Includes: Research in patients, Translational research, New approach for immunology programs: the Dana Scholars, Update: Effects of heart surgery on the brain, 25th Anniversary: The Dana-Farber Cancer Institute, Special Case: Patient H.M., Special Focus: Deep Brain Stimulation, Support for science and math education
Our science grants reflect the Foundation’s priorities: understanding the processes involved in brain and immune-related disorders; assessing the effects of experimental treatments; describing how the healthy brain and immune system work and how malfunctions lead to diseases; and adapting existing technologies and refining new techniques to improve diagnostic and treatment research and clinical practice. In 2008 we awarded almost $13 million in health and science research grants.
To draw talent into these fields, we favor new investigators with bold ideas and established investigators who wish to take a leap in a new direction or test a fledgling theory. We encourage experienced researchers to mentor newer colleagues.
We fund pilot studies to test new hypotheses about how the brain and the immune system function in health and disease. Many of our grants support small, promising studies on the first human patients, bridging the federal-funding gap between bench research and clinical trials. Scientists use the data they acquire in small studies to support their applications for federal and other funds to do extended research.
We give grants in brain and immuno-imaging, clinical neuroscience research, neuroimmunology, and human immunology. Application guidelines for each branch of research are available online. In 2008, investigators whose work we support have advanced treatments for several brain disorders, including the use of electrodes implanted in the brain (deep brain stimulation, or DBS) for intractable depression and Parkinson’s disease. Other grants have explored connections between heart disease and depression, the potential of extended-release naltrexone to reduce heroin dependence, and the possibility that certain protein markers predict the risk of Alzheimer’s disease. Others have refined techniques for imaging the brain and immune cells in action. Below are some highlights.
Research in Patients
Brain Monitoring for Preventive Care in the ICU
After a stroke, the speed and quality of care a patient receives can mean the difference between recovery and death or further injury and impairment. Under a 2005 grant, Stephan Mayer, M.D., and colleagues at New York-Presbyterian Hospital developed and tested a computerized brain monitoring system that alerts physicians, in real time, to impending problems in stroke patients being treated in intensive care units.
The system is intended to prevent further damage to brain tissue by monitoring several interrelated measures of brain oxygenation and metabolism and alerting doctors at the first signs of trouble. Using a probe inserted into the brain, the researchers discovered that two measures of adequate delivery of oxygen to brain tissues (oxygen tension and the ratio of lactate to pyruvate) can be influenced by manipulating blood pressure, temperature, and glucose. Dr. Mayer and his colleagues found a way to represent these measures together graphically and in real time so that doctors at the bedside can see what is happening and respond to it.
The system, called multimodality monitoring, tracks multiple parameters of brain physiology and function that can be affected by direct medical or surgical intervention. The researchers also plan to determine whether these measurements can predict stroke mortality and recovery.
The computer-based system, which the team continues to work on, is now used at the bedside in New York-Presbyterian’s 18 neuro-ICU units to monitor oxygen levels in the brains of comatose patients who have had hemorrhagic strokes (bleeding in the brain from a ruptured blood vessel). The software signals when oxygen levels cross the line and become insufficient, leading to brain tissue damage. Then physicians can work immediately to restore the right oxygen balance, rather than waiting for a problem to cascade into further damage.
Through this work, the team has made several important discoveries:
- Critical reductions in brain glucose levels are a marker of metabolic brain failure in coma, signaling the need to increase glucose levels.
- Contrary to contemporary thought, intensive insulin therapy, which reduces brain glucose levels, may harm brain tissue.
- Hypothermia (cooling the temperature of the brain to slow metabolic processes) can help limit brain tissue—and subsequent cognitive—damage in patients who suffer cardiac arrest, if patients regain a pulse and if cooling is provided within six hours of cardiac arrest.
Dr. Mayer’s research on hypothermia in cardiac arrest patients has led New York City to require that such patients be taken only to hospitals that have the capacity of providing hypothermia treatment. Dr. Mayer presented some of his hypothermia findings at a September 2008 forum at the New York Academy of Sciences titled “Hypothermia—From Threat to Cure,” co-sponsored by the Dana Foundation and the academy.
During two years of Dana-funded research, the team collected more than 2,500 hours of multimodal ICU data on 29 patients. Their report on the effects of insulin therapy was selected as one of the best scientific abstracts at the 2008 Society of Critical Care Medicine meeting.
The work has led to approval of a five-year National Institutes of Health (NIH) training grant for one of the investigators to study the effects of modulating hypothermia therapy on metabolism and brain oxygenation in stroke patients. It also has provided the necessary preliminary data for two additional NIH grants.
“This support has allowed us to address a significant unmet need in the clinical neurosciences, and has served as a building block toward the ultimate goal of developing a data management system that can be used in neurological intensive care units throughout the world,” Dr. Mayer said.
Solving Problems of Addiction
Roughly one-third of the 1.6 million people in U.S. prisons (as of December 2007) report a history of heroin addiction. Continued addiction is considered a major contributor to the nation’s high rate of re-incarceration, primarily due to arrests for stealing and causing harm in connection with buying heroin. Helping people kick addiction could prevent or reduce rates of incarceration and re-incarceration.
Some experts say the drug naltrexone is the perfect anti-addiction treatment; it completely blocks the effects of opiates, making relapse impossible. In addition, naltrexone produces no “high,” unlike two other available drugs for treating heroin addiction, methadone and buphenorphene, which produce slight highs and are addictive themselves.
“Naltrexone completely blocks the actions of some drugs of abuse—the person won’t get high,” said Nora Volkow, M.D., director of the National Institute on Drug Abuse (NIDA) and a member of the Dana Alliance for Brain Initiatives. “It’s a perfect example of how you can develop medications that interfere with the rewarding effects of drugs.”
But in the more than 20 years since the U.S. Food and Drug Administration (FDA) approved the oral form of naltrexone for treating heroin addiction, the drug has had mixed success. The trouble is that the oral form of naltrexone is short acting. It must be taken daily or at least several times a week, and it requires recovering addicts to summon the willpower to remain heroin-free day after day.
In 2006, the FDA approved a long-acting (monthly) injectable form of naltrexone for treating alcohol addiction. Charles O’Brien, M.D., Ph.D., and colleagues at the University of Pennsylvania headed a consortium to investigate the feasibility of providing this new form of naltrexone to prevent heroin relapse among adult parolees and probationers in five cities.
Dana funding supported clinicians’ efforts to work with the criminal justice system in the five sites during a yearlong pilot study to provide naltrexone as a therapeutic option. Adults on parole or probation with past histories of heroin addiction were invited to participate. Volunteers agreed to be tested to determine that they were heroin-free. Then they were given injections of naltrexone each month for six months, and they returned another six months later for final drug tests. The pilot study showed that the treatment sites could effectively work with their local criminal justice systems to offer the treatment without coercion. Sixty-five percent of the 30 participating adults completed their 6-month treatments, and more than three-quarters of these participants attended their 12-month follow-up appointments for tests showing they were still heroin-free.
In spring 2008, anticipating final approval of NIDA funding to expand the study, the researchers asked the Foundation for a bridge grant to continue the program into the fall. The Foundation agreed and, in October, NIDA awarded the team a $5 million grant to fully fund a large-scale study enrolling up to 400 more volunteers.
Seeking Markers for Alzheimer’s
Today Alzheimer’s disease is diagnosed on the basis of memory and related cognitive tests after other potential causes of its symptoms have been ruled out. These outward symptoms, however, develop decades after plaques of beta-amyloid peptide have begun to accumulate in the brain. Definitive diagnoses of Alzheimer’s disease occur only after death, through autopsy of the brain and confirmation of the buildup of beta-amyloid.
Dana-sponsored researchers are using brain imaging and other tools to observe and measure beta-amyloid deposits in older adults to try to predict who is at risk for developing Alzheimer’s. Such measures may help doctors foretell which adults with mild cognitive impairment are at risk of progressing to Alzheimer’s disease, as well as gauge how well anti-Alzheimer’s therapies are working. One day doctors may be able to prevent or even reverse the events leading to cognitive decline.
A promising radiologically labeled agent that appears to bind only to beta-amyloid in the brain and is visible through brain imaging was developed by researchers led by William Klunk, M.D., Ph.D., and Chester Mathis, Ph.D., of the University of Pittsburgh. Named Pittsburgh Compound-B (PIB), the fluorescent tracer temporarily “lights up” the beta-amyloid plaques so they are visible in positron emission tomography (PET) scans. Several Dana-funded studies suggest that PET imaging using PIB can provide a reliable and valid method for diagnosing Alzheimer’s disease and for differentiating it from mild cognitive impairment that does not progress to Alzheimer’s.
In 2004, a three-year Dana grant to Julie Price, Ph.D., at the University of Pittsburgh supported a study to see if PET-PIB testing reliably worked to identify and quantify levels of beta-amyloid. The researchers tested 34 adults. Some had been diagnosed with Alzheimer’s, others had mild cognitive impairment, and a third group tested normal to determine whether using the PIB tracer could differentiate these three groups. Researchers found that it could. Their results have been reproduced at more than 25 PET imaging research centers studying more than 100 adults.
In 2005, a related three-year Dana grant funded further testing of the PET-PIB method by its developers at the University of Pittsburgh in collaboration with investigators led by Kirk Frey, M.D., Ph.D., at the University of Michigan and John Morris, M.D., at Washington University in St. Louis.
Researchers at the three institutions recruited healthy volunteers and adults with mild cognitive impairment. They collected baseline information on the presence and extent of brain beta-amyloid deposits in both groups. Researchers expect that some of the adults with mild cognitive impairment will develop Alzheimer’s disease within a few years, and investigators will determine whether those who develop the disease experienced increased beta-amyloid buildup during that time. To date, the three institutions have imaged more than five dozen patients.
Consortium investigators reported in 2006 in the journal Neurology that PIB attaches in greater amounts to beta-amyloid in eight patients clinically diagnosed with Alzheimer’s disease, compared with 41 same-aged adults with no clinical symptoms of the disease (with the exception of two of these asymptomatic adults, who also showed signs of beta-amyloid deposits). Under two grants from the National Institutes of Health, researchers will continue to follow these patients for at least five more years to determine whether they eventually develop Alzheimer’s. These studies may help to validate PIB-PET testing as a reliable tool for diagnosing Alzheimer’s early, when it might be most effectively treated.
In a related study, as reported in the journal Brain in March 2008, Drs. Klunk, Mathis, and colleagues confirmed that PIB binds directly to beta-amyloid deposits in the brains of people with Alzheimer’s disease. They compared imaging results with autopsies of patients’ brains.
Drs. Klunk and Mathis were awarded the 2008 Potamkin Prize for their development of PIB. The prize recognizes researchers who have made outstanding contributions to the study of Alzheimer’s disease and related dementias.
Do Microglial Cells Go from Good to Bad in Alzheimer’s Disease?
Only one type of immune cell—the microglial cell—naturally resides in the brain and spinal cord to detect and respond to invaders or injury. Because the brain is isolated from the rest of the body by a film of cells called the blood-brain barrier, most infections and other harmful agents don’t reach vulnerable central nervous system tissue.
When damage or infection is detected in the brain, microglial cells must react quickly, producing inflammation around the damaged tissue and summoning other immune cells to enter the brain or spinal cord to fight the invader. But sometimes microglial cells overreact and produce extensive inflammation that destroys surrounding healthy tissue. In other situations, called autoimmune diseases, immune cells are summoned to attack cells in the brain’s own tissues that have been mistakenly identified as foreign invaders.
We are still in early stages of understanding how microglia operate. Scientists in labs worldwide are trying to tease out what is happening when these cells work as they should and why they sometimes go astray.
Microglia seem to cluster around the beta-amyloid deposits in the brain that are implicated in Alzheimer’s disease (AD), but scientists aren’t sure if their inflammatory actions are meant to clear the plaques away to help prevent further damage or are contributing to the destruction of tissue around plaques.
Joseph El Khoury, M.D., and colleagues at Massachusetts General Hospital used a 2006 Dana grant to explore how additional immune microglial cells are recruited into the brain from the spinal cord in mice—and what the cells do once they get there.
Dr. El Khoury found that the brains of mice with an Alzheimer’s-like disease whose brains were genetically altered to lack the brain-cell receptor CCR2 (which appears to signal microglia to migrate to the brain from the spinal cord) accumulated fewer microglial cells than mice with intact CCR2 receptors. This relative lack of microglial cells recruited into the brain correlated with early and deadly accumulation of beta-amyloid around blood vessels in the brain, and the CCR2-deprived mice died far earlier than anticipated.
The researchers didn’t expect to see such a dramatic and early response, Dr. El Khoury said. The study offers in vivo evidence that the brain’s immune system plays a protective role—at least in early Alzheimer’s disease—by mediating the clearance of beta-amyloid.
“Our data provide evidence . . . that the inflammatory response in AD is a ‘double-edged sword,’” the authors wrote in their paper published in the Journal of Neuroscience in August 2008. They hypothesized that with increasing age, microglia become less effective in preventing the buildup of beta-amyloid that characterizes Alzheimer’s disease, resulting in beta-amyloid accumulation in the brain. Too much beta-amyloid then stimulates the microglial cells to release toxic inflammatory agents, and this inflammation around amyloid plaques destroys nearby brain cells.
To further test this hypothesis, Dr. El Khoury and Changiz Guela, Ph.D., are using a new Dana grant to study human brain tissue obtained from autopsies of ten young, ten middle-aged, and ten older people. They will isolate microglia from the brain tissues and expose it to fluorescence-labeled beta-amyloid, to see if the actions of microglial cells change as a person ages.
If the results confirm that the role of microglial cells changes with age and leads to beta-amyloid buildup and deadly inflammation, the findings could eventually lead to new approaches to therapies for treating or preventing Alzheimer’s disease.
Pretesting Cancer Therapies
Patients respond to cancer drugs in different ways, and physicians often try several drugs until they find the ones that work best for a specific patient. Since cancers grow quickly, time is of the essence in finding the most effective therapies.
A new imaging technique developed by Caius Radu, M.D., and colleagues at the University of California, Los Angeles, may provide a method for quickly predicting the effectiveness of a specific drug for a specific cancer patient.
Dr. Radu’s team has devised a molecular probe whose molecules light up when viewed by positron emission tomography (PET) scanning. The probe attaches to the standard chemotherapy drug gemcitabine. In experiments with mice, the team watched as the probe—and the drug to which it was attached—was absorbed into one type of tumor, but not another.
“For the first time, we can watch a chemotherapy drug working inside the living body in real time,” Dr. Radu says of the experiments.
The researchers plan to develop probes for several other widely used chemotherapy drugs to see if the method proves to be a clinically useful diagnostic test. They plan to start testing the probe’s safety in healthy human volunteers this year. If this phase is successful, they will test the PET probe’s utility in determining which cancer patients effectively respond to gemcitabine therapy.
“The beauty of this approach is that it is completely non-invasive and without side effects,” Dr. Radu says. “If we are successful in transporting this test to a clinical setting, patients will be able to go home immediately.”
Under a 2007 Dana grant, Dr. Radu’s team also has begun to adapt their technique to studying autoimmune brain disease. They are focusing on an animal model of multiple sclerosis (MS).
Using the PET probe attached to immune T cells in mice with MS-like symptoms, the resesarchers are watching how immune T cells become activated in lymph tissues, migrate to the brain, and cross the blood-brain barrier to attack the myelin sheath that insulates nerve fibers. This research eventually may lead to finding out how to decrease immune T-cell activation in autoimmune multiple sclerosis and how to increase immune T-cell activation to fight melanoma, a cancer that often metastasizes to the brain.
Seeking Early Protection from Cancer
Cancer starts as a series of premalignant changes in a particular tissue, a process that takes a long time to progress to a clinically evident tumor. Intervening at this premalignant stage is the aim of a Dana-supported research consortium composed of Olivera J. Finn, Ph.D., at the University of Pittsburgh, and Madhav Dhodapkar, M.D., formerly of Rockefeller University and now at Yale University.
The researchers have discovered that the human immune system recognizes alterations in premalignant forms of certain cancer cells and activates immune T cells and antibodies to prevent the premalignant cells from developing into cancer cells.
The Pittsburgh group studied people with lung cancer and others who were at a high risk of developing this cancer. The Rockefeller group studied people with multiple myeloma and people with monoclonal gammopathy of undetermined significance (MGUS), who have a high risk of developing multiple myeloma.
In both groups, many of the patients with the premalignant condition—but not the patients with cancer—were found to have spontaneous T-cell immunity to the specific tumor antigen that is present on the premalignant cells and on the cancerous cells. Patients’ immune T cells “recognized” the antigen and reacted to it. This immune response is one of the strongest predictors of whether patients with MGUS will develop multiple myeloma—an even stronger predictor than genetic history, the researchers found.
But there was another surprise. “What we did not expect, and what we believe will lead to a new paradigm about cancer immunosurveillance, is that we found an even better immune response to these antigens in some healthy controls,” said Dr. Finn.
That led the researchers to examine immune responses to another tumor antigen, MUC1, in a larger group of healthy adults. Their research showed that women who carried the specific immunity to MUC1 (anti-MUC1 antibodies) were less likely to develop ovarian cancer.
Other researchers, studying chronic inflammation and viral infections, recently showed that these immune processes alter the expression of some molecules in the same way that a malignant cancer transforms molecules. For instance, some viruses, such as varicella zoster (chicken pox virus) or human cytomegalovirus, cause overexpression and mislocalization of the molecule cyclin B1.
Based on this finding and their own results, the consortium researchers have revised their original hypothesis. They now propose that infections in childhood and adolescence generate immune memory for molecules in the body that are altered by the infection, such as cyclin B1 and MUC1. Dr. Finn said, “When later in life the immune system encounters abnormal expression of these molecules on tumor cells, they can serve as targets for tumor rejection. Normal tissue is never subject to the immune attack because expression of these molecules on normal cells is normal and therefore not visible to the immune system.”
These findings support the use of MUC1 and cyclin B1 as potential preventive vaccines against multiple myeloma and lung cancer, respectively, in high-risk individuals. They also suggest that there must be other molecules of this kind. “By studying the immune system of healthy, tumor-resistant individuals, we might come up with a panel of antigens that can be used to evaluate cancer risk,” Dr. Finn said.
This work has led to the filing of two patent applications and subsequent submission of two manuscripts for publication.
In her presidential address at the American Association of Immunologists conference in 2008, Dr. Finn said she is seeing “a new paradigm emerging in tumor immunology that may have a more general application to our understanding of immunosurveillance of not only cancer, but also viral and bacterial infections. . . . I am personally energized by this possibility and have fallen even deeper in love with tumor immunology for providing me with yet another window from which to peer into the endless intricacies of the immune system.”
New Approach for Immunology Programs: The Dana Scholars
The Dana Foundation’s human immunology program was begun more than five years ago to help advance patient-oriented research on immune-based diseases, including many affecting the brain.
As we do every several years with all our grant programs, we invited a respected scientist outside our fold to take a look at what we’re doing. For immunology, we asked Professor Douglas T. Fearon, Sheila Joan Smith Professor of Immunology at University of Cambridge, to review our work. He wrote, “The projects that the Dana Foundation has supported appear to be of a uniformly high standard. I am also impressed by the breadth of subjects: they cover almost all aspects of human immunology, including infectious diseases, autoimmunity, allergy, and tumor immunology.”
Patient-oriented research has a tough time competing against basic research because it is slower, and important variables (such as age and other health factors) are more difficult to control. Clinical and translational research are generally not a feature of immunology meetings, and it accounts for a small fraction of papers in major journals. Attracting and encouraging top new investigators to the field is therefore a major challenge, but it is an important need.
In 2008, the Foundation decided to concentrate our immunology efforts on helping to meet this need.
Instead of solely continuing to support consortium research, grants awarded in 2008 also went to several promising investigators selected as Dana Scholars. These are new faculty carrying out independent research, such as postdoctoral fellows making transitions to their first faculty positions as instructors or assistant professors. Scholars are initiating or engaged in immunology studies involving patients or patient tissues. [See the Grants section for specifics.]
Five Dana Scholar awards were made in late 2008. These new investigators are exploring the pathways that immune T cells use to attack hepatitis C virus, how lung inflammation occurs in asthma, how the immune system responds to therapeutic melanoma vaccines, how certain cells help limit HIV infection from progressing to AIDS, and why some people exposed to the tuberculosis bacterium develop tuberculosis while others do not. Support also enabled several research trainees to attend an immunology meeting. In 2009, immunology funding will focus solely on Dana Scholar awards.
Update: Effects of Heart Surgery on the Brain
Dana grants have helped fund a longitudinal study led by Guy McKhann, M.D., at Johns Hopkins University. Dr. McKhann’s team is investigating heart surgery’s possible effects on the brain, based on bedside reports that surgeries such as coronary artery bypass grafting cause cognitive decline. Some researchers theorized that this effect could be due to anesthesia, or that surgery using a pump to infuse the brain with oxygen, bypassing the heart, might induce tiny blood clots, which then travel to the brain and produce “mini-strokes.”
But after the first decade of tracking bypass heart surgery patients and comparing them with several control groups, Hopkins researchers have concluded that neither of these theories is correct. The data indicate that underlying vascular disease, not heart surgery, is primarily responsible for long-term decline in cognitive functioning in people with coronary artery disease.
Also running counter to current thinking are the team’s data suggesting the following:
- Heart surgery does not increase the likelihood of depression in these patients; low mood going into the procedure is the best predictor of low mood coming out of it.
- Brain images of nearly one-quarter of the heart surgery patients showed evidence of a “silent” stroke—one that went unnoticed or undiagnosed—at some time prior to the surgery.
During the next few years, the researchers will use statistical analyses to compare the effects of the two methods of bypass surgery (on the bypass pump or off the pump) on the brain. They will also continue to track the progress of vascular disease and brain performance in more than 400 patients.
What these researchers are learning may change how doctors and patients decide on treatment options. Doctors and patients can choose surgery without worrying that the procedure will add to the risk of long-term cognitive decline.
The research was published in the May 2008 Annals of Neurology, accompanied by a review that said, in part, “This study is extremely important because it is one of the few to include a nonsurgery comparison group with known cardiovascular disease. . . . In an age of adverse events that are uncovered often belatedly, it is comforting to reconsider the assumed cognitive deleterious effects from a common and efficacious treatment for heart disease.” Dr. McKhann, who advises the Foundation on grant applications and writes a column for our Brain in the News print and online features, also wrote a review of this research for our online magazine, Cerebrum.
25th Anniversary: The Dana-Farber Cancer Institute
In 1983, the trustees of the Sidney Farber Cancer Institute renamed it the Dana-Farber Cancer Institute, following a series of grants the Foundation made to the institute, including a $10 million challenge grant in 1982. Charles A. Dana, Jr., said the award was meant “to focus the Foundation’s support in cancer research and treatment in this single place,” so the institute could build a permanent unrestricted endowment.
The Foundation had long supported the work of Sidney Farber, particularly by funding building projects for his cancer institute, including laboratories in 1962 and the Charles A. Dana Cancer Center, completed in 1976. The 1982 gift, which amounted to nearly 10 percent of the Dana Foundation’s own endowment at the time, was intended to help the cancer institute raise enough funds for a permanent endowment, protecting its work from the vagaries of variable federal grant funding and donations.
Today, the Dana-Farber Cancer Institute employs about 4,000 people who support more than 200,000 patient visits a year. It is involved in some 600 clinical trials and remains internationally renowned for its blending of cutting-edge research and clinical care. The Foundation continues to support the institute with grants each year.
Special Case: Patient H.M.
One of the most famous amnesiacs in neuroscience, Henry Gustav Molaison—known as Patient H.M.—died in 2008. In 1953, at age 27, H.M. underwent experimental surgical removal of parts of the medial temporal lobe (including the hippocampus and the amygdala) from both brain hemispheres to treat his severe epileptic seizures. He subsequently lost the ability to consolidate and store new memories, though he retained the ability to learn skills and to store information briefly.
A 1957 paper describing H.M.’s outcome by surgeon W.B. Scoville and Brenda Milner, Sc.D., of McGill University—later a Dana Alliance member—launched more than 100 subsequent studies of the biological basis of memory. The body of research on H.M. has established that there is a set of specific brain structures related to memory. [Dana podcast: Listen to H.M. speak, direct audio link]
Always willing to cooperate with researchers, H.M. said toward the end of his life that he wished to donate his brain to science upon his death; his legal conservator agreed. The Dana Foundation, along with the National Science Foundation, has funded a project to preserve this gift digitally to benefit science.
The night H.M. died, on December 2, 2008, his brain underwent nine hours in a magnetic resonance imaging (MRI) scanner, said Dana Alliance member and investigator Suzanne Corkin, Ph.D., of MIT, who had worked with Molaison for more than four decades.
Using novel computer-assisted neuroimaging techniques, researchers at the Brain Observatory of the University of California, San Diego, led by Jacopo Annese, Ph.D., will create a complete digital library of stained tissue slices that reveal microscopic anatomy far beyond the resolution of current MRI techniques. This will pinpoint the exact location and extent of H.M.’s surgically removed tissue and the conditions of the surrounding tissue.
The researchers will post the “digital map” of this special brain on the Web. Memory researchers will then be able to compare imaging studies of brain function with the H.M. brain tissue studies to validate and further explore the basis of memory in the brain.
The Web site will include information to help non-scientists understand how memory works in general, as well as to appreciate this particular case. This way, Mr. Molaison’s contributions to neuroscience will continue.
Special Focus: Deep Brain Stimulation
In the new generation of surgical approaches to treating brain disorders, deep brain stimulation (DBS) stands out for its ability, through electrodes surgically implanted in precise locations in the brain, to change the activity in specific neural circuits. DBS surgery also enables neurosurgical researchers to record the activities of single brain cells and networks of cells to understand their functions in various cognitive activities.
The surgery involves implanting electrodes in target brain areas and connecting them through an insulated wire called an “extension” to a battery operated neurostimulator device placed under the skin near the collarbone. The neurostimulator does for neurons what a pacemaker does for the heart muscle: It disrupts the rhythm of the electrical impulses and changes the circuit. And unlike the removal of brain tissue, DBS surgery can be modified—the electrical current applied to a given area can be increased, decreased, reversed, or turned off altogether.
DBS is FDA-approved only for treating two motor diseases—Parkinson’s disease and essential tremor—though the agency has given humanitarian device exemption approval for treating dystonia and obsessive-compulsive disorder. A small but growing number of researchers is investigating it as a potential treatment for highly intractable cases of thought and mood disorders, including depression. The number of people treated experimentally remains quite small, but several research groups have reported promising preliminary results. Why DBS works on mood disorder patients is still unclear.
“Ultimately, we’re going to have to understand circuits to cure disease,” said Mahlon DeLong, M.D., director of the Comprehensive Neuroscience Center at Emory University and a pioneer in using DBS for Parkinson’s Disease. (Dr. DeLong, a Dana Alliance member, cowrote an essay on DBS for the 2008 Progress Report on Brain Research.)
The Dana Foundation supports scientists working to understand circuits, from lab research exploring the functions of specific brain circuits to clinical studies of the effectiveness of DBS in treating people with severe mood disorders and in restoring communication capabilities in patients emerging from a minimally conscious state. We sponsor forums and conferences for researchers, ethicists, and others to develop guidelines for the conduct of clinical research using this technology. In an effort to offset some of the hype created by overzealous reports and people desperate for a cure, we also sponsor public forums to talk about where the field is now.
Progress on Severe Low Mood Disorders
Current research by Helen Mayberg, M.D., and her colleagues at Emory, who are using DBS to treat intractable depression, emanated from one of Dana’s first imaging grants. Through a 1995 award, Dr. Mayberg used positron emission tomography (PET) and identified the brain’s cingulate area as integral to severe depression.
“It has become apparent that we can dissect out the subcircuits involved in depression by looking at how the brain changes if you successfully treat depression with drugs or other therapies, so you can start to piece together the puzzle of what regions are most consistently affected,” said Dr. Mayberg. “Over time, we have been developing the same kind of wiring diagram for depression that has been worked out for Parkinson’s. Across our different studies, it became clear that certain things need to change in the brain in order for the depressed person to get well, which meshed with what other people were finding.”
The first patients to receive DBS for depression were participating in a study at the University of Toronto led by Dr. Mayberg and her colleague, neurosurgeon Andres Lozano, M.D., Ph.D. Dr. Mayberg and her Emory coinvestigators received Dana support to expand the number of patients participating in these initial treatment studies.
In Toronto, patients with treatment-resistant depression received DBS implants and were followed for one year. The results from the first 20 patients show that DBS is relatively safe, and it provided significant improvement in most cases, as Drs. Mayberg, Lozano, and colleagues reported in Biological Psychiatry in September 2008.
At Emory, Dr. Mayberg and her colleagues are continuing the pilot research. To date, these investigators, using an experimental design that includes placebo periods and stimulation periods, have studied 13 people and plan to increase the sample size to 40 people. They also are using brain imaging to continue to try to characterize the brain processes involved in severe depression and to define how DBS affects these brain processes.
Based on their recent work to determine how DBS affects the brain’s subcallosal cingulate gyrus and the anterior limb of the internal capsule, Dr. Mayberg and colleagues report that each area has distinct patterns of neural connections with areas of overlap in regions that are implicated in depression and in antidepressant response.
“DBS technology takes advantage of the fact that we can modulate specific circuits that are responsible for different kinds of behaviors,” said Dr. Mayberg. “In the big picture, the idea that neural systems can be modulated by electricity introduces a whole new strategy for thinking about how to influence the brain in ways that we really hadn’t conceptualized before.”
According to Dr. Mayberg, a potential problem with DBS is that many members of the general public have come to view it as an established procedure—some people even e-mail Dr. Mayberg asking for it. Treating depression “is a tremendous application of this technique,” she said during a forum in 2008 at the Dana Center in Washington, D.C. “But we are at a beginning, and we should act as such”—starting with the caveat that this deeply invasive treatment is not for all people who suffer depression, or even for a majority of them.
“There’s no such thing as minor brain surgery,” said Dr. Mayberg.
Targeting Parkinson’s Disease
Parkinson’s disease results from a loss of cells that transmit dopamine from one cell to another. As these cells die, brain signals fire improperly, and a person loses some control of body movements. Treatment with L-DOPA (an amino acid that can replenish dopamine supplies) works for a while, but eventually it leads to other movement problems in nearly 80 percent of patients.
DBS electrodes implanted in the subthalamic nucleus, which lies deep within the brain, block the uncontrolled synchronized signals that produce tremor and other symptoms in patients with Parkinson’s disease. Surgeons can have difficulty determining exactly where to place the electrodes to block the abnormal neuronal signaling—and if they place the electrode improperly, the patient can experience serious side effects.
To improve the success of DBS for people with Parkinson’s disease, neurosurgeon Peter Brown, M.D., F.R.C.P., and colleagues at the Institute of Neurology at University College, London, have been using two new techniques for determining more precisely where electrodes should be placed to produce the best results.
Through a grant awarded in 2004, the investigators found that electrical brain signaling activity of a particular frequency in the brain’s subthalamic nucleus is characteristic of Parkinson’s disease in both an animal model and in patients, and the location of neurons using that frequency for signaling shows precisely where to position the DBS electrodes for optimum benefit.
Dr. Brown’s animal research also has demonstrated that excessive signaling by these neurons reduces the brain’s capacity to code information and may contribute to Parkinson’s motor symptoms. Contrary to conventional thinking, he found that the neurons’ excessive signaling is produced by chronic, but not acute, disruption of dopamine used by the neurons to transmit their signals.
Setting Standards for Clinical Trials
In September 2007, a group of leading DBS researchers joined with philosophers, ethicists, and patients in a consensus development meeting to draft guidelines for experimental use of DBS for disorders of mood, thought, and behavior. The Foundation cosponsored the conference, along with the National Institute of Neurological Disorders and Stroke and the National Institute of Mental Health.
Clinical trials are currently exploring the use of DBS in treating depression, epilepsy, and obsessive-compulsive disorder. The September 2007 group identified 17 key points to be used as guidelines for protecting participants in clinical trials.
In 2008, those involved in drafting the guidelines reached a consensus about clinical trial designs and developed standards to protect human participants, given their potentially diminished capacity to provide valid informed consent. These guidelines will be published by the Archives of General Psychiatry in 2009.
Seeking the “Cells and Circuits” of Cognition
As a complement to clinical trials of DBS, a consortium of translational research neurosurgeons at the University of California, Los Angeles, and the universities of Iowa and Toronto are receiving grant support from Dana to undertake a broad investigation of the neuronal underpinnings of memory and emotion, the use of implanted DBS electrodes, and the possibility that DBS recording of brain cells involved in the intent to move might eventually lead to a brain-computer interface facilitating movement in spinal-cord injured patients.
Andres Lozano, M.D., at Toronto; Matthew Howard, M.D., at Iowa; and Itzhak Fried, M.D., Ph.D., at UCLA are among the pioneers in assessing the effectiveness of DBS to treat intractable brain diseases such as depression, epilepsy, Parkinson’s, and Alzheimer’s disease. In 2007, they met in Los Angeles with cognitive neuroscientists to identify the most important questions that could be asked and answered through the direct recording of brain cell activity using implanted DBS electrodes.
While little currently is known about the brain basis of human cognition, improved technologies such as functional magnetic resonance imaging (fMRI), combined with direct recordings from single cells or groups of cells in humans, have made such exploration possible.
At their respective consortium centers, the neurosurgeons implant electrodes in the brains of patients with epilepsy a few weeks prior to their planned surgery, in which specific areas of brain tissue are removed to stop seizures that cannot be controlled by medication. By stimulating the implanted electrodes, the surgeons can pinpoint the originating focus and subsequent spread of the patient’s seizures for surgical removal. But the surgeons need to spare any tissue that is vital to the patient’s cognitive or motor functions. To identify these tissues, the surgeons have the patients perform specific cognitive and motor tasks while the implanted electrodes record activities of individual cells and networks of cells. These vital areas are then marked and spared during surgery.
This process, with the consent of the patient, also provides an opportunity for the neurosurgeons to identify cells and neural networks involved in specific cognitive functions.
The consortium chose three brain functions to explore during the next few years:
- Volitional movement: Researchers will record brain cell activity as patients think about moving their arms and then actually move them—the first step toward creating a brain-computer interface that can enable people with spinal cord injuries to move their own arms and hands or robotic arms and hands.
- Emotion: The researchers will try to identify stages of emotional processing by showing patients happy, menacing, and neutral faces and recording brain cell responses to them.
- Memory: Researchers will systematically explore processes used to encode, store, and recall memories, and they will determine whether DBS can enhance these processes.
This memory study arose from a chance observation of a Toronto patient undergoing experimental DBS treatment for obesity. The patient had early Alzheimer’s disease, and DBS appeared to improve his short-term memory.
Through this research, we hope to further scientific understanding of human cognition at the level of nerve networks within the brain. This “cells and circuits” approach is designed ultimately to reveal the neural basis for human cognition and lead to the development of new therapies for diseases that impair cognition, such as neurodegenerative diseases, autism, depression, and epilepsy.
Very few centers have the capacity to undertake such research. These are the first systematic studies of their kind. “This is a formidable team, arguably the only one in the world capable of pursuing this project,” one peer reviewer wrote of the project when it was proposed. “The investigators are, quite simply, the best in the field. They have, individually and collectively, been responsible for some of the major technical advances with this approach, and they have completed some of the most remarkable work carried out with it. . . . The intellectual advances possible under this project, as well as the applications to brain disease, are quite apparent.”
Support for Science and Math Education
Many of the Dana Foundation’s science education grants support collaborations with other organizations to enhance and augment the neuroscience curricula being taught in K–12 schools. Programs include producing print and online materials that contain current, credible information about the brain; publishing teacher’s guides; holding workshops for teachers; and sponsoring talks by neuroscientists. Other grants support exchange among scientists at general conferences and at special single-subject workshops.
The Harlem DNA Laboratory
A grant in honor of Dana Alliance vice chairman James D. Watson, Ph.D., will enable New York City students in grades four and up to explore genetics and the scientific method at the new Harlem DNA Lab, a series of classrooms in the John S. Roberts Educational Complex in East Harlem. The state-of-the-art genome lab, which opened in September 2008, is a branch of the Dolan DNA Learning Center, itself part of Cold Spring Harbor Laboratory.
In half-day workshops or weeklong seminars, students learn techniques and use some of the tools of researchers on the forefront of genome study. Organizers expect up to 4,000 middle school and high school students to visit each year. One of the long-term goals for the lab is to help each student in New York City see his or her own DNA before graduating from high school.
|Cold Spring Harbor Laboratory President Bruce Stillman joins students enjoying the Harlem DNA Lab on its opening day in September 2008. (Photo courtesy of Cold Spring Harbor Laboratory) |
“Teaching our children—and the teachers who instruct them—about contemporary biology is not a luxury for the wealthiest school districts, but should be regarded as a must for our young people who will be entering the workforce in the next decade,” said Cold Spring Harbor Laboratory president Bruce Stillman during the lab’s opening ceremonies.
Dana Brain Science Educator Series
In 2008, the Dana Brain Science Educator Series, via a grant to the New York Hall of Science, gave 21 middle and high school teachers (Dana Fellows) the chance to learn more about the brain, to observe new ways to teach neuroscience in the classroom, and to develop grade-appropriate curriculum in neuroscience.
Drawing on the resources of the Dana Foundation and the Hall of Science, the Dana Fellows develop a set of content-rich lesson plans using inquiry-based methods. Fellows are expected to act as resources for colleagues and to encourage others to participate in similar professional development initiatives.
The 2008 Educator Series focused on brain damage and repair. Through lectures, panel discussions, a field trip, and an interactive lesson, the fellows explored current medications and cutting-edge treatments for such conditions as Alzheimer’s disease, mental illness, and traumatic brain injury.
Imaging and Society
Brain scans are used to illustrate science stories, to serve as evidence in trials, and even to interpret people’s political persuasions. But many scientists who use neuroimaging technology are concerned that these images are sometimes misinterpreted and misunderstood even by experts in other fields, let alone the press and the general public. For example, can a functional magnetic resonance imaging scan show that a person is lying? When we look at brain scans, does the left side of the picture correspond with the left side of the brain, or is it the right side?
Dana is supporting the Hastings Center’s three-year roundtable project, started in 2008. The project brings together researchers, clinicians, philosophers, ethicists, and anthropologists to clarify the complexities of interpreting neuroimages and, ultimately, to explain them clearly to the public. After a series of interdisciplinary group meetings on topics such as neuroimaging technology’s role in studies of addiction, aggression, and antisocial personality disorder, roundtable participants will produce background reports, a book of essays, and other materials, and they will share what they know at public symposia and briefings. Dana will participate in the sharing via our Web site and our continuing public events.
The Charles A. Dana Center at the University of Texas, Austin
The Dana Center for Mathematics and Science Education provides education leaders in Texas and nationwide with validated knowledge about teaching and learning. It supports K–12 teachers and leaders working to implement high academic standards for all students.
In the late 1990s, the Dana Center in Austin helped coordinate new math and science standards for the State of Texas. Traveling to low-performing schools across the state, Dana Center staff listen to teachers and students and help them to reorganize and focus on learning ever-more-demanding science and math curricula. Partnering with the national education organization Achieve, Inc., the Dana Center directs the Urban Mathematics Leadership Network, which brings together district and state mathematics educators from across the country to share solutions to common pedagogical problems. In 2008, network educators meeting in Washington, D.C., concentrated on applying advances in what we know about learning to the practical problem of engaging students in more rigorous curricula. People representing 22 large urban districts serving nearly 4 million American schoolchildren shared information and took home new ideas.
These districts and their leaders charged the Dana Center with three new research and development projects:
- to develop a new approach to teaching algebra to struggling students that better prepares them for success in advanced mathematics courses
- to develop a set of scientifically based strategies to increase students’ commitment to academic success—and a set of parallel strategies to increase teachers’ commitment to their students’ success
- to build a network to support people driving mathematics and science curricula in the country’s largest urban districts
Districts in the network have agreed to serve as laboratory sites for each of these tasks.
Through national and international seminars and its work with states, the Dana Center’s goal remains to help school systems produce graduates with strong math knowledge and skills, as well as an understanding of how to apply those skills in learning, work, and life.
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