In this functional magnetic resonance imaging study, we examined the effect of mild propofol sedation and propofol-induced unconsciousness on resting state brain connectivity, using graph analysis based on independent component analysis and a classical seed-based analysis. Contrary to previous propofol research, which mainly emphasized the importance of connectivity in the default mode network (DMN) and external control network (ECN), we focused on the salience network, thalamus, and brainstem. The importance of these brain regions in brain arousal and organization merits a more detailed examination of their connectivity response to propofol. We found that the salience network disintegrated during propofol-induced unconsciousness. The thalamus decreased connectivity with the DMN, ECN, and salience network, while increasing connectivity with sensorimotor and auditory/insular cortices. Brainstem regions disconnected from the DMN with unconsciousness, while the pontine tegmental area increased connectivity with the insulae during mild sedation. These findings illustrate that loss of consciousness is associated with a wide variety of decreases and increases of both cortical and subcortical connectivity. It furthermore stresses the necessity of also examining resting state connectivity in networks representing arousal, not only those associated with awareness.
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References
1.
AbulafiaR, ZalkindV, DevorM. 2009. Cerebral activity during the anesthesia-like state induced by mesopontine microinjection of pentobarbital. J Neurosci, 29:7053–7064.
2.
AlkireMT, McReynoldsJR, HahnEL, TrivediAN. 2007. Thalamic microinjection of nicotine reverses sevoflurane-induced loss of righting reflex in the rat. Anesthesiology, 107:264–272.
3.
Angeles Fernandez-GilM, Palacios-BoteR, Leo-BarahonaM, Mora-EncinasJP. 2010. Anatomy of the brainstem: a gaze into the stem of life. Semin Ultrasound CT MR, 31:196–219.
4.
AronAR, RobbinsTW, PoldrackRA. 2004. Inhibition and the right inferior frontal cortex. Trends Cogn Sci, 8:170–177.
5.
BeckmannCF, DeLucaM, DevlinJT, SmithSM. 2005. Investigations into resting-state connectivity using independent component analysis. Philos Trans R Soc Lond B Biol Sci, 360:1001–1013.
6.
Ben-SimonE, PodlipskyI, Okon-SingerH, GrubergerM, CvetkovicD, IntratorN, HendlerT. 2013. The dark side of the alpha rhythm: fMRI evidence for induced alpha modulation during complete darkness. Eur J Neurosci, 37:795–803.
7.
BirnRM, DiamondJB, SmithMA, BandettiniPA. 2006. Separating respiratory-variation-related fluctuations from neuronal-activity-related fluctuations in fMRI. Neuroimage, 31:1536–1548.
8.
BolyM, MoranR, MurphyM, BoverouxP, BrunoMA, NoirhommeQ, LedouxD, BonhommeV, BrichantJF, TononiG, LaureysS, FristonK. 2012. Connectivity changes underlying spectral EEG changes during propofol-induced loss of consciousness. J Neurosci, 32:7082–7090.
9.
BolyM, TshibandaL, VanhaudenhuyseA, NoirhommeQ, SchnakersC, LedouxD, BoverouxP, GarwegC, LambermontB, PhillipsC, LuxenA, MoonenG, BassettiC, MaquetP, LaureysS. 2009. Functional connectivity in the default network during resting state is preserved in a vegetative but not in a brain dead patient. Hum Brain Mapp, 30:2393–2400.
10.
BonnelleV, HamTE, LeechR, KinnunenKM, MehtaMA, GreenwoodRJ, SharpDJ. 2012. Salience network integrity predicts default mode network function after traumatic brain injury. Proc Natl Acad Sci U S A, 109:4690–4695.
11.
BoverouxP, VanhaudenhuyseA, BrunoMA, NoirhommeQ, LauwickS, LuxenA, DegueldreC, PlenevauxA, SchnakersC, PhillipsC, BrichantJF, BonhommeV, MaquetP, GreiciusMD, LaureysS, BolyM. 2010. Breakdown of within- and between-network resting state functional magnetic resonance imaging connectivity during propofol-induced loss of consciousness. Anesthesiology, 113:1038–1053.
12.
BrownEN, LydicR, SchiffND. 2010. General anesthesia, sleep, and coma. N Engl J Med, 363:2638–2650.
13.
BrownEN, PurdonPL, Van DortCJ. 2011. General anesthesia and altered states of arousal: a systems neuroscience analysis. Annu Rev Neurosci, 34:601–628.
14.
ChingS, CimenserA, PurdonPL, BrownEN, KopellNJ. 2010. Thalamocortical model for a propofol-induced alpha-rhythm associated with loss of consciousness. Proc Natl Acad Sci U S A, 107:22665–22670.
15.
CimenserA, PurdonPL, PierceET, WalshJL, Salazar-GomezAF, HarrellPG, Tavares-StoeckelC, HabeebK, BrownEN. 2011. Tracking brain states under general anesthesia by using global coherence analysis. Proc Natl Acad Sci U S A, 108:8832–8837.
16.
ConstantinopleCM, BrunoRM. 2011 Effects and mechanisms of wakefulness on local cortical networksNeuron, 69:1061–1068.
17.
CorfieldDR, MurphyK, JosephsO, AdamsL, TurnerR. 2001. Does hypercapnia-induced cerebral vasodilation modulate the hemodynamic response to neural activation?Neuroimage, 13:1207–1211.
18.
DamoiseauxJS, RomboutsSA, BarkhofF, ScheltensP, StamCJ, SmithSM, BeckmannCF. 2006. Consistent resting-state networks across healthy subjects. Proc Natl Acad Sci U S A, 103:13848–13853.
19.
de LeceaL, CarterME, AdamantidisA. 2012. Shining light on wakefulness and arousal. Biol Psychiatry, 71:1046–1052.
20.
De MartinoF, GentileF, EspositoF, BalsiM, Di SalleF, GoebelR, FormisanoE. 2007. Classification of fMRI independent components using IC-fingerprints and support vector machine classifiers. NeuroImage, 34:177–194.
21.
DemertziA, SodduA, FaymonvilleME, BahriMA, GosseriesO, VanhaudenhuyseA, PhillipsC, MaquetP, NoirhommeQ, LuxenA, LaureysS. 2011. Hypnotic modulation of resting state fMRI default mode and extrinsic network connectivity. Prog Brain Res, 193:309–322.
22.
DevorM, ZalkindV. 2001. Reversible analgesia, atonia, and loss of consciousness on bilateral intracerebral microinjection of pentobarbital. Pain, 94:101–112.
23.
DuannJR, IdeJS, LuoX, LiCS. 2009. Functional connectivity delineates distinct roles of the inferior frontal cortex and presupplementary motor area in stop signal inhibition. J Neurosci, 29:10171–10179.
24.
Ellison-WrightI, BullmoreE. 2010. Anatomy of bipolar disorder and schizophrenia: a meta-analysis. Schizophr Res, 117:1–12.
FairDA, CohenAL, DosenbachNU, ChurchJA, MiezinFM, BarchDM, RaichleME, PetersenSE, SchlaggarBL. 2008. The maturing architecture of the brain's default network. Proc Natl Acad Sci U S A, 105:4028–4032.
27.
FisetP, PausT, DalozeT, PlourdeG, MeuretP, BonhommeV, Hajj-AliN, BackmanSB, EvansAC. 1999. Brain mechanisms of propofol-induced loss of consciousness in humans: a positron emission tomographic study. J Neurosci, 19:5506–5513.
28.
FoxMD, SnyderAZ, VincentJL, CorbettaM, Van EssenDC, RaichleME. 2005. The human brain is intrinsically organized into dynamic, anticorrelated functional networks. Proc Natl Acad Sci U S A, 102:9673–9678.
29.
FoxeJJ, SnyderAC. 2011. The role of alpha-band brain oscillations as a sensory suppression mechanism during selective attention. Front Psychol, 2:154.
30.
GiacinoJ, FinsJJ, MachadoA, SchiffND. 2012. Central thalamic deep brain stimulation to promote recovery from chronic posttraumatic minimally conscious state: challenges and opportunities. Neuromodulation, 15:339–349.
GuldenmundP, VanhaudenhuyseA, BolyM, LaureysS, SodduA. 2012. A default mode of brain function in altered states of consciousness. Arch Ital Biol, 150:107–121.
33.
HanslmayrS, GrossJ, KlimeschW, ShapiroKL. 2011. The role of alpha oscillations in temporal attention. Brain Res Rev, 67:331–343.
34.
HorovitzSG, BraunAR, CarrWS, PicchioniD, BalkinTJ, FukunagaM, DuynJH. 2009. Decoupling of the brain's default mode network during deep sleep. Proc Natl Acad Sci U S A, 106:11376–11381.
JensenO, MazaheriA. 2010. Shaping functional architecture by oscillatory alpha activity: gating by inhibition. Front Hum Neurosci, 4:186.
37.
LachauxJP, FonluptP, KahaneP, MinottiL, HoffmannD, BertrandO, BaciuM. 2007. Relationship between task-related gamma oscillations and BOLD signal: new insights from combined fMRI and intracranial EEG. Hum Brain Mapp, 28:1368–1375.
38.
LaureysS, BolyM. 2008. The changing spectrum of coma. Nat Clin Pract Neurol, 4:544–546.
39.
LiebermanMD, CunninghamWA. 2009. Type I and Type II error concerns in fMRI research: re-balancing the scale. Soc Cogn Affect Neurosci, 4:423–428.
40.
LinnmanC, MoultonEA, BarmettlerG, BecerraL, BorsookD. 2012. Neuroimaging of the periaqueductal gray: state of the field. Neuroimage, 60:505–522.
41.
MartuzziR, RamaniR, QiuM, RajeevanN, ConstableRT. 2010. Functional connectivity and alterations in baseline brain state in humans. Neuroimage, 49:823–834.
42.
MathewsonKE, LlerasA, BeckDM, FabianiM, RoT, GrattonG. 2011. Pulsed out of awareness: EEG alpha oscillations represent a pulsed-inhibition of ongoing cortical processing. Front Psychol, 2:99.
43.
MaudouxA, LefebvreP, CabayJE, DemertziA, VanhaudenhuyseA, LaureysS, SodduA. 2012. Connectivity graph analysis of the auditory resting state network in tinnitus. Brain Res, 1485:10–21.
44.
McKeownMJ, MakeigS, BrownGG, JungTP, KindermannSS, BellAJ, SejnowskiTJ. 1998. Analysis of fMRI data by blind separation into independent spatial components. Hum Brain Mapp, 6:160–188.
45.
MenonV, UddinLQ. 2010. Saliency, switching, attention and control: a network model of insula function. Brain Struct Funct, 214:655–667.
46.
ModinosG, OrmelJ, AlemanA. 2009. Activation of anterior insula during self-reflection. PLoS One, 4:e4618.
OlsonDM, ThoyreSM, AuyongDB. 2007. Perspectives on sedation assessment in critical care. AACN Adv Crit Care, 18:380–395.
49.
PalaniyappanL, LiddlePF. 2012. Does the salience network play a cardinal role in psychosis? An emerging hypothesis of insular dysfunction. J Psychiatry Neurosci, 37:17–27.
50.
ParviziJ, DamasioA. 2001. Consciousness and the brainstem. Cognition, 79:135–160.
51.
ParviziJ, DamasioAR. 2003. Neuroanatomical correlates of brainstem coma. Brain, 126:1524–1536.
52.
PinaultD. 2011. Dysfunctional thalamus-related networks in schizophrenia. Schizophr Bull, 37:238–243.
53.
SaperCB, CanoG, ScammellTE. 2005. Homeostatic, circadian, and emotional regulation of sleep. J Comp Neurol, 493:92–98.
54.
SchiffND. 2008. Central thalamic contributions to arousal regulation and neurological disorders of consciousness. Ann N Y Acad Sci, 1129:105–118.
55.
SchiffND, FinsJJ. 2007. Deep brain stimulation and cognition: moving from animal to patient. Curr Opin Neurol, 20:638–642.
56.
SchiffND, PlumF. 2000. The role of arousal and “gating” systems in the neurology of impaired consciousness. J Clin Neurophysiol, 17:438–452.
57.
SchrouffJ, PerlbargV, BolyM, MarrelecG, BoverouxP, VanhaudenhuyseA, BrunoMA, LaureysS, PhillipsC, Pelegrini-IssacM, MaquetP, BenaliH. 2011. Brain functional integration decreases during propofol-induced loss of consciousness. Neuroimage, 57:198–205.
58.
SeeleyWW. 2008. Selective functional, regional, and neuronal vulnerability in frontotemporal dementia. Curr Opin Neurol, 21:701–707.
59.
SeeleyWW. 2010. Anterior insula degeneration in frontotemporal dementia. Brain Struct Funct, 214:465–475.
ShahSA, SchiffND. 2010. Central thalamic deep brain stimulation for cognitive neuromodulation—a review of proposed mechanisms and investigational studies. Eur J Neurosci, 32:1135–1144.
62.
SodduA, VanhaudenhuyseA, BahriMA, BrunoMA, BolyM, DemertziA, TshibandaJF, PhillipsC, StanzianoM, Ovadia-CaroS, NirY, MaquetP, PapaM, MalachR, LaureysS, NoirhommeQ. 2012. Identifying the default-mode component in spatial IC analyses of patients with disorders of consciousness. Hum Brain Mapp, 33:778–796.
VanhaudenhuyseA, DemertziA, SchabusM, NoirhommeQ, BredartS, BolyM, PhillipsC, SodduA, LuxenA, MoonenG, LaureysS. 2011. Two distinct neuronal networks mediate the awareness of environment and of self. J Cogn Neurosci, 23:570–578.
65.
VanhaudenhuyseA, NoirhommeQ, TshibandaLJ, BrunoMA, BoverouxP, SchnakersC, SodduA, PerlbargV, LedouxD, BrichantJF, MoonenG, MaquetP, GreiciusMD, LaureysS, BolyM. 2009. Default network connectivity reflects the level of consciousness in non-communicative brain-damaged patients. Brain, 133:161–171.
66.
WangDS, OrserBA. 2011. Inhibition of learning and memory by general anesthetics. Can J Anaesth, 58:167–177.
67.
WiseRG, IdeK, PoulinMJ, TraceyI. 2004. Resting fluctuations in arterial carbon dioxide induce significant low frequency variations in BOLD signal. Neuroimage, 21:1652–1664.
68.
XieG, DeschampsA, BackmanSB, FisetP, ChartrandD, DagherA, PlourdeG. 2011. Critical involvement of the thalamus and precuneus during restoration of consciousness with physostigmine in humans during propofol anaesthesia: a positron emission tomography study. Br J Anaesth, 106:548–557.
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