Edited by: Edward Taub, University of Alabama at Birmingham, USA
Reviewed by: Jack Van Honk, Utrecht University, Netherlands; Jane Allendorfer, University of Alabama at Birmingham, USA
*Correspondence: Sook-Lei Liew and Leonardo G. Cohen, Human Cortical Physiology and Neurorehabilitation Section, National Institute of Neurological Disorders and Stroke, NIH, 10 Center Drive, Bethesda, MD 20892, USA e-mail:
This article was submitted to the journal Frontiers in Human Neuroscience.
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Non-invasive brain stimulation (NIBS) may enhance motor recovery after neurological injury through the causal induction of plasticity processes. Neurological injury, such as stroke, often results in serious long-term physical disabilities, and despite intensive therapy, a large majority of brain injury survivors fail to regain full motor function. Emerging research suggests that NIBS techniques, such as transcranial magnetic (TMS) and direct current (tDCS) stimulation, in association with customarily used neurorehabilitative treatments, may enhance motor recovery. This paper provides a general review on TMS and tDCS paradigms, the mechanisms by which they operate and the stimulation techniques used in neurorehabilitation, specifically stroke. TMS and tDCS influence regional neural activity underlying the stimulation location and also distant interconnected network activity throughout the brain. We discuss recent studies that document NIBS effects on global brain activity measured with various neuroimaging techniques, which help to characterize better strategies for more accurate NIBS stimulation. These rapidly growing areas of inquiry may hold potential for improving the effectiveness of NIBS-based interventions for clinical rehabilitation.
Stroke is a leading cause of serious long-term adult disability around the world. Recovery of motor function remains highly variable despite standardized rehabilitation programs (Kwakkel et al.,
Non-invasive brain stimulation (NIBS) has been explored as a possible technical adjuvant of customarily used neurorehabilitative treatments. NIBS, which employs electrical or magnetically-induced currents to stimulate the brain through the scalp, can temporarily excite or inhibit activity in target brain regions. In this review, we first introduce the use of NIBS in basic science and clinical neuroscience, focusing on the two most commonly used NIBS techniques (transcranial magnetic stimulation,
Early studies of “therapeutic electricity” can be traced back to the late 1800s. Since then, NIBS applications have been used in a variety of settings (for reviews, see Priori,
In contrast, the use of NIBS in neurorehabilitative settings has more recently taken off, starting in the mid-2000s (Elbert et al.,
NIBS techniques have been tested in a wide array of research and clinical settings (Dayan and Cohen,
Apart from general safety considerations regarding tissue heating, magnetization of ferromagnetic objects, and magnetic field exposure for both subjects and operators, consideration must be given to potential side effects of TMS, which consist primarily of the rare induction of seizures, as well more common effects like local transient pain, headaches, and discomfort (Rossi et al.,
Compared to TMS, tDCS is relatively safer and easier to use. A vast literature supports the use of low-intensity transcranial stimulation as safe for use in humans, with only rare and relatively minor adverse effects, such as mild tingling of the scalp, minor fatigue, or itching of the scalp (Poreisz et al.,
First introduced by Barker et al. (
TMS can be used to assess neurophysiological processes and influence brain function via application of single, paired, or repetitive stimulation. In single-pulse TMS (
Repetitive TMS (
Another form of rTMS is patterned rTMS. It consists of the repetitive application of short rTMS bursts at a high stimulation frequency. The most common paradigm is theta burst stimulation (TBS, continuous cTBS or intermittent iTBS), in which short bursts of 50 Hz rTMS are applied at a rate in the theta range (5 Hz) (Huang et al.,
tDCS is applied using a battery-powered direct current (DC) generator connected to two relatively large anodal and cathodal sponge-enclosed rubber electrodes (20–35 cm2 in area) positioned over the scalp. It is thought that low amplitude currents (ranging from 0.5 to 2.0 mA) applied at the scalp can partially penetrate and reach cortical tissues (Datta et al.,
tDCS can modulate cortical excitability in a polarity-dependent fashion. While anodal stimulation increases cortical excitability, cathodal stimulation is thought to decrease it. It should be noted though that these effects, as those of facilitatory and inhibitory TMS, exhibit high interindividual variability (Ridding and Rothwell,
Special consideration should be given to the placement of the electrodes and the focality of tDCS interventions. Newer tDCS montages include bipolar and monopolar scalp stimulation, with the former consisting of both cathode and anode placed on the scalp surface, while the latter positions the “active” electrode on the scalp, with the “reference” placed on an extracephalic target (shoulder, leg, arm, etc.; Schambra et al.,
While tDCS-induced changes in cortical excitability have been related to changes in the underlying cortical neuronal activity, less is known about the specific mechanisms mediating these effects. It has been reported that carbamazepine, dextromethorphan, and the calcium channel blocker flunarizine diminish the effects of anodal tDCS on motor cortical excitability (Nitsche et al.,
tDCS has also been tested in small clinical trials evaluating corticospinal excitability, neurophysiological changes, and the modulation of behavioral variables in neurological and psychiatric diseases such as depression, chronic pain, epilepsy, neuropsychiatric disorders, and stroke, with mixed results (for reviews, see Nitsche and Paulus,
Recently, a wealth of studies have begun to demonstrate that brain stimulation leads not only to local changes in activity under the stimulated coil or electrodes, but also to distant changes in interconnected brain regions throughout the brain (for reviews, see Siebner et al.,
Successful behavior requires the concerted action of multiple brain regions. Neuroimaging studies started to provide important information on the activity of these different networks. In this setting, regions in communication with one another are thought to be highly synchronized (Biswal et al.,
Early studies demonstrated it is possible to evaluate changes in brain activity after TMS using single-photon emission computerized tomography (SPECT) (Shafran et al.,
Left M1 | High-frequency rTMS (3.125 Hz), suprathreshold | fMRI | Healthy volunteers | M1/S1, SMA, dorsal premotor cortex, cingulate motor area, putament, thalamus | Bestmann et al., |
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Left M1 | High-frequency rTMS (3.125 Hz), subthreshold | fMRI | Healthy volunteers | SMA, dorsal premotor cortex, cingulate motor area, putamen, thalamus (but at a lower intensity) | Bestmann et al., |
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Left M1 | High-frequency rTMS (4 Hz), subthreshold | fMRI | Healthy volunteers | SMA, bilateral premotor cortex | Right M1/S1 | Bestmann et al., |
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Left M1 | High-frequency rTMS (4 Hz), suprathreshold | fMRI | Healthy volunteers | Left M1/S1, SMA | Right M1/S1 | Bestmann et al., |
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Right M1 | Low-frequency rTMS (1 Hz) | fMRI | Healthy volunteers | Decreased connectivity between right M1 and SMA, bilateral anterior cerebellum, right dorsal striatum, and left M1 | Decreased SMA activity corresponded with decreased motor memory modificiation | Censor et al., |
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Left dorsal premotor cortex (PMd) | High-frequency rTMS (3 Hz), suprathreshold | fMRI | Healthy volunteers | Left PMd, left premotor ventral (PMv), right PMd, bilateral PMv, SMA, somatosensory cortex, cingulate motor area, left posterior temporal lobe, cerebellum, caudate nucleus | Bestmann et al., |
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Left dorsal premotor cortex (PMd) | High-frequency rTMS (3 Hz), subthreshold | fMRI | Healthy volunteers | Bilateral PMv, SMA, bilateral auditory cortex, bilateral thalamus, bilateral cingulate gyrus | Bestmann et al., |
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Contralesional PMd | High-frequency rTMS (11 Hz), suprathreshold | fMRI | Chronic stroke patients | Increased activity in ipsielsional sensorimotor cortex | Greater ipsilesional sensorimotor cortex activity after rTMS to contralesional PMd correlated with greater motor impairment | Bestmann et al., |
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Ipsilesional M1 | High-frequency rTMS (10 Hz), subthreshold | PET | Chronic stroke patients | Altered effective connectivity between ipsilesional M1, basal ganglia, thalamus; altered interhemispheric connectivity | Ipsilesional TMS response covaries with improvement after movement therapy | Chouinard et al., |
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Contralesional M1 | Low-frequency rTMS (1 Hz) | fMRI | Subacute stroke patient | Increased coupling between ipsilesional SMA and M1 | Inhibitory contralesional TMS improved motor performance of paretic hand; decreased influences of contralesional M1 after rTMS correlated with motor improvement | Grefkes et al., |
In healthy volunteers, Bestmann and colleagues demonstrated that suprathreshold high-frequency rTMS stimulation over M1 induces BOLD signal changes in distant cortical and subcortical regions, including the primary sensorimotor, supplementary and premotor cortices, as well as in the putamen and thalamus (Bestmann et al.,
Application of rTMS over regions other than M1 also modulates functional activity. Suprathreshold rTMS over the left dorsal premotor cortex (PMd) for example increases BOLD signal locally, under the stimulating coil, and in distant regions like the right PMd, bilateral ventral premotor cortex, SMA (Bestmann et al.,
In patients with chronic stroke, subthreshold rTMS over the ipsilesional M1 modulates interhemispheric and effective connectivity between this region, the basal ganglia and the thalamus (Chouinard et al.,
Stimulation of the contralesional PMd in chronic stroke patients induced stronger connectivity between this region and the ipsilesional primary sensorimotor cortex in individuals with greater motor impairments (Bestmann et al.,
Altogether, these studies suggest that facilitatory stimulation of ipsilesional M1 increases M1-SMA functional connectivity while inhibitory stimulation of contralesional M1 decreases contralesional but strengthens ipsilesional connectivity—a pattern that is associated with improved motor performance (Ward et al.,
tDCS also induces changes in connectivity between different brain regions, both at rest and during task performance. Initial evaluations of the influence of tDCS on cortical connectivity have primarily focused on the primary motor cortex (M1) and the DLPFC in healthy individuals (see Table
Left M1 | Right frontopolar cortex | EEG | Voluntary hand movements | Healthy volunteers | Increased intrahemispheric connectivity; increased connectivity patterns in left premotor, motor, sensorimotor regions in high- gamma 60–90 Hz range; increased synchrony in frontal and parieto-occipital regions in low-frequency (alpha and below) bands | Decreased interhemispheric connectivity | Polania et al., |
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Left M1 | Right frontopolar cortex | EEG | Resting | Healthy volunteers | Increased synchronization within frontal electrodes in theta, alpha, and beta bands | Polania et al., |
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Left M1 | Right frontopolar cortex | fMRI | Resting | Healthy volunteers | Increased coupling between left thalamus and Ml; increased connectivity between left caudate nucleus and parietal cortex | Polania et al., |
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Right frontopolar cortex | Left M1 | fMRI | Resting | Healthy volunteers | Decreased coupling between left M1 and right putamen | Polania et al., |
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Left M1 | Right frontopolar cortex | fMRI | Resting | Healthy volunteers | Increased nodal minimum path length in left sensorimotor cortex (less distant functional connectivity); increased coupling between left sensorimotor cortex and premotor and superior parietal areas | Polania et al., |
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Left M1 | Right frontopolar cortex | fMRI | Voluntary hand movements | Healthy volunteers | Decreased activity in SMA during finger tapping with anodal tDCS compared to no stimulation | Antal et al., |
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Left M1 | Right frontopolar cortex | fMRI | Resting | Healthy volunteers | No significant effects | No significant effects | Antal et al., |
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Left M1 | Right frontopolar cortex | EEG | Resting | Healthy volunteers | Increase in power density of low frequency oscillations (theta, alpha) | Increased corticospinal excitability as indexed by MEP amplitude, and increased cortical reactivity | Pellicciari et al., |
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Right frontopolar cortex | Left M1 | EEG | Resting | Healthy volunteers | Increase in power density of low frequency oscillations (theta, alpha) | Decreased corticospinal excitability as indexed by MEP amplitude, and decreased cortical reactivity | Pellicciari et al., |
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Right M1 | Left M1 | fMRI | Resting | Healthy volunteers | Increased connectivity between right Ml, PMd, bilateral SMA, and prefronal cortex | Sehm et al., |
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Right M1 | Right frontopolar cortex | fMRI | Resting | Healthy volunteers | Increased connectivity in left frontotemporal, bilateral pareital, and right cerebellar regions | Sehm et al., |
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Right M1 | Left M1 | fMRI | Resting | Healthy volunteers | Increased intracortical connectivity | Decreased interhemispheric connectivity | Sehm et al., |
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Left dlPFC | Right frontopolar cortex | fMRI | Resting | Healthy volunteers | Increased connectivity in the frontal component of the default mode network and bilateral frontoparietal networks | Keeser et al., |
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Left dlPFC | Right frontopolar cortex | fMRI | Resting | Healthy volunteers | Increased functional connectivity between prefrontal and parietal regions | Decreased spatial robustness of default mode network | Pena-Gomez et al., |
Polania and colleagues demonstrated that tDCS applied over M1 influences cortical connectivity measured with EEG, with effects more evident when studying connectivity during voluntary hand movements than during rest (Polania et al.,
The effects of tDCS on fMRI connectivity have also been studied using a graph theoretical approach. This analytical tool showed that anodal tDCS over M1 reduced the functional connectivity between the stimulated M1 and more distant regions but increased connectivity between the stimulated M1 and premotor and superior parietal regions (Polania et al.,
Studies of effects of tDCS on cortical connectivity also examined the use of different stimulating montages. A direct comparison of the effects of bilateral (with the anode over right M1 and cathode over left M1) vs. unilateral tDCS (with the anode over over right M1 and cathode over left supraorbital region) with fMRI was done in healthy volunteers (Sehm et al.,
In summary, tDCS applied over a specific region induces distant effects on network connectivity, which may conceivably impact behavior. Modulation of distant neural regions via location-specific stimulation holds intriguing possibilities. However, caution is urged when interpreting these preliminary results, since within this handful of studies, there is great variability in the experimental designs used (e.g., in the stimulation montage, period of stimulation, recording method, time of recording, type of analysis performed). In addition, there is significant interindividual variability in results depending on the state of the subject's or network's activity (state-dependency), and the task performed. Evaluation of connectivity effects of tDCS in clinical populations may contribute to the understanding of behavioral deficits in these patients (for example, O'Shea et al.,
It is possible that new NIBS stimulation paradigms using time-varying waveforms, periodical as in the case of alternating current stimulation (tACS) (Herrmann et al.,
While tDCS influences neuronal firing rates in a bimodal manner depending on its polarity, tACS seems to up- and down-regulate the firing rate affecting neuronal spike timing (Reato et al.,
In contrast, tRNS involves the application of alternating currents at different, random frequencies to the scalp. Due to its oscillatory, rather than direct current, nature, it has been proposed that tRNS ensures the application of stimulation is polarity-independent (i.e., neither anodal or cathodal; Miniussi et al.,
Following stroke, patients with the most successful recovery of motor function are those whose patterns of brain activity as measured by fMRI most resemble those present in healthy volunteers (Johansen-Berg et al.,
Given these neuroimaging patterns after stroke, it has been proposed that upregulation of activity in the ipsilesional M1 or downregulation in the contralesional M1 might contribute to improved motor control (Ward and Cohen,
Similarly, downregulating excitability in the contralesional motor cortex in chronic stroke patients was also associated with improvements in motor function, along with increased cortical motor excitability in the ipsilesional M1 and decreased cortical excitability in the contralesional M1 (Fregni et al.,
It is also possible to use simultaneous stimulation of the ipsilesional cortex, with inhibition of the contralesional M1. This appears to also produce motor gains when combined with physiotherapy which last for 1 week (Lindenberg et al.,
To this end, it should be kept in mind that there is by no means agreement on the extent or universality of these beneficial effects and that well-controlled multicenter clinical trials are required to assess this issue (Wallace et al.,
NIBS represents a novel and exciting tool to modulate cortical excitability, in specific local and distant brain regions and has been shown to alter connectivity with areas interconnected with the stimulated site. One exciting new application of NIBS is this ability to modulate functional connectivity between different interconnected regions and its proposed impact on behavior. For instance, dual-site stimulation paradigms, such as paired pulse stimulation applied repetitively could potentially modulate connectivity between two specific regions (Buch et al.,
Another line of research is based on the ability of NIBS to modulate brain intrinsic oscillatory activity as in the framework of brain-computer interface applications (Soekadar et al.,
A recent feasibility study demonstrated that it was possible to combine tDCS with MEG recording, and in addition, provide a chronic stroke patient with neurofeedback about her brain activity in motor regions in the form of a visual stimulus and a robotic orthosis that opened and closed as her hand moved (Figure
The use of NIBS in conjunction with other methods like neuroimaging or genetic analyses may prove particularly useful, not only to study what NIBS does to distributed brain activity, but also to identify predictors of response to NIBS interventions. For instance, O'Shea et al. (
Finally, emerging combinations of new methods are afforded by improvements in technology, computing, and mathematical modeling, such as simultaneous tDCS stimulation with MEG recordings (Soekadar et al.,
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
We thank Marco Sandrini for helpful feedback. This work was supported by the Intramural Research Program of the US National Institute of Neurological Disorders and Stroke (NINDS; US National Institutes of Health) and by funding from US Department of Defense in the Center for Neuroscience and Regenerative Medicine.