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Imagine being in an accident that leaves you unable to feel any sensation in your arms and fingers. Now imagine regaining that sensation, a decade later, through a mind-controlled robotic arm that is directly connected to your brain.
That is what 28-year-old Nathan Copeland experienced after he came out of brain surgery and was connected to the Brain Computer Interface (BCI), developed by researchers at the University of Pittsburgh and UPMC. In a study published online today in Science Translational Medicine, a team of experts led by Robert Gaunt, PhD, assistant professor of physical medicine and rehabilitation at Pitt, demonstrated for the first time ever in humans a technology that allows Mr. Copeland to experience the sensation of touch through a robotic arm that he controls with his brain.
“The most important result in this study is that microstimulation of sensory cortex can elicit natural sensation instead of tingling,” said study co-author Andrew B. Schwartz, PhD, distinguished professor of neurobiology and chair in systems neuroscience, Pitt School of Medicine, and a member of the University of Pittsburgh Brain Institute. “This stimulation is safe, and the evoked sensations are stable over months. There is still a lot of research that needs to be carried out to better understand the stimulation patterns needed to help patients make better movements.”
This is not the Pitt-UPMC team’s first attempt at a BCI. Four years ago, study co-author Jennifer Collinger, PhD, assistant professor, Pitt’s Department of Physical Medicine and Rehabilitation, and research scientist for the VA Pittsburgh Healthcare System, and the team demonstrated a BCI that helped Jan Scheuermann, who has quadriplegia caused by a degenerative disease. The video of Scheuermann feeding herself chocolate using the mind-controlled robotic arm was seen around the world. Before that, Tim Hemmes, paralyzed in a motorcycle accident, reached out to touch hands with his girlfriend.
But the way our arms naturally move and interact with the environment around us is due to more than just thinking and moving the right muscles. We are able to differentiate between a piece of cake and a soda can through touch, picking up the cake more gently than the can. The constant feedback we receive from the sense of touch is of paramount importance as it tells the brain where to move and by how much.
For Dr. Gaunt and the rest of the research team, that was the next step for the BCI. As they were looking for the right candidate, they developed and refined their system such that inputs from the robotic arm are transmitted through a microelectrode array implanted in the brain where the neurons that control hand movement and touch are located. The microelectrode array and its control system, which were developed by Blackrock Microsystems, along with the robotic arm, which was built by Johns Hopkins University’s Applied Physics Lab, formed all the pieces of the puzzle.
In the winter of 2004, Mr. Copeland, who lives in western Pennsylvania, was driving at night in rainy weather when he was in a car accident that snapped his neck and injured his spinal cord, leaving him with quadriplegia from the upper chest down, unable to feel or move his lower arms and legs, and needing assistance with all his daily activities. He was 18 and in his freshman year of college pursuing a degree in nanofabrication, following a high school spent in advanced science courses.
He tried to continue his studies, but health problems forced him to put his degree on hold. He kept busy by going to concerts and volunteering for the Pittsburgh Japanese Culture Society, a nonprofit that holds conventions around the Japanese cartoon art of anime, something Mr. Copeland became interested in after his accident.
Right after the accident he had enrolled himself on Pitt’s registry of patients willing to participate in clinical trials. Nearly a decade later, the Pitt research team asked if he was interested in participating in the experimental study.
After he passed the screening tests, Nathan was wheeled into the operating room last spring. Study co-investigator and UPMC neurosurgeon Elizabeth Tyler-Kabara, MD, PhD, assistant professor, Department of Neurological Surgery, Pitt School of Medicine, implanted four tiny microelectrode arrays each about half the size of a shirt button in Nathan’s brain. Prior to the surgery, imaging techniques were used to identify the exact regions in Mr. Copeland’s brain corresponding to feelings in each of his fingers and his palm.
“I can feel just about every finger—it’s a really weird sensation,” Mr. Copeland said about a month after surgery. “Sometimes it feels electrical and sometimes its pressure, but for the most part, I can tell most of the fingers with definite precision. It feels like my fingers are getting touched or pushed.”
At this time, Mr. Copeland can feel pressure and distinguish its intensity to some extent, though he cannot identify whether a substance is hot or cold, explains Dr. Tyler-Kabara.
Michael Boninger, MD, professor of physical medicine and rehabilitation at Pitt, and senior medical director of post-acute care for the Health Services Division of UPMC, recounted how the Pitt team has achieved milestone after milestone, from a basic understanding of how the brain processes sensory and motor signals to applying it in patients
“Slowly but surely, we have been moving this research forward. Four years ago we demonstrated control of movement. Now Dr. Gaunt and his team took what we learned in our tests with Tim and Jan—for whom we have deep gratitude—and showed us how to make the robotic arm allow its user to feel through Nathan’s dedicated work,” said Dr. Boninger, also a co-author on the research paper.
Dr. Gaunt explained that everything about the work is meant to make use of the brain’s natural, existing abilities to give people back what was lost but not forgotten.
“The ultimate goal is to create a system which moves and feels just like a natural arm would,” says Dr. Gaunt. “We have a long way to go to get there, but this is a great start.”
The lead author on the research publication is Sharlene N. Flesher, of Pitt. Additional authors on this research are Stephen T. Foldes, PhD, Jeffrey M. Weiss and John E. Downey, all of Pitt; and Sliman J. Bensmaia, PhD, of the University of Chicago.
Primary support for the study was provided by the Defense Advanced Research Projects Agency’s (DARPA) Revolutionizing Prosthetics program through contract N66001-10-C-4056. Additional support was provided by the Office of Research and Development, Rehabilitation Research and Development Service, US Department of Veterans Affairs, grant numbers B6789C, B7143R, and RX720 and the National Science Foundation Graduate Research Fellowship grant DGE-1247842.
Physicians and Researchers Present at the American Academy of Ophthalmology (AAO) 2016 Annual Meeting
The UPMC Department of Ophthalmology will be well-represented at the Academy of Ophthalmology (AAO) 2016 Annual Meeting in Chicago. Faculty research will be featured in both oral and poster presentations throughout the conference, including:
Friday, October 14, 2016
- Infectious Keratitis After Laser Vision Correction: How to Prevent and Treat
Presented by: Deepinder Dhaliwal, MD
- Time-Kill Comparison of Povidone Iodine to Hypochlorous Acid against Endophthalmitis Isolates of Staphylococci
Presented by: Matthew Klocek, MD
- Release of Moxifloxacin from Corneal Collagen Shields
Presented by: Siwei Zhou, MD
- A Single Thermo-Responsive Drop Containing Microspheres Loaded with Moxifloxacin Prevents Endophthalmitis in Rabbit Model
Presented by: Eric Romanowski, MS
- Serratia marcescens Induced Corneal Epithelial Cell Blebs are Mediated by a Type V Secretion System
Presented by: Robert MQ Shanks, PhD
- Insight into the Corneal Wound Healing Response: Transcriptomic and Metabolomic Analysis of Corneal Epithelial Cells Challenged by Bacteria
Presented by: Kimberly Brothers, PhD
- Virucidal Activity of Purell Hand Sanitizer against Adenovirus in vitro
Presented by: Jason Hooten, MD
Saturday, October 16, 2016
- The Case of Infectious Keratitis That Wouldn’t Go Away
Presented by: Deepinder Dhaliwal, MD
- Innovations in Glaucoma Care: Evolution & Revolution
Presented by: Nils Loewen, MD
Presented by: Andrew Eller, MD
Sunday, October 17, 2016
- How to Use OCT in Neuro-Ophthalmology
Presented by: Gabrielle Bonhomme, MD
- Advanced Suturing: Scleral and Iris Fixation of Posterior Chamber IOLs plus Intraocular Knot Tying
Presented by: Deepinder Dhaliwal, MD
- Evaluation of a New Technique of Simple Infrared-Augmented Digital Photography
Presented by: Tarek Shazly, Gabrielle Bonhomme, MD
- Trabectome-Mediated Ab Interno Trabeculectomy Combined with Baerveldt Implantation Compared to Baerveldt Tube Shunt Alone
Presented by: Nils Loewen, MD
- DMEK Demonstration for SightLife
Presented by: Deepinder Dhaliwal, MD
- Myth-Busting in Refractive and Cataract Surgery
Presented by: Deepinder Dhaliwal, mD
- Pearls for Pragmatic Microbiology in your 21st century ophthalmology practice
Presented by: Deepinder Dhaliwal, MD (senior instructor), Alex Mammen, MD, Joseph Martel, MD Ladan Espandar, MD, Rege Kowalski, MS
Monday, October 18, 2016
- AmpliVue: A New, Practical and Timely Diagnostic Test for Detecting Herpes Simplex Virus from Ocular Specimens
Presented by: Rege Kowalski, MS
- Endophthalmitis Prosphylaxis Using a Single Drop of Controlled Release Microspheres Loaded with Moxifloxacin in a Rabbit Model
Presented by: Rege Kowalski, MD, Alex Mammen, MD
- Ab Interno Approach to Schlemm Canal
Presented by: Nils Loewen, MD
- Phacoemulsification & Advanced Techniques
Presented by: Deepinder Dhaliwal, MD
Tuesday, October 19, 2016
- Advanced Refractive Cataract Surgery
Presented by: Deepinder Dhaliwal, MD
- Ab Interno Approach to Schlemm Canal
Presented by: Nils Loewen, MD
Renowned breast cancer researcher Adrian Lee, PhD, has been named director of the Institute for Precision Medicine (IPM), a joint effort by UPMC and the University of Pittsburgh to move biomedical research into personalized well-being and clinical care.
Dr. Lee, a professor in the Department of Pharmacology and Chemical Biology at Pitt, and director of the Women’s Cancer Research Center, University of Pittsburgh Cancer Institute, noted that the over-arching goal of the IPM is to help researchers and clinicians discover features about an individual’s risk of disease, select best treatments, predict most likely response, and move these insights into clinical practice. “Our approach is aimed at answering the most important question about precision medicine—that is, under what circumstances do these insights lead to better patient outcomes and reduced health care costs?” he said.
In addition to studying the hormonal regulation of breast cancer, Dr. Lee is part of the team working to implement the technology infrastructure needed for precision medicine. He succeeds Associate Vice Chancellor Jeremy Berg, Ph.D., who will remain as a senior adviser to the IPM, founded in 2013 and formerly known as the Institute for Personalized Medicine.
Under Dr. Lee, the IPM will build on a host of precision medicine efforts already underway at Pitt and UPMC, including implementation of new clinical trials and procurement of significant National Institutes of Health (NIH) and state funding.
In July, the NIH announced an award, led by Pitt’s Clinical and Translational Science Institute, that could top $46 million over five years to build the infrastructure and partnerships needed to launch the Cohort Program of President Obama’s Precision Medicine Initiative—a landmark effort to engage more than 1 million U.S. participants in providing clinical, genomic and other data that could lead to new ways of preventing and treating disease.
An example of the early progress in precision medicine at Pitt and UPMC is screening certain cardiac patients to see if they have a gene variant that makes them less likely to respond to a blood-thinning medication commonly prescribed after a stent implant. The aim is to use the pharmacogenomic test results to reduce a patient’s chances of recurrent clots and returning to the hospital.
“Pitt and UPMC are in a unique position to capitalize upon the research and clinical expertise in Pittsburgh and to lead the nation in precision medicine,” said Arthur S. Levine, MD, Pitt’s senior vice chancellor for the health sciences and John and Gertrude Petersen Dean of the School of Medicine. “Under Adrian’s leadership, the IPM will help to ensure the continued development of innovative research programs, efforts to reduce administrative and regulatory barriers, and the education of physicians in the area of personalized medicine.”
Potential IPM initiatives over the next five years include:
• Building upon current Pitt and UPMC efforts to share clinical, tissue and genomic data, enabling researchers to perform precision medicine research. The IPM also will seek out new ventures with companies and other academic centers to expand data sharing nationally.
• Positioning Pitt and UPMC for future federal and commercial precision medicine efforts. The IPM will work with the Pittsburgh Health Data Alliance —backed by UPMC, Pitt and Carnegie Mellon University—and UPMC Enterprises, the commercialization arm of UPMC, to coordinate and help fund precision medicine research.
• Leveraging clinical data and tissue collections at Pitt and UPMC. For instance, large-scale machine learning will be used on more than 288,000 unique cases in the UPMC Cancer Registry to identify predictors of disease prognosis and outcomes.
• Developing education programs and policy in precision medicine, including expansion of the role of genetic counselors.
• Facilitating the testing of precision medicine in clinical trials. This work will be integrated with studies of patient-reported outcomes and health costs to help develop new models of care.
The immunotherapy nivolumab significantly increases survival and causes fewer adverse side-effects in patients with recurrent head and neck cancer, according to a randomized trial co-led by investigators at the University of Pittsburgh Cancer Institute (UPCI), partners with UPMC CancerCenter.
The results of the international CheckMate-141 phase III clinical trial were reported Sunday in the New England Journal of Medicine, following preliminary presentations at the annual American Society of Clinical Oncology and American Association for Cancer Research meetings earlier this year. Patients on nivolumab were doing so much better than those receiving standard therapy that the trial was stopped early to allow all patients to receive it.
“Due to our clinical trial, anti-PD-1 therapies like nivolumab are now the recommended treatment for patients with this very difficult, devastating cancer,” said lead author and trial co-chair Robert Ferris, MD, PhD, UPMC Endowed Professor, and chief of the Division of Head and Neck Surgery and co-leader of the Cancer Immunology Program at UPCI.
Worldwide, more than 600,000 cases of squamous-cell carcinoma of the head and neck are diagnosed annually, and the cancer recurs in more than half the patients within three years. The cancer typically returns because it has evaded the immune system and become resistant to chemotherapy.
Alcohol and tobacco use are the two main risk factors for head and neck cancers. Infection with the human papillomavirus (HPV) also is a risk factor, and rates of head and neck cancer attributable to HPV infection have increased 250 percent over the past several decades.
Nivolumab, which belongs to a class of drugs known as immunotherapeutics, enables the body’s immune system to destroy cancer cells. It currently is approved to treat certain types of cancers, including melanoma and lung cancer.
The CheckMate-141 trial enrolled 361 patients receiving care at 64 locations worldwide for recurrent head and neck cancer that had progressed within six months of chemotherapy. From June 2014 through August 2015, the researchers randomly assigned 240 patients to receive nivolumab and 121 to receive standard therapy, which consisted of one of three chemotherapy drugs.
On average, the patients on nivolumab survived 7.5 months, versus 5.1 months for the patients on standard therapy. At one year, 36 percent of the nivolumab patients were still living, compared with 16.6 percent of the standard-care patients.
Additionally, only 13.1 percent of the patients receiving nivolumab suffered serious, quality-of-life-disrupting side effects of the treatment, compared with 35.1 percent of those receiving standard therapy.
“It is wonderful news that we have a new, better option for patients with recurrent head and neck cancer,” said Dr. Ferris. “But for the vast majority of patients, nivolumab isn’t a cure and more research is needed to find one. Perhaps even more important, we need to prevent this cancer from ever occurring. We have to help people to stop smoking or chewing tobacco, and encourage them to never start. We also need to continue to encourage children to be vaccinated against HPV.”
The trial’s other co-chair is Maura Gillison, MD, PhD, from Ohio State University. Additional US institutions that participated in the trial include University of Texas MD Anderson Cancer Center, Stanford Cancer Institute, University of Chicago, University of Michigan, Emory University, Dana-Farber Cancer Institute and Bristol-Myers Squibb.
International collaborators are located at Centre Leon Berard, Centre Antoine Lacassagne, and Institut Gustave Roussy, all in France; Fondazione IRCCS Istituto Nazionale Tumori, in Italy; The Institute of Cancer Research, in the United Kingdom; University Hospital Essen, in Germany; Hospital Universitario 12 de Octubre, in Spain; University Hospital Zurich, in Switzerland; and National Cancer Center Hospital East and Kobe University Hospital, both in Japan.
The trial was funded by Bristol-Myers Squibb, which is now seeking US Food and Drug Administration approval for the use of nivolumab in head and neck carcinoma.
Stanley Marks, MD, a leading UPMC oncologist and advocate for cancer patients throughout the western Pennsylvania region, was honored by UPMC and his medical partners at Oncology Hematology Association (OHA) through the establishment of the Stanley M. Marks – OHA Endowed Chair in Hematology/Oncology Leadership.
Every one of his 48 partners at OHA, a UPMC-owned practice, financially committed to create this chair, which also was supported by UPMC, for a total of $2.2 million.
The permanent endowment will support the recruitment and retention of outstanding leaders in the University of Pittsburgh Division of Hematology/Oncology. It also will help to train professionals devoted to research and improved treatments for patients.
Dr. Marks has directed and overseen the continued growth and success of the UPMC CancerCenter, a partner with the University of Pittsburgh Cancer Institute and now one of the largest cancer care networks in the nation.
“None of this would have been possible without the support of my colleagues and UPMC,” said Dr. Marks. “This endowment will enable us to recruit a medical and scientific star, ultimately leading to better care for our patients.”
Added Barry Lembersky, MD, “Through his decades-long leadership of OHA and the UPMC CancerCenter, Stan has made a significant impact on cancer care and research in our region and beyond. All of the physicians in OHA wish to honor his outstanding contributions and provide a legacy to benefit patients for generations to come.”
Dr. Marks serves as chairman of UPMC CancerCenter, chief of the Division of Hematology and Oncology at UPMC Shadyside, and as a clinical professor of medicine at the University of Pittsburgh School Of Medicine. He also has been named consistently as one of the “Top Physicians in Pittsburgh” and “Best Doctors of America” in hematology and medical oncology by Best Doctors®.
Quest to Cure Blindness: Pitt, UPMC Recruit World-Renowned Expert in Research and Therapies for Blindness and Vision Impairment
PITTSBURGH, Oct. 5, 2016 – One of the world’s top experts in retinal diseases, who is developing an artificial retina as well as other regenerative therapies to treat blindness and vision impairments, has been named as the chair of the Department of Ophthalmology at the University of Pittsburgh School of Medicine, director of the UPMC Eye Center, and the Eye and Ear Foundation Chair of Ophthalmology.
José-Alain Sahel, M.D., founder and director of the Vision Institute in Paris and currently a professor at the Sorbonne’s medical school Université Pierre-et-Marie-Curie, has joined UPMC and Pitt’s faculty.
Dr. Sahel is known worldwide for his expertise in vision restoration techniques. He has developed several interventions— including stem cell implantation, gene therapy, innovative pharmacologic approaches and the artificial retina—for retinitis pigmentosa, age-related macular degeneration, vascular eye disease and other vision impairments that currently are untreatable. Over the past decade he has led pioneering efforts in optogenetic vision restoration, a technique in which cells in the retina are genetically modified to express light sensitive proteins. This therapeutic technique has the potential to help patients who are blind or visually impaired as a result of a genetic defect.
He also brings a strong neuroscience perspective to ophthalmology research, such as exploring the application of brain-computer interface technology, for which Pitt and UPMC are well known.
“We are delighted that Dr. Sahel has chosen to bring his remarkable talent to UPMC where he will, with immediacy, translate laboratory advances into treatment for patients with visual impairment,” said Steve Shapiro, M.D., chief medical and scientific officer at UPMC. “His creativity and commitment to bringing everything from rigorous basic science to eyesight-saving surgery to patient care are unparalleled. With his leadership, we expect to build on the amazing accomplishments he already has achieved in Paris as well as break new ground in vision research and care.”
“Dr. Sahel is a gifted physician-scientist with a heartfelt dedication to his patients and a broad intellectual reach. His work will soon have great impact on the ophthalmology department, on bench-to-bedside treatments for patients, and also on Pitt as a whole,” said Arthur S. Levine, M.D., Pitt’s senior vice chancellor for the health sciences and John and Gertrude Petersen Dean of Medicine.
Dr. Sahel will sustain his engagement with the Vision Institute, one of the world’s largest centers of integrated research on eye diseases, through a partnership formed between the Institute, the Sorbonne, Pitt School of Medicine and UPMC.
“I am very impressed with the strong support and energy at UPMC and Pitt, and share their objectives of developing creative new treatments and diagnostic tools to better serve patients,” Dr. Sahel said. “It was clear to me during my visits that the community is warm and welcoming, and rightfully proud of its city. I look forward to contributing to these impressive academic and health care legacies.”
As director of UPMC Eye Center, which is rated among the top ophthalmology programs in the United States in the delivery of care, Dr. Sahel will see patients, particularly those with complex diseases, and will lead UPMC clinicians in the diagnosis and treatment of both common and unusual eye disorders. The UPMC Eye Center is home to an outstanding ophthalmology teaching program that trains residents and clinical fellows in their pursuit of clinical, research and clinician-scientist careers.
Dr. Sahel is a co-inventor on more than 40 patents, several of which have led to start-up companies including Fovéa Inc., which Dr. Sahel founded and later became the Ophthalmologic Division of Sanofi Aventis. He also is a scientific co-founder of GenSight Biologics Inc. and Pixium Vision Inc. He is a member of 11 editorial boards, including the Journal of Clinical Investigation and Science Translational Medicine.
He also holds the positions of Cumberlege Professor of Biomedical Sciences at the Institute of Ophthalmology, University College London, and chairman of the Departments of Ophthalmology at the Quinze-Vingts National Eye Hospital and at the Rothschild Ophthalmology Foundation, both in Paris. At the Paris-based Ophthalmology Clinical Investigation Center, he oversees more than 50 clinical trials, many of which are focused on retinal implants, gene therapy and other advanced biomedical technologies. He also heads the French National Reference Center for Retinal Dystrophies and chairs a network of more than 90 European clinical trial centers focused on retinal diseases.
He has been the recipient of numerous honors and awards, which include membership in the Legion of Honour (2008); the National Order of Merit (2002) and induction into the Collège de France, the highest honor awarded to a French scientist. He is an elected member of the Académie des sciences-Institut de France, the Académie des technologies, the Academia Ophthalmologia Internationalis and the German National Academy of Sciences. He has also received the Grand Prix for Neurosciences of the Foundation NRJ, Institut de France; the CNRS Medal of Innovation; the Foundation for Fighting Blindness Trustee Award and the Liura Liggett-Gund Award, among others. Dr. Sahel holds an honorary degree from the University of Geneva.
Dr. Sahel, who was born in Algeria, studied medicine at Strasbourg University and in Lariboisière, Saint-Louis. He received his medical degree with a Medal of the Faculty of Paris and obtained his specialty certification in ophthalmology. He completed a residency in neurology and neurosurgery at the Louis Pasteur University Hospital in Strasbourg. He also was a research fellow at the Massachusetts Eye and Ear Infirmary and a visiting scholar in the Department of Molecular and Cellular Biology at Harvard University.
The UPMC Heart and Vascular Institute has named Louis Russo, MD, clinical assistant professor of cardiothoracic surgery at the University of Pittsburgh School of Medicine, as its new director of cardiac surgery at UPMC Altoona. The new role is a homecoming for Dr. Russo, who was raised in Altoona.
“Altoona has always been the place I consider home,” said Dr. Russo, who has enjoyed spending time in Altoona on a regular basis since leaving as a young man. “My parents and many friends still live here, and now I’m back. As a homegrown surgeon from Pennsylvania, I am looking forward to providing excellent care for patients in my hometown.”
A graduate of Penn State University and board certified in general and cardiothoracic surgery, Dr. Russo earned his medical degree from Thomas Jefferson University Medical College in Philadelphia before completing his residency at Allegheny General Hospital in Pittsburgh. He previously served as director of the Ventricular Assist Device Program at Maine Medical Center, and has served as the principal investigator and co-investigator on several clinical trials. His clinical practice includes all aspects of adult cardiac surgery.
Dr. Russo joined the UPMC family in 2013 and has been caring for patients at UPMC Hamot in Erie, Pennsylvania. There, he served as vice-chairman of the Department of Cardiovascular Medicine and Surgery.
“Dr. Russo has been part of UPMC’s world-class cardiac surgery program for more than three years and has headed up UPMC Hamot’s quality efforts during that time,” said Jerry Murray, president of UPMC Altoona. “He is a seasoned surgeon who will provide a clinical connection between Pittsburgh and Altoona, and we’re confident he’ll build on the successes he had at UPMC Hamot.”
UPMC Altoona offers a wide spectrum of state-of-the-art cardiac surgery, including the latest techniques in surgical treatment of coronary artery disease and valvular heart disease. This includes coronary artery bypass grafting; aortic, mitral and tricuspid valve replacement; and repairs of mitral and tricuspid valves. In collaboration with the cardiologists from the UPMC Heart and Vascular Institute, Dr. Russo will also offer advanced anti-arrhythmic surgery.
The UPMC Heart and Vascular Institute is one of the world’s premier centers for comprehensive care, developing revolutionary devices and new models of treatment that improve the lives of those facing the most complex heart and vascular conditions.
Identifying and treating metabolic deficiencies in patients with treatment-resistant depression can improve symptoms and in some cases even lead to remission, according to new research from the University of Pittsburgh School of Medicine published online today in the American Journal of Psychiatry.
“What’s really promising about these new findings is that they indicate that there may be physiological mechanisms underlying depression that we can use to improve the quality of life in patients with this disabling illness,” said David Lewis, MD, Thomas Detre Professor and Chair of Pitt’s Department of Psychiatry.
Major depressive disorder, also referred to simply as depression, affects nearly 15 million American adults and is one of the most common mental disorders. Unfortunately, at least 15 percent of patients don’t find relief from conventional treatments such as antidepressant medications and psychotherapy, explained lead study investigator Lisa Pan, MD, professor of psychiatry, and clinical and translational science, Pitt School of Medicine. Depression also is the cause of more than two-thirds of suicides that occur annually.
The groundwork for the current study was laid five years ago when Dr. Pan and David Brent, MD, Endowed Chair in suicide studies at Pitt, treated a teen with a history of suicide attempts and long-standing depression. “Over a period of years, we tried every treatment available to help this patient, and yet he still found no relief from his depression symptoms,” she explained.
Searching for answers, Dr. Pan contacted Jerry Vockley, MD, PhD, chair of genetics, Children’s Hospital of Pittsburgh of UPMC, and David Finegold, MD, professor of human genetics at Pitt’s Graduate School of Public Health, and through a series of biochemical tests, the three discovered that the patient had a cerebrospinal fluid deficiency in biopterin, a protein involved in the synthesis of several brain signaling chemicals called neurotransmitters.
After receiving an analogue of biopterin to correct the deficiency, the patient’s depression symptoms largely disappeared and today he is a thriving college student.
The success prompted the researchers to examine other young adults with depression who were not responding to treatment, explained Dr. Pan.
In the published trial, the researchers looked for metabolic abnormalities in 33 adolescents and young adults with treatment-resistant depression and 16 controls. Although the specific metabolites affected differed among patients, the researchers found that 64 percent of the patients had a deficiency in neurotransmitter metabolism, compared with none of the controls.
In almost all of these patients, treating the underlying deficiency improved their depression symptoms, and some patients even experienced complete remission. In addition, the further along the patients progress in the treatment, the better they are getting, Dr. Pan added.
“It’s really exciting that we now have another avenue to pursue for patients for whom our currently available treatments have failed. This is a potentially transformative finding for certain groups of people with depression,” said Dr. Pan.
Additional collaborators on the study are Jerry Vockley, MD, PhD, David Brent, MD, David Finegold, MD, David Peters, PhD, Petra Martin, BS, Thomas Zimmer, BS, Anna Maria Segreti, BS, Sivan Kassiff, BS, Brian McKain, RN, MSN, Cynthia Baca, RN, MSN, Manivel Rengasamy, MD, Nicolette Walano, MS, Marion Hughes, MD, Steven Dobrowolski, PhD, Michele Pasquino, BS, Rasim Diler, MD, and James Perel, PhD, all of Pitt School of Medicine; Robert Naviaux, MD, PhD, of University of California, San Diego; Keith Hyland, PhD, of MNG Laboratories in Atlanta, Georgia; and Robert Steinfeld, MD, of University Medical Center Gottingen in Germany.
This research also was supported by funding from the American Foundation for Suicide Prevention and a Brain and Behavior Research Foundation NARSAD Young Investigator Award. Additional funding from the Beck and Lohman families through the Children’s Hospital of Pittsburgh Foundation is supporting the testing and follow up of additional patients with treatment-resistant depression and suicidal behavior, and allowing the researchers to begin to understand the underlying biological changes.
The high productivity of the University of Pittsburgh’s Vaccination Research Group (PittVax) earned the program a $5.5 million, five-year renewal from the US Centers for Disease Control and Prevention (CDC) to continue evaluation of the annual influenza vaccine and, once licensed, the respiratory syncytial virus (RSV) vaccine. The PittVax team collaborates with investigators in Pitt’s schools of Medicine and Public Health and across UPMC, including Children’s Hospital of Pittsburgh.
Starting in 2011, PittVax became one of five US Influenza Vaccine Effectiveness Network sites that provide data and analysis needed for public health officials to make or adjust recommendations for vaccination, antiviral and other treatments. PittVax is directed by Richard K. Zimmerman, MD, MPH, professor, and Tricia Nowalk, PhD, RD, associate professor, both in Pitt School of Medicine’s Department of Family Medicine.
“The information we collect and share is one of the primary data sources that the CDC uses in setting its vaccination policies and recommendations for clinicians treating patients in any given flu season,” said Dr. Zimmerman, also professor in the Pitt Graduate School of Public Health’s Department of Behavioral and Community Health Sciences. “In past years, we’ve given the evidence needed to prompt earlier and more widespread use of flu antiviral drugs. This season, our work has led to the recommendation to discontinue nasal spray flu vaccine because it has not been effective at preventing type A flu.”
The Pittsburgh site collects data from hundreds of patients seen at UPMC outpatient facilities with symptoms of an acute respiratory infection who consent to participate. They are tested to determine if they have flu or another illness, such as RSV, or simply a cold. The researchers also confirm whether or not the participants were immunized against flu earlier in the season and conduct a follow-up survey on participants’ recovery.
In the past five years, PittVax participants had the highest follow-up survey completion rate of any of the other sites and higher enrollment rates than required, with well over the 1,100 necessary participants annually. The program is supported by ongoing outbreak surveillance at six UPMC sites, with more than 14,000 respiratory virus tests performed each flu season.
These data allow PittVax and the other sites to determine if the flu vaccine—which is designed to work against the three or four strains of flu that the World Health Organization predicts most likely to be circulating when the flu vaccine is manufactured, months before flu season actually starts—is effective against whatever strains of flu ultimately circulate.
Last season, the flu vaccine was nearly 60 percent effective, which means that the chances someone vaccinated against flu would get sick with the virus were less than half the chances of illness in someone who didn’t get the flu vaccine. In the 2014-2015 season, the vaccine was only 23 percent effective, the lowest in nearly a decade, but still offered considerably more protection against flu than not being vaccinated. On average, the vaccine is about 50 to 60 percent effective.
Based on data collected from 2015 to 2016 by PittVax and other sites, the nasal spray flu vaccine often offered to children was found to be only 3 percent effective, and the CDC’s Advisory Committee on Immunization Practices recommended it not be offered this season, instead recommending the traditional influenza vaccination with a needle for everyone six months and older.
In the event of a flu pandemic—when a new strain of flu to which people have little existing immunity emerges and spreads globally—PittVax will be prepared to collect respiratory samples and conduct studies estimating how many people are affected and how well antivirals or existing flu vaccines work against it.
New with this grant, PittVax also will be prepared to collect and provide data and analysis on the effectiveness of the RSV vaccine, which is expected to be offered to older adults within the next five years, if clinical trials go well.
In his decades as a physician and family medicine and public health scientist, Dr. Zimmerman unequivocally recommends the flu vaccine for everyone included in the CDC policy.
“I’m vaccinated, my wife’s vaccinated, the kids at home are vaccinated, and I tell all my patients who should be vaccinated to get it,” said Dr. Zimmerman. “It is the single best way to avoid getting and spreading the flu, which is a deadly illness.”
PittVax is funded by CDC grant 1U01IP001035.