The Sleeping Cerebellum
Authors: Cathrin B. Canto, Yoshiyuki Onuki, Bastiaan Bruinsma, Ysbrand D. van der Werf, Chris I. De Zeeuw
Journal: Trends in Neurosciences (2017)

Sleep supports cognitive processes and sleep disturbances are associated with neuropsychiatric syndromes as well as memory impairments. To what extent the cerebellum sleeps and to what extent sleep is critical for the cerebellum-dependent memory formation and consolidation remain to be elucidated. The cerebellum shows sleep stage–dependent activity and its malfunctions can lead to changes in the sleep–wake cycle, leading to sleep disorders. The cerebral cortex and cerebellum strongly interact during both the awake state and sleep, and such interactions during sleep also contribute to consolidation of memories. Given the sleep stage–dependent character of cerebellar activity and of the neocortical–cerebellar interactions, the role of this activity and these interactions for memory consolidation might strongly depend on the precise sleep stage and sleep architecture. We sleep almost one-third of our lives and sleep plays an important role in critical brain functions like memory formation and consolidation. The role of sleep in cerebellar processing, however, constitutes an enigma in the field of neuroscience; we know little about cerebellar sleep-physiology, cerebro–cerebellar interactions during sleep, or the contributions of sleep to cerebellum-dependent memory consolidation. Likewise, we do not understand why cerebellar malfunction can lead to changes in the sleep–wake cycle and sleep disorders. In this review, we evaluate how sleep and cerebellar processing may influence one another and highlight which scientific routes and technical approaches could be taken to uncover the mechanisms underlying these interactions. We sleep almost one-third of our lives and sleep plays an important role in critical brain functions like memory formation and consolidation. The role of sleep in cerebellar processing, however, constitutes an enigma in the field of neuroscience; we know little about cerebellar sleep-physiology, cerebro–cerebellar interactions during sleep, or the contributions of sleep to cerebellum-dependent memory consolidation. Likewise, we do not understand why cerebellar malfunction can lead to changes in the sleep–wake cycle and sleep disorders. In this review, we evaluate how sleep and cerebellar processing may influence one another and highlight which scientific routes and technical approaches could be taken to uncover the mechanisms underlying these interactions. Sleep is an important brain function that supports cognitive processes such as memory retrieval, learning, attention, language processing, decision making, and even creativity [1Diekelmann S. Born J. The memory function of sleep.Nat. Rev. Neurosci. 2010; 11: 114-126Crossref PubMed Scopus (14) Google Scholar, 2Diekelmann S. Sleep for cognitive enhancement.Front. Syst. Neurosci. 2014; 8: 46Crossref PubMed Scopus (35) Google Scholar]. As a consequence, the neuronal circuitries and cellular mechanisms that underlie the transitions between wakefulness and sleep or between various sleep stages have been investigated thoroughly and have led to models about how such state transitions occur [3Saper C.B. et al.Sleep state switching.Neuron. 2010; 68: 1023-1042Abstract Full Text Full Text PDF PubMed Scopus (465) Google Scholar, 4Brown R.E. et al.Control of sleep and wakefulness.Physiol. Rev. 2012; 92: 1087-1187Crossref PubMed Scopus (373) Google Scholar]. To date, based on polysomnographic (see Glossary) measurements, sleep can be subdivided into rapid eye movement (REM) and nonrapid eye movement stages 1–3 (NREM1–3; Figure 1A) [5Berry R. et al.The AASM Manual for the Scoring of Sleep and Associated Events: Rules, Terminology, and Technical Specifications Version 2.2. American Academy of Sleep Medicine, 2015Google Scholar]. Up to this point, sleep research has mainly focused on how these states correlate across the neocortical and subcortical structures, whereas cerebellar activity has been largely ignored. This neglect is intriguing, because malfunction of the cerebellum does not only impair motor control and motor memory formation [6Krakauer J.W. Shadmehr R. Consolidation of motor memory.Trends Neurosci. 2006; 29: 58-64Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar, 7De Zeeuw C.I. et al.Spatiotemporal firing patterns in the cerebellum.Nat. Rev. Neurosci. 2011; 12: 327-344Crossref PubMed Scopus (174) Google Scholar, 8Gao Z. et al.Distributed synergistic plasticity and cerebellar learning.Nat. Rev. Neurosci. 2012; 13: 619-635Crossref PubMed Scopus (196) Google Scholar], but it may also lead to changes in the sleep–wake cycle [9Cunchillos J. De Andrés I. Participation of the cerebellum in the regulation of the sleep-wakefulness cycle. Results in cerebellectomized cats.Electroencephalogr. Clin. Neurophysiol. 1982; 53: 549-558Abstract Full Text PDF PubMed Scopus (21) Google Scholar, 10de Andrés I. et al.Functional anatomy of non-REM sleep.Front. Neurol. 2011; 2: 70Crossref PubMed Scopus (0) Google Scholar] and even cause sleep disorders [11DelRosso L.M. Hoque R. The cerebellum and sleep.Neurol. Clin. 2014; 32: 893-900Abstract Full Text Full Text PDF PubMed Google Scholar]. Furthermore, decades of behavioral and physiological research has shown the positive impact of sleep on episodic memory formation. To what extent sleep is also critical for cerebellum-dependent procedural memory formation and motor control, however, is still under fervent debate. The cerebellum is well connected with the cerebrum and the neuronal circuitry underlying sleep–wake regulation (Box 1) . In addition, many cerebellar neurons express clock genes associated with control of the circadian rhythm (Box 2). Nevertheless, a marked dearth of data exists on the relation between cerebellar processing and various sleep stages. It remains unclear whether the cerebellum enters sleep, and if so, whether cerebellar activity continues to change in line with the REM and NREM sleep stages and whether cerebellar activity may itself affect the process of sleep. Here, we review and evaluate studies of the neuronal activity of the cerebellum as well as its interactions with the cerebral cortex during sleep, address the question of how malfunctioning of the cerebellum may affect sleep, and, finally, ask to what extent sleep may affect cerebellum-dependent memory formation and memory consolidation.Box 1Neuromodulators Influencing the Wake–Sleep NetworkDistinct neuronal networks and related afferent pathways with specific monoaminergic neurotransmitters are involved in regulation of wake–sleep stages. Many of these neurotransmitters influence cerebellar activity (Figure I), but their role in regulation of cerebellar processing during sleep has been neglected. Cell populations known to project to the cerebellum and to alter the state of arousal include the cholinergic, noradrenergic, serotonergic, histaminergic, orexinergic, and dopaminergic inputs. Injections of such monoamines or agonists of their receptors into the cerebellum can facilitate wakefulness and/or consolidation of various tasks, further supporting a role for neuromodulators during sleep-related cerebellum-dependent consolidation [102Barik S. De Beaurepaire R. Dopamine D3 modulation of locomotor activity and sleep in the nucleus accumbens and in lobules 9 and 10 of the cerebellum in the rat.Prog. Neuropsychopharmacol. Biol. Psychiatry. 2005; 29: 718-726Crossref PubMed Scopus (0) Google Scholar, 103Silva-Marques B. Intracerebellar vermis histamine facilitates memory consolidation in the elevated T maze model.Neurosci. Lett. 2016; 620: 33-37Crossref PubMed Scopus (0) Google Scholar, 104van Neerven J. et al.Injections of β-noradrenergic substances in the flocculus of rabbits affect adaptation of the VOR gain.Exp. Brain Res. 1990; 141: 537Google Scholar, 105Tan H.S. et al.Effects of alpha-noradrenergic substances on the optokinetic and vestibulo-ocular responses in the rabbit: a study with systemic and intrafloccular injections.Brain Res. 1991; 562: 207-215Crossref PubMed Scopus (3) Google Scholar]. Most, if not all, of the monoaminergic systems also have widespread impact on other parts of the brain involved in sleep control. For example, the noradrenergic, serotonergic, and histaminergic neurons control the GABAergic galanin-containing neurons of the ventrolateral and median preoptic nucleus that become active during NREM [3Saper C.B. et al.Sleep state switching.Neuron. 2010; 68: 1023-1042Abstract Full Text Full Text PDF PubMed Scopus (465) Google Scholar], while orexinergic neurons can stabilize the switch between the wake–sleep-promoting networks [3Saper C.B. et al.Sleep state switching.Neuron. 2010; 68: 1023-1042Abstract Full Text Full Text PDF PubMed Scopus (465) Google Scholar, 10de Andrés I. et al.Functional anatomy of non-REM sleep.Front. Neurol. 2011; 2: 70Crossref PubMed Scopus (0) Google Scholar].Box 2Clock and Wake–Sleep-Related Genes in the CerebellumThe suprachiasmatic nucleus (SCN) of the hypothalamus, which controls and modulates the circadian rhythm, interacts with both the wake- and sleep-promoting networks [3Saper C.B. et al.Sleep state switching.Neuron. 2010; 68: 1023-1042Abstract Full Text Full Text PDF PubMed Scopus (465) Google Scholar]. Genes that regulate the rhythmicity of neurons in the SCN are called clock genes. Several clock genes, including Arntl, Nr1d1, Bmal1, Per1, Per2, and Cry1, have also been found in the Purkinje cell and granular cell layer of the cerebellum [132Rath M.F. et al.Circadian oscillators in the mouse brain: molecular clock components in the neocortex and cerebellar cortex.Cell Tissue Res. 2014; 357: 743-755Crossref PubMed Scopus (4) Google Scholar, 133Honma S. et al.Circadian oscillation of BMAL1, a partner of a mammalian clock gene clock, in rat suprachiasmatic nucleus.Biochem. Biophys. Res. Commun. 1998; 250: 83-87Crossref PubMed Scopus (0) Google Scholar]. Their expression pattern follows that of the SCN, but with a delay of 5 h [132Rath M.F. et al.Circadian oscillators in the mouse brain: molecular clock components in the neocortex and cerebellar cortex.Cell Tissue Res. 2014; 357: 743-755Crossref PubMed Scopus (4) Google Scholar, 134Rath M.F. et al.Circadian oscillations of molecular clock components in the cerebellar cortex of the rat.Chronobiol. Int. 2012; 29: 1289-1299Crossref PubMed Scopus (8) Google Scholar]. Even in vitro the cerebellum is able to express near-24-h rhythms and these rhythms can be shifted by shifting 'mealtime' exposure [135Mendoza J. et al.The cerebellum harbors a circadian oscillator involved in food anticipation.J. Neurosci. 2010; 30: 1894-1904Crossref PubMed Scopus (44) Google Scholar]. However, rhythmic clock gene expression in the cerebellum is affected in response to SCN lesioning, suggesting that the cerebellum needs input from external brain areas to maintain its rhythmicity [134Rath M.F. et al.Circadian oscillations of molecular clock components in the cerebellar cortex of the rat.Chronobiol. Int. 2012; 29: 1289-1299Crossref PubMed Scopus (8) Google Scholar, 136Mordel J. et al.The output signal of Purkinje cells of the cerebellum and circadian rhythmicity.PLoS One. 2013; 8: e58457Crossref PubMed Scopus (0) Google Scholar]. In addition to clock genes, the cerebellum also expresses various other genes showing circadian patterns; these include at least 106 sleep-related transcripts and 117 wake-related transcripts [137Cirelli C. et al.Extensive and divergent effects of sleep and wakefulness on brain gene expression.Neuron. 2004; 41: 35-43Abstract Full Text Full Text PDF PubMed Scopus (365) Google Scholar]. The genes that showed increased expression during sleep in both the cerebellar cortex and cerebellar nuclei were involved in synaptic transmission, plasticity, and membrane trafficking and maintenance. Distinct neuronal networks and related afferent pathways with specific monoaminergic neurotransmitters are involved in regulation of wake–sleep stages. Many of these neurotransmitters influence cerebellar activity (Figure I), but their role in regulation of cerebellar processing during sleep has been neglected. Cell populations known to project to the cerebellum and to alter the state of arousal include the cholinergic, noradrenergic, serotonergic, histaminergic, orexinergic, and dopaminergic inputs. Injections of such monoamines or agonists of their receptors into the cerebellum can facilitate wakefulness and/or consolidation of various tasks, further supporting a role for neuromodulators during sleep-related cerebellum-dependent consolidation [102Barik S. De Beaurepaire R. Dopamine D3 modulation of locomotor activity and sleep in the nucleus accumbens and in lobules 9 and 10 of the cerebellum in the rat.Prog. Neuropsychopharmacol. Biol. Psychiatry. 2005; 29: 718-726Crossref PubMed Scopus (0) Google Scholar, 103Silva-Marques B. Intracerebellar vermis histamine facilitates memory consolidation in the elevated T maze model.Neurosci. Lett. 2016; 620: 33-37Crossref PubMed Scopus (0) Google Scholar, 104van Neerven J. et al.Injections of β-noradrenergic substances in the flocculus of rabbits affect adaptation of the VOR gain.Exp. Brain Res. 1990; 141: 537Google Scholar, 105Tan H.S. et al.Effects of alpha-noradrenergic substances on the optokinetic and vestibulo-ocular responses in the rabbit: a study with systemic and intrafloccular injections.Brain Res. 1991; 562: 207-215Crossref PubMed Scopus (3) Google Scholar]. Most, if not all, of the monoaminergic systems also have widespread impact on other parts of the brain involved in sleep control. For example, the noradrenergic, serotonergic, and histaminergic neurons control the GABAergic galanin-containing neurons of the ventrolateral and median preoptic nucleus that become active during NREM [3Saper C.B. et al.Sleep state switching.Neuron. 2010; 68: 1023-1042Abstract Full Text Full Text PDF PubMed Scopus (465) Google Scholar], while orexinergic neurons can stabilize the switch between the wake–sleep-promoting networks [3Saper C.B. et al.Sleep state switching.Neuron. 2010; 68: 1023-1042Abstract Full Text Full Text PDF PubMed Scopus (465) Google Scholar, 10de Andrés I. et al.Functional anatomy of non-REM sleep.Front. Neurol. 2011; 2: 70Crossref PubMed Scopus (0) Google Scholar]. The suprachiasmatic nucleus (SCN) of the hypothalamus, which controls and modulates the circadian rhythm, interacts with both the wake- and sleep-promoting networks [3Saper C.B. et al.Sleep state switching.Neuron. 2010; 68: 1023-1042Abstract Full Text Full Text PDF PubMed Scopus (465) Google Scholar]. Genes that regulate the rhythmicity of neurons in the SCN are called clock genes. Several clock genes, including Arntl, Nr1d1, Bmal1, Per1, Per2, and Cry1, have also been found in the Purkinje cell and granular cell layer of the cerebellum [132Rath M.F. et al.Circadian oscillators in the mouse brain: molecular clock components in the neocortex and cerebellar cortex.Cell Tissue Res. 2014; 357: 743-755Crossref PubMed Scopus (4) Google Scholar, 133Honma S. et al.Circadian oscillation of BMAL1, a partner of a mammalian clock gene clock, in rat suprachiasmatic nucleus.Biochem. Biophys. Res. Commun. 1998; 250: 83-87Crossref PubMed Scopus (0) Google Scholar]. Their expression pattern follows that of the SCN, but with a delay of 5 h [132Rath M.F. et al.Circadian oscillators in the mouse brain: molecular clock components in the neocortex and cerebellar cortex.Cell Tissue Res. 2014; 357: 743-755Crossref PubMed Scopus (4) Google Scholar, 134Rath M.F. et al.Circadian oscillations of molecular clock components in the cerebellar cortex of the rat.Chronobiol. Int. 2012; 29: 1289-1299Crossref PubMed Scopus (8) Google Scholar]. Even in vitro the cerebellum is able to express near-24-h rhythms and these rhythms can be shifted by shifting 'mealtime' exposure [135Mendoza J. et al.The cerebellum harbors a circadian oscillator involved in food anticipation.J. Neurosci. 2010; 30: 1894-1904Crossref PubMed Scopus (44) Google Scholar]. However, rhythmic clock gene expression in the cerebellum is affected in response to SCN lesioning, suggesting that the cerebellum needs input from external brain areas to maintain its rhythmicity [134Rath M.F. et al.Circadian oscillations of molecular clock components in the cerebellar cortex of the rat.Chronobiol. Int. 2012; 29: 1289-1299Crossref PubMed Scopus (8) Google Scholar, 136Mordel J. et al.The output signal of Purkinje cells of the cerebellum and circadian rhythmicity.PLoS One. 2013; 8: e58457Crossref PubMed Scopus (0) Google Scholar]. In addition to clock genes, the cerebellum also expresses various other genes showing circadian patterns; these include at least 106 sleep-related transcripts and 117 wake-related transcripts [137Cirelli C. et al.Extensive and divergent effects of sleep and wakefulness on brain gene expression.Neuron. 2004; 41: 35-43Abstract Full Text Full Text PDF PubMed Scopus (365) Google Scholar]. The genes that showed increased expression during sleep in both the cerebellar cortex and cerebellar nuclei were involved in synaptic transmission, plasticity, and membrane trafficking and maintenance. Classically, sleep has been characterized by identifying distinct phenomena at the level of the cerebral cortex. As such, sleep has been subdivided into two core sleep stages, REM and NREM sleep, which cyclically alternate throughout the night. The characteristic sleep phenomena include K-complexes, spindles and slow waves in the various phases of NREM sleep, and theta waves during REM sleep [1Diekelmann S. Born J. The memory function of sleep.Nat. Rev. Neurosci. 2010; 11: 114-126Crossref PubMed Scopus (14) Google Scholar, 12Riedner B.A. et al.Temporal dynamics of cortical sources underlying spontaneous and peripherally evoked slow waves.Prog. Brain Res. 2011; 193: 201-218Crossref PubMed Scopus (41) Google Scholar]. Cerebellar activity during sleep was first detailed in the early 1970s. This activity was found to not only reflect the intrinsic activity of cerebellar neurons but also the activity of their afferents [7De Zeeuw C.I. et al.Spatiotemporal firing patterns in the cerebellum.Nat. Rev. Neurosci. 2011; 12: 327-344Crossref PubMed Scopus (174) Google Scholar, 13Marchesi G.F. Strata P. Climbing fibers of cat cerebellum: modulation of activity during sleep.Brain Res. 1970; 17: 145-148Crossref PubMed Scopus (19) Google Scholar, 14Marchesi G.F. Strata P. Mossy and climbing fiber activity during phasic and tonic phenomena of sleep.Pflugers Arch. 1971; 323: 219-240Crossref PubMed Scopus (19) Google Scholar]. In addition to sparsely distributed monoaminergic inputs [15Schweighofer N. et al.Cerebellar aminergic neuromodulation: towards a functional understanding.Brain Res. Rev. 2004; 44: 103-116Crossref PubMed Scopus (0) Google Scholar] (Box 1), the cerebellum receives two major afferents, the climbing fibers, originating from the inferior olive, and the mossy fibers, originating from a wide variety of sources in the brain stem [7De Zeeuw C.I. et al.Spatiotemporal firing patterns in the cerebellum.Nat. Rev. Neurosci. 2011; 12: 327-344Crossref PubMed Scopus (174) Google Scholar] (see Figure IC in Box 1). The climbing fibers and mossy fiber–parallel fiber system converge on Purkinje cells and cerebellar nuclei neurons, which form the output of the cerebellar cortex and cerebellum as a whole, respectively. Whereas activity in climbing fibers elicits so-called complex spikes in Purkinje cells, that of mossy fibers and parallel fibers modulates Purkinje cells' simple spike activity (for review, see [7De Zeeuw C.I. et al.Spatiotemporal firing patterns in the cerebellum.Nat. Rev. Neurosci. 2011; 12: 327-344Crossref PubMed Scopus (174) Google Scholar]). In cats, both climbing fibers and mossy fibers show relatively low and high levels of activity during NREM and REM, respectively [13Marchesi G.F. Strata P. Climbing fibers of cat cerebellum: modulation of activity during sleep.Brain Res. 1970; 17: 145-148Crossref PubMed Scopus (19) Google Scholar, 14Marchesi G.F. Strata P. Mossy and climbing fiber activity during phasic and tonic phenomena of sleep.Pflugers Arch. 1971; 323: 219-240Crossref PubMed Scopus (19) Google Scholar], revealing the existence of sleep-stage-dependent cerebellar activity. In the cerebral cortex, NREM sleep can be subdivided into lighter sleep stages NREM1–2 and deep slow-wave sleep (SWS). K-complexes are single slow waves occurring typically in NREM stage 2, while more continuous slow waves occur in what is considered deep sleep or stage 3 NREM sleep [12Riedner B.A. et al.Temporal dynamics of cortical sources underlying spontaneous and peripherally evoked slow waves.Prog. Brain Res. 2011; 193: 201-218Crossref PubMed Scopus (41) Google Scholar]. They have a peak frequency of less than 1 Hz and together they are the highest-amplitude waves a healthy human brain can produce, caused by large groups of neurons simultaneously alternating between a hyperpolarized down state in which the neurons are inactive, and a depolarized up -state with irregular neuronal firing that may resemble the waking state [16Steriade M. et al.A novel slow (< 1 Hz) oscillation of neocortical neurons in vivo: depolarizing and hyperpolarizing components.J. Neurosci. 1993; 13: 3252-3265Crossref PubMed Google Scholar]. These slow waves appear to be a cortically generated phenomenon, as isolated cerebral cortex preparations still produce slow waves [17Steriade M. et al.Intracellular analysis of relations between the slow (< 1 Hz) neocortical oscillation and other sleep rhythms of the electroencephalogram.J. Neurosci. 1993; 13: 3266-3283Crossref PubMed Google Scholar, 18Timofeev I. et al.Origin of slow cortical oscillations in deafferented cortical slabs.Cereb. Cortex. 2000; 10: 1185-1199Crossref PubMed Google Scholar, 19Timofeev I. Steriade M. Low-frequency rhythms in the thalamus of intact-cortex and decorticated cats.J. Neurophysiol. 1996; 76: 4152-4168Crossref PubMed Google Scholar]. Slow waves can occur in separate cortical areas but may also involve multiple cortical regions simultaneously. Spindles, which typically present as short bursts of activity at a frequency of 10–15 Hz, probably originate in the thalamus from an interaction between the intrinsic GABAergic cells of the reticular nucleus and the glutamatergic thalamocortical cells [20Steriade M. et al.Thalamic Oscillations and Signaling. John Wiley & Sons, 1990Google Scholar]. At the level of the cortex, the end result is a characteristic waxing and waning spindle -like morphology. In the cerebellum, local field potentials (LFPs) have been recorded during NREM sleep in humans since the 1970s. The fastigial and dentate nuclei of naïve epileptic patients implanted with electrodes in their cerebellar nuclei regions showed synchronous spike discharges during NREM and minor sharp potentials during REM activity [21Niedermeyer E. Uematsu S. Electroencephalographic recordings from deep cerebellar structures in patients with uncontrolled epileptic seizures.Electroencephalogr. Clin. Neurophysiol. 1974; 37: 355-365Abstract Full Text PDF PubMed Scopus (0) Google Scholar] (Figure 1B). NREM sleep-related synchronized slow waves in the fastigial nucleus turned out to be sharper than those in the dentate nucleus, suggesting region-specific sleep-related cerebellar activity [22Zhou H. et al.Cerebellar modules operate at different frequencies.Elife. 2014; 2014: 1-18Google Scholar]. Initially, clean electroencephalographic (EEG) measurements of the cerebellum could only be obtained with such invasive recordings during and/or after neurosurgery [23Teixeira M.J. et al.Deep brain stimulation of the dentate nucleus improves cerebellar ataxia after cerebellar stroke.Neurology. 2015; 85: 2075-2076Crossref PubMed Scopus (4) Google Scholar, 24Kros L. et al.Controlling cerebellar output to treat refractory epilepsy.Trends Neurosci. 2015; 38: 787-799Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar, 25Dalal S.S. et al.Oscillatory activity of the human cerebellum: the intracranial electrocerebellogram revisited.Neurosci. Biobehav. Rev. 2013; 37: 585-593Crossref PubMed Scopus (18) Google Scholar], because external EEG recordings were often contaminated with signals from the visual cortex and/or neck muscles [26Muthukumaraswamy S.D. High-frequency brain activity and muscle artifacts in MEG/EEG: a review and recommendations.Front. Hum. Neurosci. 2013; 7: 138Crossref PubMed Scopus (125) Google Scholar]. Moreover, identifying cerebellar signaling on the basis of external EEG and magnetic encephalographic data in humans was also complicated by the central location of the cerebellum and the difficulties in solving the inverse problem for estimating the current source of the EEG/magnetic encephalographic signals [27Grech R. et al.Review on solving the inverse problem in EEG source analysis.J. Neuroeng. Rehabil. 2008; 5: 25Crossref PubMed Scopus (315) Google Scholar]. New approaches involving combinations of techniques, such as combined analyses of EEG and functional magnetic resonance imaging (fMRI) or positron emission tomography (PET) imaging data, partly resolved these issues. A combination of fMRI and EEG recordings indicated that cerebellar signals during NREM1 are lower compared with those during wakefulness [28Diedrichsen J. et al.Advances in functional imaging of the human cerebellum.Curr. Opin. Neurol. 2010; 23: 382-387PubMed Google Scholar, 29Kaufmann C. et al.Brain activation and hypothalamic functional connectivity during human non-rapid eye movement sleep: an EEG/fMRI study.Brain. 2006; 129: 655-667Crossref PubMed Scopus (120) Google Scholar]. Since cerebellar fMRI signals largely reflect mossy and parallel fiber activity [28Diedrichsen J. et al.Advances in functional imaging of the human cerebellum.Curr. Opin. Neurol. 2010; 23: 382-387PubMed Google Scholar, 29Kaufmann C. et al.Brain activation and hypothalamic functional connectivity during human non-rapid eye movement sleep: an EEG/fMRI study.Brain. 2006; 129: 655-667Crossref PubMed Scopus (120) Google Scholar], these fMRI studies support the notion that mossy fibers derived from the pons also contribute to cerebellar NREM sleep stages by decreasing their excitatory drive. The results of PET studies combined with EEG recordings also pointed toward decreased cerebellar activity during the transition from pre -sleep wakefulness to SWS [30Braun A. Regional cerebral blood flow throughout the sleep-wake cycle. An H2(15)O PET study.Brain. 1997; 120: 1173-1197Crossref PubMed Scopus (816) Google Scholar, 31Kajimura N. et al.Activity of midbrain reticular formation and neocortex during the progression of human non-rapid eye movement sleep.J. Neurosci. 1999; 19: 10065-10073Crossref PubMed Google Scholar, 32Hofle N. et al.Regional cerebral blood flow changes as a function of delta and spindle activity during slow wave sleep in humans.J. Neurosci. 1997; 17: 4800-4808Crossref PubMed Google Scholar, 33Hiroki M. Cerebral white matter blood flow is constant during human non-rapid eye movement sleep: a positron emission tomographic study.J. Appl. Physiol. 2005; 98: 1846-1854Crossref PubMed Scopus (0) Google Scholar, 34Kjaer T.W. et al.Regional cerebral blood flow during light sleep – a H(2)(15)O-PET study.J. Sleep Res. 2002; 11: 201-207Crossref PubMed Scopus (0) Google Scholar]. During NREM2, cerebellar fMRI signals co-occurred with K-complexes [35Jahnke K. et al.To wake or not to wake? The two-sided nature of the human K-complex.Neuroimage. 2012; 59: 1631-1638Crossref PubMed Scopus (0) Google Scholar] and sleep spindles [36Schabus M. et al.Hemodynamic cerebral correlates of sleep spindles during human non-rapid eye movement sleep.Proc. Natl. Acad. Sci. U. S. A. 2007; 104: 13164-13169Crossref PubMed Scopus (246) Google Scholar] as measured with EEG from the neocortex, whereas during NREM3, cerebellar fMRI signals co-occurred with slow waves at the neocortex [29Kaufmann C. et al.Brain activation and hypothalamic functional connectivity during human non-rapid eye movement sleep: an EEG/fMRI study.Brain. 2006; 129: 655-667Crossref PubMed Scopus (120) Google Scholar] (Figure 1A and [37Dang-Vu T.T. et al.Spontaneous neural activity during human slow wave sleep.Proc. Natl. Acad. Sci. U. S. A. 2008; 105: 15160-15165Crossref PubMed Scopus (0) Google Scholar]). The level of slow wave density associated with fMRI bold signals in the cerebellum was positively correlated with its gray matter volume as measured with voxel-based morphometry [37Dang-Vu T.T. et al.Spontaneous neural activity during human slow wave sleep.Proc. Natl. Acad. Sci. U. S. A. 2008; 105: 15160-15165Crossref PubMed Scopus (0) Google Scholar, 38Saletin J.M. et al.Structural brain correlates of human sleep oscillations.Neuroimage. 2013; 83: 658-668Crossref PubMed Scopus (16) Google Scholar], providing possible explanations for intersubject variability of sleep EEG features as well as for interlobular differences within the cerebellum of individuals. Indeed, in both fMRI and PET studies, the reported changes in cerebellar activation have been mainly localized in the larger lobules IV, V, VI, and VII [29Kaufmann C. et al.Brain activation and hypothalamic functional connectivity during human non-rapid eye movement sleep: an EEG/fMRI study.Brain. 2006; 129: 655-667Crossref PubMed Scopus (120) Google Scholar, 30Braun A. Regional cerebral blood flow throughout the sleep-wake cycle. An H2(15)O PET study.Brain. 1997; 120: 1173-1197Crossref PubMed Scopus (816) Google Scholar, 31Kajimura N. et al.Activity of midbrain reticular formation and neocortex during the progression of human non-rapid eye movement sleep.J. Neurosci. 1999; 19: 10065-10073Crossref PubMed Google Scholar, 32Hofle N. et al.Regional cerebral blood flow changes as a function of delta and spindle activity during slow wave sleep in humans.J. Neurosci. 1997; 17: 4800-4808Crossref PubMed Google Scholar, 34Kjaer T.W. et al.