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The original protocol of Paired Associative Stimulation (PAS) in humans implies repetitive cortical and peripheral nerve stimuli, delivered at specific inter-stimulus intervals, able to elicit non-invasively long-term potentiation (LTP)- and long-term depression (LTD)-like plasticity in the human motor cortex. PAS has been designed to drive cortical LTP/LTD according to the Hebbian rule of associative plasticity. Over the last two decades, a growing number of researchers have increasingly used the PAS technique to assess cortical associative plasticity in healthy humans and in patients with movement disorders and other neuropsychiatric diseases. The present review covers the physiology, pharmacology, pathology and motor effects of PAS. Further sections of the review focus on new protocols of "modified PAS" and possible future application of PAS in neuromorphic circuits designed for brain-computer interface., (Copyright © 2017 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

The spatial extent of transcranial magnetic stimulation (TMS) is of paramount interest for all studies employing this method. It is generally assumed that the induced electric field is the crucial parameter to determine which cortical regions are excited. While it is difficult to directly measure the electric field, one usually relies on computational models to estimate the electric field distribution. Direct electrical stimulation (DES) is a local brain stimulation method generally considered the gold standard to map structure-function relationships in the brain. Its application is typically limited to patients undergoing brain surgery. In this study we compare the computationally predicted stimulation area in TMS with the DES area in six patients with tumors near precentral regions. We combine a motor evoked potential (MEP) mapping experiment for both TMS and DES with realistic individual finite element method (FEM) simulations of the electric field distribution during TMS and DES. On average, stimulation areas in TMS and DES show an overlap of up to 80%, thus validating our computational physiology approach to estimate TMS excitation volumes. Our results can help in understanding the spatial spread of TMS effects and in optimizing stimulation protocols to more specifically target certain cortical regions based on computational modeling.

Functional magnetic resonance imaging (fMRI) of brain activation during transcranial electrical stimulation is used to provide insight into the mechanisms of neuromodulation and targeting of particular brain structures. However, the passage of current through the body may interfere with the concurrent detection of blood oxygen level-dependent (BOLD) signal, which is sensitive to local magnetic fields. To test whether these currents can affect concurrent fMRI recordings we performed conventional gradient echo-planar imaging (EPI) during transcranial direct current (tDCS) and alternating current stimulation (tACS) on two post-mortem subjects. tDCS induced signals in both superficial and deep structures. The signal was specific to the electrode montage, with the strongest signal near cerebrospinal fluid (CSF) and scalp. The direction of change relative to non-stimulation reversed with tDCS stimulation polarity. For tACS there was no net effect of the MRI signal. High-resolution individualized modeling of current flow and induced static magnetic fields suggested a strong coincidence of the change EPI signal with regions of large current density and magnetic fields. These initial results indicate that (1) fMRI studies of tDCS must consider this potentially confounding interference from current flow and (2) conventional MRI imaging protocols can be potentially used to measure current flow during transcranial electrical stimulation. The optimization of current measurement and artifact correction techniques, including consideration of the underlying physics, remains to be addressed., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Sinusoidal transcranial alternating current stimulation (tACS) at 5 kHz applied for 10 min at 1 mA intensity over the hand area of the primary motor cortex (M1) results in sustained changes in cortical excitability as previously demonstrated., Objective: Here we have assessed safety aspects of this stimulation method by measuring neuron-specific enolase (NSE) levels, examining electroencephalogram (EEG) traces and analyzing anatomical data by using magnetic resonance imaging (MRI)., Methods: Altogether 18 healthy volunteers participated in the study. tACS was applied at 5 kHz for a duration of 10 min over the left M1 at an intensity of 1 mA., Results: After stimulation no significant changes were detected in NSE levels, no structural alterations were observed in the anatomical scans and no pathological changes were found in the EEG recordings., Conclusions: Our data imply that the application of tACS is safe at least within these parameters and with these applied protocols., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Transcranial direct current stimulation (tDCS) induces long-lasting NMDA receptor-dependent cortical plasticity via persistent subthreshold polarization of neuronal membranes. Conventional bipolar tDCS is applied with two large (35 cm(2)) rectangular electrodes, resulting in directional modulation of neuronal excitability. Recently a newly designed 4 × 1 high-definition (HD) tDCS protocol was proposed for more focal stimulation according to the results of computational modeling. HD tDCS utilizes small disc electrodes deployed in 4 × 1 ring configuration whereby the physiological effects of the induced electric field are thought to be grossly constrained to the cortical area circumscribed by the ring., Objective: We aim to compare the physiological effects of both tDCS electrode arrangements on motor cortex excitability., Methods: tDCS was applied with 2 mA for 10 min. Fourteen healthy subjects participated, and motor cortex excitability was monitored by transcranial magnetic stimulation (TMS) before and after tDCS., Results: Excitability enhancement following anodal and a respective reduction after cathodal stimulation occurred in both, conventional and HD tDCS. However, the plastic changes showed a more delayed peak at 30 min and longer lasting after-effects for more than 2 h after HD tDCS for both polarities, as compared to conventional tDCS., Conclusion: The results show that this new electrode arrangement is efficient for the induction of neuroplasticity in the primary motor cortex. The pattern of aftereffects might be compatible with the concept of GABA-mediated surround inhibition, which should be explored in future studies directly., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objective: Slowly ramping down initial current intensity after a minimal interval of stimulation is the de facto standard for sham stimulation in transcranial electrical stimulation research. The aim of this study is to further investigate the effectiveness of this method of blinding., Methods: We have investigated the time course of the cutaneous perception during 10 min of anodal, cathodal, and sham transcranial direct current stimulation, probing the perceived strength and site of the perceived sensation. We have also utilized post-stimulation assessment and measurements of sleepiness prior to and after the intervention. Previous exposure to tDCS has also been taken into account: the experiment has been repeated in naïve and experienced subject groups, and a group consisting of investigators who use tDCS as a research tool., Results: Although we have observed a general reduction in the perceived strength of the stimulation with time, we have not found the complete disappearance of the cutaneous perception during either the verum or the sham conditions. Experienced subjects were more likely to be able to differentiate between trials with stimulation and non-stimulation trials and to correctly identify sham and verum stimulation conditions., Conclusion: When taking only naïve and experienced subjects into account, there was no significant difference between the strength of the perceived stimulation in the verum and sham conditions. The fade-in - short stimulation - fade-out sham stimulation can be indistinguishable from verum stimulation, but not because it mimics the disappearance of the cutaneous sensations associated with the verum stimulation, but because these sensations persist also in the sham stimulation. The significance of this finding with potential confounding factors and limitations are discussed., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: The growing use of transcranial electric and magnetic (EM) brain stimulation in basic research and in clinical applications necessitates a clear understanding of what constitutes the dose of EM stimulation and how it should be reported., Methods: This paper provides fundamental definitions and principles for reporting of dose that encompass any transcranial EM brain stimulation protocol., Results: The biologic effects of EM stimulation are mediated through an electromagnetic field injected (via electric stimulation) or induced (via magnetic stimulation) in the body. Therefore, transcranial EM stimulation dose ought to be defined by all parameters of the stimulation device that affect the electromagnetic field generated in the body, including the stimulation electrode or coil configuration parameters: shape, size, position, and electrical properties, as well as the electrode or coil current (or voltage) waveform parameters: pulse shape, amplitude, width, polarity, and repetition frequency; duration of and interval between bursts or trains of pulses; total number of pulses; and interval between stimulation sessions and total number of sessions. Knowledge of the electromagnetic field generated in the body may not be sufficient but is necessary to understand the biologic effects of EM stimulation., Conclusions: We believe that reporting of EM stimulation dose should be guided by the principle of reproducibility: sufficient information about the stimulation parameters should be provided so that the dose can be replicated., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technique that has been shown to alter cortical excitability and activity via application of weak direct currents. Beyond intracortical effects, functional imaging as well as behavioral studies are suggesting additional tDCS-driven alterations of subcortical areas, however, direct evidence for such effects is scarce. We aimed to investigate the impact of tDCS on cortico-subcortical functional networks by seed functional connectivity analysis of different striatal and thalamic regions to prove tDCS-induced alterations of the cortico-striato-thalamic circuit. fMRI resting state data sets were acquired immediately before and after 10 min of bipolar tDCS during rest, with the anode/cathode placed over the left primary motor cortex (M1) and the cathode/anode over the contralateral frontopolar cortex. To control for possible placebo effects, an additional sham stimulation session was carried out. Functional coupling between the left thalamus and the ipsilateral primary motor cortex (M1) significantly increased following anodal stimulation over M1. Additionally, functional connectivity between the left caudate nucleus and parietal association cortices was significantly strengthened. In contrast, cathodal tDCS over M1 decreased functional coupling between left M1 and contralateral putamen. In summary, in this study, we show for the first time that tDCS modulates functional connectivity of cortico-striatal and thalamo-cortical circuits. Here we highlight that anodal tDCS over M1 is capable of modulating elements of the cortico-striato-thalamo-cortical functional motor circuit., (Copyright © 2011 Wiley Periodicals, Inc.)

Background: Recently we have shown that transcranial random noise (tRNS) and 140 Hz transcranial alternating current stimulations (tACS), applied over the primary motor cortex (M1) and using 10 min stimulation duration and 1 mA intensity, significantly increases cortical excitability as measured by motor evoked potentials at rest before and after stimulation., Objective/hypothesis: Here, by decreasing the stimulation intensity in 0.2 mA steps from 1.0 mA, we investigate to what extent intensity depends on the induced after-effects., Methods: All twenty-five subjects participated in two different experimental sessions each. They received tACS using 140 Hz frequency and full spectrum tRNS at five different intensities on separate days. Sham stimulation was used as a control., Results: Instead of receiving a simple threshold, unexpectedly, in these two independent data sets at threshold intensities of 0.4 mA we found a switch of the already known excitation achieved with an intensity of 1 mA to inhibition. The intermediate intensity ranges of 0.6 and 0.8 mA had no effect at all. Interestingly, the inhibition produced by 140 Hz tACS was stronger than that induced by tRNS., Conclusions: In summary, we have shown here the possibility of selectively controlling the enhancement or reduction of M1 excitability by applying different intensities of high frequency transcranial electrical stimulation., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: Transcranial direct current stimulation (tDCS) was reintroduced about a decade ago as a tool for inducing long-lasting changes in cortical excitability. Recently it has been shown that both motor and cognitive functions can be influenced by tDCS. Here, we tested the effect of tDCS on the blood-oxygen level dependent (BOLD) signal evoked by coherent visual motion using functional magnetic resonance imaging (fMRI)., Methods: The subjects underwent 10 min of cathodal and sham tDCS, applied over the right MT+. Following stimulation, random dot kinomatograms (RDK) with different percentages (10%, 30%, 50%) of coherently moving dots were presented., Results: All motion stimuli activated MT+ in both stimulation conditions. However, cathodal stimulation led to an increase in fMRI signal in MT+ when compared to sham stimulation. This effect did not depend on the coherence level of the visual stimulus., Conclusions: Here, we show for the first time, that cathodal tDCS stimulation leads to elevated fMRI signal in the human visual cortex.

Objective: We have investigated the cutaneous perception differences for anodal and cathodal transcranial direct current stimulation (tDCS) and transcranial random noise stimulation (tRNS) between two electrode configurations: a standard, rectangle-shaped, and a circle-shaped, round geometry with the same surface area, and thus, same nominal current distribution. We have aimed to find whether a smaller perimeter length and the absence of corners in the case of the round configuration would lead to altered skin perception characteristics when compared to the rectangular geometry., Methods: Twelve subjects were tested for tDCS and tRNS skin perception characteristics in the intensity range of 200-2000 μA using round and rectangular electrode configurations., Results: We have not found any substantial differences between detection thresholds, detection rates, false positive rates or consistent alterations in the sites of perceived stimulation., Conclusion: We conclude that there is no difference between the round and the rectangular electrode configurations regarding their blinding potentials., Significance: The results of this investigation indicate that the altering of the electrode geometry to a round configuration is unwarranted for better blinding purposes in future studies using tDCS and tRNS., (Copyright © 2010 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

Background and Purpose: Neuroplastic alterations of cortical excitability and activity represent the likely neurophysiological foundation of learning and memory formation. Beyond their induction, alterations of these processes by subsequent modification of cortical activity, termed metaplasticity, came into the focus of interest recently. Animal slice experiments demonstrated that neuroplastic excitability enhancements, or diminutions, can be abolished by consecutive subthreshold stimulation. These processes, termed de-potentiation, and de-depression, have so far not been explored in humans., Methods: We combined neuroplasticity induction by transcranial direct current stimulation (tDCS) applied to the hand area of primary motor cortex (M1), which can be used to induce long-lasting excitability enhancements or reductions, dependent on the polarity of stimulation, with short-lasting voluntary muscle contraction (VMC), which itself does not induce plastic cortical excitability changes. Corticospinal and intra-cortical M1 excitability were monitored by different transcranial magnetic stimulation (TMS) protocols., Results: VMC reduced or tended to reverse the anodal tDCS-driven motor cortical excitability enhancement and the cathodal tDCS-induced excitability diminution. Our findings thus demonstrate de-potentiation- and de-depression-like phenomena at the system level in the human motor cortex., Conclusion: This neurophysiological study may contribute to a better understanding of the balance between induction and reversal of plasticity associated with motor learning and rehabilitation processes.

The visual system has the most complex circuitry of all the sensory systems and it also possesses the ability to undergo induced and spontaneous neuroplastic changes. Most of what we know about the functional organization of the visual system is derived from animal experiments or by correlating circumscribed anatomical lesions in patients and their visual perceptual deficits or dysfunctions. However, in the past years, significant achievements have been made in characterizing visual information processing in the human using non-invasive neurophysiological techniques, such as electrical stimulation of the brain. Transcranial direct (tDCS) and alternating current stimulation (tACS) applied through the skull was shown to directly modulate the excitability of the motor and visual cortices in human subjects. This review article focuses on these stimulation methods and summarizes the latest results with regard to the application of these method over the visual areas in healthy subjects and clinical populations.

Alleviating the symptoms of neurological diseases by increasing cortical excitability through transcranial stimulation is an ongoing scientific challenge. Here, we tackle this issue by interfering with high frequency oscillations (80–250 Hz) via external application of transcranial alternating current stimulation (tACS) over the human motor cortex (M1). Twenty-one subjects participated in three different experimental studies and they received on separate days tACS at three frequencies (80 Hz, 140 Hz and 250 Hz) and sham stimulation in a randomized order. tACS with 140 Hz frequency increased M1 excitability as measured by transcranial magnetic stimulation-generated motor evoked potentials (MEPs) during and for up to 1 h after stimulation. Control experiments with sham and 80 Hz stimulation were without any effect, and 250 Hz stimulation was less efficient with a delayed excitability induction and reduced duration. After-effects elicited by 140 Hz stimulation were robust against inversion of test MEP amplitudes seen normally under activation. Stimulation at 140 Hz reduced short interval intracortical inhibition, but left intracortical facilitation, long interval cortical inhibition and cortical silent period unchanged. Implicit motor learning was not facilitated by 140 Hz stimulation. High frequency stimulation in the ripple range is a new promising non-invasive brain stimulation protocol to increase human cortical excitability during and after the end of stimulation.

Background: Modulation of the serotonergic system affects long-term potentiation (LTP) and long-term depression (LTD), the likely neurophysiologic derivates of learning and memory formation, in animals and slice preparations. Serotonin-dependent modulation of plasticity has been proposed as an underlying mechanism for depression. However, direct knowledge about the impact of serotonin on neuroplasticity in humans is missing. Here we explore the impact of the serotonin reuptake blocker citalopram on plasticity induced by transcranial direct current stimulation (tDCS) in humans in a single-blinded, placebo-controlled, randomized crossover study., Methods: In 12 healthy subjects, anodal excitability-enhancing or cathodal excitability-diminishing tDCS was applied to the motor cortex under a single dose of 20-mg citalopram or placebo medication. Motor cortex excitability was monitored by single-pulse transcranial magnetic stimulation (TMS)., Results: Under placebo medication, anodal tDCS enhanced, and cathodal tDCS reduced, excitability for about 60-120 min. Citalopram enhanced and prolonged the facilitation induced by anodal tDCS, whereas it turned cathodal tDCS-induced inhibition into facilitation., Conclusions: Serotonin has a prominent impact on neuroplasticity in humans, which is in favor for facilitatory plasticity. Taking into account serotonergic hypoactivity in depression, this might explain deficits of learning and memory formation. Moreover, the results suggest that for therapeutic brain stimulation in depression and other neuropsychiatric diseases (e.g., in neurorehabilitation), serotonergic reinforcement may enhance facilitatory aftereffects and thereby increase the efficacy of these tools.

Objective: Invasive stimulation of the motor cortex has been used for years to alleviate chronic intractable pain in humans. In our study, we have investigated the effect of transcranial direct current stimulation (tDCS), a noninvasive stimulation method, for manipulating the excitability of cortical motor areas on laser evoked potentials (LEP) and acute pain perception. DESIGNS AND SETTINGS: The amplitude of the N1, N2, and P2 LEP components of 10 healthy volunteers were evaluated prior to and following anodal, cathodal, and sham stimulation of the primary motor cortex. In a separate experiment subjective, pain rating scores of 16 healthy subjects in two perceptual categories (warm sensation, mild pain) were also analyzed., Results: Cathodal tDCS significantly reduced the amplitude of N2 and P2 components compared with anodal or sham stimulation. However, neither of the tDCS types modified significantly the laser energy values necessary to induce moderate pain. In a separate experiment, cathodal stimulation significantly diminished mild pain sensation only when laser-stimulating the hand contralateral to the side of tDCS, while anodal stimulation modified warm sensation., Conclusions: The possible underlying mechanisms of our findings in view of recent neuroimaging studies are discussed. To our knowledge this study is the first to demonstrate the mild antinociceptive effect of tDCS over the primary motor cortex in healthy volunteers.

Purpose: EMG-triggered electrostimulation (EMG-ES) may improve the motor performance of affected limbs of hemiparetic stroke patients even in the chronic stage. This study was designed to characterize cortical activation changes following intensified EMG-ES in chronic stroke patients and to identify predictors for successful rehabilitation depending on disease severity., Methods: We studied 9 patients with severe residual hemiparesis, who underwent 8 weeks of daily task-orientated multi-channel EMG-ES of the paretic arm. Before and after treatment, arm function was evaluated clinically and cortical activation patterns were assessed with functional MRI (fMRI) and/or transcranial magnetic stimulation (TMS)., Results: As response to therapy, arm function improved in a subset of patients with more capacity in less affected subjects, but there was no significant gain for those with Box & Block test values below 4 at inception. The clinical improvement, if any, was accompanied by an ipsilesional increase in the sensorimotor cortex (SMC) activation area in fMRI and enhanced intracortical facilitation (ICF) as revealed by paired TMS. The SMC activation change in fMRI was predicted by the presence or absence of motor-evoked potentials (MEPs) on the affected side., Conclusions: The present findings support the notion that intensified EMG-ES may improve the arm function in individual chronic hemiparetic stroke patients but not in more severely impaired individuals. Functional improvements are paralleled by increased ipsilesional SMC activation and enhanced ICF supporting neuroplasticity as contributor to rehabilitation. The clinical score at inception and the presence of MEPs have the best predictive potential.

Noninvasive cortical stimulation techniques, such as transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS), have proved to be powerful tools for establishing causal relationships between brain regions and their functions. In the present study, we demonstrate that a new technique called transcranial alternating current stimulation (tACS) can interact with ongoing rhythmic activities in the visual cortex in a frequency-specific fashion and induce visual experiences (phosphenes). We delivered an oscillatory current over the occipital cortex with tACS. In order to observe interactions with ongoing cortical rhythms, we compared the effects of delivering tACS under conditions of light ("Light" condition) or darkness ("Dark" condition). Stimulation over the occipital cortex induced perception of continuously flickering light most effectively when the beta frequency range was applied in an illuminated room, whereas the most effective stimulation frequency shifted to the alpha frequency range during testing in darkness. Stimulation with theta or gamma frequencies did not produce any visual phenomena. The shift of the effective stimulation frequency indicates that the frequency dependency is caused by interactions with ongoing oscillatory activity in the stimulated cortex. Our results suggest that tACS can be used as a noninvasive tool for establishing a causal link between rhythmic cortical activities and their functions.

Transcranial direct current stimulation (tDCS) was recently reintroduced as a tool for inducing relatively long-lasting changes in cortical excitability in focal brain regions. Anodal stimulation over the primary motor cortex enhances cortical excitability, whereas cathodal stimulation decreases it. Prior studies have shown that enhancement of D2 receptor activity by pergolide consolidates tDCS-generated excitability diminution for up to 24 hours and that cathodal stimulation of the primary motor cortex diminishes experimentally induced pain sensation and reduces the N2-P2 amplitude of laser-evoked potentials immediately poststimulation. In the present study, we investigated the effect of pergolide and cathodal tDCS over the primary motor cortex on laser-evoked potentials and acute pain perception induced with a Tm:YAG laser in a double-blind, randomized, placebo-controlled, crossover study. The amplitude changes of laser-evoked potentials and subjective pain rating scores of 12 healthy subjects were analyzed prior to and following 15 minutes cathodal tDCS combined with pergolide or placebo intake at five different time points. Our results indicate that the amplitude of the N2 component was significantly reduced following cathodal tDCS for up to two hours. Additionally, pergolide prolonged the effect of the cathodal tDCS for up to 24 hours, and a significantly lowered pain sensation was observed for up to 40 minutes. Our study is a further step toward clinical application of cathodal tDCS over the primary motor cortex using pharmacological intervention to prolong the excitability-diminishing effect on pain perception for up to 24 hours poststimulation. Furthermore, it demonstrates the potential for repetitive daily stimulation therapy for pain patients.

Noninvasive transcranial stimulation is being increasingly used by clinicians and neuroscientists to alter deliberately the status of the human brain. Important applications are the induction of virtual lesions (for example, transient dysfunction) to identify the importance of the stimulated brain network for a certain sensorimotor or cognitive task, and the induction of changes in neuronal excitability, synaptic plasticity or behavioral function outlasting the stimulation, for example, for therapeutic purposes. The aim of this article is to review critically the properties of the different currently used stimulation protocols, including a focus on their particular strengths and weaknesses, to facilitate their appropriate and conscientious application.

Transcranial direct current stimulation (tDCS) is a non-invasive method of modulating levels of cortical excitability. In this study, data gathered over a number of previously conducted experiments before and after tDCS, has been re-analyzed to investigate correlations between sex differences with respect to neuroplastic effects. Visual evoked potentials (VEPs), phosphene thresholds (PTs), and contrast sensitivity measurements (CSs) are used as indicators of the excitability of the primary visual cortex. The data revealed that cathodally induced excitability effects 10 min post stimulation with tDCS, showed no significant difference between genders. However, stimulation in the anodal direction revealed sex-specific effects: in women, anodal stimulation heightened cortical excitability significantly when compared to the age-matched male subject group. There was no significant difference between male and female subjects immediately after stimulation. These results indicate that sex differences exist within the visual cortex of humans, and may be subject to the influences of modulatory neurotransmitters or gonadal hormones which mirror short-term neuroplastic effects.

Membrane potentials and spike sequences represent the basic modes of cerebral information processing. Both can be externally modulated in humans by quite specific techniques: transcranial direct current stimulation (tDCS) and repetitive transcranial magnetic stimulation (rTMS). These methods induce reversible circumscribed cortical excitability changes, either excitatory or inhibitory, outlasting stimulation in time. Experimental pharmacological interventions may selectively enhance the duration of the aftereffects. Whereas rTMS induces externally triggered changes in the neuronal spiking pattern and interrupts or excites neuronal firing in a spatially and temporally restricted fashion, tDCS modulates the spontaneous firing rates of neurons by changing resting-membrane potential. The easiest and most common way of evaluating the cortical excitability changes is by applying TMS to the motor cortex, since it allows reproducible quantification through the motor-evoked potential. Threshold determinations at the visual cortex or psychophysical methods usually require repeated and longer measurements and thus more time for each data set. Here, results derived from the use of tDCS in visual perception, including contrast as well as motion detection and visuo-motor coordination and learning, are summarised. It is demonstrated that visual functions can be transiently altered by tDCS, as has been shown for the motor cortex previously. Up- and down-regulation of different cortical areas by tDCS is likely to open a new branch in the field of visual psychophysics.

Purpose: In the motor cortex (M1), transcranial direct current stimulation (tDCS) can effectively prime excitability changes that are evoked by a subsequent train of repetitive transcranial magnetic stimulation (rTMS). The authors examined whether tDCS can also prime the cortical response to rTMS in the human visual cortex., Methods: In nine healthy subjects, the authors applied tDCS (10 minutes; +/-1 mA) to the occipital cortex. After tDCS, they applied a 20-second train of 5 Hz rTMS at 90% of phosphene threshold (PT) intensity. A similar rTMS protocol had previously demonstrated a strong priming effect of tDCS on rTMS-induced excitability changes in M1. PTs were determined with single-pulse TMS before and immediately after tDCS and twice after rTMS., Results: Anodal tDCS led to a transient decrease in PT, and subsequent 5 Hz rTMS induced an earlier return of the PT back to baseline. Cathodal tDCS produced a short-lasting increase in PT, but 5 Hz rTMS did not influence the tDCS-induced increase in PT. In a control experiment on four subjects, a 20-second train of occipital 5 Hz rTMS left the PT unchanged, whereas a 60-second train produced a similar decrease in PT as anodal tDCS alone., Conclusions: Compared with previous work on the M1, tDCS and rTMS of the visual cortex only produce short-lasting changes in cortical excitability. Moreover, the priming effects of tDCS on subsequent rTMS conditioning are relatively modest. These discrepancies point to substantial differences in the modifiability of human motor and visual cortex.

Previous studies have observed that prolonged adaptation to a face will bias the perception of a subsequent one. This phenomenon is known as figural or face after-effect. Although currently the topic of face adaptation enjoys utmost popularity, we still don't know much about the neural process underlying it. The aim of the present study was to determine, using transcranial direct current stimulation (tDCS), how the retinotopically organised primary visual cortex (V1) and higher-level, non-retinotopic right lateral temporo-parietal areas interact with facial adaptation processing. Seventeen healthy subjects received 10 min anodal, cathodal or sham stimulation over these areas during a facial adaptation task. Cathodal stimulation of the right temporo-parietal cortex reduces the magnitude of facial adaptation while stimulation over the V1 results in no significant effects. These data imply that mainly lateral temporo-parietal cortical areas play role in facial adaptation and in facial gender discrimination, supporting the idea that the observed after-effects are the result of high-level, configurational adaptation mechanisms.

Objective: Transcranial direct current stimulation (tDCS) has an influence on the excitability of the human motor cortex measured by motor evoked potentials (MEPs) after transcranial magnetic stimulation. Low and high frequency (HFOs) components of somatosensory evoked potentials (SEPs) were studied questioning whether a comparable effect can be observed after applying tDCS to the human somatosensory cortex., Methods: Multichannel median nerve SEPs were recorded before and after applying tDCS of 1mA over a period of 9min with the cathode placed over the somatosensory cortex and the anode over the contralateral forehead and vice versa in a second session. The source activity of the N20, N30 and HFOs was evaluated before and after application of tDCS., Results: After cathodal tDCS to the somatosensory cortex we found a significant reduction of the N20 source amplitude while there was no effect after anodal stimulation. For the N30 component and HFOs no change in source activity was observed., Conclusions: Corresponding to the results for the motor cortex a sustained reduction of the excitability of the somatosensory cortex after cathodal tDCS was shown., Significance: We demonstrated differential effects of tDCS on the high and low frequency components of SEPs confirming the hypothesis of locally and functionally distinct generators of these two components.

Weak transcranial direct current stimulation (tDCS) of the human motor cortex results in excitability shifts which occur during and after stimulation. These excitability shifts are polarity-specific with anodal tDCS enhancing excitability, and cathodal reducing it. To explore the origin of this excitability modulation in more detail, we measured the input-output curve and motor thresholds as global parameters of cortico-spinal excitability, and determined intracortical inhibition and facilitation, as well as facilitatory indirect wave (I-wave) interactions. Measurements were performed during short-term tDCS, which elicits no after-effects, and during other tDCS protocols which do elicit short- and long-lasting after-effects. Resting and active motor thresholds remained stable during and after tDCS. The slope of the input-output curve was increased by anodal tDCS and decreased by cathodal tDCS. Anodal tDCS of the primary motor cortex reduced intracortical inhibition and enhanced facilitation after tDCS but not during tDCS. Cathodal tDCS reduced facilitation during, and additionally increased inhibition after its administration. During tDCS, I-wave facilitation was not influenced but, for the after-effects, anodal tDCS increased I-wave facilitation, while cathodal tDCS had only minor effects. These results suggest that the effect of tDCS on cortico-spinal excitability during a short period of stimulation (which does not induce after-effects) primarily depends on subthreshold resting membrane potential changes, which are able to modulate the input-output curve, but not motor thresholds. In contrast, the after-effects of tDCS are due to shifts in intracortical inhibition and facilitation, and at least partly also to facilitatory I-wave interaction, which is controlled by synaptic activity.

Transcranial direct current stimulation (tDCS) of the primary motor hand area (M1) can produce lasting polarity-specific effects on corticospinal excitability and motor learning in humans. In 16 healthy volunteers, O positron emission tomography (PET) of regional cerebral blood flow (rCBF) at rest and during finger movements was used to map lasting changes in regional synaptic activity following 10 min of tDCS (+/-1 mA). Bipolar tDCS was given through electrodes placed over the left M1 and right frontopolar cortex. Eight subjects received anodal or cathodal tDCS of the left M1, respectively. When compared to sham tDCS, anodal and cathodal tDCS induced widespread increases and decreases in rCBF in cortical and subcortical areas. These changes in rCBF were of the same magnitude as task-related rCBF changes during finger movements and remained stable throughout the 50-min period of PET scanning. Relative increases in rCBF after real tDCS compared to sham tDCS were found in the left M1, right frontal pole, right primary sensorimotor cortex and posterior brain regions irrespective of polarity. With the exception of some posterior and ventral areas, anodal tDCS increased rCBF in many cortical and subcortical regions compared to cathodal tDCS. Only the left dorsal premotor cortex demonstrated an increase in movement related activity after cathodal tDCS, however, modest compared with the relatively strong movement-independent effects of tDCS. Otherwise, movement related activity was unaffected by tDCS. Our results indicate that tDCS is an effective means of provoking sustained and widespread changes in regional neuronal activity. The extensive spatial and temporal effects of tDCS need to be taken into account when tDCS is used to modify brain function.

While there is strong evidence for the central role of the human MT+/V5 in motion processing, its involvement in motion adaptation is still the subject of debate. We used transcranial direct current stimulation (tDCS) to test whether MT+/V5 is part of the neural network involved in the long-term adaptation-induced motion after-effect in humans. It was found that both cathodal and anodal stimulation over MT+/V5 resulted in a significant reduction of the perceived motion after-effect duration, but had no effect on performance in a luminance-change-detection task used to determine attentional load during adaptation. Our control experiment excluded the possibility that the observed MT+/V5 stimulation effects were due to a diffused modulation of the early cortical areas, i.e. by the stimulation applied over MT+/V5. These results provide evidence that external modulation of neural excitability in human MT+/V5 affects the strength of perceived motion after-effect and support the involvement of MT+/V5 in motion adaptation processes.

Background: Rapid-rate repetitive transcranial magnetic stimulation (rTMS) can produce a lasting increase in cortical excitability in healthy subjects or induce beneficial effects in patients with neuropsychiatric disorders; however, the conditioning effects of rTMS are often subtle and variable, limiting therapeutic applications. Here we show that magnitude and direction of after-effects induced by rapid-rate rTMS depend on the state of cortical excitability before stimulation and can be tuned by preconditioning with transcranial direct current stimulation (tDCS)., Methods: Ten healthy volunteers received a 20-sec train of 5-Hz rTMS given at an intensity of individual active motor threshold to the left primary motor hand area. This interventional protocol was preconditioned by 10 min of anodal, cathodal, or sham tDCS. We used single-pulse TMS to assess corticospinal excitability at rest before, between, and after the two interventions., Results: The 5-Hz rTMS given after sham tDCS failed to produce any after-effect, whereas 5-Hz rTMS led to a marked shift in corticospinal excitability when given after effective tDCS. The direction of rTMS-induced plasticity critically depended on the polarity of tDCS conditioning., Conclusions: Preconditioning with tDCS enhances cortical plasticity induced by rapid-rate rTMS and can shape the direction of rTMS-induced after-effects.

The excitability of the cerebral cortex can be modulated by various transcranial stimulation techniques. Transcranial direct current stimulation (tDCS) offers the advantage of portable equipment and could, therefore, be used for ambulatory modulation of brain excitability. However, modulation of cortical excitability by tDCS has so far mostly been shown by indirect measures. Therefore, we examined whether tDCS has a direct behavioral/perceptional effect. We compared tactile discrimination of vibratory stimuli to the left ring finger prior to, during and after tDCS applied for 7 min at 1-mA current intensity in 13 subjects. Stimulation was pseudorandomized into cathodal, anodal and sham conditions in a within-subject design. The active electrode was placed over the corresponding somatosensory cortex at C4 according to the 10-20 EEG system and the reference electrode at the forehead above the contralateral orbita. Cathodal stimulation compared with sham induced a prolonged decrease of tactile discrimination, while anodal and sham stimulation did not. Thus, cortical processing can be modulated in a behaviorally/perceptually meaningful way by weak transcranial current stimulation applied through portable technology. This finding offers a new perspective for the treatment of conditions characterized by alterations of cortical excitability.

Weak transcranial DC stimulation (tDCS) of the human motor cortex results in excitability shifts during and after the end of stimulation, which are most probably localized intracortically. Anodal stimulation enhances excitability, whereas cathodal stimulation reduces it. Although the after-effects of tDCS are NMDA receptor-dependent, nothing is known about the involvement of additional receptors. Here we show that pharmacological strengthening of GABAergic inhibition modulates selectively the after-effects elicited by anodal tDCS. Administration of the GABA(A) receptor agonist lorazepam resulted in a delayed, but then enhanced and prolonged anodal tDCS-induced excitability elevation. The initial absence of an excitability enhancement under lorazepam is most probably caused by a loss of the anodal tDCS-generated intracortical diminution of inhibition and enhancement of facilitation, which occurs without pharmacological intervention. The reasons for the late-occurring excitability enhancement remain unclear. Because intracortical inhibition and facilitation are not changed in this phase compared with pre-tDCS values, excitability changes originating from remote cortical or subcortical areas could be involved.

Performance of visuo-motor tasks requires the transfer of visual data to motor performance and depends highly on visual perception and cognitive processing, mainly during the learning phase. The primary aim of this study was to determine if the human middle temporal (MT)+/V5, an extrastriate visual area that is known to mediate motion processing, and the primary motor cortex are involved in learning of visuo-motor coordination tasks. To pursue this, we increased or decreased MT+/V5, primary contralateral motor (M1) and primary visual cortex excitability by 10 min of anodal or cathodal transcranial direct current stimulation in healthy human subjects during the learning phase of a visually guided tracking task. The percentage of correct tracking movements increased significantly in the early learning phase during anodal stimulation, but only when the left V5 or M1 was stimulated. Cathodal stimulation had no significant effect. Also, stimulation of the primary visual cortex was not effective for this kind of task. Our data suggest that the areas V5 and M1 are involved in the early phase of learning of visuo-motor coordination.

Recent experimental work in animals has emphasized the importance of homeostatic plasticity as a means of stabilizing the properties of neuronal circuits. Here, we report a phenomenon that indicates a homeostatic pattern of cortical plasticity in healthy human subjects. The experiments combined two techniques that can produce long-term effects on the excitability of corticospinal output neurons: transcranial direct current stimulation (TDCS) and repetitive transcranial magnetic stimulation (rTMS) of the left primary motor cortex. "Facilitatory preconditioning" with anodal TDCS caused a subsequent period of 1 Hz rTMS to reduce corticospinal excitability to below baseline levels for >20 min. Conversely, "inhibitory preconditioning" with cathodal TDCS resulted in 1 Hz rTMS increasing corticospinal excitability for at least 20 min. No changes in excitability occurred when 1 Hz rTMS was preceded by sham TDCS. Thus, changing the initial state of the motor cortex by a period of DC polarization reversed the conditioning effects of 1 Hz rTMS. These preconditioning effects of TDCS suggest the existence of a homeostatic mechanism in the human motor cortex that stabilizes corticospinal excitability within a physiologically useful range.

Purpose: Transcranial direct current stimulation (tDCS) has been shown to modify the perception threshold of phosphenes elicited by transcranial magnetic stimulation (TMS). The current study was undertaken to examine whether tDCS, when applied over the occipital cortex, is also able to affect visual-evoked potentials (VEPs), which characterize occipital activation in response to visual stimulation, in a polarity-specific way., Method: For this purpose, VEPs evoked by sinusoidal luminance grating in an on/off mode were recorded before, immediately after, and 10, 20, and 30 minutes after the end of 5, 10, or 15 minutes of anodal or cathodal tDCS of the primary visual cortex., Results: Significant effects were observed only when low-contrast visual stimuli were applied. Cathodal stimulation decreased, whereas anodal stimulation increased the amplitude of the N70 component. The effect of cathodal stimulation was significant immediately after and 10 minutes after the end of stimulation, if the stimulation duration was sufficiently long (i.e., 10-15 minutes). An increase of N70 amplitude by anodal stimulation was significant only 10 minutes after the end of the 15 minutes tDCS. Cathodal stimulation tended also to affect the amplitude of the P100 component; however, the effect of stimulation was inverse. The amplitude increased immediately after the end of cathodal stimulation. In contrast, anodal stimulation did not affect the P100. The latencies of the N70 and the P100 were not affected by tDCS., Conclusions: tDCS appears to be a suitable method of inducing reversible excitability changes in a polarity-specific way, not only in the motor but also in the primary visual cortex. The duration of the induced aftereffects depends not only on stimulation duration but also on stimulation polarity. Cathodal stimulation seems to be more effective, in line with previous reports on the motor cortex.

tDCS appears to be a promising tool in neuroplasticity research with some perspectives in clinical neurophysiology. It is closely related to modulation of cortical excitability and activity which are key mechanisms for modulating neuroplasticity. Long-term potentiation and long-term depression-like effects have been shown to be involved in learning processes in animal studies so far. Stimulation with weak direct currents is capable of inducing stimulation-polarity-dependent, prolonged, diminutions or elevations of cortical activity and excitability, most probably elicited by a hyper- or depolarisation of resting membrane potentials. Moreover, these modulations are functionally important, since they affect learning processes and epileptic activity. Here excitability changes have been accomplished in the human by non-invasive transcranial direct current stimulation (tDCS). They share some important features with these well-known neuroplastic changes: The duration of the effects depends on stimulation duration and intensity, they are of intracortical origin, and the prolonged effects depend on NMDA-receptor activity. Thus, this technique is a promising method in the field of neuroplastic research in animals and humans and could evolve as a therapeutic tool in some neuro-psychiatric disorders which benefit from modulation of cortical excitability.

Objective: To induce prolonged motor cortical excitability reductions by transcranial direct current stimulation in the human., Methods: Cathodal direct current stimulation was applied transcranially to the hand area of the human primary motor cortex from 5 to 9 min in separate sessions in twelve healthy subjects. Cortico-spinal excitability was tested by single pulse transcranial magnetic stimulation. Transcranial electrical stimulation and H-reflexes were used to learn about the origin of the excitability changes. Neurone specific enolase was measured before and after the stimulation to prove the safety of the stimulation protocol., Results: Five and 7 min direct current stimulation resulted in motor cortical excitability reductions, which lasted for minutes after the end of stimulation, 9 min stimulation induced after-effects for up to an hour after the end of stimulation, as revealed by transcranial magnetic stimulation. Muscle evoked potentials elicited by transcranial electric stimulation and H-reflexes did not change. Neurone specific enolase concentrations remained stable throughout the experiments., Conclusions: Cathodal transcranial direct current stimulation is capable of inducing prolonged excitability reductions in the human motor cortex non-invasively. These changes are most probably localised intracortically.

Small moving sensations, so-called moving phosphenes are perceived, when V5, a visual area important for visual motion analysis, is stimulated by transcranial magnetic stimulation (TMS). However, it is still a matter of debate if only V5 takes part in movement perception or other visual areas are also involved in this process. In this study we tested the involvement of V1 in the perception of moving phosphenes by applying transcranial direct current stimulation (tDCS) to this area. tDCS is a non-invasive stimulation technique known to modulate cortical excitability in a polarity-specific manner. Moving and stationary phosphene thresholds (PT) were measured by TMS before, immediately after and 10, 20 and 30 min after the end of 10 min cathodal and anodal tDCS in nine healthy subjects. Reduced PTs were detected immediately and 10 min after the end of anodal tDCS while cathodal stimulation resulted in an opposite effect. Our results show that the excitability shifts induced by V1 stimulation can modulate moving phosphene perception. tDCS elicits transient, but yet reversible effects, thus presenting a promising tool for neuroplasticity research.

Interindividual anatomical differences in the human cortex can lead to suboptimal current directions and may result in response variability of transcranial electrical stimulation methods. These differences in brain anatomy require individualized electrode stimulation montages to induce an optimal current density in the targeted area of each individual subject. We aimed to explore the possible modulatory effects of 140 Hz transcranial alternating current stimulation (tACS) on the somatosensory cortex using personalized multi-electrode stimulation montages. In two randomized experiments using either tactile finger or median nerve stimulation, we measured by evoked potentials the plasticity aftereffects and oscillatory power changes after 140 Hz tACS at 1.0 mA as compared to sham stimulation (n = 17, male = 9). We found a decrease in the power of oscillatory mu-rhythms during and immediately after tactile discrimination tasks, indicating an engagement of the somatosensory system during stimulus encoding. On a group level both the oscillatory power and the evoked potential amplitudes were not modulated by tACS neither after tactile finger stimulation nor after median nerve stimulation as compared to sham stimulation. On an individual level we could however demonstrate that lower angular difference (i.e., differences between the injected current vector in the target region and the source orientation vector) is associated with significantly higher changes in both P20/N20 and N30/P30 source activities. Our findings suggest that the higher the directionality of the injected current correlates to the dipole orientation the greater the tACS-induced aftereffects are. [ABSTRACT FROM AUTHOR]

Background: Vision loss after optic neuropathy is considered irreversible. Here, repetitive transorbital alternating current stimulation (rtACS) was applied in partially blind patients with the goal of activating their residual vision. Methods: We conducted a multicenter, prospective, randomized, double-blind, sham-controlled trial in an ambulatory setting with daily application of rtACS (n = 45) or sham-stimulation (n = 37) for 50 min for a duration of 10 week days. A volunteer sample of patients with optic nerve damage (mean age 59.1 yrs) was recruited. The primary outcome measure for efficacy was super-threshold visual fields with 48 hrs after the last treatment day and at 2-months follow-up. Secondary outcome measures were near-threshold visual fields, reaction time, visual acuity, and resting-state EEGs to assess changes in brain physiology. Results: The rtACS-treated group had a mean improvement in visual field of 24.0% which was significantly greater than after sham-stimulation (2.5%). This improvement persisted for at least 2 months in terms of both within- and between-group comparisons. Secondary analyses revealed improvements of near-threshold visual fields in the central 5° and increased thresholds in static perimetry after rtACS and improved reaction times, but visual acuity did not change compared to shams. Visual field improvement induced by rtACS was associated with EEG power-spectra and coherence alterations in visual cortical networks which are interpreted as signs of neuromodulation. Current flow simulation indicates current in the frontal cortex, eye, and optic nerve and in the subcortical but not in the cortical regions. Conclusion: rtACS treatment is a safe and effective means to partially restore vision after optic nerve damage probably by modulating brain plasticity. This class 1 evidence suggests that visual fields can be improved in a clinically meaningful way. Trial Registration: ClinicalTrials.gov [ABSTRACT FROM AUTHOR]

Increasing sensitivity of modern evaluation tools allows for the study of weaker electric stimulation effects on neural populations. In the current study we examined the effects of sham continuous theta burst (cTBS) transcranial magnetic stimulation to the left dorsolateral prefrontal cortex (DLPFC) upon somatosensory evoked potentials (SEP) and frontal-parietal phase coupling of alpha and beta bands. Sham TMS results in an induced electric field amplitude roughly 5% that of real TMS with a similar spatial extent in cortex. Both real and sham cTBS reduced the amplitude of the frontal P14-N30 SEP and increased local phase coupling in the alpha-beta frequency bands of left frontal cortex. In addition, both sham and real cTBS increased frontal-parietal phase coupling in the alpha-beta bands concomitant with an increase in amplitude of parietal P50-N70 complex. These data suggest that weak electric fields from sham cTBS can affect both local and downstream neuronal circuits, though in a different manner than high strength TMS. [ABSTRACT FROM AUTHOR]