Arousal and sleep represent fundamental physiological domains, and alterations in the form of insomnia (difficulty falling or staying asleep) or hypersomnia (increased propensity for falling asleep or increased sleep duration) are prevalent clinical problems. Current first-line treatments include psychotherapy and pharmacotherapy. Despite significant success, a number of patients do not benefit sufficiently. Progress is limited by an incomplete understanding of the -neurobiology of insomnia and hypersomnia. This work summarizes current concepts of the regulation of arousal and sleep and its modulation through noninvasive brain stimulation (NIBS), including transcranial magnetic, current, and auditory stimulation. Particularly, we suggest: (1) characterization of patients with sleep problems – across diagnostic entities of mental disorders – based on specific alterations of sleep, including alterations of sleep slow waves, sleep spindles, cross-frequency coupling of brain oscillations, local sleep-wake regulation, and REM sleep and (2) targeting these with specific NIBS techniques. While evidence is accumulating that the modulation of specific alterations of sleep through NIBS is feasible, it remains to be tested whether this translates to clinically relevant effects and new treatment developments.

1.
Xie
L
,
Kang
H
,
Xu
Q
,
Chen
MJ
,
Liao
Y
,
Thiyagarajan
M
, et al.
Sleep drives metabolite clearance from the adult brain
.
Science
.
2013
Oct
;
342
(
6156
):
373
7
.
[PubMed]
0036-8075
2.
Cirelli
C
,
Tononi
G
.
Molecular neurobiology of sleep
.
Handb Clin Neurol
.
2011
;
98
:
191
203
.
[PubMed]
0072-9752
3.
Baglioni
C
,
Nanovska
S
,
Regen
W
,
Spiegelhalder
K
,
Feige
B
,
Nissen
C
, et al.
Sleep and mental disorders: A meta-analysis of polysomnographic research
.
Psychol Bull
.
2016
Sep
;
142
(
9
):
969
90
.
[PubMed]
0033-2909
4.
Riemann
D
,
Baglioni
C
,
Bassetti
C
,
Bjorvatn
B
,
Dolenc Groselj
L
,
Ellis
JG
, et al.
European guideline for the diagnosis and treatment of insomnia
.
J Sleep Res
.
2017
Dec
;
26
(
6
):
675
700
.
[PubMed]
0962-1105
5.
Baglioni
C
,
Altena
E
,
Bjorvatn
B
,
Blom
K
,
Bothelius
K
,
Devoto
A
, et al.
The European Academy for Cognitive Behavioural Therapy for Insomnia: an initiative of the European Insomnia Network to promote implementation and dissemination of treatment
.
J Sleep Res
.
2020
Apr
;
29
(
2
):
e12967
.
[PubMed]
0962-1105
6.
Krone
L
,
Frase
L
,
Piosczyk
H
,
Selhausen
P
,
Zittel
S
,
Jahn
F
, et al.
Top-down control of arousal and sleep: fundamentals and clinical implications
.
Sleep Med Rev
.
2017
Feb
;
31
:
17
24
.
[PubMed]
1087-0792
7.
Lüthi
A
.
Sleep Spindles: Where They Come From, What They Do
.
Neuroscientist
.
2014
Jun
;
20
(
3
):
243
56
.
[PubMed]
1073-8584
8.
Di Lazzaro
V
,
Oliviero
A
,
Pilato
F
,
Saturno
E
,
Dileone
M
,
Mazzone
P
, et al.
The physiological basis of transcranial motor cortex stimulation in conscious humans
.
Clin Neurophysiol
.
2004
Feb
;
115
(
2
):
255
66
.
[PubMed]
1388-2457
9.
Massimini
M
,
Ferrarelli
F
,
Esser
SK
,
Riedner
BA
,
Huber
R
,
Murphy
M
, et al.
Triggering sleep slow waves by transcranial magnetic stimulation
.
Proc Natl Acad Sci USA
.
2007
May
;
104
(
20
):
8496
501
.
[PubMed]
0027-8424
10.
Jefferys
JG
.
Nonsynaptic modulation of neuronal activity in the brain: electric currents and extracellular ions
.
Physiol Rev
.
1995
Oct
;
75
(
4
):
689
723
.
[PubMed]
0031-9333
11.
Nitsche
MA
,
Paulus
W
.
Excitability changes induced in the human motor cortex by weak transcranial direct current stimulation
.
J Physiol
.
2000
Sep
;
527
(
Pt 3
):
633
9
.
[PubMed]
0022-3751
12.
Fröhlich
F
,
McCormick
DA
.
Endogenous electric fields may guide neocortical network activity
.
Neuron
.
2010
Jul
;
67
(
1
):
129
43
.
[PubMed]
0896-6273
13.
Keeser
D
,
Meindl
T
,
Bor
J
,
Palm
U
,
Pogarell
O
,
Mulert
C
, et al.
Prefrontal transcranial direct current stimulation changes connectivity of resting-state networks during fMRI
.
J Neurosci
.
2011
Oct
;
31
(
43
):
15284
93
.
[PubMed]
0270-6474
14.
Keeser
D
,
Padberg
F
,
Reisinger
E
,
Pogarell
O
,
Kirsch
V
,
Palm
U
, et al.
Prefrontal direct current stimulation modulates resting EEG and event-related potentials in healthy subjects: a standardized low resolution tomography (sLORETA) study
.
Neuroimage
.
2011
Mar
;
55
(
2
):
644
57
.
[PubMed]
1053-8119
15.
Nitsche
MA
,
Cohen
LG
,
Wassermann
EM
,
Priori
A
,
Lang
N
,
Antal
A
, et al.
Transcranial direct current stimulation: state of the art 2008
.
Brain Stimul
.
2008
Jul
;
1
(
3
):
206
23
.
[PubMed]
1935-861X
16.
Nitsche
MA
,
Paulus
W
.
Transcranial direct current stimulation—update 2011
.
Restor Neurol Neurosci
.
2011
;
29
(
6
):
463
92
.
[PubMed]
0922-6028
17.
Guerra
A
,
Pogosyan
A
,
Nowak
M
,
Tan
H
,
Ferreri
F
,
Di Lazzaro
V
, et al.
Phase Dependency of the Human Primary Motor Cortex and Cholinergic Inhibition Cancelation During Beta tACS.
Cereb Cortex N Y N
1991
. 2016 Oct;26(10):3977–90.
18.
Nakazono
H
,
Ogata
K
,
Kuroda
T
,
Tobimatsu
S
.
Phase and Frequency-Dependent Effects of Transcranial Alternating Current Stimulation on Motor Cortical Excitability
.
PLoS One
.
2016
Sep
;
11
(
9
):
e0162521
.
[PubMed]
1932-6203
19.
Raco
V
,
Bauer
R
,
Tharsan
S
,
Gharabaghi
A
.
Combining TMS and tACS for Closed-Loop Phase-Dependent Modulation of Corticospinal Excitability: A Feasibility Study
.
Front Cell Neurosci
.
2016
May
;
10
:
143
.
[PubMed]
1662-5102
20.
Fehér
KD
,
Nakataki
M
,
Morishima
Y
.
Phase-Dependent Modulation of Signal Transmission in Cortical Networks through tACS-Induced Neural Oscillations
.
Front Hum Neurosci
.
2017
Sep
;
11
:
471
.
[PubMed]
1662-5161
21.
Marshall
L
,
Mölle
M
,
Hallschmid
M
,
Born
J
.
Transcranial direct current stimulation during sleep improves declarative memory
.
J Neurosci
.
2004
Nov
;
24
(
44
):
9985
92
.
[PubMed]
0270-6474
22.
Frase
L
,
Piosczyk
H
,
Zittel
S
,
Jahn
F
,
Selhausen
P
,
Krone
L
, et al.
Modulation of Total Sleep Time by Transcranial Direct Current Stimulation (tDCS)
.
Neuropsychopharmacology
.
2016
Sep
;
41
(
10
):
2577
86
.
[PubMed]
0893-133X
23.
Frase
L
,
Maier
JG
,
Zittel
S
,
Freyer
T
,
Riemann
D
,
Normann
C
, et al.
Bifrontal Anodal Transcranial Direct Current Stimulation (tDCS) Improves Daytime Vigilance and Sleepiness in a Patient With Organic Hypersomnia Following Reanimation
.
Brain Stimul
.
2015
Jul-Aug
;
8
(
4
):
844
6
.
[PubMed]
1935-861X
24.
Frase
L
,
Selhausen
P
,
Krone
L
,
Tsodor
S
,
Jahn
F
,
Feige
B
, et al.
Differential effects of bifrontal tDCS on arousal and sleep duration in insomnia patients and healthy controls.
Brain Stimulat.
2019
Jan DOI:
25.
Lafon
B
,
Henin
S
,
Huang
Y
,
Friedman
D
,
Melloni
L
,
Thesen
T
, et al.
Low frequency transcranial electrical stimulation does not entrain sleep rhythms measured by human intracranial recordings
.
Nat Commun
.
2017
Oct
;
8
(
1
):
1199
.
[PubMed]
2041-1723
26.
Perl
O
,
Arzi
A
,
Sela
L
,
Secundo
L
,
Holtzman
Y
,
Samnon
P
, et al.
Odors enhance slow-wave activity in non-rapid eye movement sleep. J Neurophysiol.
2016
01;115(5):2294–302.
27.
Colrain
IM
.
The K-complex: a 7-decade history
.
Sleep
.
2005
Feb
;
28
(
2
):
255
73
.
[PubMed]
0161-8105
28.
Halász
P
.
K-complex, a reactive EEG graphoelement of NREM sleep: an old chap in a new garment
.
Sleep Med Rev
.
2005
Oct
;
9
(
5
):
391
412
.
[PubMed]
1087-0792
29.
Riedner
BA
,
Hulse
BK
,
Murphy
MJ
,
Ferrarelli
F
,
Tononi
G
.
Temporal dynamics of cortical sources underlying spontaneous and peripherally evoked slow waves
.
Prog Brain Res
.
2011
;
193
:
201
18
.
[PubMed]
0079-6123
30.
Velluti
RA
.
Interactions between sleep and sensory physiology
.
J Sleep Res
.
1997
Jun
;
6
(
2
):
61
77
.
[PubMed]
0962-1105
31.
Fontanini
A
,
Spano
P
,
Bower
JM
.
Ketamine-xylazine-induced slow ([{LT}] 1.5 Hz) oscillations in the rat piriform (olfactory) cortex are functionally correlated with respiration
.
J Neurosci
.
2003
Sep
;
23
(
22
):
7993
8001
.
[PubMed]
0270-6474
32.
Fontanini
A
,
Bower
JM
.
Slow-waves in the olfactory system: an olfactory perspective on cortical rhythms
.
Trends Neurosci
.
2006
Aug
;
29
(
8
):
429
37
.
[PubMed]
0166-2236
33.
Ngo
HV
,
Martinetz
T
,
Born
J
,
Mölle
M
.
Auditory closed-loop stimulation of the sleep slow oscillation enhances memory
.
Neuron
.
2013
May
;
78
(
3
):
545
53
.
[PubMed]
0896-6273
34.
Wong
EH
,
Yocca
F
,
Smith
MA
,
Lee
CM
.
Challenges and opportunities for drug discovery in psychiatric disorders: the drug hunters’ perspective
.
Int J Neuropsychopharmacol
.
2010
Oct
;
13
(
9
):
1269
84
.
[PubMed]
1461-1457
35.
Schutte-Rodin
S
,
Broch
L
,
Buysse
D
,
Dorsey
C
,
Sateia
M
.
Clinical guideline for the evaluation and management of chronic insomnia in adults
.
J Clin Sleep Med
.
2008
Oct
;
4
(
5
):
487
504
.
[PubMed]
1550-9389
36.
Hall-Porter
JM
,
Schweitzer
PK
,
Eisenstein
RD
,
Ahmed
HA
,
Walsh
JK
.
The effect of two benzodiazepine receptor agonist hypnotics on sleep-dependent memory consolidation
.
J Clin Sleep Med
.
2014
Jan
;
10
(
1
):
27
34
.
[PubMed]
1550-9389
37.
Riemann
D
,
Nissen
C.
Sleep and Psychotropic Drugs.
Oxf Handb Sleep Sleep Disord.
2012
Mar DOI:
38.
Riemann
D
,
Nissen
C
,
Palagini
L
,
Otte
A
,
Perlis
ML
,
Spiegelhalder
K
.
The neurobiology, investigation, and treatment of chronic insomnia
.
Lancet Neurol
.
2015
May
;
14
(
5
):
547
58
.
[PubMed]
1474-4422
39.
Riemann
D
,
Spiegelhalder
K
,
Feige
B
,
Voderholzer
U
,
Berger
M
,
Perlis
M
, et al.
The hyperarousal model of insomnia: a review of the concept and its evidence
.
Sleep Med Rev
.
2010
Feb
;
14
(
1
):
19
31
.
[PubMed]
1087-0792
40.
Spiegelhalder
K
,
Regen
W
,
Feige
B
,
Holz
J
,
Piosczyk
H
,
Baglioni
C
, et al.
Increased EEG sigma and beta power during NREM sleep in primary insomnia
.
Biol Psychol
.
2012
Dec
;
91
(
3
):
329
33
.
[PubMed]
0301-0511
41.
Riedner
BA
,
Goldstein
MR
,
Plante
DT
,
Rumble
ME
,
Ferrarelli
F
,
Tononi
G
, et al.
Regional Patterns of Elevated Alpha and High-Frequency Electroencephalographic Activity during Nonrapid Eye Movement Sleep in Chronic Insomnia: A Pilot Study
.
Sleep (Basel)
.
2016
Apr
;
39
(
4
):
801
12
.
[PubMed]
0302-5128
42.
Baglioni
C
,
Regen
W
,
Teghen
A
,
Spiegelhalder
K
,
Feige
B
,
Nissen
C
, et al.
Sleep changes in the disorder of insomnia: a meta-analysis of polysomnographic studies
.
Sleep Med Rev
.
2014
Jun
;
18
(
3
):
195
213
.
[PubMed]
1087-0792
43.
Mander
BA
,
Marks
SM
,
Vogel
JW
,
Rao
V
,
Lu
B
,
Saletin
JM
, et al.
β-amyloid disrupts human NREM slow waves and related hippocampus-dependent memory consolidation
.
Nat Neurosci
.
2015
Jul
;
18
(
7
):
1051
7
.
[PubMed]
1097-6256
44.
Wolf
E
,
Kuhn
M
,
Normann
C
,
Mainberger
F
,
Maier
JG
,
Maywald
S
, et al.
Synaptic plasticity model of therapeutic sleep deprivation in major depression
.
Sleep Med Rev
.
2016
Dec
;
30
:
53
62
.
[PubMed]
1087-0792
45.
Castrén
E
.
Is mood chemistry?
Nat Rev Neurosci
.
2005
Mar
;
6
(
3
):
241
6
.
[PubMed]
1471-003X
46.
Kuhn
M
,
Mainberger
F
,
Feige
B
,
Maier
JG
,
Mall
V
,
Jung
NH
, et al.
State-Dependent Partial Occlusion of Cortical LTP-Like Plasticity in Major Depression
.
Neuropsychopharmacology
.
2016
Oct
;
41
(
11
):
2794
.
[PubMed]
0893-133X
47.
Tononi
G
,
Cirelli
C
.
Sleep and the price of plasticity: from synaptic and cellular homeostasis to memory consolidation and integration
.
Neuron
.
2014
Jan
;
81
(
1
):
12
34
.
[PubMed]
0896-6273
48.
Kuhn
M
,
Wolf
E
,
Maier
JG
,
Mainberger
F
,
Feige
B
,
Schmid
H
, et al.
Sleep recalibrates homeostatic and associative synaptic plasticity in the human cortex
.
Nat Commun
.
2016
Aug
;
7
(
1
):
12455
.
[PubMed]
2041-1723
49.
Landsness
EC
,
Goldstein
MR
,
Peterson
MJ
,
Tononi
G
,
Benca
RM
.
Antidepressant effects of selective slow wave sleep deprivation in major depression: a high-density EEG investigation
.
J Psychiatr Res
.
2011
Aug
;
45
(
8
):
1019
26
.
[PubMed]
0022-3956
50.
Clawson
BC
,
Durkin
J
,
Aton
SJ
.
Form and Function of Sleep Spindles across the Lifespan
.
Neural Plast
.
2016
;
2016
:
6936381
.
[PubMed]
1687-5443
51.
Göder
R
,
Graf
A
,
Ballhausen
F
,
Weinhold
S
,
Baier
PC
,
Junghanns
K
, et al.
Impairment of sleep-related memory consolidation in schizophrenia: relevance of sleep spindles?
Sleep Med
.
2015
May
;
16
(
5
):
564
9
.
[PubMed]
1389-9457
52.
Lustenberger
C
,
Boyle
MR
,
Alagapan
S
,
Mellin
JM
,
Vaughn
BV
,
Fröhlich
F
.
Feedback-Controlled Transcranial Alternating Current Stimulation Reveals a Functional Role of Sleep Spindles in Motor Memory Consolidation.
Curr Biol CB.
2016
22;26(16):2127–36.
53.
Mikutta
C
,
Feige
B
,
Maier
JG
,
Hertenstein
E
,
Holz
J
,
Riemann
D
, et al.
Phase-amplitude coupling of sleep slow oscillatory and spindle activity correlates with overnight memory consolidation
.
J Sleep Res
.
2019
Dec
;
28
(
6
):
e12835
.
[PubMed]
0962-1105
54.
Bergmann
TO
,
Born
J
.
Phase-Amplitude Coupling: A General Mechanism for Memory Processing and Synaptic Plasticity?
Neuron
.
2018
Jan
;
97
(
1
):
10
3
.
[PubMed]
0896-6273
55.
Maier
JG
,
Kuhn
M
,
Mainberger
F
,
Nachtsheim
K
,
Guo
S
,
Bucsenez
U
, et al.
Sleep orchestrates indices of local plasticity and global network stability in the human cortex
.
Sleep (Basel)
.
2018
Dec
;
•••
:
[PubMed]
0302-5128
56.
Riemann
D
,
Spiegelhalder
K
,
Nissen
C
,
Hirscher
V
,
Baglioni
C
,
Feige
B
.
REM sleep instability—a new pathway for insomnia?
Pharmacopsychiatry
.
2012
Jul
;
45
(
5
):
167
76
.
[PubMed]
0176-3679
57.
Feige
B
,
Al-Shajlawi
A
,
Nissen
C
,
Voderholzer
U
,
Hornyak
M
,
Spiegelhalder
K
, et al.
Does REM sleep contribute to subjective wake time in primary insomnia? A comparison of polysomnographic and subjective sleep in 100 patients
.
J Sleep Res
.
2008
Jun
;
17
(
2
):
180
90
.
[PubMed]
0962-1105
58.
Feige
B
,
Nanovska
S
,
Baglioni
C
,
Bier
B
,
Cabrera
L
,
Diemers
S
, et al.
Insomnia-perchance a dream? Results from a NREM/REM sleep awakening study in good sleepers and patients with insomnia
.
Sleep (Basel)
.
2018
May
;
41
(
5
):
[PubMed]
0302-5128
59.
Wassing
R
,
Benjamins
JS
,
Dekker
K
,
Moens
S
,
Spiegelhalder
K
,
Feige
B
, et al.
Slow dissolving of emotional distress contributes to hyperarousal
.
Proc Natl Acad Sci USA
.
2016
Mar
;
113
(
9
):
2538
43
.
[PubMed]
0027-8424
60.
McNamara
P
,
Auerbach
S
,
Johnson
P
,
Harris
E
,
Doros
G
.
Impact of REM sleep on distortions of self-concept, mood and memory in depressed/anxious participants
.
J Affect Disord
.
2010
May
;
122
(
3
):
198
207
.
[PubMed]
0165-0327
61.
Voss
U
,
Holzmann
R
,
Hobson
A
,
Paulus
W
,
Koppehele-Gossel
J
,
Klimke
A
, et al.
Induction of self awareness in dreams through frontal low current stimulation of gamma activity
.
Nat Neurosci
.
2014
Jun
;
17
(
6
):
810
2
.
[PubMed]
1097-6256
62.
Vyazovskiy
VV
,
Olcese
U
,
Hanlon
EC
,
Nir
Y
,
Cirelli
C
,
Tononi
G
.
Local sleep in awake rats
.
Nature
.
2011
Apr
;
472
(
7344
):
443
7
.
[PubMed]
0028-0836
63.
Nobili
L
,
De Gennaro
L
,
Proserpio
P
,
Moroni
F
,
Sarasso
S
,
Pigorini
A
, et al.
Local aspects of sleep: observations from intracerebral recordings in humans
.
Prog Brain Res
.
2012
;
199
:
219
32
.
[PubMed]
0079-6123
64.
James
SN
,
Cheung
CH
,
Rommel
AS
,
McLoughlin
G
,
Brandeis
D
,
Banaschewski
T
, et al.
Peripheral Hypoarousal but Not Preparation-Vigilance Impairment Endures in ADHD Remission
.
J Atten Disord
.
2017
Mar
;(
Mar
):
1087054717698813
.
[PubMed]
1087-0547
65.
Miano
S
,
Amato
N
,
Foderaro
G
,
Pezzoli
V
,
Ramelli
GP
,
Toffolet
L
, et al.
Sleep phenotypes in attention deficit hyperactivity disorder
.
Sleep Med
.
2019
Aug
;
60
:
123
31
.
[PubMed]
1389-9457
66.
Soehner
AM
,
Kaplan
KA
,
Harvey
AG
.
Prevalence and clinical correlates of co-occurring insomnia and hypersomnia symptoms in depression
.
J Affect Disord
.
2014
;
167
:
93
7
.
[PubMed]
0165-0327
67.
Brain disorders? Precisely | Science [Internet]. [cited 2019 Mar 18]. Available from: http://science.sciencemag.org/content/348/6234/499
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