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The subcortical belly of sleep: New possibilities in neuromodulation of basal ganglia?

  • Center For Neurodegenerative Diseases and the Aging Brain
  • Danish Epilepsy Centre & Aarhus University

Abstract and Figures

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 enables 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.
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The subcortical belly of sleep: New possibilities in neuromodulation of
basal ganglia?
Harutomo Hasegawa
, 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
article info
Article history:
Received 19 November 2019
Received in revised form
22 February 2020
Accepted 9 March 2020
Available online 22 April 2020
Basal ganglia
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, specically 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
license (
Since the rst 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 [1]. The structures comprising the basal ganglia are the
corpus striatum, globus pallidus (GP), subthalamic nucleus (STN)
and substantia nigra (SN) [2]. The functional organisation of the
basal ganglia is highly conserved from the lamprey, suggesting that
it serves a fundamental role in vertebrate phylogeny [3]. 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 [10].
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: (I. Rosenzweig).
Contents lists available at ScienceDirect
Sleep Medicine Reviews
journal homepage:
1087-0792/©2020 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (
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 signicant
progress in number of clinical interventions that allow intracranial
recordings from the human brain during sleep [18]. 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 directand indirectpathways gained
popularity [19](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 [20].
Whilst this model was useful for modelling the pathophysiology
of movement disorders, it has been superseded by newer
anatomical studies [21] and the conception of the brain as a dy-
namic organ rather than a static structure with input/output rou-
tines [22]. Recent studies have signicantly 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 [21].
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
[23]. 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 [24] and the subthalamic
nucleus, the medial border of which merges with the lateral hy-
pothalamus [16].
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 [25]. 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 [26],
reduced time spent in wakefulness [27], increased time spent in
REM sleep [12] and reduction in NREM sleep with nucleus
accumbens (NAc) core lesions [27].
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 [28]. Aden-
osine A
receptors are expressed on medium spiny neurons
5-HT 5-hydroxytryptamine
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
NE norepinephrine
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
PSG polysomnography
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 [29]. The A
receptor in the NAc shell has
been found to mediate the arousal effect of caffeine [30], as well as
chemogenetic and optogenetic stimulation of A
expressing neu-
rons in the NAc core promoted sleep [31]. 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)[32].
Some studies suggest that dopaminergic effects on striatal
neurons may also inuence sleep. Rats decient in dopamine af-
ferents to the striatum were found to spend more time awake [33]
and microdialysis in rodents found high extracellular uid dopa-
mine in the NAc during waking and low levels in NREM sleep [34].
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-
uences on sleep, such as staying awake during a boring lecture
[35]. 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 [38]. It remains difcult 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 [39].
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 [11]. 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 [40]. 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 [41]. 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 [42]. 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-linein
NREM sleep, during which the striatum exhibits typical oscillatory
activity [25].
Pallidum and sleep
The function of the globus pallidus during the sleep-wake
cycle may be reected 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 [33] and electrical [45] stimulation of the GPe in
rats signicantly 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 ring pattern in the globus
pallidus did not change signicantly throughout the sleep-
wake cycle (although the rate was higher in waking and
REM than in slow wave sleep) [46], 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 ring 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 [47]. Lesioning the STN in rats did not have
an effect on sleep architecture [27]. 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 ndings difcult 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 [52]. 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 [53]. The CM-
PF projections also innervate the globus pallidus [1], 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 [54]. Whether or not
thalamocortical oscillations inuence 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 outow 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 [55]. However, few imaging
studies have considered the role of the basal ganglia in a priori
hypotheses [56]. Most recent sleep imaging studies do not mention
the basal ganglia other than comment on their involvement in
passing [57].
The ascending arousal systems were shown active during REM
but not during slow wave sleep [15]. Similar ndings 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 [57] but the signicance of this is difcult
to interpret.
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 ow in pre-
sleep waking, slow wave sleep, REM sleep and post-sleep waking
conditions [15]. They found that slow wave sleep was associated
with a global reduction in CBF compared to waking and REM [15].
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 signicant 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 [18]. 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) [61]
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 [61]. 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 ring 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 [56] and
VIM in patients with myoclonic tremor and myoclonic epilepsy
[62]. 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 ndings support the involvement of the STN in sleep,
but their signicance is difcult 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) [63] study and the common average in the Urrestarazu
et al. (2009) [47] 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 [70], how such mechanisms result
in simultaneous localised (STN) and distributed (scalp) oscillations
and how they relate to the activity of specic anatomical networks
is unknown. Interestingly, no association was found between GPi
LFP spectra and that of the scalp [56]. This may indicate an element
of functional segregation, although further studies are required to
support such hypotheses. Kempf et al. [62]studied gamma activity
in VIM across sleep stages in 2 subjects, and found that ~70 Hz
gamma activity (nely tuned gamma) was present in awake but
absent in NREM sleep, and recurred intermittently in REM [62].
They concluded that nely tuned gamma activity may be an indi-
cator of activity of the ascending arousal system [62]. 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 ndings 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 uctuation 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 [67]. In the study by
H. Hasegawa et al. / Sleep Medicine Reviews 52 (2020) 101317 5
Velasco (2002) [67], scalp vertex waves signicantly 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) [71] 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 [71]. As the recordings
performed by both Velasco et al. [67] and Wennberg and Lozano
[71] 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
temporal asynchrony.
A more potent nding that weighs against reference electrode
or volume conduction effects is that subcortical sleep potentials
have also been recorded from bipolar contacts in the STN [47] and
thalamic anterior nucleus [68]. Urrestarazu et al. (2009) [47] 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 [47].
Some sleep spindles were also seen at the same time in Cz. Tsai
et al. (2010) [68] 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 [68]. Fluc-
tuations in local eld potentials broadly reect uctuations in
intracellular activity [72,73]. Whilst changes in potentials seen on a
bipolar montage are often attributed to local changes in neuronal
activity [74], this may not always be the case [75] and these ndings
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 ndings 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 [77], the polarity reversal of
the K-complex when cortical and subcortical recordings are
compared [79] and the fact that stimulation of cortical areas induce
Table 1
Sleep potential recorded from subcortical structures in humans.
Study Patients Electrode Placement Monopolar or bipolar Subcortical
sleep rhythm
Urrestarazu et al. (2009) [47]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) [67]N¼5, Lennox-Gastaut
CM Monopolar (ipsilateral
Vertex waves,
Vertex waves occurred in
scalp rst, spindles occurred
in thalamus rst
Moiseeva et al. (1969) [61]N¼11, diagnosis
not specied
Globus pallidus, putamen,
hypothalamus, ventrolateral &
posterior thalamic nucleus,
hypothalamus, STN, substantia nigra)
Not documented Spindles Abstract only
Salih et al. (2009) [56]N¼7, dystonia GPi Bipolar K-complexes
Subcortical potentials
occurred in association
with scalp.
Tsai et al. (2010) [68]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) [65]N¼7, epilepsy, PD Centromedian nucleus, anterior
nucleus, STN
Monopolar to Cz, Pz or
sphenoidal electrode
Vertex waves
Sleep potentials occurred
simultaneously and in
opposite polarities
Abbreviations: CM (centromedian nucleus), GPi (globus pallidus internus), PD (Parkinson's disease), STN (subthalamic nucleus).
Table 2
Sleep characteristics before and after DBS.
Study DBS
Sleep measure Effect
Iranzo et al. (2002) [49] STN PSG, clinical interview,
PSQI showed signicant improvement. PSG
showed more continuous sleep.
Hjort et al. (2004) [116] STN Parkinson Disease
Sleep Scale
Improves sleep quality mainly due to motor improvement
Cicolin et al. (2004) [48] STN PSG Improvement in sleep architecture but not PLM or RBD
Baumann-Vogel et al. (2017) [82] STN PSG, ESS, Zurich
sleep questionnaire
DBS reduced sleepiness and improved some PSG
parameters but did not normalise sleep.
Tolleson et al. (2016) [84] GPi PSG No effect on sleep parameters
Lim et al. (2009) [86] PPN PSG DBS onincreased REM time compared to DBS off
Arnulf et al. (2010) [85] 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 [76]. It is difcult to reconcile these
ndings with the observation of K-complexes on bipolar STN [47]
and GPi [56] 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 insufcient data in these
small number of studies to fully explain these ndings. One po-
tential explanation for subcortical spindles and K-complexes is
neuronal synchronization [70]. Thalamic spindles are synchronized
across the length of an electrode, and this is dependent on feedback
from the cortex [80]. If such a mechanism is responsible, the nd-
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 [68].
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 [71], 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 identied remains a fertile eld 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 generatedand discourse such
as the propagation of sleep potentialsbe 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 onand offconditions [86](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, difcult 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 [36] but also because the mechanism of action of
DBS remains poorly understood [87]. Interestingly, improvement in
sleep was not seen after GPi DBS for Parkinson's disease [84],
although more studies are required to draw implications based on
this observation. Patients who had PPN DBS for Parkinson's disease
[85] or progressive supranuclear palsy [86] 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 veries ndings 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 insufcient 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 [88] and 88% with Huntington's disease [89]
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 difcult 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 [37]. Parkinson's disease is associated with
the widest variety of sleep disorders but this may reect 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 [90]. The SLD has descending connections with spinal motor
neurons and is an important part of the REM switch [91]. 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 [93]. Higher prevalence of periodic limb movement disorder in
RBD patients has been argued to reect 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 [96]. For instance, nigro-caudate dopami-
nergic deafferentation has been argued as a principal biomarker of
RBD [96], 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 decit 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 [99]
have been linked to early neuronal loss in the medial caudate [100].
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 ef-
ciency and excessive daytime sleepiness have all been reported (for
in-depth review see [101]). Reduced N3 and REM stage and an
increased sleep spindle density have also been observed in HD
patients [101].
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 signicantly 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 [102]). Sleep pathology has been
described in this patient population, with evidence for reduced
total sleep time and sleep efciency, 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
[104 ].
Similar to OCD patients, dysfunction of basal ganglia has been
suggested as central to pathology underlying development of
addiction and substance abuse disorders [102]. 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 ve to ten times more likely to
have sleep issues, and presence of this comorbidity has signicant
impact on severity of addiction, remission and the related relapse
prospects, as well as prevalence of affective symptomatology and
depression [105]. 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 [106]. 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
[106]. Within that context, of note are ndings 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 decit
hyperactivity disorder (ADHD), characterized by symptoms of age-
inappropriate inattention, hyperactivity and impulsivity [108 ], and
schizophrenia [109]. In recent comprehensive assessment of sleep
disorders and their correlates in patients with early psychosis,
sleep disorders were signicantly 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 ndings 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 [111], these may lend to irrelevant external or internal stimuli
being marked as of overvalued/delusional signicance, due to
their temporal association of the stimuli with striatal signalling
[109]. Following that concept, arguably, the aberrant association
within dorsal regions of the striatum may be tied to signalling
Table 3
Sleep disturbance in disorders affecting the basal ganglia.
Disease Basal ganglia involvement Associated sleep disorders
Parkinson disease [36,88] Nigrostriatal degeneration Nocturnal awakening
Sleep fragmentation
Periodic limb movements/RLS
REM behaviour disorder (RBD)
Obstructive sleep apnoea
Excessive daytime sleepiness
Huntington's disease [117] Striatal degeneration Nocturnal awakening
Increased nocturnal movements
RWA, PLM, RBD reported in a minority of patients
Progressive supranuclear palsy [118] Neuronal loss and gliosis Nocturnal awakening
RBD reported in a minority of patients
Wilson's disease [119] Copper deposition Excessive daytime sleepiness
Poor nocturnal sleep
Cataplexy-like episodes
Pantothenate kinase-associated neurodegeneration (PKAN) [120] 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 [110]. Impaired reality assessment
may further increase vigilance in any affected individual and lead to
decreased sleep efciency, 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
decits [104,113].
The reciprocal connections between the basal ganglia and the
sleep-wake circuitry, and the experimental ndings reviewed in
this paper point to an important role of the basal ganglia in sleep
(Fig. 2). A major challenge is to dene the role of specic 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 nds some experimental support
[43]. There is also evidence to suggest that the striatum, GPi and
STN adopt rhythmic oscillations during NREM sleep. More studies
are required to conrm these ndings 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 [115] 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.
Conicts 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 nancial relationships that could
be construed as a potential conict 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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Practice points
The modulatory role for the basal ganglia in sleep regula-
tion is suggested by:
1) emerging evidence that the striatum, GPi and STN
structures adopt rhythmic oscillations during NREM
2) their active role in processing sensorimotor, cognitive
and affective information during wake and sleep states;
3) emerging molecular studies on the sleep and wake pro-
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Research agenda
Future studies should decipher the precise role of the basal
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1) including the homeostatic and cognitive mechanisms
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... 16 Resting-state functional connectivity (rs-FC) of cortical networks was calculated as the average Fisher-transformed correlation between the time courses of each pair of regions within or between 12 cortical networks defined by the Gordon atlas. In addition, rs-FC between the 12 cortical networks and 19 subcortical regions were also calculated (appendix pp [10][11][19][20][21][22][23][24][25][26][27][28]. In total, there were 306 unique functional connectivity measures. ...
... We next examined how sleep duration affects the intrinsic functional organisation of brain networks in the developing Linear fit brain at baseline and at 2-year follow-up. At baseline, we found that 93 of the 306 unique functional connections showed a significant difference between the sufficient sleep and insufficient sleep groups (all false discovery rate corrected p<0·05; appendix pp [10][11][19][20][21][22][23][24][25][26][27][28]. Noticeably, four out of the five connectivities that had a Cohen's d value greater than 0·15 involved regions of the basal ganglia, which plays a core role in regulating the sleep-wake cycle. ...
... Noticeably, four out of the five connectivities that had a Cohen's d value greater than 0·15 involved regions of the basal ganglia, which plays a core role in regulating the sleep-wake cycle. 26 Additionally, the effect sizes of sleep duration on all 306 available functional connectivities were significantly correlated with that in the 2-year follow-up (r=0·54, 95% CI 0·45-0·61; p<0·0001; figure 2). These results suggest that certain functional connectivity measures are consistently susceptible to insufficient sleep over time. ...
Background: Although the American Academy of Sleep Medicine suggests at least 9 h of sleep per day for 6–12-year-olds, children in recent generations often report sleeping less than this amount. Because early adolescence is a crucial period for neurocognitive development, we aimed to investigate how insufficient sleep affects children's mental health, cognition, brain function, and brain structure over 2 years. Methods: In this propensity score matched, longitudinal, observational cohort study, we obtained data from a population-based sample of 9–10-year-olds from 21 US study sites in the ongoing Adolescent Brain Cognitive Development (ABCD) study. Participants were categorised as having sufficient sleep or insufficient sleep on the basis of a cutoff of 9 h sleep per day. Using propensity score matching, we matched these two groups of participants on 11 key covariates, including sex, socioeconomic status, and puberty status. Participants were excluded from our analysis if they did not pass a baseline resting-state functional MRI quality check or had missing data for the covariates involved in propensity score matching. Outcome measures retrieved from the ABCD study were behavioural problems, mental health, cognition, and structural and resting-state functional brain measures, assessed at baseline and at 2-year follow-up. We examined group differences on these outcomes over those 2 years among all eligible participants. We then did mediation analyses of the neural correlates of behavioural changes induced by insufficient sleep. Findings: Between Sept 1, 2016, and Oct 15, 2018, 11 878 individuals had baseline data collected for the ABCD study, of whom 8323 were eligible and included in this study (4142 participants in the sufficient sleep group and 4181 in the insufficient sleep group). Follow-up data were collected from July 30, 2018, to Jan 15, 2020. We identified 3021 matched sufficient sleep–insufficient sleep pairs at baseline and 749 matched pairs at 2-year follow-up, and observed similar differences between the groups in behaviour and neural measures at both timepoints; the effect sizes of between-group differences in behavioural measures at these two timepoints were significantly correlated with each other (r=0·85, 95% CI 0·73–0·92; p<0·0001). A similar pattern was observed in resting-state functional connectivity (r=0·54, 0·45–0·61; p<0·0001) and in structural measures (eg, in grey matter volume r=0·61, 0·51–0·69; p<0·0001). We found that cortico–basal ganglia functional connections mediate the effects of insufficient sleep on depression, thought problems, and crystallised intelligence, and that structural properties of the anterior temporal lobe mediate the effect of insufficient sleep on crystallised intelligence. Interpretation: These results provide population-level evidence for the long-lasting effect of insufficient sleep on neurocognitive development in early adolescence. These findings highlight the value of early sleep intervention to improve early adolescents' long-term developmental outcomes.
... To date, the nature and functions of sleep remain poorly understood [10,11], but it is generally considered to be an active process with a unique fingerprint of neuronal circuitry inhibitions and activations, and with associated physiological consequences throughout the entire body [12][13][14][15]. ...
... Wake-and sleep-promoting mechanisms are summarized in Table 1. Note that fast neurotransmitters like glutamate and GABA are now considered central to sleep-wake regulatory systems, with monoaminergic and cholinergic arousal systems serving a modulatory role [12,21]. ...
... Insomnia is common in people with epilepsy, with an estimated prevalence of up to 50% [30]. Moreover, about 10-35% of people with epilepsy suffer from comorbid obstructive sleep apnea (OSA), with significantly higher incidence in those with refractory Table 1 Wake-and sleep-promoting mechanisms in the brain (adapted from [12]). ...
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Poor sleep and daytime sleepiness are common in people with epilepsy. Sleep disorders can disrupt seizure control and in turn sleep and vigilance problems can be exacerbated by seizures and by antiepileptic treatments. Nevertheless, these aspects are frequently overlooked in clinical practice and a clear agreement on the evidence-based guidelines for managing common sleep disorders in people with epilepsy is lacking. Recently, recommendations to standardize the diagnostic pathway for evaluating patients with sleep-related epilepsies and comorbid sleep disorders have been presented. To build on these, we adopted the Delphi method to establish a consensus within a group of experts and we provide practical recommendations for identifying and managing poor night-time sleep and daytime sleepiness in people with epilepsy. We recommend that a comprehensive clinical history of sleep habits and sleep hygiene should be always obtained from all people with epilepsy and their bed partners. A psychoeducational approach to inform patients about habits or practices that may negatively influence their sleep or their vigilance levels should be used, and strategies for avoiding these should be applied. In case of a suspected comorbid sleep disorder an appropriate diagnostic investigation should be performed. Moreover, the possible presence of sleep fragmentation induced by sleep-related seizures should be ruled out. Finally, the dose and timing of antiepileptic medications and other co-medications should be optimized to improve nocturnal sleep and avoid daytime sedation.
... This has become a topic of interest in recent years, where studies have investigated differences in grey matter (GM) and subcortical regions between insomniacs and non-insomniac older adults [14][15][16]. Although there is certain variability on the areas related to the report of insomnia across studies, findings in prefrontal areas, putamen or thalamus are more consistent, suggesting that they might participate in insomnia status [14,15,17,18]. Despite the participation of prefrontal or subcortical regions in insomnia, it remains unclear how these structural brain changes may align with measures of the actual severity of the reported insomnia. ...
... The cortico-striato-thalamo-cortical loop has multiple neurocognitive functions including regulating arousals along with cognitive and affective functions. The striatum, formed by putamen and caudate, is specially involved in sleep regulation [17]. In physiological terms, putamen regulates arousal by inhibitory GABAergic projections to pallidum and thalamus, promoting cortical activity and wakefulness [48]. ...
... We found no relationship, however, with thalamic volumes. Although it is known that subcortical structures participate in sleep regulation, further studies specifically evaluating which subcortical changes directly relate to insomnia are needed [17]. ...
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Background There is an increasing awareness that sleep disturbances are a risk factor for dementia. Prior case-control studies suggested that brain grey matter (GM) changes involving cortical (i.e, prefrontal areas) and subcortical structures (i.e, putamen, thalamus) could be associated with insomnia status. However, it remains unclear whether there is a gradient association between these regions and the severity of insomnia in older adults who could be at risk for dementia. Since depressive symptoms and sleep apnea can both feature insomnia-related factors, can impact brain health and are frequently present in older populations, it is important to include them when studying insomnia. Therefore, our goal was to investigate GM changes associated with insomnia severity in a cohort of healthy older adults, taking into account the potential effect of depression and sleep apnea as well. We hypothesized that insomnia severity is correlated with 1) cortical regions responsible for regulation of sleep and emotion, such as the orbitofrontal cortex and, 2) subcortical regions, such as the putamen. Methods 120 healthy subjects (age 74.8±5.7 years old, 55.7% female) were recruited from the Hillblom Healthy Aging Network at the Memory and Aging Center, UCSF. All participants were determined to be cognitively healthy following a neurological evaluation, neuropsychological assessment and informant interview. Participants had a 3T brain MRI and completed the Insomnia Severity Index (ISI), Geriatric Depression Scale (GDS) and Berlin Sleep Questionnaire (BA) to assess sleep apnea. Cortical thickness (CTh) and subcortical volumes were obtained by the CAT12 toolbox within SPM12. We studied the correlation of CTh and subcortical volumes with ISI using multiple regressions adjusted by age, sex, handedness and MRI scan type. Additional models adjusting by GDS and BA were also performed. Results ISI and GDS were predominantly mild (4.9±4.2 and 2.5±2.9, respectively) and BA was mostly low risk (80%). Higher ISI correlated with lower CTh of the right orbitofrontal, right superior and caudal middle frontal areas, right temporo-parietal junction and left anterior cingulate cortex ( p <0.001, uncorrected FWE). When adjusting by GDS, right ventral orbitofrontal and temporo-parietal junction remained significant, and left insula became significant ( p <0.001, uncorrected FWE). Conversely, BA showed no effect. The results were no longer significant following FWE multiple comparisons. Regarding subcortical areas, higher putamen volumes were associated with higher ISI ( p <0.01). Conclusions Our findings highlight a relationship between insomnia severity and brain health, even with relatively mild insomnia, and independent of depression and likelihood of sleep apnea. The results extend the previous literature showing the association of specific GM areas (i.e, orbitofrontal, insular and temporo-parietal junction) not just with the presence of insomnia, but across the spectrum of severity itself. Moreover, our results suggest subcortical structures (i.e., putamen) are involved as well. Longitudinal studies are needed to clarify how these insomnia-related brain changes in healthy subjects align with an increased risk of dementia.
... Striatopallidal medium spiny neurons projecting to external GP have adenosine receptors (A 2A ) which could promote sleep. Chemogenetic activation of these A 2A neurons increased sleep duration and, on the other hand, chemogenetic inhibition decreased sleep time in a mice model [12]. Also, lesions of the GP in rats produced sleep fragmentation and significantly decreased the amount of sleep [12], which is the predominant sleep complaint in PKAN. ...
... Chemogenetic activation of these A 2A neurons increased sleep duration and, on the other hand, chemogenetic inhibition decreased sleep time in a mice model [12]. Also, lesions of the GP in rats produced sleep fragmentation and significantly decreased the amount of sleep [12], which is the predominant sleep complaint in PKAN. Intrinsic factors such as reduced mobility, prominent axial involvement or associated skeletal deformities could alter sleep continuity and interfere with turning in bed, favoring the supine position, a known risk factor for OSAS [13]. ...
Background Pantothenate kinase-associated neurodegeneration (PKAN) is a rare neurologic disorder included in the group of neurodegeneration with brain iron accumulation diseases (NBIA). Information regarding sleep in patients with PKAN is limited. Objectives To describe the clinical and polysomnographic characteristics of sleep in six patients with genetically confirmed PKAN. Methods The evaluation included a clinical interview, sleep questionnaires -Epworth Sleepiness Scale (ESS), Pittsburgh Sleep Quality Index (PSQI) and Hospital Anxiety and Depression Scale (HADS)- and a video-polysomnography (VPSG). In addition to standard sleep measures we manually quantified sleep spindle density in stage N2 and of rapid eye movements in REM sleep comparing the results with matched controls. Quantification of EMG activity in REM sleep was performed following standard criteria. Results All the patients reported at least one sleep complaint, most commonly sleep fragmentation (4/6) and sleep onset insomnia (3/6). ESS and PSQI were abnormal in 3/6 and 4/6, respectively. VPSG showed in 4/6 decreased ocular movements during REM sleep, an increase in sleep spindles in 3/6 (all of them with deep brain pallidal stimulation), an absence of slow wave sleep in 2 and undifferentiated NREM sleep and delayed sleep phase in one. Three patients had an abnormal sleep apnea/hypopnea index, and 2 periodic limb movements of sleep. REM sleep muscular atonia was preserved in all. Conclusions Sleep disorders are common in patients with PKAN. Although our sample is small and heterogeneous, with different symptomatic treatments possibly influencing the results, it suggests that evaluation of sleep should be considered in their management.
... sleep, the fatigue of the body disappears and the function is restored, which plays a pivotal role in maintaining normal body functions [3,4]. Postoperative sleep disorders manifest sleep rhythm disorder or sleep structure and phase change, which occurred about 42% [5]. ...
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Background Postoperative sleep disorder is common and may cause aggravated postoperative pain, delirium, and poor prognosis. We accessed the effect of intraoperative intravenous dexmedetomidine on postoperative sleep quality in patients with endoscopic sinus surgery. Methods This single-center, double-blind, placebo-controlled randomized clinical trial enrolled a total of 110 participants aged 18 years to 65 years who were scheduled to receive endoscopic sinus surgery. Placebo (normal saline) or dexmedetomidine infusion (load dose 0.5 μg kg ⁻¹ over 10 min, followed by maintenance dose 0.2 ug kg ⁻¹ h ⁻¹ ) during surgery. The primary outcome was postoperative sleep quality. Secondary outcomes were postoperative Ramsay sedation scores, Visual Analog Scale (VAS) scores, serum cortisol, 5-hydroxytryptamine (5-HT) and hypocretin, delirium, and postoperative nausea and vomiting (PONV). Results Among enrolled 110 patients, 55 were randomized to administer intraoperative dexmedetomidine and placebo. In total, 14 patients (7 in each group) were excluded because of protocol deviations, and 96 patients (48 in each group) were included in the per-protocol analysis. The dexmedetomidine group had a significantly higher sleep efficiency index(SEI) (66.85[3.00] vs 65.38[3.58]), the ratio of rapid eye movement sleep to total sleep(REM)(13.63[1.45] vs 12.38[2.11]) and lower arousal index (AI) (7.20[1.00] vs 8.07[1.29]), higher Ramsay sedation score at post-operation 1 h, 12 h point, lower VAS scores at post-operation 1 h, 12 h, 24 h point, lower cortisol, higher 5-HT and hypocretin in serum than the placebo group. Conclusion In this randomized clinical trial, dexmedetomidine can improve the sleep quality of patients undergoing endoscopic sinus surgery. These results suggest that this therapy may be a viable strategy to enhance postoperative sleep quality in patients with endoscopic sinus surgery. Trial registration The study was approved by the Bethune International Peace Hospital Ethics Committee (2021-KY-129) and registered in the Chinese Clinical Trial Registry (, 28/09/2021).
... There is considerable evidence that exogenous cannabinoids indirectly modulate DA activity [49][50][51] with ramifications for development of CUD and CWS. The striatum, comprised of the nucleus accumbens (NAc), dorsal medial (DMS) and dorsal lateral striatal (DLS) subregions, is a major site of DA action in the brain and is involved in many behaviors associated with drug abuse and withdrawal symptoms [52], as well as sleep [53], making it an interesting nexus THC action and withdrawal phenomena. ...
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Withdrawal symptoms are observed upon cessation of cannabis use in humans. Although animal studies have examined withdrawal symptoms following exposure to delta-9-tetrahydrocannabinol (THC), difficulties in obtaining objective measures of spontaneous withdrawal using paradigms that mimic cessation of use in humans have slowed research. The neuromodulator dopamine (DA) is affected by chronic THC treatment and plays a role in many behaviors related to human THC withdrawal symptoms. These symptoms include sleep disturbances that often drive relapse, and emotional behaviors like irritability and anhedonia. We examined THC withdrawal-induced changes in striatal DA release and the extent to which sleep disruption and behavioral maladaptation manifest during abstinence in a mouse model of chronic THC exposure. Using a THC treatment regimen known to produce tolerance, we measured electrically elicited DA release in acute brain slices from different striatal subregions during early and late THC abstinence. Long-term polysomnographic recordings from mice were used to assess vigilance state and sleep architecture before, during, and after THC treatment. We additionally assessed how behaviors that model human withdrawal symptoms are altered by chronic THC treatment in early and late abstinence. We detected altered striatal DA release, sleep disturbances that mimic clinical observations, and behavioral maladaptation in mice following tolerance to THC. Altered striatal DA release, sleep, and affect-related behaviors associated with spontaneous THC abstinence were more consistently observed in male mice. These findings provide a foundation for preclinical study of directly translatable non-precipitated THC withdrawal symptoms and the neural mechanisms that affect them.
... ; 1101/2022 worth mentioning that all of these subcortical regions (except the right cerebellum) are a part of the basal ganglia, which plays a core role in regulating the sleep-wake cycle (Hasegawa et al., 2020). This convergence of disturbed connectivity patterns between cortical functional networks and the basal ganglia in the IS group suggest that the disruption of sleep loss on subcortical brain functions can merge very early, even in the developing brain. ...
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Importance: Adolescents nowadays often get insufficient sleep. Yet, the long-term adverse effects of sleep loss on developing brain and behavior remains unknown. Objective: To determine whether insufficient sleep leads to long-lasting impacts on mental health, cognition, and brain development in adolescents across two years. Design: This longitudinal study utilized a public dataset, the Adolescent Brain Cognitive Development (ABCD) study, which is an ongoing study starting from 2016. Setting: Data were collected from 21 research sites in the U.S. Participants: 11,875 9-10-year-olds were recruited using stratified sampling in order to reflect the diversity of the U.S. population. Intervention: Individuals with sufficient versus insufficient sleep (< 9 hours per day for adolescents) were compared after controlling for age (months), sex, race, puberty status, and other 7 covariates based on propensity score matching. Main Outcomes and Measures: Behavior problems, cognition, mental health assessments, resting-state functional connectivity, gray matter volume, cortical area, cortical thickness, and structural connectivity (Fractional anisotropy) were collected and preprocessed by the ABCD study. Independent-sample t-tests and meditation analysis were performed to investigate the effects of insufficient sleep. Results: 3021 matched pairs (50.7% male) were identified based on baseline assessment, with mean (SD) age of 119.5 (7.5) months. In baseline, sufficient sleep is associated less behavioral problems on 18 of 20 assessments, e.g. depress (95% CI of mean difference: -0.28 to -0.47, false discovery rate (FDR)-corrected p < .001, Cohen's d = -0.20), better cognitive performance on 7 of 10 assessments, such as crystal cognition (95% CI: 0.81 to 1.50, FDR-corrected p < .001, Cohen's d = 0.17), better functional connection between cortical regions and basal ganglia (all FDR-corrected p < .05, Cohen's d >0.15), and large structure in ACC and temporal pole (all FDR-corrected p < .05, Cohen's d >0.09). Similar patterns of effect of sufficient sleep were found in FL2 (749 pairs remained) e.g. Cohen's d of function connectivity at baseline was correlated with Cohen's d of that at FL2 (r = 0.54, 95% CI: 0.45 to 0.61, p < 1e-10). Mediation and longitudinal mediation analysis revealed that identified brain measures (e.g. gray matter volume of left temporal pole) at baseline mediated the effect of sufficient sleep on behavioral assessments (e.g. crystal cognition) at baseline and at FL2 (95% CI did not encompass 0, p < 0.05 on 100,000 random-generated bootstrapped samples). Conclusions and Relevance: These results provide strong population-level evidence for the long-lasting detrimental effects of insufficient sleep on mental health, cognition, and brain function and structure in adolescents. The current study identified potential neural mechanisms of adverse effect of insufficient sleep in adolescents, which might provide a theoretical grounding for sleep intervention programs to improve the long-term developmental outcomes in adolescents.
... The striatum was separated out for the detection of various autophagic markers including beclin1 (autophagy initiation marker), LC3II (autophagosome marker), and p62 (autophagy flux marker). We selected the striatum because it has been implicated in sleep regulation (reviewed in [37]) and shown sensitive to sleep disruption [26] but has received less attention compared to other regions such as the hippocampus and frontal cortex. The results showed that 5 days of SF significantly increased beclin1 levels (1.27 ± 0.05 fold, p < 0.05), LC3II levels (1.33 ± 0.07 fold, p < 0.05), and p62 levels (1.35 ± 0.06 fold, p < 0.05) ( Figure 1A,B) compared to sham. ...
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In this study, we investigated autophagy, glial activation status, and corticotropin releasing factor (CRF) signaling in the brains of mice after 5 days of sleep fragmentation (SF). Three different brain regions including the striatum, hippocampus, and frontal cortex were selected for examination based on roles in sleep regulation and sensitivity to sleep disruption. For autophagy, we monitored the levels of various autophagic induction markers including beclin1, LC3II, and p62 as well as the levels of lysosomal associated membrane protein 1 and 2 (LAMP1/2) and the transcription factor EB (TFEB) which are critical for lysosome function and autophagy maturation stage. For the status of microglia and astrocytes, we determined the levels of Iba1 and GFAP in these brain regions. We also measured the levels of CRF and its cognate receptors 1 and 2 (CRFR1/2). Our results showed that 5 days of SF dysregulated autophagy in the striatum and hippocampus but not in the frontal cortex. Additionally, 5 days of SF activated microglia in the striatum but not in the hippocampus or frontal cortex. In the striatum, CRFR2 but not CRFR1 was significantly increased in SF-experienced mice. CRF did not alter its mRNA levels in any of the three brain regions assessed. Our findings revealed that autophagy processes are sensitive to short-term SF in a region-specific manner and suggest that autophagy dysregulation may be a primary initiator for brain changes and functional impairments in the context of sleep disturbances and disorders.
Background and purpose: While excessive daytime sleepiness can predate Parkinson's disease in late-life, its association with parkinsonian-like (P-L) symptoms in middle age are unknown. Since neurodegeneration can appear decades before a diagnosis of Parkinson's disease, identifying clinical features associated with this early progression is important. The purpose of this study was to determine the association of daytime sleepiness with P-L symptoms in a population-based sample of middle-aged Korean adults. Methods: During 2013 and 2014, daytime sleepiness and P-L symptoms were assessed in 2,063 males and females aged 50-64 years who were participating in the Korean Genome and Epidemiology Study. The severity of daytime sleepiness was quantified by the score on the Epworth Sleepiness Scale (ESS). Self-reported P-L symptoms included nine motor disorders commonly associated with Parkinson's disease. Participants with parkinsonism and related conditions are excluded. Results: The prevalence of excessive daytime sleepiness (ESS score >10) was 7.0%. The frequencies of P-L symptoms ranged from 0.5% (for "trouble buttoning buttons") to 18.4% (for "handwriting smaller than it once was"). After adjustment for covariates and multiple testing, the relative odds of P-L symptoms comparing the 80th and 20th percentiles of ESS scores was 1.6 (p=0.001) for "voice is softer than it once was," 2.1 (p<0.001) for "balance when walking is poor," and 1.5 (p=0.002) for "loss of facial expression." The prevalence of excessive daytime sleepiness increased from 6.3% to 19.8% when the number of symptoms increased from zero to three (p=0.004). Conclusions: In Korean adults aged 50-64 years, daytime sleepiness is significantly associated with P-L symptoms. Whether coexisting daytime sleepiness and P-L symptoms predate extrapyramidal and other impairments in later life warrants further investigation.
Background Survivors of pediatric acute lymphoblastic leukemia (ALL) are at increased risk of neurocognitive weakness in the areas of attention, executive function, and processing speed. Although fatigue and sleep disturbances are frequent complications of ALL therapy and associated with cognitive functions, the impact of fatigue and sleep profiles during active ALL treatment on posttreatment neurocognitive performance has received limited attention. Methods Pediatric patients (n = 120) with ALL (diagnosed 2011–2016) who completed fatigue and sleep questionnaires at four time points during active treatment were enrolled in a study of neurocognitive performance. Latent class growth analysis identified subgroups of patients with similar sleep and fatigue profiles during treatment. Neurocognitive performance collected >6 months post treatment on 40 participants was compared between latent classes using multivariable linear regression models. Results Participants (57.5% male and 79.1% Hispanic or non-Hispanic White) were classified into one of two fatigue and sleep profiles: Class 1 characterized by mild fatigue and sleep disturbances during treatment (50.8%), and Class 2 characterized by higher levels of fatigue and sleep disturbances (49.2%). Posttreatment cognitive performance was in the normal range for most measures, but significantly below normative means for executive function, verbal short-term memory, attention, and distractability measures. Compared to Class 1, Class 2 demonstrated significantly (p < .05) poorer posttreatment neurocognitive performance, particularly in measures of attention. Conclusions Our findings indicate that fatigue and sleep disturbances during the first year of pediatric ALL therapy may impact long-term neurocognitive performance. Sleep and fatigue may be targets for intervention to preserve cognitive functioning in survivors.
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Objective Although not typical of Parkinson’s disease (PD), caudate dopaminergic dysfunction can occur in early stages of the disease. However, its frequency and longitudinal implications in large cohorts of recently diagnosed patients remain to be established. We investigated the occurrence of caudate dopaminergic dysfunction in the very early phases of PD (<2 years from diagnosis) using ¹²³ I-FP-CIT single photon emission CT and determined whether it was associated with the presence or subsequent development of cognitive impairment, depression, sleep and gait problems. Methods Patients with PD and healthy controls were identified from the Parkinson’s Progression Markers Initiative (PPMI) database. We defined a clinically significant caudate dysfunction as ¹²³ I-FP-CIT binding <–2 SDs compared with the controls’ mean and categorised three groups accordingly (no reduction, unilateral reduction, bilateral reduction). All statistical analyses were adjusted for mean putamen binding. Results At baseline, 51.6% of 397 patients had normal caudate dopamine transporter binding, 26.0% had unilateral caudate involvement, 22.4% had bilaterally impaired caudate. Compared with those with a baseline normal caudate function, at the4-year follow-up patients with a baseline bilateral caudate involvement showed a higher frequency of cognitive impairment (p<0.001) and depression (p<0.001), and worse cognitive (p<0.001), depression (<0.05) and gait (<0.001) ratings. Significant caudate involvement was observed in 83.9% of the population after 4 years (unilateral 22.5%, bilateral 61.4%). Conclusions Early significant caudate dopaminergic denervation was found in half of the cases in the PPMI series. Baseline bilateral caudate involvement was associated with increased risk of developing cognitive impairment, depression and gait problems over the next 4 years.
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Huntington’s chorea (Huntington’s disease, HD) is a genetic disorder caused by autosomal dominant mutation, leading to progressive neurodegenerative changes in the central nervous system. Involuntary movements such as chorea occur typically in HD patients, accompanied by progressive cognitive and psychiatric disturbances. Other common symptoms of HD are circadian and sleep abnormalities, which are observed from the earliest stages of the disease or even before the occurrence of clinical symptoms. The most common sleep problems reported by HD patients include insomnia, difficulties in falling asleep, frequent nocturnal awakenings, and excessive daytime sleepiness. Also, specific changes in sleep architecture have been identified in HD. In this paper, we review studies on sleep and circadian rhythm disorders in HD. We outline findings concerning sleep patterns and disturbances of circadian rhythms in HD patients, as well as the role of psychiatric disorders and motor disorders in HD patients’ sleep problems. We also discuss problems related to the different methods of diagnosing sleep disorders in HD. Furthermore, the adverse effects of medication used for the treatment of core HD symptoms as one of the sources of sleep disturbances in HD are emphasized. In conclusion, the diversity and complexity of the determinants of sleep and circadian rhythm disorders in HD are highlighted. Finally, the relevance of effective treatment to improve patients’ functioning and quality of life as well as the potential relief of their cognitive and emotional symptoms is addressed.
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Dopamine is involved in numerous neurological processes, and its deficiency has been implicated in Parkinson’s disease, whose patients suffer from severe sleep disorders. Destruction of nigrostriatal dopaminergic neurons or dorsal striatum disrupts the sleep–wake cycle. However, whether striatal dopamine levels correlate with vigilance states still remains to be elucidated. Here, we employed an intensity-based genetically encoded dopamine indicator, dLight1.1, to track striatal dopamine levels across the spontaneous sleep–wake cycle and the dopaminergic response to external stimuli. We found that the striatal dLight1.1 signal was at its highest during wakefulness, lower during non-rapid eye movement (non-REM or NREM) sleep, and lowest during REM sleep. Moreover, the striatal dLight1.1 signal increased significantly during NREM sleep-to-wake transitions, while it decreased during wake-to-NREM sleep transitions. Furthermore, different external stimuli, such as sudden door-opening of the home cage or cage-change to a new environment, caused striatal dopamine release, whereas an unexpected auditory tone did not. Finally, despite both modafinil and caffeine being wake-promoting agents that increased wakefulness, modafinil increased striatal dopamine levels while caffeine did not. Taken together, our findings demonstrated that striatal dopamine levels correlated with the spontaneous sleep–wake cycle and responded to specific external stimuli as well as the stimulant modafinil.
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The mesolimbic hypothesis has been a central dogma of schizophrenia for decades, positing that aberrant functioning of midbrain dopamine projections to limbic regions causes psychotic symptoms. Recently, however, advances in neuroimaging techniques have led to the unanticipated finding that dopaminergic dysfunction in schizophrenia is greatest within nigrostriatal pathways, implicating the dorsal striatum in the pathophysiology and calling into question the mesolimbic theory. At the same time our knowledge of striatal anatomy and function has progressed, suggesting new mechanisms via which striatal dysfunction may contribute to the symptoms of schizophrenia. This Review draws together these developments, to explore what they mean for our understanding of the pathophysiology, clinical manifestations, and treatment of the disorder.
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Sleep disturbance is known to be associated with psychosis, but sleep disorders (eg, insomnia, nightmare disorder, sleep apnea) have rarely been investigated. We aimed to provide the first detailed assessment of sleep disorders and their correlates in patients with early psychosis. Sixty outpatients aged between 18 and 30 with nonaffective psychosis were assessed for sleep disorder presence, severity, and treatment using a structured diagnostic interview, sleep diaries, and actigraphy. Psychotic experiences, mood, and psychological wellbeing were also measured. Forty-eight patients (80%) had at least one sleep disorder, with insomnia and nightmare disorder being the most common. Comorbidity of sleep disorders within this group was high, with an average of 3.3 sleep disorders per patient. Over half of the sleep disorders had been discussed with a clinician but almost three-quarters had received no treatment. Treatment according to clinical guidelines was rare, occurring in only 8% of cases (n = 13). Sleep disorders were significantly associated with increased psychotic experiences, depression, anxiety, fatigue, and lower quality of life. Sleep disorders are very common in patients with psychosis, may have wide-ranging negative effects, and merit routine assessment and treatment in psychiatric practice.
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This review focuses on the cognitive neuroscience of Attention Deficit Hyperactivity Disorder (ADHD) based on functional magnetic resonance imaging (fMRI) studies and on recent clinically relevant applications such as fMRI-based diagnostic classification or neuromodulation therapies targeting fMRI deficits with neurofeedback (NF) or brain stimulation. Meta-analyses of fMRI studies of executive functions (EFs) show that ADHD patients have cognitive-domain dissociated complex multisystem impairments in several right and left hemispheric dorsal, ventral and medial fronto-cingulo-striato-thalamic and fronto-parieto-cerebellar networks that mediate cognitive control, attention, timing and working memory (WM). There is furthermore emerging evidence for abnormalities in orbital and ventromedial prefrontal and limbic areas that mediate motivation and emotion control. In addition, poor deactivation of the default mode network (DMN) suggests an abnormal interrelationship between hypo-engaged task-positive and poorly “switched off” hyper-engaged task-negative networks, both of which are related to impaired cognition. Translational cognitive neuroscience in ADHD is still in its infancy. Pattern recognition analyses have attempted to provide diagnostic classification of ADHD using fMRI data with respectable classification accuracies of over 80%. Necessary replication studies, however, are still outstanding. Brain stimulation has been tested in heterogeneously designed, small numbered proof of concept studies targeting key frontal functional impairments in ADHD. Transcranial direct current stimulation (tDCS) appears to be promising to improve ADHD symptoms and cognitive functions based on some studies, but larger clinical trials of repeated stimulation with and without cognitive training are needed to test clinical efficacy and potential costs on non-targeted functions. Only three studies have piloted NF of fMRI-based frontal dysfunctions in ADHD using fMRI or near-infrared spectroscopy, with the two larger ones finding some improvements in cognition and symptoms, which, however, were not superior to the active control conditions, suggesting potential placebo effects. Neurotherapeutics seems attractive for ADHD due to their safety and potential longer-term neuroplastic effects, which drugs cannot offer. However, they need to be thoroughly tested for short- and longer-term clinical and cognitive efficacy and their potential for individualized treatment.
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So-called idiopathic rapid eye movement (REM) sleep behaviour disorder (RBD), formerly seen as a rare parasomnia, is now recognized as the prodromal stage of an α-synucleinopathy. Given the very high risk that patients with idiopathic RBD have of developing α-synucleinopathies, such as Parkinson disease (PD), PD dementia, dementia with Lewy bodies or multiple system atrophy, and the outstandingly high specificity and very long interval between the onset of idiopathic RBD and the clinical manifestations of α-synucleinopathies, the prodromal phase of this disorder represents a unique opportunity for potentially disease-modifying intervention. This Review provides an update on classic and novel biomarkers of α-synuclein-related neurodegeneration in patients with idiopathic RBD, focusing on advances in imaging and neurophysiological, cognitive, autonomic, tissue-specific and other biomarkers. We discuss the strengths, potential weaknesses and suitability of these biomarkers for identifying RBD and neurodegeneration, with an emphasis on predicting progression to overt α-synucleinopathy. The role of video polysomnography in providing quantifiable and potentially treatment-responsive biomarkers of neurodegeneration is highlighted. In light of all these advances, and the now understood role of idiopathic RBD as an early manifestation of α-synuclein disease, we call for idiopathic RBD to be reconceptualized as isolated RBD.
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Dysfunction of the striatum is frequently associated with sleep disturbances. However, its role in sleep-wake regulation has been paid little attention even though the striatum densely expresses adenosine A2A receptors (A2ARs), which are essential for adenosine-induced sleep. Here we showed that chemogenetic activation of A2AR neurons in specific subregions of the striatum induced a remarkable increase in non-rapid eye movement (NREM) sleep. Anatomical mapping and immunoelectron microscopy revealed that striatal A2AR neurons innervated the external globus pallidus (GPe) in a topographically organized manner and preferentially formed inhibitory synapses with GPe parvalbumin (PV) neurons. Moreover, lesions of GPe PV neurons abolished the sleep-promoting effect of striatal A2AR neurons. In addition, chemogenetic inhibition of striatal A2AR neurons led to a significant decrease of NREM sleep at active period, but not inactive period of mice. These findings reveal a prominent contribution of striatal A2AR neuron/GPe PV neuron circuit in sleep control.
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Dysfunction of the striatum is frequently associated with sleep disturbances. However, its role in sleep-wake regulation has been paid little attention even though the striatum densely expresses adenosine A2A receptors (A2ARs), which are essential for adenosine-induced sleep. Here we showed that chemogenetic activation of A2AR neurons in specific subregions of the striatum induced a remarkable increase in non-rapid eye movement (NREM) sleep. Anatomical mapping and immunoelectron microscopy revealed that striatal A2AR neurons innervated the external globus pallidus (GPe) in a topographically organized manner and preferentially formed inhibitory synapses with GPe parvalbumin (PV) neurons. Moreover, lesions of GPe PV neurons abolished the sleep-promoting effect of striatal A2AR neurons. In addition, chemogenetic inhibition of striatal A2AR neurons led to a significant decrease of NREM sleep at active period, but not inactive period of mice. These findings reveal a prominent contribution of striatal A2AR neuron/GPe PV neuron circuit in sleep control.
Over the last few decades, advances in human and animal‐based techniques have greatly enhanced our understanding of the neural mechanisms underlying psychiatric disorders. Many of these studies have indicated connectivity between and alterations within basal ganglia structures to be particularly pertinent to the development of symptoms associated with several of these disorders. Here we summarize the connectivity, molecular composition, and function of sites within basal ganglia neurocircuits. Then we review the current literature from both human and animal studies concerning altered basal ganglia function in four common psychiatric disorders; obsessive compulsive disorder, substance‐related and addiction disorders, major depressive disorder, generalized anxiety disorder, and schizophrenia. Finally, we present a model based upon the findings these studies that highlights the striatum as a particularly attractive target for restoring normal function to basal ganglia neurocircuits altered within psychiatric disorder patients. This article is protected by copyright. All rights reserved.