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| Deep Brain Stimulation shows promise for patients with chronic, treatment resistant Anorexia Nervosa Posted: 05 Mar 2013 09:00 PM PST In a world first, a team of researchers at the Krembil Neuroscience Centre and the University Health Network have shown that Deep Brain Stimulation (DBS) in patients with chronic, severe and treatment-resistant Anorexia Nervosa (anorexia) helps some patients achieve and maintain improvements in body weight, mood, and anxiety.
The results of this trial, entitled Deep Brain Stimulation of the Subcallosal Cingulate Area for Treatment-Refractory Anorexia Nervosa: A Phase I Pilot Trial, are published today in the medical journal The Lancet. The study is a collaboration between lead author Dr. Nir Lipsman a neurosurgery resident at the University of Toronto and PhD student at the Krembil Neuroscience Centre; Dr. Andres Lozano, a neurosurgeon, at the Krembil Neuroscience Centre of Toronto Western Hospital and a professor and chairman of neurosurgery at the University of Toronto, whose research lab was instrumental in conducting the DBS research; and Dr. Blake Woodside, medical director of Canada’s largest eating disorders program at Toronto General Hospital and a professor of psychiatry at the University of Toronto. The phase one safety trial investigated the procedure in six patients who would likely continue with a chronic illness and/or die a premature death because of the severity of their condition. The study’s participants had an average age of 38, and a mean duration of illness of 18 years. In addition to the anorexia, all patients, except one, also suffered from psychiatric conditions such as major depressive disorder and obsessive-compulsive disorder. At the time of the study, all patients currently, or had previously, suffered multiple medical complications related to their anorexia ? altogether, the six patients had a history of close to 50 hospitalizations during their illnesses. Study participants were treated with Deep Brain Stimulation (DBS), a neurosurgical procedure that moderates the activity of dysfunctional brain circuits. Neuroimaging has shown that there are both structural and functional differences between anorexia patients and healthy controls in brain circuits which regulate mood, anxiety, reward and body-perception. Patients were awake when they underwent the procedure which implanted electrodes into a specific part of the brain involved with emotion, and found to be highly important in disorders such as depression. During the procedure, each electrode contact was stimulated to look for patient response of changes in mood, anxiety or adverse effects. Once implanted, the electrodes were connected to an implanted pulse generator below the right clavicle, much like a heart pacemaker. Testing of patients was repeated at one, three, and six-month intervals after activation of the pulse generator device. After a nine-month period following surgery, the team observed that three of the six patients had achieved weight gain which was defined as a body-mass index (BMI) significantly greater than ever experienced by the patients. For these patients, this was the longest period of sustained weight gain since the onset of their illness. Furthermore, four of the six patients also experienced simultaneous changes in mood, anxiety, control over emotional responses, urges to binge and purge and other symptoms related to anorexia, such as obsessions and compulsions. As a result of these changes, two of these patients completed an inpatient eating disorders program for the first time in the course of their illness. “We are truly ushering in a new of era of understanding of the brain and the role it can play in certain neurological disorders,” says Dr. Lozano. “By pinpointing and correcting the precise circuits in the brain associated with the symptoms of some of these conditions, we are finding additional options to treat these illnesses.” While the treatment is still considered experimental, it is believed to work by stimulating a specific area of the brain to reverse abnormalities linked to mood, anxiety, emotional control, obsessions and compulsions all of which are common in anorexia. In some cases after surgery, patients are then able to complete previously unsuccessful treatments for the disease. The research may not only provide an additional therapy option for these patients in the future, but also furthers practitioners’ understanding of anorexia and the factors that cause it to be persistent. “There is an urgent need for additional therapies to help those suffering from severe anorexia,” says Dr. Woodside. “Eating disorders have the highest death rate of any mental illness and more and more women are dying from anorexia. Any treatment that could potentially change the natural course of this illness is not just offering hope but saving the lives for those that suffer from the extreme form of this condition.” A leading international expert in the field of DBS research, Dr. Lozano has been exploring the potential of DBS to treat a variety of conditions. Most recently, his team began the first ever DBS trial of patients with early Alzheimer’s disease, and showed that stimulation may help improve memory. This trial has now entered its second phase and expanded to medical centres in the United States. Anorexia Nervosa is an eating disorder and psychiatric condition characterized by food restriction, body distortion and an overwhelming fear of gaining weight. Death rates from anorexia can be as high as 15%, and a further 15% to 20% of those with anorexia develop a chronic course of the condition that is unresponsive to traditional treatments. Research has shown that addressing the emotional symptoms, psychological issues and other mental illnesses associated with anorexia ? rather than solely treating low body weight ? is linked to lower rates of relapse and improved treatment outcomes. ### UHN researchers hope to expand their study, and to design a trial that will determine the long-term impact of DBS in a larger number of patients with treatment-resistant anorexia nervosa. For additional information about the study, including eligibility criteria and contact information, contact dbs@uhnresearch.ca This research was made possible by a grant from the Klarman Family Foundation Grants Program in Eating Disorders Research and a Fellowship from the Canadian Institutes of Health Research (CIHR). About Krembil Neuroscience Centre The Krembil Neuroscience Centre (KNC), located at Toronto Western Hospital, is home to one of the largest combined clinical and research neurological facilities in North America. Since opening in 2001, KNC has been recognized as a world leader through its research achievements, education and exemplary patient care. The centre focuses on the advancement, detection and treatment of neurological diseases and specializes in movement disorders, dementias, stroke, spinal cord injury, blinding eye diseases, epilepsy and cancer-related conditions For more information please visit http://www.krembil.com About Toronto General Hospital Toronto General Hospital is a partner in University Health Network, along with Toronto Western, the Princess Margaret Cancer Centre and Toronto Rehabilitation Institute. The scope of research and complexity of cases at Toronto General Hospital have made it a national and international source for discovery, education and patient care. It has one of the largest hospital-based research programs in Canada, with major research in cardiology, transplantation, surgical innovation, infectious diseases, genomic medicine and rehabilitation. Toronto General Hospital is a research and teaching hospital affiliated with the University of Toronto. http://www.uhn.ca About University Health Network University Health Network consists of Toronto General and Toronto Western Hospitals, the Princess Margaret Cancer Centre, and Toronto Rehabilitation Institute. The scope of research and complexity of cases at University Health Network has made it a national and international source for discovery, education and patient care. It has the largest hospital-based research program in Canada, with major research in cardiology, transplantation, neurosciences, oncology, surgical innovation, infectious diseases, genomic medicine and rehabilitation medicine. University Health Network is a research hospital affiliated with the University of Toronto. http://www.uhn.ca Contact: Alexa Giorgi, Senior Public Affairs Advisor |
| Circuitry of cells involved in immunity, autoimmune diseases exposed Posted: 05 Mar 2013 09:00 PM PST New work from the Broad Institute’s Klarman Cell Observatory, Brigham and Women’s Hospital, Harvard University, MIT, and Yale University expands the understanding of how one type of immune cell ? known as a T helper 17 or Th17 cell ? develops, and how its growth influences the development of immune responses. By figuring out how these cells are “wired,” the researchers make a surprising connection between autoimmunity and salt consumption, highlighting the interplay of genetics and environmental factors in disease susceptibility. The results of their work appear in three companion papers in Nature this week.
The researchers concentrated on T cells because of their important roles in clearing foreign pathogens and in various autoimmune diseases. “The question we wanted to pursue was: how does the highly pathogenic, pro-inflammatory T cell develop?” said Vijay Kuchroo, co-director of the Center for Infection and Immunity at Brigham and Women’s Hospital’s Biomedical Research Institute and a Broad associate member. Kuchroo is also a professor of neurology at Harvard Medical School. “Once we have a more nuanced understanding of the development of the pathogenic Th17 cells, we may be able to pursue ways to regulate them or their function.” The human immune system is in a state of delicate balance: too little activity leaves a person vulnerable to foreign invaders, but too much activity threatens to harm the body it ought to protect. When this delicate balance is broken, it can lead to autoimmune diseases. But little is known about the molecular circuitry that maintains ? or upsets ? such a fine equilibrium. “We wanted to understand how the body gets the right kinds of immune cells in the right amount, and how it keeps those cells at the right activity level so that they are not too active but also not underactive,” said Aviv Regev, a Broad Institute core member and an associate professor of biology at MIT. Regev is also an Early Career Scientist at Howard Hughes Medical Institute and the director of the Klarman Cell Observatory at the Broad. “The value in doing an unbiased analysis is that we’re able to understand a lot more about the molecular biology at play and identify novel players in this process.” Th17 cells can promote inflammation that is important for protection against pathogens, but they have also been implicated in diseases like multiple sclerosis, psoriasis, rheumatoid arthritis, and ankylosing spondylitis. Treatment options for some of these diseases, such as psoriasis, include manipulating T cell function. David Hafler’s group at Yale University studies human autoimmune diseases in general and the role of Th17 cells in particular, and has collaborated with Kuchroo’s group for many years. “These are not diseases of bad genes alone or diseases caused by the environment, but diseases of a bad interaction between genes and the environment,” said Hafler, Gilbert H. Glaser Professor of Neurology, professor of immunobiology, chair of Department of Neurology, and senior author of one of this week’s Nature papers. Some genes have been previously tied to Th17 development, but the research team wanted a more comprehensive view. One of the challenges of studying cell development, however, is that cells, particularly immune cells, change and evolve over time. The researchers chose to take frequent snapshots ? 18 over the course of three days ? to see what was happening within the T cells as they grew from naïve cells into more specialized Th17 cells. From these snapshots, they used computational algorithms to begin to stitch together a network of molecular changes happening as the cells matured. With this initial information in hand, the researchers systematically tested their model by silencing genes one-by-one, which could help reveal the most important points in the network and untangle their biological meaning. To do so, they needed a technology that would allow them to silence genes without perturbing the cells in the process. Although RNA interference (RNAi) is a powerful way to turn off individual genes, most RNAi techniques rely on viruses as delivery vehicles. When scientists tried to perturb the T cells using these traditional techniques, cells either changed or died, limiting the effectiveness of these strategies. “This was a real challenge,” said Kuchroo. “Every time we tried to downregulate a gene with existing technologies, the cell would change. We didn’t know if we were looking at the right thing. We needed a new technology ? something that could have a dramatic but precise effect.” A solution came from an unlikely source. Harvard professor and Broad associate member Hongkun Park and his lab in the departments of chemistry and chemical biology and of physics had been working on a computer-chip-like structure to interact with brain cells. Co-first authors Alex Shalek and Jellert Gaublomme along with other lab members had developed a bed of silicon nanowires ? miniscule needles designed to pierce cells. “We learned that we could use these needles to deliver molecules into cells in a minimally invasive fashion,” said Park. “And as Vijay and Aviv taught me, there are lots of things that this allows you to do that you could not do before. It’s been an eye-opening experience.” Just as the thin needle of a syringe can be inserted into the skin and cause no more than a small pinching sensation, nanowires can be inserted into cells, causing minimal disruption. Using this new technology, the team teased apart the network, piece by piece, by deleting each of the key genes required in the development of Th17 cells. With the help of co-first author Nir Yosef, a postdoc at the Broad and Brigham and Women’s Hospital, the team found that Th17 cells are governed by two networks, seemingly at odds with each other: one network positively regulates the cells, coaxing them to increase in number while suppressing the development of other cells. The other negatively regulates them, having the opposite effect. “It’s a system in perfect tension,” said Regev. “It both suppresses and promotes Th17 cell creation, keeping the cells at equilibrium.” Through this analysis, one particular gene stood out to the researchers: SGK1. The gene plays an important role in the cells’ development, and when turned off in mice, Th17 cells are not produced. SGK1 had not been described in T cells before, but it has been found in cells in the gut and in kidneys, where it plays a role in absorbing salt. Based on this, two teams of researchers set out to test the connection between salt and autoimmunity ? Kuchroo, Regev, and their colleagues working with mouse cells and mouse models, and Hafler’s team working with human cells. Through efforts led by co-first author and Brigham and Women’s Hospital postdoc Chuan Wu, the team found that they could induce more severe forms of autoimmune diseases, and at higher rates, in mice fed a high-salt diet than in those that were fed a normal mouse diet. Kuchroo notes though that the high-salt diet alone did not cause autoimmune diseases ? the researchers had to induce disease, in this case by injecting a self-antigen to prompt the mouse immune system to respond. “It’s not just salt, of course,” Kuchroo said. “We have this genetic architecture ? genes that have been linked to various forms of autoimmune diseases, and predispose a person to developing autoimmune diseases. But we also suspect that environmental factors ? infection, smoking, and lack of sunlight and Vitamin D ? may play a role. Salt could be one more thing on the list of predisposing environmental factors that may promote the development of autoimmunity.” “One important question is: how can one think of these results in the context of human health?” said Regev. “It’s premature to say, ‘You shouldn’t eat salt because you’ll get an autoimmune disease.’ We’re putting forth an interesting hypothesis ? a connection between salt and autoimmunity ? that now must be tested through careful epidemiological studies in humans.” The researchers plan to harness the cell circuitry data to identify and follow up on potential drug targets. Kuchroo notes that the published work and future studies are only possible because of the interdisciplinary team brought together by shared questions about cell circuitry. “We often work in isolation in our areas of expertise, but this is the kind of work I could not have done in my own lab, and that Hongkun and Aviv could not have done in their respective labs,” said Kuchroo. “We needed this unique combination of tools and technologies to come together around this problem. Looking forward, we’ll need the tools and intellect of different disciplines in order to solve big problems in biology and medicine.” ### Support for this work was provided by the National Human Genome Research Institute, the National Institutes of Health, National Multiple Sclerosis Society, the Klarman Cell Observatory, Guthy Jackson Foundation, and the Austrian Science Fund. This press release was provided by the Broad Institute. Brigham and Women’s Hospital (BWH) is a 793-bed nonprofit teaching affiliate of Harvard Medical School and a founding member of Partners HealthCare. BWH has more than 3.5 million annual patient visits, is the largest birthing center in New England and employs more than 15,000 people. The Brigham’s medical preeminence dates back to 1832, and today that rich history in clinical care is coupled with its national leadership in patient care, quality improvement and patient safety initiatives, and its dedication to research, innovation, community engagement and educating and training the next generation of health care professionals. Through investigation and discovery conducted at its Biomedical Research Institute (BRI), BWH is an international leader in basic, clinical and translational research on human diseases, involving nearly 1,000 physician-investigators and renowned biomedical scientists and faculty supported by nearly $625 million in funding. BWH continually pushes the boundaries of medicine, including building on its legacy in organ transplantation by performing the first face transplants in the U.S. in 2011. BWH is also home to major landmark epidemiologic population studies, including the Nurses’ and Physicians’ Health Studies, OurGenes and the Women’s Health Initiative. For more information and resources, please visit BWH’s online newsroom. The Eli and Edythe L. Broad Institute of MIT and Harvard was founded in 2003 to empower this generation of creative scientists to transform medicine with new genome-based knowledge. The Broad Institute seeks to describe all the molecular components of life and their connections; discover the molecular basis of major human diseases; develop effective new approaches to diagnostics and therapeutics; and disseminate discoveries, tools, methods and data openly to the entire scientific community. Founded by MIT, Harvard and its affiliated hospitals, and the visionary Los Angeles philanthropists Eli and Edythe L. Broad, the Broad Institute includes faculty, professional staff and students from throughout the MIT and Harvard biomedical research communities and beyond, with collaborations spanning over a hundred private and public institutions in more than 40 countries worldwide. For further information about the Broad Institute, go to www.broadinstitute.org. Contact: Marjorie Montemayor-Quellenberg |
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