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Changing Minds

Ron AltermanFor Parkinson's disease patients, a task as simple as pouring a cup of coffee in the morning can be a challenge. A degenerative disease that affects more than one million people nationwide, the neurological disorder is the result of the death of brain cells, which leads to difficulty with basic motor functions. Despite great advances in neuroscience, the inner workings of the human brain-which might explain how or why these cells die-remain a mystery.

"The more we learn about the circuitry of the brain, the better we can understand the neuroscience underlying disorders, which should ultimately lead to better medical therapies," says Ron L. Alterman, M.D., chief of neurosurgery within the Roberta and Stephen R. Weiner Department of Surgery at Beth Israel Deaconess Medical Center and a world leader in deep brain stimulation surgery to treat movement disorders like Parkinson's disease (PD). "If we can identify the specific site within the brain responsible for a neurological disorder, we now have tools to disrupt or correct its abnormal activity."

More than 600 distinct disorders affect the brain and nervous system and afflict an estimated 50 million Americans each year. In the last decade, scientists have challenged the long-standing theory that the human brain is hardwired and unable to adapt or change, opening up previously unimaginable treatment opportunities. From talk therapy and medication to electrical stimulation and genetic alterations, there have been various attempts at treating one of the body's most complex and elusive organ systems.

Clif SaperUntil only recently, however, most have been focused on symptom management rather than a cure. "The exciting part to me is that we now have at our fingertips ways to change the brain to improve function and correct problems that have been caused by various diseases," says Clifford Saper, M.D., Ph.D., chief of the Department of Neurology, who is researching approaches to introduce and manipulate genes in specific neurons, or nerve cells, in the brain. "Restoring or repairing the brain is a critical next step, and I think we are at that threshold."
 
At BIDMC, neurologists, neurosurgeons, and neuroscientists are on the leading edge of techniques to better treat these complicated conditions and pioneering approaches to understand the mechanisms of the brain with the goal of improving function and eradicating disease. Among those techniques is deep brain stimulation (DBS), a method traditionally used to treat movement disorders such as PD, tremor, or dystonia. The therapy requires a surgical procedure to implant a thin wire equipped with stimulating electrodes into a specific target deep within the brain. The electrodes are connected to a pacemaker implanted under the skin that, like a pacemaker for the heart, delivers electrical impulses directly to the target to regulate its abnormal activity. Alterman has been a leader in using this method to treat various movement disorders. The technique has proven highly effective over the last 20 years and safe for treating selected patients long term.

The Parkinson's Disease and Movement Disorder Clinic at BIDMC, which is a National Parkinson's Foundation Center of Excellence, is uniquely experienced when it comes to selecting appropriate patients for DBS. The medical center first offered the procedure in 1994 as a part of a pivotal North American clinical trial led at BIDMC by Daniel Tarsy, M.D., the clinic's director. In October 2011, Alterman joined BIDMC neurosurgeon Efstathios Papavassiliou, M.D., who has been performing the procedure here since 2003. "If you are going to offer invasive surgery to patients, you want to be sure that it is a risk worth taking," says Ludy Shih, M.D., director of the deep brain stimulation program. "We give each patient an individualized overall assessment, seeing if personal quality-of-life concerns correlate with the expected effects of DBS. Our multidisciplinary team is expert not only in terms of weighing this decision for each individual patient but also at understanding and troubleshooting the complications that can arise."

Ludy ShihOnly 10 to 20 percent of PD patients are good candidates for the surgery. But for those who qualify, the effect on their symptoms can be quite profound. "Patients who are relieved of their involuntary movements are so grateful to no longer have to be writhing uncomfortably, sometimes in pain, and embarrassed by some of these movements," says Shih. "For many people, medicationresistant tremor and other involuntary movements interfere with basic activities like holding a cup or writing. Recovering these functions is now possible through the use of techniques like deep brain stimulation."

Neurologists and neurosurgeons are exploring innovative ways to expand the use of DBS beyond movement disorders to include the treatment of epilepsy and psychiatric illnesses such as obsessive compulsive disorders and chronic depression. "If deep brain stimulation turns out to be as effective as we think it might be, the global health impact of that advance would be enormous," Alterman says. The challenge is that the precise therapy must pinpoint a specific area of the brain-and the trick is figuring out that target for each disorder. "The key is: can we discover new targets to treat new disorders and expand the use of this technology, which has had really a profound impact on the treatment of these disorders?" he says.

With this in mind, researchers at BIDMC are investigating a potential new form of DBS, known as responsive deep brain stimulation, to treat epilepsy. Rather than providing ongoing stimulation, the new device will monitor electrical brain activity continuously and stimulate specific targets to short circuit seizures as they occur. "We intend to be serious participants in the development of this type of neuromodulatory technology for the treatment of epilepsy," Alterman says.

To achieve this goal, BIDMC requires funding to fuel the research to bring new treatments to reality. "Outside support helps to not only carry out some of the major projects we have in mind already, but it also allows physicians and investigators to nurture ideas that may have a significant impact on clinical care and science," Shih says. "DBS is such an exciting field because scientifically it is fascinating, but importantly, it has direct clinical relevance today." While DBS has shown remarkable benefits for patients, Alterman acknowledges it is not a permanent solution and further innovation is essential. "The goal is to find biological therapies that alter the natural history of the disease to prevent or reverse the degenerative process so deep brain stimulation is not even necessary," he says. Thanks to technology developed over the last decade, researchers at BIDMC are rapidly moving in that direction and are among the few scientists that are able to implant engineered genes into the brains of animal models to change the function of specific neurons and modify behavior. With additional research, human clinical trials are within reach. "I think that this particular set of technologies is a game changer and will actually make a big difference in the way we do our work in the future," Saper says.

Brad LowellDivision of Endocrinology researcher Brad Lowell, M.D., Ph.D., has built a foundation of basic research in this area that puts BIDMC ahead of the field. For the last two decades, he has excelled in developing lines of genetically engineered mice designed to express a protein called cre-recombinase. The protein manipulates nerve cells so they can be targeted for modification or activation by an external stimulus, such as light or chemicals. "You can control the activity of any neuron by delivering certain genes to those neurons," he says. Lowell's team is using his established expertise with this method, along with new technologies, to determine the function of specific neurons and how they talk to each other to regulate feeding behavior. "We are one of the few labs in the world using these technologies to address the wiring diagram," Lowell says. "We can make new lines of genetically engineered mice that express cre-recombinase in different neurons as fast as anybody in the world. We know the important ones to make and the important questions to ask."

To map the connections between neurons and control them, Lowell's team is also using viral vectors to deliver genes to cells. Researchers introduce a deactivated, noninfectious version of the virus, known as a viral vector, into a selected nerve cell of the mouse's brain. The virus is engineered to allow it to enter cells and inject them with genetic code. The illness-causing genes have been removed from the virus, so it only inserts the genes they have been engineered to deliver. The genes then produce proteins that allow the nerve cells to be manipulated.

Following implantation of the new genes, the nerve cells are normal until they are activated by the investigator. Researchers can "turn on" the neuron by stimulating it with either light, a method called optogenetics, or with chemicals, a technique known as DREADDs (Designer Receptor Exclusively Activated by Designer Drug). In optogenetics, light is delivered to the nerve cell by implanting a fiber-optic cable into the brain and attaching the other end to a laser. When the light is presented to an identified feeding neuron in the brain of a mouse, that mouse will be instantly stimulated to start eating. With the DREADDs approach, the designer drug used to activate the receptor is a normally innocuous chemical that has no effect on animals that have not been injected with the viral vector. But once the designer drug is administered, animals who have had the DREADDs implanted into their brain can be driven to eat, sleep, or perform other behaviors, depending on which DREADD has been injected and in what site of the brain.

While Lowell is using the technology to map the connections in the brain, the technique also has clinical possibilities. "It turns out that viral vectors are an extremely good way to implant new genes into cells in the brain," says Saper, who is hoping to use this technology to control the debilitating symptoms of the world's most complex neurological conditions. "It is an incredible way to manipulate the brain."

Bridging the gap between animal models and human clinical trials is a challenge. "We know it works," Saper says, adding that philanthropic support is essential to take the research to the next level. "It's not like we would have to come up with any new technology here; we use these viral vectors and DREADDs every day in our labs. The next step is just to apply the proven methods to yet another species-which just happens to be us." With further knowledge of how the brain is wired and where to focus treatment, this technology could have profound implications for how we target the sudden onset of epilepsy or the debilitating effects of PD and eating disorders, among a host of other neurological and psychiatric diseases. "You have to have people who have the technologies," Saper says. "You have to have people with vision about how to apply them, and they all have to be in the same place working together in order to do that. I think we are uniquely situated to carry this forward."

Contact Information

Office of Development
Beth Israel Deaconess Medical Center
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Boston, MA 02215
(617) 667-7330
(617) 667-7340 (fax)
development@bidmc.harvard.edu