The subcortical belly of sleep: New possibilities in neuromodulation of
, Richard Selway
, Valentina Gnoni
, Sandor Beniczky
Steve C.R. Williams
, Meir Kryger
, Luigi Ferini-Strambi
, Peter Goadsby
Guy D. Leschziner
, Keyoumars Ashkan
, Ivana Rosenzweig
Sleep and Brain Plasticity Centre, Department of Neuroimaging, Institute of Psychiatry, Psychologyand Neuroscience (IoPPN), King's College London (KCL),
Department of Neurosurgery, King's College Hospital, London, UK
Sleep Disorders Centre, Guy's and St Thomas' Hospital, London, UK
Danish Epilepsy Centre, Dianalund, Denmark
Aarhus University Hospital, Aarhus, Denmark
Department of Neuroimaging, IoPPN, KCL, UK
Pulmonary, Critical Care and Sleep Medicine, Yale School of Medicine, Connecticut, USA
a Vita-Salute San Raffaele, Milan, Italy
NIHR-Wellcome Trust Clinical Research Facility, SLaM Biomedical Research Centre, King's College London, London, UK
Department of Neurology, Guy's and St Thomas' Hospital (GSTT) &Clinical Neurosciences, KCL, UK
Received 19 November 2019
Received in revised form
22 February 2020
Accepted 9 March 2020
Available online 22 April 2020
Early studies posited a relationship between sleep and the basal ganglia, but this relationship has
received little attention recently. It is timely to revisit this relationship, given new insights into the
functional anatomy of the basal ganglia and the physiology of sleep, which has been made possible by
modern techniques such as chemogenetic and optogenetic mapping of neural circuits in rodents and
intracranial recording, functional imaging, and a better understanding of human sleep disorders. We
discuss the functional anatomy of the basal ganglia, and review evidence implicating their role in sleep.
Whilst these studies are in their infancy, we suggest that the basal ganglia may play an integral role in
the sleep-wake cycle, speciﬁcally by contributing to a thalamo-cortical-basal ganglia oscillatory network
in slow-wave sleep which facilitates neural plasticity, and an active state during REM sleep which en-
ables the enactment of cognitive and emotional networks. A better understanding of sleep mechanisms
may pave the way for more effective neuromodulation strategies for sleep and basal ganglia disorders.
©2020 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND
Since the ﬁrst description of the corpus striatum by Thomas
Willis in 1664, our conception of the basal ganglia has changed
from a collection of static structures to parts of a dynamic network,
supporting a diverse range of functions within the central nervous
system . The structures comprising the basal ganglia are the
corpus striatum, globus pallidus (GP), subthalamic nucleus (STN)
and substantia nigra (SN) . The functional organisation of the
basal ganglia is highly conserved from the lamprey, suggesting that
it serves a fundamental role in vertebrate phylogeny . The basal
ganglia have classically been considered in relation to movement
disorders [4,5], but their wider role in the integration of sensori-
motor, cognitive and affective functions has increasingly been
recognised [6,7]. For example, the involvement of the STN in
cognitive processing and emotional valence has recently been
demonstrated in humans using intracranial recordings [8,9], and
the effects of basal ganglia disorders and their effects on non-motor
symptoms is well established .
Early studies posited a relationship between the basal ganglia
and sleep [11,12] but this relationship has subsequently received
relatively little attention such that they are almost ignored in recent
discussions on the functional neuroanatomy of sleep but see
*Corresponding author. Sleep and Brain Plasticity Centre, Department of Neu-
roimaging, Institute of Psychiatry, Psychology and Neuroscience, Box 089, De
Crespigny Park, London, SE5 8AF, UK.
E-mail address: firstname.lastname@example.org (I. Rosenzweig).
Contents lists available at ScienceDirect
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1087-0792/©2020 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Sleep Medicine Reviews 52 (2020) 101317
[13e15] for important discussions. It is timely to reconsider the role
of the basal ganglia in sleep given emerging insights into the
functional anatomy of the basal ganglia [1,16,17] and signiﬁcant
progress in number of clinical interventions that allow intracranial
recordings from the human brain during sleep . Does activity in
the basal ganglia follow changes instigated by sleep mechanisms in
the reticular activating system, or do the basal ganglia play an
intrinsic role in regulating the sleep/waking cycle? We review the
functional neuroanatomy of the basal ganglia and discuss the im-
plications for the functions and neuromodulation of sleep.
Functional anatomy of the basal ganglia
In the 1990s, the model of basal ganglia as a series of segregated
loops consisting of the ‘direct’and ‘indirect’pathways gained
popularity (Figure S1). In this model, GABAergic neurons from
the striatum project monosynaptically to the globus pallidus
internus (GPi) and substantia nigra reticulata (SNr) in the direct
pathway and polysynaptically to the GPi/SNr via the globus pallidus
externus (GPe) and subthalamic nucleus (STN) in the indirect
pathway. As the predominant output of the basal ganglia is inhib-
itory from the GPi/SnR to the thalamus, the direct pathway inhibits
the GPi/SNr and releases thalamic and cortical neurons, whilst the
indirect pathway excites the GPi/SNr and inhibits thalamic and
cortical neurons. Hypokinetic movement disorders (such as Par-
kinson's disease) arise due to excess activity of the indirect pathway
whereas hyperkinetic disorders (such as dystonia) arise due to
excess activity of the direct pathway .
Whilst this model was useful for modelling the pathophysiology
of movement disorders, it has been superseded by newer
anatomical studies  and the conception of the brain as a dy-
namic organ rather than a static structure with input/output rou-
tines . Recent studies have signiﬁcantly expanded our
understanding of the anatomical and functional connections of the
basal ganglia. The striatum serves as the gateway and major inte-
grating centre of the basal ganglia, receiving afferent input from the
whole brain, around half of which consists of a topographical
projection from the cerebral cortex. This information is channelled
through the GPi, SNr, GPe and STN, with each nucleus having
extensive connections with each other and variably to the cerebral
cortex, thalamus, hypothalamus, limbic system, basal forebrain,
brainstem nuclei and cerebellum (Supplemental Table S1 and S2,
Fig. 1). Animal studies have formed the basis of models of basal
ganglia function in humans, as the functional organisation of the
basal ganglia is highly conserved and nearly identical in rodents
and primates .
Role of the basal ganglia in sleep
Anatomical relations between the basal ganglia and structures
regulating the sleep-wake cycle
The connections of the basal ganglia nuclei make it likely that
they play an active, rather than passive, role in sleep. There are
reciprocal connections between the basal ganglia and every part of
the sleep-wake circuit: the cerebral cortex, brainstem nuclei, basal
forebrain, thalamus, and hypothalamus (Supplemental Table S2 &
Fig. 1). The ascending arousal system has been conceptualised in
terms of ventral and dorsal streams based on early experiments
. However, it is now apparent that various components of the
basal ganglia receive direct input from components of the
ascending arousal system and may in fact be an integral part of it.
There are other anatomical areas where boundaries between
structures are indistinct such as the ventral striatum (nucleus
accumbens and olfactory tubercle) and pallidum which merges
with the basal forebrain and amygdala  and the subthalamic
nucleus, the medial border of which merges with the lateral hy-
Striatum and sleep
The rich innervation of the striatum from the cerebral cortex,
thalamus, brainstem and other areas suggests that it may play an
important role in sleep. Recordings from the striatum in rodents
show that rhythmic changes accompany the sleep-wake cycle; slow
wave bursts in NREM sleep and desynchronization in the waking
and REM state . A variety of animal studies have demonstrated
changes to sleep patterns that accompany lesions in the striatum,
including changes in time spent in waking and NREM sleep ,
reduced time spent in wakefulness , increased time spent in
REM sleep  and reduction in NREM sleep with nucleus
accumbens (NAc) core lesions .
Recent studies on adenosine receptors have also highlighted the
role of the striatum in sleep. A variety of adenosine receptor sub-
types are found throughout the body and in the brain, for example
in the basal forebrain where adenosine A
receptors are believed to
promote sleep by inhibiting wake-promoting neurons . Aden-
receptors are expressed on medium spiny neurons
CM centromedian nucleus
CNS central nervous system
ESS Epworth Sleepiness Scale
GABA Gamma amino butyric acid
GPi globus pallidus internus
LC locus coeruleus
LDT laterodorsal tegmental nucleus
MCH melanin concentrating hormone
NREM non rapid eye movement
OX-SAP orexin-2-saporin conjugate
PB parabrachial nucleus
PD Parkinson's disease
PLM periodic limb movements
PPN pedunculopontine nucleus
PPT pedunculopontine-tegmental nucleus
PSQI Pittsburgh Sleep Quality Index
RBD REM behaviour disorder
REM rapid eye movement
RLS restless legs syndrome
RWA REM without atonia
SLD sublaterodorsal nucleus
SNc substantia nigra compacta
SNr substantia nigra reticulata
STN subthalamic nucleus
TMN tuberomamillary nucleus
VLPO ventrolateral preoptic nucleus
VTA ventral tegmental area
H. Hasegawa et al. / Sleep Medicine Reviews 52 (2020) 1013172
projecting to the GPe . The A
receptor in the NAc shell has
been found to mediate the arousal effect of caffeine , as well as
chemogenetic and optogenetic stimulation of A
rons in the NAc core promoted sleep . Lesions of GPe neurons
associated with A
expressing striatopallidal neurons abolished its
sleep-promoting effect, suggesting that this striatum-GPe pathway
forms part of a sleep-promoting circuit mediated by A
(see Fig. 2,pathway 5).
Some studies suggest that dopaminergic effects on striatal
neurons may also inﬂuence sleep. Rats deﬁcient in dopamine af-
ferents to the striatum were found to spend more time awake 
and microdialysis in rodents found high extracellular ﬂuid dopa-
mine in the NAc during waking and low levels in NREM sleep .
Given that dopamine D
receptors are co-expressed with A
ceptors on striatopallidal neurons, it has been speculated that
dopamine from the VTA may mediate cognitive-motivational in-
ﬂuences on sleep, such as staying awake during a boring lecture
. Additional support of the role of the striatum in sleep is given
by the high prevalence of sleep disorders in patients with Parkinson
disease and Huntington's disease, both of which involve striatal
dysfunction [36,37]. Both adenosine and dopamine act on multiple
receptor subtypes throughout the striatum, rest of the basal ganglia
and the body and may exert wake-sleep effects through different
mechanisms . It remains difﬁcult to assign a sleep-wake role to
a neurotransmitter alone, and it would be important for future
work to address the spatial topography and receptor subtypes of
the relevant neurons within the striatum and the efferent con-
nections through the basal ganglia by which they may connect to
known sleep and wake promoting centres .
The relationship between the striatum and REM sleep is of in-
terest. In cats, acetylcholine increases in the caudate nucleus during
REM compared to NREM and waking states . In humans, PET
and MRI studies show reductions in CBF in the striatum on going
from waking to NREM sleep, and an increase in REM compared to
NREM . The striatum is one of the most densely innervated
cholinergic structures of the brain. The aspiny interneurons account
for the majority of this, but there is a proportion accounted for by
projections from the brainstem and basal forebrain which has been
demonstrated in humans . The cholinergic innervation is part of
the ascending arousal system and is active during waking and REM
Fig. 1. Relationships of the basal ganglia nuclei, with selected interactions between hypothalamus, thalamus, cerebellum and habenula. Abbreviations: DRN (dorsal raphe nucleus),
GPe (globus pallidus externus, GPi (globus pallidus internus), PPN (pedunculopontine nucleus), RF (reticular formation), SNc (substantia nigra compacta), SNr (substantia nigra
reticulata), STN (subthalamic nucleus), VTA (ventral tegmental area).
H. Hasegawa et al. / Sleep Medicine Reviews 52 (2020) 101317 3
sleep . Cholinergic innervation may be an important part of
REM networks which allow the brain to draw on cognitive, affective
and memory circuits via the basal ganglia that facilitate dreams and
memory consolidation [43,44]. This function may be ‘off-line’in
NREM sleep, during which the striatum exhibits typical oscillatory
Pallidum and sleep
The function of the globus pallidus during the sleep-wake
cycle may be reﬂected in the activity of the striatum, as the
GABAergic input from medium spiny neurons forms a sub-
stantial part of its afferent input. Several studies in rodents
have demonstrated changes in the sleep-wake pattern with
lesioning or stimulation of the pallidum. Lesioning the GPe and
GPi in rats led to decreased sleep, increased total wakefulness
and fragmentation of sleep-wake behaviour including more
sleep-wake transitions and shortened sleep bouts [27,33].
Optogenetic  and electrical  stimulation of the GPe in
rats signiﬁcantly increased nREM and REM sleep time. One
could speculate that this could be due to reduced inhibitory
output to the thalamus, but there is not enough evidence to
support this and, in addition the lesions in the animals were
incomplete. Of interest is that the ﬁring pattern in the globus
pallidus did not change signiﬁcantly throughout the sleep-
wake cycle (although the rate was higher in waking and
REM than in slow wave sleep) , suggesting that, in contrast
to the striatum, its functions may span across vigilance states
and that its intrinsic functions may not be related to levels of
STN and sleep
Recording from the STN in rodents and humans across the sleep-
wake cycle shows that neurons change from random discharge in
waking to a rhythmic bursting pattern in slow wave sleep, and
increase its ﬁring rate in REM sleep [46,47]. In humans, spindles
and K-complexes are seen in stage 2 of NREM sleep and delta and
theta activity in stage 3 . Lesioning the STN in rats did not have
an effect on sleep architecture . Several studies have reported
improvements in sleep following STN DBS [48e51], but the variety
of factors that may impact on sleep after deep brain stimulation
render these ﬁndings difﬁcult to interpret.
Fig. 2. Role of the basal ganglia in sleep pathways.
H. Hasegawa et al. / Sleep Medicine Reviews 52 (2020) 1013174
Thalamo-basal ganglia connections and sleep
The thalamus is traditionally considered as a station that con-
nects the basal ganglia outputs from the GPi and SNr to the cerebral
cortex, but there are extensive thalamic afferent connections to the
basal ganglia as well as efferent input to the thalamus from the GPe
and STN. Thalamostriate projections arise from the midline and
intralaminar nuclei and from the dorsomedial and VA/VL nuclei,
and project to functionally discrete areas of the striatum . The
midline and medial intralaminar nuclei project to ventral (limbic)
striatal areas whereas the more lateral intralaminar nuclei have
connections with dorsolateral caudate and putamen . The CM-
PF projections also innervate the globus pallidus , substantia
nigra and subthalamic nucleus. The thalamic nuclei provide direct
feedback to the basal ganglia as well as to the cerebral cortex. The
thalamocortical neurons and thalamic reticular nucleus have well
established roles in the physiology of sleep . Whether or not
thalamocortical oscillations inﬂuence basal ganglia activity or
whether there exist distinct thalamo-basal ganglia oscillations re-
mains to be determined. The intralaminar and reticular nucleus of
the thalamus receive afferent input from the major outﬂow of the
basal ganglia through GPi, GPe and SNr, and project back to the
striatum, GPi, GPe and STN as well as to the cerebral cortex, and
receives ascending input from the monoaminergic and cholinergic
ascending arousal systems. These anatomical relationships suggest
that the thalamus plays a role beyond a relay station, but more
studies are required to decipher the role of thalamo-basal ganglia
interactions in sleep and wakefulness.
Functional imaging studies of sleep that highlight the
involvement of the basal ganglia
Functional imaging with PET and fMRI has increasingly been
used to investigate the functional anatomy of sleep, often with
concurrent EEG in a block design to identify imaging differences
between waking, NREM and REM sleep . However, few imaging
studies have considered the role of the basal ganglia in a priori
hypotheses . Most recent sleep imaging studies do not mention
the basal ganglia other than comment on their involvement in
The ascending arousal systems were shown active during REM
but not during slow wave sleep . Similar ﬁndings were found in
subsequent PET and MRI studies [15,40,58e60]. Reduced connec-
tivity of the inferior parietal lobule with the caudate in light sleep
was found in a fMRI study  but the signiﬁcance of this is difﬁcult
In an important study highlighting the importance of the basal
ganglia in sleep, Braun et al., 1997 performed a PET study in healthy
sleep-deprived subjects and compared cerebral blood ﬂow in pre-
sleep waking, slow wave sleep, REM sleep and post-sleep waking
conditions . They found that slow wave sleep was associated
with a global reduction in CBF compared to waking and REM .
The most statistically robust changes occurred in the basal ganglia
ethe posterior putamen and caudate nucleus. Other decreases
were seen in the pontine tegmentum, basal forebrain, cerebellar
hemispheres, thalamus, paralimbic areas, mesial temporal struc-
tures and higher association cortical areas, suggesting diminished
activity overall. There was a signiﬁcant increase from slow wave
sleep to REM in the putamen and caudate nucleus, and also basal
forebrain, cerebellum, limbic areas, insula, the sensorimotor, visual
and auditory association cortices, and all regions of the brainstem
and thalamus, suggesting that there is a generalised activation in
REM, and in some areas such as the pontine tegmentum, midbrain,
basal forebrain, cerebellar vermis, and caudate nucleus, even more
so than in the waking state.
Reports of patients undergoing interventions in the basal
Intracranial recording during sleep from deep brain structures from
DBS electrodes in humans
Deep brain stimulation (DBS) is increasingly used to treat a va-
riety of neurological disorders including Parkinson's disease, dys-
tonia, tremor, pain, and epilepsy . Several studies have utilised
LFP recordings from externalised DBS electrodes with poly-
somnography to investigate the role of subcortical structures in
sleep in humans [47,56,61e69].
In one of the earliest reports, Moiseeva et al. (1969) 
described recordings during sleep from 11 patients, with electrodes
in various locations including the subthalamic nucleus, pallidum,
putamen, caudate nucleus, substantia nigra, ventrolateral and
posterior thalamus and hypothalamus . They reported that the
electrical patterns corresponding to the various stages of sleep
develop in different ways in different structures. Theyalso reported
changes in the ﬁring rate in the subthalamic nucleus, ventral
thalamic area and hippocampus during the development of sleep,
and concluded that these structures play an essential role in sleep
Spectral analysis of the subcortical LFP in sleep has been re-
ported in four studies, with electrodes in the STN in patients with
Parkinson disease [47,63], GPi in patients with dystonia  and
VIM in patients with myoclonic tremor and myoclonic epilepsy
. STN recordings were found to resemble those of the scalp,
with higher frequencies dominating the power spectra in awake
and REM, and slower frequencies predominating in NREM sleep
[47,63]. These ﬁndings support the involvement of the STN in sleep,
but their signiﬁcance is difﬁcult to interpret. The STN LFPs were
analysed in bipolar derivations across the DBS electrode contacts
(0e1, 1e2 and 2e3) in both studies and the scalp EEG was refer-
enced to bipolar (F3eC3, P3eO1, F4eC4, P4eO2) in the Thompson
et al. (2017)  study and the common average in the Urrestarazu
et al. (2009)  study. Whilst the observation that similar fre-
quencies dominate both the scalp and subcortical LFPs during sleep
may be in support of the action of a thalamocortical mechanism
regulating the sleep-wake cycle , how such mechanisms result
in simultaneous localised (STN) and distributed (scalp) oscillations
and how they relate to the activity of speciﬁc anatomical networks
is unknown. Interestingly, no association was found between GPi
LFP spectra and that of the scalp . This may indicate an element
of functional segregation, although further studies are required to
support such hypotheses. Kempf et al. studied gamma activity
in VIM across sleep stages in 2 subjects, and found that ~70 Hz
gamma activity (‘ﬁnely tuned gamma’) was present in awake but
absent in NREM sleep, and recurred intermittently in REM .
They concluded that ﬁnely tuned gamma activity may be an indi-
cator of activity of the ascending arousal system . This hy-
pothesis also requires further empirical evidence to support it.
Vertex waves, K-complexes and sleep spindles have been
recorded during sleep from various subcortical structures (Table 1).
These ﬁndings raise questions about the role of the subcortical
structures in sleep, and of the origin and function of sleep
The appearance of sleep potentials at distant locations occurring
in close temporal association indicates that the same ﬂuctuation in
potential difference occurs between the pairs of recording elec-
trodes in the respective locations. This could be explained by neural
propagation, volume conduction or activity at a common reference
electrode. That this occurs due to volume conduction is less likely
given that on some occasions sleep spindles appeared indepen-
dently, either in the scalp or CM nucleus . In the study by
H. Hasegawa et al. / Sleep Medicine Reviews 52 (2020) 101317 5
Velasco (2002) , scalp vertex waves signiﬁcantly preceded the
thalamic counterpart (by 42 ±5 ms) and CM spindles preceded
their scalp counterpart (by 512 ±50 ms), leading the authors to
suggest that vertex waves originate in the scalp whilst sleep spin-
dles originate in the thalamus, whereas Wennberg and Lozano
(2002)  reported that sleep potentials appeared simultaneously
in the scalp and subcortical structures but with opposite polarity,
leading them to conclude that subcortical sleep potentials are
volume conducted from the cerebral cortex . As the recordings
performed by both Velasco et al.  and Wennberg and Lozano
 utilised monopolar references, it could be argued that activity
at the common reference electrode could have generated the waves
in the two distant locations, although this would not explain the
A more potent ﬁnding that weighs against reference electrode
or volume conduction effects is that subcortical sleep potentials
have also been recorded from bipolar contacts in the STN  and
thalamic anterior nucleus . Urrestarazu et al. (2009)  re-
ported the presence of spindles and K complexes in bipolar STN
LFPs during stage 2 sleep, although only in 6 out of 10 patients .
Some sleep spindles were also seen at the same time in Cz. Tsai
et al. (2010)  found that sleep spindles occurred simultaneously
on the scalp and in the thalamic anterior nucleus on bipolar re-
cordings, but K complexes were only seen on the scalp . Fluc-
tuations in local ﬁeld potentials broadly reﬂect ﬂuctuations in
intracellular activity [72,73]. Whilst changes in potentials seen on a
bipolar montage are often attributed to local changes in neuronal
activity , this may not always be the case  and these ﬁndings
raise the question of why monopolar and bipolar recordings should
both generate sleep potentials of similar morphology in close
temporal association in the scalp and subcortical structures.
The K complex is considered to arise in the cortex of the cerebral
hemispheres rather than the subcortical structures [76,77]. A
number of ﬁndings support this hypothesis, including the wide-
spread spatial distribution of the K-complex over the cerebral
hemispheres on intracranial recordings [74,76,78], the electro-
graphic and physiological association of the K complex with the
cortically-generated slow oscillation , the polarity reversal of
the K-complex when cortical and subcortical recordings are
compared  and the fact that stimulation of cortical areas induce
Sleep potential recorded from subcortical structures in humans.
Study Patients Electrode Placement Monopolar or bipolar Subcortical
Urrestarazu et al. (2009) N¼10, PD STN Bipolar subcortical,
EEG common average
Some spindles occurred
simultaneously in Cz.
Subcortical spindles not
recorded in all patients.
Half of patients recorded
during daytime naps rather
than nocturnal sleep
Velasco et al. (2002) N¼5, Lennox-Gastaut
CM Monopolar (ipsilateral
Vertex waves occurred in
scalp ﬁrst, spindles occurred
in thalamus ﬁrst
Moiseeva et al. (1969) N¼11, diagnosis
Globus pallidus, putamen,
hypothalamus, ventrolateral &
posterior thalamic nucleus,
hypothalamus, STN, substantia nigra)
Not documented Spindles Abstract only
Salih et al. (2009) N¼7, dystonia GPi Bipolar K-complexes
occurred in association
Tsai et al. (2010) N¼3, epilepsy Anterior nucleus Bipolar Spindles Spindles occurred at the
same time in anterior nucleus
and scalp. K complexes only
seen on scalp potentials.
Wennberg &Lozano (2003) N¼7, epilepsy, PD Centromedian nucleus, anterior
Monopolar to Cz, Pz or
Sleep potentials occurred
simultaneously and in
Abbreviations: CM (centromedian nucleus), GPi (globus pallidus internus), PD (Parkinson's disease), STN (subthalamic nucleus).
Sleep characteristics before and after DBS.
Sleep measure Effect
Iranzo et al. (2002)  STN PSG, clinical interview,
PSQI showed signiﬁcant improvement. PSG
showed more continuous sleep.
Hjort et al. (2004)  STN Parkinson Disease
Improves sleep quality mainly due to motor improvement
Cicolin et al. (2004)  STN PSG Improvement in sleep architecture but not PLM or RBD
Baumann-Vogel et al. (2017)  STN PSG, ESS, Zurich
DBS reduced sleepiness and improved some PSG
parameters but did not normalise sleep.
Tolleson et al. (2016)  GPi PSG No effect on sleep parameters
Lim et al. (2009)  PPN PSG DBS ‘on’increased REM time compared to DBS ‘off’
Arnulf et al. (2010)  PPN Behavioural Low frequency stimulation led to arousal whereas high
frequency stimulation led to REM sleep
Abbreviations: ESS (Epworth Sleepiness Scale), GPi (globus pallidus internus), PLM (periodic limb movements), PPN (pedunculopontine nucleus), PSG (polysomnography), PSQI
(Pittsburgh Sleep Quality Index), RBD (REM behaviour disorder), STN (subthalamic nucleus).
H. Hasegawa et al. / Sleep Medicine Reviews 52 (2020) 1013176
K-complex-like waveforms . It is difﬁcult to reconcile these
ﬁndings with the observation of K-complexes on bipolar STN 
and GPi  recordings.
These studies indicate that sleep oscillations and potentials
occur and are similar on the scalp and a variety of subcortical
structures, and that sleep potentials may be associated or dissoci-
ated from scalp potentials but there is insufﬁcient data in these
small number of studies to fully explain these ﬁndings. One po-
tential explanation for subcortical spindles and K-complexes is
neuronal synchronization . Thalamic spindles are synchronized
across the length of an electrode, and this is dependent on feedback
from the cortex . If such a mechanism is responsible, the ﬁnd-
ings demonstrating sleep potentials in the basal ganglia would
greatly extend the scope of the role of the basal ganglia in sleep. It
has been hypothesized that the slow (<1 Hz) oscillation may group
spindles and delta waves [54,70]. If this is the case, one would
expect to see slow oscillations in the basal ganglia, but this has not
been well described .
Confounding issues in these studies are the diversity of targets
and recording methodologies, the reliability of data, particularly
with older studies in which the accuracy of measurement may be
uncertain , the limitations on what can be concluded from LFP
measurements which necessarily include volume conducted ef-
fects, and the fact that these studies are all performed on patients
with underlying medical conditions on medication. Whilst the
latter factor is unavoidable in intracranial recording studies in
humans, it would be helpful to have a strategic approach to intra-
cranial sleep studies within which results can be compares across
On some level, the neural processes that give rise to the various
oscillations and potentials must cause the profound behavioural
and cognitive changes that accompany the various stages of sleep.
Whether or not the oscillations and patterns themselves can be
traced back to neuroanatomical pathways and/or whether their
corresponding physiological, cognitive and behavioural correlates
can be identiﬁed remains a fertile ﬁeld for further investigation. It is
tempting to use EEG waveforms (whether scalp or intracranial) as a
bridge to connect neurophysiology and behaviour but its limita-
tions must always be borne in mind. Could concepts such as ‘the
location where sleep potentials are generated’and discourse such
as ‘the propagation of sleep potentials’be misguided? Is there a site
of origin? Are waveforms truly propagated or does it appear so by
the way in which the EEG trace is constructed, and what relevance
does it have to underlying neural activity? Important questions
remain, but there is probably enough evidence from these intra-
cranial studies in humans to suggest that it is premature to discount
the role of the basal ganglia in sleep.
Sleep EEG in patients who have had DBS electrodes internalized: the
effect of subcortical stimulation on sleep
The study of sleep behaviour and EEG sleep architecture in pa-
tients after their DBS systems have been internalised also shed
some light on how modulation of basal ganglia activity affect sleep
and its rhythms. Most studies involve patients with Parkinson's
disease who have undergone STN implantation and examined sleep
behaviour and architecture before and after DBS [48,81e85] or after
DBS in DBS ‘on’and ‘off’conditions (Table 2).
These studies suggest that for STN stimulation there is a clear
effect towards improvement of sleep on both subjective and
objective measures. It is, however, difﬁcult to infer the mechanism
by which STN stimulation leads to improved sleep in these situa-
tions because of the multiple aetiologies of sleep disorders in Par-
kinson's disease  but also because the mechanism of action of
DBS remains poorly understood . Interestingly, improvement in
sleep was not seen after GPi DBS for Parkinson's disease ,
although more studies are required to draw implications based on
this observation. Patients who had PPN DBS for Parkinson's disease
 or progressive supranuclear palsy  have shown an
improvement in sleep with low stimulation and induction of REM
at high frequency stimulation, suggesting that stimulation directly
affects sleep regulating pathways and veriﬁes ﬁndings from
anatomical studies suggesting that this region plays a crucial role in
sleep regulation. Due to the variability of PPN anatomy and current
spread it is impossible to specify which pathways are being acti-
vated in such situations. Therefore the most that can be concluded
is that STN DBS leads to an improvement in sleep. The study pro-
tocols adopted to date, that of performing PSG before and after or
during on and off DBS, are insufﬁcient to study mechanisms of
action. This will require a careful study whereby the parameters of
stimulation are varied and the effects of this observed on behaviour
and sleep architecture.
Sleep disorders in patients with disease affecting the basal ganglia
Sleep disorders are highly prevalent in psychiatric and neuro-
logic diseases which affect the basal ganglia. Up to 98% of patients
with Parkinson disease  and 88% with Huntington's disease 
report nocturnal sleep problems. In most cases the basal ganglia
pathology is part of a wider process affecting other parts of the
nervous system and it is difﬁcult to implicate the basal ganglia as
the cause of the sleep disturbance (Table 3). The cause of the sleep
disturbance is often multifactorial and may include the persistence
of motor symptoms at night, pain or discomfort, depression and
anxiety, medical problems such as arthritis or nocturia, and medi-
cation side-effects. The pathophysiology of disease may also
directly affect sleep-wake regulating centres. For example, Hun-
tington's disease (HD) is characterised by striatal degeneration but
also involves hypothalamic degeneration, and altered expression of
circadian clock genes in the hypothalamus was found in a mouse
model of this condition . Parkinson's disease is associated with
the widest variety of sleep disorders but this may reﬂect the
prevalence of the condition and a high number of studies in this
patient group in comparison with others.
Study of sleep disorders in basal ganglia disease may reveal
important connections between the functional anatomy of sleep
and the pathophysiology of disease. A good example is the case of
REM behaviour disorder (RBD), which involves loss of muscle ato-
nia in REM sleep and enactment of dreams. A careful study of the
association of RBD with various degenerative condition affecting
the basal ganglia and brainstem has highlighted the sub-
laterodorsal nucleus (SLD) as an important mediator of this con-
dition . The SLD has descending connections with spinal motor
neurons and is an important part of the REM switch . The onset
of RBD decades before clinical presentation of Parkinson's disease
(PD) and other synucleinopathies suggests that PD begins outside
the basal ganglia [90,92]. Stimulation of the SnR attenuates REM
atonia, which suggests that the basal ganglia may have a role in
regulating REM, REM atonia and therefore may also be involved in
RBD . Higher prevalence of periodic limb movement disorder in
RBD patients has been argued to reﬂect their shared basal ganglia
etiology [94,95]. Moreover, some authors have even hypothesised
that earlier onset of RBD or PD in a course of neurodegeneration
may depend on whether the dorsal or ventral part of the brainstem
are initially involved . For instance, nigro-caudate dopami-
nergic deafferentation has been argued as a principal biomarker of
RBD , with several recent studies demonstrating an early
involvement of caudate and ventral striatum in PD patients with
overall worse outcomes, and with an increased risk of developing
sleep issues with debilitating cognitive and mood problems [96,97].
H. Hasegawa et al. / Sleep Medicine Reviews 52 (2020) 101317 7
In keeping, neuroimaging studies of PD have consistently demon-
strated uneven dopaminergic deﬁcit within the striatum, with
more severe involvement of the posterior putamen and a relative
sparing of the head of caudate nucleus [97,98]. Perhaps in similar
vein, sleep disturbances and striking mood pathology in HD 
have been linked to early neuronal loss in the medial caudate .
While there is no homogenous pattern of sleep disorders in pa-
tients with HD, insomnia, increased sleep onset latency, decrease in
total sleep time, frequent nocturnal awakenings, REM sleep disor-
ders, increased motor activity during sleep, decreased sleep efﬁ-
ciency and excessive daytime sleepiness have all been reported (for
in-depth review see ). Reduced N3 and REM stage and an
increased sleep spindle density have also been observed in HD
The relationship between basal ganglia and psychiatric disor-
ders has traditionally been either ignored, or at best considered
subservient to historically widely recognised links with motor and
other neurologic disorders. However, the awareness for the pivotal
role of basal ganglia neurocircuitry in the pathology of major psy-
chiatric disorders has signiﬁcantly improved within the last few
decades (as comprehensively reviewed in [102,103]). In keeping
with this, DBS of basal ganglia has also been increasingly recog-
nised as a promising treatment of severe and refractory psychiatric
disorders. For example, in patients with obsessiveecompulsive
disorder (OCD), which is characterized by chronic intrusive
thoughts or impulses (obsessions) and ritualistic and repetitive
actions (compulsions), DBS treatment of two main regions, the
striatal region (including the caudate nucleus, NAc, anterior limb of
the internal capsule, and the ventral capsule) and the STN, has
shown promising results in reducing OCD symptoms, and in nor-
malising connectivity within corticobasal ganglia and thalamo-
cortical circuits (for review see ). Sleep pathology has been
described in this patient population, with evidence for reduced
total sleep time and sleep efﬁciency, a delayed sleep onset and
offset and an increased prevalence of delayed sleep phase disorder
[104 ]. Comorbid sleep issues have also been recognised as an
important moderating factor in the prognosis and severity of OCD
Similar to OCD patients, dysfunction of basal ganglia has been
suggested as central to pathology underlying development of
addiction and substance abuse disorders . Hence, given the
grave impact and socio-economic consequences that such disor-
ders pose to the individual and the society, the relationship be-
tween substance abuse and sleep has emerged as an area of great
interest for clinicians and researchers (see [105 ]. Patients with
substance abuse have been shown ﬁve to ten times more likely to
have sleep issues, and presence of this comorbidity has signiﬁcant
impact on severity of addiction, remission and the related relapse
prospects, as well as prevalence of affective symptomatology and
depression . Analogously to demonstrated links between
ventral striatum, sleep and aberrant behaviors in RBD, PD, HD and
OCD, hypoactivity (or hyperactivity) of the ventral striatum (VS)
has similarly been reported in substance users . Of note,
ventral striatum has long been recognised as a central region of
the reward circuit, and its role in drug addiction and in the
persistence of maladaptive behaviors such as compulsion to seek
the drug, has long been been hypothesised [106 ]. More recently, a
low-frequency DBS of the dorsal VS has been shown useful in
treatment of refractory opioid addiction [106 ], whilst, in past,
high-frequency DBS of the VS has also been shown effective in
reducing symptoms of addiction to alcohol, nicotine, and heroin
. Within that context, of note are ﬁndings of a recent study
that suggested that high activity of VS may buffer against the
experience of depressive symptoms, associated with sleep dis-
turbances [107 ]. The aberrant activity of VS, with or without
associated anhedonia and apathy, has been implicated in several
other psychiatric disorders, such are for example attention deﬁcit
hyperactivity disorder (ADHD), characterized by symptoms of age-
inappropriate inattention, hyperactivity and impulsivity [108 ], and
schizophrenia . In recent comprehensive assessment of sleep
disorders and their correlates in patients with early psychosis,
sleep disorders were signiﬁcantly associated with increased psy-
chotic experiences, depression, anxiety, fatigue, and lower quality
of life [110 ]. The authors highlighted strong links between sleep
disorders and psychosis, and suggested that their ﬁndings suggest
that comorbid sleep pathology may have wide-ranging negative
effects, and that it hence merits routine assessment and treatment
in psychiatric practice [110 ].
In conclusion, while the translational neuroscience of mecha-
nistic corelates that may bind sleep disorders and neuropsychiatric
disorders with dysfunction of nigrostriatal pathways is far from
clear, some speculative theoretical patterns have emerged. For
instance, in genetically predisposed individuals and or under
extreme conditions, such as psychosis, where the central nervous
system pathology may lead to excessive dopamine striatal tran-
sients , these may lend to irrelevant external or internal stimuli
being marked as of overvalued/delusional ‘signiﬁcance’, due to
their temporal association of the stimuli with striatal signalling
. Following that concept, arguably, the aberrant association
within dorsal regions of the striatum may be tied to signalling
Sleep disturbance in disorders affecting the basal ganglia.
Disease Basal ganglia involvement Associated sleep disorders
Parkinson disease [36,88] Nigrostriatal degeneration Nocturnal awakening
Periodic limb movements/RLS
REM behaviour disorder (RBD)
Obstructive sleep apnoea
Excessive daytime sleepiness
Huntington's disease  Striatal degeneration Nocturnal awakening
Increased nocturnal movements
RWA, PLM, RBD reported in a minority of patients
Progressive supranuclear palsy  Neuronal loss and gliosis Nocturnal awakening
RBD reported in a minority of patients
Wilson's disease  Copper deposition Excessive daytime sleepiness
Poor nocturnal sleep
Pantothenate kinase-associated neurodegeneration (PKAN)  Iron deposition Reduced total sleep time
Abbreviations: PLM (periodic limb movements), RBD (REM behaviour disorder), RLS (restless legs syndrome), RWA (REM without atonia).
H. Hasegawa et al. / Sleep Medicine Reviews 52 (2020) 1013178
threat-related information, and possibly lead to delusions or indeed
to nightmares (if they occur during REM), which are both
frequently persecutory in nature . Impaired reality assessment
may further increase vigilance in any affected individual and lead to
decreased sleep efﬁciency, which may in turn further affect striatal
dopaminergic functioning [112 ]. Comparably to this theoretical
construct, the association with the ventral striatal regions may
result in the hypervigilance, insomnia, and unexpected or aberrant
reward associations leading to addictions, obsessions and attention
The reciprocal connections between the basal ganglia and the
sleep-wake circuitry, and the experimental ﬁndings reviewed in
this paper point to an important role of the basal ganglia in sleep
(Fig. 2). A major challenge is to deﬁne the role of speciﬁc neuronal
populations and their relationship to cellular oscillations and scalp
EEG rhythms. The role of the basal ganglia in processing sensori-
motor, cognitive and affective information is well established, and
it would be reasonable to hypothesize that these processes may
continue during sleep, particularly in REM sleep, which draws on
these processes in the emergence of conscious experience in
dreaming, a hypothesis which ﬁnds some experimental support
. There is also evidence to suggest that the striatum, GPi and
STN adopt rhythmic oscillations during NREM sleep. More studies
are required to conﬁrm these ﬁndings and their relationship to
thalamocortical oscillations, including the prospect for a
thalamocortical-basal ganglia oscillatory network for neural plas-
ticity and memory consolidation. On the other hand, patients in
whom parts of the basal ganglia are absent [114 ] indicate that
sleep can be sustained without those structures. This may suggest
a facilitating, rather than constitutive role of the basal ganglia in
sleep. Sleep is accompanied by profound changes in the motor
system, which may be facilitated by the basal ganglia. The obser-
vation that many movement disorders which are presumably of
basal ganglia can disappear during sleep  give support to this,
and may signal an untapped resource for neuromodulation. The
precise role of the basal ganglia in the different aspects of sleep,
including the homeostatic and cognitive mechanisms involved in
going to sleep, the regulation of stages of sleep, the effect of sleep
on muscle tone, memory effects, sleep disorders and dreaming
and the regulation of consciousness, all merit further study. This
would hopefully bring us toward a better understanding of why
living organisms have been designed to sleep.
Conﬂicts of interest
All authors were involved in reviewing and drafting of the
manuscript. The authors declare that the research was conducted in
the absence of any commercial or ﬁnancial relationships that could
be construed as a potential conﬂict of interest.
This work was supported by the Wellcome Trust [103952/Z/14/
Z]. We are particularly grateful to Dr Gill Brown, Communication &
Graphic Design at London College of Communication (UAL), on her
help and artisanship with the Figures.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
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