By Brenda Dickinson
Anesthesiology research is advancing in new directions under the leadership of Ralph Lydic, Ph.D., Bert La Du Professor of Anesthesiology and Associate Chair for Research. In August of 1999, Dr. Lydic and Helen A. Baghdoyan, Ph.D. moved both of their research laboratories to U-M from The Pennsylvania State University. They were accompanied by three Ph.D. students, Jackie Vazquez, Diana Tanase, and Chris Douglas. Currently, the research leaders are recruiting students, technicians, and postdoctoral fellows interested in anesthesiology and neuroscience research.
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Left to Right: Renee Bernard, Daniela Hangan, |
Drs. Lydic and Baghdoyan each have ten year’s of experience in anesthesiology research at Penn State’s College of Medicine. Their funded research aims to understand how anesthetic and analgesic drugs eliminate consciousness, block perception of pain, and depress autonomic control. “A key programmatic goal,” Lydic said, “is to eliminate barriers and enhance interaction between basic and clinical research. This unified research initiative is consistent with the U-M Mission Statement and is essential for developing into one of the premier anesthesiology research programs in the country.” Their funded research from the National Institutes of Health (NIH) has demonstrated that natural sleep provides an important model for understanding the brain mechanisms by which consciousness is altered during anesthesia and sedation. “Sleep and anesthesia are distinctly different states but they share many similar traits,” Lydic said. “These trait similarities provide an important tool for understanding the brain basis of both sleep and anesthesia.”
A convenient overview of the scientist’s research is provided by their support from the NIH. Dr. Baghdoyan is in the 12th year of an National Institutes of Mental Health (NIMH) funded research program aiming to understand how the brain stem regulates levels of arousal. The focus of this research is on the neurotransmitter acetylcholine (ACh). Her studies involve characterizing ACh levels in specific brain regions during sleep and anesthesia. “These studies are providing new information on how sleep and different anesthetic molecules alter ACh levels. This neurotransmitter is known to be essential for maintenance of normal, waking consciousness,” Baghdoyan said. “This line of investigation also is directly relevant to the NIMH mission, because many disorders of mood are also accompanied by disorders of arousal state control. Understanding how the brain regulates arousal is providing insights into brain mechanisms regulating affective states.”
Lydic’s laboratory was the first to show that the same cholinergic mechanisms regulating sleep also can cause state- dependent respiratory depression. “Breathing is depressed during the loss of wakefulness produced by anesthesia and by natural sleep,” Lydic said. “This clinically significant problem is the basis for current funding by the National Heart, Lung, and Blood Institutes (NHLBI) to help elucidate the neuronal mechanism causing state-dependent respiratory depression. As a result of clinical and basic research, anesthesiology has made major advances in patient safety. Part of the art and science of modern anesthesiology involves knowing how to eliminate consciousness and perception of pain without depressing breathing. The NHLBI also has a keen interest in understanding why breathing is depressed during natural sleep. Current data suggest three to five percent of the population suffers from obstructive sleep apnea (OSA) syndrome. Affected individuals stop breathing up to 300 times a night and OSA has been associated with hypertension, stroke, and diminished quality of life. Interestingly, as with the anesthetized patient, OSA patients breath normally while awake.”
Drs. Lydic and Baghdoyan are co-principle investigators of an NHLBI funded research program focused on opioid-induced rapid eye movement (REM) sleep inhibition. Opioids continue to provide a major drug for clinical management of pain, but opioids, like general anesthetics, can have unwanted side effects. One such side effect is inhibition of REM sleep, the dreaming phase of sleep. “This unwanted side effect of opioids has been documented in the substance abuse literature since the 1960s but investigated in the context of anesthesiology only since the early 1990s,” Dr. Lydic said. “Understanding the mechanisms by which opioids inhibit sleep has particular relevance for anesthesiology. Sleep deprivation can contribute to postsurgical disorientation experienced by some older patients, and for all of us sleep deprivation is known to impair immune function. To date, this research program has identified brain regions and specific opioid receptors that can inhibit REM sleep.”
Since coming to the U-M, the scientists have been funded as co-investigators on a fourth NIH grant. The goal of this research program is to develop mouse models for studies of sleep and state-dependent respiratory depression. “The mouse genome is incredibly close to the human genome,” Dr. Lydic said, “and sleep is a quantitative phenotype regulated by many genes plus the environment. The mouse genome will be complete before the human genome, and mouse genetics continues to provide an important model for the exploding field of molecular medicine.” Dr. Baghdoyan added that there are strains of mice with enhanced or diminished sensitivity to anesthetics and there are certain sleep disorders which are known to have a genetic component. “Several genomic regions have been shown by quantitative trait loci (QTL) to regulate arousal state. Most recently, a gene has been identified that controls the expression of the sleep disorder narcolepsy in dogs and mice.” For Dr. Lydic, “One exciting goal of this research program is to provide phenotype characterization for neuronal systems known to regulate levels of arousal. Such data will be relevant for improved understanding of both sleep and anesthesia.”
One of the things that attracted the pair to the Department of Anesthesiology at the U-M is the potential for collaboration. “During our interviews we learned of ongoing anesthesiology research into the effects of surgery on blood-borne factors that alter autonomic control and on cytokines which are known to alter sleep. Anesthesiology research on conscious sedation relates in important ways to our pre-clinical studies of arousal state control, and we are particularly keen to interact with our anesthesiology colleagues who are studying opioids and pain,” Lydic said. They are interested in helping foster cross disciplinary collaborations. “The breadth of knowledge in anesthesiology provides a unique and privileged opportunity for collaborations that blur traditional boundaries. For example, anesthesia and analgesia are products of the nervous system. This fact provides a natural opportunity for interactions with neuroscience. Like the Departments of Pharmacology and Physiology, the neuroscience community at U-M has been very welcoming. We’ve already mentioned the relationship between anesthesia and sleep, and the U-M Department of Neurology has a world famous sleep disorders clinic and research facility,” Dr. Lydic said. “Anesthesiology research has the advantage of spanning from molecular to behavioral levels of analysis. This broad range of expertise encourages a diversified research portfolio and fosters a sense of respect for research of all flavors.” As for research in the department, Dr. Baghdoyan said, “We are here as a resource to help anesthesiology faculty and staff initiate new projects and direct them to funding opportunities that will promote their research.”
Drs. Lydic and Baghdoyan are building their laboratories at U-M during the day, and are building a life in Ann Arbor in the evenings. “We look forward to making new friends and having an opportunity to contribute to this special community,” Dr. Lydic said. They like the diversity of Ann Arbor and the wealth of educational opportunities. Their daughter, Lauren, completed the intensive Russian language program at U-M this summer before returning to Smith College where she is a sophomore.
Ralph Lydic, Ph.D., is Bert La Du Professor of Anesthesiology, Associate Chair for Research, and Professor of Physiology. He received his Ph.D. in Neurophysiology from the Texas Tech University School of Medicine in 1979, and is currently a member of the University of Michigan Neuroscience Program. His postdoctoral training at Harvard Medical School was supported by a National Research Service Award. From 1984 to 1986, he was an Assistant Professor of Physiology & Biophysics and Psychiatry at Harvard Medical School. From 1986 to 1989 he served as Associate Professor of Anesthesia and Director of Anesthesia and Neuroscience Research at The Pennsylvania State University College of Medicine. In 1991, Dr. Lydic became a Professor of Anesthesia, and in 1998 was awarded the first Julien F. Biebuyck endowed professorship in the Department of Anesthesia at Penn State’s College of Medicine. Current service activities include membership on the Respiratory and Applied Physiology review panel at the National Institutes of Health, and he is the president-elect of the U.S. Sleep Research Society.
Helen A. Baghdoyan, Ph.D., is Professor of Anesthesiology and Professor of Pharmacology at the University of Michigan. She also is a member of the Neuroscience Program. She received her Ph.D. in Neuropsycho-pharmacology in 1980 from The University of Connecticut. She was a National Institute of Mental Health (NIMH) Fellow in the Department of Psychiatry at Harvard Medical School from 1980 to 1984, and joined the faculty there in 1987 as Assistant Professor of Psychiatry (Neuroscience). She then moved to The Pennsylvania State University College of Medicine where she served as Associate Professor of Anesthesia and Pharmacology from 1993 until 1998. Dr. Baghdoyan was the first woman at Penn State’s College of Medicine to become a tenured Professor of Anesthesia. Her research has been supported by grants from the NIMH since 1989 and her current NIMH award will support her research through 2004. Dr. Baghdoyan serves as Chair of the National Institutes of Health Integrative, Functional, and Cognitive Neuroscience (IFCN-3) Grant Review Committee. In addition to their individual research programs, Drs. Lydic and Baghdoyan also have collaborative projects. Recently, they co-edited the 700 page “Handbook of Behavioral State Control: Cellular and Molecular Mechanisms,” published by CRC Press in 1999.
