Program Director/Principal Investigator (Last, First, Middle): Malhotra, Atul, MD PROJECT SUMMARY (Seeinstructions): Immediate goals: To apply newer electromyographic techniques to upper airway muscles with a view towards identifying important therapeutic targets in obstructive sleep apnea. Career development goals: To provide sufficient time for mentoring of trainees and research activities. Research project: Obstructive sleep apnea is an important disease due to its high prevalence and well established neurocognitive and cardiovascular sequelae. Treatment of this disease remains problematic since the existing therapies are either poorly tolerated or have variable efficacy, leading many to advocate for further research into underlying mechanisms. Prior research has established in the importance of the upper airway muscles (such as the genioglossus and tensor palatini) in the pathogenesis of sleep apnea. However, multi-unit electromyographic recordings provide an average representation of innumerable motor units yielding fairly incomplete information about the behavior of individual motor units. We have begun a series of studies using high frequency sampling of the electromyogram to define the various motor units within the genioglossus muscle. These newer studies have revealed marked complexity in the behavior of the genioglossus muscle, with 6 distinct firing patterns being identifiable. A rise or fall in the genioglossal multiunit EMG is therefore difficult to interpret since these changes could be mediated by any of a number of individual motor unit firing changes. We have observed specific units that may be most critical for the maintenance of pharyngeal patency. Such units would thus we logical therapeutic targets which we can address with our neuroanatomy collaborators. We have also begun studies using single fiber EMGs and MacroEMGs which a view towards performing more quantitative assessments of various upper airway muscles. These newer EMG techniques will allow us to assess the mechanisms underlying the high level of activity seen in the EMG of sleep apnea patients as compared with controls, since there is currently an ongoing controversy as to whether this high activity represents high central drive to the muscle versus an effect of denervation. This K24 award would allow us to pursue interesting hypotheses that may ultimately lead to new treatments for sleep apnea, but will certainly yield insights into disease pathogenesis. This award will also allow the PI to dedicate more time to training young investigators in the field of sleep and respiratory physiology. The need for an investigator pipeline has been termed a crisis (Sleep. 2006 29:1260)

Public Health Relevance

Obstructive sleep apnea is strongly implicated in motor vehicle accidents as well as high blood pressure and stroke. How easily an individual wakes up from sleep (arousal threshold) is something that may be important in why sleep apnea occurs. We propose studies that will examine the role of the arousal threshold with an ultimate goal of developing new treatments for sleep apnea to prevent its serious complications. PROJECT/

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Midcareer Investigator Award in Patient-Oriented Research (K24)
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Special Emphasis Panel (ZHL1-CSR-R (F1))
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Twery, Michael
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Brigham and Women's Hospital
United States
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Sands, Scott A; Terrill, Philip I; Edwards, Bradley A et al. (2018) Quantifying the Arousal Threshold Using Polysomnography in Obstructive Sleep Apnea. Sleep 41:
Sands, Scott A; Mebrate, Yoseph; Edwards, Bradley A et al. (2017) Resonance as the Mechanism of Daytime Periodic Breathing in Patients with Heart Failure. Am J Respir Crit Care Med 195:237-246
Rukhadze, Irma; Carballo, Nancy J; Bandaru, Sathyajit S et al. (2017) Catecholaminergic A1/C1 neurons contribute to the maintenance of upper airway muscle tone but may not participate in NREM sleep-related depression of these muscles. Respir Physiol Neurobiol 244:41-50
Zaremba, Sebastian; Shin, Christina H; Hutter, Matthew M et al. (2016) Continuous Positive Airway Pressure Mitigates Opioid-induced Worsening of Sleep-disordered Breathing Early after Bariatric Surgery. Anesthesiology 125:92-104
Shin, Wonchul; Jen, Rachel; Li, Yanru et al. (2016) Tailored treatment strategies for obstructive sleep apnea. Respir Investig 54:2-7
Sweeney, Daniel A; Akrami, Kevan; Malhotra, Atul (2016) Improved Outcomes in Critically Ill Patients With AIDS: How Does This Trend Continue? Crit Care Med 44:446-7
Altintas, Nejat; Mutlu, Levent Cem; Akkoyun, Dursun Cayan et al. (2016) Effect of CPAP on New Endothelial Dysfunction Marker, Endocan, in People With Obstructive Sleep Apnea. Angiology 67:364-74
Beitler, Jeremy R; Majumdar, Rohit; Hubmayr, Rolf D et al. (2016) Volume Delivered During Recruitment Maneuver Predicts Lung Stress in Acute Respiratory Distress Syndrome. Crit Care Med 44:91-9
Sands, Scott A; Owens, Robert L; Malhotra, Atul (2016) New Approaches to Diagnosing Sleep-Disordered Breathing. Sleep Med Clin 11:143-52
Woodell, Tyler B; Hughes-Austin, Jan M; Tran, Tiffany V et al. (2016) Associations between cystatin C-based eGFR, ambulatory blood pressure parameters, and in-clinic versus ambulatory blood pressure agreement in older community-living adults. Blood Press Monit 21:87-94

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