Application of Transcranial Electric Stimulation (tDCS, tACS, tRNS)
From Motor-Evoked Potentials Towards Modulation of Behaviour
Abstract
Abstract. Low-intensity transcranial electrical stimulation (tES) techniques are a group of noninvasive brain stimulation approaches, where currents are applied with intensities ranging between 0.4 and 2 mA through the human scalp. The most frequently used tES methods are transcranial direct current (tDCS), alternating current (tACS), and random noise stimulation (tRNS). These methods have been shown to induce changes in cortical excitability and activity during and after the stimulation in a reversible manner. It was observed that while anodal and cathodal tDCS acts on the membrane potentials by depolarizing or hyperpolarizing them, tACS probably modifies cortical oscillations. tRNS, that is a special form of tACS, might act through affecting the signal-to-noise ratio in the brain. Currently, an exponentially increasing number of studies have been published regarding the effects of tES on physiological processes and cognition. The aim of this review is to summarize the basic aspects of tES methods.
During the last 35 years a number of modern, widely used noninvasive electrical brain stimulation (NIBS) techniques have been developed. Low-intensity transcranial electrical stimulation or weak transcranial electrical stimulation (tES) methods are a group of NIBS techniques where currents with low intensities (typically 1–2 mA) are applied through the intact scalp (for a review, see Paulus, 2011). These techniques, though not capable of inducing neuronal firing directly in a resting cell, modulate spontaneous firing rates of cortical neurons and induce changes in cortical excitability which can outlast the duration of the stimulation (Nitsche & Paulus, 2000, 2001). tES methods include transcranial direct current stimulation (tDCS), transcranial alternating current stimulation (tACS) and a special form of tACS, transcranial random noise stimulation (tRNS). With regard to the taxonomy, in addition to the physical classification of tES methods based on the current waveform that we are currently using (direct or alternating current) and electrode montage (e.g., motor cortex stimulation), the functional characteristics of the stimulation based on the outcome, for example, excitatory versus inhibitory stimulation, are generally used for further differentiation of the methods (Guleyupoglu, Schestatsky, Edwards, Fregni, & Bikson, 2013).
Although the number of published reviews is increasing in this field, most of them are focusing on one of the aspects of the stimulation (e.g., tDCS effects on cognition) or giving a general picture related to the physiological effects of the stimulation (e.g., excitation-inhibition). Furthermore, the number of reviews discussing the application of other tES methods, such as tACS and tRNS, is limited. Therefore, we aim to give a basic but not oversimplified introduction to tES methods for students, scientists, and health practitioners, who want to start or have just started using tES methods and require information about elementary taxonomy, terminology, and application of the stimulation. The advantages and disadvantages of different electric stimulation methods are also discussed.
General Aspects of the Stimulation
The mode of application of the stimulation is similar in the case of all low-intensity tES interventions. The current is delivered by a battery-driven stimulator using a pair of rubber electrodes wrapped in a viscose sponge that is soaked in isotonic saline solution. The electrodes may also be fixed with conductive electrode paste. Stimulation is applied over the homogeneous skin without abrasion. Generally, one electrode is defined as the target electrode, which is positioned above the cortical region of interest. The other electrode is usually referred to as the reference, or return electrode (Bikson, Datta, Rahman, & Scaturro, 2010). Usually, the electrode size is between 16 and 35 cm2, however, it can also be reduced to for example, 3.5 cm2 by keeping current density (quotient of the applied intensity and the interfacing electrode surface area) constant. tDCS hereby is able to modulate more focal areas, for example, changing the excitability of small hand muscles (abductor digiti minimi and first dorsal interosseus muscle) differentially (Nitsche et al., 2007). The return electrode is physiologically also active, when placed over another cortical area. To reduce a possibly confounding effect of the return electrode, an extracephalic montage can be used (Moliadze, Antal, & Paulus, 2010b) or the size of the electrode can be increased in order to reduce the current density to subthreshold levels, that is, a current density, which does not elicit physiological or functional effects (Nitsche et al., 2007).
Cutaneous sensations, such as itching, tingling, or burning sensations, may occur dose-dependently during the application of tDCS at the electrode-skin interface. For a long time it was widely assumed in the literature that these phenomena associated with the stimulation were mostly restricted only to the initial phase of the intervention (e.g., Fregni & Pascual-Leone, 2007). Only few reports described persistent sensations outlasting the initial phase of the active stimulation (Dundas, Thickbroom, & Mastaglia, 2007) and the presence of similar phenomena after the cessation of sham stimulation (Gandiga, Hummel, & Cohen, 2006). Our studies clearly imply the cutaneous sensations do not disappear completely either during the active or during the sham condition (Ambrus, Paulus, & Antal, 2010; Antal et al., 2008; Poreisz, Boros, Antal, & Paulus, 2007). The application of tRNS and tACS over the scalp induces less sensation compared with tDCS (Ambrus et al., 2010; Fertonani, Ferrari, & Miniussi, 2015).
Computer modeling studies suggest that High-Definition tDCS (HD-tDCS), a variant of tDCS, might represent a significant improvement of the physical focality of the stimulation compared to the conventional design. HD-tDCS can be performed via disk-shaped electrodes with 8 mm diameter; the target electrode is surrounded by four return electrodes at for example, 3 cm distance over the primary motor cortex (M1; Datta et al., 2009). Needless to say, the size of the stimulated brain area even with small electrodes is generally clearly larger than the surface of the electrode due to the spreading of the current, in particular cerebrospinal fluid (CSF). The complex cortical geometry combined with the high conductivity of the CSF that covers the cortex gives rise to a very distinctive electric field distribution in the cortex, with a strong component confined to the bottom of sulci under or very near the electrodes and a weaker tangential component that covers large areas of the gyri between the two electrodes (Miranda, Mekonnen, Salvador, & Ruffini, 2013). Any stimulation probably induces not only local but also remote effects (Lang et al., 2005), which are at least partially functional connectivity-driven (Polania, Nitsche, & Paulus, 2011).
A standard procedure for quantifying the effects of a tES technique is to measure the amplitude and time course of motor-evoked potentials (MEPs), by using transcranial magnetic stimulation (TMS; Nitsche & Paulus, 2000). Since this is a quite straightforward, efficient, and simple outcome parameter, according to our estimations, about 80% of the tES studies in healthy subjects were done using the motor cortex as a model. In analogy, effects of tES techniques can be assessed at the visual cortex by evaluating changes of TMS intensity thresholds that can elicit phosphenes before and after intervention (e.g., Antal, Kincses, Nitsche, & Paulus, 2003a, 2003b; Antal, Nitsche, & Paulus, 2003), or other physiological parameters (Antal, Kincses, Nitsche, Bartfai, & Paulus, 2004).
Transcranial Direct Current Stimulation (tDCS)
Transcranial direct current stimulation (tDCS) is the most widely utilized of the tES techniques. The intensity of the current delivered by tDCS is not sufficiently high to induce action potentials directly in resting cells; tDCS polarizes neuronal membrane potentials and it increases or decreases the spontaneous firing rate of the affected neurons (Creutzfeldt, Fromm, & Kapp, 1962). The anode is defined as the electrode where the current enters the body and the cathode is defined as any electrode where the current exits the body. The conventional tDCS paradigm uses a single current amplitude during the course of stimulation except for one ramp-up and ramp-down period (typically a 10–30 s linear ramp). Ramp-up and-down periods are introduced in order to minimize the probability of the appearance of sudden skin and visual sensations induced by retinal stimulation after switching on or off the stimulation abruptly. The current flow is not restricted to the area underneath the electrodes, but rather spreads around the vicinity and into the neural tissue between the electrodes (Miranda et al., 2013; Opitz, Paulus, Will, Antunes, & Thielscher, 2015; Ruffini, Fox, Ripolles, Miranda, & Pascual-Leone, 2014).
Physiologically, two main effects of tDCS should be discerned. During stimulation, tDCS induces a subthreshold modulation of membrane potentials. Sufficiently long stimulation results in long-term potentiation or depression (LTP- and LTD)-like aftereffects. For the membrane-polarizing effects, it has been shown that current flow direction in relation to neuronal orientation determines the effects of stimulation. It seems to be relevant that the electrical field meets the long axis of a neuron to cause effects, and the orientation of the long axis of the neuron in relation to the electrical field, and not stimulation polarity per se, determines the direction of the effects (Kabakov, Muller, Pascual-Leone, Jensen, & Rotenberg, 2012). Moreover, with regard to a single neuron, current has to flow in and out of the neuron at different areas, and thus each neuron affected by tDCS will experience de- and hyperpolarizing effects at different sub-compartments. The physiologically relatively uniform effect might be caused by compartmental differences of susceptibility for polarization effects. Ion channels and receptors are more densely packed at the soma and axon level of neurons, as compared to dendrites, which might lead to the assumption that these compartments are the most relevant for tDCS effects. Indeed, cell-culture experiments suggest that anodal tDCS hyperpolarizes the membrane potential in the apical dendritic regions and depolarizes it in the somatic region, whereas the cathode has a reversed effect (Radman et al., 2009). However, the situation is more complex in the human brain, where gyration might result in heterogeneous orientation of electrical fields in relation to neurons, and thus result in antagonistic alterations of excitability in single neurons, as proposed by the results of a modeling study (Reato et al., 2013). Nevertheless, the impact of tDCS on excitability alterations at least in the human motor cortex, but also animal cortices, seems to be fairly homogeneous for the target region (Bindman, Lippold, & Redfearn, 1964; Nitsche & Paulus, 2000, 2001). Not only in animal models and modeling studies, but also for the human brain a polarization effect of tDCS on neuronal membranes is suggested because block of voltage-gated ion channels in healthy subjects, which should reduce depolarization, prevents effects of anodal tDCS on excitability (Nitsche, Fricke, et al., 2003). Moreover, the effects of tDCS in human beings seem to be primarily localized intracortically, including cortico-cortical afferents (Boros, Poreisz, Munchau, Paulus, & Nitsche, 2008).
If applied for a few minutes, tDCS induces excitability alterations, which can last for over 1 hr after the end of stimulation (Nitsche, Nitsche, et al., 2003; Nitsche & Paulus, 2001). These excitability alterations probably reflect calcium-dependent plastic changes driven by the glutamatergic system: Previous studies found that NMDA receptor block abolished anodal and cathodal stimulation-induced excitability alterations, whereas an NMDA receptor agonist prolonged, and calcium channel block abolished anodal tDCS-induced facilitation (Nitsche, Fricke, et al., 2003; Nitsche, Liebetanz, et al., 2004). Besides these effects, neuromodulators can also have a complex nonlinear impact on tDCS-induced neuroplasticity. Amphetamine and serotonin boost excitability-enhancing effects of anodal tDCS (Nitsche, Grundey, et al., 2004; Nitsche et al., 2009), whereas the excitability-diminishing effects of cathodal tDCS are prolonged by dopaminergic agents (Kuo, Paulus, & Nitsche, 2008; Monte-Silva et al., 2009; Monte-Silva, Liebetanz, Grundey, Paulus, & Nitsche, 2010). Thus, respective combination of drugs and stimulation might be suited to boost tDCS effects in future studies. In addition to neuronal effects on glutamatergic synapses, it has also been suggested that in the development of the aftereffects both glial cells (Ruohonen & Karhu, 2012) and non-synaptic mechanisms may play a role (Ardolino, Bossi, Barbieri, & Priori, 2005).
Using tDCS, the current polarity is the main determinant. Polarity-specific physiological aftereffects of tDCS are most consistently observed in the motor domain (see above), where in a medium dose range anodal tDCS leads to an increase of cortical excitability whereas cathodal tDCS decreases it. Similar effects were identified for visual cortex stimulation (e.g., Antal, Kincses, et al., 2004). However, the extent to which anodal and cathodal sources produce net effects on excitation and inhibition might also depend on the macroscopic geometry of the stimulated area (see above), and the state of the target region (see below), and is essentially determined by task performance (Antal, Terney, Poreisz, & Paulus, 2007). According to the antagonistic physiological effects of anodal and cathodal stimulation observed by M1 stimulation, a frequently made assumption is that anodal tDCS should improve, while cathodal tDCS should decrease cognitive abilities. However, the bipolar effects found by M1 stimulation cannot be translated one-to-one to the cognitive domain (Jacobson, Koslowsky, & Lavidor, 2012). Performance-improving effects of anodal tDCS were demonstrated for various cognitive functions including working memory (e.g., Zaehle, Sandmann, Thorne, Jancke, & Herrmann, 2011), executive functions (e.g., Dockery, Hueckel-Weng, Birbaumer, & Plewnia, 2009), declarative memory (e.g., Javadi & Walsh, 2012), and implicit learning (e.g., de Vries et al., 2010), but anodal tDCS also impaired categorization (e.g., Ambrus et al., 2011b) and performance in an episodic memory test (Zwissler et al., 2014). Cathodal tDCS has been shown to decrease performance of working memory (e.g., Berryhill, Wencil, Branch Coslett, & Olson, 2010; Marshall, Molle, Siebner, & Born, 2005), and verbal fluency (Iyer et al., 2005), but enhanced executive functions (Dockery et al., 2009) and complex motion perception (Antal, Nitsche, et al., 2004), improved episodic memory (Zwissler et al., 2014) and led to behavioral improvement (Dockery et al., 2009; Pirulli, Fertonani, & Miniussi, 2014). Several factors may explain this variability in the cognitive domain. Task characteristics such as “noisiness” might be relevant (Antal, Nitsche, et al., 2004). In case of a non-noisy condition, excitability-enhancing stimulation will foster the task-relevant activation pattern to cross the activation threshold, and therefore improve performance, whereas excitability-diminishing stimulation will reduce activation. In contrast, in a “noisy” task, excitability-enhancing stimulation will enhance the probability that pre-activated suboptimal neuronal activation patterns cross the activation threshold, whereas excitability-diminishing stimulation would reduce suboptimal activation patterns to subthreshold level, but keeping the optimal pattern, which should show the strongest activation, supra-threshold. Indeed, respective effects of tDCS have been shown for a random dot protocol (Antal, Nitsche, et al., 2004). In further accordance, it was observed that the effects of tDCS depend on the strength of the signal (the neural activity operational to the task)-to-noise (random neural activity) ratio (Dockery et al., 2009; Miniussi, Harris, & Ruzzoli, 2013).
Recent papers suggest that also in the motor domain the interindividual variability to tDCS is higher, than it was reported previously (López-Alonso, Cheeran, Río-Rodríguez, & Fernández-Del-Olmo, 2014; Wiethoff, Hamada, & Rothwell, 2014). Attempts to explain variability include calculation of local skull bone thinnings, which may serve as current pathways independent of the exact positioning of larger electrodes (Opitz et al., 2015).
Current density is also an important parameter of tDCS, with larger current densities resulting in stronger effects, at least within certain limits (e.g., Bastani & Jaberzadeh, 2013). Too high current densities can however, result in reverse effects (Batsikadze, Moliadze, Paulus, Kuo, & Nitsche, 2013).
Stimulation duration affects the duration and magnitude of the aftereffects. To obtain only acute effects on excitability, which are membrane polarization-driven, but include no synaptic plasticity, 4 s stimulation duration is well suited (Nitsche, Nitsche, et al., 2003; Nitsche & Paulus, 2000). Stimulation for 3 min or longer induces aftereffects. Longer stimulation duration leads to more pronounced changes (Nitsche & Paulus, 2000, 2001); although the relationship is not strictly linear. For example, the application of anodal tDCS for 26 min resulted in inhibitory aftereffects, probably due to calcium overflow (Batsikadze et al., 2013). However, 2 × 13 min anodal tDCS with an interval of 20 min resulted in LTP-like effects, which lasted for more than 24 hr after stimulation, in principal accordance with the rationale of animal experimentation’s protocols to induce late phase LTP (Reymann & Frey, 2007). When combined with a task, repeated application of tDCS can also result in long-lasting effects. For example, the performance improvement caused by anodal tDCS over the M1 in a sequential visual isometric pinch task, which was trained during five consecutive days, was still present 3 months later, compared to sham stimulation (Reis et al., 2009).
However, for stimulation of other cortical areas (e.g., visual cortex) different results might be achieved. In a recently published paper, Pirulli et al. (2014) showed that introducing short breaks (2 min) or using different stimulation durations (9 vs. 22 min) during the tDCS over the visual cortex in combination with a learning task did not play any role for the impact on cognitive performance.
Timing of stimulation is also an important issue, especially with regard to cognitive neuroscience experiments. It has been reported that anodal tDCS over M1 during execution of a motor sequence-learning task, which involves this area, enhanced performance (Nitsche, Schauenburg, et al., 2003), while anodal tDCS before the execution of the task did not lead to task performance alterations (Kuo, Unger, et al., 2008). Interestingly tDCS of the premotor cortex improved performance only during consolidation, which includes premotor contribution, but not during the initial learning process (Nitsche et al., 2010). In accordance, Stagg et al. (2011) observed that application of tDCS during performance of an explicit sequence-learning task led to modulation of behavior in a polarity-specific manner: relative to sham stimulation, anodal tDCS was associated with faster learning and cathodal tDCS with slower learning. Application of tDCS prior to performance of the sequence-learning task led to slower learning after both anodal and cathodal tDCS. These results suggest that it is relevant to stimulate the respective task-involved area during its task-related activation. This might be especially important for learning processes, in which task-related plasticity might be boosted by tDCS-generated plasticity. Related to this point, the state of the cortex during stimulation is also a determining factor regarding the effects of tDCS (Silvanto, Muggleton, & Walsh, 2008). For example, aftereffects are significantly modulated by cognitive and motor activities, compared to the resting conditions (Antal et al., 2007). Applying a motor task during stimulation a decrease in MEP amplitude independently from the type of the stimulation was observed.
Interindividual differences, such as genetic and gender differences, may modulate the effects of tDCS. The brain-derived neurotrophic factor (BDNF) has been shown to play a role in the mechanisms of neuroplasticity induction, giving rise to cellular events resulting in LTP and LTD (e.g., Mei, Nagappan, Ke, Sacktor, & Lu, 2011; Schinder & Poo, 2000). In a retrospective analysis Antal and colleagues identified different efficacy of stimulation, when they compared individuals with different alleles of the Val66Met single nucleotide polymorphism of the BDNF gene (Antal et al., 2010): The heterozygotes (Val66Met) reacted stronger to tDCS, independent from stimulation polarity. However, with increased number of the subjects, this effect lost its significance (Chaieb, Antal, Ambrus, & Paulus, 2014). With regard to MEP measurements women seemed to have longer inhibitory aftereffects after cathodal stimulation. However, in the visual cortex cathodally induced excitability effects showed no significant difference between genders whereas in women anodal stimulation heightened cortical excitability significantly when compared to the age-matched male subject group (Chaieb, Antal, & Paulus, 2008; Kuo, Paulus, & Nitsche, 2006).
In summary, apart from stimulation parameters, such as polarity, current density, and duration of the stimulation, the state of the subjects or patients before and during stimulation, gender, genetic polymorphisms, time of day, hormonal status, and others may modify the final outcome. Thus the appropriate application of tDCS highly depends on skilled applications. It is thus not surprising that meta-analyses on explorative studies, which take respective factors not systematically into account, will end up with negative results, if studies differ in these parameters.
Transcranial Alternating Current Stimulation (tACS)
In transcranial alternating current stimulation (tACS), the externally applied alternating current is assumed to entrain endogenous neural oscillations possibly by increasing the power of oscillations or the phase-locking index between the driving and endogenous oscillations (Ali, Sellers, & Frohlich, 2013; Antal et al., 2008; Cecere, Rees, & Romei, 2015; Helfrich, Schneider, et al., 2014; Neuling, Rach, & Herrmann, 2013). tACS as a method was developed in order to study and better understand the causal relationship between brain oscillations and cognitive functions and as a possible therapeutic tool trying to restore disturbed oscillations in different neurological diseases, such as Parkinson’s disease and schizophrenia. tACS is a form of tES involving application of sinusoidal current across the scalp with a given frequency (Antal et al., 2008; Helfrich, Schneider, et al., 2014; Kar & Krekelberg, 2014; Moliadze, Antal, & Paulus, 2010a; Neuling et al., 2013; Neuling, Rach, Wagner, Wolters, & Herrmann, 2012; Zaehle, Rach, & Herrmann, 2010). tACS lacks the polarity constraint observed by tDCS. During one half cycle of an oscillation, one electrode serves as anode and the other as cathode and current strength increases and decreases following the half sine wave. During the other half cycle, the pattern reverses. In the case of tACS the frequency, intensity, and phase are the major influencing parameters regarding the efficacy of the intervention.
Transcranial alternating current stimulation (tACS) can be applied in a wide frequency range such as at conventional EEG frequencies (0.1–80 Hz), or in the so-called “ripple” range (140 Hz, see below) (Moliadze et al., 2010a). As with tDCS, the effects of tACS as revealed by TMS may not correlate with other types of assessments. For example, only a nonsignificant trend toward MEP amplitude inhibition following 10 Hz AC stimulation over M1 was observed in an early study at a low amplitude of 0.4 mA (Antal et al., 2008), while 10 Hz stimulation improved visuomotor implicit learning slightly, using a serial reaction time task. Please note that this dissociation between MEP excitability changes and implicit learning under tACS was also evident, when using higher frequencies (Moliadze et al., 2010a). 140 Hz stimulation induced the largest MEP increase, whereas 250 Hz tACS improved implicit motor learning.
In a study using 20 Hz tACS over M1 and placing the return electrode over the parietal cortex, increased corticospinal excitability was observed as compared to the usual contralateral frontal electrode (Feurra, Paulus, Walsh, & Kanai, 2011). On the other side it slowed down voluntary movements using a visuomotor task (Pogosyan, Gaynor, Eusebio, & Brown, 2009) but in parallel it increased beta coherence between scalp-recorded activity and electromyographic activity (EMG) of the first dorsal interosseus muscle. By using low-intensity tACS of 250 μA with 25 and 40 Hz lucid dreaming was facilitated (Voss et al., 2014).
Whereas TMS over the occipital cortex can elicit cortical phosphenes, tACS at much lower intensities of up to about 1 mA most likely induces only retinal phosphenes, in particular if at least one of the electrodes is close to the eyes, in a frequency- and intensity-dependent way (Paulus, 2010; Schutter & Hortensius, 2010; Turi et al., 2013). However, tACS can probably influence visual cortical functions at a subthreshold level as shown by modification of TMS-induced phosphene thresholds (Kanai, Paulus, & Walsh, 2010). Cortical contrast-discrimination thresholds were decreased only during 60 Hz tACS, but not during 40 and 80 Hz stimulations (Laczó, Antal, Niebergall, Treue, & Paulus, 2012). tACS applied over the parieto-occipital (PO9 and PO10 according to the 10-20 EEG system) electrode positions at the individual alpha frequency range induced an entrainment of the applied oscillatory activity (Zaehle et al., 2010). When the stimulation frequency was fixed at 6 and 10 Hz, tACS impaired performance in the visual detection task (Brignani, Ruzzoli, Mauri, & Miniussi, 2013).
tACS applied outside the EEG frequency range (140 Hz and in the low kHz range) increases motor cortical excitability in a similar way as tDCS with 1 mA intensity (Chaieb, Antal, & Paulus, 2011; Moliadze et al., 2010a). Stimulation at 80 Hz remains without an effect, while 250 Hz clearly had a delayed onset and shorter lasting response, compared to the MEP increase observed during and after 140 Hz tACS.
The effect of tACS is intensity-dependent, there is some evidence that inhibitory networks respond at lower stimulation intensities than excitatory networks. A trend in a first study (Antal et al., 2008) using a low intensity of 0.4 mA over M1 toward MEP inhibition following 10 Hz AC stimulation was confirmed later with higher frequencies (140 Hz) (Moliadze, Atalay, Antal, & Paulus, 2012). Whereas 0.2 mA intensity had no effect, an intensity of 0.4 mA led to MEP inhibition, 0.6 and 0.8 mA did not provide a significant effect (Moliadze et al., 2012). Again, with 1 mA a significant increase of the MEP amplitudes was obtained. This suggests that stimulation applied at 0.4 mA intensity may inhibit intracortical facilitatory effects on corticospinal motoneurons or the inhibitory circuits are preferentially excited with lower intensities.
The effect of tACS also depends on the state of the brain before and during stimulation: It was recently documented that the aftereffects of tACS applied at the individual alpha frequency level may depend on the individual endogenous power (Neuling et al., 2013). Similar results were observed by Cecere et al. (2015): For stimulation at the individual alpha frequency or ± 2 Hz frequency over the occipital cortex during a sound-induced double-flash illusion task, only the individual alpha frequency stimulation improved performance.
With regard to higher frequencies, opposing effects at beta and gamma frequencies depending on timing of the administration of tACS during a motor task do exist (Joundi, Jenkinson, Brittain, Aziz, & Brown, 2012). Using a visually driven go-no-go task, stimulation at 20 Hz required a significant slowing of force production in the go task, however, stimulation in no-go trials, where the triggered motor task involved inhibition, led to a major reduction in force generation. In contrast, 70 Hz tACS was ineffective during no-go cues, but increased performance during go trials.
When using more than two electrodes, it is possible to manipulate the phase of the stimulation, which refers to the angle of the sinusoid relative to different electrodes, enabling antiphase or in-phase stimulation. Stimulating the left frontal and parietal cortex by 6 Hz tACS in phase, cognitive performance in a delayed letter discrimination task was improved, when stimulating out of phase it was worsened (Polania, Nitsche, Korman, Batsikadze, & Paulus, 2012). At the temporal cortex using 10 Hz with a DC offset it was found that manipulation of the phase resulted in different auditory detection thresholds (Neuling et al., 2012). Nevertheless, the DC offset used in this study leaves open the possibility of a DC effect. A bilateral 40 Hz stimulation was administered over the visual cortex with a 180° phase difference between hemispheres, while subjects were presented with bistable motion stimuli (Struber, Rach, Trautmann-Lengsfeld, Engel, & Herrmann, 2014). In this task a visual stimulus switches between horizontal and vertical apparent motion thought to indicate interhemispheric gamma coupling. The authors observed that with the increase in interhemispheric gamma band coherence the portion of perceived horizontal motion decreased when the 40 Hz stimulation was applied, but there was no change during 6 Hz stimulation. It was suggested that this is probably related to the functional decoupling of the two hemispheres that resulted in an impaired motion perception.
The physiological mechanisms of tACS are less well understood compared to tDCS. Computational network simulation studies combined with in vitro experiments showed the possibility of entraining neural oscillations by applying external electric fields of relatively low amplitudes (minimum estimated cortical electric field of 0.2 mV/mm), if intrinsic frequency was closely matched with the externally applied electric field (Fröhlich & McCormick, 2010; Reato et al., 2010; Schmidt et al., 2014). In human experiments tACS applied in the EEG range is believed to mainly entrain with or synchronize neuronal networks and might enhance the information transfer and speed up processing (e.g., Butts et al., 2007; Helfrich, Knepper, et al., 2014; Helfrich, Schneider, et al., 2014; Struber et al., 2014; Voss et al., 2014; Zaehle et al., 2010). On the other side the repeated modification of the synapse once exposed to an alternating electrical field might also alter the associated biochemical mechanisms, such as accumulation of calcium in the presynaptic nerve terminals leading to short-term synaptic plastic effects (Citri & Malenka, 2008).
Transcranial Random Noise Stimulation (tRNS)
tRNS is the noninvasive application of a low-intensity alternating current where the intensity and the frequency of the current vary in a randomized manner. tRNS was developed with the intent to desynchronize pathological cortical rhythms (Terney, Chaieb, Moliadze, Antal, & Paulus, 2008) but additional putative mechanisms, such as stochastic resonance (Stacey & Durand, 2000), may be relevant (see below). The stimulation is biphasic, like with tACS and various forms of noise may be applied. In a typical study during tRNS, a frequency spectrum between 0.1 Hz and 640 Hz (full spectrum) or 101–640 Hz (high-frequency stimulation) is applied. The probability function of the RN current stimulation may follow a Gaussian or bell-shaped curve with zero mean and a variance, for which 99% of all generated current levels are between ± 1 mA. In the frequency domain all coefficients of the random sequence have a similar size (“white noise”). It was observed that the high-frequency subdivision between 100 and 640 Hz of the whole tRNS spectrum is functionally responsible for alteration of excitability at least in the M1 and clearly superior to low-frequency stimulation (Terney et al., 2008).
Although their modes of action might differ, tRNS had an effect comparable to that of anodal tDCS on MEP development over time, that is enhancing the cortical excitability of the targeted cortical area; Terney and colleagues have shown that 10 min of tRNS applied over the M1 with 1 mA intensity can cause excitatory aftereffects lasting up to 1.5 hr, and is capable of improving the performance in the acquisition and early consolidation phase of an implicit motor learning task (Terney et al., 2008). Effects of high-frequency tRNS were also demonstrated by Fertonani, Pirulli, and Miniussi (2011). In this study tRNS was applied to the visual cortices of healthy subjects. A significant enhancement in a visual perceptual learning task was observed. This improvement was significantly higher than the improvement obtained with anodal tDCS. Stimulation of the parietal cortex during the application of a paradigm assessing the ability to discriminate numerosity yielded better and longer lasting improvement (up to 16 weeks post-training) of the precision of the task compared with cognitive training in the absence of stimulation (Cappelletti et al., 2013). Furthermore, this improvement induced by parietal tRNS was transferred to proficiency in other parietal lobe-based quantity judgments, that is, time and space discrimination. In contrast, application of tRNS to the right DLPFC impaired categorical learning in a prototype distortion task (Ambrus et al., 2011a). With regard to the effect of tRNS on working memory performance, a study showed no effect of stimulation over the DLPFC (Mulquiney, Hoy, Daskalakis, & Fitzgerald, 2011). These results demonstrate that, depending on the learning regime, tRNS can induce long-term enhancement of cognitive and brain functions.
The physiological mechanisms of tRNS are not completely clarified yet, it is so far not clear if tRNS may interfere with ongoing network oscillations as mentioned in the original publication (Terney et al., 2008), with homeostatic mechanisms (Fertonani et al., 2011) or induces plastic changes in the brain. One potential effect of tRNS might be improvement of the signal-to-noise ratio in the central nervous system and the sensitization of sensory processing (Miniussi et al., 2013; Moss, Ward, & Sannita, 2004). It was suggested that tRNS may increase synchronization of neural firing through amplification of subthreshold oscillatory activity, which in turn reduces the amount of endogenous noise (Miniussi et al., 2013). Besides this, the effects of tRNS might be associated with repetitive opening of Na+ channels, as it was observed in a study investigating the application of alternating current stimulation to rat hippocampal slices (Schoen & Fromherz, 2008). Indeed, the sodium-channel blocker carbamazepine and the GABA-A agonist lorazepam showed a tendency toward decreasing the efficacy of the stimulation (Chaieb, Antal, & Paulus, 2015). Finally, it is proposed that tRNS might induce long-term hemodynamic changes in the human brain that might be related to neuroplastic reorganization. A recent study reported that the repeated bifrontal application of tRNS for five days enhanced the speed of both calculation- and memory-recall-based arithmetic learning (Snowball et al., 2013). These behavioral improvements were associated with defined hemodynamic responses consistent with more efficient neurovascular coupling within the left DLPFC. Six months later the behavioral and physiological modifications in the stimulated group relative to sham controls were still present.
Conclusion
Generally, tES methods seem to be an efficient tool to alter cortical excitability and cognition and behavior. One of the main advantages of tES techniques is that they can not only disrupt, but can also improve definite cortical functions that makes the identification of the involvement of a target area in cognitive processing easier. The performance improvement induced by an “easy-to-handle” stimulator might result in future options to improve functions in everyday life of patients. However, several limitations do apply. Especially, with regard to stimulation of specific areas, a disadvantage of tES is its low focality. This limitation will probably be solved in the near future by modification of stimulation electrodes and protocols. Furthermore, the physiological effects have been most extensively tested for M1. Psychological and behavioral effects show variability between studies, which might be intrinsic to neuromodulatory approaches in general.
The main advantage of tACS and tRNS, compared to tDCS, is the direction insensitivity of the stimulation and the higher skin perception threshold during stimulation. However, the more recent methods of tACS and tRNS will not replace tDCS. Each method has advantages and disadvantages mentioned in this review; they may be combined, the parameter space is large and obviously has an indefinitely number of possibilities. Hypothesis-driven approaches based on brain neurophysiology are expected to provide the largest progress in future.
Walter Paulus is director and chair of the Department for Clinical Neurophysiology at the University Medical Center Göttingen, Germany. His research interest is modulation of human cortical neuroplasticity by transcranial stimulation methods and investigation of human cortical physiology by transcranial magnetic stimulation.
Michael A. Nitsche is director of the Department of Psychology and Neurosciences at the Leibniz Research Centre for Working Environment and Human Factors in Dortmund, Germany. His main research interest is the physiological Foundation of cognition and behavior, including noninvasive brain stimulation, neuropsychopharmacology, and functional imaging.
Andrea Antal is a Group Leader at the Department for Clinical Neurophysiology at the University Medical Center Göttingen, Germany. Her research interest is in developing new methods in order to induce and modulate neuroplastic changes in the human brain.
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