Purposely, we aim to review critically the studies in the literature that applied tDCS, tACS, and osc-tDCS to regulate sleep and vigilance patterns. Specifically, the spotlight of this work is to provide a systematic overview of the studies that aimed to increase Slow-Wave Sleep (SWS) or sleepiness and, conversely, of works that aimed to enhance vigilance and to reduce sleepiness levels, analyzing electrophysiological and behavioral evidence in healthy subjects. Finally, we analyze the possible application of tCSs on several clinical conditions, including psychiatric or organic disturbances and sleep disorders.

Here, we explore this issue with specific reference to stimulation with direct current, i.e., transcranial Direct Current Stimulation (tDCS), and stimulation with time-varying current, i.e., transcranial Alternating Current Stimulation (tACS) and oscillatory tDCS (osc-tDCS). After a brief discussion on the mechanisms of action, we examine evidence in support of tCS efficiency in modulating electroencephalographic (EEG) rhythms.

Recently, tCSs have been used during sleep or during quiet or active wake to influence sleep and arousal patterns. The sleep-wake regulation mechanism has still to be fully understood. For many years, the prevalent view considered a bottom-up direction of sleep control from subcortical to cortical structures. Specifically, the sleep-regulating circadian and homeostatic signals are integrated into the Ascending Reticular Activating System (ARAS), originating in the brainstem [ 4 ]; this system projects to the thalamus and the cortex by two distinct pathways. Therefore, high activity in the ARAS forms a wake-promoting system, whereas low activity is necessary for the occurrence of sleep [ 5 ]. In more recent years, the top-down component in the control of sleep regulation has been highlighted. Evidence from animal studies shows that slow oscillations are generated by a complex interaction between neocortex and thalamus [ 5 ]; neurons of IV-VI layers represent the primary oscillator of the cortico-thalamo-cortical feedback loop [ 6 9 ]. These populations induce synchronized rhythmic fluctuation of membrane potential in the sense of hyperpolarized Down state and depolarized Up state. The depolarization of the Up state flows as a traveling wave to cortical layers and areas and the thalamus [ 10 ]. This loop seems to be orchestrated by a subgroup of GABAergic interneurons. The activation of reticular thalamic neurons induces a bisynaptic inhibition of thalamo-cortical neurons, making them the intermediary between cortico-thalamic and thalamo-cortical neurons [ 11 12 ]. The inhibition of thalamo-cortical neurons induces an excitatory thalamo-cortical signal, which closes the loop [ 6 13 ]. The cortical component (top-down pathway), so far neglected, plays a pivotal role in sleep/arousal regulation.

Transcranial Current Stimulations (tCSs) are a family of neuromodulatory techniques that, via the application of low-intensity current on the scalp, can modify cortical activity influencing motor, emotional and cognitive functions [ 1 2 ]. tCSs are defined as Non-Invasive Brain Stimulations in that they act on brain physiology but do not involve surgical implantations (e.g., Deep Brain Stimulation) [ 3 ]. As tCSs show small side effects, they offer a viable and promising tool to modulate cortical activity in a quite predictable, safe, economic, and non-invasive manner.

Therefore, all these results show the capability of these types of techniques of modulating cortical activity and, moreover, stress the importance of setting the appropriate stimulation parameters, such as polarity and the frequency, taking into account the brain state activity, and choosing the appropriate area target of stimulation, for reaching specific goals.

The efficacy of osc-tDCS has been shown in different studies [ 39 40 ] that used it to boost or disrupt specific cerebral activity. Similar to tACS, the consistency between the stimulation frequency and the ongoing cortical activity in the target area plays a fundamental role in determining the stimulation outcomes. For instance, a stimulation oscillating at 0.75 Hz was able to increase slow oscillations (0.5–1 Hz), when applied during the first part of the night [ 39 ]—a period rich in slow waves—whereas stimulating at 5 Hz (theta range) did not increase but reduced the slow oscillations. On the other hand, applying this frequency of stimulation (5 Hz) during REM sleep induces enhancement of the gamma activity [ 40 ]. This result might seem contradictory since no increase in the theta activity was reported; however, boosting the theta rhythm, which is inherent to REM stage [ 41 43 ] but not extremely expressed at the moment of stimulation, might have synchronized gamma band activity via cross-frequency functional coupling mechanism [ 40 ]. Interestingly, D’Atri and coworkers [ 44 ] applied 5 Hz and 0.8 Hz oscillatory stimulations in a resting wake period, characterized by a more rapid activity than SWS, and found a frequency-specific enhancement of theta oscillations along with cross-frequency increases in slow oscillations induced by the 5 Hz stimulation compared to the 0.8 Hz stimulation [ 44 ]. Regarding the role of the stimulation polarity, empirical findings seem to support a more robust efficacy of the anodal oscillatory stimulation compared to the cathodal one [ 39 45 ]. This is directly shown in a study that compared the two oscillating stimulations (cathodal vs. anodal) showing a larger effectiveness of the anodal one [ 46 ].

It should be underlined that the efficacy in inducing resonance phenomena by means of time-varying stimulations critically depend on the physiological rhythmic activity spontaneously expressed by the target area. For instance, in an eye-closed condition, characterized by alpha activity, alpha-tACS can induce resonance between frequency of stimulation and ongoing cerebral activity, whereas beta-tACS cannot [ 37 ]. Furthermore, applying alpha-tACS to the areas that preferentially oscillate at this frequency (such as the occipital cortex [ 38 ]) induces greater increases of EEG power at the given frequency than stimulating other regions (i.e., temporal cortex [ 18 ]).

At cortical level, the synchronization of the firing rate with the variations of the electric field results in increases of the EEG spectral power at the frequency of the applied current. For example, theta-tACS during wakefulness can enhance the theta activity [ 33 34 ]. Voss and coworkers found out that stimulating the fronto-temporal area at 40 Hz and, to a lesser degree, at 25 Hz, during Rapid Eye Movement (REM) sleep, leads to local increase in gamma activity [ 35 ]. Lustenberger and colleagues [ 36 ] applied a feedback-controlled 12 Hz tACS on frontal areas during non-REM (NREM) sleep, stimulating only when spindles occurred. This approach selectively enhanced cortical synchronization in spindle frequency range, without altering the sleep architecture.

tACS and osc-tDCS share the modality of the current injection with tDCS, but they stimulate with a time-varying current intensity. In tACS protocols, an alternating current is applied, and, in most cases, the current has a sinusoidal wave form. The transcranial application of alternating current induces periodic shifts in the transmembrane potential, alternating depolarizing and hyperpolarizing effects as a function of the phase shift. In other words, the stimulation at a given frequency drives the cortical network to oscillate at the stimulation frequency with a greater amplitude (resonance phenomenon). In osc-tDCS, tDCS and tACS are combined, resulting in a polarized stimulation that benefits from both the effect of direct current on cortical excitability and the synchronizing effect of the alternating current on the ongoing brain activity. According to Bergman [ 32 ], the mechanism by which osc-tDCS exerts its effects may depend, as with tACS, on the shifting the membrane potential repeatedly back and forth in an oscillating manner.

At macroscopic level, the modulation of the firing rate by tDCS results in changes of cortical activity in specific frequency bands, as measured by EEG. Summarizing the results from the different EEG studies with tDCS, anodal stimulation has been linked to increases of beta power [ 25 28 ] and reduction of delta, theta, and alpha power [ 26 30 ], while cathodal stimulation results in the reduction of beta and gamma power [ 25 ], and the increase of theta and delta power [ 31 ]. From a physiological point of view, EEG patterns characterized by higher power in high-frequency bands paralleled by lower power at low frequencies, as with those induced by anodal tDCS, are associated with cortical desynchronization and alert state.

Regarding the ability of these paradigms of stimulation to modulate cortical activity, it is important to consider that different techniques take advantage of different mechanisms of action. Transcranial Direct Current Stimulations (tDCS) devices comprise a battery-powered current generator that delivers a constant electrical current flow via two or more surface electrodes (cathode and anode) placed over the scalp. During the stimulation, the current flows from the anode to the cathode [ 14 ] influencing the excitability of the neuronal populations (pyramidal cells), underlying the stimulation electrodes. Specifically, the external current field forces the arrangements of intracellular ions, altering the distribution of the internal charge and modifying the resting transmembrane potential [ 15 ]. Generally speaking, the direction of the induced effects mainly depends on the polarity of stimulation: anodal stimulation induces a sub-threshold depolarization [ 15 ] resulting in increases of the average firing rate [ 16 ], whereas cathodal stimulation induces the opposite effects. On the one hand, numerous studies modeling tCSs-induced intracranial current flow have shown that a large amount of the applied current is short-circuited by the skin [ 17 19 ]. In this sense, the magnitude of the current density, manipulated through different shape/size of the electrode assembly and current intensity applied result pivotal in determining the proportion of current that arrives intracranially [ 19 ]. On the other hand, the complexity of brain morphology implies that it is the direction of the current relative to the orientation of the target neural pathway that determines the effect of stimulation [ 20 ]. In particular, a current with a soma-dendrite direction causes hyperpolarization of the soma and suppresses the action potentials of the neural population; on the contrary, a dendrite-soma direction of the current induces depolarization of the soma [ 21 22 ]. Accordingly, stimulation with the same polarity could induce different effects in function of the electrode placement since the direction and the strength of the effects depend on the relative position of anode and cathode with respect to the direction of the pyramidal cells in the stimulated area [ 23 ]. Furthermore, it is worth noting that the inter-electrode distance (i.e., the cephalic or extracephalic position of the “return” electrode), the inhibitory or excitatory connections of the target area, as well as the whole set of cortical and subcortical regions through which the current flows, affect the amplitude of the local and global cortical effects of the stimulation [ 23 24 ].

3. Promoting Sleepiness

From an electrophysiological point of view, promoting sleepiness, sleep, or a “good-quality sleep” can be referred in modulations of cortical activity resulting in enhancements of theta and alpha activity during the wake or Slow-Wave Activity (SWA, 0.5–4 Hz) during sleep.

Historically, the application of an external current to induce sleep-like states goes back to the beginning of the 20th century [ 47 ]: electrosleep therapy used a pulsating direct current for 30 to 120 min, with the electrodes attached to eyes and mastoids [ 48 ]. Since the studies using this technique are dated, most of them lack methodological rigor (e.g., no control with sham condition or no EEG measures) and sometimes show contrasting results that may depend on electrical characteristic of the device used or other methodological issues such as, for example, the duration of stimulation [ 49 ]. Anyway, even if a large amount of electrosleep studies applied the stimulation on clinical populations (see Section 5 ), this technique resulted in improvement of sleep also in normal subjects [ 50 ]. From the first promising evidence reporting effects on sleep, anxiety, and depression [ 48 ], there was a growing interest in the study of these stimulations that leads to the recent development of tCSs. Accordingly, in the last few decades, many studies used tCSs during sleep or during quiet or active wake to enhance SWA, affect sleep propensity, or to ameliorate qualitative and quantitative sleep parameters.

51,52,53,54,55,56,57,60,51,52,53,54,57, Most of the studies available in the literature applied the stimulation during NREM sleep stage 2 or SWS, to boost the SWA [ 39 58 ]. According to empirical evidence pointing out that frontal areas are the first regions that “fall asleep” [ 59 61 ], and that SWA is predominant in frontal areas during sleep [ 62 63 ], these studies stimulated frontal regions and obtained an enhancement of SWA spectral power, both in normal subjects [ 39 55 ] and in patients [ 56 58 ].

52,54,56,57, Anodal oscillatory stimulation at 0.75 Hz (slow osc-tDCS) in frontal areas during sleep stage 2 of a diurnal nap [ 51 53 ] or during nocturnal sleep [ 39 58 ] can induce a frequency-specific enhancement of SWA, compared to sham, with little or no disturbing effects induced by stimulation. Marshall and colleagues [ 39 ] applied the stimulation on fronto-lateral locations, in five 5-min blocks with 1 min free of stimulation interval, after 4 min of stage 2, a period in which sleep becomes deeper and cerebral activity slows down, evolving into SWS. The stimulation locally enhanced the EEG power in the slow oscillation range (0.5–1 Hz) as revealed by the analysis of the 1-min intervals. This effect was frequency-specific, since only 0.75 Hz stimulation was effective in enhancing SWA, whereas the 5 Hz stimulation reduced SWA [ 39 ].

53, Among the mentioned studies, some were conducted on elderly populations [ 52 54 ]. These studies applied oscillatory stimulation at 0.75 Hz on the frontal areas, delivered in five blocks, each lasting 5 min, with 1 min [ 52 ] or 1 min and 40 s [ 53 54 ] intervals free of stimulation, with the current intensity varying between 0 and 260 µA. Since sleep in elderly is disrupted, fragmented, and contains less SWS, the enhancement of slow oscillatory activity induced by slow oscillatory-tDCS in this population might be considered as a relevant finding, supporting the feasibility to ameliorate sleep quality by transcranial stimulations. Besides the positive and clear effect on sleep, an enhancement of SWS by slow oscillatory-tDCS in older subjects could also have beneficial effects on the physiological cognitive decline observed in this population, since the reduction of SWS has been associated with deterioration of different cognitive functions, such as memory [ 53 ] (see Section 5 ). Other evidence in older adults shows contrasting results [ 64 65 ]; for example, the same oscillatory stimulation (0.75 Hz) did not induce an enhancement either in sleep parameters or sleep-associated memory task. Differences in the experimental protocols (for example, stimulation procedures) and features of elderly sleep may account for the different results. For instance, Eggert and coworkers [ 64 ] applied a ramping period at the beginning and at the end of each stimulation interval to reduce skin sensation; as observed by Ladenbauer and colleagues [ 53 ], this ramping mode might have prevented the short-lasting stimulation-dependent entrainment of slow oscillation activity. Moreover, in this study the stimulus-free periods were not controlled and because elderly sleep is lighter and fragmented, it is thus possible that the stimulation did not occur in stage 2, but, instead, in lighter stages, preventing the resonance phenomenon between the ongoing activity and stimulation frequency.

In a very recent study, Sheng and coworkers [ 66 ] applied at frontal location an anodal high-definition-tDCS to improve sleep in the elderly and found an effective enhancement of sleep duration and a reported feeling of improved sleep.

Since evidence regarding older adults is conflicting, to evaluate the efficiency of tCSs on this specific population, future studies are needed.

We have already discussed the efficacy of 0.75 Hz stimulation in boosting SWA when it is applied during NREM sleep. When the same stimulation is applied during a wake period, one could expect a slightly different outcome, since during wakefulness our brain shows an EEG pattern of activity characterized by higher frequency waves with a smaller amplitude, compared to sleep. An oscillatory stimulation at 0.75 Hz in frontal areas during quiet wake (current intensity range 0–260 µA) enhanced slow-frequency (0.4–1.2 Hz) EEG activity in the area closest to the stimulation [ 45 ]. Additionally, 0.75 Hz anodal osc-tDCS increased also the theta activity, across electrode sites, showing the capability of this specific stimulation in inducing not only frequency-specific effects (the delta enhancement) but also cross-frequency outcomes (the theta increase). Since resting-state EEG is characterized by alpha and theta activity (the latter rhythm considered as a marker of sleepiness) it is reasonable to wonder if theta-tDCS (5 Hz) could induce a larger resonance effect than 0.75 Hz tDCS, also affecting the sleepiness level. In line with this, D’Atri and coworkers [ 46 ] compared these two frequencies of stimulation and found a post-stimulation significant enhancement of delta and theta activity after anodal stimulation at 5 Hz, compared to 0.75 Hz stimulation, combined to an increase of subjective sleepiness.

Moreover, in a recent sham-controlled study, D’Atri and coworkers [ 67 ] applied bilateral theta-tACS (5 Hz) at a fronto-temporal location for 10 min, during resting state, and found a posterior enhancement in theta power and a centro-frontal increase in alpha activity in the post-stimulation EEG, consistent with the increase of the sleep propensity after the stimulation. Interestingly, this effect was not only restricted to the specific bin corresponding to the stimulation frequency, but, instead, involved all the theta frequency band, as well as the alpha band with a peak at the 10 Hz bin, showing not only the entrainment of cortical oscillation, but perhaps also a more general synchronizing effect induced by the alternating stimulation [ 67 ].

All the aforementioned studies included a sham stimulation; the comparison with a control condition is fundamental to control for the placebo effect and to directly attribute the outcome to the stimulation rather than to other factors, such as the experimental procedure itself. Since only in very rare cases, the participants recognized the active stimulation (e.g., two subjects on a total sample of 18 in [ 53 ]), applying the stimulation for few seconds and then slowly ramping down the current intensity is shown to be an efficacious control condition [ 68 ].

In summary, all the aforementioned studies show not only the capability of these techniques to carry out a frequency-specific and cross-frequency modulation of cortical activity, but also provide evidence in support of tCS efficacy in inducing sleepiness and in boosting sleep and improving sleep quality, as assessed by electrophysiological and subjective measurement.