REVIEW

The Neurophysiology of Sleep in Parkinson’s Disease

Hengameh Zahed, MD, PhD,1* Jose Rafael Pantoja Zuzuarregui, MD,1 Ro’ee Gilron, PhD,2 Timothy Denison, PhD,3
Philip A. Starr, MD, PhD,2 and Simon Little, MBBS, MRCP, PhD1

1
Department of Neurology, University of California, San Francisco, San Francisco, California, USA
2
Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA
3
Institute of Biomedical Engineering and MRC Brain Network Dynamics Unit, University of Oxford, Oxford, UK

A B S T R A C T : Sleep disturbances are among the most
common nonmotor complications of Parkinson’s disease
(PD), can present in prodromal stages, and progress with
advancing disease. In addition to being a symptom of neu-
rodegeneration, sleep disturbances may also contribute to
disease progression. Currently, limited options exist to
modulate sleep disturbances in PD. Studying the neuro-
physiological changes that affect sleep in PD at the cortical
and subcortical level may yield new insights into mecha-
nisms for reversal of sleep disruption. In this article, we
review cortical and subcortical recording studies of sleep
in PD with a particular focus on dissecting reported
electrophysiological changes. These studies show that
slow-wave sleep and rapid eye movement sleep are both
notably disrupted in PD. We further explore the impact of
these electrophysiological changes and discuss the poten-
tial for targeting sleep via stimulation therapy to modify
PD-related motor and nonmotor symptoms. © 2021
International Parkinson and Movement Disorder Society
Key Words: sleep; electrophysiology; Parkinson’s
disease; deep brain stimulation

Sleep is a fundamental biological process driven by particular appreciation of the strong association
distinct electrophysiological rhythms within the brain.1 between PD and sleep disorders has emerged.9-11
It has been found to be vital to health and severely A wide spectrum of sleep disorders have been impli-
disrupted in neurodegenerative disorders such as cated in PD, encompassing disorders of sleep–wake
Alzheimer’s disease and Parkinson’s disease (PD).2,3 transition as well as parasomnias involving abnormal
From the first essay by James Parkinson on “the shak- movements during various phases of sleep.11-15 The
ing palsy,” PD has foremost been considered a move- most common PD-associated disturbances in sleep–
ment disorder.4 However, the last 2 decades have wake transitioning include increased sleep latency, fre-
brought an explosion in our understanding of the myr- quent awakenings, and sleep fragmentation, resulting in
iad nonmotor manifestations of PD.5-8 More recently, a wakefulness after sleep onset (WASO) and reduced
total sleep time.6,16-25 The parasomnias associated with
PD have also gained much attention and include rapid
-*Correspondence
- - - - - - - - - - - - - - -to:- - Dr.
- - - Hengameh
- - - - - - - - - Zahed,
- - - - - - MD,
- - - -PhD
- - - -505
- - - Parnassus
---------- eye movement sleep behavior disorder (RBD), periodic
Ave., Box 0114, M-798, San Francisco, CA 94143, USA; E-mail: limb movements in sleep (PLMS), and restless legs syn-
hengameh.zahed@ucsf.edu
drome.12-14 Sleep disorders such as RBD can even be
Relevant conflicts of interest/financial disclosures: Drs. Zahed, the first prodromal symptom of PD prior to the emer-
Zuzuarregui, and Little have no financial disclosures or conflicts of inter-
est. Dr. Gilron consults for Rune Labs and is funded by NIH grant gence of formal motor symptoms.10,26,27 Altogether,
UH3NS100544 (PI: Starr). Dr. Denison is a technical consultant for Syn- sleep disorders were the second most prevalent non-
chron, Cortec Neuro and has received speaker fees from Medtronic
Inc. and stock in Medtronic and Bioinduction (<1%). Dr. Starr has
motor complaint among a large cohort of PD patients,
research support from Boston Scientific Inc. and Medtronic Inc. affecting about 64% of patients (PRIAMO study).6
Funding agencies: Funding was provided by the Defence Advanced Sleep dysfunction in PD also represents a significant
Research Project Agency (DARPA) - grant number HR001118S0041. strain on caregivers and can predict earlier transfer to
Received: 7 December 2020; Revised: 2 February 2021; Accepted: 16 nursing homes.28-30 Sleep disorders therefore impact
February 2021 the majority of patients with PD and produce trouble-
Published online in Wiley Online Library some symptoms for which currently limited treatment
(wileyonlinelibrary.com). DOI: 10.1002/mds.28562 options exist.31-33

Movement Disorders, 2021 1

Z A H E D E T A L
A better understanding of the ways in which the elec-
trophysiological rhythm of sleep is disrupted in PD may
lead to new avenues for treating this significant and dis-
abling symptom. With this goal in mind, in this review
we provide a general synthesis of the current knowledge
of sleep pathophysiology in PD with a particular focus
on electrophysiology. We explore the impact of these
electrophysiological changes and discuss the potential
for targeting sleep via stimulation therapy to modify
PD-related motor and nonmotor symptoms.
Overview of Normal Sleep
Physiology
Sleep is broadly classified into alternating stages of
rapid eye movement (REM) and non-REM (NREM)
based on electroencephalogram (EEG), electrooculo-
gram, and electromyogram (EMG) recordings during
polysomnography (PSG).34 NREM sleep is notable for
slow rolling or no eye movements, parasympathetic
dominance, and rarity of dreams.35,36 EEG in NREM is
dominated by larger-amplitude lower-frequency delta
(0–4 Hz) and theta (4–7 Hz) activity.34,36 NREM is fur-
ther divided into 3 stages (N1–N3).34 N1 is the lightest
sleep stage and defined by the loss of more than 50% of
the posterior dominant alpha (8–12 Hz) rhythm that is
typical in a healthy awake state. N2 is characterized by
the emergence of sleep spindles (brief transient oscilla-
tions in the 12- to 14-Hz range, sometimes referred to as
the “sigma” band) and K-complexes (sharp high-voltage
biphasic waves lasting more than 0.5 seconds). N3, also
referred to as slow-wave sleep (SWS), is the deepest stage
of sleep and is characterized by the dominance of slow
delta waves (0.5–2 Hz), comprising at least 20% of any
given sleep epoch.34,36,37 REM sleep, on the other hand,
is associated with vivid dreaming and is characterized by
a low-amplitude mixed-frequency desynchronized EEG
(similar to wakefulness), rapid eye movements, and typi-
cally low muscle tone on chin EMG.34,36,38
Cortical Electrophysiological
Changes in PD During Sleep — EEG
Numerous PSG-based case–control studies examining
sleep in PD have demonstrated distinct changes in each
of the different sleep stages.16,17,19,20,22-24,39-61
NREM Sleep
Numerous studies in patients with PD have demon-
strated alterations in the total amount of NREM and
its electrophysiological markers and spectral proper-
ties.17,23,25,39,40,42,44,50-52,54,55,61 These changes seem to
be especially notable in stages N2 and N3. Although
N1 overall appears to be slightly increased in PD
2 Movement Disorders, 2021
patients,19,25,42 fewer studies have specifically evaluated
this sleep stage.
N2
Studies in PD have shown mixed results regarding the
total amount and percentage of N2,19,22,41,42,45,46
although a recent meta-analysis suggests that the per-
centage of N2 is modestly reduced in patients with PD.25
More notably, however, N2 sleep seems electrophysio-
logically altered in PD patients. Among the most distinc-
tive electrophysiological features of NREM sleep are K-
complexes and sleep spindles, which are found in N2
sleep.36,62,63 Many studies investigating changes in
NREM in PD have focused on these distinctive features.
In one of the earliest studies on sleep dysfunction in PD,
Comella et al found a qualitative reduction in K-complex
and spindle formation as well as reduced amplitude of
the delta waveform in 10 PD patients on dopaminergic
medications.40 Other studies have also found quantita-
tive reductions in K-complexes39 and reduced spindle
amplitude and density in treated PD patients.50,52,55
Spindle density appears even further reduced in PD
patients with dementia55,57 and also appears reduced in
patients with prodromal RBD.51 Although 1 study found
no differences in the quantity or density of K-complexes
or sleep spindles in a group of 12 treated PD patients
compared with controls, the patients in this study had
on average shorter disease duration, lower UPDRS
scores, and lower daily doses of levodopa.44 Two addi-
tional studies did not directly investigate sleep spindles,
but rather used sigma band power after spectral analysis
in NREM as proxy.42,54 In these studies medication-
naive early-stage PD patients exhibited increased sigma
power in NREM compared with healthy controls and
initiation of dopaminergic medications normalized this
change back to the level in controls.42,54 Caution should
be exercised in using sigma power to infer sleep spindles,
as this may overestimate sleep spindle frequency through
inclusion of prefrontal sustained electrocorticographic
(ECoG) activity with sleep spindle estimates.64 Nonethe-
less, the contrast with previously mentioned studies
showing reduced spindles in treated later-stage PD
patients suggests that changes in sleep spindles and K-
complexes in PD may be dynamic, dependent on disease
stage, and modulated by dopaminergic medications.
N3
The total amount and percentage of N3 sleep and its
stability in PD have also been shown to be reduced in
individual and meta-analysis studies.20,25,50 However, not
all individual studies have found a statistically significant
change, possibly because of smaller sample sizes limiting
statistical power or other variabilities in patient demo-
graphics.19,41,42,45,48,55 Furthermore, the reduction in N3
appears to be progressive with disease duration.17,22
 N E U R O P H Y S I O L O G Y O F S L E E P I N P A R K I N S O N ’ S

As expected from the decrease in the percentage of
N3, slow-wave activity (SWA), which is defined as the
spectral power in the range of 0.75–4.5 Hz65 and is
most pronounced in N3, is also reduced in patients
with PD.23,25,42,55 Amato et al evaluated 36 patients
with PD at various disease stages and found decreased
SWA in patients with PD compared with 12 age-
matched controls (Fig. 1A).23 This was especially nota-
ble in early-night sleep, which has a higher N3 and
SWA content compared with later sleep. Moreover,
SWA was further reduced in patients with more
advanced disease compared with patients with early-
stage disease, again highlighting the progressive decline
in deep sleep in PD. Another study in 9 previously
medication-naive early-stage PD patients also found
decreased power in the low-delta band (0.78–1.2 Hz) in
NREM of PD patients compared with 10 age-matched
controls.42 Although they did not distinguish between
N2 or N3 in their analysis, the low-delta power is likely
more reflective of the slow waves typical of N3. Last, a
study by Latreille et al also showed reduced amplitude
of the slow waves themselves (waves in the range of
0.1–4 Hz) in PD patients compared with controls,
although the percentage of N3 or density of slow waves
did not differ between groups in this study.55 Taken
together, these studies demonstrate that N3 is also sig-
nificantly disrupted in PD with SWA reducing as PD
progresses. Interestingly, the amount and stability of
N3 may distinguish PD patients from controls.50
REM Sleep
The association between REM sleep behavior disor-
der (RBD) and synucleinopathies such as PD is well rec-
ognized.66-76 RBD is a parasomnia manifested by
simple or complex motor behavior during REM sleep.
The polysomnographic features of RBD include
increased electromyographic tone with or without overt
dream enactment behavior during REM sleep.74 The
frequency of RBD has been estimated at about 33%–
60% in PD.73 Reduction in muscle atonia during REM
sleep appears to be a characteristic finding in early PD
(<3 years’ disease duration), even in patients with no
personal account of symptoms to suggest RBD.48 Fur-
thermore, numerous studies show that RBD is a pro-
dromal symptom in PD.76-81
However, PD-associated REM alterations extend
beyond the behavioral disruption in RBD and loss of
muscle atonia. Several studies have found that total
REM time, percentage of sleep spent in REM, and
REM density are decreased in PD.16,17,19,20,25,43,45,58,60
As in NREM, the reduction in REM may progress with
disease duration.17 REM sleep also appears electro-
physiologically disturbed in PD. Several studies have
found an increase in the high-theta/alpha power in
REM in medication-naive patients with early PD versus
controls.41,54,82 On the other hand, no between-group
differences in EEG power for any frequency bands were
found during REM in PD patients on their usual dopa-
minergic medications compared with controls.83 This
discrepancy raises the possibility that dopaminergic
medications dampen electrophysiological changes in
REM in PD, although this needs to be further evalu-
ated. Comorbidities such as dementia and depression
that can accompany PD may also alter the spectral
properties of REM sleep. For example, PD patients
who later developed dementia showed higher absolute
delta and theta power and a higher slowing ratio
(defined as the ratio of the power of ([delta + theta]/
[alpha + beta]) in REM at baseline compared with con-
trols and PD patients who did not go on to develop
dementia.57 PD patients with depression also showed

FIG 1. Slow-wave activity is reduced in PD patients and correlates with disease progression. (A) reduced slow wave activity (SWA) in NREM of PD
patients compared with controls. SWA is reduced in early PD and more so in advanced disease, especially in early night (dark blue line) compared with
late night (light blue line). CTL, control; DNV, de novo; ADV, advanced (adapted from Amato et al, 2018). (B) Plot of axial UPDRS III scores slow-wave
energy (SWE; defined as accumulated power in the SWA band). Higher SWE predicts slower progression of axial motor symptoms. Red lines, 95%
confidence interval (adapted from Schreiner et al, 2019). [Color figure can be viewed at wileyonlinelibrary.com]

Movement Disorders, 2021 3

Z A H E D E T A L
increased delta in REM compared with nondepressed
patients.61 However, caution should be exercised in
attributing the observed sleep changes to the presence
of these comorbidities versus another confounding
modifier. For example, patients who later developed
dementia were also older, had more advanced disease,
and were on higher levodopa-equivalent doses.
Summary of PSG-Based Studies
Taken together, the above studies provide objective evi-
dence that sleep is electrophysiologically and behaviorally
disrupted in PD with relative loss of critical N2, N3, and
REM stages. It is important to acknowledge that certain
caveats limit the broad applicability of these case–control
studies. Many studies have been based on a single-night
PSG and limited by small sample sizes, low power, and
high heterogeneity (Tables 1 and 2). Sex, age, disease
duration, presence of RBD, medication status, cognitive
impairment, and presence or absence of an adaptation
night (a night of adjustment with the sleep recording set-
tings) contribute to heterogeneity between studies.25 Fur-
thermore, the presence of comorbidities and non-PD
medications, which could serve as cofounders, are not
described in many studies. For example, some studies
suggest that nocturnal motor symptoms (rigidity,
reemergence of tremor in light sleep, PLMS),84 pain,59
nocturia,85 and hallucinations40,86,87 can contribute to
sleep changes, although such symptoms are not always
systematically evaluated. Finally, the majority of these
studies describe group-level differences, which limits
inferences on whether the identified spectral changes
index disease progression or represent dynamic within-
subject biomarkers. Despite these caveats, 2 meta-
analyses of PSG-based studies in PD patients have con-
firmed the reductions in total sleep time (TST) and per-
centages of N2, N3, and REM sleep and increases in
percentage of time spent in lighter sleep (N1) and REM
latency.25,88 The time spent in N3 and the ability to
maintain NREM and REM sleep may be potential bio-
markers of PD.50 Furthermore, reductions in N3 and
REM appear progressive with disease duration.17
Subcortical Electrophysiological
Recording in PD During Sleep
Although our knowledge of sleep in PD has been
mostly informed by PSG/EEG analysis as detailed
above, PD more profoundly affects deep brain struc-
tures including the basal ganglia. Therefore, studying
the subcortical neurophysiological changes during
sleep in PD, and their relation to the cortical changes
observed will also be important and may yield
additional insights. Fortunately, recent studies using
intracranial recordings from patients who have under-
gone deep brain stimulation (DBS) implantation have
4 Movement Disorders, 2021
provided a window through which PD-associated sleep
changes can be studied in subcortical structures.
Although for these invasive subcortical recordings nor-
mal controls are absent, within and across subject com-
parisons plus animal models provide a context for
interpretation.
NREM Sleep
The earliest intracranial sleep recordings in patients
with PD used multiunit activity (MUA) and micro-
recordings of single units.89,90 Analysis of the MUA
mean firing frequency from electrodes implanted in
basal ganglia nuclei (caudate and globus pallidus) of
PD patients showed that slow subcortical oscillations
are increased during deep sleep relative to wakefulness
and REM sleep. This demonstrates that neurons in the
basal ganglia undergo slow oscillations similar to that
detected via EEG from the cortex during NREM.
Microrecordings of single units in PD patients undergo-
ing bilateral subthalamic nucleus (STN) implantation
after a prolonged period of dopaminergic therapy
washout similarly showed that sleep modulates the fir-
ing pattern of STN neurons.90 Specifically, the mean
spiking frequency in these neurons decreased during
sleep, as they adopted a more irregular and burst-like
pattern of firing.90 This burst-like pattern has also been
seen subcortically in normal rats91 and vervet mon-
keys92 during SWS, correlating with slow oscillations.
These results implicate deep basal ganglia structures in
the physiology of sleep and suggest that many of the
canonical oscillatory findings seen with PSG are para-
lleled subcortically.
Later studies have mostly used local field potential
(LFP) recordings to investigate electrophysiological
changes during sleep. The LFP is the summation of
synchronous activity in a population of neurons and
can be detected from macroelectrodes on clinical DBS
leads.93 Thompson et al recently recorded from 10 PD
patients undergoing unilateral STN-DBS implantation
with concurrent PSG for 1 night in the “off” dopami-
nergic state.94 Frequency domain spectral analysis of
the LFP recordings in these patients showed conserved
spectral patterns among the canonical frequency bands
of sleep, similar to cortical recordings with EEG dur-
ing PSG. Specifically, overall subjects exhibited higher
delta and theta power during NREM compared with
wakefulness, whereas they exhibited higher beta and
gamma power in wakefulness relative to NREM.
However, they found significant across-subject vari-
ability in the relative power of subcortical frequency
bands between different sleep stages, suggesting indi-
vidual subcortical spectral fingerprints during sleep
per subject (Fig. 2B).
Multiple studies have previously established a strong
relationship between excessive subcortical beta
 N E U R O P H Y S I O L O G Y O F S L E E P I N P A R K I N S O N ’ S

TABLE 1. Summary of PSG-based studies during sleep in patients with PD

PD
duration, Adaptation N2 – findings in PD compared
Study Sample Size Age, mean mean Medications night with control Parameters of interest

Brunner, 9 PD (DNV) 65.3  3.8 3.4  0.6 Med naive at Y Increased sigma/beta power. Sigma: 11.7–16.0 Hz
2002, 10 controls 61.2  2.2 N/A baseline DA meds resulted in decrease
Mov and post- in sigma/beta power back
Disord DA med to level of controls.
Christensen, 15 PD + RBD 62.4  5.2 N/R Usual meds N Reduced spindle density in Automated spindle
2014, Clin 15 PD − RBD 61.9  6.1 RBD and PD  RBD. detection + visual
Neurophys 15 iRBD 60.1  7.4 scoring per AASM
15 controls 58.3  9.5 Sleep spindles:
11–16 Hz, last
0.5–3 s, no
amplitude criteria
Christensen, 36 PD 65.4  6.4 3.6  4.5 Usual meds N Reduced stability in control/
2014, J 31 RBD 62.9  8.6 N/A PLM group compared with
Neurosci 25 PLMS 56.9  11.8 N/A iRBD/PD group.
Methods 23 controls 56.7  10.2 N/A
Christensen, 15 PD 62.7  5.8 6.7  4.5 Usual meds N Reduced sleep density Visual scoring per
2015, 15 controls 62.9  5.9 N/A AASM
Front Hum Sleep spindles:
Neurosci 11–16 Hz, last
0.5–3 s, no
amplitude criteria
Comella, 10 PD (ADV) 68  5 13  5 Usual meds Y Qualitative reduction in K- Visual scoring per R&K
1993, Ann complex and spindles. criteria
Neurol Reduced delta amplitude.
Emser, 12 PD 54.7  6.7 N/R Usual meds Y Reduced K-complex and Visual scoring per R&K
1988, J 12 controls 53.4  8.6 spindle density. criteria
Neurol
Happe, 12 PD 64.8  6.4 6.3  4.5 Usual meds N No difference in quantity or Visual scoring per R&K
2004, J 10 controls 65.2  10.7 N/A density of K-complexes or criteria
Neurol sleep spindles.
Latreille, 68 PD without 63.0  8.5 4.1  3.1 Usual meds N Reduced sigma power in Sigma: 12–15 Hz
2016, dementia 70.2  7.6 5.7  4.5 parietal leads of PDD
Brain (PDnD) 64.8  10.9 N/A compared with PDnD
18 later developed patients and controls.
dementia (PDD)
44 controls
Latreille, 68 PD without 63.0  8.5 4.1  3.1 Usual meds N Reduced spindle density. Automated spindle
2015, dementia 70.2  7.6 5.7  4.5 PDD had even lower density, detection
Neurobiol (PDnD) 65.0  10.9 N/A amplitude, and frequency
Aging 18 later developed of sleep spindles.
dementia (PDD)
47 controls
Liu, 2019, 26 PD 67.0  8.6 5.2  4.4 Usual meds N Increased amplitude of frontal Delta: 0.5–4 Hz
Med Sci + depression 66.2  5.9 4.0  3.1 delta and theta in PD Theta: 4–8 Hz
Monit 12 PD − 67.0  0.8 N/A compared with controls,
depression irrespective of depression.
20 controls Higher frontal theta in PD with
depression compared with
PD without depression.
Margis, 8 PD (DNV) 64.9  6.1 3.0  2.7 Med naive Y Increased alpha and sigma Delta: 0.5–3.5 Hz
2015, Clin 9 controls 64.8  6.3 N/A activity and reduced delta Theta: 4–7.5 Hz
Neurophys power (left parietal), Alpha: 8–10 Hz
Sigma: 11–16 Hz
PD
duration, Adaptation N3 — findings in PD Parameters of
Study Sample Size Age, mean mean Medications night compared with control interest

Amato, 2018, 9 DNV (med 52.6  3.13 2.30  0.6 Usual meds Y Decreased SWA in PD SWA: spectral
Ann Neurol naive) 61.6  3.56 7.05  1.5 early sleep delta power. power in range
13 ADV 61.4  2.84 9.98  1.7 DNV > ADV > DYS of 0.75–4.5 Hz

(Continues)

Movement Disorders, 2021 5

Z A H E D E T A L

TABLE 1. Continued

PD
duration, Adaptation N3 — findings in PD Parameters of
Study Sample Size Age, mean mean Medications night compared with control interest

14 DYS 56.1  2.98 N/A

12 controls
Brunner, 2002, 9 PD (DNV) 65.3  3.8 3.4  0.6 Med naive at Y Decreased low-delta power. Low delta:
Mov Disord 10 controls 61.2  2.2 N/A baseline DA meds further decreased 0.78–1.2 Hz
Reanalyzed post- the low-delta power.
DA med (42-
day mean)
Christensen, 36 PD 65.4  6.4 3.6  4.5 Usual meds N Lower amount and stability
2014, J 31 RBD 62.9  8.6 N/A of N3 in RBD and iPD vs
Neurosci 25 PLMS 56.9  11.8 N/A PLM and control.
Methods 23 controls 56.7  10.2 N/A
Latreille, 2015, 68 PD without 63.0  8.5 4.1  3.1 Usual meds N Reduced amplitude of slow Slow waves:
Neurobiol dementia 70.2  7.6 5.7  4.5 waves in PD irrespective >75 mV
Aging (PDnD) 65.0  10.9 N/A of dementia. and <4 Hz
18 later No difference in density of
developed slow waves.
dementia
(PDD)
47 controls
PD
duration, Adaptation REM – findings in PD Parameters of
Study Sample Size Age, mean mean Medications night compared with control interest

Christensen, 2014, J 36 PD 65.4  6.4 3.6  4.5 Usual meds N Lower amount and stability
Neurosci Methods 31 RBD 62.9  8.6 N/A of REM in RBD and iPD
25 PLMS 56.9  11.8 N/A vs PLM and control.
23 controls 56.7  10.2 N/A
Gagnon, 2004, Neurology 7 PD + RBD 68.4  7.5 5.4  6.0 Usual meds N No between-group
8 PD-RBD 61.0  7.3 5.5  2.9 differences in EEG power
15 controls 65.5  6.3 N/A for any frequency band
during REM.
Latreille, 2016, Brain 68 PD — no 63.0  8.5 4.1  3.1 Usual meds N Higher absolute delta and Delta: 0.5–4 Hz
baseline 70.2  7.6 5.7  4.5 theta power and slowing Theta: 4–8 Hz
dementia 64.8  10.9 N/A ratio at baseline in PD Alpha: 8–13 Hz
18 later patients who later Beta: 13–32 Hz
developed developed dementia Slowing ratio:
dementia compared with other (delta + theta)/
(PDD) groups. (alpha + beta)
44 controls
Liu, 2019, Med Sci Monit 26 PD + depression 67.0  8.6
12 PD − depression 66.2  5.9
20 controls 67.0  0.8
5.2  4.4 Usual meds N Increased depressed nondepressed PD. Delta: 0.5–4 Hz
4.0  3.1 delta in PD
N/A compared
with
Margis, 2015, Clin 8 PD (DNV) 64.9  6.1 3.0  2.7 Med Naive Y Increased right frontal Alpha: 8–10 Hz
Neurophys 9 controls 64.8  6.3 N/A alpha, decreased relative Sigma: 11–16 Hz
beta power in the right Beta: 16.5–30 Hz
occipital region in PD.
Wetter, 2001, Mov Disord 17 PD (DNV) 65.9  2.9 3.4  0.6 Med naive Y Increased high-theta/alpha High-theta/alpha:
10 controls 64.5  2.2 N/A in PD. 7.8–10.5 Hz

oscillations and the “off” dopamine state in PD during
wakefulness.95-100 Therefore, the earliest study using
LFP recordings during sleep in PD patients focused spe-
cifically on the STN beta signal.101 They found that STN
beta power is suppressed during NREM sleep compared
with wakefulness. Notably, the beta reduction in NREM
was immediate after sleep onset and was so profound
that only 3 of 10 patients showed an identifiable beta
peak in NREM sleep, whereas almost all patients had a
well-defined peak in the beta band during wakefulness.
It remains unknown how this finding compares with
control subjects and whether the presence or absence of

6 Movement Disorders, 2021

 N E U R O P H Y S I O L O G Y
an identifiable subcortical beta peak in NREM correlates
with any sleep-related symptoms. However, studies in
primate models suggest that increased STN beta power
in NREM sleep may be associated with insomnia sever-
ity.102 In a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
primate model, both a decrease in slow oscillatory activ-
ity and an increase in beta oscillations in the basal gang-
lia nuclei were seen during NREM sleep (Fig. 3A).
Increased beta activity was associated with insomnia
severity, and beta power was found to increase before
spontaneous awakenings. It is important to note that the
PSG/EEG studies in human subjects have so far not
detected a global increase in beta power in NREM in PD
patients compared with controls. This difference could
be related to mechanistic differences between 1-methyl-
4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model and
idiopathic PD.103 Specifically, MPTP causes highly selec-
tive neurotoxicity for dopaminergic neurons, whereas in
PD neurodegeneration is much more diffuse and involves
many different nuclei including those critical to sleep reg-
ulation.104 In addition, MPTP produces an acute fulmi-
nant presentation compared with PD, which does not
account for the chronicity and slower development of
symptoms in PD. Nonetheless, it would be of great inter-
est to see whether an association between increased
NREM subcortical beta power and awakening or other
sleep-related symptoms can also be seen in patients
with PD.
REM Sleep
REM sleep also appears to modulate basal ganglia
beta oscillations. Urrestarazu et al showed that during
REM sleep high-beta activity (20–30 Hz) in STN is
slightly higher than during wakefulness and clearly
higher than during NREM, but the low-beta range
activity (13–20 Hz) was lower than in wakefulness.101
In addition, REM sleep in 4 of 5 patients showed a
peak in the frequency range between the alpha and beta
bands (10–15 Hz) that was not observed in wakefulness
or NREM.
More recent subcortical recordings have shown that
STN-beta power in REM sleep is generally between
NREM and wakefulness, although with significant vari-
ability both within and among subjects.94 Some of this
variability may be attributable to wearing off of dopa-
minergic medications during the later part of the night,
which suppresses subcortical beta.95,96 Supporting this,
within each subject, beta power increased between the
first and fourth quarters of the night across all sleep
stages. However, there may also be other explanations
for the variability as there appears to be a possible link
between beta oscillations and another cardinal feature
of sleep dysfunction in PD — loss of atonia during
REM. In the study by Urrestarazu et al the subcortical
beta peak during REM was more pronounced during
O F S L E E P I N P A R K I N S O N ’ S
segments of REM without atonia (but without observ-
able movements) compared with REM with atonia
(Fig. 3B).100 However, the relationship between beta
activity and tone in REM is likely not simple, as
another study showed that normal REM atonia is also
associated with increased subcortical beta activity.105
Interestingly, the increase in beta during REM atonia in
the latter study was concurrent with the emergence of
subcortical biphasic sharp field potentials that resem-
bled pontogeniculo-occipital (PGO) waves (seen in cats
during sleep) and preceded onset of muscular atonia.
Therefore, it is possible that an interaction between
subcortical beta oscillations and PGO-like waves deter-
mines expression of muscular activity during REM. It
would be of great interest for future studies to more
directly investigate whether beta power in REM is asso-
ciated with loss of REM atonia and RBD in patients
with PD.
Summary of Subcortical Studies
Altogether, these studies of intracranial recordings in
PD patients show that STN activity is modulated by
sleep and that spectral patterns in STN activity corre-
late with sleep stages. Given the conservation of the
spectral patterns from STN-LFP recordings, several
studies have shown that it is possible to accurately clas-
sify sleep stages from subcortical LFP recordings alone
using various automated machine-learning methods
with high sensitivity and specificity (Fig. 2).94,106,107
The subcortical studies also raise intriguing hypotheses
regarding the role of NREM and REM beta power in
PD-associated sleep dysfunction that require further
investigation.
Some important caveats and limitations apply to
these studies. These studies so far have focused investi-
gation on sleep physiology in the STN and subcortical
involvement in sleep in other basal ganglia nuclei such
as the GPi and the thalamus remains largely unknown.
Similar to the PSG studies, the intracranial studies so
far have also been based on a single night of sleep and
understandably limited by small sample sizes and het-
erogeneity in the patient population. Furthermore, most
intracranial studies have been performed in the immedi-
ate postoperative period, leaving open the possibility
that periprocedural parameters (such as use of anes-
thetics and microlesional effects associated with sur-
gery) could affect the findings, although 1 study
completed a month after surgery showed consistent
results.107 Newer-generation DBS devices that allow
chronic (multinight) sensing in addition to stimulation,
however, open up exciting opportunities.108,109 Con-
current cortical and subcortical LFP recordings from
such devices will facilitate investigation of chronic neu-
rophysiological changes outside the perioperative win-
dow and can provide information about subcortical
Movement Disorders, 2021 7
8
Z A H E D

TABLE 2. Summary of subcortical recording studies during sleep in patients with PD

E T

PD
Sample duration, Sites of Type of Timing of Parameters of
Study Size Age, mean mean recording recording recording Medications Major findings interest
A L

Movement Disorders, 2021

Chen, 2019, IEEE 12 PD 54.8  8.2 10.1  4.0 Bilateral LFP 1 month post-DBS >8 hours off short- STN LFP recordings can be used to Sleep staging per
STN implantation acting DA meds accurately stage sleep. AASM criteria.
>24 hours off long- Power of delta, theta, and alpha Delta: 1–4 Hz
acting DA meds bands increase in NREM and Theta: 4–8 Hz
decrease in wakefulness and REM. Alpha: 8–13 Hz
Beta and gamma power decrease in Beta: 13–35 Hz
NREM and increase in REM. Gamma band:
Alpha, beta, and gamma bands 35–50 Hz
contribute the most to
classification.
Christensen, 2019, J 9 PD 60.1  9.5 10.6  4.6 Unilateral LFP NR NR STN LFP recordings can be used to Delta: 0–3 Hz
Sleep Res STN accurately stage sleep. Theta: 3–7 Hz
Alpha: 7–13 Hz
Low beta:
13–20 Hz
High beta:
20–30 Hz
Low gamma:
30–90 Hz
Moiseeva, 1986, EEG 7 PD NR NR Caudate Multiunit NR NR Slow subcortical oscillations increase NR
Clin Neurophys 1 nucleus, activity during deep sleep relative to
epilepsy globus (MUA) wakefulness and REM sleep.
pallidus
Stefani, 2006, Exp 9 PD NR NR Bilateral Single units NR >12 days off meds Mean spiking frequency in STN NR
Brain Res STN neurons is reduced in sleep as
they adopt a more irregular and
burst-like pattern of firing.
Thompson, 2018, 10 PD 58.4  10.5 N/R Unilateral LFP 3 weeks post-DBS 7.5 hours off meds Delta activity in NREM > awake state. Delta: 0–3 Hz
JNNP STN implantation Beta activity in NREM < awake and Theta: 3–7 Hz
REM. Alpha: 7–13 Hz
LFP recordings from STN differentiate Beta: 13–30 Hz
between sleep stages. Gamma: 30–90 Hz
Urrestarazu, 2009, 10 PD 62.2  5 11.4  6.3 Bilateral LFP 2–4 days post- “Off” state Beta activity in STN LFP of NREM < Sleep staging per
Mov Disord STN DBS wakefulness or REM. R&K criteria.
implantation Beta activity during REM without Beta: 15–30 Hz
atonia (but without observable
movements) > REM with atonia.
 N E U R O P H Y S I O L O G Y O F S L E E P I N P A R K I N S O N ’ S

FIG 2. STN-LFP signals index sleep stages in classical power bands. (A) Representative spectrogram of the LFP recording acquired over the course of
1 full night’s sleep from deep brain stimulation (DBS) electrode implanted into the subthalamic nucleus (STN). A PSG-informed hypnogram (red line)
assessed by a sleep expert is aligned with the LFP recordings. AWM, awake with movement; AWOM, awake without movement; REM, rapid eye move-
ment; N1–N3, nonrapid eye movement stages 1–3 (adapted from Christensen et al, 2018). (B) Plots comparing the relative frequency contribution of
each spectral band with different sleep stages show shared sleep-stage dependent spectral patterns across subjects, although with some notable
across-subject variability. Each individual plot highlights the distribution of the power of a given frequency band to different stages of sleep for 10 differ-
ent subjects (adapted from Thompson et al, 2018). [Color figure can be viewed at wileyonlinelibrary.com]

changes and their relationship to cortical changes that
would not be possible from classical PSG studies.
Impact of Sleep Disturbances on
Parkinson’s Disease
Pathophysiology
Although the electrophysiological classification of
sleep has been well established, the function of sleep
and its cellular and electrophysiological hallmarks is
still being determined. Emerging evidence suggests that
sleep plays a critical role in the pathophysiology of
neurodegenerative diseases more broadly.2,3 This link
was first investigated in Alzheimer’s disease (AD),
where studies have established a strong bidirectional
relationship between sleep disruption and increased
amyloid-β deposition.110-115 There is now emerging evi-
dence that sleep dysfunction may also be a risk factor
for PD progression.10,116 Sleep appears to serve a cellu-
lar and metabolic restorative function by regulating
waste clearance and maintaining metabolic homeostasis
through effects on the glymphatic system.117 Early
work suggests that the efficacy of glymphatic fluid
transport correlates with the prevalence of slow-wave
activity during sleep and that flow stops with the onset

Movement Disorders, 2021 9

Z A H E D E T A L

FIG 3. Alterations in subcortical beta signal during NREM and REM sleep in PD. (A) Parkinsonism in an MPTP-induced primate model is associated with
an increase in beta oscillations in the basal ganglia nuclei during NREM. GPe, globus pallidus externa; GPi, globus pallidus interna; STN, subthalamic
nucleus; FP, field potential (adapted from Mizrahi et al, 2020). (B) Spectral analysis of STN-LFP in PD patients shows a notable beta-band peak during
REM, which is further accentuated in REM without atonia (adapted from Urrestarazu et al, 2008). [Color figure can be viewed at wileyonlinelibrary.com]

of wakefulness.118 As such, a decrease in NREM and
SWS in particular, as shown to occur in PD, may also
result in reduced clearance of brain waste including
alpha-synuclein aggregates. It is important to note that
because inclusions of aggregated α-synuclein in PD are
predominantly intracellular,119 the relative impact of
the clearance of abnormal proteins by the glymphatic
system during sleep in PD remains unclear.120 Nonethe-
less, α-synuclein similar to amyloid-β, has been found
present in the brain extracellular fluid and cerebrospi-
nal fluid at higher concentrations during wakefulness
than during sleep121 and higher even after sleep disrup-
tion.122 This suggests that the sleep deficits observed in
PD in the short term may exacerbate symptoms and in
the long term accelerate pathology and contribute to
disease progression, as shown in AD.113 Supporting
this, motor improvement after sleep has been noted in
some patients with PD and referred to as “sleep
benefit,” although a direct link between this sleep bene-
fit and function of the glymphatic system in PD is
unproven.123,124 However, a bidirectional relationship
between sleep disturbances and disease progression is
also suggested by studies showing that the overall
amount of SWS is inversely related to motor progres-
sion in PD (Fig. 1B) and that poor sleep quality can be
predictive of more rapid gait deterioration.125,126 Fur-
ther work is needed to establish a causal relationship
between sleep disturbances in PD and disease progres-
sion, but these early studies are notable.
A further proposed function of sleep is the regulation
of neural activity to achieve synaptic homeostasis and
optimal plasticity as well as memory consolida-
tion.127-131 More specifically, the synaptic homeostasis
hypothesis suggests that sleep reestablishes neuronal
synaptic homeostasis after plastic changes made during
the awake state, thereby playing an active role in

10 Movement Disorders, 2021

 N E U R O P H Y S I O L O G Y
consolidation of memory.127,129,132-135 Studies using
visual, auditory, and motor learning tasks have shown
improved learning after a night of sleep and an increase
in SWS correlating with a postsleep performance
enhancement in healthy adults.136-144 These studies sug-
gest that the increased sleep fragmentation and
decreased SWS and REM observed in PD could result
in worsened cognition and memory consolidation,
which may in turn impact next-day cognitive perfor-
mance. Supporting this, one measure of working mem-
ory improved following a sleep interval in PD patients
on dopaminergic medication and the degree of
improvement positively correlated with the amount of
SWS.145 Other studies have shown that sleep changes
in PD, and in particular the presence of RBD and the
number of state changes during sleep, are associated
with and can be predictive of future development of
cognitive decline and dementia.26,146-148 These findings
suggest that overnight changes in sleep architecture in
PD may accelerate PD-associated cognitive decline
through worsening consolidation of memory and poor
maintenance of protein clearance, synaptic homeostasis,
and plasticity.
Can Sleep Disturbances Seen in PD
Be Reversed?
The mechanisms responsible for sleep-related changes
in PD are likely multifactorial and include impact of
PD-related symptoms, medications, and direct effects of
the disease on sleep neurophysiology via effects on
structures that regulate sleep.11,12 Although determin-
ing the relative significance of each has been challeng-
ing, there has been a recent appreciation that basal
ganglia nuclei play an integral role in sleep–wake cycle
regulation and that PD-induced dysfunction in these
subcortical structures may directly alter sleep.149-153
Regardless of the exact cause, numerous interventions
have been tried in subjects both with and without PD
to rebalance sleep activity, in particular to enhance
SWS. These include medications (including dopaminer-
gic agents),154-157 exercise,158 as well as various inva-
sive and noninvasive brain stimulation modalities.
Effects of Noninvasive Stimulation on Sleep
Various modes of noninvasive stimulation have been
used in the last decade to modulate aspects of sleep
such as SWS and have shown effects on subsequent
memory function.159-162 For example, employing
acoustic stimulation phase-locked to the upslope of
endogenous sleep slow waves to increase SWS,163,164
several groups have shown performance improvement
in declarative memory tasks such as word-pair reten-
tion in healthy subjects.165-169 This technique has also
shown promise in a clinical population, increasing
O F S L E E P I N P A R K I N S O N ’ S
postsleep word recall in patients with amnestic-pattern
mild cognitive impairment (MCI).170 Others have used
transcranial electrical stimulation to induce slow-
oscillating field potentials during early NREM sleep
and have also observed improved performance on vari-
ous memory tasks (such as declarative or motor mem-
ory) in healthy subjects,171-173 older adults,174 and
patients with MCI.175 These studies, although in the
early stage, suggest noninvasive brain stimulation can
alter sleep and impact memory.165 To date, only a few
studies have delivered daytime noninvasive transcranial
stimulation in patients with PD and measured the
impact on sleep.176-180 Despite varied methodologies
and stimulation sites, these studies have shown some
modest improvements in sleep latency and fragmenta-
tion, nocturnal awakenings, and subjective fatigue.
Whether such approaches could have greater efficacy
by directly targeting specific sleep stages overnight in
PD remains unknown.
Effect of Conventional DBS on Sleep
DBS is an established and highly effective treatment
that has been utilized for more than 30 years to treat
motor symptoms of PD.181-183 Although DBS is cur-
rently predominantly used to treat motor symptoms,
other PD-related nonmotor symptoms including sleep
may also benefit from DBS.152,153,184 Some studies have
shown improvement in various sleep-related metrics in
PD after DBS implantation, although effects may vary
with site and frequency of stimulation. Globally,
improvements in TST and sleep efficiency, reductions in
WASO, and subjective improvements in sleep quality
and insomnia have been noted after DBS.185-198 Several
studies have also found specific increases in total REM
sleep,199-201 whereas 1 study also found improvement
in time spent in SWS but not REM.195 These improve-
ments after DBS seem enduring, as the largest long-term
follow-up study showed sustained improvements in
subjective sleep quality 3 years after bilateral STN DBS
implantations in patients with PD.202 Although encour-
aging, the mechanisms by which DBS may improve
sleep in PD is not clear. It is possible that DBS acts
through improving motor symptoms, although some
studies suggest that stimulation at specific nuclei may
directly alter sleep physiology.194
These studies so far have used conventional DBS,
which delivers stimulation continuously irrespective of
a patient’s clinical or neural state. Although this
approach has been reasonably effective for motor
symptom management, a number of studies during
wakefulness have shown that delivering stimulation
according to neural biomarkers of clinical state (adap-
tive DBS) during the day can further improve motor
symptoms and reduce side effects.203-207 With the
recent emergence of sensing-enabled DBS devices, it will
Movement Disorders, 2021 11
Z A H E D E T A L
soon be possible to target sleep more precisely in PD
and deliver circadian-controlled and sleep-stage-
targeted adaptive DBS.108 This is particularly promising
in PD, as important groundwork has already shown
that it is possible to classify sleep stages using subcorti-
cal LFP signals alone.94,106,107 This could herald the
possibility of improving sleep and quality of life and
perhaps even improving nex-day function and/or alter-
ing disease progression via improving sleep in PD. Of
course, extensive further research is needed to demon-
strate a more precise link between specific sleep stages
and rhythms with next-day functioning, as well as rig-
orous safety testing of adaptive DBS in sleep to ensure
that it does not worsen sleep or motor and cognitive
outcomes. If successful, however, this approach may
have ramifications even beyond PD and may serve as a
prototype for other neurological diseases for which
sleep is a comorbidity such as other neurodegenerative
disorders and epilepsy.208-212
Conclusions
The studies reviewed here collectively elucidate severe
sleep disruptions in PD. Not only is total sleep reduced,
but sleep also appears more fragmented and less restor-
ative in PD, with reduced SWS and REM sleep stages.
The reviewed cortical and subcortical electrophysiologi-
cal changes during sleep in PD suggest that, although
the network changes are widespread, the basal ganglia
structures involved in PD play important roles in main-
tenance of sleep, sleep–wake transitions, and motor
control during sleep. Given the critical function of sleep
in brain health, it is not surprising that the research to
date shows that sleep disruption in PD leads to worse
motor and cognitive symptoms and possible accelerated
disease progression. As such, sleep dysfunction in PD
represents a so far untapped potential therapeutic tar-
get. Emerging technologies such as sensing-enabled
DBS devices have the potential to greatly increase our
understanding of the electrophysiological and network
changes that occur during sleep in PD and track these
signals across disease progression. Furthermore, they
open the window to new therapeutic avenues to selec-
tively modulate sleep with the hopes of improving
motor and nonmotor symptoms.
Acknowledgments: The authors thank Dr. Jenny Zitser for additional
feedback on the review. Funding was provided by the Defence Advanced
Research Project Agency (DARPA) - grant number HR001118S0041.
References
1. Weber F, Dan Y. Circuit-based interrogation of sleep control.
Nature 2016;538:51–59.
2. Iranzo A. Sleep in Neurodegenerative Diseases. Sleep Med Clin
2016;11:1–18.
12 Movement Disorders, 2021
3. Malhotra RK. Neurodegenerative Disorders and sleep. Sleep Med
Clin 2018;13:63–70.
4. Parkinson J. An Essay on the Shaking Palsy. London: Sherwood,
Neely and Jones; 1817.
5. Simuni T, Sethi K. Nonmotor manifestations of Parkinson’s dis-
ease. Ann Neurol 2008;64(Suppl 2):S65–S80.
6. Barone P, Antonini A, Colosimo C, et al. The PRIAMO study: a
multicenter assessment of nonmotor symptoms and their impact on
quality of life in Parkinson’s disease. Mov Disord 2009;24:
1641–1649.
7. Poewe W. Non-motor symptoms in Parkinson’s disease. Eur J
Neurol 2008;15:14–20.
8. AHV S, Chaudhuri KR, Jenner P. Non-motor features of Parkinson
disease. Nat Rev Neurosci 2017;18:509.
9. Mantovani S, Smith SS, Gordon R, O’sullivan JD. An overview of
sleep and circadian dysfunction in Parkinson’s disease. J Sleep Res
2018;27:e12673.
10. Bohnen NI, MTM H. Sleep disturbance as potential risk and pro-
gression factor for Parkinson’s disease. J Parkinsons Dis 2009;9:
603–614.
11. LHM K, Breen DP. New awakenings: current understanding of
sleep dysfunction and its treatment in Parkinson’s disease. J Neurol
2020;267:288–294.
12. Comella CL. Sleep disorders in Parkinson’s disease: an overview.
Mov Disord 2007;22(Suppl 17):S367–S373.
13. Bhidayasiri R, Sringean J, Rattanachaisit W, Truong DD. The
sleeping brain in Parkinson’s disease: a focus on REM sleep behav-
iour disorder and related parasomnias for practicing neurologists.
J Neurol Sci 2017;374:32–37.
14. Lenka A, Herath P, Mittal SO, et al. Sleep disturbances in patients
with Parkinson’s disease: it’s time to wake up! Ann Mov Disord
2018;1:8.
15. Tandberg E, Larsen JP, Karlsen K. A community-based study of
sleep disorders in patients with Parkinson’s disease. Mov Disord
1998;13:895–899.
16. Apps MC, Sheaff PC, Ingram DA, Kennard C, Empey DW.
Respiration and sleep in Parkinson’s disease. J Neurol Neurosurg
Psychiatry 1985;48:1240–1245.
17. Diederich NJ, Vaillant M, Mancuso G, Lyen P, Tiete J. Progressive
sleep ‘destructuring’in Parkinson’s disease. A polysomnographic
study in 46 patients. Sleep Med 2005;6:313–318.
18. Gjerstad MD, Wentzel-Larsen T, Aarsland D, Larsen JP. Insomnia
in Parkinson’s disease: frequency and progression over time.
J Neurol Neurosurg Psychiatry 2007;78:476–479.
19. Yong M-H, Fook-Chong S, Pavanni R, Lim L-L, Tan E-K. Case
Control Polysomnographic Studies of Sleep Disorders in
Parkinson’s Disease. PLoS ONE. 2011;6(7):e22511. http://dx.doi.
org/10.1371/journal.pone.0022511.
20. Wailke S, Herzog J, Witt K, Deuschl G, Volkmann J. Effect of
controlled-release levodopa on the microstructure of sleep in
Parkinson’s disease. Eur J Neurol 2011;18:590–596.
21. Ratti P-L, Nègre-Pagès L, Pérez-Lloret S, et al. Subjective sleep dys-
function and insomnia symptoms in Parkinson’s disease: insights
from a cross-sectional evaluation of the French CoPark cohort.
Parkinsonism Relat Disord 2015;21:1323–1329.
22. Selvaraj VK, Keshavamurthy B. Sleep dysfunction in Parkinson’s
disease. J Clin Diagn Res 2016;10:OC09–OC12.
23. Amato N, Manconi M, Möller JC, et al. Levodopa-induced dyski-
nesia in Parkinson disease: sleep matters. Ann Neurol 2018;84:
905–917.
24. Cai G-E, Luo S, Chen L-N, Lu J-P, Huang Y-J, Ye Q-Y. Sleep frag-
mentation as an important clinical characteristic of sleep disorders
in Parkinson’s disease: a preliminary study. Chin Med J 2019;132:
1788–1795.
25. Zhang Y, Ren R, Sanford LD, et al. Sleep in Parkinson’s disease: a
systematic review and meta-analysis of polysomnographic findings.
Sleep Med Rev 2020;51:101281.
 N E U R O P H Y S I O L O G Y
26. Postuma RB, Bertrand J-A, Montplaisir J, et al. Rapid eye move-
ment sleep behavior disorder and risk of dementia in Parkinson’s
disease: a prospective study. Mov Disord 2012;27:720–726.
27. Tekriwal A, Kern DS, Tsai J, Ince NF, Wu J, Thompson JA,
Abosch A. REM sleep behaviour disorder: prodromal and mecha-
nistic insights for Parkinson’s disease. J Neurol Neurosurg Psychia-
try 2017;88:445–451.
28. D’Amelio M, Terruso V, Palmeri B, et al. Predictors of caregiver
burden in partners of patients with Parkinson’s disease. Neurol Sci
2009;30:171–174.
29. Bartolomei L, Pastore A, Meligrana L, et al. Relevance of sleep
quality on caregiver burden in Parkinson’s disease. Neurol Sci
2018;39:835–839.
30. Happe S, Berger K, FAQT Study Investigators. The association
between caregiver burden and sleep disturbances in partners of
patients with Parkinson’s disease. Age Ageing 2002;31:349–354.
31. WGH O, de Weerd AW. The prevalence of sleep disorders in
patients with Parkinson’s disease. A self-reported, community-
based survey. Sleep Med 2002;3:147–149.
32. Politis M, Wu K, Molloy S, Bain PG, Chaudhuri KR, Piccini P.
Parkinson’s disease symptoms: the patient’s perspective. Mov
Disord 2010;25:1646–1651.
33. Chahine LM, Amara AW, Videnovic A. A systematic review of the
literature on disorders of sleep and wakefulness in Parkinson’s dis-
ease from 2005 to 2015. Sleep Med Rev 2017;35:33–50.
34. Berry RB, Brooks R, Gamaldo CE, Harding SM, Lloyd RM,
Marcus CL, Vaughn BV. The AASM Manual for the Scoring of
Sleep and Associated Events: Rules, Terminology and Technical
Specifications. American Academy of Sleep Medicine 2018;2(5).
35. Aserinsky E, Kleitman N. Two types of ocular motility occurring in
sleep. J Appl Physiol 1955;8:1–10.
36. Malhotra RK, Avidan AY. Sleep stages and scoring technique.
Atlas of Sleep Medicine. In Chokroverty, S. & Thomas RJ (eds).
pp. 77–99. Elsevier, Philadelphia, PA, 2014.
37. Léger D, Debellemaniere E, Rabat A, Bayon V, Benchenane K,
Chennaoui M. Slow-wave sleep: from the cell to the clinic. Sleep
Med Rev 2018;41:113–132.
38. Peever J, Fuller PM. The biology of REM sleep. Curr Biol 2017;27:
R1237–R1248.
39. Emser W, Brenner M, Stober T, Schimrigk K. Changes in nocturnal
sleep in Huntington’s and Parkinson’s disease. J Neurol 1988;235:
177–179.
40. Comella CL, Tanner CM, Ristanovic RK. Polysomnographic sleep
measures in Parkinson’s disease patients with treatment-induced
hallucinations. Ann Neurol 1993;34:710–714.
41. Wetter TC, Brunner H, Högl B, Yassouridis A, Trenkwalder C,
Friess E. Increased alpha activity in REM sleep in de novo patients
with Parkinson’s disease. Mov Disord 2001;16:928–933.
42. Brunner H, Wetter TC, Hogl B, Yassouridis A, Trenkwalder C,
Friess E. Microstructure of the non-rapid eye movement sleep elec-
troencephalogram in patients with newly diagnosed Parkinson’s
disease: effects of dopaminergic treatment. Mov Disord 2002;17:
928–933.
43. Maria B, Sophia S, Michalis M, Charalampos L, Andreas P,
John ME, Nikolaos SM. Sleep breathing disorders in patients with
idiopathic Parkinson’s disease. Respir Med 2003;97:1151–1157.
44. Happe S, Anderer P, Pirker W, Klösch G, Gruber G, Saletu B,
Zeitlhofer J. Sleep microstructure and neurodegeneration as mea-
sured by [123I]β-CIT SPECT in treated patients with Parkinson’s
disease. J Neurol 2004;251:1465–1471.
45. Shpirer I, Miniovitz A, Klein C, et al. Excessive daytime sleepiness
in patients with Parkinson’s disease: a polysomnography study.
Mov Disord 2006;21:1432–1438.
46. Cochen De Cock V, Abouda M, Leu S, et al. Is obstructive sleep
apnea a problem in Parkinson’s disease? Sleep Med 2010;11:
247–252.
47. Sixel-Döring F, Trautmann E, Mollenhauer B, Trenkwalder C.
Age, drugs, or disease: what alters the macrostructure of sleep in
Parkinson’s disease? Sleep Med 2012;13:1178–1183.
O F S L E E P I N P A R K I N S O N ’ S
48. Diederich NJ, Rufra O, Pieri V, Hipp G, Vaillant M. Lack of polys-
omnographic non-REM sleep changes in early Parkinson’s disease.
Mov Disord 2013;28:1443–1446.
49. Breen DP, Vuono R, Nawarathna U, Fisher K, Schneerson JM,
Reddy AB, Barker RA. Sleep and circadian rhythm regulation in
early Parkinson disease. JAMA Neurol 2014;71:589–595.
50. JAE C, Zoetmulder M, Koch H, et al. Data-driven modeling of sleep
EEG and EOG reveals characteristics indicative of pre-Parkinson’s
and Parkinson’s disease. J Neurosci Methods 2014;235:262–276.
51. JAE C, Kempfner J, Zoetmulder M, et al. Decreased sleep spindle
density in patients with idiopathic REM sleep behavior disorder
and patients with Parkinson’s disease. Clin Neurophysiol 2014;
125:512–519.
52. JAE C, Nikolic M, Warby SC, et al. Sleep spindle alterations in
patients with Parkinson’s disease. Front Hum Neurosci 2015;
9:233.
53. Ehrminger M, Leu-Semenescu S, Cormier F, et al. Sleep aspects on
video-polysomnography in LRRK2 mutation carriers. Mov Disord
2015;30:1839–1843.
54. Margis R, Schönwald SV, Carvalho DZ, GJL G, CRM R. NREM
sleep alpha and sigma activity in Parkinson’s disease: evidence for
conflicting electrophysiological activity? Clin Neurophysiol 2015;
126:951–958.
55. Latreille V, Carrier J, Lafortune M, et al. Sleep spindles in
Parkinson’s disease may predict the development of dementia.
Neurobiol Aging 2015;36:1083–1090.
56. Imbach LL, Sommerauer M, Poryazova R, et al. Bradysomnia in
Parkinson’s disease. Clin Neurophysiol 2016;127:1403–1409.
57. Latreille V, Carrier J, Gaudet-Fex B, et al. Electroencephalographic
prodromal markers of dementia across conscious states in
Parkinson’s disease. Brain 2016;139:1189–1199.
58. Schroeder LA, Rufra O, Sauvageot N, Fays F, Pieri V,
Diederich NJ. Reduced rapid eye movement density in Parkinson
disease: a Polysomnography-based case-control study. Sleep 2018;
39:2133–2139.
59. Fu Y-T, Mao C-J, Ma L-J, et al. Pain correlates with sleep distur-
bances in Parkinson’s disease patients. Pain Pract 2018;18:29–37.
60. González-Naranjo JE, Alfonso-Alfonso M, Grass-Fernandez D,
et al. Analysis of sleep macrostructure in patients diagnosed with
Parkinson’s disease. Behav Sci 2019;9(1):6. https://doi.org/10.3390/
bs9010006.
61. Liu K, Ma Q, Wang M. Comparison of quantitative electroenceph-
alogram during sleep in depressed and non-depressed patients with
Parkinson’s disease. Med Sci Monit 2019;25:1046–1052.
62. Gennaro LD, De Gennaro L, Ferrara M. Sleep spindles: an over-
view. Sleep Med Rev 2003;7:423–440.
63. Colrain IM. The K-complex: a 7-decade history. Sleep 2005;28:
255–273.
64. Nakamura M, Uchida S, Maehara T, et al. Sleep spindles in human
prefrontal cortex: an electrocorticographic study. Neurosci Res
2003;45:419–427.
65. Achermann P, Dijk DJ, Brunner DP, Borbély AA. A model of
human sleep homeostasis based on EEG slow-wave activity: quanti-
tative comparison of data and simulations. Brain Res Bull 1993;31:
97–113.
66. Sforza E, Krieger J, Petiau C. REM sleep behavior disorder: clinical
and physiopathological findings. Sleep Med Rev 1997;1:57–69.
67. Comella CL, Nardine TM, Diederich NJ, Stebbins GT.
Sleep-related violence, injury, and REM sleep behavior disorder in
Parkinson’s disease. Neurology 1998;51:526–529.
68. Olson EJ, Boeve BF, Silber MH. Rapid eye movement sleep behav-
iour disorder: demographic, clinical and laboratory findings in
93 cases. Brain 2000;123(Pt 2):331–339.
69. Boeve BF, Silber MH, Ferman TJ, Lucas JA, Parisi JE. Association
of REM sleep behavior disorder and neurodegenerative disease
may reflect an underlying synucleinopathy. Mov Disord 2001;16:
622–630.
70. Grandas F, Iranzo A. Nocturnal problems occurring in Parkinson’s
disease. Neurology 2004;63:S8–S11.
Movement Disorders, 2021 13
Z A H E D E T A L
71. Iranzo A, Santamaría J, Rye DB, et al. Characteristics of idiopathic
REM sleep behavior disorder and that associated with MSA and
PD. Neurology 2005;65:247–252.
72. Gagnon J-F, Postuma RB, Mazza S, Doyon J, Montplaisir J.
Rapid-eye-movement sleep behaviour disorder and neurodegenera-
tive diseases. Lancet Neurol 2006;5:424–432.
73. Boeve BF, Silber MH, Saper CB, et al. Pathophysiology of REM
sleep behaviour disorder and relevance to neurodegenerative dis-
ease. Brain 2007;130:2770–2788.
74. Boeve BF. REM sleep behavior disorder: updated review of the
core features, the REM sleep behavior disorder-neurodegenerative
disease association, evolving concepts, controversies, and future
directions. Ann NY Acad Sci 2010;1184:15–54.
75. Howell MJ, Schenck CH. Rapid eye movement sleep behavior dis-
order and Neurodegenerative disease. JAMA Neurol 2015;72:
707–712.
76. Postuma RB, Berg D. Prodromal Parkinson’s disease: the decade
past, the decade to come. Mov Disord 2019;34:665–675.
77. Schenck CH, Bundlie SR, Mahowald MW. Delayed emergence of a
parkinsonian disorder in 38% of 29 older men initially diagnosed
with idiopathic rapid eye movement sleep behavior disorder.
Neurology 1996;46:388–393.
78. Schenck CH. REM behavior disorder (RBD): delayed emergence of
parkinsonism and/or dementia in 65% of older men initially diag-
nosed with idiopathic RBD, and an analysis of the minimum &
maximum tonic and/or phasic electromyographic abnormalities
found during REM sleep. Sleep 2003;26:A316.
79. Iranzo A, Molinuevo JL, Santamaría J, Serradell M, Martí MJ,
Valldeoriola F, Tolosa E. Rapid-eye-movement sleep behaviour dis-
order as an early marker for a neurodegenerative disorder: a
descriptive study. Lancet Neurol 2006;5:572–577.
80. Postuma RB, Lang AE, Massicotte-Marquez J, Montplaisir J.
Potential early markers of Parkinson disease in idiopathic REM
sleep behavior disorder. Neurology 2006;66:845–851.
81. Iranzo A. Sleep-wake changes in the premotor stage of Parkinson
disease. J Neurol Sci 2011;310:283–285.
82. Mouret J. Differences in sleep in patients with Parkinson’s disease.
Electroencephalogr Clin Neurophysiol 1975;38:653–657.
83. Gagnon J-F, Fantini ML, Bédard M-A, et al. Association between
waking EEG slowing and REM sleep behavior disorder in PD with-
out dementia. Neurology 2004;62:401–406.
84. Askenasy JJ, Yahr MD. Parkinsonian tremor loses its alternating
aspect during non-REM sleep and is inhibited by REM sleep.
J Neurol Neurosurg Psychiatry 1990;53:749–753.
85. Lees AJ, Blackburn NA, Campbell VL. The nighttime problems of
Parkinson’s disease. Clin Neuropharmacol 1988;11:512–519.
86. Manni R, Pacchetti C, Terzaghi M, Sartori I, Mancini F, Nappi G.
Hallucinations and sleep-wake cycle in PD: a 24-hour continuous
polysomnographic study. Neurology 2002;59:1979–1981.
87. Zhu J, Zhong M, Yan J, et al. Nonmotor symptoms affect sleep
quality in early-stage Parkinson’s disease patients with or without
cognitive dysfunction. Front Neurol 2020;11:292.
88. Peeraully T, Yong M-H, Chokroverty S, Tan E-K. Sleep and
Parkinson’s disease: a review of case-control polysomnography
studies. Mov Disord 2012;27:1729–1737.
89. Moiseeva NI, Aleksanian ZA. Slow-wave oscillations of the multi-
unit activity average frequency in the human brain during drowsi-
ness and sleep. Electroencephalogr Clin Neurophysiol 1986;63:
431–437.
90. Stefani A, Galati S, Peppe A, et al. Spontaneous sleep modulates
the firing pattern of parkinsonian subthalamic nucleus. Exp Brain
Res 2006;168:277–280.
91. Urbain N, Gervasoni D, Soulière F, et al. Unrelated course of
subthalamic nucleus and globus pallidus neuronal activities across
vigilance states in the rat. Eur J Neurosci 2000;12:3361–3374.
92. Mizrahi-Kliger AD, Kaplan A, Israel Z, Bergman H.
Desynchronization of slow oscillations in the basal ganglia during
natural sleep. Proc Natl Acad Sci USA 2018;115:E4274–E4283.
14 Movement Disorders, 2021
93. Brown P, Williams D. Basal ganglia local field potential activity:
character and functional significance in the human. Clin
Neurophysiol 2005;116:2510–2519.
94. Thompson JA, Tekriwal A, Felsen G, et al. Sleep patterns in
Parkinson’s disease: direct recordings from the subthalamic
nucleus. J Neurol Neurosurg Psychiatry 2018;89:95–104.
95. Kühn AA, Kupsch A, Schneider G, Brown P. Reduction in sub-
thalamic 8-35 Hz oscillatory activity correlates with clinical
improvement in Parkinson’s disease. Eur J Neurosci 2006;23:
1956–1960.
96. Ray NJ, Jenkinson N, Wang S, et al. Local field potential beta
activity in the subthalamic nucleus of patients with Parkinson’s dis-
ease is associated with improvements in bradykinesia after dopa-
mine and deep brain stimulation. Exp Neurol 2008;213:108–113.
97. Kühn AA, Tsui A, Aziz T, et al. Pathological synchronisation in the
subthalamic nucleus of patients with Parkinson’s disease relates to
both bradykinesia and rigidity. Exp Neurol 2009;215:380–387.
98. Neumann W-JJ, Staub-Bartelt F, Horn A, Schanda J,
Schneider G-H, Brown P, Kühn AA. Long term correlation of sub-
thalamic beta band activity with motor impairment in patients with
Parkinson’s disease. Clin Neurophysiol 2017;128:2286–2291.
99. Steiner LA, Neumann W-J, Staub-Bartelt F, et al. Subthalamic beta
dynamics mirror Parkinsonian bradykinesia months after
neurostimulator implantation. Mov Disord 2017;32:1183–1190.
100. Brittain J-S, Sharott A, Brown P. The highs and lows of beta activ-
ity in cortico-basal ganglia loops. Eur J Neurosci 2014;39:
1951–1959.
101. Urrestarazu E, Iriarte J, Alegre M, et al. Beta activity in the sub-
thalamic nucleus during sleep in patients with Parkinson’s disease.
Mov Disord 2009;24:254–260.
102. Mizrahi-Kliger AD, Kaplan A, Israel Z, Deffains M, Bergman H.
Basal ganglia beta oscillations during sleep underlie Parkinsonian
insomnia. Proc Natl Acad Sci U S A 2020;117(29):17359–17368.
https://doi.org/10.1073/pnas.2001560117.
103. Porras G, Li Q, Bezard E. Modeling Parkinson’s disease in pri-
mates: The MPTP model. Cold Spring Harb Perspect Med 2012;2:
a009308.
104. Bové J, Prou D, Perier C, Przedborski S. Toxin-induced models of
Parkinson’s disease. NeuroRx 2005;2:484–494.
105. Fernández-Mendoza J, Lozano B, Seijo F, et al. Evidence of sub-
thalamic PGO-like waves during REM sleep in humans: a deep
brain polysomnographic study. Sleep 2009;32:1117–1126.
106. Christensen E, Abosch A, Thompson JA, Zylberberg J. Inferring
sleep stage from local field potentials recorded in the subthalamic
nucleus of Parkinson’s patients. J Sleep Res 2019;28:e12806.
107. Chen Y, Gong C, Hao H, et al. Automatic sleep stage classification
based on subthalamic local field potentials. IEEE Trans Neural Syst
Rehabil Eng 2019;27:118–128.
108. Starr PA. Totally implantable bidirectional neural prostheses: a
flexible platform for innovation in neuromodulation. Front
Neurosci 2018;12:1–5.
109. Gilron R, Little S, Perrone R, Wilt R, de Hemptinne C. Chronic
wireless streaming of invasive neural recordings at home for circuit
discovery and adaptive stimulation. bioRxiv 2020. https://doi.org/
10.1101/2020.02.13.948349.
110. Shokri-Kojori E, Wang G-J, Wiers CE, et al. β-Amyloid accumula-
tion in the human brain after one night of sleep deprivation. Proc
Natl Acad Sci U S A 2018;115:4483–4488.
111. Holth J, Patel T, Holtzman DM. Sleep in Alzheimer’s disease -
beyond amyloid. Neurobiol Sleep Circadian Rhythms 2017;
2:4–14.
112. Ju Y-ES, Lucey BP, Holtzman DM. Sleep and Alzheimer disease
pathology—a bidirectional relationship. Nat Rev Neurol 2014;10:
115–119.
113. Wang C, Holtzman DM. Bidirectional relationship between sleep
and Alzheimer’s disease: role of amyloid, tau, and other factors.
Neuropsychopharmacology 2020;45:104–120.
114. Irwin MR, Vitiello MV. Implications of sleep disturbance and
inflammation for Alzheimer’s disease dementia. Lancet Neurol
2019;18:296–306.
 N E U R O P H Y S I O L O G Y
115. HVV N, Claassen J, Dresler M. Sleep: slow wave activity predicts
amyloid-β accumulation. Curr Biol 2020;30:R1371–R1373.
116. Leng Y, Musiek ES, Hu K, Cappuccio FP, Yaffe K. Association
between circadian rhythms and neurodegenerative diseases. Lancet
Neurol 2019;18:307–318.
117. Xie L, Kang H, Xu Q, et al. Sleep drives metabolite clearance from
the adult brain. Science 2013;342:373–377.
118. Hablitz LM, Vinitsky HS, Sun Q, et al. Increased glymphatic influx
is correlated with high EEG delta power and low heart rate in mice
under anesthesia. Sci Adv 2019;5:eaav5447.
119. Kim WS, Kågedal K, Halliday GM. Alpha-synuclein biology in
Lewy body diseases. Alzheimers Res Ther 2014;6:73.
120. Sundaram S, Hughes RL, Peterson E, et al. Establishing a frame-
work for neuropathological correlates and glymphatic system func-
tioning in Parkinson’s disease. Neurosci Biobehav Rev 2019;103:
305–315.
121. Nedergaard M, Goldman SA. Glymphatic failure as a final com-
mon pathway to dementia. Science 2020;370:50–56.
122. Holth JK, Fritschi SK, Wang C, et al. The sleep-wake cycle regu-
lates brain interstitial fluid tau in mice and CSF tau in humans.
Science 2019;363:880–884.
123. Currie LJ, Bennett JP Jr, Harrison MB, Trugman JM, Wooten GF.
Clinical correlates of sleep benefit in Parkinson’s disease. Neurol-
ogy 1997;48:1115–1117.
124. Högl BE, Gómez-Arévalo G, García S, et al. A clinical, pharmaco-
logic, and polysomnographic study of sleep benefit in Parkinson’s
disease. Neurology 1998;50:1332–1339.
125. O’Dowd S, Galna B, Morris R, et al. Poor sleep quality and pro-
gression of gait impairment in an incident Parkinson’s disease
cohort. J Parkinsons Dis 2017;7:465–470.
126. Schreiner SJ, Imbach LL, Werth E, et al. Slow-wave sleep and
motor progression in Parkinson disease. Ann Neurol 2019;85:
765–770.
127. Diekelmann S, Born J. The memory function of sleep. Nat Rev
Neurosci 2010;11:114–126.
128. Wang G, Grone B, Colas D, Appelbaum L, Mourrain P. Synaptic
plasticity in sleep: learning, homeostasis and disease. Trends
Neurosci 2011;34:452–463.
129. Tononi G, Cirelli C. Sleep and the price of plasticity: from synaptic
and cellular homeostasis to memory consolidation and integration.
Neuron 2014;81:12–34.
130. Caverzasio S, Caverzasio S, Amato N, et al. Brain plasticity and
sleep: implication for movement disorders. Neurosci Biobehav Rev
2018;86:21–35.
131. Navarro-Lobato I, Genzel L. The up and down of sleep: from mol-
ecules to electrophysiology. Neurobiol. Learn Mem 2019;
160:3–10.
132. Maquet P. The role of sleep in learning and memory. Science 2001;
294:1048–1052.
133. Gais S, Born J. Declarative memory consolidation: mechanisms act-
ing during human sleep. Learn Mem 2004;11:679–685.
134. Walker MP, Stickgold R. Sleep-dependent learning and memory
consolidation. Neuron 2004;44:121–133.
135. Stickgold R. Sleep-dependent memory consolidation. Nature 2005;
437:1272–1278.
136. Karni A, Tanne D, Rubenstein BS, Askenasy JJ, Sagi D.
Dependence on REM sleep of overnight improvement of a percep-
tual skill. Science 1994;265:679–682.
137. Gais S, Plihal W, Wagner U, Born J. Early sleep triggers memory
for early visual discrimination skills. Nat Neurosci 2000;3:
1335–1339.
138. Stickgold R, James L, Hobson JA. Visual discrimination learning
requires sleep after training. Nat Neurosci 2000;3:1237–1238.
139. Laureys S, Peigneux P, Perrin F, Maquet P. Sleep and motor skill
learning. Neuron 2002;35:5–7.
140. Walker MP, Brakefield T, Morgan A, Hobson JA, Stickgold R.
Practice with sleep makes perfect: sleep-dependent motor skill
learning. Neuron 2002;35:205–211.
O F S L E E P I N P A R K I N S O N ’ S
141. Maquet P, Schwartz S, Passingham R, Frith C. Sleep-related con-
solidation of a visuomotor skill: brain mechanisms as assessed by
functional magnetic resonance imaging. J Neurosci 2003;23:
1432–1440.
142. Gottselig JM, Hofer-Tinguely G, Borbély AA, Regel SJ,
Landolt H-P, Rétey JV, Achermann P, Sleep and rest facilitate audi-
tory learning. Neuroscience 2004;127:557–561.
143. Huber R, Ghilardi MF, Massimini M, Tononi G. Local sleep and
learning. Nature 2004;430:78–81.
144. Terpening Z, Naismith S, Melehan K, Gittins C, Bolitho S,
Lewis SJ. The contribution of nocturnal sleep to the consolidation
of motor skill learning in healthy ageing and Parkinson’s disease.
J Sleep Res 2013;22:398–405.
145. Scullin MK, Trotti LM, Wilson AG, Greer SA, Bliwise DL.
Nocturnal sleep enhances working memory training in Parkinson’s
disease but not Lewy body dementia. Brain 2012;135:2789–2797.
146. Vendette M. REM sleep behavior disorder predicts cognitive
impairment in Parkinson disease without dementia. Neurology
2007;69:1843–1849.
147. Pagano G, De Micco R, Yousaf T, Wilson H, Chandra A,
Politis M. REM behavior disorder predicts motor progression and
cognitive decline in Parkinson disease. Neurology 2018;91:
e894–e905.
148. EST S, Sobreira-Neto MA, Pena-Pereira MA, Chagas MHN,
Fernandes RMF, Eckeli AL, Tumas V. Global cognitive perfor-
mance is associated with sleep efficiency measured by poly-
somnography in patients with Parkinson’s disease. Psychiatry Clin
Neurosci 2019;73:248–253.
149. Lazarus M, Huang Z-L, Lu J, Urade Y, Chen J-F. How do the
basal ganglia regulate sleep–wake behavior? Trends Neurosci
2012;35:723–732.
150. Lazarus M, Chen J-F, Urade Y, Huang Z-L. Role of the basal
ganglia in the control of sleep and wakefulness. Curr Opin
Neurobiol 2013;23:780–785.
151. Stoffers D, Altena E, van der Werf YD, et al. The caudate: a key
node in the neuronal network imbalance of insomnia? Brain 2014;
137:610–620.
152. Hasegawa H, Selway R, Gnoni V, et al. The subcortical belly of
sleep: new possibilities in neuromodulation of basal ganglia? Sleep
Med Rev 2020;52:101317.
153. JRP Z, Ostrem JL. The impact of deep brain stimulation on sleep
in Parkinson’s disease: an update. JPD 2020;10:393–404.
154. Schrempf W, Fauser M, Wienecke M, et al. Rasagiline improves
polysomnographic sleep parameters in patients with Parkinson’s
disease: a double-blind, baseline-controlled trial. Eur J Neurol
2008;25:672–679.
155. Walsh JK, Zammit G, Schweitzer PK, Ondrasik J, Roth T.
Tiagabine enhances slow wave sleep and sleep maintenance in pri-
mary insomnia. Sleep Med 2006;7:155–161.
156. Feld GB, Wilhelm I, Ma Y, et al. Slow wave sleep induced by
GABA agonist tiagabine fails to benefit memory consolidation.
Sleep 2013;36:1317–1326.
157. Walsh JK, Snyder E, Hall J, et al. Slow wave sleep enhancement
with gaboxadol reduces daytime sleepiness during sleep restriction.
Sleep 2008;31:659–672.
158. Amara AW, Wood KH, Joop A, et al. Randomized, controlled trial
of exercise on objective and subjective sleep in Parkinson’s disease.
Mov Disord 2020;35:947–958.
159. Wilckens KA, Ferrarelli F, Walker MP, Buysse DJ. Slow-wave
activity enhancement to improve cognition. Trends Neurosci 2018;
41:470–482.
160. Zhang Y, Gruber R. Can slow-wave sleep enhancement improve
memory? A review of current approaches and cognitive outcomes.
Yale J Biol Med 2019;92:63–80.
161. Malkani RG, Zee PC. Brain stimulation for improving sleep and
memory. Sleep Med Clin 2020;15:101–115.
162. Herrero Babiloni A, Bellemare A, Beetz G, Vinet SA, Martel MO,
Lavigne GJ, De Beaumont L. The effects of non-invasive brain
stimulation on sleep disturbances among different neurological and
Movement Disorders, 2021 15
Z A H E D E T A L
neuropsychiatric conditions: a systematic review. Sleep Med Rev
2021;55:101381.
163. Ngo H-VV, Miedema A, Faude I, Martinetz T, Mölle M, Born J.
Driving sleep slow oscillations by auditory closed-loop
stimulation-a self-limiting process. J Neurosci 2015;35:6630–6638.
164. Garcia-Molina G, Tsoneva T, Jasko J, et al. Closed-loop system to
enhance slow-wave activity. J Neural Eng 2018;15:066018.
165. Ngo H-VV, Martinetz T, Born J, Mölle M. Auditory closed-loop
stimulation of the sleep slow oscillation enhances memory. Neuron
2013;78:545–553.
166. Ong JL, Lo JC, Chee NI, Santostasi G, Paller KA, Zee PC,
Chee MW. Effects of phase-locked acoustic stimulation during a
nap on EEG spectra and declarative memory consolidation. Sleep
Med 2016;20:88–97.
167. Leminen MM, Virkkala J, Saure E, et al. Enhanced memory con-
solidation via automatic sound stimulation during non-REM sleep.
Sleep 2017;40(3):zsx003.
168. Papalambros NA, Santostasi G, Malkani RG, Braun R,
Weintraub S, Paller KA, Zee PC. Acoustic enhancement of sleep
slow oscillations and concomitant memory improvement in older
adults. Front Hum Neurosci 2017;11:109.
169. Ong JL, Patanaik A, NIYN C, Lee XK, Poh JH, MWL C. Auditory
stimulation of sleep slow oscillations modulates subsequent mem-
ory encoding through altered hippocampal function. Sleep 2009;
42:zsy031.
170. Papalambros NA, Weintraub S, Chen T, et al. Acoustic enhance-
ment of sleep slow oscillations in mild cognitive impairment. Ann
Clin Transl Neurol 2019;6:1191–1201.
171. Marshall L, Helgadóttir H, Mölle M, Born J. Boosting slow oscilla-
tions during sleep potentiates memory. Nature 2016;444:610–613.
172. Lustenberger C, Boyle MR, Foulser AA, Mellin JM, Fröhlich F.
Feedback-controlled Transcranial alternating current stimulation
reveals a functional role of sleep spindles in motor memory consoli-
dation. Curr Biol 2016;26:2127–2136.
173. Ketz N, Jones AP, Bryant NB, Clark VP, Pilly PK. Closed-loop
slow-wave tACS improves sleep-dependent long-term memory gen-
eralization by modulating endogenous oscillations. J Neurosci
2018;38:7314–7326.
174. Westerberg CE, Florczak SM, Weintraub S, Mesulam MM,
Marshall L, Zee PC, Paller KA. Memory improvement via slow-
oscillatory stimulation during sleep in older adults. Neurobiol
Aging 2015;36:2577–2586.
175. Ladenbauer J, Ladenbauer J, Külzow N, de Boor R, Avramova E,
Grittner U, Flöel A. Promoting sleep oscillations and their func-
tional coupling by Transcranial stimulation enhances memory con-
solidation in mild cognitive impairment. J Neurosci 2017;37:
7111–7124.
176. van Dijk KD, EIS M, EJW VS, Berendse HW, van der Werf YD.
Beneficial effect of transcranial magnetic stimulation on sleep in
Parkinson’s disease. Mov Disord 2009;24:878–884.
177. Arias P, Vivas J, Grieve KL, Cudeiro J. Double-blind, randomized,
placebo controlled trial on the effect of 10 days low-frequency
rTMS over the vertex on sleep in Parkinson’s disease. Sleep Med
2010;11:759–765.
178. Antczak J, Maria R, Marta B, et al. The influence of repetitive
transcranial magnetic stimulation on sleep in Parkinson’s disease.
Biocybern Biomed Eng 2011;31:35–46.
179. Forogh B, Arbabi A, Rafiei M, et al. Repeated sessions of trans-
cranial direct current stimulation evaluation on fatigue and day-
time sleepiness in Parkinson’s disease. Neurol Sci 2017;38:
249–254.
180. Hadoush H, Al-Sharman A, Khalil H, Banihani SA, Al-Jarrah M.
Sleep quality, depression, and quality of life after bilateral anodal
Transcranial direct current stimulation in patients with Parkinson’s
disease. Med Sci Monit Basic Res 2018;24:198–205.
181. Okun MS, Foote KD. Parkinson’s disease DBS: what, when, who
and why? The time has come to tailor DBS targets. Expert Rev
Neurother 2010;10:1847–1857.
182. Larson PS. Deep brain stimulation for movement disorders.
Neurotherapeutics 2014;11:465–474.
16 Movement Disorders, 2021
183. Lozano AM, Lipsman N, Bergman H, et al. Deep brain stimula-
tion: current challenges and future directions. Nat Rev Neurol
2009;15:148–160.
184. Sharma VD, Sengupta S, Chitnis S, Amara AW. Deep brain stimu-
lation and sleep-wake disturbances in Parkinson disease: a review.
Front Neurol 2018;9:697.
185. Arnulf I, Bejjani BP, Garma L, et al. Improvement of sleep architec-
ture in PD with subthalamic nucleus stimulation. Neurology 2000;
55:1732–1734.
186. Iranzo A, Valldeoriola F, Santamaria J, Tolosa Em Rumia J. Sleep
symptoms and polysomnographic architecture in advanced
Parkinson’s disease after chronic bilateral subthalamic stimulation.
J Neurol Neurosurg Psychiatry 2002;72(5):661–664.
187. Monaca C, Orsancak C, Jacquesson JM, et al. Effects of bilateral
subthalamic stimulation on sleep in Parkinson’s disease. J Neurol
2004;251:214–218.
188. Cicolin A, Ozsancak C, Jacquesson JM, et al. Effects of deep brain
stimulation of the subthalamic nucleus on sleep architecture in par-
kinsonian patients. Sleep Med 2004;5:207–210.
189. Hjort N, Østergaard K, Dupont E. Improvement of sleep quality in
patients with advanced Parkinson’s disease treated with deep brain
stimulation of the subthalamic nucleus. Mov Disord 2019;19:
196–199.
190. Lyons KE, Pahwa R. Effects of bilateral subthalamic nucleus stimu-
lation on sleep, daytime sleepiness, and early morning dystonia in
patients with Parkinson disease. J Neurosurg 2006;104:502–505.
191. Weaver FM, Follett K, Stern M, et al. Bilateral deep brain stimula-
tion vs best medical therapy for patients with advanced Parkinson
disease: a randomized controlled trial. JAMA 2009;301:63–73.
192. Arnulf I, Ferraye M, Fraix V, et al. Sleep induced by stimulation in
the human pedunculopontine nucleus area. Ann Neurol 2010;67:
546–549.
193. Follett KA, Weaver FM, Stern M, et al. Pallidal versus subthalamic
deep-brain stimulation for Parkinson’s disease. N Engl J Med
2010;362:2077–2091.
194. Qiu MH, Chen MC, Wu J, Nelson D, Lu J. Deep brain stimulation
in the globus pallidus externa promotes sleep. Neuroscience 2016;
322:115–120.
195. Baumann-Vogel H, Imbach LL, Sürücü O, Stieglitz L,
Waldvogel D, Baumann CR, Werth E. The impact of subthalamic
deep brain stimulation on sleep-wake behavior: a prospective elec-
trophysiological study in 50 Parkinson patients. Sleep 2017;40(5):
zsx033. http://dx.doi.org/10.1093/sleep/zsx033.
196. Liu Y, Zhang L, Chen W, et al. Subthalamic nucleus deep brain
stimulation improves sleep in Parkinson’s disease patients: a retro-
spective study and a meta-analysis. Sleep Med 2020;74:301–306.
197. Dafsari HS, Ray-Chaudhuri K, Ashkan K, et al. Beneficial effect of
24-month bilateral subthalamic stimulation on quality of sleep in
Parkinson’s disease. J Neurol 2020;267:1830–1841.
198. Castillo PR, Middlebrooks EH, Grewal SS, Okromelidze L,
Meschia JF, Quinones-Hinojosa A, Uitti RJ. Globus Pallidus
Externus deep brain stimulation treats insomnia in a patient with
Parkinson disease. Mayo Clin Proc 2020;95:419–422.
199. Romigi A, Placidi F, Peppe A, et al. Pedunculopontine nucleus
stimulation influences REM sleep in Parkinson’s disease. Eur J
Neurol 2008;15:e64–e66.
200. Lim AS, Moro E, Lozano AM, et al. Selective enhancement of
rapid eye movement sleep by deep brain stimulation of the human
pons. Ann Neurol 2009;66:110–114.
201. Nishida N, Murakami T, Kadoh K, et al. Subthalamic nucleus deep
brain stimulation restores normal rapid eye movement sleep in
Parkinson’s disease. Mov Disord 2011;26:2418–2422.
202. Choi J-H, Kim HJ, Lee JY, Yoo D, Im JH, Paek SH, Jeon B.
Long-term effects of bilateral subthalamic nucleus stimulation on sleep
in patients with Parkinson’s disease. PLoS One 2019;14:e0221219.
203. Little S, Pogosyan A, Neal S, et al. Adaptive deep brain stimulation
in advanced Parkinson disease. Ann Neurol 2013;74:449–457.
204. Little S, Tripoliti E, Beudel M, et al. Adaptive deep brain stimula-
tion for Parkinson’s disease demonstrates reduced speech side
 N E U R O P H Y S I O L O G Y O F S L E E P I N P A R K I N S O N ’ S

effects compared to conventional stimulation in the acute setting.
J Neurol Neurosurg Psychiatry 2016;87:1388–1389.
205. Little S, Beudel M, Zrinzo L, et al. Bilateral adaptive deep brain
stimulation is effective in Parkinson’s disease. J Neurol Neurosurg
Psychiatry 2016;87(7):717–721.
206. Beudel M, Brown P. Adaptive deep brain stimulation in
Parkinson’s disease. Parkinsonism Relat Disord 2016;22:
S123–S126.
207. Velisar A, Syrkin-Nikolau J, Blumenfeld Z, Trager MH, Afzal MF,
Prabhakar V, Bronte-Stewart H. Dual threshold neural closed loop
deep brain stimulation in Parkinson disease patients. Brain Stimul
2019;12:868–876.
208. Daley JT, JL DW. Sleep, circadian rhythms, and epilepsy. Curr
Treat Options Neurol 2018;20:47.
209. Frauscher B, Gotman J. Sleep, oscillations, interictal discharges,
and seizures in human focal epilepsy. Neurobiol Dis 2019;127:
545–553.
210. Zhang Y, Ren R, Yang L, et al. Sleep in Huntington’s disease: a
systematic review and meta-analysis of polysomongraphic findings.
Sleep 2019;42:zz154.
211. Tanigaki WK, Rossetti MA, Rocha NP, Stimming EF. Sleep dys-
function in Huntington’s disease: perspectives from patients.
J Huntingtons Dis 2020;9(4):345–352.
212. Jin B, Aung T, Geng Y, Wang S. Epilepsy and its interaction with
sleep and circadian rhythm. Front Neurol 2020;11:327.

Movement Disorders, 2021 17

 SGML and CITI Use Only
DO NOT PRINT

Author Roles
Dr. Zahed and Dr. Little jointly wrote the first draft of the article and reviewed and revised the article. Dr. Zahed
prepared the article for submission. Drs. Zuzuarregui, Gilron, Denison, and Starr reviewed and critiqued the article
and offered additional insights.