Michael C.K. Khoo received his BSc(Eng) degree in Mechanical Engineering from the Imperial College of Science and Technology, University of London, in 1976, and the M.S. and Ph.D. degrees in Biomedical Engineering from Harvard University in 1977 and 1981, respectively. Before joining the faculty at USC in 1983, Dr. Khoo worked as a research engineer on a collaborative project involving the Veterans Administration Medical Center (West Roxbury), Brigham and Women's Hospital (Boston) and the Massachusetts Institute of Technology. Dr. Khoo has been the recipient of a Research Career Development Award from the National Institutes of Health and a Career Investigator Award from the American Lung Association. He is principal investigator of one of the Core Projects in the Biomedical Simulations Resource, a national center funded by the NIH National Institute of Biomedical Imaging and Bioengineering, dedicated to advancing the state of the art in biomedical modeling and computer simulation. He is also the co-principal investigator of an NIH training grant in Biomedical Imaging Informatics, and co-Director of Education and Outreach for the NSF-funded Engineering Research Center on Biomimetic Microelectronic Systems. Dr. Khoo is a Fellow of the American Institute of Medical and Biological Engineering (AIMBE) and the Biomedical Engineering Society (BMES). He has been BME Department Chair since 2003.
Research
Some two to four percent of the U.S. population are believed to suffer from sleep apnea. The cumulative evidence suggests that these people are more likely to develop various forms of cardiovascular disease, including hypertension, stroke, coronary heart disease and heart failure. Understanding the relationship between sleep apnea and cardiovascular disease forms the primary focus of Dr. Khoo’s research interests. Sleep apnea involves the dynamic interaction of three major physiological control systems: respiratory, cardiovascular and sleep regulation. To delineate cause from effect in the complex dynamics that arise from these interactions, Dr. Khoo and his students employ a combination of “structured” (or parametric) modeling and closed-loop minimal modeling approaches to analyze and interpret physiological data obtained from noninvasive studies in humans. These approaches require the application of control theory, system identification techniques and computer simulation. The Khoo laboratory collaborates closely with physician-scientists and physiologists from Childrens Hospital of Los Angeles, USC Keck School of Medicine, Case-Western Reserve University, Boston University, and University of Melbourne.
Recent and ongoing studies in this laboratory include the following:
(1) To better quantify the long-term effects of sleep apnea on autonomic cardiovascular control, a closed-loop minimal model has been used to identify abnormalities in the mechanisms that mediate heart-rate variability and blood pressure variability. The gains of the baroreflex and respiratory-cardiac coupling mechanisms were found to be substantially lower in sleep apnea patients compared to normals in both wakefulness and sleep. However, long-term (~6 months) therapy with continuous positive airway pressure (CPAP) was found to restore baroreflex and respiratory-cardiac coupling gains toward normality. Application of the minimal model to pediatric subjects has demonstrated that the detrimental effects of sleep apnea on autonomic function in childhood are different from those found in adults. The following are examples of recent publications in this area:
(a) Belozeroff V, Berry RB, Sassoon CSH, Khoo MCK. Effects of CPAP therapy on cardiovascular variability in obstructive sleep apnea: a closed-loop analysis. Am. J. Physiol. (Heart Circ. Physiol.) 282:H110-H121, 2002.
(b) Jo JA, Blasi A, Valladares E, Juarez R, Baydur A, Khoo MCK. Model-based assessment of autonomic control in obstructive sleep apnea syndrome during sleep. Am J Respir Crit Care Med 2003; 167:128-136.
(c) Jo JA, Blasi A, Valladares E, Juarez R, Baydur A, Khoo MCK. Determinants of heart rate variability in obstructive sleep apnea during wakefulness and sleep. Am J Physiol Heart Circ Physiol 2005; 288:H1103-1112.
(2) The minimal model of autonomic cardiovascular control has been extended to incorporate the nonlinear effects of respiration and blood pressure, as well as the interaction between respiration and blood pressure, on heart rate variability. The extended model takes the form of a Volterra-Wiener structure, along with application of the Laguerre expansion technique to reduce parametrization. Analysis of data using this approach has shown that the magnitudes of these nonlinear interactions are substantially reduced in subjects with sleep apnea.
(a) Jo J, Khoo MCK, Blasi A, Baydur A, Juarez R. Detection of autonomic abnormality in obstructive sleep apnea using a nonlinear model of heart rate variability. Proc 2nd Joint EMBS-BMES Conference, p.1554-1555, 2002.
(b) Jo, J.A.; Blasi, A.; Baydur, A.; Juarez, R.; Khoo, M.C.K. Nonlinear assessment of autonomic function in obstructive sleep apnea during long-term CPAP therapy. Proc. 25th Ann. Intl. Conf. of the IEEE Engineering in Medicine and Biology Society, Vol.1, pp.346-349, 2003.
(3) The minimal model has also been extended for applicability to conditions under which the cardiovascular autonomic control system is in a time-varying state. Such conditions include the period immediately following transient arousal from sleep, as well as during the response to cold face stimulation. Studies from Dr. Khoo’s lab have shown that, in sleep apneics, the model components that are sympathetically mediated exhibit significantly less reactivity to input changes than the corresponding components in normal controls. In normals, sympathetic reactivity is also reduced in REM sleep vis-à-vis NREM sleep. More recently, we have refined the time-varying minimal model and applied it as a means for quantitative daytime assessment of autonomic function in children with sleep apnea.
(a) Blasi, A, Jo J, Valladares E, Juarez R, Baydur A, Khoo MCK. Autonomic cardiovascular control following transient arousal from sleep: A time-varying closed-loop model. IEEE Trans. Biomed. Eng. 2006; 53:74-82.
(b) Blasi, A, Jo J, Valladares E, Juarez R, Baydur A, Khoo MCK. Time-varying analysis of autonomic control during arousal from sleep in obstructive sleep apnea syndrome. Proc 25th Annual EMBS Conference, p.350-353, 2003.
(c ) Chaicharn J, Lin Z, Chen ML, Keens TG,Ward SLD, Khoo MCK. Time-varying closed-loop modeling of autonomic control in pediatric Obstructive Sleep Apnea Syndrome during cold face stimulation. Proc 28th Annual IEEE EMBS Conference, 2006.
(4) The group has developed and continues to extend a comprehensive cardiorespiratory control model, named “PNEUMA”, that allows the simulation of physiological responses to a wide variety of conditions, including the 24-hour sleep-wake cycle, hypoxia-induced periodic breathing, Cheyne-Stokes respiration in congestive heart failure, and obstructive sleep apnea. It can be used to investigate the effects of interventions such as hypercapnic or hypoxic gas administration, the Valsalva and Mueller maneuvers, and the application of continuous positive airway pressure or simple mechanical ventilation. PNEUMA is implemented using SIMULINK® (The Mathworks, Natick, MA).
(a) Fan H, Khoo MCK. PNEUMA: a comprehensive cardiorespiratory model. Proc 2nd Joint EMBS-BMES Conference, p.1533-1534, 2002.
(b) Ivanova OV, Khoo MCK. Simulation of spontaneous cardiovascular variability using PNEUMA. Proc 26th Annual IEEE EMBS Conference, p.3901-3904, 2004.
(5) Some members of Dr. Khoo’s group are analyzing datasets extracted from the multi-center Sleep Heart Health Study in order to determine whether respiration-adjusted spectral indices of heart rate variability are correlated with indices that reflect the severity of sleep-disordered breathing. As well, these investigations are addressing the issue of whether the patterns of ultradian rhythmicity are altered in patients with sleep-disordered breathing.
(a) Tretriluxana, S., S. Redline, S.A. Surovec, D.J. Gottlieb, and M.C.K. Khoo. Changes in ultradian heart rate variability rhythm in sleep-disordered breathing. Sleep 28:A198-A199, 2005.
(b) Wang, W., S. Tretriluxana, S. Redline, S. Surovec, D. Gottlieb and M.C.K. Khoo. Sleep-disordered breathing and cardiac autonomic function in a community-based sample: age-related differences. Proceedings of the American Thoracic Society 3:A197, 2006.
