What Is the Involvement of the Cerebellum During Sleep?

Compared with the advances in the elucidation of the role of brainstem and hypothalamus in the control of wakefulness and sleep stages,¹ the functions of the cerebellum during sleep remain relatively unexplored.² However, the activity in the cerebellum changes concomitantly with that of the neocortex during distinct sleep stages, as shown, for example, with a simultaneous recoding of sleep EEG and regional blood flow or fMRI signals in the cerebellum in humans.^2-10 Electrophysiologic studies show variation in the firing rate of Purkinje and cerebellar nuclear cells according to the neocortical sleep stage.^11-15 Recent studies show hippocampal-cerebellar interactions both during non-REM (NREM) and REM sleep¹⁶ and suggest a cerebellar contribution to the generation of sleep spindles in the neocortex.¹⁵ There are several potential pathways for the coordination of neocortical or hippocampal regions with cerebellar activity during sleep (Figure). This reciprocal communication may provide a potential basis for the consolidation of motor learning and other cognitive functions.^17-22 The cerebellum is affected in several disorders associated with sleep disturbances.^23-25 However, the contribution of the cerebellum to the normal regulation of sleep and its role in sleep disorders are still incompletely understood. Elucidating the role of the cerebellum in the control of arousal and sleep-wake cycle has potential clinical and therapeutic implications.

Figure. Activity of the Cerebellum During Sleep.

The cerebellum is strongly and reciprocally interconnected with the neocortex in a topographic and functionally specific manner through the corticopontocerebellar and cerebellothalamocortical pathways. The corticocerebellar connections through the pontine nuclei convey neocortical activity during sleep stages to cerebellar circuits. The deep cerebellar nuclei project to different thalamic targets, thus affecting several thalamocortical networks. There is also evidence of bidirectional connections between the hippocampus and cerebellum that may be relevant for their interactions during sleep. Tractography studies show a direct pathway between the cerebellum and hippocampus, and tracer studies show possible multiple convergent pathways from the deep cerebellar nuclei to the hippocampus, including relays through the medial septum and supramammillary nucleus of the hypothalamus or through the thalamus. The cerebellar activity during sleep reflects the neocortical states. Activity of Purkinje cells and deep cerebellar nuclei was found to be progressively reduced during progression toward slow-wave sleep. During NREM sleeps, cerebellar signals are lower compared with those during wakefulness and occur coincident to sleep spindles and slow waves at the neocortex. Hippocampal slow waves were found to be phase-locked to cerebellar delta oscillations, and sharp-wave ripple activity were phase-locked to the upstate of cerebellar delta oscillations. Studies in cats and monkeys show that Purkinje cell activity is increased during REM sleep, but a study in mice showed decreased Purkinje cell activity in this stage. Recordings in cats showed an increased activity of the cerebellar nuclei during REM sleep, particularly during the REM periods. During REM sleep, hippocampal theta oscillations were accompanied by widespread cerebellar delta and very fast oscillations associated with phasic sharp potentials. NREM = non-REM.

Cerebellar Connections Relevant for Its Involvement During Sleep

The cerebellum is strongly and reciprocally interconnected with the neocortex in a topographic and functionally specific manner through the corticopontocerebellar and cerebellothalamocortical pathways²⁶ (Figure). The corticocerebellar connections through the pontine nuclei convey neocortical activity during sleep stages to cerebellar circuits. The deep cerebellar nuclei project to different thalamic targets, including the ventrolateral, ventromedial, and centrolateral nuclei, thus affecting several thalamocortical networks; the impact of this cerebellar output varies among different thalamic targets.²⁷

There is also evidence of bidirectional connections between the hippocampus and cerebellum,^28-30 which may be involved in the processing of self-motion information required for navigation^31,32 and spatio-temporal prediction of movements.³³ These interactions may be relevant for the interactions between the cerebellum and hippocampus during sleep.¹⁶ There are several potential pathways connecting these structures.²⁹ Human tractography studies show a direct pathway between the cerebellum and hippocampus.³⁴ Tracer studies in mice show that the hippocampus receives projections from topographically restricted regions of cerebellar cortex through multiple convergent pathways from the deep cerebellar nuclei, including a possible single-relay pathway involving the medial septum and the supramammillary nucleus.²⁸ There is also evidence for a projection from the cerebellar nuclei to the hippocampal circuit through the thalamus.³⁰

The cerebellum receives inputs from neuromodulatory systems regulating arousal and wake-sleep cycle. They include cholinergic inputs from the pedunculopontine nucleus³⁵; noradrenergic inputs from the locus coeruleus³⁶; serotonergic inputs from the raphe nuclei³⁷; histaminergic input from the tuberomammillary nucleus³⁸; and orexin/hypocretin inputs from the posterior lateral hypothalamus.³⁹ In turn, the cerebellum projects to several brain regions involved in the control of arousal and sleep. For example, studies in rodents revealed a direct projection of Purkinje cells in the posterior vermis to the medial parabrachial nucleus⁴⁰; this nucleus has a critical role in the maintenance of arousal.^41,42 Reciprocal connections between the cerebellum and hypothalamus may also be relevant in controlling the behavioral state.⁴³

Cerebellar Activity During the Sleep-Wake Cycle in Humans

Studies combining EEG and fMRI or PET indicate that cerebellar activity during sleep reflects the neocortical states.² In general, these studies indicate reduced cerebellar activity during NREM sleep compared with that during wakefulness.^3-10,44 During NREM stage 1, cerebellar signals are lower compared with those during wakefulness⁴; during NREM stage 2, they co-occur with K-complexes⁴⁴ and sleep spindles⁴⁵; and during NREM stage 3, they co-occur with slow waves at the neocortex.^6,7 By contrast, both the cerebellar hemispheres and vermis show an increased activity during REM sleep.^3,8,9 A pioneering study in humans with epilepsy implanted with electrodes in the deep cerebellar nuclei showed spike discharges synchronized with slow waves during NREM sleep and minor sharp potentials during REM sleep.¹² Functional connectivity within cortico-cerebellar networks remains intact during sleep but differs both between different sleep stages and brain network involved.^46-48

Electrophysiology of the Cerebellum During the Sleep-Wake Cycle

Studies using simultaneous recordings of single neurons and neuronal ensembles at high spatiotemporal resolution have provided insight into stage-dependent cerebellar activity during sleep.^2,11,12 The changes in the activity of the cerebellar circuits during the sleep-wake cycle reflect changes in its afferent glutamatergic excitatory inputs from the mossy and climbing fiber systems.⁴⁹ For example, a study in rats showed that the excitatory responses of Purkinje cells to glutamate is modulated during the spontaneous sleep-waking cycle, with a progressive decrease as sleep proceeded toward slow-wave sleep and phasic changes in amplitude during REM sleep.⁵⁰ Another study showed that during NREM sleep, synchronized cortical activity was phase-locked with activity in the granule cell layer and inferior olivary nucleus and with inhibition of single-unit activity in the deep cerebellar nuclei.⁵¹ Similarly, studies in cats showed reduced firing in the deep cerebellar nuclei (fastigial and interpositus) as the animal passed from quiet wakefulness to slow-wave sleep.¹³ A study in monkeys showed that during NREM sleep, the cerebellum exhibits fluctuating firing patterns and reciprocal fast and slow oscillation similar to those in the neocortex.¹⁵ Both single-unit and population recordings showed functional connectivity between the primary motor cortex and cerebellum during slow waves and sleep spindles.¹⁵ Casualty measures revealed directional flow of information from the motor cortex to the cerebellum during slow waves (consistent with their neocortical origin) and a surprising reversal of directionality from the cerebellum to the thalamus and neocortex during spindle events.¹⁵ These observations suggest a cerebellar contribution to neocortical sleep spindles.¹⁵ Studies in cats and monkeys show that a simple spike activity generated by the parallel fiber input to the Purkinje cell is increased during REM sleep,¹⁴ whereas complex spike activity generated by the climbing fiber input is lowest in this sleep stage.¹¹ By contrast, a study in mice showed decreased Purkinje cell activity in REM sleep, which may be compatible with the loss of muscle tone during this stage.⁵² Recordings in cats showed an increased activity of the cerebellar nuclei during REM sleep, particularly during the REM periods.¹³

The hippocampus may modulate cerebellar activity during sleep. A directional influence of the hippocampus on the cerebellum is supported by studies in anesthetized rats; electrical stimulation of the fornix elicited both short mossy fiber-mediated and longer-latency climbing fiber-mediated responses within the cerebellar cortex.⁵³ A study with simultaneous recording from the hippocampus and cerebellum in male mice showed that local field potential oscillations were coordinated between these structures across sleep stages, both in spatially segregated cerebellar lobules and, globally, across the cerebellar cortex.¹⁶ This study indicates the presence of multiple, bidirectional, and coordinated physiologic events in the cerebello-hippocampal network during sleep centered around prominent delta oscillations.¹⁶ During NREM sleep, hippocampal slow waves where phase-locked to cerebellar delta-oscillations and drove cerebellar local field potential activity; hippocampal sharp-wave ripple activity evoked local field modulation in all recorded cerebellar regions, particularly in lobule VI of the dorsal vermis.¹⁶ Hippocampal sharp-wave ripples were phase-locked to the upstate of cerebellar delta oscillations, resembling what occurs with neocortical sleep spindles and delta activity, and believed to facilitate memory consolidation.^54,55 During REM sleep, hippocampal theta oscillations were accompanied by widespread cerebellar delta and very fast oscillations associated with phasic sharp potentials; cerebellar delta oscillations modulated both hippocampal theta and local cerebellar very high–frequency oscillations.¹⁶ Discrete phasic sharp potentials synchronized across cerebellar regions triggered sharp-wave ripple suppression.¹⁶ These cerebellar phasic sharp potentials may represent ponto-geniculo-occipital waves, which are phase-locked to the hippocampal theta rhythms and may have a role in coordinating long-range network dynamics underlying sleep-dependent cognitive processes such as fear extinction memory.⁵⁶

The cerebellum may also have a role in the transition from sleep to wakefulness. A study in mouse cerebellum showed an increased firing of Purkinje cells associated with a concomitant decreased activity in the deep cerebellar nuclei at the transition between NREM sleep and wakefulness.⁵² This is apparently paradoxical given that the prominent excitatory glutamatergic input from the deep cerebellar nuclei to the thalamus may have a critical role for the maintenance of arousal.^57,58 By contrast, the firing of deep cerebellar nucleus neurons remained relatively stable during the transition from REM sleep to wakefulness despite the increased activity of Purkinje cells.⁵² The deep cerebellar nuclei contain inhibitory neurons that inhibit the glutamatergic projection neurons.⁵⁹ This suggests that an increased activity of Purkinje cells at the sleep-wake transition may increase or stabilize cerebellar output through disinhibition of the cerebellar projection to the thalamus.⁵² Acetylcholine is released in the cerebellum during REM sleep⁶⁰ and may antagonize the inhibitory effects of Purkinje cells on the deep cerebellar nuclei during the transition from REM sleep to wakefulness.⁶⁰

Sleep and Learning in the Cerebellum

Sleep is necessary for the optimal consolidation of procedural learning, such as motor sequential skills, a process that involves the cerebellum.^{18,19,21,61,62} For example, activity in the cerebellar cortex is related with the level of consolidation of procedural motor memories during sleep.²⁰ Synaptic plasticity at various levels of the intrinsic cerebellar circuits^63,64 may be important in this process. Simultaneous EEG and fMRI recordings in humans conducted during sleep after a motor sequence learning task showed an overnight enhancement in performance, reflecting consolidation.¹⁷ This was associated with the reactivation of regions within the striato-cerebello-cortical network recruited during training on the task and was time-locked to spindles.¹⁷ As discussed earlier, recent evidence indicates that the cerebellum may drive neocortical sleep spindles¹⁵ and exhibits delta oscillations phase-locked to hippocampal sharp-wave ripples,¹⁶ which may contribute to the global physiologic context for memory consolidation.^54,55,65 The cerebellar nuclei may be an important target of plasticity for the effects of sleep on the consolidation of motor memories, as shown in studies on eyeblink-conditioned responses.^66-69 A study in mice showed that sleep deprivation within 4 hours after eyeblink conditioning impaired consolidation, whereas sleep directly after conditioning promoted consolidation of this motor memory.²²

Potential Clinical Implications

Despite the evidence of the interaction of cerebellum with the neocortex and hippocampus across sleep stages, experimental lesion studies have provided conflicting results regarding the importance of the cerebellum in sleep control. In cats, lesions in the cerebellar vermis and hemispheres resulted in an increased mean duration of NREM and total duration of REM periods and a decreased mean number of sleep periods during the sleep-wake cycle,^57,70 whereas lesions of the superior cerebellar peduncle resulted in a decreased mean duration and total time of NREM and REM sleep.⁵⁷ However, a study on conditional pancreas-associated transcription factor 1a knockout mice, which lack cerebellar cortex and its related structures, showed similar wake and NREM sleep time and similar numbers of sleep spindles as control mice; these knockouts showed reduced slow wave activity during wakefulness, NREM sleep, and REM sleep.⁷¹ This would indicate that the cerebellum may be involved in the generation of slow waves but does not seem to have a major role in sleep-wake control.⁷¹ In humans, surgical lesions of different portions of the cerebellum were associated with different disturbances in sleep regulation; in one study, paleocerebellar (anterior lobe) lesions were associated with the reduction of NREM sleep and an increase in REM sleep, whereas neocerebellar (posterior lobe) lesions altered both the transition between wake and sleep and sleep maintenance.⁷²

Several disorders affecting the cerebellum are associated with sleep disturbances, but the contribution of the cerebellum to these sleep abnormalities are yet to be fully understood.^23,24,73 Genetic disorders associated with cerebellar malformation may manifest with sleep disturbances; the typical example is the Joubert syndrome characterized by cerebellar vermis hypoplasia and sleep apnea.⁷⁴ Patients with obstructive sleep apnea have altered functional cerebrocerebellar connectivity related to sleep fragmentation and hypoxia during sleep.⁷⁵ Neurodegenerative disorders affecting the cerebellum such as hereditary ataxias or multiple system atrophy are frequently associated with sleep disturbances including REM sleep behavior disorder, insomnia, excessive daytime sleepiness, obstructive and central sleep apnea, periodic leg movement in sleep, and restless legs syndrome (RLS).^24,25 However, these disorders also affect brainstem areas critically involved in the control of arousal and sleep stages. Voxel-based morphometry shows a regional decrease of cerebellar gray matter volume loss in patients with RLS.⁷⁶ Sequence variants of the BTBD9 gene involved in iron metabolism are a risk factor linked to RLS.^77,78 Studies in the Btbd9 knockout mice model of RLS showed decreased activities in the cerebellum, especially in lobules VIII, X, and the deep cerebellar nuclei, and hyperactivity of Purkinje cells associated with motor restlessness and sleep disruption.^79,80

Perspective

Whereas the precise role of the cerebellum in regulating sleep is yet to be more thoroughly investigated, its involvement during the sleep-wake cycle may have implications for motor learning and other cognitive processes, through interactions with both the neocortex and hippocampus. Similarly, the contribution of cerebellar dysfunction to sleep abnormalities in neurodegenerative disorders is still to be further characterized. Several questions remain. The function of the human cerebellum in controlling or fine tuning the sleep-wake cycle may be difficult to fully elucidate on the bases of current electrophysiologic studies or the consequence of cerebellar loss resulting from large lesions or knockout models. The complex organization of the cerebellar cortex⁶⁴ and deep cerebellar nuclei,⁵⁹ including a wide variety of excitatory and inhibitory neurons and local circuits, requires a careful interpretation of the results obtained with recordings on single cells or neuronal ensembles. The cerebellum has connections with the parabrachial nucleus and hypothalamic regions involved in the control of cardiovascular function and respiration,^81-83 suggesting that cerebellar dysfunction may contribute to sleep-related cardiorespiratory dysfunction in disorders such as multiple system atrophy and sudden infant death syndrome. Therefore, much is yet to be learned about the involvement of the cerebellum during sleep.

Glossary

fMRI

functional MRI

NREM

non-REM

RLS

restless legs syndrome

Study Funding

No targeted funding reported.

Disclosure

E. Benarroch has no disclosures relevant to the manuscript. Go to Neurology.org/N for full disclosures.