Transcranial direct current stimulation (tDCS) is a safe, non-invasive technique for transiently modulating the balance of excitation and inhibition within the human brain. It has been reported that anodal tDCS can reduce both GABA mediated inhibition and GABA concentration within the human motor cortex. As GABA mediated inhibition is thought to be a key modulator of plasticity within the adult brain, these findings have broad implications for the future use of tDCS. It is important, therefore, to establish whether tDCS can exert similar effects within non-motor brain areas. The aim of this study was to assess whether anodal tDCS could reduce inhibitory interactions within the human visual cortex. Psychophysical measures of surround suppression were used as an index of inhibition within V1. Overlay suppression, which is thought to originate within the lateral geniculate nucleus (LGN), was also measured as a control. Anodal stimulation of the occipital poles significantly reduced psychophysical surround suppression, but had no effect on overlay suppression. This effect was specific to anodal stimulation as cathodal stimulation had no effect on either measure. These psychophysical results provide the first evidence for tDCS-induced reductions of intracortical inhibition within the human visual cortex.
► Transcranial direct current stimulation (tDCS) modulates explicit sequence learning. ► Anodal tDCS applied during the task speeds motor learning. ► Anodal tDCS applied before the task slows motor learning. ► Cathodal tDCS slows the rate of learning in both cases.
Transcranial direct current stimulation (tDCS) is attracting increasing interest as a therapeutic tool for neurorehabilitation, particularly after stroke, because of its potential to modulate local excitability and therefore promote functional plasticity. Previous studies suggest that timing is important in determining the behavioural effects of brain stimulation. Regulatory metaplastic mechanisms exist to modulate the effects of a stimulation intervention in a manner dependent on prior cortical excitability, thereby preventing destabilization of existing cortical networks. The importance of such timing dependence has not yet been fully explored for tDCS. Here, we describe the results of a series of behavioural experiments in healthy controls to determine the importance of the relative timing of tDCS for motor performance. Application of tDCS during an explicit sequence-learning task led to modulation of behaviour 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. By contrast, regardless of the polarity of stimulation, tDCS had no significant effect on performance of a simple reaction time task. These results are consistent with the idea that anodal tDCS interacts with subsequent motor learning in a metaplastic manner and suggest that anodal stimulation modulates cortical excitability in a manner similar to motor learning.
Motor cortex; Human; Reaction times
The primary motor cortex (M1) is the main effector structure implicated in the generation of voluntary movements and is directly involved in motor learning. The intrinsic horizontal neuronal connections of M1 exhibit short-term and long-term plasticity, which is a strong substrate for learning-related map reorganization. Transcranial direct current stimulation (tDCS) applied for few minutes over M1 has been shown to induce relatively long-lasting plastic alterations and to modulate motor performance. Here we test the hypothesis that the relatively long-lasting synaptic modification induced by tDCS over M1 results in the alteration of associations among populations of M1 neurons which may be reflected in changes of its functional architecture. fMRI resting-state datasets were acquired immediately before and after 10 minutes of tDCS during rest, with the anode/cathode placed over the left M1. For each functional dataset, grey-matter voxels belonging to Brodmann area 4 (BA4) were labelled and afterwards BA4 voxel-based synchronization matrices were calculated and thresholded to construct undirected graphs. Nodal network parameters which characterize the architecture of functional networks (connectivity degree, clustering coefficient and characteristic path-length) were computed, transformed to volume maps and compared before and after stimulation. At the dorsolateral-BA4 region cathodal tDCS boosted local connectedness, while anodal-tDCS enhanced long distance functional communication within M1. Additionally, the more efficient the functional architecture of M1 was at baseline, the more efficient the tDCS-induced functional modulations were. In summary, we show here that it is possible to non-invasively reorganize the intrinsic functional architecture of M1, and to image such alterations.
Transcranial direct current stimulation (tDCS) is a non-invasive technique that has been found to modulate the excitability of neurons in the brain. The polarity of the current applied to the scalp determines the effects of tDCS on the underlying tissue: anodal tDCS increases excitability, whereas cathodal tDCS decreases excitability. Research has shown that applying anodal tDCS to the non-dominant motor cortex can improve motor performance for the non-dominant hand, presumably by means of changes in synaptic plasticity between neurons. Our previous studies also suggest that applying cathodal tDCS over the dominant motor cortex can improve performance for the non-dominant hand; this effect may result from modulating inhibitory projections (interhemispheric inhibition) between the motor cortices of the two hemispheres. We hypothesized that stimultaneously applying cathodal tDCS over the dominant motor cortex and anodal tDCS over the non-dominant motor cortex would have a greater effect on finger sequence performance for the non-dominant hand, compared to stimulating only the non-dominant motor cortex. Sixteen right-handed participants underwent three stimulation conditions: 1) dual-hemisphere – with anodal tDCS over the non-dominant motor cortex, and cathodal tDCS over the dominant motor cortex, 2) uni-hemisphere – with anodal tDCS over the non-dominant motor cortex, and 3) sham tDCS. Participants performed a finger-sequencing task with the non-dominant hand before and after each stimulation. The dependent variable was the percentage of change in performance, comparing pre- and post-tDCS scores.
A repeated measures ANOVA yielded a significant effect of tDCS condition (F(2,30) = 4.468, p = .037). Post-hoc analyses revealed that dual-hemisphere stimulation improved performance significantly more than both uni-hemisphere (p = .021) and sham stimulation (p = .041).
We propose that simultaneously applying cathodal tDCS over the dominant motor cortex and anodal tDCS over the non-dominant motor cortex produced an additive effect, which facilitated motor performance in the non-dominant hand. These findings are relevant to motor skill learning and to research studies of motor recovery after stroke.
Transcranial direct current stimulation (tDCS) and transcranial random noise stimulation (tRNS) consist in the application of electrical current of small intensity through the scalp, able to modulate perceptual and motor learning, probably by changing brain excitability. We investigated the effects of these transcranial electrical stimulation techniques in the early and later stages of visuomotor learning, as well as associated brain activity changes using functional magnetic resonance imaging (fMRI). We applied anodal and cathodal tDCS, low-frequency and high-frequency tRNS (lf-tRNS, 0.1–100 Hz; hf-tRNS 101–640 Hz, respectively) and sham stimulation over the primary motor cortex (M1) during the first 10 minutes of a visuomotor learning paradigm and measured performance changes for 20 minutes after stimulation ceased. Functional imaging scans were acquired throughout the whole experiment. Cathodal tDCS and hf-tRNS showed a tendency to improve and lf-tRNS to hinder early learning during stimulation, an effect that remained for 20 minutes after cessation of stimulation in the late learning phase. Motor learning-related activity decreased in several regions as reported previously, however, there was no significant modulation of brain activity by tDCS. In opposition to this, hf-tRNS was associated with reduced motor task-related-activity bilaterally in the frontal cortex and precuneous, probably due to interaction with ongoing neuronal oscillations. This result highlights the potential of lf-tRNS and hf-tRNS to differentially modulate visuomotor learning and advances our knowledge on neuroplasticity induction approaches combined with functional imaging methods.
Electrophysiological studies in humans and animals suggest that noninvasive neurostimulation methods such as transcranial direct current stimulation (tDCS) can elicit long-lasting , polarity-dependent  changes in neocortical excitability. Application of tDCS can have significant and selective behavioral consequences that are associated with the cortical location of the stimulation electrodes and the task engaged during stimulation [3–8]. However, the mechanism by which tDCS affects human behavior is unclear. Recently, functional magnetic resonance imaging (fMRI) has been used to determine the spatial topography of tDCS effects [9–13], but no behavioral data were collected during stimulation. The present study is unique in this regard, in that both neural and behavioral responses were recorded using a novel combination of left frontal anodal tDCS during an overt picture-naming fMRI study. We found that tDCS had significant behavioral and regionally specific neural facilitation effects. Furthermore, faster naming responses correlated with decreased blood oxygen level-dependent (BOLD) signal in Broca's area. Our data support the importance of Broca's area within the normal naming network and as such indicate that Broca's area may be a suitable candidate site for tDCS in neurorehabilitation of anomic patients, whose brain damage spares this region.
► This is a novel application of concurrent A-tDCS and fMRI during speech production ► Left frontal A-tDCS speeds up spoken naming responses ► Left frontal A-tDCS elicits a regionally specific neural effect in Broca's area ► Decreased BOLD signal in Broca's area correlates with faster naming responses
Transcranial direct current stimulation (tDCS) over the primary motor cortex (M1) has been shown to induce changes in motor performance and learning. Recent studies indicate that tDCS is capable of modulating widespread neural network properties within the brain. However the temporal evolution of online- and after-effects of tDCS on functional connectivity (FC) within and across the stimulated motor cortices (M1) still remain elusive. In the present study, two different tDCS setups were investigated: (i) unilateral M1 tDCS (anode over right M1, cathode over the contralateral supraorbital region) and (ii) bilateral M1 tDCS (anode over right M1, cathode over left M1). In a randomized single-blinded cross-over design, 12 healthy subjects underwent functional magnetic resonance imaging at rest before, during and after 20 min of either bi-, unilateral, or sham M1 tDCS. Seed-based FC analysis was used to investigate tDCS-induced changes across and within M1. We found that bilateral M1 tDCS induced (a) a decrease in interhemispheric FC during stimulation and (b) an increase in intracortical FC within right M1 after termination of the intervention. While unilateral M1 tDCS also resulted in similar effects during stimulation, no such changes could be observed after termination of tDCS. Our results provide evidence that depending on the electrode montage, tDCS acts upon a modulation of either intracortical and/or interhemispheric processing of M1.
tDCS; functional connectivity; primary motor cortex; unilateral tDCS; bilateral tDCS; interhemispheric; intracortical
Succinic semialdehyde dehydrogenase (SSADH) deficiency is a rare autosomal recessive disorder of GABA degradation leading to elevations in brain GABA and γ-hydroxybutyric acid (GHB). The effect of chronically elevated GABA and GHB on cortical excitability is unknown. We hypothesized that use-dependent downregulation of GABA receptor expression would promote cortical disinhibition rather than inhibition, predominantly via presynaptic GABAergic mechanisms.
We quantified the magnitude of excitation and inhibition in primary motor cortex (M1) in patients with SSADH deficiency, their parents (obligate heterozygotes), age-matched healthy young controls, and healthy adults using single and paired pulse transcranial magnetic stimulation (TMS).
Long interval intracortical inhibition was significantly reduced and the cortical silent period was significantly shortened in patients with SSADH deficiency compared to heterozygous parents and control groups.
Since long interval intracortical inhibition and cortical silent period are thought to reflect GABAB receptor–mediated inhibitory circuits, our results point to a particularly GABAB-ergic motor cortex dysfunction in patients with SSADH deficiency. This human phenotype is consistent with the proposed mechanism of use-dependent downregulation of postsynaptic GABAB receptors in SSADH deficiency animal models. Additionally, the results suggest autoinhibition of GABAergic neurons. This first demonstration of altered GABAB-ergic function in patients with SSADH deficiency may help to explain clinical features of the disease, and suggest pathophysiologic mechanisms in other neurotransmitter-related disorders. Neurology® 2012;79:47–54
During the development of sensory systems, receptive fields are modified by stimuli in the environment. This is thought to rely on learning algorithms that are sensitive to correlations in spike timing between cells, but the manner in which developing circuits selectively exploit correlations that are related to sensory inputs is unknown. We recorded from neurons in the developing optic tectum of Xenopus laevis and found that repeated presentation of moving visual stimuli induced receptive field changes that reflect the properties of the stimuli and that this form of learning was disrupted when GABAergic transmission was blocked. Consistent with a role for spike timing–dependent mechanisms, GABA blockade altered spike-timing patterns in the tectum and increased correlations between cells that would affect plasticity at intratectal synapses. This is a previously unknown role for GABAergic signals in development and highlights the importance of regulating the statistics of spiking activity for learning.
It is well recognized that the number and effectiveness of synapses in the adult brain change in response to learning and that similar processes contribute to the restoration of function after central nervous system damage. It is possible to use non-invasive methods of brain stimulation in humans (transcranial magnetic stimulation, TMS; or transcranial direct current stimulation, TDCS) to study and even manipulate these processes. Initial studies are now underway to test whether modification of synaptic plasticity by neurostimulation can improve recovery of motor function in patients after stroke.
Early in postnatal life correlated GABAergic activity in the hippocampus is thought to play a crucial role in synaptogenesis and in the development of adult neuronal networks. Unlike adulthood, at this developmental stage, mossy fibers (MF) which are the axons of granule cells, release GABA into CA3 principal cells and interneurons. Here, we tested the hypothesis that at MF-CA3 connections, tonic activation of GABAB autoreceptors by GABA is responsible for the low probability of release and synapse silencing. Blocking GABAB receptors with CGP55845 enhanced the probability of GABA release and switched on silent synapses while the opposite was observed with baclofen. Both these effects were presynaptic and were associated with changes in paired-pulse ratio and coefficient of variation. In addition, enhancing the extracellular GABA concentration by repetitive stimulation of MF or by blocking the GABA transporter GAT-1, switched off active synapses, an effect that was prevented by CGP55845. In the presence of CGP55845, stimulation of MF-induced synaptic potentiation. The shift of EGABA from the depolarizing to the hyperpolarizing direction with bumetanide, a blocker of the cation-chloride co-transporter NKCC1, prevented synaptic potentiation and caused synaptic depression, suggesting that the depolarizing action of GABA observed in the presence of CGP55845 is responsible for the potentiating effect. It is proposed that, activation of GABAB receptors by spillover of GABA from MF terminals reduces the probability of release and contributes to synapses silencing. This would act as a filter to prevent excessive activation of the auto-associative CA3 network and the emergence of seizures.
mossy fiber-CA3 synapses; immature hippocampus; probability of GABA release; GABAA-mediated synaptic currents; GABAB autoreceptors; GABA transporters; frequency-dependent synaptic depression
Learning interference occurs when learning something new causes forgetting of an older memory (retrograde interference) or when learning a new task disrupts learning of a second subsequent task (anterograde interference). This phenomenon, described in cognitive, sensory and motor domains, limits our ability to learn multiple tasks in close succession. It has been suggested that the source of interference is competition of neural resources, although the neuronal mechanisms are unknown. Learning induces long-term potentiation (LTP) that can ultimately limit the ability to induce further LTP, a phenomenon known as occlusion. In humans we quantified the magnitude of occlusion of anodal transcranial direct current stimulation (A-tDCS)-induced increased excitability after learning a skill task as an index of the amount of LTP-like plasticity used. We found that retention of a newly acquired skill, as reflected by performance in the second day of practice, is proportional to the magnitude of occlusion. Moreover, the degree of behavioral interference was correlated with the magnitude of occlusion. Individuals with larger occlusion after learning the first skill were (1) more resilient to retrograde interference and (2) experienced larger anterograde interference when training a second task, as expressed by decreased performance of the learned skill in the second day of practice. This effect was not observed if sufficient time elapsed between training the 2 skills and LTP-like occlusion was not present. These findings suggest competition of LTP-like plasticity is a factor that limits the ability to remember multiple tasks trained in close succession.
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, H215O 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.
finger movements; human motor cortex; positron emission tomography; regional cerebral blood flow; transcranial direct current stimulation
The ability to learn a rule to guide behavior is crucial for cognition and executive function. However, in a constantly changing environment, flexibility in terms of learning and changing rules is paramount. Research suggests there may be common underlying causes for the similar rule learning impairments observed in many psychiatric disorders. One of these common anatomical manifestations involves deficits to the GABAergic system, particularly in the frontal cerebral cortical regions. Many common anti-epileptic drugs and mood stabilizers activate the GABA system with the reported adverse side effects of cognitive dysfunction. The mouse reversal/set-shifting test was used to evaluate effects in mice given topiramate, which is reported to impair attention in humans. Here we report that in mice topiramate prevents formation of the attentional set, but does not alter reversal learning. Differences in the GABA system are also found in many neuropsychiatric disorders that are more common in males, including schizophrenia and autism. Initial findings with the reversal/set-shifting task excluded female subjects. In this study, female mice tested on the standard reversal/set-shifting task showed similar reversal learning, but were not able to form the attentional set. The behavioral paradigm was modified and when presented with sufficient discrimination tasks, female mice performed the same as male mice, requiring the same number of trials to reach criterion and form the attentional set. The notable difference was that female mice had an extended latency to complete the trials for all discriminations. In summary, the reversal/set-shifting test can be used to screen for cognitive effects of potential therapeutic compounds in both male and female mice.
Reversal learning; Attentional set-shift; Topiramate; GABA; Female
It has been hypothesized that the generalization patterns that accompany learning carry the signatures of the neural systems that are engaged in that learning. Reach adaptation in force fields has generalization patterns that suggest primary engagement of a neural system that encodes movements in the intrinsic coordinates of joints and muscles, and lesser engagement of a neural system that encodes movements in the extrinsic coordinates of the task. Among the cortical motor areas, the intrinsic coordinate system is most prominently represented in the primary sensorimotor cortices. Here, we used transcranial direct current stimulation (tDCS) to alter mechanisms of synaptic plasticity and found that when it was applied to the motor cortex, it increased generalization in intrinsic coordinates but not extrinsic coordinates. However, when tDCS was applied to the posterior parietal cortex, it had no effects on learning or generalization in the force field task. The results suggest that during force field adaptation, the component of learning that produces generalization in intrinsic coordinates depends on the plasticity in the sensorimotor cortex.
Noninvasive brain stimulation has developed as a promising tool for cognitive neuroscientists. Transcranial magnetic (TMS) and direct current (tDCS) stimulation allow researchers to purposefully enhance or decrease excitability in focal areas of the brain. The purpose of this paper is to review information on the use of TMS and tDCS as research tools to facilitate motor memory formation, motor performance and motor learning in healthy volunteers. Studies implemented so far have mostly focused on the ability of TMS and tDCS to elicit relatively short lasting motor improvements and the mechanisms underlying these changes have been only partially investigated. Despite limitations including the scarcity of data, work that has been already accomplished raises the exciting hypothesis that currently available noninvasive transcranial stimulation techniques could modulate motor learning and memory formation in healthy humans and potentially in patients with neurological and psychiatric disorders.
This study was undertaken to test the hypothesis that a combination of excitatory anodal transcranial direct current stimulation (tDCS) to the contralateral motor cortex and inhibitory cathodal tDCS to the ipsilateral motor cortex of the motor performing hand (Bi-tDCS) would elicit more implicit motor sequence learning than anodal tDCS applied to the contralateral motor cortex alone (Uni-tDCS).
Eleven healthy right-handed adults underwent a randomized crossover experiment of Uni-tDCS, Bi-tDCS, or sham stimulation. Subjects performed a 12-digit finger sequence serial reaction time task with the right hand at baseline (Pre), at immediately (Post 1), and 24 hours after stimulation (Post 2). The ratios of reaction times of predetermined repeating sequence versus random sequence were subjected to statistical analysis.
The paired t test showed that reaction time ratios were significant decreased by all stimulation types at Post 1 versus Pre (P < 0.01). However, mean reaction time ratios showed a significant decrease after Uni-tDCS (P < 0.01) and Bi-tDCS (P < 0.01), but only a marginal decreased after Sham (P = 0.05) at Post 2, which suggests that motor sequence learning is consolidated by Uni-tDCS and Bi-tDCS, but only partially consolidated by sham stimulation. No significant differences were observed between Uni-tDCS and Bi-tDCS in terms of in reaction time ratios at Post 1 or 2.
No significant difference was found between Uni-tDCS and Bi-tDCS in terms of induced implicit motor sequence learning, but tDCS led to greater consolidation of the learned motor sequence than sham stimulation. These findings need to be tested in the context of stroke hand motor rehabilitation.
TDCS; Motor learning; Cortical stimulation; Implicit learning
Transcranial direct current stimulation (tDCS) is a novel neuromodulatory tool that has seen early transition to clinical trials, although the high variability of these findings necessitates further studies in clinically relevant populations. The majority of evidence into effects of repeated tDCS is based on research in the human motor system, but it is unclear whether the long-term effects of serial tDCS are motor-specific or transferable to other brain areas. This study aimed to examine whether serial anodal tDCS over the visual cortex can exogenously induce long-term neuroplastic changes in the visual cortex. However, when the visual cortex is affected by a cortical lesion, up-regulated endogenous neuroplastic adaptation processes may alter the susceptibility to tDCS. To this end, motion perception was investigated in the unaffected hemifield of subjects with unilateral visual cortex lesions. Twelve subjects with occipital ischemic lesions participated in a within-subject, sham-controlled, double-blind study. MRI-registered sham or anodal tDCS (1.5 mA, 20 min) was applied on five consecutive days over the visual cortex. Motion perception was tested before and after stimulation sessions and at 14- and 28-day follow-up. After a 16-day interval an identical study block with the other stimulation condition (anodal or sham tDCS) followed. Serial anodal tDCS over the visual cortex resulted in an improvement in motion perception, a function attributed to MT/V5. This effect was still measurable at 14- and 28-day follow-up measurements. Thus, this may represent evidence for long-term tDCS-induced plasticity and has implications for the design of studies examining the time course of tDCS effects in both the visual and motor systems.
transcranial direct current stimulation; visual system; motor system; translational research; motion perception; neuroplasticity; learning
Adaptation to a novel visuomotor transformation has revealed important principles regarding learning and memory. Computational and behavioral studies have suggested that acquisition and retention of a new visuomotor transformation are distinct processes. However, this dissociation has never been clearly shown. Here, participants made fast reaching movements while unexpectedly a 30-degree visuomotor transformation was introduced. During visuomotor adaptation, subjects received cerebellar, primary motor cortex (M1) or sham anodal transcranial direct current stimulation (tDCS), a noninvasive form of brain stimulation known to increase excitability. We found that cerebellar tDCS caused faster adaptation to the visuomotor transformation, as shown by a rapid reduction of movement errors. These findings were not present with similar modulation of visual cortex excitability. In contrast, tDCS over M1 did not affect adaptation, but resulted in a marked increase in retention of the newly learnt visuomotor transformation. These results show a clear dissociation in the processes of acquisition and retention during adaptive motor learning and demonstrate that the cerebellum and primary motor cortex have distinct functional roles. Furthermore, they show that is possible to enhance cerebellar function using tDCS.
adaptation; cerebellum; direct current stimulation; learning; motor cortex
Motor recovery after stroke depends on the integrity of ipsilesional motor circuits and interactions between the ipsilesional and contralesional hemispheres. In this sham-controlled randomized trial, we investigated whether noninvasive modulation of regional excitability of bilateral motor cortices in combination with physical and occupational therapy improves motor outcome after stroke.
Twenty chronic stroke patients were randomly assigned to receive 5 consecutive sessions of either 1) bihemispheric transcranial direct current stimulation (tDCS) (anodal tDCS to upregulate excitability of ipsilesional motor cortex and cathodal tDCS to downregulate excitability of contralesional motor cortex) with simultaneous physical/occupational therapy or 2) sham stimulation with simultaneous physical/occupational therapy. Changes in motor impairment (Upper Extremity Fugl-Meyer) and motor activity (Wolf Motor Function Test) assessments were outcome measures while functional imaging parameters were used to identify neural correlates of motor improvement.
The improvement of motor function was significantly greater in the real stimulation group (20.7% in Fugl-Meyer and 19.1% in Wolf Motor Function Test scores) when compared to the sham group (3.2% in Fugl-Meyer and 6.0% in Wolf Motor Function Test scores). The effects outlasted the stimulation by at least 1 week. In the real-stimulation group, stronger activation of intact ipsilesional motor regions during paced movements of the affected limb were found postintervention whereas no significant activation changes were seen in the control group.
The combination of bihemispheric tDCS and peripheral sensorimotor activities improved motor functions in chronic stroke patients that outlasted the intervention period. This novel approach may potentiate cerebral adaptive processes that facilitate motor recovery after stroke.
Classification of evidence:
This study provides Class I evidence that for adult patients with ischemic stroke treated at least 5 months after their first and only stroke, bihemispheric tDCS and simultaneous physical/occupational therapy given over 5 consecutive sessions significantly improves motor function as measured by the Upper Extremity Fugl-Meyer assessment (raw change treated 6.1 ± 3.4, sham 1.2 ± 1.0).
= corticospinal tract;
= fluid-attenuated inversion recovery;
= laterality index;
= Medical Research Council;
= physical/occupational therapy;
= repetitive transcranial magnetic stimulation;
= transcranial direct current stimulation;
= Upper Extremity Fugl-Meyer assessment;
= Wolf Motor Function Test.
γ-aminobutyric acid type B (GABA-B) receptor mediates the inhibitory transmission of γ-aminobutyric acid in the mammalian nervous system, being present in neurons and also in glial cells. Recently the presence of GABA-B has been demonstrated in Schwann cells (SC) suggesting its contribution in regulating the cell fate, maturation, and plasticity. Here, we further support the functional presence of GABA-B receptor in SC plasma membrane. By confocal microscopy immunofluorescence we provide evidences that GABA-B localization on the cell elongated processes correlates with the morphological changes occurring in the differentiated SC. In vivo most of the GABA-B receptors seem to be present in non-myelinating SC, which are committed to ensheath the nociceptive fibers. Therefore, we argue that GABA-B receptors do not control exclusively the in vivo differentiation yielding the myelinating SC, but are also fundamental in regulating the SC plasticity versus the non-myelinating state. Data from the literature and our recent findings corroborate the role of the GABAergic system and GABA-B receptors in the peripheral nervous system, opening new perspectives on the mechanisms controlling the differentiation of SC.
GABA; actin; cAMP; myelin; non-myelinating cells
Several lines of evidence suggest that deficits in γ-aminobutyric acid (GABA) inhibitory neurotransmission are implicated in the pathophysiology of schizophrenia, bipolar disorder, major depressive disorder and obsessive–compulsive disorder. Cortical inhibition refers to a neurophysiological process, whereby GABA inhibitory interneurons selectively attenuate pyramidal neurons. Transcranial magnetic stimulation (TMS) represents a noninvasive technique to measure cortical inhibition, excitability and plasticity in the cortex. These measures were traditionally specific to the motor cortex, which is an important limitation when nonmotor neurophysiological processes are of primary interest. Recently, TMS has been combined with electroencephalography (EEG) to derive such measurements directly from the cortex. This review focuses on neurophysiological studies related to inhibitory and excitatory TMS paradigms, linking dysfunctional GABAergic neurotransmission to disease states. We review evidence that suggests cortical inhibition deficits among psychiatric populations and demonstrate how each disorder has a specific neurophysiological response to treatment. We conclude by discussing the future directions of TMS combined with EEG, demonstrating the potential to identify biological markers of neuropsychiatric disorders.
Continuous theta burst stimulation (cTBS) is a novel transcranial stimulation technique that causes significant inhibition of synaptic transmission for ≤1 h when applied over the primary motor cortex (M1) in humans. Here we use magnetic resonance spectroscopy to define mechanisms mediating this inhibition by noninvasively measuring local changes in the cortical concentrations of γ-aminobutyric acid (GABA) and glutamate/glutamine (Glx). cTBS to the left M1 led to an increase in GABA compared with stimulation at a control site without significant change in Glx. This direct evidence for increased GABAergic interneuronal activity is framed in terms of a new hypothesis regarding mechanisms underlying cTBS.
Therapies for motor recovery after stroke or traumatic brain injury are still not satisfactory. To date the best approach seems to be the intensive physical therapy. However the results are limited and functional gains are often minimal. The goal of motor training is to minimize functional disability and optimize functional motor recovery. This is thought to be achieved by modulation of plastic changes in the brain. Therefore, adjunct interventions that can augment the response of the motor system to the behavioural training might be useful to enhance the therapy-induced recovery in neurological populations. In this context, noninvasive brain stimulation appears to be an interesting option as an add-on intervention to standard physical therapies. Two non-invasive methods of inducing electrical currents into the brain have proved to be promising for inducing long-lasting plastic changes in motor systems: transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS). These techniques represent powerful methods for priming cortical excitability for a subsequent motor task, demand, or stimulation. Thus, their mutual use can optimize the plastic changes induced by motor practice, leading to more remarkable and outlasting clinical gains in rehabilitation. In this review we discuss how these techniques can enhance the effects of a behavioural intervention and the clinical evidence to date.
Background: Since motor learning is a key component for stroke recovery, enhancing motor skill learning is a crucial challenge for neurorehabilitation. Transcranial direct current stimulation (tDCS) is a promising approach for improving motor learning. The aim of this trial was to test the hypothesis that dual-tDCS applied bilaterally over the primary motor cortices (M1) improves online motor skill learning with the paretic hand and its long-term retention. Methods: Eighteen chronic stroke patients participated in a randomized, cross-over, placebo-controlled, double bind trial. During separate sessions, dual-tDCS or sham dual-tDCS was applied over 30 min while stroke patients learned a complex visuomotor skill with the paretic hand: using a computer mouse to move a pointer along a complex circuit as quickly and accurately as possible. A learning index involving the evolution of the speed/accuracy trade-off was calculated. Performance of the motor skill was measured at baseline, after intervention and 1 week later. Results: After sham dual-tDCS, eight patients showed performance worsening. In contrast, dual-tDCS enhanced the amount and speed of online motor skill learning compared to sham (p < 0.001) in all patients; this superiority was maintained throughout the hour following. The speed/accuracy trade-off was shifted more consistently after dual-tDCS (n = 10) than after sham (n = 3). More importantly, 1 week later, online enhancement under dual-tDCS had translated into superior long-term retention (+44%) compared to sham (+4%). The improvement generalized to a new untrained circuit and to digital dexterity. Conclusion: A single-session of dual-tDCS, applied while stroke patients trained with the paretic hand significantly enhanced online motor skill learning both quantitatively and qualitatively, leading to successful long-term retention and generalization. The combination of motor skill learning and dual-tDCS is promising for improving post-stroke neurorehabilitation.
transcranial direct current stimulation; motor skill learning; stroke; interhemispheric rivalry; neurorehabilitation