Arousal Pathways and Emergence From Sedation

Summary

Emergence from sedation involves an increase in both the level of consciousness and arousal. Some insight to the neural core of consciousness was gained in the recent past. Our research objective is to characterize for the first time the spatiotemporal mobilization of the ascending reticular activating system during emergence from sedation; stated otherwise - to capture the neural core of arousal. To achieve this objective we plan to utilize the advanced imaging modality of EEG-fMRI. In short, volunteers will be placed in the MRI. Following baseline recordings they will be sedated with a continuous drip of propofol, titrated to deep sedation. Once in that sedation level, propofol administration will cease until emerging to an awake-calm/light sedation. Continuous EEG recordings and fMRI scans will be taken, both task specific (auditory oddball) and resting-fMRI. Analyses will focus (but will not be restricted to) on constituents of the ascending reticular activating system. The expected advances of this proposal are: 1. Emergence from sedation (and anesthesia) is one of the critical stages and least elucidated area in the practice of anesthesia. Delayed awakening of varying degree is not uncommon after anesthesia and may have a number of different causes, individual or combined, which may be both drug or non-drug related, thus causing a diagnostic dilemma. Eventually - better insight into this subject will lead to better clinical practice and better understanding why patients emerge in such a diverse and sometimes unexpected manner. 2. Knowledge of the internal structure underlying arousal from anesthesia will help develop / upgrade brain monitors that could tell the anesthesiologist the patient's level of consciousness and prediction of arousal. 3. A detailed reproducible mapping of the arousal process may serve as the core of a drug screening platform for drugs that may expedite patient arousal. 4. Elucidation of the arousal paradigm from sedation will enhance our knowledge of physiological sleep. Research hypothesis Return of consciousness is a complex phenomenon comprising of interplay between the cortex and deeper brain structures. We hypothesize that the activation signature is conserved and similar between subjects. Furthermore, we hypothesize that inter-subject variability will arise mainly in the time domain, as evident from the clinical observation of variable time to emergence in different patients.

Timeline

Start

2014-10

Primary completion

2015-12

Completion

2016-12

Publications

• Background Brown EN, Lydic R, Schiff ND. General anesthesia, sleep, and coma. N Engl J Med. 2010 Dec 30;363(27):2638-50. doi: 10.1056/NEJMra0808281. No abstract available.
• Background Lee U, Mashour GA, Kim S, Noh GJ, Choi BM. Propofol induction reduces the capacity for neural information integration: implications for the mechanism of consciousness and general anesthesia. Conscious Cogn. 2009 Mar;18(1):56-64. doi: 10.1016/j.concog.2008.10.005. Epub 2008 Dec 2.
• Background Breshears JD, Roland JL, Sharma M, Gaona CM, Freudenburg ZV, Tempelhoff R, Avidan MS, Leuthardt EC. Stable and dynamic cortical electrophysiology of induction and emergence with propofol anesthesia. Proc Natl Acad Sci U S A. 2010 Dec 7;107(49):21170-5. doi: 10.1073/pnas.1011949107. Epub 2010 Nov 15.
• Background Hwang E, Kim S, Han K, Choi JH. Characterization of phase transition in the thalamocortical system during anesthesia-induced loss of consciousness. PLoS One. 2012;7(12):e50580. doi: 10.1371/journal.pone.0050580. Epub 2012 Dec 7.
• Background Alkire MT, Hudetz AG, Tononi G. Consciousness and anesthesia. Science. 2008 Nov 7;322(5903):876-80. doi: 10.1126/science.1149213.
• Background Tononi G. An information integration theory of consciousness. BMC Neurosci. 2004 Nov 2;5:42. doi: 10.1186/1471-2202-5-42.
• Background Tononi G, Koch C. The neural correlates of consciousness: an update. Ann N Y Acad Sci. 2008 Mar;1124:239-61. doi: 10.1196/annals.1440.004.
• Background Franks NP. General anaesthesia: from molecular targets to neuronal pathways of sleep and arousal. Nat Rev Neurosci. 2008 May;9(5):370-86. doi: 10.1038/nrn2372.
• Background Brown EN, Purdon PL, Van Dort CJ. General anesthesia and altered states of arousal: a systems neuroscience analysis. Annu Rev Neurosci. 2011;34:601-28. doi: 10.1146/annurev-neuro-060909-153200.
• Background Saper CB, Chou TC, Scammell TE. The sleep switch: hypothalamic control of sleep and wakefulness. Trends Neurosci. 2001 Dec;24(12):726-31. doi: 10.1016/s0166-2236(00)02002-6.
• Background Solt K. General anesthesia: activating a sleep switch? Curr Biol. 2012 Nov 6;22(21):R918-9. doi: 10.1016/j.cub.2012.09.033.
• Background Baumann CR, Bassetti CL. Hypocretins (orexins) and sleep-wake disorders. Lancet Neurol. 2005 Oct;4(10):673-82. doi: 10.1016/S1474-4422(05)70196-4.
• Background Kelz MB, Sun Y, Chen J, Cheng Meng Q, Moore JT, Veasey SC, Dixon S, Thornton M, Funato H, Yanagisawa M. An essential role for orexins in emergence from general anesthesia. Proc Natl Acad Sci U S A. 2008 Jan 29;105(4):1309-14. doi: 10.1073/pnas.0707146105. Epub 2008 Jan 14.
• Background Langsjo JW, Alkire MT, Kaskinoro K, Hayama H, Maksimow A, Kaisti KK, Aalto S, Aantaa R, Jaaskelainen SK, Revonsuo A, Scheinin H. Returning from oblivion: imaging the neural core of consciousness. J Neurosci. 2012 Apr 4;32(14):4935-43. doi: 10.1523/JNEUROSCI.4962-11.2012.
• Background Mukamel EA, Pirondini E, Babadi B, Wong KF, Pierce ET, Harrell PG, Walsh JL, Salazar-Gomez AF, Cash SS, Eskandar EN, Weiner VS, Brown EN, Purdon PL. A transition in brain state during propofol-induced unconsciousness. J Neurosci. 2014 Jan 15;34(3):839-45. doi: 10.1523/JNEUROSCI.5813-12.2014.
• Background Purdon PL, Pierce ET, Mukamel EA, Prerau MJ, Walsh JL, Wong KF, Salazar-Gomez AF, Harrell PG, Sampson AL, Cimenser A, Ching S, Kopell NJ, Tavares-Stoeckel C, Habeeb K, Merhar R, Brown EN. Electroencephalogram signatures of loss and recovery of consciousness from propofol. Proc Natl Acad Sci U S A. 2013 Mar 19;110(12):E1142-51. doi: 10.1073/pnas.1221180110. Epub 2013 Mar 4.
• Background Moruzzi G, Magoun HW. Brain stem reticular formation and activation of the EEG. Electroencephalogr Clin Neurophysiol. 1949 Nov;1(4):455-73.
• Background Schmidt C, Collette F, Leclercq Y, Sterpenich V, Vandewalle G, Berthomier P, Berthomier C, Phillips C, Tinguely G, Darsaud A, Gais S, Schabus M, Desseilles M, Dang-Vu TT, Salmon E, Balteau E, Degueldre C, Luxen A, Maquet P, Cajochen C, Peigneux P. Homeostatic sleep pressure and responses to sustained attention in the suprachiasmatic area. Science. 2009 Apr 24;324(5926):516-9. doi: 10.1126/science.1167337.
• Background Garcia-Rill E, Kezunovic N, Hyde J, Simon C, Beck P, Urbano FJ. Coherence and frequency in the reticular activating system (RAS). Sleep Med Rev. 2013 Jun;17(3):227-38. doi: 10.1016/j.smrv.2012.06.002. Epub 2012 Oct 6.
• Background Schroter MS, Spoormaker VI, Schorer A, Wohlschlager A, Czisch M, Kochs EF, Zimmer C, Hemmer B, Schneider G, Jordan D, Ilg R. Spatiotemporal reconfiguration of large-scale brain functional networks during propofol-induced loss of consciousness. J Neurosci. 2012 Sep 12;32(37):12832-40. doi: 10.1523/JNEUROSCI.6046-11.2012.
• Background Marsh B, White M, Morton N, Kenny GN. Pharmacokinetic model driven infusion of propofol in children. Br J Anaesth. 1991 Jul;67(1):41-8. doi: 10.1093/bja/67.1.41.
• Background Ramsay MA, Savege TM, Simpson BR, Goodwin R. Controlled sedation with alphaxalone-alphadolone. Br Med J. 1974 Jun 22;2(5920):656-9. doi: 10.1136/bmj.2.5920.656.
• Background Meir-Hasson Y, Kinreich S, Podlipsky I, Hendler T, Intrator N. An EEG Finger-Print of fMRI deep regional activation. Neuroimage. 2014 Nov 15;102 Pt 1:128-41. doi: 10.1016/j.neuroimage.2013.11.004. Epub 2013 Nov 15.
• Background Abraham E, Hendler T, Shapira-Lichter I, Kanat-Maymon Y, Zagoory-Sharon O, Feldman R. Father's brain is sensitive to childcare experiences. Proc Natl Acad Sci U S A. 2014 Jul 8;111(27):9792-7. doi: 10.1073/pnas.1402569111. Epub 2014 May 27.
• Background Weinstein M, Ben-Sira L, Levy Y, Zachor DA, Ben Itzhak E, Artzi M, Tarrasch R, Eksteine PM, Hendler T, Ben Bashat D. Abnormal white matter integrity in young children with autism. Hum Brain Mapp. 2011 Apr;32(4):534-43. doi: 10.1002/hbm.21042.
• Background Ben Bashat D, Kronfeld-Duenias V, Zachor DA, Ekstein PM, Hendler T, Tarrasch R, Even A, Levy Y, Ben Sira L. Accelerated maturation of white matter in young children with autism: a high b value DWI study. Neuroimage. 2007 Aug 1;37(1):40-7. doi: 10.1016/j.neuroimage.2007.04.060. Epub 2007 May 18.

Drugs

Indications

No indication recorded.