University of Tennessee College of Medicine Knoxville

The mission of the Anesthesiology Research Division is to advance basic and clinical research aiming to enhance understanding of anesthetic mechanisms and improve clinical care. The Anesthesiology Research Division invites active interaction with the clinical faculty and residents in the Department of Anesthesiology, the medical center, the main campus and Oak Ridge National Laboratory. The division provides the bench laboratory skills and equipment to facilitate clinical research projects.

Neuropharmacology of Sleep and Anesthesia

About Helen Baghdoyan, Ph.D.

My desire for a career in neuroscience was kindled at the Jackson Laboratory in Bar Harbor, Maine where I won an undergraduate student research scholarship. Once I realized that chemistry and biology could be used to understand the brain basis of behavior, I knew that I would devote my research career to neuroscience. During my postdoctoral and junior faculty years at Harvard Medical School I studied the neurochemical mechanisms that regulate normal behavioral states such as sleep and wakefulness. These studies, and my position in the Department of Psychiatry, led me to an interest in disorders of mood and cognition. My professorial appointments in anesthesiology at the medical schools of Pennsylvania State University and the University of Michigan encouraged me to extend my research to altered states of consciousness caused by anesthetic drugs. The National Institute of Mental Health recognizes the relevance of these studies and has provided continuous funding for my research since 1989. My appointments as Professor of Anesthesiology, Professor of Psychology, and Beaman Professor, combined with a joint appointment at Oak Ridge National Laboratory provide a unique opportunity to advance a mechanistic understanding of naturally occurring and drug-induced states of consciousness.

Why This Matters

Disturbed sleep is a characteristic of major mental illnesses, and sleep disruption worsens psychiatric symptoms. This relationship implies the existence of common neurobiological mechanisms regulating sleep, thought processes, and affect. Anesthetics are used safely but the mechanism by which they produce a loss of consciousness and protection from the trauma of pain remains one of the great, unanswered questions in biomedical research.

These nine drawings representing the human brain schematize behavioral-state-specific and brain-region-specific changes in chemical transmission in two brain regions, the cerebral cortex and the pontine reticular formation. Colored lines represent projections from three distinct groups of chemically coded brain nuclei: monoaminergic (red), cholinergic (green), and GABAergic (blue). The density of the colored dots located at the schematized neuronal terminals ( —< ) indicates that neurotransmitter levels vary in a state-specific and brain-region-specific manner. For example, at the top of the brain, in the cortex, levels of monoamines (such as norepinephrine and serotonin) are greatest during wakefulness, lower during the non-rapid eye movement (NREM) phase of sleep, and lowest during the dreaming, or rapid eye movement (REM) phase of sleep. In contrast, acetylcholine levels (green dots) in the cortex are greatest during wakefulness and REM sleep, whereas cortical levels of GABA (blue dots) are greatest only during NREM sleep. The ability to generate normal sleep cycles is fundamentally important for health, and understanding the neurochemical regulation of sleep contributes to advances in sleep disorders medicine and the mechanisms by which general anesthetics causes a loss of waking consciousness. Abbreviations: BF, basal forebrain; DR, dorsal raphé nucleus; LC, locus coeruleus; LDT-PPT, laterodorsal and pedunculopontine tegmental nuclei; PHA, posterior hypothalamic area; PRF, pontine reticular formation; SC, spinal cord; Th, thalamus; VLPAG, ventrolateral periaqueductal gray. (from: Baghdoyan and Lydic, The neurochemistry of sleep and wakefulness. In: Basic Neurochemistry, edited by ST Brady, RW Albers, DL Price, and GJ Siegel. Elsevier, pp 982-999, 2012.)


Blood and Blood Coagulation

Anesthesiologists know blood, inside and out. They administer more blood to patients than any other group of medical specialists. For a decade, anesthesiologists at the UT Graduate School of Medicine have researched platelet and whole blood functions to find better care for their patients. Recently, a collaborative team led by Robert M. Craft, M.D., Professor and Residency Program Director in the Department of Anesthesiology, has been investigating blood coagulation in a variety of clinical situations.

"Traditional tests examine the coagulation properties of blood's individual components but not how they work together," Craft says. "The coagulation cascade cannot be adequately assessed by isolating the parts." The team, which also includes Russell Langdon M.D., is utilizing a process called thromboelastography (TEG) that determines the rigidity of whole blood during coagulation. "TEG can tell us which aspect of the coagulation cascade is at fault and allows us to get these assessments in real time," Craft explains. Specifically, TEG is currently being utilized by the Anesthesiology lab to study coagulation disorders in stroke and trauma patients.

Why This Matters

"Our care affects all branches of medicine, so our research reflects this," Craft says of the collaborative spirit evident in the diversity of research in his department.

Physicians must understand the actions and reactions of blood during medical procedures, and collaborative research led by anesthesiologists will bolster that understanding to bring about improved patient safety, better care and more promising outcomes. Specifically, the current projects are designed to help predict and prevent complications from stroke, as well as better treat the bleeding disorders associated with traumatic injury.

These research endeavors assist in the training of tomorrow's clinician researchers as well as maintaining the state of the art knowledge of the clinical staff. The projects also provide training for pre and post-doctoral students interested in careers in biomedical research. Support for these research projects is funded by the T.K. Beene Anesthesiology Gift Fund.


Sleep, Cognition, and Neuropsychiatric Disorders

The Sleep, Cognition, and Neuropsychiatric Disorders research effort is led by Subimal Datta, Ph.D. Dr. Datta’s research combines interests in cellular and molecular mechanisms underlying basic sleep-wake processes, consciousness, learning and memory, and pathophysiology of a number of neuropsychiatric disorders (e.g., anxiety, depression and addiction). Cutting edge multidisciplinary approaches (anatomical, physiological, pharmacological, and cellular and molecular techniques) are being used to study these neurobiological mechanisms in freely behaving rats.

Dr. Datta’s research on basic mechanisms of sleep-wake behavior is focused on identifying specific brain areas, cell types, neurotransmitter receptors, intracellular signaling systems, and genes that are critical for the regulation of rapid eye movement (REM) sleep and dreaming. Based on experimental evidence, he developed the “Cellular-Molecular-Network” model of REM sleep regulation. This model not only explains the neurobiological mechanisms of REM sleep, but also identifies possible mechanisms of consciousness and dreaming. The ultimate goal of this research is to understand the basic mechanisms of consciousness and sleep regulation and thereby find causes and cures for sleep disorders. Future research of Dr. Datta will explore how different anesthetics can be used safely to understand the cellular and molecular mechanisms of consciousness.

Why This Matters

Normal sleep architecture is critical for psychological and emotional well being. Disrupted sleep architecture is a hallmark feature of many psychiatric disorders, including Post-Traumatic-Stress-Disorder (PTSD) and depression. Dr. Datta’s research on pathophysiological mechanisms among PTSD, depression, and sleep architecture disturbances in animal model is key to the development of rational behavioral and pharmacological therapies for these persistent and debilitating disorders in human.

Sleep confers a beneficial effect on learning and memory. Dr. Datta’s pre-clinical research is exploring how the stages of sleep are involved in different stages of memory formation. One of his key discoveries is that activation of a small group of glutamatergic cells in the brainstem is critical for memory consolidation, one of the major steps of long-term memory formation. Dr. Datta believes the continued progress of this work will be important in the development of behavioral and pharmacological therapies for the debilitating cognitive dysfunction in sleep related neurological and psychiatric disorders (including PTSD and addiction). Knowledge gained by understanding the cellular and molecular mechanisms and the underlying actions of anesthetics will be an asset for developing pharmacological therapies to treat PTSD and other anxiety disorders.


Perioperative Outcomes Research

Anesthesiology as a specialty has seen dramatic increases in patient safety. Mortality rates following general anesthesia have fallen from about 1 in 10,000 in the 1980’s to 1 in 250,000 in 2015. Likewise, complications associated with the perioperative period such as myocardial infarction or acute kidney injuries are rare events. Anesthesiologists still strive to improve patient care and their subsequent outcomes despite the low frequency of complications.

One way to combat the difficulties associated with the investigation of rare complications is to combine data from like-minded investigators from across the world. The advent of electronic medical records has enabled perioperative data to be readily pooled from multiple centers. In 2009 under the direction of Jerry L. Epps. M.D., The University of Tennessee Graduate School of Medicine's Department of Anesthesiology became the 7th member of the Multicenter Perioperative Outcomes Group (MPOG). MPOG is a consortium of 47 anesthesiology and surgical departments of institutions with perioperative information systems. Each uses a structured electronic anesthesia information management system that replaces the paper pre-, intra- and post-operative anesthesia records. Research centered on perioperative outcomes focuses primarily on observational studies that evaluate the relative benefits and risks of different therapeutic treatments or interventions to advance knowledge and improve patient care.

Why This Matters

As an example, one of the greatest concerns of an anesthesiologist is to anesthetize a patient only to find out that oxygen cannot be provided through the use of a face mask or placement of a breathing tube due to unforeseen patient abnormalities. Research regarding difficult mask ventilation combined with difficult laryngoscopy is extremely limited even though each technique serves as a rescue for one another. As one of four tertiary care centers participating in a Multicenter Perioperative Outcomes Group study, the Department of Anesthesiology analyzed 492,239 adult cases and identified independent predictors of both difficult mask ventilation and difficult laryngoscopy. An easy to use risk scale was established. As a result, other anesthesia providers can use this information to predict which patients would be difficult to both mask ventilate and intubate thus avoiding a life-threatening condition.


Neurochemistry of Anesthesia, Pain, and Sleep

The neurochemistry of anesthesia, pain, and sleep research initative pursues two lines of ongoing NIH-funded investigation. Opioids are a standard of care for pain management but have the unwanted side effect of respiratory depression. This side effect is of special concern for obese patients with sleep apnea. Lydic’s laboratory is testing the hypothesis that leptin protein, secreted by fat cells, modulates opioid-induced respiratory depression. A second line of investigation aims to identify brain chemicals as biomarkers for states of pain, sleep, and anesthesia. Lydic’s research career has focused on the brain mechanisms regulating states of consciousness.

Ralph Lydic, Ph.D. is the Robert H. Cole Endowed Professor of Neuroscience and Professor of Psychology at the University of Tennessee. He is the co-director of anesthesiology research at The University of Tennessee Graduate School of Medicine and he holds a joint appointment at Oak Ridge National Laboratory. His studies on brain regulation of sleep, anesthesia, and pain have been funded continuously for three decades by the National Institutes of Health (NIH). Lydic is a recipient of the Excellence in Research award from The American Society of Anesthesiologists. Lydic’s current service work includes editorial board membership on four international journals; he reviews grant applications for the U.S. Army and for the governments of Canada, Israel, and the Netherlands. He chairs the External Advisory Council for the National Space Biomedical Research Institute. Lydic is committed to education and more than 70 students have earned co-authorship on publications from his laboratory. Lydic co-produced the first massively open online course (MOOC) on the topic of sleep via the University of Michigan and the Coursera platform. More than 3,000 students worldwide registered for the initial offering of this course.

Why this Matters

The clinical relevance of this line of research is clear from NIH statistics indicating that 40 million Americans suffer from chronic sleep disorders, 60 million have frequent insomnia and another 20 million have occasional sleep problems. Sleep disorders negatively impact quality of life, and chronic disorders of sleep are associated with increased morbidity and mortality. In spite of the negative impact of disordered sleep, treatments remain limited to symptom relief because the underlying brain mechanisms are not understood. Sleep and anesthesia are distinctly different states that share some similar traits. These trait similarities suggest that studies of sleep states can also help understand states of anesthesia. In the United States, anesthesia is administered to more than 20 million patients each year, yet exactly how anesthetics produces their desired effects remain unknown.