George Mashour - US grants

? DESCRIPTION (provided by applicant): Although the field of anesthesiology has played a leadership role in promoting patient safety, there is still no standard monitor for the target orga of general anesthesia: the brain. The lack of reliable neurophysiologic monitoring can result in patient complications because of insufficient anesthesia (e.g., awareness and post- traumatic stress disorder) as well as excessive anesthesia (e.g., delayed emergence, delirium, neurotoxicity). A number of commercially-available brain monitors are currently used in the operating room, but such devices have shown limited utility and are often based on proprietary or empirical algorithms. Recent advances in neurobiology herald the possibility of a more sophisticated era of brain monitoring and improved patient safety. What is needed is the identification of measurable neurophysiological features of general anesthesia that are informed by the neurobiology of consciousness. We have gathered compelling data in human surgical patients that frontal-to-parietal connectivity in the brain is suppressed by all major classes of anesthetics. However, important questions remain regarding the measurement of information transfer in the brain, the underlying neural mechanisms of this suppressed connectivity and the clinical relevance of the findings. The objective for this application is a deeper understanding of the neurobiological principles of cortical connectivity patterns during consciousness and anesthesia as well as the relevance of such patterns for clinical care. We will achieve this objective by conducting innovative studies with computational brain network models, mechanistic experiments in the non-human primate brain, and a clinical study of surgical patients throughout the perioperative period. These studies will have a positive impact by advancing the neurobiology of anesthetic mechanisms, advancing network science in general, and making a key translational step toward novel brain monitoring strategies for surgical and critical care patients.

PROJECT SUMMARY / ABSTRACT The relationship between sleep and general anesthesia is of great clinical relevance given the high prevalence of patients with sleep disorders or insufficient sleep undergoing major surgery. To date, there is an incomplete understanding of how mechanisms that regulate anesthetic state transitions and sleep homeostasis interact. The preoptic region is a critical node for sleep regulation. The median preoptic nucleus (MnPO) regulates both state transitions and sleep homeostasis, making it a key, yet virtually unexplored, substrate for sleep- anesthesia interactions. Preliminary data obtained for this application suggest that distinct neuronal subpopulations within MnPO control the transition to and from general anesthesia as well as sleep-wake oscillations. Our long-term goal is to understand the neurobiological and clinical relationship between sleep and general anesthesia. The goal of the proposed studies is to examine the role of GABAergic and glutamatergic neurons in the MnPO and ventrolateral preoptic nucleus (VLPO) in sleep homeostasis and general anesthesia. The proposed studies will use Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) to test the hypothesis that the MnPO is a primary site for arousal state control, and that GABAergic and glutamatergic neurons in the MnPO regulate different aspects of sleep-wake states and general anesthesia. Aim 1 will use DREADDs for selective activation of GABAergic and glutamatergic neurons in the MnPO and VLPO to probe a causal relationship in controlling anesthetic induction, emergence, and post- anesthesia sleep-wake behaviors. In a second set of experiments we will test whether DREADD manipulations of MnPO and VLPO differentially alter corticocortical functional connectivity during wakefulness and general anesthesia. Aim 2 will assess the role of GABAergic and glutamatergic neurons in the MnPO and VLPO in sleep-wake regulation. Analysis of c-Fos immunoreactivity will reveal putative downstream targets of MnPO and VLPO neurons in sleep/wake-related areas. Additional experiments will determine whether activation of GABAergic neurons in the MnPO during general anesthesia can accelerate the anesthetic- induced recovery of sleep debt accrued during previous sleep deprivation. The proposed experiments will significantly advance our understanding of the mechanisms that regulate sleep-anesthesia interactions. These data will also provide a novel paradigm of how a single brain region (in this case, the MnPO) can control anesthetic induction and emergence through GABAergic and glutamatergic mechanisms, respectively.

Contact PD/PI: Mashour, George Alexander The Michigan Institute for Clinical & Health Research (MICHR) is a catalytic hub that significantly impacts the translation of investigative science into innovative improvements in clinical care and health policy. Our objective is to empower researchers and research communities within and outside the University of Michigan (U-M), creating a positive impact on health across local, regional, national, and global scales. We will achieve this objective through the following overarching specific aims: 1) Innovate and implement effective educational approaches to developing a skilled and diverse translational research workforce; 2) Catalyze effective research with community partnerships to accelerate the translation of breakthroughs that benefit society; 3) Promote clinical and translational research across translational phases and across the lifespan; 4) Advance research methods and processes that enable higher quality clinical and translational research; 5) Develop, demonstrate, and disseminate informatics innovations that facilitate the translation of biomedical discoveries to health impact. MICHR aspires to have a unique, substantial, measurable, and recognizable impact on U-M and the health of our communities. In order to achieve this with efficiency, we have critically evaluated pre- existing strengths and emerging opportunities across the institutional research landscape. MICHR will enhance and develop partnerships with major research and regulatory units on campus to develop an efficient pipeline that accelerates the translation and implementation of discoveries while also promoting cross-cutting signature initiatives that engage research and community members from all phases of translation. Project Summary/Abstract Page 257 Contact PD/PI: Mashour, George Alexander

ABSTRACT It is estimated that >300 million patients worldwide undergo major surgery each year, a feat that would have been impossible without the discovery of general anesthesia in the mid-19th century. The specialty of anesthesiology now spans operating rooms, intensive care units, and pain clinics; in addition to insensate surgery, anesthesiology has contributed widely to the field of medicine as a whole with innovations such as cardiopulmonary resuscitation and critical care medicine. Anesthesiology has been a recognized leader in patient safety and quality improvement, with dramatic reductions in intraoperative mortality over the past five decades. Despite these important clinical contributions that make modern medicine possible, the academic development of anesthesiology has not kept pace with other fields of medicine. National Institutes of Health (NIH) funding is generally lower in anesthesiology compared with other disciplines. There is, in our opinion, an urgent need to direct energy and resources to securing the future of academic anesthesiology. We believe that junior academic anesthesiologists and associated trainees represent key targets for high-impact interventions. In the current status quo, junior anesthesiologist-scientists often work in silos within individual departments or within isolated fields. Based on preliminary data, they perceive limited access to the mentorship of a broad array of senior leaders in the field and?perhaps more importantly?they feel disconnected from one another. Furthermore, there is a significant potential to engage junior academic anesthesiologists and trainees in the creation of positive impact through translational research. We propose a series of career development conferences for anesthesiology T32 fellows nationwide as well as research-oriented trainees that will help them navigate the translational research continuum and turn their discoveries into benefits for patients and their communities. These conferences will promote NIH scientific goals by providing mentorship to rising scholars, educating and engaging them in translational principles, enabling scientific collaborations, and stimulating new lines of research. Our strategic goal is to help empower the current and upcoming generations of junior academic anesthesiologists in order to secure the future of academic anesthesiology so that we may continue to make innovative contributions to medicine and society.

Project Summary The Expanded Access (EA) program of the Food and Drug Administration (FDA) provides an opportunity for patients who either lack therapeutic options or who are ineligible for clinical trials to potentially benefit from the clinical use of experimental drugs, biologics, and medical devices. This process represents one of the most immediate forms of translation because an experimental therapy is administered directly to an individual patient in need. However, the individual nature of EA interventions, the silos of care environments utilizing them, and the lack of standardized reporting have led to the inability to make broader inferences about safety or therapeutic potential. A more coordinated approach to EA that can achieve greater integration and yield more robust information could be transformative for the care of patients with rare or refractory disease. The NIH Clinical and Translational Science Awards (CTSA) consortium is an ideal network to develop innovative methods for regulatory navigation and support, oversight, and delivery of investigational products through EA. We therefore propose a CTSA-based program focused on Transforming Expanded Access to Maximize Support and Study (TEAMSS). Our long-term goal is to advance clinical care and translational research by improving patient access to experimental therapies through a federated, national consortium for EA interventions. The goal of this application is to develop a CTSA-based network that can demonstrate successful multisite integration of EA programs, leading to dissemination of best practices. We will pursue this goal by accomplishing the following specific aims: Develop, demonstrate, and disseminate best practices of network-based Expanded Access programs across the CTSA consortium; Develop a network for cohort-based Expanded Access programs; Create a database to standardize Expanded Access data reporting and develop a body of real-world data. The expected outcome of these aims is to demonstrate that a network-based approach to EA interventions and outcomes is both feasible and beneficial. We also expect to have achieved a thorough landscape assessment of EA infrastructure at each TEAMSS hub, as well as the successful dissemination of best practices that are applicable across the CTSA consortium. This will create a positive impact by, for the first time, creating a foundation for an integrated, nationwide approach to EA that can improve care for the most vulnerable patients.

DESCRIPTION (provided by applicant): The University of Michigan (UM) is one of the largest and most highly ranked public universities in the country, and a major center for graduate and post-graduate research training. The Ann Arbor campus is home to 19 schools and colleges, and UM faculty and students embrace inter- and multi-disciplinary training and research. Because of this, UM typically ranks in the top five universities in total research expenditures nationally, totaling $1.24B in 2010-2011. This proposed new NIGMS T32 Postdoctoral Training Program in Anesthesiology will provide support to post-doctoral trainees interested in careers in academic anesthesiology, and who embrace the interdisciplinary nature of of our institution. This T32 will heavily borrow from the UM Clinical and Translational Sciences Award (CTSA), which has been very successful at creating a number of innovative post-doctoral training programs for translational biomedical researchers. A unique aspect of this T32 program is that our mentoring teams, curricula, and research projects emphasize that successful anesthesiology researchers need to be competent in performing (and leading) inter-disciplinary research. We envision this process involving teams of individuals who include scientists that can successfully bi-directionally translate scientific knowledge from bench to bedside to practice - and back. Thus, all of our trainees will have a program designed that will provide them a necessarily deep understanding (i.e., walk the walk) of a particular scientific discipline combined with a broad understanding (i.e., talk the talk) of the terminology and issues facing their colleagues in other disciplines and/or related to points along the translational continuum.

PROJECT SUMMARY/ABSTRACT Advances in the field of anesthesiology have made the administration and maintenance of general anesthesia a relatively safe and well-controlled procedure. In contrast, emergence from anesthesia is passive and a poorly controlled process with an unclear neurobiology. We recently showed that a subanesthetic dose of ketamine during exposure to isoflurane counterintuitively accelerated the recovery from anesthesia, increased levels of acetylcholine in prefrontal cortex (PFC), and restored PFC connectivity to posterior cortex. Subsequently, we reported that cholinergic stimulation of PFC by local carbachol infusion restored wakefulness despite continuous exposure to clinically-relevant concentrations of general anesthesia. These data suggest that cholinergic processes in PFC control behavioral arousal and can be harnessed to accelerate recovery from anesthesia. However, mechanistic understanding is lacking. Our long-term goal is to understand the neurobiological processes that mediate recovery from physiologic, pharmacologic, and pathologic states of unconsciousness. The overall objective of the proposed studies is to identify the neural circuits through which PFC stimulation by local carbachol infusion or systemic delivery of subanesthetic ketamine produces accelerated recovery from general anesthesia. The central hypothesis, supported by our preliminary data, is that the reciprocal circuit of PFC and basal forebrain regulates behavioral arousal, and that subanesthetic ketamine co-opts this pathway to hasten recovery from general anesthesia. The rationale for the proposed research is that it will yield fundamental mechanistic knowledge of the neural pathways involved in arousal and recovery of consciousness. To test our hypothesis, we will pursue the following three specific aims and approaches in a rat model: 1) Demonstrate that PFC acts through basal forebrain to control behavioral arousal - we will stimulate PFC by local carbachol infusion with or without concurrent tetrodotoxin (TTX)- mediated inactivation of basal forebrain or selective chemogenetic inhibition of basal forebrain cholinergic and GABAergic neurons, which have been implicated in wakefulness, 2) Determine the role of basal forebrain projections to PFC in controlling behavioral arousal - we will chemogenetically stimulate basal forebrain cholinergic or GABAergic neurons, with or without concurrent TTX-mediated PFC inactivation. To confirm a causal role for acetylcholine in PFC in ketamine-induced accelerated recovery from anesthesia, we will infuse cholinergic antagonists into PFC during systemic delivery of subanesthetic ketamine, and 3) Determine the role of cortical connectivity and complexity in behavioral arousal - we will use carbachol/ketamine- induced recovery from anesthesia as a model system to dissect the state vs. anesthetic drug effects on functional cortical connectivity and spatiotemporal complexity. The proposed research is significant because we expect it to provide fundamental mechanistic understanding of the role of the PFC in behavioral arousal and recovery from anesthesia, with translational implications.

PROJECT SUMMARY / ABSTRACT The University of Michigan (U-M) is one of the largest and most highly ranked public universities in the country as well as a major center for graduate and post-graduate research training. The Ann Arbor campus is home to 19 schools and colleges, and U-M faculty and students embrace multidisciplinary training and research. With almost $1.5B in annual research expenditures, U-M is the top public university in research spending in the United States; more than half a billion of annual awards go to the Medical School. Within this broader environment of excellence, the U-M Department of Anesthesiology has reached an unprecedented level of research success, as evidenced by increased NIH awards (current #1 ranking for anesthesiology departments) and other sources of funding; increased quantity and quality of publications; high-level institutional research roles; and national research leadership in fields (such as precision medicine and translational science) that transcend traditional boundaries of the field. The department has a created a supportive and nurturing environment for developing the research workforce and the anesthesiology T32 training program has become the centerpiece of our career development program. Our first T32 graduates are active academic anesthesiologists leading multidisciplinary research teams, with continued support and mentorship from senior faculty members. Their success in high-level publications and NIH grant applications suggests a positive impact of our T32 program. In the next phase, we hope to enhance professional growth through stronger partnership with our institutional CTSA program and its Career Development Academy, develop more effective mentors through formal training, leverage our institutional and national roles to connect T32 fellows to expert perspectives from different fields and different institutions, and enhance the diversity of our applicants and trainees. We are deeply committed to helping diverse clinician-scientists become ethical and outstanding researchers, leaders in their field, committed mentors, and change agents who contribute to the public good through a positive impact on medicine, science, and society.