Sepsis-associated encephalopathy (SAE) is a frequent severe complication of sepsis and the systemic inflammatory response syndrome, associated with high mortality and long-term neurologic consequences in surviving patients. One of the main clinical signs of SAE are discontinuous sleep periods that are fragmented by frequent awakenings. Although this brain state fragmentation strongly impacts the functionality of the nervous and other systems, its underlying network mechanisms are still poorly understood. In this work, we therefore aim to characterize the properties and dynamics of brain oscillatory states in response to SAE in an acute rat model of sepsis induced by high-dose lipopolysaccharide (LPS; 10 mg/kg). To focus on intrinsically generated brain state dynamics, we used a urethane model that spares oscillatory activity in rapid eye movement (REM)-like and nonrapid eye movement (NREM)-like sleep states. Intraperitoneal LPS injection led to a robust instability of both oscillatory states resulting in several folds more state transitions. We identified opposing shifts in low-frequency oscillations (1-9 Hz) in REM and NREM-like states under influence of LPS. This resulted in increased similarity between both states. Moreover, the state-space jitter in both states increased as well, pointing to higher within-state instability. The reduction of interstate spectral distances in 2-D state space, combined with increased within-state jitter might represent a key factor in changing the energy landscape of brain oscillatory state attractors, and hence lead to altered sleep architecture. Their emergence during sepsis might point to a mechanism underlying severe sleep fragmentation as described both in sepsis patients and SAE animal models.

Biomedical Center Faculty of Medicine in Pilsen Charles University Pilsen 323 00 Czech Republic

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Allison T, Cicchetti DV (1976) Sleep in mammals: ecological and constitutional correlates. Science 194:732–734. 10.1126/science.982039 PubMed DOI

Amit DJ, Amit DJ (1989) Modeling brain function: the world of attractor neural networks. Cambridge: Cambridge University Press.

Annane D, Sharshar T (2015) Cognitive decline after sepsis. Lancet Respir Med 3:61–69. 10.1016/S2213-2600(14)70246-2 PubMed DOI

Azabou E, Magalhaes E, Braconnier A, Yahiaoui L, Moneger G, Heming N, Annane D, Mantz J, Chrétien F, Durand MC, Lofaso F, Porcher R, Sharshar T; Groupe d’Explorations Neurologiques en Réanimation (GENER) (2015) Early standard electroencephalogram abnormalities predict mortality in septic intensive care unit patients. PLoS One 10:e0139969. 10.1371/journal.pone.0139969 PubMed DOI PMC

Baracchi F, Ingiosi AM, Raymond RM, Opp MR (2011) Sepsis-induced alterations in sleep of rats. Am J Physiol Regul Integr Comp Physiol 301:R1467–R1478. 10.1152/ajpregu.00354.2011 PubMed DOI PMC

Beynon AL, Coogan AN (2010) Diurnal, age, and immune regulation of interleukin-1β and interleukin-1 type 1 receptor in the mouse suprachiasmatic nucleus. Chronobiol Int 27:1546–1563. 10.3109/07420528.2010.501927 PubMed DOI

Bolton CF (1987) Electrophysiologic studies of critically ill patients. Muscle Nerve 10:129–135. 10.1002/mus.880100205 PubMed DOI

Bourne RS, Mills GH, Minelli C (2008) Melatonin therapy to improve nocturnal sleep in critically ill patients: encouraging results from a small randomised controlled trial. Crit Care 12:R52. 10.1186/cc6871 PubMed DOI PMC

Boyko Y, Jennum P, Toft P (2017) Sleep quality and circadian rhythm disruption in the intensive care unit: a review. Nat Sci Sleep 9:277–284. 10.2147/NSS.S151525 PubMed DOI PMC

Carlson DE, Chiu WC, Scalea TM (2006) Cecal ligation and puncture in rats interrupts the circadian rhythms of corticosterone and adrenocortical responsiveness to adrenocorticotrophic hormone. Crit Care Med 34:1178–1184. 10.1097/01.CCM.0000207340.24290.3C PubMed DOI

Cavadini G, Petrzilka S, Kohler P, Jud C, Tobler I, Birchler T, Fontana A (2007) TNF-α suppresses the expression of clock genes by interfering with E-box-mediated transcription. Proc Natl Acad Sci U S A 104:12843–12848. 10.1073/pnas.0701466104 PubMed DOI PMC

Chavan SS, Huerta PT, Robbiati S, Valdes-Ferrer SI, Ochani M, Dancho M, Frankfurt M, Volpe BT, Tracey KJ, Diamond B (2012) HMGB1 mediates cognitive impairment in sepsis survivors. Mol Med 18:930–937. 10.2119/molmed.2012.00195 PubMed DOI PMC

Cirelli C (2006) Cellular consequences of sleep deprivation in the brain. Sleep Med Rev 10:307–321. 10.1016/j.smrv.2006.04.001 PubMed DOI

Clement EA, Richard A, Thwaites M, Ailon J, Peters S, Dickson CT (2008) Cyclic and sleep-like spontaneous alternations of brain state under urethane anaesthesia. PLoS One 3:e2004. 10.1371/journal.pone.0002004 PubMed DOI PMC

Cui YH, Zhou SF, Liu Y, Wang S, Li F, Dai RP, Hu ZL, Li CQ (2021) Injection of anti-proBDNF attenuates hippocampal-dependent learning and memory dysfunction in mice with sepsis-associated encephalopathy. Front Neurosci 15:665757. 10.3389/fnins.2021.665757 PubMed DOI PMC

Czempik PF, Pluta MP, Krzych ŁJ (2020) Sepsis-associated brain dysfunction: a review of current literature. Int J Environ Res Public Health 17:5852. 10.3390/ijerph17165852 PubMed DOI PMC

Diniz Behn CG, Klerman EB, Mochizuki T, Shih-Chieh L, Scammell T (2010) Abnormal sleep/wake dynamics in orexin knockout mice. Sleep 33:297–306. 10.1093/sleep/33.3.297 PubMed DOI PMC

Donoghue T, Haller M, Peterson EJ, Varma P, Sebastian P, Gao R, Noto T, Lara AH, Wallis JD, Knight RT, Shestyuk A, Voytek B (2020) Parameterizing neural power spectra into periodic and aperiodic components. Nat Neurosci 23:1655–1665. 10.1038/s41593-020-00744-x PubMed DOI PMC

Dzierzewski JM, Donovan EK, Kay DB, Sannes TS, Bradbrook KE (2020) Sleep inconsistency and markers of inflammation. Front Neurol 11:1042. 10.3389/fneur.2020.01042 PubMed DOI PMC

Gao R, Ji M, Gao D, Yang R, Zhang S, Yang J, Shen J (2017a) Neuroinflammation-induced downregulation of hippocampacal neuregulin 1-ErbB4 signaling in the parvalbumin interneurons might contribute to cognitive impairment in a mouse model of sepsis-associated encephalopathy. Inflammation 40:387–400. 10.1007/s10753-016-0484-2 PubMed DOI

Gao R, Peterson EJ, Voytek B (2017b) Inferring synaptic excitation/inhibition balance from field potentials. NeuroImage 158:70–78. 10.1016/j.neuroimage.2017.06.078 PubMed DOI

Gervasoni D, Lin S-C, Ribeiro S, Soares ES, Pantoja J, Nicolelis MAL (2004) Global forebrain dynamics predict rat behavioral states and their transitions. J Neurosci 24:11137–11147. 10.1523/JNEUROSCI.3524-04.2004 PubMed DOI PMC

Gofton TE, Young GB (2012) Sepsis-associated encephalopathy. Nat Rev Neurol 8:557–566. 10.1038/nrneurol.2012.183 PubMed DOI

Götz T, Baumbach P, Huonker R, Kranczioch C, Witte OW, Debener S, Klingner C, Brunkhorst FM, Günther A (2016) Slowed peak resting frequency and MEG overactivation in survivors of severe sepsis and septic shock. Clin Neurophysiol 127:1247–1253. 10.1016/j.clinph.2015.07.021 PubMed DOI

Gullo F, Amadeo A, Donvito G, Lecchi M, Costa B, Constanti A, Wanke E (2014) Atypical “seizure-like” activity in cortical reverberating networks in vitro can be caused by LPS-induced inflammation: a multi-electrode array study from a hundred neurons. Front Cell Neurosci 8:361. 10.3389/fncel.2014.00361 PubMed DOI PMC

Haller M, Donoghue T, Peterson E, Varma P, Sebastian P, Gao R, Noto T, Knight RT, Shestyuk A, Voytek B (2018) Parameterizing neural power spectra. bioRxiv 299859. 10.1101/299859. PubMed DOI PMC

Hopfield JJ (1982) Neural networks and physical systems with emergent collective computational abilities. Proc Natl Acad Sci U S A 79:2554–2558. 10.1073/pnas.79.8.2554 PubMed DOI PMC

Hosokawa K, Gaspard N, Su F, Oddo M, Vincent J-L, Taccone FS (2014) Clinical neurophysiological assessment of sepsis-associated brain dysfunction: a systematic review. Crit Care 18:674. 10.1186/s13054-014-0674-y PubMed DOI PMC

Imbach LL, Sommerauer M, Poryazova R, Werth E, Valko PO, Scammell TE, Baumann CR (2016) Bradysomnia in Parkinson’s disease. Clin Neurophysiol 127:1403–1409. 10.1016/j.clinph.2015.08.012 PubMed DOI

Ji MH, Lei L, Gao D, Tong J, Wang Y, Yang J (2020a) Neural network disturbance in the medial prefrontal cortex might contribute to cognitive impairments induced by neuroinflammation. Brain Behav Immun 89:133–144. 10.1016/j.bbi.2020.06.001 PubMed DOI

Ji M, Li S, Zhang L, Gao Y, Zeng Q, Mao M, Yang J (2020b) Sepsis induced cognitive impairments by disrupting hippocampal parvalbumin interneuron-mediated inhibitory network via a D4-receptor mechanism. Aging (Albany NY) 12:2471–2484. 10.18632/aging.102755 PubMed DOI PMC

Kafa IM, Bakirci S, Uysal M, Kurt MA (2010) Alterations in the brain electrical activity in a rat model of sepsis-associated encephalopathy. Brain Res 1354:217–226. 10.1016/j.brainres.2010.07.049 PubMed DOI

Kapás L, Hansen MK, Chang H-Y, Krueger JM (1998) Vagotomy attenuates but does not prevent the somnogenic and febrile effects of lipopolysaccharide in rats. Am J Physiol 274:R406–R411. 10.1152/ajpregu.1998.274.2.R406 PubMed DOI

Kaplan PW, Rossetti AO (2011) EEG patterns and imaging correlations in encephalopathy: encephalopathy part II. J Clin Neurophysiol 28:233–251. 10.1097/WNP.0b013e31821c33a0 PubMed DOI

Kinoshita H, Kushikata T, Takekawa D, Hirota K (2021) Perioperative abnormal electroencephalography in a later-stage elderly with septic shock: a case report. JA Clin Rep 7:5. 10.1186/s40981-020-00409-5 PubMed DOI PMC

Krueger JM, Kubillus S, Shoham S, Davenne D (1986) Enhancement of slow-wave sleep by endotoxin and lipid A. Am J Physiol 251:R591–R597. 10.1152/ajpregu.1986.251.3.R591 PubMed DOI

Kurita T, Takata K, Morita K, Uraoka M, Sato S (2010) The influence of endotoxemia on the electroencephalographic and antinociceptive effects of isoflurane in a swine model. Anesth Analg 110:83–88. 10.1213/ANE.0b013e3181c22146 PubMed DOI

Lancel M, Crönlein J, Müller-Preuss P, Holsboer F (1995) Lipopolysaccharide increases EEG delta activity within non-REM sleep and disrupts sleep continuity in rats. Am J Physiol 268:R1310–R1318. 10.1152/ajpregu.1995.268.5.R1310 PubMed DOI

Lanza G, DelRosso LM, Ferri R (2022) Sleep and homeostatic control of plasticity. Handb Clin Neurol 184:53–72. 10.1016/B978-0-12-819410-2.00004-7 PubMed DOI

Leemburg S, Gao B, Cam E, Sarnthein J, Bassetti CL (2018) Power spectrum slope is related to motor function after focal cerebral ischemia in the rat. Sleep. 10.1093/sleep/zsy132. PubMed DOI

Loh M, Rolls E, Deco G (2007) Statistical fluctuations in attractor networks related to schizophrenia. Pharmacopsychiatry 40:S78–S84. 10.1055/s-2007-990304 DOI

Mamad O, Islam MN, Cunningham C, Tsanov M (2018) Differential response of hippocampal and prefrontal oscillations to systemic LPS application. Brain Res 1681:64–74. 10.1016/j.brainres.2017.12.036 PubMed DOI PMC

Oddo M, Carrera E, Claassen J, Mayer SA, Hirsch LJ (2009) Continuous electroencephalography in the medical intensive care unit. Crit Care Med 37:2051–2056. 10.1097/CCM.0b013e3181a00604 PubMed DOI

Ohta A, Sitkovsky M (2001) Role of G-protein-coupled adenosine receptors in downregulation of inflammation and protection from tissue damage. Nature 414:916–920. 10.1038/414916a PubMed DOI

Opp MR (2005) Cytokines and sleep. Sleep Med Rev 9:355–364. 10.1016/j.smrv.2005.01.002 PubMed DOI

Pagliardini S, Gosgnach S, Dickson CT (2013) Spontaneous sleep-like brain state alternations and breathing characteristics in urethane anesthetized mice. PLoS One 8:e70411. 10.1371/journal.pone.0070411 PubMed DOI PMC

Pereira de Souza Goldim M, et al.. (2020) Sickness behavior score is associated with neuroinflammation and late behavioral changes in polymicrobial sepsis animal model. Inflammation 43:1019–1034. 10.1007/s10753-020-01187-z PubMed DOI

Reichert CF, Deboer T, Landolt H-P (2022) Adenosine, caffeine, and sleep–wake regulation: state of the science and perspectives. J Sleep Res 31:e13597. 10.1111/jsr.13597 PubMed DOI PMC

Rhee C, et al. (2017) Incidence and trends of sepsis in US hospitals using clinical vs claims data, 2009-2014. JAMA 318:1241–1249. 10.1001/jama.2017.13836 PubMed DOI PMC

Riazi K, Galic MA, Pittman QJ (2010) Contributions of peripheral inflammation to seizure susceptibility: cytokines and brain excitability. Epilepsy Res 89:34–42. 10.1016/j.eplepsyres.2009.09.004 PubMed DOI

Richards KC, Bairnsfather L (1988) A description of night sleep patterns in the critical care unit. Heart Lung 17:35–42. PubMed

Rolls ET (2021) Brain computations: what and how. Oxford: Oxford University Press.

Rosengarten B, Krekel D, Kuhnert S, Schulz R (2012) Early neurovascular uncoupling in the brain during community acquired pneumonia. Crit Care 16:R64. 10.1186/cc11310 PubMed DOI PMC

Sánchez-López A, Silva-Pérez M, Escudero M (2018) Temporal dynamics of the transition period between nonrapid eye movement and rapid eye movement sleep in the rat. Sleep 10.1093/sleep/zsy121. PubMed DOI

Schmitt K, Holsboer-Trachsler E, Eckert A (2016) BDNF in sleep, insomnia, and sleep deprivation. Ann Med 48:42–51. 10.3109/07853890.2015.1131327 PubMed DOI

Schoch SF, Werth E, Poryazova R, Scammell TE, Baumann CR, Imbach LL (2017) Dysregulation of sleep behavioral states in narcolepsy. Sleep 10.1093/sleep/zsx170. PubMed DOI

Semmler A, Hermann S, Mormann F, Weberpals M, Paxian SA, Okulla T, Schäfers M, Kummer MP, Klockgether T, Heneka MT (2008) Sepsis causes neuroinflammation and concomitant decrease of cerebral metabolism. J Neuroinflammation 5:38. 10.1186/1742-2094-5-38 PubMed DOI PMC

Siegle JH, López AC, Patel YA, Abramov K, Ohayon S, Voigts J (2017) Open Ephys: an open-source, plugin-based platform for multichannel electrophysiology. J Neural Eng 14:e045003. 10.1088/1741-2552/aa5eea PubMed DOI

Song IA, Park HY, Oh TK (2021) Sleep disorder and long-term mortality among sepsis survivors: a nationwide cohort study in South Korea. Nat Sci Sleep 13:979–988. 10.2147/NSS.S319769 PubMed DOI PMC

Sonneville R, Verdonk F, Rauturier C, Klein IF, Wolff M, Annane D, Chretien F, Sharshar T (2013) Understanding brain dysfunction in sepsis. Ann Intensive Care 3:15. 10.1186/2110-5820-3-15 PubMed DOI PMC

Spira AP, Chen-Edinboro LP, Wu MN, Yaffe K (2014) Impact of sleep on the risk of cognitive decline and dementia. Curr Opin Psychiatry 27:478–483. 10.1097/YCO.0000000000000106 PubMed DOI PMC

Straver JS, Keunen RWM, Stam CJ, Tavy DLJ, de Ruiter GR, Smith SJ, Thijs LG, Schellens RGA, Gielen G (1998) Nonlinear analysis of EEG in septic encephalopathy. Neurol Res 20:100–106. 10.1080/01616412.1998.11740490 PubMed DOI

Tononi G, Cirelli C (2014) Sleep and the price of plasticity: from synaptic and cellular homeostasis to memory consolidation and integration. Neuron 81:12–34. 10.1016/j.neuron.2013.12.025 PubMed DOI PMC

Urdanibia-Centelles O, Nielsen RM, Rostrup E, Vedel-Larsen E, Thomsen K, Nikolic M, Johnsen B, Møller K, Lauritzen M, Benedek K (2021) Automatic continuous EEG signal analysis for diagnosis of delirium in patients with sepsis. Clin Neurophysiol 132:2075–2082. 10.1016/j.clinph.2021.05.013 PubMed DOI

Wang Y, Wei H, Tong J, Ji M, Yang J (2020) pSynGAP1 disturbance-mediated hippocampal oscillation network impairment might contribute to long-term neurobehavioral abnormities in sepsis survivors. Aging 12:23146–23164. 10.18632/aging.104080 PubMed DOI PMC

Weinhouse GL, Schwab RJ (2006) Sleep in the critically ill patient. Sleep 29:707–716. 10.1093/sleep/29.5.707 PubMed DOI

Weinhouse GL, Schwab RJ, Watson PL, Patil N, Vaccaro B, Pandharipande P, Ely EW (2009) Bench-to-bedside review: delirium in ICU patients - importance of sleep deprivation. Crit Care 13:234. 10.1186/cc8131 PubMed DOI PMC

Yamanashi T, Marra PS, Crutchley KJ, Wahba NE, Malicoat JR, Sullivan EJ, Akers CC, Nicholson CA, Herrmann FM, Karam MD, Noiseux NO, Kaneko K, Shinozaki E, Iwata M, Cho HR, Lee S, Shinozaki G (2021) Mortality among patients with sepsis associated with a bispectral electroencephalography (BSEEG) score. Sci Rep 11:14211. 10.1038/s41598-021-93588-9 PubMed DOI PMC

Zamore Z, Veasey SC (2022) Neural consequences of chronic sleep disruption. Trends Neurosci 45:678–691. 10.1016/j.tins.2022.05.007 PubMed DOI PMC

Zhang L, Gao YZ, Zhao CJ, Xia JY, Yang JJ, Ji MH (2023) Reduced inhibitory and excitatory input onto parvalbumin interneurons mediated by perineuronal net might contribute to cognitive impairments in a mouse model of sepsis-associated encephalopathy. Neuropharmacology 225:109382. 10.1016/j.neuropharm.2022.109382 PubMed DOI