Sawtooth waves (STW) are bursts of frontocentral slow oscillations recorded in the scalp electroencephalogram (EEG) during rapid eye movement (REM) sleep. Little is known about their cortical generators and functional significance. Stereo-EEG performed for presurgical epilepsy evaluation offers the unique possibility to study neurophysiology in situ in the human brain. We investigated intracranial correlates of scalp-detected STW in 26 patients (14 women) undergoing combined stereo-EEG/polysomnography. We visually marked STW segments in scalp EEG and selected stereo-EEG channels exhibiting normal activity for intracranial analyses. Channels were grouped in 30 brain regions. The spectral power in each channel and frequency band was computed during STW and non-STW control segments. Ripples (80-250 Hz) were automatically detected during STW and control segments. The spectral power in the different frequency bands and the ripple rates were then compared between STW and control segments in each brain region. An increase in 2-4 Hz power during STW segments was found in all brain regions, except the occipital lobe, with large effect sizes in the parietotemporal junction, the lateral and orbital frontal cortex, the anterior insula, and mesiotemporal structures. A widespread increase in high-frequency activity, including ripples, was observed concomitantly, involving the sensorimotor cortex, associative areas, and limbic structures. This distribution showed a high spatiotemporal heterogeneity. Our results suggest that STW are associated with widely distributed, but locally regulated REM sleep slow oscillations. By driving fast activities, STW may orchestrate synchronized reactivations of multifocal activities, allowing tagging of complex representations necessary for REM sleep-dependent memory consolidation.SIGNIFICANCE STATEMENT Sawtooth waves (STW) present as scalp electroencephalographic (EEG) bursts of slow waves contrasting with the low-voltage fast desynchronized activity of REM sleep. Little is known about their cortical origin and function. Using combined stereo-EEG/polysomnography possible only in the human brain during presurgical epilepsy evaluation, we explored the intracranial correlates of STW. We found that a large set of regions in the parietal, frontal, and insular cortices shows increases in 2-4 Hz power during scalp EEG STW, that STW are associated with a strong and widespread increase in high frequencies, and that these slow and fast activities exhibit a high spatiotemporal heterogeneity. These electrophysiological properties suggest that STW may be involved in cognitive processes during REM sleep.

Analytical Neurophysiology Lab Montreal Neurological Institute and Hospital McGill University Montreal Quebec H3A 2B4 Canada

Brno Epilepsy Center 1st Department of Neurology St Anne's University Hospital and Faculty of Medicine Masaryk University Brno Czech Republic 656 91 Brno

Center for Sleep Medicine and Respiratory Diseases Hospices Civils de Lyon Lyon 1 University Lyon F 69000 France

Lyon Neuroscience Research Center Centre National de la Recherche Scientifique Unité Mixte de Recherche 5292 Institut National de la Santé et de la Recherche Médicale U1028 Lyon F 69000 France

Montreal Neurological Institute and Hospital McGill University Montreal Quebec H3A 2B4 Canada

See more in PubMed

Amzica F, Steriade M (1996) Progressive cortical synchronization of ponto-geniculo-occipital potentials during rapid eye movement sleep. Neuroscience 72:309–314. 10.1016/0306-4522(96)00012-7 PubMed DOI

Andrillon T, Nir Y, Cirelli C, Tononi G, Fried I (2015) Single-neuron activity and eye movements during human REM sleep and awake vision. Nat Commun 6:7884. 10.1038/ncomms8884 PubMed DOI PMC

Balzamo E. (1980) States of wakefulness and ponto-geniculo-cortical activities (PGC) in Papio anubis (author's transl). Electroencephalogr Clin Neurophysiol 48:694–705. 10.1016/0013-4694(80)90426-5 PubMed DOI

Bassetti CL, Aldrich MS (2001) Sleep electroencephalogram changes in acute hemispheric stroke. Sleep Med 2:185–194. 10.1016/S1389-9457(00)00071-X PubMed DOI

Berger R, Olley P, Oswald I (1962) The EEG, eye movements and dreams of the blind. Q J Exp Psychol 14:183–186. 10.1080/17470216208416534 DOI

Bernardi G, Betta M, Ricciardi E, Pietrini P, Tononi G, Siclari F (2019) Regional delta waves in human rapid-eye movement sleep. J Neurosci 39:2686–2697. PubMed PMC

Berry RB, Brooks R, Gamaldo CE, Harding SM, Lloyd R, Marcus CL, Vaughn BV (2017) The AASM manual for the scoring of sleep and associated events: rules, terminology and technical specifications, Version 2.4. Darien, IL: American Academy of Sleep Medicine.

Boyce R, Williams S, Adamantidis A (2017) REM sleep and memory. Curr Opin Neurobiol 44:167–177. 10.1016/j.conb.2017.05.001 PubMed DOI

Broughton R, Hasan J (1995) Quantitative topographic electroencephalographic mapping during drowsiness and sleep onset. J Clin Neurophysiol 12:372–386. PubMed

Callaway CW, Lydic R, Baghdoyan HA, Hobson JA (1987) Pontogeniculooccipital waves: spontaneous visual system activity during rapid eye movement sleep. Cell Mol Neurobiol 7:105–149. 10.1007/BF00711551 PubMed DOI PMC

Campana C, Zubler F, Gibbs S, de Carli F, Proserpio P, Rubino A, Cossu M, Tassi L, Schindler K, Nobili L (2017) Suppression of interictal spikes during phasic rapid eye movement sleep: a quantitative stereo-electroencephalography study. J Sleep Res 26:606–613. 10.1111/jsr.12533 PubMed DOI

Carskadon MA, Dement WC (2017) Normal human sleep: an overview. In: Principles and practice of sleep medicine, Ed 6 (Kryger MH, Dement WC, eds), pp 15–24. Philadelphia: Elsevier.

Clemens Z, Molle M, Eross L, Barsi P, Halasz P, Born J (2007) Temporal coupling of parahippocampal ripples, sleep spindles and slow oscillations in humans. Brain 130:2868–2878. 10.1093/brain/awm146 PubMed DOI

Clemens Z, Weiss B, Szucs A, Eross L, Rasonyi G, Halasz P (2009) Phase coupling between rhythmic slow activity and gamma characterizes mesiotemporal rapid-eye-movement sleep in humans. Neuroscience 163:388–396. 10.1016/j.neuroscience.2009.06.044 PubMed DOI

Datta S. (1997) Cellular basis of pontine ponto-geniculo-occipital wave generation and modulation. Cell Mol Neurobiol 17:341–365. 10.1023/a:1026398402985 PubMed DOI PMC

Datta S, Mavanji V, Ulloor J, Patterson EH (2004) Activation of phasic pontine-wave generator prevents rapid eye movement sleep deprivation-induced learning impairment in the rat: a mechanism for sleep-dependent plasticity. J Neurosci 24:1416–1427. 10.1523/JNEUROSCI.4111-03.2004 PubMed DOI PMC

De Carli F, Proserpio P, Morrone E, Sartori I, Ferrara M, Gibbs SA, De Gennaro L, Lo Russo G, Nobili L (2016) Activation of the motor cortex during phasic rapid eye movement sleep. Ann Neurol 79:326–330. 10.1002/ana.24556 PubMed DOI PMC

Dement W, Kleitman N (1957) Cyclic variations in EEG during sleep and their relation to eye movements, body motility, and dreaming. Electroencephalogr Clin Neurophysiol 9:673–690. 10.1016/0013-4694(57)90088-3 PubMed DOI

Diekelmann S, Born J (2010) The memory function of sleep. Nat Rev Neurosci 11:114–126. 10.1038/nrn2762 PubMed DOI

Drouin S, Kochanowska A, Kersten-Oertel M, Gerard IJ, Zelmann R, De Nigris D, Beriault S, Arbel T, Sirhan D, Sadikot AF, Hall JA, Sinclair DS, Petrecca K, DelMaestro RF, Collins DL (2017) IBIS: an OR ready open-source platform for image-guided neurosurgery. Int J Comput Assist Radiol Surg 12:363–378. 10.1007/s11548-016-1478-0 PubMed DOI

Ermis U, Krakow K, Voss U (2010) Arousal thresholds during human tonic and phasic REM sleep. J Sleep Res 19:400–406. 10.1111/j.1365-2869.2010.00831.x PubMed DOI

Frauscher B, von Ellenrieder N, Dubeau F, Gotman J (2015) Scalp spindles are associated with widespread intracranial activity with unexpectedly low synchrony. Neuroimage 105:1–12. 10.1016/j.neuroimage.2014.10.048 PubMed DOI PMC

Frauscher B, Joshi S, von Ellenrieder N, Nguyen DK, Dubeau F, Gotman J (2018a) Sharply contoured theta waves are the human correlate of ponto-geniculo-occipital waves in the primary visual cortex. Clin Neurophysiol 129:1526–1533. 10.1016/j.clinph.2018.04.605 PubMed DOI

Frauscher B, von Ellenrieder N, Zelmann R, Rogers C, Nguyen DK, Kahane P, Dubeau F, Gotman J (2018b) High-frequency oscillations in the normal human brain. Ann Neurol 84:374–385. 10.1002/ana.25304 PubMed DOI

Frauscher B, von Ellenrieder N, Zelmann R, Dolezalova I, Minotti L, Olivier A, Hall J, Hoffmann D, Nguyen DK, Kahane P, Dubeau F, Gotman J (2018c) Atlas of the normal intracranial electroencephalogram: neurophysiological awake activity in different cortical areas. Brain 141:1130–1144. 10.1093/brain/awy035 PubMed DOI

Geisler P, Meier-Ewert K, Matsubayshi K (1987) Rapid eye movements, muscle twitches and sawtooth waves in the sleep of narcoleptic patients and controls. Electroencephalogr Clin Neurophysiol 67:499–507. 10.1016/0013-4694(87)90051-4 PubMed DOI

Gross DW, Gotman J (1999) Correlation of high-frequency oscillations with the sleep-wake cycle and cognitive activity in humans. Neuroscience 94:1005–1018. 10.1016/s0306-4522(99)00343-7 PubMed DOI

Ishiguro T, Hanamura S, Okata T (1979) The saw-tooth wave associated with small nystagmus: a study on a narcoleptic patient and her family. Sleep Res 8:195.

Ives JR. (2005) New chronic EEG electrode for critical/intensive care unit monitoring. J Clin Neurophysiol 22:119–123. 10.1097/01.wnp.0000152659.30753.47 PubMed DOI

Jain A, Dubes R (1988) Algorithms for clustering data. Upper Saddle River, NJ: Prentice-Hall.

Jain SV, Glauser TA (2014) Effects of epilepsy treatments on sleep architecture and daytime sleepiness: an evidence-based review of objective sleep metrics. Epilepsia 55:26–37. 10.1111/epi.12478 PubMed DOI

Ji D, Wilson MA (2007) Coordinated memory replay in the visual cortex and hippocampus during sleep. Nat Neurosci 10:100–107. 10.1038/nn1825 PubMed DOI

Jiang X, Gonzalez-Martinez J, Halgren E (2019) Coordination of human hippocampal sharpwave ripples during NREM sleep with cortical theta bursts, spindles, downstates, and upstates. J Neurosci 39:8744–8761. 10.1523/JNEUROSCI.2857-18.2019 PubMed DOI PMC

Jouvet M, Michel F (1959) [Electromyographic correlations of sleep in the chronic decorticate and mesencephalic cat]. C R Seances Soc Biol Fil 153:422–425. PubMed

Jouvet M, Michel F, Mounier D (1960) [Comparative electroencephalographic analysis of physiological sleep in the cat and in man]. Rev Neurol (Paris) 103:189–205. PubMed

Lachaux JP, Axmacher N, Mormann F, Halgren E, Crone NE (2012) High-frequency neural activity and human cognition: past, present and possible future of intracranial EEG research. Prog Neurobiol 98:279–301. 10.1016/j.pneurobio.2012.06.008 PubMed DOI PMC

Landman B, Warfield S (2012) 2012 workshop on multi-atlas labeling. Create Space Indendant Publushing Plateform. Scotts Valley, CA.

Latreille V, von Ellenrieder N, Peter-Derex L, Dubeau F, Gotman J, Frauscher B (2020) The human K-complex: insights from combined scalp-intracranial EEG recordings. Neuroimage 213:116748. 10.1016/j.neuroimage.2020.116748 PubMed DOI

Lim AS, Lozano AM, Moro E, Hamani C, Hutchison WD, Dostrovsky JO, Lang AE, Wennberg RA, Murray BJ (2007) Characterization of REM-sleep associated ponto-geniculo-occipital waves in the human pons. Sleep 30:823–827. 10.1093/sleep/30.7.823 PubMed DOI PMC

Louie K, Wilson MA (2001) Temporally structured replay of awake hippocampal ensemble activity during rapid eye movement sleep. Neuron 29:145–156. 10.1016/s0896-6273(01)00186-6 PubMed DOI

Luppi PH, Fort P (2019) Sleep-wake physiology. Handb Clin Neurol 160:359–370. 10.1016/B978-0-444-64032-1.00023-0 PubMed DOI

Michel F, Jeannerod M, Mouret J, Rechtschaffen A, Jouvet M (1964) [On the mechanisms of activity of points at the level of the visual system during the paradoxal phase of sleep]. C R Seances Soc Biol Fil 158:103–106. PubMed

Montgomery SM, Sirota A, Buzsaki G (2008) Theta and gamma coordination of hippocampal networks during waking and rapid eye movement sleep. J Neurosci 28:6731–6741. 10.1523/JNEUROSCI.1227-08.2008 PubMed DOI PMC

Nelson JP, McCarley RW, Hobson JA (1983) REM sleep burst neurons, PGO waves, and eye movement information. J Neurophysiol 50:784–797. 10.1152/jn.1983.50.4.784 PubMed DOI

Nir Y, Staba RJ, Andrillon T, Vyazovskiy VV, Cirelli C, Fried I, Tononi G (2011) Regional slow waves and spindles in human sleep. Neuron 70:153–169. 10.1016/j.neuron.2011.02.043 PubMed DOI PMC

Pearl PL, LaFleur BJ, Reigle SC, Rich AS, Freeman AA, McCutchen C, Sato S (2002) Sawtooth wave density analysis during REM sleep in normal volunteers. Sleep Med 3:255–258. 10.1016/s1389-9457(01)00142-3 PubMed DOI

Peigneux P, Laureys S, Fuchs S, Delbeuck X, Degueldre C, Aerts J, Delfiore G, Luxen A, Maquet P (2001) Generation of rapid eye movements during paradoxical sleep in humans. Neuroimage 14:701–708. 10.1006/nimg.2001.0874 PubMed DOI

Peter-Derex L, Comte JC, Mauguière F, Salin PA (2012) Density and frequency caudo-rostral gradients of sleep spindles recorded in the human cortex. Sleep 35:69–79. 10.5665/sleep.1588 PubMed DOI PMC

Pfurtscheller G, Lopes da Silva FH (1999) Event-related EEG/MEG synchronization and desynchronization: basic principles. Clin Neurophysiol 110:1842–1857. 10.1016/s1388-2457(99)00141-8 PubMed DOI

Pinto LR Jr, Peres CA, Russo RH, Remesar-Lopez AJ, Tufik S (2002) Sawtooth waves during REM sleep after administration of haloperidol combined with total sleep deprivation in healthy young subjects. Braz J Med Biol Res 35:599–604. 10.1590/s0100-879x2002000500013 PubMed DOI

Raichle ME, MacLeod AM, Snyder AZ, Powers WJ, Gusnard DA, Shulman GL (2001) A default mode of brain function. Proc Natl Acad Sci USA 98:676–682. 10.1073/pnas.98.2.676 PubMed DOI PMC

Rasch B, Born J (2013) About sleep's role in memory. Physiol Rev 93:681–766. 10.1152/physrev.00032.2012 PubMed DOI PMC

Rechtschaffen A, Kales A (1968) A manual of standardized terminology, techniques and scoring system for sleep stage of human subjects. Los Angeles: Brain Information Service/Brain Research Institute, University of California.

Rodenbeck A, Binder R, Geisler P, Danker-Hopfe H, Lund R, Raschke F, Weeß HG, Schulz H (2006) A review of sleep EEG patterns: I. A compilation of amended rules for their visual recognition according to Rechtschaffen and Kales. Somnologie 10:159–175. 10.1111/j.1439-054X.2006.00101.x DOI

Sato S, McCutchen C, Graham B, Freeman A, von Albertini-Carletti I, Alling DW (1997) Relationship between muscle tone changes, sawtooth waves and rapid eye movements during sleep. Electroencephalogr Clin Neurophysiol 103:627–632. 10.1016/S0013-4694(97)00072-2 PubMed DOI

Siegel H, McCutchen C, Dalakas MC, Freeman A, Graham B, Alling D, Sato S (1999) Physiologic events initiating REM sleep in patients with the postpolio syndrome. Neurology 52:516–522. 10.1212/WNL.52.3.516 PubMed DOI

Siegel J. (2011) REM sleep. In: Principles and practice of sleep medicine, Ed 5 (Kryger MH, Dement WC, eds, pp 92–111. St. Louis: Elsevier Saunders.

Simor P, Gombos F, Szakadat S, Sandor P, Bodizs R (2016) EEG spectral power in phasic and tonic REM sleep: different patterns in young adults and children. J Sleep Res 25:269–277. 10.1111/jsr.12376 PubMed DOI

Simor P, van Der Wijk G, Gombos F, Kovács I (2019) The paradox of rapid eye movement sleep in the light of oscillatory activity and cortical synchronization during phasic and tonic microstates. Neuroimage 202:116066. 10.1016/j.neuroimage.2019.116066 PubMed DOI

Simor P, van der Wijk G, Nobili L, Peigneux P (2020) The microstructure of REM sleep: why phasic and tonic? Sleep Med Rev 52:101305. 10.1016/j.smrv.2020.101305 PubMed DOI

Snyder EW, Dustman RE, Johnson RL (1978) Sawtooth waves: concomitants of rapid eye movement sleep in monkeys. Electroencephalogr Clin Neurophysiol 45:111–113. 10.1016/0013-4694(78)90348-6 PubMed DOI

Staresina BP, Bergmann TO, Bonnefond M, van der Meij R, Jensen O, Deuker L, Elger CE, Axmacher N, Fell J (2015) Hierarchical nesting of slow oscillations, spindles and ripples in the human hippocampus during sleep. Nat Neurosci 18:1679–1686. 10.1038/nn.4119 PubMed DOI PMC

Steriade M. (2003) The corticothalamic system in sleep. Front Biosci 8:d878–d899. 10.2741/1043 PubMed DOI

Steriade M, McCormick DA, Sejnowski TJ (1993) Thalamocortical oscillations in the sleeping and aroused brain. Science 262:679–685. 10.1126/science.8235588 PubMed DOI

Szurhaj W, Derambure P (2006) Intracerebral study of gamma oscillations in the human sensorimotor cortex. Prog Brain Res 159:297–310. 10.1016/S0079-6123(06)59020-X PubMed DOI

Vega-Bermudez F, Szczepanski S, Malow B, Sato S (2005) Sawtooth wave density analysis during REM sleep in temporal lobe epilepsy patients. Sleep Med 6:367–370. 10.1016/j.sleep.2005.02.005 PubMed DOI

von Ellenrieder N, Gotman J, Zelmann R, Rogers C, Nguyen DK, Kahane P, Dubeau F, Frauscher B (2020) How the human brain sleeps: direct cortical recordings of normal brain activity. Ann Neurol 87:289–301. 10.1002/ana.25651 PubMed DOI

Walker MP, van der Helm E (2009) Overnight therapy? The role of sleep in emotional brain processing. Psychol Bull 135:731–748. 10.1037/a0016570 PubMed DOI PMC

Wehrle R, Kaufmann C, Wetter TC, Holsboer F, Auer DP, Pollmacher T, Czisch M (2007) Functional microstates within human REM sleep: first evidence from fMRI of a thalamocortical network specific for phasic REM periods. Eur J Neurosci 25:863–871. 10.1111/j.1460-9568.2007.05314.x PubMed DOI

Yasoshima A, Hayashi H, Iijima S, Sugita Y, Teshima Y, Shimizu T, Hishikawa Y (1984) Potential distribution of vertex sharp wave and saw-toothed wave on the scalp. Electroencephalogr Clin Neurophysiol 58:73–76. 10.1016/0013-4694(84)90202-5 PubMed DOI