the universe. And its workings have remained largely mysterious, hidden deep within the folds of gray matter.

Until now.

At UW-Madison and elsewhere, researchers are using cutting-edge imaging technologies to watch as the living, buzzing brain goes about its business.

Dozens of researchers on the UW-Madison campus are using the technologies to figure out how our brains work in health and in illness, to better understand everything from anxiety in children to Alzheimer’s in the elderly. The science has even brought within reach the possibility of solving mysteries that have perplexed us for centuries. What does it mean to be conscious?

The ability to see the brain working has opened up not only new realms of knowledge about how the brain functions; it is leading to new treatments for seemingly intractable psychiatric disorders.

The successes have brought brain imaging and its promise into the media spotlight. Recently, President Barack Obama announced he intends to initiate a concerted, nationwide effort aimed at using the newest technologies to map the brain, in much the same way researchers sequenced the human genome. The breadth and ambition of the initiative has been compared to John F. Kennedy’s challenge to land a man on the moon.

The idea remains in its earliest stages, and UW-Madison brain research experts say the university’s role in the project is not yet clear.

But UW-Madison seems ideally situated to play a major role in the effort. The university has gained worldwide attention for its brain studies, partly due to the prominence and imaginative work of Richard Davidson, the neuroscientist who founded and heads the Center for the Investigation of Healthy Minds at the Waisman Center and the researcher who helped lead the way toward today’s groundbreaking work. The university was among the earliest to adapt imaging devices first used for clinical diagnoses to studies of the brain.

Just last week, Madison was in the international spotlight for the latest of several visits by the Dalai Lama, who has developed a close relationship with Davidson because of the scientist’s imaging studies of meditation’s beneficial impacts on the brain.

Helping move past trauma

Jack Nitschke, a UW-Madison researcher in psychiatry, has seen the damage wrought by anxiety — especially to veterans who return from war with emotional scars. Now with brain imaging, he and his colleagues are finding new ways to help those with post-traumatic stress disorder.

Nitschke can see the flow of blood and oxygen to working parts of the brain using functional magnetic resonance imaging, or fMRI.

“It’s tremendously exciting to see into a human brain and to see how things can change from moment to moment,” Nitschke said. “Thirty years ago we would have had to cut somebody’s brain open to see that.”

After the brain scan, the vets go through classes in which they practice either mindfulness martial arts or yoga-based breathing exercises. Imaging conducted after the classes showed marked improvements in the function of and communication between two brain structures involved in the illness — the amygdala, which governs emotions such as fear, and the anterior cingulate, believed to have a role in filtering information that is funneled into the amygdala.

In other words, the veterans were able to actually alter the operation of their brains through the meditative practices.

“It was transforming,” Nitschke said.

Studying stress and anxiety

Sociologist Marilyn Essex has been following 560 children since 1990, gathering information on their families and stress.

“If you can see differences in stress levels in a family, does that tell us whether a child will develop anxiety stress disorder?” Essex asked. “Can we find a biological mechanism?”

Eventually, Essex focused on the body’s production of cortisol, a stress hormone. She collected saliva samples from the children and was able to find a telling relationship between high stress levels in the children and levels of the hormone. Specifically, studies of teenage girls in the group showed heightened levels of cortisol were linked to more symptoms of anxiety.

But Essex said the advent of imaging opened up new possibilities for understanding exactly what was happening in the brains of the children she studies. She is now working with Cory Burghy, a developmental neuroscientist, and Rasmus Birn, a physicist, to image the brains of many of the children, looking for connections between regions and structures and differences in the brains of those with anxiety disorders and those without.

They have found links between activity in the amygdala and the prefrontal cortex, and they will continue probing for how the relationship between these structures might be affecting the production of cortisol.

Combining behavior and images

Other researchers have combined behavioral studies and imaging to link high levels of stress to a broad range of health problems, from diabetes to heart disease.

Marcia Slattery is a UW-Madison psychiatrist who, like Essex, has long conducted behavioral studies of youngsters to better understand the impacts of stress. Her studies have focused on a system in the brain composed of the hypothalamus, a structure that receives messages from the body’s nervous system, and the pituitary and adrenal glands, which produce stress-related hormones.

Through behavioral studies, Slattery has examined how different people respond to stressful situations. With imaging, she has been able to zero in on the areas of the brain most involved in controlling how we deal with stress. She has found that certain parts of the brain serve as filters that determine whether we perceive stress as threatening. Chronic stress results in a blunting of the normal response from the hypothalamus-pituitary-adrenal complex and that leads to hormonal changes that can result in heightened risk for inflammatory and immune system illnesses.

Though imaging offers striking new ways to probe more deeply into the brain, Slattery said researchers should not become so enamored that they forget the science begins and ends with real people and learning how to better help them.

“The point is,” she said, “OK, what do we do with it? This is about quality of life. This is about how a family functions. This is about how a kid does in school.”

Illuminating Alzheimer’s

While Essex and Slattery are finding ways to use imaging to illuminate problems during life’s early years, others are bringing the technology to bear on one of the most perplexing maladies of the elderly — Alzheimer’s.

Imaging has opened up new windows on the disease, according to Sterling Johnson, a neuropsychologist at UW-Madison. He has used imaging, for example, to trace heretofore unknown neural connections between a structure called the posterior cingulate and the hippocampus, where memory resides and where the plaque that distinguishes the disease can be most damaging. Perhaps, he said, there is a connection between the onset of Alzheimer’s and the disruption of the messaging between the two areas.

“The implication,” Johnson said, “is that by better understanding the networks, we can better understand how they have been compromised.”

Barbara Bendlin, an assistant professor of geriatrics, also studies Alzheimer’s and has used imaging to study connections between the onset of Alzheimer’s and metabolic disorders, such as diabetes or metabolic syndrome, which is characterized by obesity and high levels of cholesterol and blood sugar. She’s also studying the brain’s white matter, the networks of neurons between structures and along which important messages travel, and whether deterioration of those tracks may be a precursor to Alzheimer’s.

One of the most powerful advantages of imaging in the study of Alzheimer’s, both Johnson and Bendlin said, is the new ability to look at both healthy and diseased brains and see the subtle changes — even in middle age — that could spur intervention.

“The old way of looking at brains in Alzheimer’s patients was under a microscope after patients had passed away,” Johnson said. “But what imaging has allowed us to do is look at somebody prior to the development of symptoms to see what evidence of Alzheimer’s might be present. We’re trying to see what risk factors predict the disease.”

Studying prisoners

Other scientists have struck out in some surprising and unusual directions.

Joe Newman, a UW-Madison clinical psychologist, and Mike Koenigs, a behavioral psychologist, have taken portable imaging machines into Wisconsin prisons to study the brains of inmates. They found what Newman called “widespread” abnormalities in the brains of inmates diagnosed as psychopathic. There were differences in the size of brain structures, especially those involved in emotion, and profound differences in connectivity.

The work has reverberated through the nation’s criminal courts system and raised troubling questions about just punishment and sentences. Can someone be held responsible for a crime if a physical malfunction of the brain caused the illegal behavior? Koenigs said it is a question for society, not science.

“We’re not in the business of guilt and innocence,” Koenigs said.

Looking for consciousness

Giulio Tononi, a psychiatrist and neuroscientist at UW-Madison, has perhaps taken imaging to the most unexpected of places. He has used the technologies to study sleep and consciousness. He has even conducted experiments in which he was able to create a visual image of consciousness, showing parts of a patient’s brain lighting up and coming to life as the individual emerged from a coma.

Tononi, who holds the Distinguished Chair in Consciousness Science at UW-Madison, has at least one practical end in mind for his studies. He hopes to create a device that would allow a numerical assessment of a patient’s awareness, a machine that could be used to help inform decisions about everything from the administration of anesthesia to whether someone should be removed from life support.

Despite all of these eye-opening advances in brain science, nearly every researcher warns that imaging technologies are in their infancy and today’s techniques have many shortcomings. After all, they point out, none of the imaging techniques allows researchers to take pictures of neurons actually working. The transmission of information along the brain’s miles of neural wiring can only be inferred by the flow of blood and oxygen. And just because we can see a particular part of the brain fire into action during a particular test, that doesn’t mean we can easily tell why or how that structure is involved.

But Davidson and others say the future likely holds advances in imaging capabilities and resulting discoveries that will make today’s science seem as dated as a Model T Ford.

“Compared to what we’ll learn in the next 20 years,” Davidson said, “we’re at the beginning.”

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