Journey to the Center of the Mind

Neuroscience at Pitt: Asking the big questions is leading to some very big answers.

Scientists study the depths of Earth and the infinity of space. Surgeons transplant hearts, bioengineers grow transgenic corn, and architects build towering skyscrapers. And yet, while we know the secrets to many of nature’s mysteries, one within the human body—the brain—in many ways remains elusive.

On a practical level, the brain controls all body functions from heart rate to emotion, from movement to memory, and even plays a mysterious role in determining how we respond as individuals to illness. In this way, the brain is a regulating force in the saga of nature vs. nurture—how we react to outside stimuli affects our heart rates and our immune systems. In collusion with our genetic backgrounds, the brain is perhaps the most important element in human longevity.

According to the National Institute of Neurological Disorders and Stroke, some 50 million people in the United States suffer from neurological disorders ranging from Huntington’s disease and muscular dystrophy to trauma and infectious diseases to Alzheimer’s disease and Parkinson’s disease. Another 44.3 million people, according to the National Institute of Mental Health (NIMH), have a mental disorder, such as depression, anxiety, or schizophrenia. The combined annual cost of these ills—more than 1,000 of them—tops $548 billion, according to the Society for Neuroscience.

Such figures prompted Congress to declare the 1990s the “Decade of the Brain,” to highlight the need for research. At the time, the University of Pittsburgh was in position to acquire an ever-growing share of government funds that were becoming available to start solving some of the most vexing problems of the mind.

Throughout that decade, Pitt built itself into an international leader in brain research. The University focused its strength in basic and clinical science with synergistic interaction between the two, forging efforts in cognitive neuroscience through the Center for the Neural Basis of Cognition (CNBC), one of the top five such programs in the world. A joint initiative of Pitt and neighboring Carnegie Mellon University, CNBC is focusing its research efforts to discover the neural substrate in the human brain that allows us to think, plan, remember, and act. CNBC also is unique in that it promotes interaction among many different types of scientists who take a wide variety of approaches to understand neural function. Collaborators in this kind of atmosphere come from areas ranging from bioengineering to neurological surgery to rehabilitation science to robotics. In addition, the center serves as a model for productive and creative interaction between the two universities.

Along the way, Pitt also collected a concentration of researchers in the up-and-coming field of neurodegeneration and cell-death mechanisms. Both efforts have become areas of excellence in Pitt’s Alzheimer’s Disease Research Center (ADRC) and the Department of Psychiatry.

Now, a decade later, biological psychiatry research programs—just one facet of neuroscience research at Pitt—account for one fifth of the NIMH’s extramural budget, despite competition from such institutions as Harvard University and Johns Hopkins University. And each year that slice of the pie grows larger.

Collaborative Quality

It hasn’t been easy getting to the point where Pitt is on the verge of becoming the number one spot in the world for neuroscience, but the way in which the University went about building its programs can serve as a lesson in the power of calculated risk-taking and intuitiveness.

Much of the growth of the University and the University of Pittsburgh Medical Center over the past two decades has come about due to the vision of leaders like Thomas Detre, retired senior vice chancellor for the health sciences, and Arthur S. Levine, current senior vice chancellor for the health sciences and dean of the School of Medicine. Detre came to Pitt in 1973 from Yale University and immediately began to recruit some of the top researchers in psychiatry and neuroscience. Pitt’s research community, in turn, embraced the idea of collaboration early on out of a desire to do more interesting research and because of the amazing quality collaboration brings to the sciences. That spirit has continued, and thrived, since Levine took the reins in 1998 after 31 years with the National Institutes of Health (NIH).

“Here,” says Peter L. Strick, professor of neurobiology, psychiatry, and neurological surgery, VA Senior Research Career Scientist, and codirector of the CNBC, “interaction is the rule rather than the exception. At some places, people collaborate because they’re not good enough to cut it on their own. At this place, people are good enough to cut it, and they use collaboration because everyone brings something to the table. The sum is greater than the parts.”

Part of the collaborative experience in neuroscience research at Pitt starts with the concept of porous boundaries among the departments. This model of research has engendered such novel ventures as the Initiative for Neurobehavioral Genetics. One of the first of its kind anywhere, the initiative has taken on the task of looking at biological phenotypes and banking genetic material to foster molecular genetic research into chronic diseases.

“Here’s a venture, housed administratively in psychology in Arts and Sciences, which gets a good portion of its funding from deans and chairs for whom I’m not even a faculty member,” says Stephen Manuck, professor of psychology. Manuck, as one of the founders of the initiative, sought seed funding from NIH, the Department of Psychiatry, and several departments within the School of Medicine.

“That’s an unprecedented circumstance on most college campuses,” he says.

The work is paying off. With this spirit of collaboration as the backdrop, Pitt has recruited the best scientists in the neuroscience field and offered to support research that is incredibly expensive, allowing Pitt to achieve a critical mass that hasn’t even begun to peak yet.

In fact, the December 2002 issue of Physiology & Behavior featured Pitt in its first special issue to summarize the research efforts of one institution. According to the journal’s editor, the choice was based on a number of reasons, but “foremost is the fact that a critical mass of scientists and scholars doing stellar research exists there. In point of fact, I understand that if time and space were not factors, twice as many reports from local faculty could have been solicited. Another reason is related to the organization of scholars interested in the neurosciences in Pittsburgh.”

At Pitt, scientists are leading the way in getting to the roots of brain development, conducting research to learn how neurons communicate, how brain systems grow from conception, and how the brain can heal itself when damaged. Moreover, Pitt is renowned for its investigation into the relationship between mind and body, a vital link that received little attention in medical training until researchers here began learning that the health of the mind is vital for the health of the body. Thanks to work conducted at Pitt, science now knows that behavioral processes play a vital role in cardiovascular medicine, addictions, and immunology.

Beyond Freud

The breadth of neuroscience research at the University of Pittsburgh runs from basic cellular science to developing medications to building prostheses to replace damaged limbs. It includes work conducted at the Department of Psychiatry and Western Psychiatric Institute and Clinic (WPIC), one of the largest centers in the world for research into psychiatric and neurological disorders. The Department of Psychiatry, based in WPIC, received more than $70 million from NIH in fiscal year 2002-03, placing it solidly in the top spot in the nation. Research conducted there runs the gamut from depression to schizophrenia to Parkinson’s and Alzheimer’s diseases.

The University’s work in cognitive and computational neuroscience, in fact, is paving the way to the discovery of the inner workings of thought and higher brain function—how humans see and hear, how language develops, and why people experience such a vast array of emotions and desires, the very things that make humans human.

Sigmund Freud never had the luxury of knowing what Pitt scientists know. Much behavior can be related to a series of chemical reactions, and when that chemistry is thrown off, whether through unlucky gene expression or environmental factors, an individual may develop any of hundreds of mood or behavior disorders. Doctors treat these disorders with medications and talk therapy; with time, most people recover, or at least live relatively functional lives. This was not always so.

As recently as the early 1970s, the best care most people could expect to receive, whether at Pitt’s WPIC or anywhere else, was based on Freud’s psychoanalytic approach. At Pitt, that changed with Detre’s arrival and the subsequent conversion of WPIC from a center for “couch-based” therapy to a world leader in biological psychiatry.

Among the researchers studying the root causes of mental illness is Anthony Grace, Arts and Sciences professor of neuroscience and psychiatry. In his lab, Grace and his colleagues are uncovering the basic neurobiological processes that underlie psychiatric disorders. That includes looking at the biochemical processes, such as alterations in the dopamine system, that cause deficits in mood that are present in most psychiatric disorders as well as in neurological disorders like Huntington’s, Alzheimer’s, and Parkinson’s diseases.

Grace’s team has done extensive research on a small almond-shaped structure in the forebrain called the amygdala, which is involved in the expression of emotion and emotional response to outside stimuli. Grace is looking particularly at how the region processes information derived from what individuals hear, smell, and feel.

For example, when one hears a loud noise, such as a barking dog, the amygdala sets in motion a reaction for our fight-or-flight response that is moderated or confirmed once the prefrontal cortex determines the risk: whether or not the dog is chained or charging.

The dopamine system is an important component in the brain’s ability to process the information as it is gathered by the auditory cortex, passed to the amygdala, then sent to the prefrontal cortex for review. When it works, it serves people well as an early warning system. When the dopamine system is out of whack, it creates havoc: If there is too much dopamine in a person’s brain, stimuli like noise and odors can create paranoia; if there is too little, emotional response is subdued and affect is deadened.

The crucial part played by the amygdala in emotional processing probably allowed humans to avoid becoming dinner for prehistoric predators and to evolve into the dominant species on earth. But when problems arise in the amygdala’s structure or metabolism, it becomes a major player in mental illness. In 1997, Pitt researchers were the first to discover that such abnormalities in the amygdala might be responsible for many symptoms associated with depression, anxiety, and panic attacks.

Other Pitt researchers, such as David A. Lewis, professor of psychiatry and neuroscience, and Judy Cameron, associate professor of psychiatry, hope to learn the underlying roots of devastating cognitive disorders such as schizophrenia.

Current research in Lewis’ lab is examining the importance of stress in altering the development of neural circuitry and brain structures involved in complex cognitive processes like working memory.

In addition, Lewis’ team is looking at what happens during the human maturation process that could lead to schizophrenia. One major area of study in this regard is synaptic pruning. From birth through the first two or three years of life, a child’s neurons grow multitudes of axons—long thread-like fibers that connect neurons to one another, similar to a highway system connecting cities—in response to external stimuli.

For instance, neurons grow axons to connect the retina of the eye to the visual cortex. During this period of growth, neurons grow many more axons than are necessary to get the job done. Then, from about age three through adolescence, a remarkable weeding process called synaptic pruning takes place. This process eliminates the weaker connections between neurons and strengthens the stronger ones.

One of Lewis’ main research interests is to find out how problems during this pruning may lead to cognitive deficits, one of the primary disabilities in schizophrenia.

The University also is a center of excellence in the study of mental and neurological illness in the aging. Not long ago, many people, doctors included, regarded illnesses like depression, sleep problems, and dementia as normal parts of aging, something to be expected and accepted.

Research at Pitt has done much to erase this perception, and now the University is one of most well regarded centers for geriatric psychiatry in the nation. A big part of that work has been conducted through the Alzheimer’s Disease Research Center, under the direction of Steven T. DeKosky, professor and chair of neurology.

Recently, William Klunk, associate professor of psychiatry, and Chester Mathis, professor of radiology, led a team that developed what has become known as Pittsburgh Compound B, a radiopharmaceutical that, when injected into a patient undergoing a positron emission tomography (PET) scan, will adhere to amyloid plaques—the telltale sign of Alzheimer’s in the brain. Compound B is the first to successfully cross the gauntlet of tiny capillaries that shields the brain from potentially harmful substances and highlight the plaques, making them visible in a living patient. Until the development of Compound B, these plaques could be confirmed only during an autopsy.

According to DeKosky, Compound B could prove to be a valuable tool in helping doctors determine the effectiveness of treatments being developed to target the development of these plaques and to use as a research tool to look at the course of the disease. This development was so important, Discover Magazine named it number 40 among the top 100 scientific achievements of 2002.

Meanwhile, in the Department of Neurological Surgery, Pitt is breaking new ground in other areas of the brain: in work on brain tumor management, stereotaxic radiosurgery, movement disorders, and vascular malformations. The gamma knife, for instance, a radiosurgery device brought to Pitt in 1987 by L. Dade Lunsford, chair of the department, has been a key component of Pitt’s Center for Image-Guided Neurosurgery—an international source for innovative technology development in neurosurgery. A recent study conducted by Douglas Kondziolka, codirector of the center, found that treating benign brain tumors with gamma knife radiosurgery resulted in long-term tumor control in 95 percent of patients.

Illuminations

Two decades ago, the inner workings of thought and behavior were hidden from the eyes of scientists. The best they could do was speculate on the origins and structures involved in higher cognitive processes through research on primates or on people with brain injuries.

That was then. Today, there has been a quantum leap in knowledge due to the development of tools like functional magnetic resonance imaging (fMRI), PET, and computed tomography. (These tools, all found at Pitt, are complemented by a new Brain Imaging Research Center, set up on Pittsburgh’s South Side under the guidance of Levine, senior vice chancellor for the health sciences and dean of the School of Medicine, one of his many contributions to neuroscience research at Pitt since his arrival.) Pitt researchers were among the first to embrace these technologies in the past 20 years, and they have quickly gained a reputation for illuminating how neuronal interactions are involved in behavior.

One researcher at CNBC has used fMRI to see into the brains of living human subjects and analyze brain activity associated with cognition and emotion. This work has provided science with not only insights into the neural mechanisms at work in thought but also information that can help develop more effective therapies for various mental disorders.

One part of this research is a study that showed the brain is capable of anticipating situations in which errors are likely to be made so that it may guard against them before they happen. He discovered that the portion of the brain called the anterior cingulate cortex detects competition between two possible, yet incompatible, responses to a situation, then provides a signal for the brain to pay more attention and avoid the error.

Such a situation might occur when an American drives a car in England. In America, the highways and driving patterns are familiar, so the brain doesn’t have to put much thought into the process. Put the same driver in England, where traffic moves on opposite sides of the road, and his anterior cingulate cortex kicks into high gear, alerting his brain that things are different—so the brain, in turn, pays more attention to keeping the car in the correct driving lane.

The environment has a hand in just about everything we do, whether we realize it or not. Animals, humans included, acquire information from the environment and use that information to guide their behavior. Pitt researchers are trying to understand how memory and learning help us survive in a variable environment.

The Talk of the Brain

All these brain systems would not exist if there were not a biological process in place that allowed for neurons to grow, communicate, and adapt.

Laura Lillien, associate professor of neurobiology, is examining the mechanisms that regulate cell proliferation, fate determination, and migration in the cerebral cortex—in English, how central nervous system cells are born, how they come to specialize in their tasks, and how they get to their final place in the brain.

During an individual’s embryonic stage, much of what determines whether a neural cell will become a neuron responsible for signaling, or a supporting glial cell, is its exposure to environmental factors, including proteins that determine the cell’s role and its position in the central nervous system. Lillien’s lab is working to define the molecular basis of differences in neural stem cells.

Meanwhile, Stephen Meriney, associate professor of neuroscience, is studying mechanisms that control synaptic plasticity in the nervous system. The research in his lab is giving scientists a greater understanding of what happens inside a nerve terminal that leads to synaptic transmission—one nerve talking to another.

Researchers in the lab of Karl Kandler, assistant professor of neurobiology, take the process a step further by focusing on how neuronal circuits are established and modified during brain development. Neuronal activity—hearing a sound or learning language—during the early stages of life is necessary for the brain to form neural networks. These networks allow us to have normal vision, hearing, and movement. Kandler’s work may help shed light on what problems can occur in this process and when they might happen during development.

The Mind-Body Connection

Behavior and physical health are interconnected at nearly every level. During the past 30 years Pitt has established its reputation as the premier research center for mind-body connections through the Pittsburgh Mind-Body Center, a joint Pitt-Carnegie Mellon program led by Karen A. Matthews.

Research at the center includes studying the effects of mild, everyday stresses—such as having too much work to do in the allotted time, and preparing and giving a speech—on risk for a heart attack. One lab is looking into the effects of everyday stresses on long-term health, including identifying the neural systems involved in stress response and understanding how changes in those systems affect the physiological systems, such as behavior, neuroendocrine function, cardiovascular function, and glucose tolerance. The experiments are closing in on identifying the physiological traits that leave some people more vulnerable to affective disorders than others.

In another area under this umbrella, Anna Marsland, assistant professor of psychology, conducted a groundbreaking study using the hepatitis B vaccination to look at the role of neuroticism, or negative affect, in immune response. She found people with this trait—people who are moody, nervous, and easily stressed—had a lower immune system response to the vaccine, providing a vital link between a personality trait and an objective health measure. This raises the possibility that people with certain personalities may have less protective immune responses.

The Big Questions

The University, naturally, has no designs on slowing down. The NIH and other funding institutions have noticed the exceptional research fostered in such a collaborative atmosphere, sending tens of millions of dollars to Pitt each year.

“Good science doesn’t happen in isolation,” says Strick. “Our critical mass and collaborative spirit are letting us study the big issues—what is the neural basis of consciousness, of memory? What’s the basis of reading and language acquisition? This is a place where people can ask the really big questions.”

And very often, their asking leads to big answers.