CIM

eISSN 2635-9162 / https://chronobiologyinmedicine.org

Chronobiol Med 2022;4(4):141-151 / https://doi.org/10.33069/cim.2022.0030

REVIEW ARTICLE

Application of Transcranial Direct Current

Stimulation in Sleep Disturbances
Young-Ji Lee1, Bong-Jo Kim2,3, Cheol-Soon Lee1,2, Boseok Cha2,3, So-Jin Lee2,3,
Jae-Won Choi3, Eunji Lim1, Nuree Kang3, and Dongyun Lee1,2
1
Department of Psychiatry, Gyeongsang National University Changwon Hospital, Changwon, Korea
2
Department of Psychiatry, Gyeongsang National University College of Medicine, Jinju, Korea
3
Department of Psychiatry, Gyeongsang National University Hospital, Jinju, Korea

Sleep disturbances are common across all age groups, and they encompass a broad range of impairments of daytime functioning and comor-
bid various clinical conditions. However, current treatment methods for sleep disturbances have several limitations. As the ‘top-down’ path-
way is known to play an important role in sleep-wake regulation, and as neuronal activity abnormalities have been reported as a potential
pathological mechanism of sleep disturbances, the use of non-invasive brain stimulation—such as transcranial direct current stimulation (tDCS)
in treating sleep disturbances—has emerged. In the present review, we first explain the mechanism of tDCS, and we also introduce recent
studies that have applied tDCS to sleep disorders, along with other sleep-related tDCS studies. In conclusion, many studies have achieved
improvements in sleep state, although some of these studies have reported inconsistent effects of tDCS according to the protocol and the
conditions used. Further studies are needed to explore the optimal protocols to use when applying tDCS in each sleep disturbance and to
enhance the evidence on the clinical efficacy of tDCS.
Keywords: Transcranial direct current stimulation; Sleep disorders; Sleep quality; Sleep

Received: November 29, 2022 Revised: December 12, 2022 Accepted: December 13, 2022
Corresponding author: Dongyun Lee, MD, PhD, Department of Psychiatry, Gyeongsang National University College of Medicine, Gyeongsang National University
Changwon Hospital, 11 Samjeongja-ro, Seongsan-gu, Changwon 51472, Korea.
Tel: 82-55-214-3801, E-mail: [email protected]
cc This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-

nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

INTRODUCTION is substantially higher (30%–35%) [6,7]. In the US, the total direct
and indirect costs associated with insomnia have been estimated
Sleep is known to be a key factor for adaptation to the environ- to be as high as 100 billion dollars per year [8]. Moreover, insom-
ment and survival [1]. Acute sleep deprivation and chronic sleep nia exacerbates and increases the risk of not only many neuropsy-
restriction impair alertness, vigilant attention, learning, memory chiatric disorders such as depression and dementia [9-12] but also
retention, mood, and motivation [2]. Sleep disorders also nega- various medical disorders, including cardiovascular [13,14], en-
tively affect some brain pathologies, and sleep disturbances are docrine [15,16], and immunological diseases [17,18]. Sleep dis-
commonly comorbid with many medical and neurological prob- turbance has also recently been shown to be a risk factor for sui-
lems, including neurodegenerative disorders [3]. According to cide [19-21]. Therefore, the importance of its treatment has been
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edi- increasingly highlighted. In general, pharmacological treatment
tion (DSM-5), sleep disorders encompass various types of distur- and cognitive behavioral therapy (CBT) are used for the treat-
bances related to the patient’s dissatisfaction regarding the quali- ment of insomnia in general. However, medications for insomnia
ty, timing, and amount of sleep, and they lead to daytime distress may have side effects, including drowsiness, dizziness, and im-
and impairment [4]. Sleep disturbances are common across all paired cognitive function, so the use of medication for insomnia
age groups [5]. Insomnia is the most common sleep disorder, and may require special attention [22-24]. CBT requires skilled spe-
the prevalence of chronic insomnia is approximately 10%; how- cialists and periodic hospital visits, so it is not easy to use in daily
ever, the one-year incidence rate of simple insomnia symptoms medical environments [25,26]. In addition, even with those ther-

Copyright © 2022 Korean Academy of Sleep Medicine 141

142 / CIM tDCS in Sleep Disturbances

apies, insomnia persists in approximately 30% of patients [27]. rons in the cortex under the electrode and depolarizes the apical
Therefore, it might be meaningful to find an alternative treatment dendrite, thus inhibiting the resting potential from moving away
for sleep. from the action potential, and thereby reducing the neuronal ac-
Recently, non-invasive brain stimulation methods have come tivity in the stimulation region [34,35,39,40].
to largely be used as alternative or adjunctive treatment for many In addition, studies have shown that the effects of tDCS seem
neurological and neuropsychiatric disorders [27]. Among them, to last beyond the acute alteration of the membrane potential and
transcranial direct current stimulation (tDCS) is emerging in a may last more than several hours depending on the stimulation
broad range of research fields, as it is able to non-invasively and parameters [35,39-43]. Several studies have shown that the an-
rapidly modulate brain functions such as memory, and as it has ode electrode stimulation of tDCS activates NMDA receptors
been applied as a potential treatment for various neuropsychiat- and decreases neurotransmission by the inhibitory neurotrans-
ric disorders over the past few decades. tDCS is the technique that mitter gamma-aminobutyric acid (GABA) [35,40]. This process
changes neuronal membrane potential by flowing subthreshold is considered to be related to the long-term potentiation of neu-
direct current (1–2 mA) to the brain through an electrode at- roplasticity in which the effect of tDCS is long-lasting [44]. It has
tached to the scalp [28,29]. Anode stimulation induces depolar- also been reported that cathode electrode stimulation inhibits
ization of neurons to promote neuronal activity, and cathode neuronal activity by interfering with the action of glutamate.
stimulation induces hyperpolarization of neurons to suppress Moreover, tDCS may affect the regulation of the acetylcholine,
neuronal activity [30,31]. As neuronal activity abnormalities have serotonin, and dopamine systems [35,40].
been reported as a major pathological mechanism of sleep disor- In addition to the above, the effect of tDCS has also been re-
ders [32], there has been an increase in studies therapeutically ported by brain model simulation [45]. Brain model simulation
using tDCS for sleep disorders. Therefore, we review studies that uses a finite element method that enables the modelling of com-
have applied tDCS to sleep disorders, and we also examine other plex brain structure and tissue characteristics that are similar to
sleep-related tDCS studies. those of a real brain, and it confirms the effect of the electricity ap-
plied to the scalp on the cerebral cortex [46]. Since the white mat-
MECHANISM OF TRANSCRANIAL ter acts as a wire through which signals are transmitted between
DIRECT CURRENT STIMULATION neurons, it becomes a path through which current flows when
tDCS is applied. According to the results of studies with diffu-
tDCS is one of the transcranial electrical stimulation techniques sion tensor imaging and brain model simulation, the anisotropy
that involves the application of weak direct current that is less of white matter substantially affects the diffusion and stimulation
than the current used when delivering electroconvulsive therapy effect of direct current stimulation, so it is presumed that tDCS
or repetitive transcranial magnetic stimulation to the scalp through activates the interaction between neurons through white matter,
two or more electrodes [33,34]. In general, the device used for thereby having a stimulating effect on the brain [39,47].
tDCS consists of a current generator and two electrodes, an an-
ode and a cathode [35,36]. The anode is the electrode through APPLICATION OF TRANSCRANIAL
which current enters the body, and the cathode is the electrode DIRECT CURRENT STIMULATION
through which current exits the body. IN SLEEP DISTURBANCES
The current generated by tDCS is weak, and because of the re-
sistance of living tissues such as the scalp and skull, only about The ‘bottom-up’ pathway has continually been shown to be im-
10%–20% of the current flowing to the scalp reaches the cerebral portant in sleep-wake cycle regulation. The ascending reticular
cortex and changes the activity of cranial nerves [37]. It is known activation system originates in the brain stem and aminergic, cho-
than this transmitted current does not induce an action potential linergic, and GABAergic neurotransmission project via thalamo-
in the neuron, but it instead regulates the resting membrane po- cortical neurons into the cortex [48-51]. Pharmacologic treatment
tential of the neuron and is thus in an alteration of the neuron’s of sleep disturbances primarily targets this ‘bottom-up’ pathway;
excitability, thereby changing the spontaneous discharge rate of however, it is associated with limitations in terms of adverse ef-
the neuron and N-methyl-D-aspartic acid (NMDA) receptor ac- fects and treatment efficiency [52]. Recently, an approach target-
tivation [38,39]. ing the ‘top-down’ pathway of sleep-wake regulation with non-in-
The anode is the electrode through which current enters the vasive brain stimulation has been emerging. The cortico-thalamo-
body, and the cathode is the electrode through which current ex- cortical feedback loop plays an important role in regulating arousal
its the body. Stimulation of the anode electrode hyperpolarizes and sleep [49,53]. Cortical neurons and synchronized slow activ-
the apical dendrite of pyramidal neurons of the cerebral cortex at ity underlying the occurrence of consolidated sleep serve as the
the stimulation site, and it depolarizes soma, which changes the primary oscillators of the cortico-thalamo-cortical feedback loop
resting potential of the cerebral cortex close to the action poten- [50,54,55]. Regional synchronization of neural activity [56] and
tial, thus increasing neuronal activity. Conversely, stimulation of reduced metabolism in the prefrontal cortex [57] are the charac-
the cathode electrode hyperpolarizes the soma of pyramidal neu- teristics of sleep. The frontal cortex has been identified as being
 Young-Ji Lee, et al CIM / 143

important for sleep induction and maintenance [58]. Increased sleep time (TST) and sleep efficiency were significantly decreased
electroencephalogram (EEG) beta activity during non-rapid eye after the anodal stimulation, in comparison to the sham stimula-
movement (NREM) sleep reflecting elevated metabolism in the tion, and there was no significant change observed after cathodal
prefrontal cortex is a marker of arousal and the subjective percep- stimulation. However, because of the ceiling effect in good sleep-
tion of poor sleep [57,59]. er, a potential effect of cathodal stimulation might have been missed.
Still, after 3 years, the same researchers conducted a study on pa-
Transcranial direct current stimulation and slow wave tients with insomnia using the same protocol, and they did not
activity observe any changes in objective or subjective sleep [72]. It is pre-
During NREM sleep, the neuronal membrane potential exhib- sumed that healthy adults without insomnia could respond to ex-
its broadly synchronized slow subthreshold oscillations in the citatory stimulation, as cortical activity is not so high, while pa-
cerebral cortex, and the oscillations are revealed as consisting of tients with insomnia already had sufficient cortical hyperactivity
slow-wave activity (SWA) in EEG [60]. SWA (0.5–4.0 Hz) is con- not to respond to anodal tDCS [31,51]. Therefore, the develop-
sidered to be a marker of restorative function and related to ben- ment of applicable tDCS protocols according to cortical activity
eficial functions of sleep, such as learning, cognitive performance levels will need to be considered in future studies. Zhou et al. [73]
enhancement, and mood stabilization [61,62]. Since SWA is ini- conducted a randomized, double-blinded controlled study on
tiated in the cerebral cortex [63], it can be induced in a top-down adults with insomnia and major depressive disorder. tDCS treat-
manner by stimulating the cortical regions of the sleep regulation ment was applied with the anode placed left dorsolateral prefron-
system. Therefore, an increasing number of studies has investigat- tal cortex (L-DLPFC) and the cathode placed right dorsolateral
ed the effects of electric current inducing potential oscillation on prefrontal cortex (R-DLPFC) at an intensity of 2 mA for 20 ses-
the activity of cortical networks and sleep. It was also hypothe- sions. Compared to the sham tDCS group, the active tDCS group
sized that a weak current could similarly make or promote the ac- showed improved sleep in the form of decreased Pittsburgh Sleep
tivity of the sleep spindle and slow oscillation, as well as sleep-de- Quality Inventory (PSQI) total scores, along with increased TST,
pendent memory consolidation [1,51,64,65]. Slow oscillatory sleep efficiency, and rapid eye movement (REM) latency. Com-
tDCS (so-tDCS) studies have been conducted based on this hy- pared to the results of these studies, it may be necessary in future
pothesis. However, some recent studies have indicated that so- studies to explore if more sessions using a similar protocol could
tDCS does not improve memory consolidation despite increasing induce more effective results.
SWA and spindle activity [66-69]; however, any definite conclu- Harvey et al. [74] conducted a randomized, parallel, double-
sions could be controversial and there is therefore a need for fur- blind, sham-controlled study on elderly individuals suffering from
ther refinement [70,71]. Saebipour et al. [65] conducted a study chronic pain and insomnia. Either the anodal tDCS over prima-
of the application of so-tDCS (0.75 Hz) with an intensity ranging ry motor cortex (M1) (C3 or C4) at an intensity of 2 mA or sham
from 0 to 260 μA during stage 2 of NREM sleep in six patients tDCS for 5 consecutive days was applied. There was no observed
with either sleep maintenance or non-restorative sleep insomnia difference between the active tDCS group and the sham group in
with the goal of resonating their brain waves to the frequency of terms of objective or subjective sleep. Jun et al. [75] performed a
sleep slow-wave. Anodes were placed on F3 and F4, and cathodes randomized, double-blind, sham-controlled study on seven pa-
were placed on the mastoids. As a result, so-tDCS significantly tients with primary chronic insomnia. Subjects were treated with
increased stage 3 NREM and significantly decreased stage 1 anodal stimulation (n=3), cathodal stimulation (n=2), or sham
NREM and wake time after sleep onset (Table 1). Although so- tDCS (n=2) over R-DLPFC (F8) target electrode and left acromi-
tDCS showed a beneficial effect on sleep, there are some difficul- on reference electrode at an intensity 2 mA. The respective ses-
ties involved in applying tDCS during sleep, so studies have also sions were conducted daily between 5 Pm and 7 Pm for five con-
been conducted to examine the effect of daytime tDCS on sleep secutive sessions. Although there is a limitation in the ability to
disturbances. evaluate the effect with a small number of patients, the anodal
simulation group showed a tendency toward increased TST, de-
Application of transcranial direct current stimulation creased sleep latency, and increased sleep efficiency, and the cath-
in insomnia odal and sham groups showed no difference. Sleep questionnaires
Patients with insomnia have been shown to exhibit increased did not find any improvement in subjective sleep. Charest et al.
cortical excitability; therefore, the modulation of cortical excit- [76] performed a randomized, single-blinded study on healthy
ability is an interesting approach to managing insomnia [31,32]. young adults (student-athletes) with insomnia. Bi-frontal cath-
Frase et al. [50] conducted separate single sessions of sham stim- odal stimulation was executed at an intensity of 2 mA for two ses-
ulation, anodal stimulation, and cathodal stimulation over the sions. In this study, the results only showed subjective sleep im-
bi-frontal (FP1/FP2) target electrodes and the bi-parietal (P3/P4) provement on the questionnaires (PSQI), Epworth Sleepiness
return electrodes at the intensity of 2 mA on healthy adults with- Scale (ESS), Insomnia Severity Index (ISI), and the Athlete Sleep
out sleep disturbance. Moreover, PSG and resting EEG were mea- Screening Questionnaire (ASSQ); however, there was no objec-
sured after each stimulation session. As a result of this study, total tive improvement on polysomnography (PSG) (Table 1). More-
144 / CIM tDCS in Sleep Disturbances

Table 1. Transcranial direct current stimulation findings from studies on sleep

Age, years Brain stimulation
Study Subjects Sleep-related findings
mean (SD) Sites Parameters
Insomnia
Saebipour 6 34 (7) Anodes on bilateral Anodal so-tDCS Increase stage 3 NREM,
et al. [65] DLPFC 0–260 μA sleep efficiency
Cathodes on the 1 session Decrease stage 1 NREM, WASO
mastoid No other changes in subjective
sleep quality
Frase 19 43.8 (15.1) Anodes on bi-frontal 2 mA No improvement in objective
et al. [72] cortex (FP1/FP2) 3 sessions (separate or subjective sleep
Cathodes on bi-parietal single sessions of sham,
cortex (P3/P4) anodal and cathodal
stimulation)
Zhou 47 active 43.9 (11.2) Anode on L-DLPFC 2 mA In active group:
et al. [73] 43 sham 40.5 (8.3) Cathode on R-DLPFC 20 sessions Improvement in subjective sleep
Increase TST, sleep efficiency,
REM latency
Harvey 6 active 72 (6) Anodes on M1 Anodal tDCS No difference in objective or
et al. [74] 8 sham 71 (8) (C3 or C4) 2 mA subjective sleep between the
Cathodes on bi-supra 5 sessions active tDCS group and the sham
orbital area group
Charest 15 active 22.1 (1.8) Anodes on frontal cortex Cathodal tDCS Subjective sleep improvement
et al. [76] 15 sham 20.1 (2.0) Cathodes on 2 mA (on PSQI, ESS, ISI, ASSQ)
bi-frontal pole 2 sessions No changes in objective sleep
on PSG
Hypersomnia
Galbiati 8 35.0 (15.5) Anode on L-DLPFC Anodal tDCS Improvements in subjective
et al. [106] Cathode on contralateral 2 mA daytime sleepiness, sleep quality,
orbit 12 sessions and attention
RLS
Koo 11 anode 44.1 (13.4) Active on vertex Anodal & cathodal Between active and sham group:
et al. [107] 11 cathode 47.3 (11.0) (M1 specific the leg area) tDCS No subjective difference in PSQI,
11 sham 46.0 (10.1) Reference on suboccipital 2 mA IRLSSGRS
cortex 5 sessions No objective difference in EEG,
event-related spectral
perturbation
Sleep quality
Sheng Elderly 67.6 (4.7) One anode on L-DLPFC HD-tDCS Longer sleep duration,
et al. [78] 16 active 65.8 (5.2) 4 cathodes, the peripheral 1.5 mA Decrease functional connectivity
15 sham area of L-DLPFC 10 sessions between DMN and subcortical
networks in HD-tDCS group
Goerigk MDD 44.6 (11.8) Anode on L-DLPFC 2 mA Decrease insomnia-related score
et al. [83] 94 tDCS 41.8 (12.5) Cathode on R-DLPFC 22 sessions on HAMD in tDCS group
91 escitalopram 40.9 (12.9)
60 placebo
Li et al. [84] MDD 44.79 (15.25) Anode on F3 2 mA No difference in sleep structure
19 active 43.61 (11.89) Cathode on F4 10 sessions Improve early awakening scores
18 sham in HDRS-24, and decrease iMSE
for the REM stage in active group
Minichino Euthymic patients 41.9 (12.62) Anode on L-DLPFC Anodal and Improve PSQI scores
et al. [89] with bipolar Cathode on R-cerebellar cathodal tDCS
disorder cortex 1 mA
25 20 sessions
D’Urso Children with ASD 11 (1.15) Anode on L-DLPFC Anodal and Improvement of sleep
et al. [90] 7 Cathode on R-cerebellar cathodal tDCS disturbances (self-rated
cortex 1 mA observation sheets by caregivers)
20 sessions prior to improvement of other
symptoms from the first week
and this improvement was
maintained over three-month
follow-up
 Young-Ji Lee, et al CIM / 145

Table 1. Transcranial direct current stimulation findings from studies on sleep (continued)
Age, years Brain stimulation
Study Subjects Sleep-related findings
mean (SD) Sites Parameters
Qiu et al. [91] Children with ASD Aged 24–79 Anode on L-DLPFC (F3) 1 mA As a secondary outcome,
22 active months Cathode on R-shoulder 15 sessions improved sleep condition
21 sham (CSHQ)
Forogh 12 active 61.33 (N/A) Anode on L-DLPFC Anodal with Only fatigue reduction at any
et al. [92] 11 sham 64.81 (N/A) Cathode on R-DLPFC occupational therapy time point, however no
0.06 mA significant change in daytime
8 sessions sleepiness
Hadoush Parkinson’s disease 62 (N/A) 2 anodes between and Bilateral anodal tDCS Decrease total PSQI score,
et al. [93] 21 over L- and R-M1 and 1 mA and sleep latency sub-score
DLPFC (FC1, FC2) 10 sessions Correlation (+) between
2 cathodes on decreases in PSQI score and
bi-supraorbital areas GDS score, as well as an increase
(FP1, FP2) in health-related quality of life
questionnaire score
Hadoush Parkinson’s disease 63.0 (9.5) 2 anodes between and Bilateral anodal tDCS Effects on melatonin serum level,
et al. [94] 25 61.0 (9.3) over L- and R- M1 and 1 mA sleep quality, and depression and
6 female DLPFC (FC1, FC2) 10 sessions associations (+) between these
19 male 2 cathodes on changes
bi-supraorbital areas
(FP1, FP2)
Dobbs Parkinson’s disease 66.9 (5.4) Anode on L-DLPFC Anodal home based No improvement in sleep
et al. [95] 15 Cathode on tDCS + cognitive components
R-supraorbital region training
2 mA
10 sessions
Samartin-Veiga Fibromyalgia 49.38 (8.83) 4 groups (anode on Anodal tDCS Improvement of sleep quality,
et al. [96] All female 50.55 (8.89) L-M1, DLPFC, OIC, 2 mA continued 6 months later,
34 M1 50.21 (8.20) and sham) 15 sessions however, no difference among
33 DLPFC 50.67 (8.88) the 4 groups
33 OIC
30 sham
Caumo Fibromyalgia Aged 30-65 Anode on L-DLPFC Home-based bifrontal Improvement in sleep quality
et al. [97] 32 active Cathode on R-DLPFC tDCS in tDCS group
16 sham 2 mA
20 sessions
Quality
Brietzke Fibromyalgia 48.6 (N/A) Anode on L-DLPFC Anodal tDCS Improvements in pain scores
et al. [98] 10 active 49.7 (N/A) 2 mA and sleep quality
10 sham 60 sessions
Roizenblatt Fibromyalgia 54.8 (9.3) Anode on either M1 Anodal tDCS Decrease arousals improve sleep
et al. [99] 11 active M1 54.2 (7.4) or L-DLPFC 2 mA architecture, sleep efficiency
11 active L-DLPFC 50.8 (10.2) Cathode o supraorbital 15 sessions (only in M1 group)
10 sham region Worsen sleep efficiency and sleep
parameters (sleep latency and
REM latency) in L-DLPFC
group
Pinto Sjogren’s syndrome 55.8 (8.5) Anode on R-DLPFC (F4) 2 mA Small but significant difference
et al. [100] 18 active 53.1 (10.3) Cathode on L-DLPFC (F3) 5 sessions in sleep by PSQI in tDCS group
18 sham (secondary outcome)
Chalah Multiple sclerosis 43.14 (10.01) Anode on L-DLPFC (F3) Bifrontal tDCS Subjective improvement of
et al. [101] crossover Cathode on R-DLPFC (F4) 2 mA daytime sleepiness (ESS)
7 5 sessions No objective improvement
of sleep (actigraphy)
Kim Painful diabetic 59.60 (13.15) Anode on M1 (C3) Anodal tDCS Reduced pain and increased
et al. [102] polyneuropathy 63.50 (8.75) Anode on L-DLPFC (F3) 2 mA the pressure pain threshold
20 active M1 61.60 (10.27) Cathode on contralateral 5 sessions in M1 group
20 active DLPFC supraorbital area However, no difference in sleep
20 sham among the three groups
De Icco Chronic migraine 48.3 (9.6) Anodes on M1 (C3 or C4) Anodal tDCS Adjuvant effects to detoxication
et al. [103] and medication 50.1 (9.6) Cathode on contralateral 2 mA however, no differences in sleep
Overuse headache 46.4 (9.7) supraorbital region 5 sessions between study groups
10 active
10 sham
146 / CIM tDCS in Sleep Disturbances

Table 1. Transcranial direct current stimulation findings from studies on sleep (continued)
Age, years Brain stimulation
Study Subjects Sleep-related findings
mean (SD) Sites Parameters
Acler Post-polio 61.4 (5.9) 2 anodes on bi-premotor Anodal tDCS Improved PSQI score in active
et al. [104] syndrome cortex (C3, C4) 1.5 mA group
16 active 1 cathode on L-shoulder 15 sessions
16 sham
Ahn Elderly with knee 61.20 (7.23) Anode on M1 Anodal home-based Improvement of clinical pain
et al. [105] osteoarthritis Cathode on supraorbital tDCS severity and sleep disturbances
20 area 2 mA (PROMIS sleep disturbances)
10 sessions
DLPFC, dorsolateral prefrontal cortex; tDCS, transcranial direct current stimulation; NREM, non-rapid eye movement; WASO, wake after sleep
oncet; L-, left; R-, right; TST, total sleep time; REM, rapid eye movement; M1, primary motor cortex; PSQI, Pittsburgh Sleep Quality Index; ESS,
Epworth Sleepiness Scale; ISI, Insomnia Severity Index; ASSQ, Athlete Sleep Screening Questionnaire; RLS, restless leg syndrome; PSG, polysom-
nography; IRLSSGRS, the International Restless Legs Syndrome Study Group Rating Scale; EEG, electroencephalogram; HD, high definition;
DMN, default mode network; MDD, major depressive disorder; HAMD, Hamilton Depression Rating Scale; HDRS-24, 24-item Hamilton De-
pression Rating Scale; iMSE, intrinsic multi-scale entropy; ASD, autism spectrum disorder; CSHQ, Children’s Sleep Habits Questionnaire; GDS,
Geriatric Depression Scale; OIC, operculo-insular cortex; PROMIS, Patient-Reported Outcomes Measurement System

over, Etoom et al. [77] plans to conduct a large, prospective, dou- the DMN-subcortical network is positively related to sleep chang-
ble-blinded randomized controlled trial to assess the effect of a es in older adults. Moreover, most studies examining patients
bilateral anodal tDCS protocol in sleep management among ath- with other accompanying conditions used a similar stimulation
letes with sleep disturbances. That study plans to recruit partici- site and similar protocols of tDCS on insomnia patients to con-
pants from May 2022 to December 2023. Two anodes will be firm the improvement of sleep quality; however, they also used
placed over R- and L-DLPFC (F4 and F3) and two cathodes (ref- slightly different protocols for the characteristics of each disease.
erence electrodes) will be placed over the left and right supraor- There have also been a number of studies that have derived sleep
bital areas (FP1 and FP2), and tDCS will be applied with an in- quality as a secondary outcome despite not using it as a primary
tensity of 1.5 mA six times over two weeks. outcome.

Application of transcranial direct current stimulation Psychiatric disoreders

on sleep quality acompanying other clinical conditions Goerigk et al. [83] randomized patients with major depressive
There are various forms of evidence estimating that sleep dis- disorder into an escitalopram group, a tDCS group, and a place-
turbances accompanying other clinical conditions may be asso- bo group. In that study, tDCS was applied by placing the anode
ciated with disturbances of cortical and subcortical pathways on L-DLPFC and by placing the cathode on R-DLPFC at 2 mA
[49,51]. There have been various studies involving patients with for 22 sessions. As a result, the escitalopram group showed no sig-
various psychiatric, neurological, or medical diseases, or the el- nificant difference in the score of insomnia-related questions on
derly, despite not targeting insomnia patients. Sheng et al. [78] the Hamilton Depression Rating Scale (HAM-D), while the tDCS
applied the high-definition tDCS (HD-tDCS), using many spe- group showed a significant decrease in that score compared to the
cialized compact scalp electrodes to supply current for more spa- corresponding score of the placebo group. In another study, Li et
tially selective stimulation in healthy older adults without any al. [84] aimed to determine the effects of daytime tDCS on sleep
neurological and psychiatric disorders. This HD-tDCS protocol EEG in patients with major depressive disorder. Ten sessions were
consisted of one anode on L-DLPFC (F3) and four cathodes on conducted over 2 weeks with anodal stimulation over F3 and cath-
the peripheral area of L-DLPFC at an intensity of 1.5 mA inten- odal stimulation over F4 at 2 mA intensity. PSG was used to record
sity, and it was conducted over 10 sessions. Participants were as- sleep EEG signals, and the sleep EEG signals were analyzed using
sessed through resting-state functional magnetic resonance im- the intrinsic multi-scale entropy (iMSE) method. There was no
aging (resting state fMRI) and several sleep questionnaires such difference in sleep structure; however, the active tDCS group showed
as PSQI. As a result, sleep duration was found to be longer and some significant differences such as improved early awakening
functional connectivity between the default mode network (DMN) scores in the Hamilton Depression Rating Scale (HDRS-24) and
and subcortical networks was found to be decreased in the HD- significantly decreased iMSE after tDCS active stimulation for the
tDCS group. The results of recent studies showed that relatively REM stage. REM sleep disturbances are considered to be charac-
lower connectivity within DMN is associated with better sleep teristic sign of depression. It is known that REM sleep latency de-
quality [79,80] and that the subcortical network also mediates creases and that the proportion of REM increases in depressed
promoting sleep by reducing the inhibitory modulation of the patients [85,86], and that high complexity of sleep EEG is related
arousal system and regulating sleep depth [81,82]. Therefore, the with poor sleep quality. Entropy indicates the complexity of the
results of this study suggest that the decoupling connectivity of EEG signals [87,88] (Table 1).
 Young-Ji Lee, et al CIM / 147

Minichino et al. [89] aimed to improve the sleep quality of eu- [94] investigated any potential changes in melatonin serum level,
thymic patients with bipolar disorder by tDCS with the anode sleep functions, and depression in patients with Parkinson’s dis-
placed over L-DLPFC (Fp1) and the cathode placed over the right ease. This study used two bilateral anodes over the left FC1 and
cerebellar cortex at an intensity of 2 mA for 15 daily sessions for right FC2 and two cathodes over the FP1 and FP2, and it applied
3 weeks. PSQI scores after tDCS treatment were significantly im- between 8:30–10:30 Am at the current intensity 1 mA for 10 ses-
proved compared to baseline. As both the prefrontal cortex and sions, like the former study. As the results of this study, bilateral
the cerebellum are known to play a role in regulating sleep pro- anodal tDCS showed potential therapeutic effects on melatonin
cesses, the stimulation protocol of this study could be presumed serum level, sleep quality, and depression in patients with Parkin-
to modulate prefrontal-thalamic-cerebellar circuits while improv- son’s disease, as well as associations between these changes [94].
ing sleep quality (Table 1). Dobbs et al. [95] performed a study with a remotely supervised
D’Urso et al. [90] conducted a tDCS study that considered chil- tDCS protocol paired with cognitive training for patients with
dren with autism spectrum disorder. Similar to the studies by Parkinson’s disease. This protocol consisted of anode over the L-
Minichino et al. [89], the cathode was placed on the right cere- DLPFC and cathode over the right supraorbital region at the in-
bellar hemisphere (corresponding to the cerebellar lobule VII on tensity of 2 mA for 10 sessions; however, there was no improve-
the scalp) and the anode was placed on L-DLPFC (F3). All par- ment in sleep components (Table 1).
ticipants underwent 20 daily consecutive sessions of 1.0 mA. Ac-
cording to the self-rated observation sheets completed by care- Fibromyalgia
givers, improvement of sleep disturbances was observed prior to Samartin-Veiga et al. [96] aimed to establish the optimal area of
improvement of other symptoms from the first week of tDCS, tDCS by randomly assigning female patients with fibromyalgia
and this improvement was maintained over 3-month follow-up. to four groups (left M1, DLPFC, operculo-insular cortex, and
Qiu et al. [91] investigated the modulation effect of 15 sessions sham). Patients in each group received 15 sessions of 2 mA anod-
delivered over 3 weeks of tDCS with the anode placed at L-DLP- al tDCS. Although an improvement of sleep quality was shown
FC (F3), and the cathode placed at the right shoulder at 1 mA in- and continued 6 months later, there was no difference among the
tensity in children with autism spectrum disorder. As a secondary four groups. Caumo et al. [97] performed randomized, double-
outcome, sleep condition, as measured by Children’s Sleep Hab- blind trials on female patients with fibromyalgia. The tDCS group
its Questionnaire, was found to be significantly improved com- was treated with 20-sessions of home-based tDCS with the an-
pared to the sham group (Table 1). ode placed at L-DLPFC, at an intensity of 2 mA. The tDCS group
showed an improvement in sleep quality. Brietzke et al. [98] also
Parkinson’s disease conducted a tDCS study involving patients in fibromyalgia. An-
In Parkinson’s disease, both L- and R-DLPFC, supplementary odal stimulation was applied by the anode placed over L-DLPFC
motor area, premotor area, and M1 are all involved in sleep func- at an intensity of 2 mA for 60 sessions. There were significant im-
tions [92,93]. Forogh et al. [92] performed a randomized, double- provements in pain scores and sleep quality. Roizenblatt et al. [99]
blind, sham-controlled parallel study considering patients with investigated whether tDCS treatment is associated with changes
Parkinson’s disease. In the tDCS group, the anode was placed over in sleep structure in fibromyalgia. Patients were randomized into
L-DLPFC (F3) and the cathode was placed over R-DLPFC (F4) the sham group and groups with tDCS over M1 (M1 group) and
with a current intensity of 0.06 mA/cm2 for eight sessions in 2 tDCS over L-DLPFC (DLPFC group). For the M1 group, the an-
weeks, and all subjects engaged in occupational therapy just after ode was placed on M1 (C3) and the cathode was placed on the
each session. Two questionnaires about fatigue and daytime sleepi- contralateral supraorbital area, and for the DLPFC group, the an-
ness were checked just before/after treatment and with a 3-month ode was placed on L-DLPFC (F3) and the cathode was placed on
follow-up. This study only showed a significant effect on fatigue the contralateral supraorbital area. This study protocol consisted
reduction at any time point, however no significant change in day- of 15 sessions conducted at an intensity of 2 mA. Sleep efficiency
time sleepiness. In 2018, Hadoush et al. [93] also conducted a and sleep parameters such as sleep latency and REM latency wors-
study involving patients with Parkinson’s disease. tDCS had two ened after L-DLPFC stimulation. Conversely, only M1 stimula-
anodes set over the left FC1 and right FC2, which are between tion significantly reduced arousal and significantly improved
and over the left and right M1 and DLPFC to stimulate these both sleep architecture, sleep efficiency, and pain (Table 1).
areas, and two cathodes over the left and right supraorbital areas
(FP1, FP2), respectively. Moreover, it was applied between 9 Am– The other conditions
12 Pm at an intensity of 1 mA for 10 sessions. In the case of this Pinto et al. [100] conducted a study about applying tDCS to
study, total PSQI score, and sleep latency domain sub-scores were treat fatigue in patients with Sjogren’s syndrome. The settings of
all decreased significantly. It was also reported that there was a tDCS consisted of five consecutive sessions with the anode placed
correlation between decreases in PSQI score and Geriatric De- over R-DLPFC (F4) and the cathode placed over L-DLPFC (F3)
pression Scale score, as well as an increase in health-related quality at an intensity of 2 mA. Among the secondary outcomes, sleep
of life questionnaire score. In 2021, researchers including Hadoush showed a small but significant difference in the tDCS group by
148 / CIM tDCS in Sleep Disturbances

PSQI (Table 1). creased cortical excitability [31]; therefore, Galbiati et al. [106]
Chalah et al. [101] conducted a pilot randomized sham-con- applied anodal tDCS over L-DLPFC and cathodal electrode over
trolled crossover study involving patients with multiple sclerosis. the contralateral orbit for a total of 12 sessions over 4 weeks to
The subjects were treated by tDCS at an intensity of 2 mA over patients with idiopathic hypersomnia. They found improvements
five daily sessions with the anode placed over L-DLPFC (F3) and in subjective daytime sleepiness, sleep quality, and attention (de-
the cathode placed over R-DLPFC (F4). This study resulted in a creased reaction times with Attentional Network Task) (Table 1).
subjective improvement of daytime sleepiness according to the
ESS, but there was no objective improvement of sleep measures Application of transcranial direct current stimulation
checked by actigraphy (Table 1). in restless leg syndrome
Kim et al. [102] investigated the effect of tDCS in patients with In patients with restless leg syndrome (RLS), EEG spectral
painful diabetic polyneuropathy. All participants were divided analysis of waking-resting conditions revealed increased high
into three groups: the M1, DLPFC, and sham groups. Similar to beta band power. This result might reflect a hyperexcitable sen-
the protocol of a former study [99], for the M1 group, the anode sorimotor cortex and an impairment of intracortical inhibitory
was placed on M1 (C3) and the cathode was placed on the con- pathways, which represent the pathophysiology of RLS [31,32].
tralateral supraorbital area, and for the DLPFC group, the anode Koo et al. [107] conducted a double-blind, randomized, sham-
was placed on L-DLPFC (F3) and the cathode was placed on the controlled, three-arm proof-of-concept clinical trial involving RLS
contralateral supraorbital area. tDCS protocol consisted of five patients. The subjects had the primary motor cortex (particularly
sessions at an intensity of 2 mA. As a result, tDCS over the M1 re- the leg areas) stimulated at an intensity of 2 mA for a total of five
duced pain and increased the pressure pain threshold significant- daily sessions with the active electrode placed on the vertex (Cz)
ly, versus the DLPFC and the sham group. However, there was no and the reference electrode placed over the suboccipital region.
significant change in sleep quality as assessed by TST and number Stimulation was administered between 5 Pm–7 Pm. As a result,
of awakenings among the three groups (Table 1). there was no difference in the scores of PSQI and the Internation-
De Icco et al. [103] aimed to evaluate the effects of five daily al Restless Legs Syndrome Study Group Rating Scale, or in the ob-
sessions of anodal tDCS over M1 (C3 or C4) contralateral to the jective neurophysiological evidence of cortical excitability (elec-
prevalent migraine pain side at 2 mA intensity, by considering pa- troencephalography data; event-related spectral perturbation)
tients with chronic pain and medication overuse headache. In the (Table 1).
results, tDCS showed adjuvant effects to detoxication in the man-
agement of patient with chronic migraine and medication over- CONCLUSIONS
use headache; however, there were no significant differences in
sleep condition between study groups (Table 1). To this point, to investigate the applicability of tDCS for sleep
Acler et al. [104] conducted a study considering patients with disturbances, the results of studies examining the mechanism of
post-polio syndrome. In this study, tDCS was set with two anodes tDCS and the effects of tDCS on sleep disturbances have been re-
on the right and left premotor cortex and one cathode above the viewed. There is accumulating initial evidence that tDCS can be
left shoulder at an intensity of 1.5 mA for 15 sessions. After tDCS effective in improving various sleep disturbances and sleep qual-
was applied, the PSQI score was improved significantly compared ity as well as neurophysiological evidence for the action of tDCS.
to the sham group (Table 1). In addition, tDCS has the advantages of being portable, simple to
Ahn et al. [105] conducted a home-based self-administered operate, and relatively safe, in terms of mechanical characteristics,
tDCS study in older adults with knee osteoarthritis. Anodal home- and it may be applied to patients with a wide range of neurologi-
based stimulation was applied by the anode over M1 and cathode cal, medical, and psychiatric conditions in which sleep is deterio-
over supraorbital area at a 2 mA intensity for 10 sessions. Upon rated, to improve other comorbid symptoms as well as sleep prob-
completion of the tDCS sessions, clinical pain severity and sleep lems. However, despite these evidences and advantages, caution
disturbances were improved (Table 1). should be taken when interpreting these studies results. There
As such, in studies with chronic pain and movement disorder have only been a few studies performed according to each disease
such as Parkinson’s disease and fibromyalgia, M1 and DLPFC and condition; heterogeneous tDCS protocols were applied to
were often targeted. Although there were some exceptions, such each study, several studies were conducted with a small number
as no difference between each target group [96] or only improve- of subjects, and some of the studies were conducted using un-
ment in symptoms other than sleep [103], related studies with sin- controlled, quasi-experimental methods. In the future, it will be
gle or co-targeting M1 and applied more sessions of tDCS than necessary to find the optimal tDCS protocols and parameters for
ten, reported sleep improvements in general (Table 1). each sleep disorder, and there will be a need for large-scale, well-
controlled studies to demonstrate repeated and consistent results
Application of transcranial direct current stimulation on each sleep disorder and each protocol.
in hypersomnia
The pathophysiology of hypersomnia is associated with de-
 Young-Ji Lee, et al CIM / 149

Funding Statement 8. Taddei-Allen P. Economic burden and managed care considerations for
the treatment of insomnia. Am J Manag Care 2020;26(4 Suppl):S91-S96.
None
9. Khurshid KA. Comorbid insomnia and psychiatric disorders: an update.
Innov Clin Neurosci 2018;15:28-32.
Conflicts of Interest 10. Bombois S, Derambure P, Pasquier F, Monaca C. Sleep disorders in aging
The authors have no potential conflicts of interest to disclose and dementia. J Nutr Health Aging 2010;14:212-217.
11. Chen PL, Lee WJ, Sun WZ, Oyang YJ, Fuh JL. Risk of dementia in patients
with insomnia and long-term use of hypnotics: a population-based retro-
Availability of Data and Material spective cohort study. PLoS One 2012;7:e49113.
Data sharing not applicable to this article as no datasets were 12. de Almondes KM, Costa MV, Malloy-Diniz LF, Diniz BS. Insomnia and
risk of dementia in older adults: systematic review and meta-analysis. J
generated or analyzed during the study. Psychiatr Res 2016;77:109-115.
13. Javaheri S, Redline S. Insomnia and risk of cardiovascular disease. Chest
Author Contributions 2017;152:435-444.
14. Hsu CY, Chen YT, Chen MH, Huang CC, Chiang CH, Huang PH, et al.
Conceptualization: Young-Ji Lee. Data curation: Young-Ji Lee. The association between insomnia and increased future cardiovascular
Methodology: Dongyun Lee. Investigation: Young-Ji Lee. Soft- events: a nationwide population-based study. Psychosom Med 2015;77:
ware: Young-Ji Lee. Validation: Cheol-Soon Lee. Writing—origi- 743-751.
15. Morgan D, Tsai SC. Sleep and the endocrine system. Crit Care Clin 2015;31:
nal draft: Young-Ji Lee. Writing—review & editing: Bong-Jo Kim,
403-418.
Cheol-Soon Lee, Boseok Cha, So-Jin Lee, Jae-Won Choi, Eunji 16. Morris CJ, Aeschbach D, Scheer FA. Circadian system, sleep and endocri-
Lim, Nuree Kang, Dongyun Lee. nology. Mol Cell Endocrinol 2012;349:91-104.
17. Imeri L, Opp MR. How (and why) the immune system makes us sleep.
Nat Rev Neurosci 2009;10:199-210.
ORCID iDs 18. Bryant PA, Trinder J, Curtis N. Sick and tired: does sleep have a vital role
Young-Ji Lee in the immune system? Nat Rev Immunol 2004;4:457-467.
https://orcid.org/0000-0003-0201-2518 19. Bishop TM, Walsh PG, Ashrafioun L, Lavigne JE, Pigeon WR. Sleep, sui-
cide behaviors, and the protective role of sleep medicine. Sleep Med 2020;
Bong-Jo Kim 66:264-270.
https://orcid.org/0000-0003-2419-7306 20. McCall WV, Blocker JN, D’Agostino R Jr, Kimball J, Boggs N, Lasater B, et
Cheol-Soon Lee al. Insomnia severity is an indicator of suicidal ideation during a depres-
sion clinical trial. Sleep Med 2010;11:822-827.
https://orcid.org/0000-0003-1479-6962
21. Franzen PL, Buysse DJ. Sleep disturbances and depression: risk relation-
Boseok Cha ships for subsequent depression and therapeutic implications. Dialogues
https://orcid.org/0000-0002-3309-8863 Clin Neurosci 2008;10:473-481.
22. Gray SL, LaCroix AZ, Hanlon JT, Penninx BW, Blough DK, Leveille SG, et
So-Jin Lee
al. Benzodiazepine use and physical disability in community-dwelling old-
https://orcid.org/0000-0003-2904-9206 er adults. J Am Geriatr Soc 2006;54:224-230.
Jae-Won Choi 23. Chang CM, Wu EC, Chen CY, Wu KY, Liang HY, Chau YL, et al. Psycho-
https://orcid.org/0000-0002-4516-1954 tropic drugs and risk of motor vehicle accidents: a population-based case-
control study. Br J Clin Pharmacol 2013;75:1125-1133.
Eunji Lim 24. Wilt TJ, MacDonald R, Brasure M, Olson CM, Carlyle M, Fuchs E, et al.
https://orcid.org/0000-0003-3967-8524 Pharmacologic treatment of insomnia disorder: an evidence report for a
Nuree Kang clinical practice guideline by the American College of Physicians. Ann In-
tern Med 2016;165:103-112.
https://orcid.org/0000-0001-7630-4033 25. Morin CM. Cognitive-behavioral approaches to the treatment of insom-
Dongyun Lee nia. J Clin Psychiatry 2004;65 Suppl 16:33-40.
https://orcid.org/0000-0002-3977-3663 26. Koffel E, Bramoweth AD, Ulmer CS. Increasing access to and utilization
of cognitive behavioral therapy for insomnia (CBT-I): a narrative review. J
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