Slow oscillations and insomnia
J Sleep Res. (2015) 24, 518–525
Slow oscillating transcranial direct current stimulation during sleep has a sleep-stabilizing effect in chronic insomnia: a pilot study MOHAMMAD R. SAEBIPOUR1, MOHAMMAD T. JOGHATAEI1,2, ALI YOONESSI3,4, KHOSRO SADEGHNIIAT-HAGHIGHI5, N I M A K H A L I G H I N E J A D 6 and S O R O U S H K H A D E M I 7 1 School of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran; 2Cellular and Molecular Medical Research Center, Iran University of Medical Sciences, Tehran, Iran; 3School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran; 4National Brain Mapping Centre, Tehran, Iran; 5Occupational Sleep Research Center, Tehran University of Medical Sciences, Tehran, Iran; 6Institute of Cognitive Neuroscience, University College London, London, UK; and 7School of Physics, Sharif University of Technology, Tehran, Iran
Keywords brain wave entrainment, sleep stabilization, brain stimulation, slow-wave sleep enhancement Correspondence Mohammad T. Joghataei Professor of Neurosciences, Iran University of Medical Sciences, Hemmat Highway Tehran, Iran. Tel.: +98 21 88622615; fax: +98 21 88622689; e-mail: [email protected] Accepted in revised form 15 March 2015; received 1 August 2014 DOI: 10.1111/jsr.12301
SUMMARY
Recent evidence suggests that lack of slow-wave activity may play a fundamental role in the pathogenesis of insomnia. Pharmacological approaches and brain stimulation techniques have recently offered solutions for increasing slow-wave activity during sleep. We used slow (0.75 Hz) oscillatory transcranial direct current stimulation during stage 2 of non-rapid eye movement sleeping insomnia patients for resonating their brain waves to the frequency of sleep slow-wave. Six patients diagnosed with either sleep maintenance or non-restorative sleep insomnia entered the study. After 1 night of adaptation and 1 night of baseline polysomnography, patients randomly received sham or real stimulation on the third and fourth night of the experiment. Our preliminary results show that after termination of stimulations (sham or real), slow oscillatory transcranial direct current stimulation increased the duration of stage 3 of non-rapid eye movement sleep by 33 26 min (P = 0.026), and decreased stage 1 of non-rapid eye movement sleep duration by 22 17.7 min (P = 0.028), compared with sham. Slow oscillatory transcranial direct current stimulation decreased stage 1 of non-rapid eye movement sleep and wake time after sleep-onset durations, together, by 55.4 51 min (P = 0.045). Slow oscillatory transcranial direct current stimulation also increased sleep efficiency by 9 7% (P = 0.026), and probability of transition from stage 2 to stage 3 of non-rapid eye movement sleep by 20 17.8% (P = 0.04). Meanwhile, slow oscillatory transcranial direct current stimulation decreased transitions from stage 2 of non-rapid eye movement sleep to wake by 12 6.7% (P = 0.007). Our preliminary results suggest a sleep-stabilizing role for the intervention, which may mimic the effect of sleep slowwave-enhancing drugs.
INTRODUCTION Primary insomnia (PI) is defined as a non-restorative sleep accompanied by problems in initiating or maintaining of sleep, in the absence of clinically significant medical, neurological or psychiatric disorder. Having PI for more than 3 months is referred to as chronic insomnia, a
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persistent condition that in the long-term decreases the quality of life, and increases the risk of morbidity and mortality due to physical and mental illnesses (Dew et al., 2003). Global and growing epidemics of insufficient sleep, insulin resistance and obesity are suggested to be mechanistically correlated (Lucassen et al., 2012). It is estimated that in the ª 2015 European Sleep Research Society
Effect of slow oscillating tDCS in chronic insomnia USA about 10% of the population have chronic insomnia, which imposes annually a burden of $13.9 billion (Walsh, 2004). Planning and goal-directed performance heavily relies on vigilance or sustained attention, which are impaired after insufficient sleep (Van Dongen et al., 2003), and impaired daytime functioning composes the majority of insomnia global burden (Daley et al., 2009). During sleep, the brain activity slows down and produces an electroencephalography (EEG) feature comprising of the activity in the 0.5- to 4-Hz frequency band, namely slow-wave activity (SWA). SWA seems to have a basic role in the restorative function of sleep and is correlated with subsequent daytime functioning. Experimental disruption of SWA will lead to lightness and fragmentation of sleep, to increased daytime sleep propensity, and to impairment of daytime functioning (Dijk, 2009). Current available sleep aids, which are used to improve sleep initiation or treat insufficient sleep quantity, did not succeed in improving daytime functioning, probably as a result of suppressing SWA (Rosenberg, 2006; Zisapel, 2007). Benzodiazepines are a good example in this regard (Dijk, 2010). There is also no consensus surrounding the effect of Z drugs, such as zaleplon or zolpidem that act on benzodiazepine-specific subunit sites, on promoting sleep without decreasing the amount of deep sleep (Arbon et al., 2010; Lundahl et al., 2012) or maintaining next day performance (Otmani et al., 2008). Some observations imply that in PI, sensory gating and stimulus-related increase of K-complexes are not complete (Hairston et al., 2010). K-complexes are thought to be forerunners of SWA (De Gennaro et al., 2000). The spontaneous K-complexes are more likely to occur prior to transition from stage 2 of sleep to SWA compared with transition to rapid eye movement (REM) sleep (Nicholas et al., 2006), indicating their sleep-deepening effect. Rhythmic K-complexes group ‘sleep spindles’, which are suggested as another oscillation-based sensory gating mechanism in the sleep (Amzica and Steriade, 2002; Dang-Vu et al., 2010; Wimmer et al., 2012). Therefore, sleep maintenance insomnia can be considered as an inability to produce or maintain slow brain oscillations. Comparing with good sleepers, sleep EEG analysis of patients with PI shows elevated power of higher frequencies such as 13–40 Hz (Hairston et al., 2010; Krystal et al., 2002; Perlis et al., 2001). Interestingly, SWA-enhancing drugs reduce wake time after sleep-onset (WASO), which is dose-dependent (Dijk et al., 2012; Walsh et al., 2006b). They also can improve sustained attention the following day (Walsh et al., 2006a). Though the therapeutic value of these drugs is still not sufficient to consider them as a practical solution for insomnia, they have highlighted the value of SWA and approaches for enhancing SWA (Walsh, 2009). Normally, slow oscillations, such as spontaneous K-complexes, originate intracortically (Timofeev et al., 2012) and propagate throughout the entire cortex. It has been shown that rhythmic transcranial magnetic stimulation at 0.8 Hz, rhythmic acoustic stimulation (0.8 Hz) and sleeping in a 0.25ª 2015 European Sleep Research Society
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Hz rocking bed can all deepen sleep by increasing SWA (Bayer et al., 2011; Massimini et al., 2007; Ngo et al., 2013). Being in SWA stage is concurrent with approximately 20% lesser chance of shifting to wakefulness or stage 1 compared with being in stage 2 or REM sleep (Walsh, 2009). Specifically, it has been shown that lower frequencies such as 0.75Hz oscillation, might play a partial role in sleep maintenance and development of sleep (Ferri et al., 2005). Activity of neurons and neuronal networks can be resonated to an externally induced oscillatory electrical field (Womelsdorf et al., 2007). Transcranial direct current stimulation (tDCS) is a simple and non-invasive method for focally stimulating or inhibiting cortical regions of the human brain. Marshall et al. (2006a) showed that brain wave entrainment with deep sleep frequency (0.75 Hz) during stage 2 of nonREM (NREM) sleep (N2) by slow oscillating tDCS (sotDCS) can facilitate endogenous slow oscillations and simultaneously enhance spindle counts and EEG power within the slow spindle frequency range (Marshall et al., 2006a). It was recently shown that this method has a durable effect and reduces the decay of SWA for the rest of the night (Reato et al., 2013). Givin the existing evidence that sotDCS can increase SWA in normal individuals, and that this change in EEG pattern can influence relevant functional brain networks, we hypothesized that 0.75-Hz sotDCS may be helpful for insomniacs who suffer from lack of SWA. Specifically, we were looking for lasting effect of this intervention in the short term. MATERIALS AND METHODS Patients Patients were recruited by referral and advertisement. Patients with the chief complaint of fragmented or nonrestorative sleep were visited by an expert psychiatrist for diagnosis of chronic PI. Six patients with PI (four males, two females) completed the study (flow chart of patients is shown in Supplementary Information S1). Patients with sleep-interfering neurological or psychiatric disorder, unstable medical disorder, addiction, pregnancy, implanted pacemaker, history of head injury or skull fracture, and history or family history of epilepsy were excluded from the study. We also excluded patients who had sleep-onset insomnia, because electrical stimulation must be applied during establishment of NREM sleep. Patients were asked to avoid caffeine intake, nap or using hypnotics the day before the experiment. Polysomonography (PSG) Polysomnography was performed using a Sandman Elite (Embla, Kanata, Ontario, Canada) device. EEG of C3-A2, O1-A2, O2-A1 and C4-A1, plus electrooculogram and electromyogram of chin were used for offline sleep staging. Sleep
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scoring was based on the American Academy of Sleep Medicine Sleep Scoring Manual, 2007. A cordless robotic arm was used to disconnect the PSG device from the patient box during stimulation periods (Supplementary Information S2). The device automatically disconnected stimulation electrodes when connecting the PSG cable through the release of two push-button switches equipped in the robotic arm. Conversely, after each 5 min of stimulation, the robotic arm simultaneously disconnected stimulation and restored PSG recording for 1 min (Fig. 1). This exact procedure was also performed during the sham pseudostimulation to ensure that the patients are blind to the stimulation protocol. After scoring of sleep stages by a sleep specialist, the period between termination of stimulations and morning awakening was selected for within-group comparison. SPSS statistics version 22 IBM, USA was used for statistical analyses. Data were exported to MATLAB R2010a (The MathWorks, Natick, MA, USA) to calculate sleep state transition probabilities. To determine the probability of sleep stage transitions, a custom MATLAB function was written to read the ‘.txt’ file produced by Sandman Embla Polysomnography System. This function detects different steps and events, counts the number of each one of them and counts the number of transitions between steps. Slow oscillatory transcranial direct current stimulation Slow oscillatory transcranial direct current stimulation (sotDCS) was performed with a two-channel battery-based independent and isolated synchronized stimulator (Hidranco., Tehran, Iran; for detailed specifications of the device, see Supplementary Information S3), which could be controlled remotely via its wireless management system. The stimulations were conducted based on a related published protocol (Marshall et al., 2006b). Anodes were placed on F3 and F4, and cathodes on the mastoids using a clip connector with 8mm-diameter disposable pre-gelled adhesive Ag/AgCl electrodes. Two separate battery-driven circuits stimulated each hemisphere of the brain synchronously. The stimulating current had a trapezoid shape in which the current reaches 260 lA from 0 in 0.33 s, maintaining at 260 lA for 0.33 s, returning to 0 in 0.33 s, and after 0.33 s at 0 current the cycle
Sham or real stimulation period
Sleep onset
repeats (Marshall et al., 2006b). Therefore, the duration of each cycle was 1.33 s, and we had a regular pattern of 0.75 Hz stimulation (Fig. 2). The maximal voltage of stimulation was 10 V, and electrode resistance between the ipsilateral stimulation sites was between 5 and 15 kOhm. Stimulation started after establishment of stage 2 or deeper NREM sleep for at least 8 epochs by online scoring of PSG. Then, after every 5 min of stimulation, the stimulation stopped and PSG monitoring continued for 1 min to ensure continuity of sleep (we had five episodes of stimulation, hence the total duration of stimulation was about 25 min). Procedure The study protocol was approved by the ethical committee of Iran University of Medical Sciences (Approval number: 4324/ 12-10- 1389 – ﻡ ﺕ/)ﺍ. The procedure was explained to the participants, and after obtaining written informed consent they were enrolled in the study. The experiment had a randomized crossover repeated measures design, and was performed over four non-consecutive nights in Baharloo Hospital Sleep Research Center, which is affiliated with Tehran University of Medical Sciences. The first night was for adaptation. A baseline PSG was performed on the second night. On the third night, patients randomly received either sotDCS or sham stimulation, while both patients and the sleep scorer were blinded to the intervention. On the fourth night, the patients who received sotDCS on the third night were exposed to sham stimulation and the other half received sotDCS. The fourth night of the experiment was at least 1 week after the third night. In each session, PSG started at 23:30 hours ( 30 min), based on their preferred sleeping time from the interview, and ended after subjects woke up in the morning. The criterion for awakening of patients was 08:00 hours. After electrode removal, subjects filled out a sleep quality questionnaire. Data analysis Sleep-onset latency and sleep efficiency were obtained from whole-night PSG data. We then set the ‘lights off’ at the exact time of termination of stimulations (sham or real), and
Selected period for PSG data comparison about lasting effect of sham or real otDCS
A 1 min block of stimulation free for PSG recording (ensuring about continuity of sleep)
Lights off A 5 min block of stimulation (sham or real)
Lights on
Figure 1. Schematic diagram of study procedure. Data from the period between the end of stimulation and participant’s awakening were selected for comparing the effects of stimulation. ª 2015 European Sleep Research Society
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Figure 2. Pattern of slow oscillatory transcranial direct current stimulation. The stimulating current was oscillating between 0 and 260 lA, three times in every 4 s, compromising a 0.75-Hz stimulation pattern.
resulting PSG data were used for comparison between groups. We initially determined all sleep stage transitions and durations. We used paired-sample t-test (two-sided) for comparing means in sleep stage durations and means of probabilities of transition between sleep stages in both groups. We also performed EEG spectral analysis using MATLAB 2014b and EEGLAB v 13.4.4b. PSG data were converted to EDF format and imported to the EEGLAB; the sampling rate was 256 Hz. EEG data were filtered between 0.1 and 30 Hz, and artefact removal was performed by observing. The first 1min stimulation-free intervals in both sham and real stimulations groups were specifically investigated for assessing the effect of sotDCS on subjects’ EEG spectral power. In EEGLAB, the frequency of spectrum plotting was limited to 0.1–30 Hz. EEGLAB parametric statistics with a statistical threshold of 0.05 and Bonferroni correction were chosen for computing the first independent variable statistics. RESULTS The patient’s mean age was 34 7 years. One of the patients had severe insomnia with an Insomnia Severity Index (ISI) of 24, and other patients had moderate clinical insomnia (ISI = 19 3). According to ISI interpretation guidelines, ISI scores of 15–21 are categorized as moderate, and from 22 to 28 as severe clinical insomnia. No change on the mood level of patients was revealed by analysing the Beck depression inventory questionnaire before and after the intervention. Sleep-onset latency did not differ between sham and stimulation (P = 0.45, t5 = 0.818). The total sleep period also did not change significantly (P = 0.279, t5 = 1.213). Sleep recording after termination of stimulation (sham or real) showed that patients had on average 33 26 min longer duration of N3 (P = 0.026, t5 = 3.138) and 22 17.7 min shorter N1 (P = 0.028, t5 = 3.07) after receiving sotDCS compared with sham. sotDCS decreased N1 and WASO durations together by 55.4 51 min (P = 0.045, t5 = 2.644; Fig. 3). sotDCS increased sleep efficiency (total sleep duration divided by the time spent in bed) by 9 7% (P = 0.026, t5 = 3.13). Additional analysis revealed that in the first hour after termination of the stimulation, duration of N3 on average increased by 19 11.5 min (P = 0.01, t5 = 4.056) compared with the sham group. This increase, for the first 90 min after termination of stimulation, was about 26.3 20 min (P = 0.023, t5 = 3.237). ª 2015 European Sleep Research Society
Figure 3. Effect of slow oscillatory transcranial direct current stimulation (sotDCS) on durations of sleep stages. The sleep period after termination of sham or real stimulation was used to make comparison between groups (*P ≤ 0.05).
Slow oscillatory transcranial direct current stimulation increased the probability of transition from N2 to N3 by 20 17.8% (P = 0.04, t5 = 2.753), while it decreased the probability of transition from N2 to wakefulness by 12 6.7% compared with sham (P = 0.007, t5 = 4.347; Fig. 4; Table 1).
Figure 4. Transition probability change schematic diagram. Slow oscillatory transcranial direct current stimulation (sotDCS) decreased the probability of transition from N2 to wakefulness, and increased the probability of transition from N2 to N3 compared with sham (*P ≤ 0.05, **P ≤ 0.01).
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Table 1 Changes in means of sleep stage transition normalized probabilities induced by sotDCS
Stage transition
Mean probability on sham night (%)
Mean probability on stimulation night (%)
N3?N2 N3?N1 N3?W N2?N3 N2?N1 N2?R N2?W N1?N3 N1?N2 N1?R N1?W R?N2 R?N1 R?W W?N2 W?N1 W?R
78.56 2.81 1.96 32.55 26.57 11.09 29.79 0.69 61.65 14.64 23.02 5.42 35.73 58.85 6.1 92.12 1.79
96.23 0 3.77 52.63 18.52 11.04 17.81 2.02 55.7 21.27 21.01 18.33 24.17 57.5 3.62 93.61 2.78
Mean probability change (%) 17.7 2.8 1.8 20.1 8.1 0.05 12 1.3 6 6.6 2 12.9 11.6 1.4 2.5 1.5 0.99
40.9 5.1 8.9 17.9* 10.3 11.9 6.7** 4.1 26.6 20.4 11.1 16.2 13.5 21.3 7.6 11.2 8.1
The probability of transition from N2 to wakefulness decreased, and from N2 to N3 increased significantly by 0.75 Hz sotDCS (*P ≤ 0.05, **P ≤ 0.01).
Spectral analysis of the first 1-min EEG recording interval revealed that 5 min of real stimulation increased average power at frequencies below 1 Hz relative to the same interval in the sham group (P ≤ 0.05; Fig. 5). Figure 6 shows the pattern of EEG (C4-A1) after termination of sotDCS and robotic reconnection of PSG cable in one
subject. This pattern is suggestive of brain wave modulation by sotDCS. Subjective rating of restorative sleep and next day functioning was assessed using a Likert sleep scale in which ‘very bad’, ‘bad’, ‘fair’, ‘good’ or ‘very good’ were scored as 1–5, respectively. A non-significant improvement was observed for both items. One patient reported a mild transient headache the day after the stimulation. Subject 1 with ISI 24 noticed that, unlike other nights with numerous awakenings, he had a more stable sleep in the stimulation night. He described the effect of sotDCS on his sleep to be as powerful as 0.5 mg of clonazepam, without its morning dizziness. He reported his daily functioning as: After several months I felt energetic and I could concentrate, so I performed many of my fallen into arrears jobs, called my friends and planned for future activities. Subject number 3 reported that, despite the little sleep he had in the stimulation night, he woke up early in the morning refreshed, performed his routine daily duties and, regardless of being used to an afternoon nap, he did not have a tendency to nap during that day. Meanwhile, he specifically reported that his blue mood status did not elevate. Other subjects did not describe any prominent improvement in sleep quality and daily functioning. DISCUSSION Electroencephalographic spectral power analysis of the first 1-min window after stimulation shows that sleeping brain rhythm in patients with insomnia can be modulated by
Figure 5. Mean electroencephalographic (EEG) spectral power change. After 5 min of slow oscillatory transcranial direct current stimulation (sotDCS), the mean EEG spectral power below 1 Hz significantly increased in the real stimulation group in comparison with the sham group. The shaded area indicates the region in the spectrum with a significant mean difference, with a P-value of less than 0.05.
Figure 6. Brain wave after termination of stimulation. The recorded pattern of electroencephalographic oscillations from one subject just after termination of stimulation and robotic reconnection of polysomonography cable (C4-A1). ª 2015 European Sleep Research Society
Effect of slow oscillating tDCS in chronic insomnia sotDCS. Decreased duration of light sleep and WASO in the sotDCS group is similar to features observed after hypnotic use. A decrease in the probability of transition from N2 to wake state beside an increase in transition from N2 to N3 also indicates a sleep-stabilizing effect. According to the protocol used in our study, the duration of stimulation was limited to 25 min in the first hour of sleep. Interestingly, the increased duration of N3, and decreased duration of WASO and lighter sleep periods occurred in the stimulation-free sleep. In a recent study, it was shown that 20 min transcranial alternating current stimulation (tACS) with individualized alpha frequency can leave a sustained after-effect on EEG endogenous power for at least 30 min (Neuling et al., 2013). A form of brain plasticity, which is called spike timingdependent plasticity (STDP), has been proposed for the observed after-effects of tACS. Neural circuits have specific resonance frequencies. When the frequency of an externally induced driving force is matched with a neural circuit resonance frequency, STDP can strengthen synapses in these circuits (Zaehle et al., 2010). Researchers showed that 25 min of 0.75-Hz transcranial electrical stimulation during stage 2 of NREM sleep reduces the decay of SWA in the remainder of the night, implicating a homeostatic effect on later sleep (Reato et al., 2013). This study also has offered an explanation for a unidirectional increase in firing rate by showing that sotDCS increases the firing rate of cortical neurons during UP-states without decreasing the firing rate during DOWN-states (Reato et al., 2013). This may have some implications for those brain regions that are active during SWA, such as parahippocampal gyrus, cerebellum and brainstem, in which the brain activity significantly increases, and is consistently synchronized to the slow oscillations (Dang-Vu et al., 2008; Kaufmann et al., 2006). Stronger activity in those active regions in the first hours of sleep may have a positive effect on establishment of a deeper sleep. Moreover, there is evidence implicating that activation of cortical nitric oxide (NO)-producing neurons or ‘sleep active cells’ might have some roles in SWA production through an NO-dependent mechanism. Activation of these neurons is directly related to NREM sleep time, NREM bout duration and SWA power during NREM sleep (Morairty et al., 2013). NO can affect neuronal activity through modulation of gap junction permeability. Sleep active cells have long-range projections within the cortex, and NO is especially a largescale modulator of brain activity (Gerashchenko et al., 2011). Taken together, we speculate that our sotDCS may increase NO production via unidirectional increase in activity (firing rate) of sleep active cells in the cortex. Considering that it takes quite a while before NO completely dissolves, it may play a role in the lasting effect of our stimulation. Finally, some researchers believe that SWA has a chaotic behaviour during sleep, and sleep regulation might be considered as a deterministic non-linear process (Ferri et al., ª 2015 European Sleep Research Society
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1996). Dynamic systems are highly sensitive to initial conditions (Banerjee, 2006), therefore, our intervention at the first states of sleep may impose some considerable influences on large-scale chaotic behaviour of SWA. CONCLUSION This pilot study demonstrated that increasing the SWA by 0.75 Hz sotDCS in patients with insomnia has a sleepdeepening effect. However, its effect on the subjective rating of sleep quality and next day functioning was not conclusive. Simultaneous use of other stimulation methods to increase SWA may improve these findings. Fortunately, rhythmic acoustic stimulation does not need to be time limited and can be used the whole night. Because of the complex and diverse pathophysiology behind different subtypes of insomnia, the existing insomnia categorization should be expanded based on factors such as insomnia severity, age, sex, electrophysiological characteristics such as spindle count, coexisting subclinical conditions, and degree of responsiveness to brainwave entrainment interventions. This modification will provide a better interpretation of non-pharmacological approaches and would be helpful for finding patients who may benefit more from sotDCS during NREM sleep. In addition, a long-term multisession intervention is needed to elucidate if this method can resolve the persistent nature of chronic insomnia, which may be derived from long-term maladaptive brain plasticity processes. Sleeping in a place different from one’s own bed by itself can affect the quality of sleep. Having wires on the head and being monitored may also produce an uncomfortable feeling that may prevent normal sleep. Sleep laboratory admission is also very costly, and in the long term it will not be feasible for the patients to come to sleep labs to have a night of deeper sleep. Therefore, what could be a possible practical utility of such a complicated method of sleep deepening that is far more difficult than taking a pill? Home-based PSG tele-monitoring systems and lightweight head-mounted smart EEG devices may facilitate applicability of non-pharmacological approaches for management of persistent insomnia. However, developing a comprehensive user-friendly set-up needs interdisciplinary research and long-term clinical trials. This approach may have utility in other disorders as well. For example, in chronic fatigue syndrome, despite no considerable change in conventional PSG measures of sleep, EEG analysis has revealed that NREM sleep stages are associated with 20% lower power of 0.5–0.8 Hz EEG band (Le Bon et al., 2012). Hence, it will be important to find the effects of 0.75 Hz sotDCS in this syndrome. In many psychiatric disorders, such as bipolar disorders, a main feature in sleep architecture is lack of SWA. Sleep manipulation and SWA enhancement in specialized sleep centres may open a new horizon for translational research in the control and treatment of psychiatric disorders with sleep disturbances.
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ACKNOWLEDGEMENTS The authors thank Prof. Hamid Mostafavi Abdolmaleki, Dr Frahad Fatehi and Dr Elnaz Rouhi for their comments on the manuscript; Prof. Reza Nilipour and Dr Mirfarhad Ghalebandi for their useful advice in the study design; Dr Mashiyyat Mohammadzadeh and Dr Hossein Mostafavi for their technical assistance. Kind cooperation provided by Baharloo Hospital Sleep Lab personnel through the course of this research project was greatly appreciated. This research was supported by Iran University of Medical Sciences and registered as a clinical trial in IRCT (main ID: IRCT2012070910218N1).
AUTHORS CONTRIBUTIONS MRS, MTJ & AY study conception and design. MRSS and KS-H acquisition of data. KS-H, MRS, NK, SK & MTJ analysis and interpretation of data. MRS, MTJ, AY, NK & SK drafting of manuscript. MRS, NK, MTJ, AY & KS-H critical revision.
CONFLICT OF INTEREST The authors have no conflict of interest to declare.
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SUPPORTING INFORMATION Additional Supporting Information may be found in the online version of this article: Figure S1. Flowchart of patients. Figure S2. Post real/sham stimulation hypnograms in patient 1. Figure S3. Post real/sham stimulation hypnograms in patient 2. Figure S4. Post real/sham stimulation hypnograms in patient 3. Figure S5. Post real/sham stimulation hypnograms in patient 4. Figure S6. Post real/sham stimulation hypnograms in patient 5. Figure S7. Post real/sham stimulation hypnograms in patient 6.
J Sleep Res. (2015) 24, 518–525
Slow oscillating transcranial direct current stimulation during sleep has a sleep-stabilizing effect in chronic insomnia: a pilot study MOHAMMAD R. SAEBIPOUR1, MOHAMMAD T. JOGHATAEI1,2, ALI YOONESSI3,4, KHOSRO SADEGHNIIAT-HAGHIGHI5, N I M A K H A L I G H I N E J A D 6 and S O R O U S H K H A D E M I 7 1 School of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran; 2Cellular and Molecular Medical Research Center, Iran University of Medical Sciences, Tehran, Iran; 3School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran; 4National Brain Mapping Centre, Tehran, Iran; 5Occupational Sleep Research Center, Tehran University of Medical Sciences, Tehran, Iran; 6Institute of Cognitive Neuroscience, University College London, London, UK; and 7School of Physics, Sharif University of Technology, Tehran, Iran
Keywords brain wave entrainment, sleep stabilization, brain stimulation, slow-wave sleep enhancement Correspondence Mohammad T. Joghataei Professor of Neurosciences, Iran University of Medical Sciences, Hemmat Highway Tehran, Iran. Tel.: +98 21 88622615; fax: +98 21 88622689; e-mail: [email protected] Accepted in revised form 15 March 2015; received 1 August 2014 DOI: 10.1111/jsr.12301
SUMMARY
Recent evidence suggests that lack of slow-wave activity may play a fundamental role in the pathogenesis of insomnia. Pharmacological approaches and brain stimulation techniques have recently offered solutions for increasing slow-wave activity during sleep. We used slow (0.75 Hz) oscillatory transcranial direct current stimulation during stage 2 of non-rapid eye movement sleeping insomnia patients for resonating their brain waves to the frequency of sleep slow-wave. Six patients diagnosed with either sleep maintenance or non-restorative sleep insomnia entered the study. After 1 night of adaptation and 1 night of baseline polysomnography, patients randomly received sham or real stimulation on the third and fourth night of the experiment. Our preliminary results show that after termination of stimulations (sham or real), slow oscillatory transcranial direct current stimulation increased the duration of stage 3 of non-rapid eye movement sleep by 33 26 min (P = 0.026), and decreased stage 1 of non-rapid eye movement sleep duration by 22 17.7 min (P = 0.028), compared with sham. Slow oscillatory transcranial direct current stimulation decreased stage 1 of non-rapid eye movement sleep and wake time after sleep-onset durations, together, by 55.4 51 min (P = 0.045). Slow oscillatory transcranial direct current stimulation also increased sleep efficiency by 9 7% (P = 0.026), and probability of transition from stage 2 to stage 3 of non-rapid eye movement sleep by 20 17.8% (P = 0.04). Meanwhile, slow oscillatory transcranial direct current stimulation decreased transitions from stage 2 of non-rapid eye movement sleep to wake by 12 6.7% (P = 0.007). Our preliminary results suggest a sleep-stabilizing role for the intervention, which may mimic the effect of sleep slowwave-enhancing drugs.
INTRODUCTION Primary insomnia (PI) is defined as a non-restorative sleep accompanied by problems in initiating or maintaining of sleep, in the absence of clinically significant medical, neurological or psychiatric disorder. Having PI for more than 3 months is referred to as chronic insomnia, a
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persistent condition that in the long-term decreases the quality of life, and increases the risk of morbidity and mortality due to physical and mental illnesses (Dew et al., 2003). Global and growing epidemics of insufficient sleep, insulin resistance and obesity are suggested to be mechanistically correlated (Lucassen et al., 2012). It is estimated that in the ª 2015 European Sleep Research Society
Effect of slow oscillating tDCS in chronic insomnia USA about 10% of the population have chronic insomnia, which imposes annually a burden of $13.9 billion (Walsh, 2004). Planning and goal-directed performance heavily relies on vigilance or sustained attention, which are impaired after insufficient sleep (Van Dongen et al., 2003), and impaired daytime functioning composes the majority of insomnia global burden (Daley et al., 2009). During sleep, the brain activity slows down and produces an electroencephalography (EEG) feature comprising of the activity in the 0.5- to 4-Hz frequency band, namely slow-wave activity (SWA). SWA seems to have a basic role in the restorative function of sleep and is correlated with subsequent daytime functioning. Experimental disruption of SWA will lead to lightness and fragmentation of sleep, to increased daytime sleep propensity, and to impairment of daytime functioning (Dijk, 2009). Current available sleep aids, which are used to improve sleep initiation or treat insufficient sleep quantity, did not succeed in improving daytime functioning, probably as a result of suppressing SWA (Rosenberg, 2006; Zisapel, 2007). Benzodiazepines are a good example in this regard (Dijk, 2010). There is also no consensus surrounding the effect of Z drugs, such as zaleplon or zolpidem that act on benzodiazepine-specific subunit sites, on promoting sleep without decreasing the amount of deep sleep (Arbon et al., 2010; Lundahl et al., 2012) or maintaining next day performance (Otmani et al., 2008). Some observations imply that in PI, sensory gating and stimulus-related increase of K-complexes are not complete (Hairston et al., 2010). K-complexes are thought to be forerunners of SWA (De Gennaro et al., 2000). The spontaneous K-complexes are more likely to occur prior to transition from stage 2 of sleep to SWA compared with transition to rapid eye movement (REM) sleep (Nicholas et al., 2006), indicating their sleep-deepening effect. Rhythmic K-complexes group ‘sleep spindles’, which are suggested as another oscillation-based sensory gating mechanism in the sleep (Amzica and Steriade, 2002; Dang-Vu et al., 2010; Wimmer et al., 2012). Therefore, sleep maintenance insomnia can be considered as an inability to produce or maintain slow brain oscillations. Comparing with good sleepers, sleep EEG analysis of patients with PI shows elevated power of higher frequencies such as 13–40 Hz (Hairston et al., 2010; Krystal et al., 2002; Perlis et al., 2001). Interestingly, SWA-enhancing drugs reduce wake time after sleep-onset (WASO), which is dose-dependent (Dijk et al., 2012; Walsh et al., 2006b). They also can improve sustained attention the following day (Walsh et al., 2006a). Though the therapeutic value of these drugs is still not sufficient to consider them as a practical solution for insomnia, they have highlighted the value of SWA and approaches for enhancing SWA (Walsh, 2009). Normally, slow oscillations, such as spontaneous K-complexes, originate intracortically (Timofeev et al., 2012) and propagate throughout the entire cortex. It has been shown that rhythmic transcranial magnetic stimulation at 0.8 Hz, rhythmic acoustic stimulation (0.8 Hz) and sleeping in a 0.25ª 2015 European Sleep Research Society
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Hz rocking bed can all deepen sleep by increasing SWA (Bayer et al., 2011; Massimini et al., 2007; Ngo et al., 2013). Being in SWA stage is concurrent with approximately 20% lesser chance of shifting to wakefulness or stage 1 compared with being in stage 2 or REM sleep (Walsh, 2009). Specifically, it has been shown that lower frequencies such as 0.75Hz oscillation, might play a partial role in sleep maintenance and development of sleep (Ferri et al., 2005). Activity of neurons and neuronal networks can be resonated to an externally induced oscillatory electrical field (Womelsdorf et al., 2007). Transcranial direct current stimulation (tDCS) is a simple and non-invasive method for focally stimulating or inhibiting cortical regions of the human brain. Marshall et al. (2006a) showed that brain wave entrainment with deep sleep frequency (0.75 Hz) during stage 2 of nonREM (NREM) sleep (N2) by slow oscillating tDCS (sotDCS) can facilitate endogenous slow oscillations and simultaneously enhance spindle counts and EEG power within the slow spindle frequency range (Marshall et al., 2006a). It was recently shown that this method has a durable effect and reduces the decay of SWA for the rest of the night (Reato et al., 2013). Givin the existing evidence that sotDCS can increase SWA in normal individuals, and that this change in EEG pattern can influence relevant functional brain networks, we hypothesized that 0.75-Hz sotDCS may be helpful for insomniacs who suffer from lack of SWA. Specifically, we were looking for lasting effect of this intervention in the short term. MATERIALS AND METHODS Patients Patients were recruited by referral and advertisement. Patients with the chief complaint of fragmented or nonrestorative sleep were visited by an expert psychiatrist for diagnosis of chronic PI. Six patients with PI (four males, two females) completed the study (flow chart of patients is shown in Supplementary Information S1). Patients with sleep-interfering neurological or psychiatric disorder, unstable medical disorder, addiction, pregnancy, implanted pacemaker, history of head injury or skull fracture, and history or family history of epilepsy were excluded from the study. We also excluded patients who had sleep-onset insomnia, because electrical stimulation must be applied during establishment of NREM sleep. Patients were asked to avoid caffeine intake, nap or using hypnotics the day before the experiment. Polysomonography (PSG) Polysomnography was performed using a Sandman Elite (Embla, Kanata, Ontario, Canada) device. EEG of C3-A2, O1-A2, O2-A1 and C4-A1, plus electrooculogram and electromyogram of chin were used for offline sleep staging. Sleep
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scoring was based on the American Academy of Sleep Medicine Sleep Scoring Manual, 2007. A cordless robotic arm was used to disconnect the PSG device from the patient box during stimulation periods (Supplementary Information S2). The device automatically disconnected stimulation electrodes when connecting the PSG cable through the release of two push-button switches equipped in the robotic arm. Conversely, after each 5 min of stimulation, the robotic arm simultaneously disconnected stimulation and restored PSG recording for 1 min (Fig. 1). This exact procedure was also performed during the sham pseudostimulation to ensure that the patients are blind to the stimulation protocol. After scoring of sleep stages by a sleep specialist, the period between termination of stimulations and morning awakening was selected for within-group comparison. SPSS statistics version 22 IBM, USA was used for statistical analyses. Data were exported to MATLAB R2010a (The MathWorks, Natick, MA, USA) to calculate sleep state transition probabilities. To determine the probability of sleep stage transitions, a custom MATLAB function was written to read the ‘.txt’ file produced by Sandman Embla Polysomnography System. This function detects different steps and events, counts the number of each one of them and counts the number of transitions between steps. Slow oscillatory transcranial direct current stimulation Slow oscillatory transcranial direct current stimulation (sotDCS) was performed with a two-channel battery-based independent and isolated synchronized stimulator (Hidranco., Tehran, Iran; for detailed specifications of the device, see Supplementary Information S3), which could be controlled remotely via its wireless management system. The stimulations were conducted based on a related published protocol (Marshall et al., 2006b). Anodes were placed on F3 and F4, and cathodes on the mastoids using a clip connector with 8mm-diameter disposable pre-gelled adhesive Ag/AgCl electrodes. Two separate battery-driven circuits stimulated each hemisphere of the brain synchronously. The stimulating current had a trapezoid shape in which the current reaches 260 lA from 0 in 0.33 s, maintaining at 260 lA for 0.33 s, returning to 0 in 0.33 s, and after 0.33 s at 0 current the cycle
Sham or real stimulation period
Sleep onset
repeats (Marshall et al., 2006b). Therefore, the duration of each cycle was 1.33 s, and we had a regular pattern of 0.75 Hz stimulation (Fig. 2). The maximal voltage of stimulation was 10 V, and electrode resistance between the ipsilateral stimulation sites was between 5 and 15 kOhm. Stimulation started after establishment of stage 2 or deeper NREM sleep for at least 8 epochs by online scoring of PSG. Then, after every 5 min of stimulation, the stimulation stopped and PSG monitoring continued for 1 min to ensure continuity of sleep (we had five episodes of stimulation, hence the total duration of stimulation was about 25 min). Procedure The study protocol was approved by the ethical committee of Iran University of Medical Sciences (Approval number: 4324/ 12-10- 1389 – ﻡ ﺕ/)ﺍ. The procedure was explained to the participants, and after obtaining written informed consent they were enrolled in the study. The experiment had a randomized crossover repeated measures design, and was performed over four non-consecutive nights in Baharloo Hospital Sleep Research Center, which is affiliated with Tehran University of Medical Sciences. The first night was for adaptation. A baseline PSG was performed on the second night. On the third night, patients randomly received either sotDCS or sham stimulation, while both patients and the sleep scorer were blinded to the intervention. On the fourth night, the patients who received sotDCS on the third night were exposed to sham stimulation and the other half received sotDCS. The fourth night of the experiment was at least 1 week after the third night. In each session, PSG started at 23:30 hours ( 30 min), based on their preferred sleeping time from the interview, and ended after subjects woke up in the morning. The criterion for awakening of patients was 08:00 hours. After electrode removal, subjects filled out a sleep quality questionnaire. Data analysis Sleep-onset latency and sleep efficiency were obtained from whole-night PSG data. We then set the ‘lights off’ at the exact time of termination of stimulations (sham or real), and
Selected period for PSG data comparison about lasting effect of sham or real otDCS
A 1 min block of stimulation free for PSG recording (ensuring about continuity of sleep)
Lights off A 5 min block of stimulation (sham or real)
Lights on
Figure 1. Schematic diagram of study procedure. Data from the period between the end of stimulation and participant’s awakening were selected for comparing the effects of stimulation. ª 2015 European Sleep Research Society
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Figure 2. Pattern of slow oscillatory transcranial direct current stimulation. The stimulating current was oscillating between 0 and 260 lA, three times in every 4 s, compromising a 0.75-Hz stimulation pattern.
resulting PSG data were used for comparison between groups. We initially determined all sleep stage transitions and durations. We used paired-sample t-test (two-sided) for comparing means in sleep stage durations and means of probabilities of transition between sleep stages in both groups. We also performed EEG spectral analysis using MATLAB 2014b and EEGLAB v 13.4.4b. PSG data were converted to EDF format and imported to the EEGLAB; the sampling rate was 256 Hz. EEG data were filtered between 0.1 and 30 Hz, and artefact removal was performed by observing. The first 1min stimulation-free intervals in both sham and real stimulations groups were specifically investigated for assessing the effect of sotDCS on subjects’ EEG spectral power. In EEGLAB, the frequency of spectrum plotting was limited to 0.1–30 Hz. EEGLAB parametric statistics with a statistical threshold of 0.05 and Bonferroni correction were chosen for computing the first independent variable statistics. RESULTS The patient’s mean age was 34 7 years. One of the patients had severe insomnia with an Insomnia Severity Index (ISI) of 24, and other patients had moderate clinical insomnia (ISI = 19 3). According to ISI interpretation guidelines, ISI scores of 15–21 are categorized as moderate, and from 22 to 28 as severe clinical insomnia. No change on the mood level of patients was revealed by analysing the Beck depression inventory questionnaire before and after the intervention. Sleep-onset latency did not differ between sham and stimulation (P = 0.45, t5 = 0.818). The total sleep period also did not change significantly (P = 0.279, t5 = 1.213). Sleep recording after termination of stimulation (sham or real) showed that patients had on average 33 26 min longer duration of N3 (P = 0.026, t5 = 3.138) and 22 17.7 min shorter N1 (P = 0.028, t5 = 3.07) after receiving sotDCS compared with sham. sotDCS decreased N1 and WASO durations together by 55.4 51 min (P = 0.045, t5 = 2.644; Fig. 3). sotDCS increased sleep efficiency (total sleep duration divided by the time spent in bed) by 9 7% (P = 0.026, t5 = 3.13). Additional analysis revealed that in the first hour after termination of the stimulation, duration of N3 on average increased by 19 11.5 min (P = 0.01, t5 = 4.056) compared with the sham group. This increase, for the first 90 min after termination of stimulation, was about 26.3 20 min (P = 0.023, t5 = 3.237). ª 2015 European Sleep Research Society
Figure 3. Effect of slow oscillatory transcranial direct current stimulation (sotDCS) on durations of sleep stages. The sleep period after termination of sham or real stimulation was used to make comparison between groups (*P ≤ 0.05).
Slow oscillatory transcranial direct current stimulation increased the probability of transition from N2 to N3 by 20 17.8% (P = 0.04, t5 = 2.753), while it decreased the probability of transition from N2 to wakefulness by 12 6.7% compared with sham (P = 0.007, t5 = 4.347; Fig. 4; Table 1).
Figure 4. Transition probability change schematic diagram. Slow oscillatory transcranial direct current stimulation (sotDCS) decreased the probability of transition from N2 to wakefulness, and increased the probability of transition from N2 to N3 compared with sham (*P ≤ 0.05, **P ≤ 0.01).
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Table 1 Changes in means of sleep stage transition normalized probabilities induced by sotDCS
Stage transition
Mean probability on sham night (%)
Mean probability on stimulation night (%)
N3?N2 N3?N1 N3?W N2?N3 N2?N1 N2?R N2?W N1?N3 N1?N2 N1?R N1?W R?N2 R?N1 R?W W?N2 W?N1 W?R
78.56 2.81 1.96 32.55 26.57 11.09 29.79 0.69 61.65 14.64 23.02 5.42 35.73 58.85 6.1 92.12 1.79
96.23 0 3.77 52.63 18.52 11.04 17.81 2.02 55.7 21.27 21.01 18.33 24.17 57.5 3.62 93.61 2.78
Mean probability change (%) 17.7 2.8 1.8 20.1 8.1 0.05 12 1.3 6 6.6 2 12.9 11.6 1.4 2.5 1.5 0.99
40.9 5.1 8.9 17.9* 10.3 11.9 6.7** 4.1 26.6 20.4 11.1 16.2 13.5 21.3 7.6 11.2 8.1
The probability of transition from N2 to wakefulness decreased, and from N2 to N3 increased significantly by 0.75 Hz sotDCS (*P ≤ 0.05, **P ≤ 0.01).
Spectral analysis of the first 1-min EEG recording interval revealed that 5 min of real stimulation increased average power at frequencies below 1 Hz relative to the same interval in the sham group (P ≤ 0.05; Fig. 5). Figure 6 shows the pattern of EEG (C4-A1) after termination of sotDCS and robotic reconnection of PSG cable in one
subject. This pattern is suggestive of brain wave modulation by sotDCS. Subjective rating of restorative sleep and next day functioning was assessed using a Likert sleep scale in which ‘very bad’, ‘bad’, ‘fair’, ‘good’ or ‘very good’ were scored as 1–5, respectively. A non-significant improvement was observed for both items. One patient reported a mild transient headache the day after the stimulation. Subject 1 with ISI 24 noticed that, unlike other nights with numerous awakenings, he had a more stable sleep in the stimulation night. He described the effect of sotDCS on his sleep to be as powerful as 0.5 mg of clonazepam, without its morning dizziness. He reported his daily functioning as: After several months I felt energetic and I could concentrate, so I performed many of my fallen into arrears jobs, called my friends and planned for future activities. Subject number 3 reported that, despite the little sleep he had in the stimulation night, he woke up early in the morning refreshed, performed his routine daily duties and, regardless of being used to an afternoon nap, he did not have a tendency to nap during that day. Meanwhile, he specifically reported that his blue mood status did not elevate. Other subjects did not describe any prominent improvement in sleep quality and daily functioning. DISCUSSION Electroencephalographic spectral power analysis of the first 1-min window after stimulation shows that sleeping brain rhythm in patients with insomnia can be modulated by
Figure 5. Mean electroencephalographic (EEG) spectral power change. After 5 min of slow oscillatory transcranial direct current stimulation (sotDCS), the mean EEG spectral power below 1 Hz significantly increased in the real stimulation group in comparison with the sham group. The shaded area indicates the region in the spectrum with a significant mean difference, with a P-value of less than 0.05.
Figure 6. Brain wave after termination of stimulation. The recorded pattern of electroencephalographic oscillations from one subject just after termination of stimulation and robotic reconnection of polysomonography cable (C4-A1). ª 2015 European Sleep Research Society
Effect of slow oscillating tDCS in chronic insomnia sotDCS. Decreased duration of light sleep and WASO in the sotDCS group is similar to features observed after hypnotic use. A decrease in the probability of transition from N2 to wake state beside an increase in transition from N2 to N3 also indicates a sleep-stabilizing effect. According to the protocol used in our study, the duration of stimulation was limited to 25 min in the first hour of sleep. Interestingly, the increased duration of N3, and decreased duration of WASO and lighter sleep periods occurred in the stimulation-free sleep. In a recent study, it was shown that 20 min transcranial alternating current stimulation (tACS) with individualized alpha frequency can leave a sustained after-effect on EEG endogenous power for at least 30 min (Neuling et al., 2013). A form of brain plasticity, which is called spike timingdependent plasticity (STDP), has been proposed for the observed after-effects of tACS. Neural circuits have specific resonance frequencies. When the frequency of an externally induced driving force is matched with a neural circuit resonance frequency, STDP can strengthen synapses in these circuits (Zaehle et al., 2010). Researchers showed that 25 min of 0.75-Hz transcranial electrical stimulation during stage 2 of NREM sleep reduces the decay of SWA in the remainder of the night, implicating a homeostatic effect on later sleep (Reato et al., 2013). This study also has offered an explanation for a unidirectional increase in firing rate by showing that sotDCS increases the firing rate of cortical neurons during UP-states without decreasing the firing rate during DOWN-states (Reato et al., 2013). This may have some implications for those brain regions that are active during SWA, such as parahippocampal gyrus, cerebellum and brainstem, in which the brain activity significantly increases, and is consistently synchronized to the slow oscillations (Dang-Vu et al., 2008; Kaufmann et al., 2006). Stronger activity in those active regions in the first hours of sleep may have a positive effect on establishment of a deeper sleep. Moreover, there is evidence implicating that activation of cortical nitric oxide (NO)-producing neurons or ‘sleep active cells’ might have some roles in SWA production through an NO-dependent mechanism. Activation of these neurons is directly related to NREM sleep time, NREM bout duration and SWA power during NREM sleep (Morairty et al., 2013). NO can affect neuronal activity through modulation of gap junction permeability. Sleep active cells have long-range projections within the cortex, and NO is especially a largescale modulator of brain activity (Gerashchenko et al., 2011). Taken together, we speculate that our sotDCS may increase NO production via unidirectional increase in activity (firing rate) of sleep active cells in the cortex. Considering that it takes quite a while before NO completely dissolves, it may play a role in the lasting effect of our stimulation. Finally, some researchers believe that SWA has a chaotic behaviour during sleep, and sleep regulation might be considered as a deterministic non-linear process (Ferri et al., ª 2015 European Sleep Research Society
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1996). Dynamic systems are highly sensitive to initial conditions (Banerjee, 2006), therefore, our intervention at the first states of sleep may impose some considerable influences on large-scale chaotic behaviour of SWA. CONCLUSION This pilot study demonstrated that increasing the SWA by 0.75 Hz sotDCS in patients with insomnia has a sleepdeepening effect. However, its effect on the subjective rating of sleep quality and next day functioning was not conclusive. Simultaneous use of other stimulation methods to increase SWA may improve these findings. Fortunately, rhythmic acoustic stimulation does not need to be time limited and can be used the whole night. Because of the complex and diverse pathophysiology behind different subtypes of insomnia, the existing insomnia categorization should be expanded based on factors such as insomnia severity, age, sex, electrophysiological characteristics such as spindle count, coexisting subclinical conditions, and degree of responsiveness to brainwave entrainment interventions. This modification will provide a better interpretation of non-pharmacological approaches and would be helpful for finding patients who may benefit more from sotDCS during NREM sleep. In addition, a long-term multisession intervention is needed to elucidate if this method can resolve the persistent nature of chronic insomnia, which may be derived from long-term maladaptive brain plasticity processes. Sleeping in a place different from one’s own bed by itself can affect the quality of sleep. Having wires on the head and being monitored may also produce an uncomfortable feeling that may prevent normal sleep. Sleep laboratory admission is also very costly, and in the long term it will not be feasible for the patients to come to sleep labs to have a night of deeper sleep. Therefore, what could be a possible practical utility of such a complicated method of sleep deepening that is far more difficult than taking a pill? Home-based PSG tele-monitoring systems and lightweight head-mounted smart EEG devices may facilitate applicability of non-pharmacological approaches for management of persistent insomnia. However, developing a comprehensive user-friendly set-up needs interdisciplinary research and long-term clinical trials. This approach may have utility in other disorders as well. For example, in chronic fatigue syndrome, despite no considerable change in conventional PSG measures of sleep, EEG analysis has revealed that NREM sleep stages are associated with 20% lower power of 0.5–0.8 Hz EEG band (Le Bon et al., 2012). Hence, it will be important to find the effects of 0.75 Hz sotDCS in this syndrome. In many psychiatric disorders, such as bipolar disorders, a main feature in sleep architecture is lack of SWA. Sleep manipulation and SWA enhancement in specialized sleep centres may open a new horizon for translational research in the control and treatment of psychiatric disorders with sleep disturbances.
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ACKNOWLEDGEMENTS The authors thank Prof. Hamid Mostafavi Abdolmaleki, Dr Frahad Fatehi and Dr Elnaz Rouhi for their comments on the manuscript; Prof. Reza Nilipour and Dr Mirfarhad Ghalebandi for their useful advice in the study design; Dr Mashiyyat Mohammadzadeh and Dr Hossein Mostafavi for their technical assistance. Kind cooperation provided by Baharloo Hospital Sleep Lab personnel through the course of this research project was greatly appreciated. This research was supported by Iran University of Medical Sciences and registered as a clinical trial in IRCT (main ID: IRCT2012070910218N1).
AUTHORS CONTRIBUTIONS MRS, MTJ & AY study conception and design. MRSS and KS-H acquisition of data. KS-H, MRS, NK, SK & MTJ analysis and interpretation of data. MRS, MTJ, AY, NK & SK drafting of manuscript. MRS, NK, MTJ, AY & KS-H critical revision.
CONFLICT OF INTEREST The authors have no conflict of interest to declare.
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SUPPORTING INFORMATION Additional Supporting Information may be found in the online version of this article: Figure S1. Flowchart of patients. Figure S2. Post real/sham stimulation hypnograms in patient 1. Figure S3. Post real/sham stimulation hypnograms in patient 2. Figure S4. Post real/sham stimulation hypnograms in patient 3. Figure S5. Post real/sham stimulation hypnograms in patient 4. Figure S6. Post real/sham stimulation hypnograms in patient 5. Figure S7. Post real/sham stimulation hypnograms in patient 6.
