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1.  Bihemispheric brain stimulation facilitates motor recovery in chronic stroke patients(Podcast)(e–Pub ahead of print)(LOE Classification) 
Neurology  2010;75(24):2176-2184.
Objective:
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.
Methods:
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.
Results:
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.
Conclusions:
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).
GLOSSARY
= 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.
doi:10.1212/WNL.0b013e318202013a
PMCID: PMC3013585  PMID: 21068427
2.  Predicting behavioural response to TDCS in chronic motor stroke☆ 
Neuroimage  2014;85(Pt 3):924-933.
Transcranial direct current stimulation (TDCS) of primary motor cortex (M1) can transiently improve paretic hand function in chronic stroke. However, responses are variable so there is incentive to try to improve efficacy and or to predict response in individual patients. Both excitatory (Anodal) stimulation of ipsilesional M1 and inhibitory (Cathodal) stimulation of contralesional M1 can speed simple reaction time. Here we tested whether combining these two effects simultaneously, by using a bilateral M1–M1 electrode montage, would improve efficacy. We tested the physiological efficacy of Bilateral, Anodal or Cathodal TDCS in changing motor evoked potentials (MEPs) in the healthy brain and their behavioural efficacy in changing reaction times with the paretic hand in chronic stroke. In addition, we aimed to identify clinical or neurochemical predictors of patients' behavioural response to TDCS. There were three main findings: 1) unlike Anodal and Cathodal TDCS, Bilateral M1–M1 TDCS (1 mA, 20 min) had no significant effect on MEPs in the healthy brain or on reaction time with the paretic hand in chronic stroke patients; 2) GABA levels in ipsilesional M1 predicted patients' behavioural gains from Anodal TDCS; and 3) although patients were in the chronic phase, time since stroke (and its combination with Fugl–Meyer score) was a positive predictor of behavioural gain from Cathodal TDCS. These findings indicate the superiority of Anodal or Cathodal over Bilateral TDCS in changing motor cortico-spinal excitability in the healthy brain and in speeding reaction time in chronic stroke. The identified clinical and neurochemical markers of behavioural response should help to inform the optimization of TDCS delivery and to predict patient outcome variability in future TDCS intervention studies in chronic motor stroke.
Highlights
•Ipsilesional M1 GABA levels predict motor gains from Anodal TDCS in chronic stroke.•Time since stroke and Fugl–Meyer score jointly predict response to Cathodal TDCS.•Bilateral motor cortex TDCS did not reliably change motor evoked potentials.•Bilateral motor cortex TDCS did not reliably change manual reaction time.
doi:10.1016/j.neuroimage.2013.05.096
PMCID: PMC3899017  PMID: 23727528
Motor stroke; Plasticity; TDCS; Brain stimulation; Magnetic resonance spectroscopy; GABA
3.  The role of contralesional dorsal premotor cortex after stroke as studied with concurrent TMS-fMRI 
Contralesional dorsal premotor cortex (cPMd) may support residual motor function following stroke. We performed two complementary experiments to explore how cPMd might perform this role in a group of chronic human stroke patients. First, we used paired-coil transcranial magnetic stimulation (TMS) to establish the physiological influence of cPMd on ipsilesional primary motor cortex (iM1) at rest. We found that this influence became less inhibitory/more facilitatory in patients with greater clinical impairment. Second, we applied TMS over cPMd during functional magnetic resonance imaging (fMRI) in these patients to examine the causal influence of cPMd TMS on the whole network of surviving cortical motor areas in either hemisphere, and whether these influences changed during affected hand movement. We confirmed that hand grip-related activation in cPMd was greater in more impaired patients. Furthermore, the peak ipsilesional sensorimotor cortex activity shifted posteriorly in more impaired patients. Critical new findings were that concurrent TMS-fMRI results correlated with the level of both clinical impairment and neurophysiological impairment (i.e., less inhibitory/more facilitatory cPMd-iM1 measure at rest as assessed with paired-coil TMS). Specifically, greater clinical and neurophysiological impairment was associated with a stronger facilitatory influence of cPMd TMS on BOLD signal in posterior parts of ipsilesional sensorimotor cortex during hand grip, corresponding to the posteriorly shifted sensorimotor activity seen in more impaired patients. Contralesional PMd TMS was not found to influence activity in other brain regions in either hemisphere. This state-dependent influence on ipsilesional sensorimotor regions may provide a mechanism by which cPMd supports recovered function after stroke.
doi:10.1523/JNEUROSCI.5642-09.2010
PMCID: PMC3044467  PMID: 20826657
residual motor function; interhemispheric inhibition; grip force; effective connectivity; motor systems; concurrent TMS-fMRI
4.  Dual-hemisphere tDCS facilitates greater improvements for healthy subjects' non-dominant hand compared to uni-hemisphere stimulation 
BMC Neuroscience  2008;9:103.
Background
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.
Results
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).
Conclusion
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.
doi:10.1186/1471-2202-9-103
PMCID: PMC2584652  PMID: 18957075
5.  Induction of cortical plasticity and improved motor performance following unilateral and bilateral transcranial direct current stimulation of the primary motor cortex 
BMC Neuroscience  2013;14:64.
Background
Transcranial direct current stimulation (tDCS) is a non-invasive technique that modulates the excitability of neurons within the primary motor cortex (M1). Research shows that anodal-tDCS applied over the non-dominant M1 (i.e. unilateral stimulation) improves motor function of the non-dominant hand. Similarly, previous studies also show that applying cathodal tDCS over the dominant M1 improves motor function of the non-dominant hand, presumably by reducing interhemispheric inhibition. In the present study, one condition involved anodal-tDCS over the non-dominant M1 (unilateral stimulation) whilst a second condition involved applying cathodal-tDCS over the dominant M1 and anodal-tDCS over non-dominant M1 (bilateral stimulation) to determine if unilateral or bilateral stimulation differentially modulates motor function of the non-dominant hand. Using a randomized, cross-over design, 11 right-handed participants underwent three stimulation conditions: 1) unilateral stimulation, that involved anodal-tDCS applied over the non-dominant M1, 2) bilateral stimulation, whereby anodal-tDCS was applied over the non-dominant M1, and cathodal-tDCS over the dominant M1, and 3) sham stimulation. Transcranial magnetic stimulation (TMS) was performed before, immediately after, 30 and 60 minutes after stimulation to elucidate the neural mechanisms underlying any potential after-effects on motor performance. Motor function was evaluated by the Purdue pegboard test.
Results
There were significant improvements in motor function following unilateral and bilateral stimulation when compared to sham stimulation at all-time points (all P < 0.05); however there was no difference across time points between unilateral and bilateral stimulation. There was also a similar significant increase in corticomotor excitability with both unilateral and bilateral stimulation immediately post, 30 minutes and 60 minutes compared to sham stimulation (all P < 0.05). Unilateral and bilateral stimulation reduced short-interval intracortical inhibition (SICI) immediately post and at 30 minutes (all P < 0.05), but returned to baseline in both conditions at 60 minutes. There was no difference between unilateral and bilateral stimulation for SICI (P > 0.05). Furthermore, changes in corticomotor plasticity were not related to changes in motor performance.
Conclusion
These results indicate that tDCS induced behavioural changes in the non-dominant hand as a consequence of mechanisms associated with use-dependant cortical plasticity that is independent of the electrode arrangement.
doi:10.1186/1471-2202-14-64
PMCID: PMC3701480  PMID: 23815634
Transcranial Direct Current Stimulation; Motor Cortex Plasticity; Motor Performance
6.  Cortical Reorganization after Experimental Traumatic Brain Injury: A Functional Autoradiography Study 
Journal of Neurotrauma  2013;30(13):1137-1146.
Abstract
Cortical sensorimotor (SM) maps are a useful readout for providing a global view of the underlying status of evoked brain function, as well as a gross overview of ongoing mechanisms of plasticity. Recent evidence in the rat controlled cortical impact (CCI) injury model shows that the ipsilesional (injured) hemisphere is temporarily permissive for axon sprouting. This would predict that size and spatial alterations in cortical maps may occur much earlier than previously tested and that they might be useful as potential markers of the postinjury plasticity period as well as indicators of outcome. We investigated the evolution of changes in brain activation evoked by affected hindlimb electrical stimulation at 4, 7, and 30 days following CCI or sham injury over the hindlimb cortical region of adult rats. [14C]-iodoantipyrine autoradiography was used to quantitatively examine the local cerebral blood flow changes in response to hindlimb stimulation as a marker for neuronal activity. The results show that although ipsilesional hindlimb SM activity was persistently depressed from 4 days, additional novel regions of ipsilesional activity appeared concurrently within SM barrel and S2 regions as well as posterior auditory cortex. Simultaneously with this was the appearance of evoked activity within the intact, contralesional cortex that was maximal at 4 and 7 days, compared to stimulated sham-injured rats, where activation was solely unilateral. By 30 days, however, contralesional activation had greatly subsided and existing ipsilesional activity was enhanced within the same novel cortical regions that were identified acutely. These data indicate that significant reorganization of the cortical SM maps occurs after injury that evolves with a particular postinjury time course. We discuss these data in terms of the known mechanisms of plasticity that are likely to underlie these map changes, with particular reference to the differences and similarities that exist between rodent models of stroke and traumatic brain injury.
doi:10.1089/neu.2012.2785
PMCID: PMC3700473  PMID: 23305562
autoradiography; blood flow; cortical contusion injury; plasticity
7.  Polarity and timing-dependent effects of transcranial direct current stimulation in explicit motor learning 
Neuropsychologia  2011;49(5):800-804.
Research highlights
► 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.
doi:10.1016/j.neuropsychologia.2011.02.009
PMCID: PMC3083512  PMID: 21335013
Motor cortex; Human; Reaction times
8.  Parietofrontal integrity determines neural modulation associated with grasping imagery after stroke 
Brain  2012;135(2):596-614.
Chronic stroke patients with heterogeneous lesions, but no direct damage to the primary sensorimotor cortex, are capable of longitudinally acquiring the ability to modulate sensorimotor rhythms using grasping imagery of the affected hand. Volitional modulation of neural activity can be used to drive grasping functions of the paralyzed hand through a brain–computer interface. The neural substrates underlying this skill are not known. Here, we investigated the impact of individual patient's lesion pathology on functional and structural network integrity related to this volitional skill. Magnetoencephalography data acquired throughout training was used to derive functional networks. Structural network models and local estimates of extralesional white matter microstructure were constructed using T1-weighted and diffusion-weighted magnetic resonance imaging data. We employed a graph theoretical approach to characterize emergent properties of distributed interactions between nodal brain regions of these networks. We report that interindividual variability in patients’ lesions led to differential impairment of functional and structural network characteristics related to successful post-training sensorimotor rhythm modulation skill. Patients displaying greater magnetoencephalography global cost-efficiency, a measure of information integration within the distributed functional network, achieved greater levels of skill. Analysis of lesion damage to structural network connectivity revealed that the impact on nodal betweenness centrality of the ipsilesional primary motor cortex, a measure that characterizes the importance of a brain region for integrating visuomotor information between frontal and parietal cortical regions and related thalamic nuclei, correlated with skill. Edge betweenness centrality, an analogous measure, which assesses the role of specific white matter fibre pathways in network integration, showed a similar relationship between skill and a portion of the ipsilesional superior longitudinal fascicle connecting premotor and posterior parietal visuomotor regions known to be crucially involved in normal grasping behaviour. Finally, estimated white matter microstructure integrity in regions of the contralesional superior longitudinal fascicle adjacent to primary sensorimotor and posterior parietal cortex, as well as grey matter volume co-localized to these specific regions, positively correlated with sensorimotor rhythm modulation leading to successful brain–computer interface control. Thus, volitional modulation of ipsilesional neural activity leading to control of paralyzed hand grasping function through a brain–computer interface after longitudinal training relies on structural and functional connectivity in both ipsilesional and contralesional parietofrontal pathways involved in visuomotor information processing. Extant integrity of this structural network may serve as a future predictor of response to longitudinal therapeutic interventions geared towards training sensorimotor rhythms in the lesioned brain, secondarily improving grasping function through brain–computer interface applications.
doi:10.1093/brain/awr331
PMCID: PMC3286199  PMID: 22232595
motor learning; skill; stroke; rehabilitation; brain–computer interface; imagery
9.  Predicting functional motor potential in chronic stroke patients using diffusion tensor imaging 
Human Brain Mapping  2011;33(5):1040-1051.
Electrophysiological and neuroimaging studies suggest that the integrity of ipsilesional and inter-hemispheric motor circuits is important for motor recovery after stroke. However, the extent to which each of these tracts contributes to the variance in outcome remains unclear. We examined whether diffusion tensor imaging (DTI)-derived measures of corticospinal and transcallosal tracts predict motor improvement in an experimental neurorehabilitation trial. 15 chronic stroke patients received bihemispheric transcranial direct current stimulation and simultaneous physical/occupational therapy for five consecutive days. Motor impairment was assessed prior to and after the intervention. At baseline, the patients underwent DTI; probabilistic fiber tracking was used to reconstruct the pyramidal tract (PT), alternate descending motor fibers (aMF) and transcallosal fibers connecting primary motor cortices (M1-M1). Ipsilesional corticospinal tracts (PT, aMF) and M1-M1 showed significantly decreased fractional anisotropy (FA) and increased directional diffusivities when compared to age-matched healthy controls. Partial correlations revealed that greater gains in motor functions were related to higher FA values and lower directional diffusivities of transcallosal and ipsilesional corticospinal tracts. M1-M1 diffusivity had the greatest predictive value. An additional slice-by-slice analysis of FA values along the corticospinal tracts demonstrated that the more the ipsilesional FA profiles of patients resembled those of healthy controls, the greater their functional improvement. In conclusion, our study shows that DTI-derived measures can be used to predict functional potential for subsequent motor recovery in chronic stroke patients. Diffusivity parameters of individual tracts and tract combinations may help in assessing a patient’s individual recovery potential and in determining optimal neurorehabilitative interventions.
doi:10.1002/hbm.21266
PMCID: PMC3175010  PMID: 21538700
alternate motor fibers; corticospinal tract; directional diffusivity; fractional anisotropy; inter-hemispheric interaction; motor impairment; pyramidal tract; transcallosal fibers
10.  Prediction of Motor Function Recovery after Subcortical Stroke: Case Series of Activation PET and TMS Studies 
Annals of Rehabilitation Medicine  2012;36(4):501-511.
Objective
To examine whether the pattern of brain activation induced by a motor task and the motor responses to transcranial magnetic stimulation (TMS) have prognostic implications for motor recovery after stroke.
Method
Ten patients with first-ever subcortical stroke (55.7±17.3 years, 5 ischemic and 5 hemorrhagic) underwent 2 FDG PET studies under different conditions (1: rest, 2: activation with a specific motor task) at 37.7±25.2 days after stroke. The regions showing more than a 10% increase in glucose metabolism on subtraction images during activation and rest were considered to be significantly activated. Cortical excitability of intracortical inhibition (ICI) and intracortical facilitation (ICF) were assessed using the TMS from both abductor pollicis brevis muscles within 7 days of PET scans. Recovery of motor function was assessed at the point of the neurological plateau.
Results
The presence of a motor response at the plegic site to TMS and normal intracortical inhibition, and facilitation patterns in the unaffected hemisphere were found to be related to good recovery. An association between an ipsilesional activation on PET and good motor recovery was also observed, but this was significantly weaker than that between TMS measured cortical excitability and motor recovery.
Conclusion
Integrity of the ipsilesional corticospinal pathway, normalized contralesional intracortical excitability, and task-related activation in the ipsilesional hemisphere were found to predict post-stroke motor recovery significantly.
doi:10.5535/arm.2012.36.4.501
PMCID: PMC3438417  PMID: 22977776
Stroke; Motor recovery; PET; Transcranial magnetic stimulation; Activation pattern
11.  Motor system activation after subcortical stroke depends on corticospinal system integrity 
Brain : a journal of neurology  2006;129(0 3):809-819.
Movement-related brain activation patterns after subcortical stroke are characterized by relative overactivations in cortical motor areas compared with controls. In patients able to perform a motor task, overactivations are greater in those with more motor impairment. We hypothesized that recruitment of motor regions would shift from primary to secondary motor networks in response to impaired functional integrity of the corticospinal system (CSS). We measured the magnitude of brain activation using functional MRI during a motor task in eight chronic subcortical stroke patients. CSS functional integrity was assessed using transcranial magnetic stimulation to obtain stimulus/response curves for the affected first dorsal interosseus muscle, with a shallower gradient representing increasing disruption of CSS functional integrity. A negative correlation between the gradient of stimulus/response curve and magnitude of task-related brain activation was found in several motor-related regions, including ipsilesional posterior primary motor cortex [Brodmann area (BA) 4p], contralesional anterior primary motor cortex (BA 4a), bilateral premotor cortex, supplementary motor area, intraparietal sulcus, dorsolateral prefrontal cortex and contralesional superior cingulate sulcus. There were no significant positive correlations in any brain region. These results suggest that impaired functional integrity of the CSS is associated with recruitment of secondary motor networks in both hemispheres in an attempt to generate motor output to spinal cord motoneurons. Secondary motor regions are less efficient at generating motor output so this reorganization can only be considered partially successful in reducing motor impairment after stroke.
doi:10.1093/brain/awl002
PMCID: PMC3717515  PMID: 16421171
functional brain imaging; motor recovery; motor system; stroke
12.  Characterizing relationships of DTI, fMRI, and motor recovery in stroke rehabilitation utilizing brain-computer interface technology 
The relationship of the structural integrity of white matter tracts and cortical activity to motor functional outcomes in stroke patients is of particular interest in understanding mechanisms of brain structural and functional changes while recovering from stroke. This study aims to probe these underlying mechanisms using diffusion tensor imaging (DTI) and fMRI measures. We examined the structural integrity of the posterior limb of the internal capsule (PLIC) using DTI and corticomotor activity using motor-task fMRI in stroke patients who completed up to 15 sessions of rehabilitation therapy using Brain-Computer Interface (BCI) technology. We hypothesized that (1) the structural integrity of PLIC and corticomotor activity are affected by stroke; (2) changes in structural integrity and corticomotor activity following BCI intervention are related to motor recovery; (3) there is a potential relationship between structural integrity and corticomotor activity. We found that (1) the ipsilesional PLIC showed significantly decreased fractional anisotropy (FA) values when compared to the contralesional PLIC; (2) lower ipsilesional PLIC-FA values were significantly associated with worse motor outcomes (i.e., ipsilesional PLIC-FA and motor outcomes were positively correlated.); (3) lower ipsilesional PLIC-FA values were significantly associated with greater ipsilesional corticomotor activity during impaired-finger-tapping-task fMRI (i.e., ipsilesional PLIC-FA and ipsilesional corticomotor activity were negatively correlated), with an overall bilateral pattern of corticomotor activity observed; and (4) baseline FA values predicted motor recovery assessed after BCI intervention. These findings suggest that (1) greater vs. lesser microstructural integrity of the ipsilesional PLIC may contribute toward better vs. poor motor recovery respectively in the stroke-affected limb and demand lesser vs. greater cortical activity respectively from the ipsilesional motor cortex; and that (2) PLIC-FA is a promising biomarker in tracking and predicting motor functional recovery in stroke patients receiving BCI intervention.
doi:10.3389/fneng.2014.00031
PMCID: PMC4114288  PMID: 25120466
DTI; FA; fMRI; motor recovery; stroke rehabilitation; BCI
13.  Effects of Transcranial Direct Current Stimulation (tDCS) on Human Regional Cerebral Blood Flow 
NeuroImage  2011;58(1):26-33.
Transcranial direct current stimulation (tDCS) can up- and down-regulate cortical excitability depending on current direction, however our abilities to measure brain-tissue effects of the stimulation and its after-effects have been limited so far. We used regional cerebral blood flow (rCBF), a surrogate measure of brain activity, to examine regional brain-tissue and brain-network effects during and after tDCS. We varied the polarity (anodal and cathodal) as well as the current strength (0.8 to 2.0 mA) of the stimulation. Fourteen healthy subjects were randomized into receiving either anodal or cathodal stimulation (two subjects received both, one week apart) while undergoing Arterial Spin Labeling (ASL) in the MRI scanner with an alternating off-on sampling paradigm. The stimulating, MRI-compatible electrode was placed over the right motor region and the reference electrode over the contralateral supraorbital region. SPM5 was used to process and extract the rCBF data using a 10mm spherical volume-of-interest (VOI) placed in the motor cortex directly underneath the stimulating scalp electrode. Anodal stimulation induced a large increase (17.1%) in rCBF during stimulation, which returned to baseline after the current was turned off, but exhibited an increase in rCBF again in the post-stimulation period. Cathodal stimulation induced a smaller increase (5.6%) during stimulation, a significant decrease compared to baseline (−6.5%) after cessation, and a continued decrease in the post-stimulation period. These changes in rCBF were all significant when compared to the pre-stimulation baseline or to a control region. Furthermore, for anodal stimulation, there was a significant correlation between current strength and the increase in rCBF in the on-period relative to the pre-stimulation baseline. The differential rCBF after-effects of anodal (increase in resting state rCBF) and cathodal (decrease in resting state rCBF) tDCS support findings of behavioral and cognitive after-effects after cathodal and anodal tDCS. We also showed that tDCS not only modulates activity in the brain region directly underlying the stimulating electrode but also in a network of brain regions that are functionally related to the stimulated area. Our results indicate that ASL may be an excellent tool to investigate the effects of tDCS and its stimulation parameters on brain activity.
doi:10.1016/j.neuroimage.2011.06.018
PMCID: PMC3155947  PMID: 21703350
14.  Polarity-specific effects of motor transcranial direct current stimulation on fMRI resting state networks☆ 
Neuroimage  2014;88(100):155-161.
Transcranial direct current stimulation (tDCS) has been used to modify motor performance in healthy and patient populations. However, our understanding of the large-scale neuroplastic changes that support such behavioural effects is limited. Here, we used both seed-based and independent component analyses (ICA) approaches to probe tDCS-induced modifications in resting state activity with the aim of establishing the effects of tDCS applied to the primary motor cortex (M1) on both motor and non-motor networks within the brain. Subjects participated in three separate sessions, during which resting fMRI scans were acquired before and after 10 min of 1 mA anodal, cathodal, or sham tDCS. Cathodal tDCS increased the inter-hemispheric coherence of resting fMRI signal between the left and right supplementary motor area (SMA), and between the left and right hand areas of M1. A similar trend was documented for the premotor cortex (PMC). Increased functional connectivity following cathodal tDCS was apparent within the ICA-generated motor and default mode networks. Additionally, the overall strength of the default mode network was increased. Neither anodal nor sham tDCS produced significant changes in resting state connectivity. This work indicates that cathodal tDCS to M1 affects the motor network at rest. In addition, the effects of cathodal tDCS on the default mode network support the hypothesis that diminished top-down control may contribute to the impaired motor performance induced by cathodal tDCS.
Highlights
•Resting state BOLD fMRI data was acquired before and after tDCS applied to M1.•Cathodal tDCS increased inter-hemispheric correlations between the M1 hand areas.•Cathodal tDCS increased connectivity in ICA-generated motor and default networks.•Cathodal tDCS increased the overall strength of the default network.
doi:10.1016/j.neuroimage.2013.11.037
PMCID: PMC3991849  PMID: 24287440
Transcranial direct current stimulation; Resting state connectivity; Functional MRI; Independent component analysis; Motor; Default mode
15.  Non-Invasive Brain Stimulation Enhances the Effects of Melodic Intonation Therapy 
Research has suggested that a fronto-temporal network in the right hemisphere may be responsible for mediating melodic intonation therapy’s (MIT) positive effects on speech recovery. We investigated the potential for a non-invasive brain stimulation technique, transcranial direct current stimulation (tDCS), to augment the benefits of MIT in patients with non-fluent aphasia by modulating neural activity in the brain during treatment with MIT. 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. We applied anodal-tDCS to the posterior inferior frontal gyrus of the right hemisphere, an area that has been shown both to contribute to singing through the mapping of sounds to articulatory actions and to serve as a key region in the process of recovery from aphasia, particularly in patients with large left hemisphere lesions. The stimulation was applied while patients were treated with MIT by a trained therapist. Six patients with moderate to severe non-fluent aphasia underwent three consecutive days of anodal-tDCS + MIT, and an equivalent series of sham-tDCS + MIT. The two treatment series were separated by 1 week, and the order in which the treatments were administered was randomized. Compared to the effects of sham-tDCS + MIT, anodal-tDCS + MIT led to significant improvements in fluency of speech. These results support the hypothesis that, as the brain seeks to reorganize and compensate for damage to left hemisphere language centers, combining anodal-tDCS with MIT may further recovery from post-stroke aphasia by enhancing activity in a right hemisphere sensorimotor network for articulation.
doi:10.3389/fpsyg.2011.00230
PMCID: PMC3180169  PMID: 21980313
melodic intonation therapy; transcranial direct current stimulation; tDCS; Broca’s aphasia; stroke; neurorehabilitation; singing
16.  Enhanced Motor Learning Following Task-Concurrent Dual Transcranial Direct Current Stimulation 
PLoS ONE  2013;8(12):e85693.
Objective
Transcranial direct current stimulation (tDCS) of the primary motor cortex (M1) has beneficial effects on motor performance and motor learning in healthy subjects and is emerging as a promising tool for motor neurorehabilitation. Applying tDCS concurrently with a motor task has recently been found to be more effective than applying stimulation before the motor task. This study extends this finding to examine whether such task-concurrent stimulation further enhances motor learning on a dual M1 montage.
Method
Twenty healthy, right-handed subjects received anodal tDCS to the right M1, dual tDCS (anodal current over right M1 and cathodal over left M1) and sham tDCS in a repeated-measures design. Stimulation was applied for 10 mins at 1.5 mA during an explicit motor learning task. Response times (RT) and accuracy were measured at baseline, during, directly after and 15 mins after stimulation. Motor cortical excitability was recorded from both hemispheres before and after stimulation using single-pulse transcranial magnetic stimulation.
Results
Task-concurrent stimulation with a dual M1 montage significantly reduced RTs by 23% as early as with the onset of stimulation (p<0.01) with this effect increasing to 30% at the final measurement. Polarity-specific changes in cortical excitability were observed with MEPs significantly reduced by 12% in the left M1 and increased by 69% in the right M1.
Conclusion
Performance improvement occurred earliest in the dual M1 condition with a stable and lasting effect. Unilateral anodal stimulation resulted only in trendwise improvement when compared to sham. Therefore, task-concurrent dual M1 stimulation is most suited for obtaining the desired neuromodulatory effects of tDCS in explicit motor learning.
doi:10.1371/journal.pone.0085693
PMCID: PMC3871525  PMID: 24376893
17.  Volumetric Effects of Motor Cortex Injury on Recovery of Ipsilesional Dexterous Movements 
Experimental neurology  2011;231(1):56-71.
Damage to the motor cortex of one hemisphere has classically been associated with contralateral upper limb paresis, but recent patient studies have identified deficits in both upper limbs. In non-human primates, we tested the hypothesis that the severity of ipsilesional upper limb motor impairment in the early post-injury phase depends on the volume of gray and white matter damage of the motor areas of the frontal lobe. We also postulated that substantial recovery would accompany minimal task practice and that ipsilesional limb recovery would be correlated with recovery of the contralesional limb. Gross (reaching) and fine hand motor functions were assessed for 3-12 months post-injury using two motor tests. Volumes of white and gray matter lesions were assessed using quantitative histology. Early changes in post-lesion motor performance were inversely correlated with white matter lesion volume indicating that larger lesions produced greater decreases in ipsilesional hand movement control. All monkeys showed improvements in ipsilesional hand motor skill during the post-lesion period, with reaching skill improvements being positively correlated with total lesion volume indicating larger lesions were associate with greater ipsilesional motor skill recovery. We suggest that reduced trans-callosal inhibition from the lesioned hemisphere may play a role in the observed skill improvements. Our findings show that significant ipsilesional hand motor recovery is likely to accompany injury limited to frontal motor areas. In humans, more pronounced ipsilesional motor deficits that invariably develop after stroke may, in part, be a consequence of more extensive subcortical white and gray matter damage.
doi:10.1016/j.expneurol.2011.05.015
PMCID: PMC3153606  PMID: 21703261
brain injury; hand; dexterity
18.  Effect of Stimulation Polarity of Transcranial Direct Current Stimulation on Non-dominant Hand Function 
Objective
To evaluate motor excitability and hand function on the non-dominant side according to the polarity of transcranial direct current stimulation (tDCS) on the motor cortex in a healthy person.
Method
tDCS was applied to the hand motor cortex for 15 minutes at an intensity of 1 mA in 28 healthy right-handed adults. Subjects were divided randomly into four groups: an anodal tDCS of the non-dominant hemisphere group, a cathodal tDCS of the non-dominant hemisphere group, an anodal tDCS of the dominant hemisphere group, and a sham group. We measured the motor evoked potential (MEP) in the abductor pollicis brevis and Jabsen-Taylor hand function test (JTT) in the non-dominant hand prior to and following tDCS. All study procedures were done under double-blind design.
Results
There was a significant increase in the MEP amplitude and a significant improvement in the JTT in the non-dominant hand following anodal tDCS of the non-dominant hemisphere (p<0.05). But there was no change in JTT and a significant decrease in the MEP amplitude in the non-dominant hand following cathodal tDCS on the non-dominant hemisphere and anodal tDCS of the dominant hemisphere.
Conclusion
Non-dominant hand function is improved by increased excitability of the motor cortex. Although motor cortex excitability is decreased in a healthy person, non-dominant hand function is maintained. A homeostatic mechanism in the brain might therefore be involved in preserving this function. Further studies are warranted to examine brain functions to clarify this mechanism.
doi:10.5535/arm.2012.36.1.1
PMCID: PMC3309318  PMID: 22506229
tDCS; Transcranial direct current stimulation; Jabsen-Taylor hand function test; Cortical excitability
19.  Characterizing the application of transcranial direct current stimulation in human pharyngeal motor cortex 
Transcranial direct current stimulation (tDCS) is a novel intervention that can modulate brain excitability in health and disease; however, little is known about its effects on bilaterally innervated systems such as pharyngeal motor cortex. Here, we assess the effects of differing doses of tDCS on the physiology of healthy human pharyngeal motor cortex as a prelude to designing a therapeutic intervention in dysphagic patients. Healthy subjects (n = 17) underwent seven regimens of tDCS (anodal 10 min 1 mA, cathodal 10 min 1 mA, anodal 10 min 1.5 mA, cathodal 10 min 1.5 mA, anodal 20 min 1 mA, cathodal 20 min 1 mA, Sham) on separate days, in a double blind randomized order. Bihemispheric motor evoked potential (MEP) responses to single-pulse transcranial magnetic stimulation (TMS) as well as intracortical facilitation (ICF) and inhibition (ICI) were recorded using a swallowed pharyngeal catheter before and up to 60 min following the tDCS. Compared with sham, both 10 min 1.5 mA and 20 min 1 mA anodal stimulation induced increases in cortical excitability in the stimulated hemisphere (+44 ± 17% and +59 ± 16%, respectively; P < 0.005) whereas only 10 min 1.5 mA cathodal stimulation induced inhibition (−26 ± 4%, P = 0.02). There were neither contralateral hemisphere changes nor any evidence for ICI or ICF in driving the ipsilateral effects. In conclusion, anodal tDCS can alter pharyngeal motor cortex excitability in an intensity-dependent manner, with little evidence for transcallosal spread. Anodal stimulation may therefore provide a useful means of stimulating pharyngeal cortex and promoting recovery in dysphagic patients.
doi:10.1152/ajpgi.00294.2009
PMCID: PMC2850087  PMID: 19815630
swallowing; pharynx; plasticity
20.  Theta Burst Stimulation in the Rehabilitation of the Upper Limb: A Semirandomized, Placebo-Controlled Trial in Chronic Stroke Patients 
Background
Noninvasive cortical stimulation could represent an add-on treatment to enhance motor recovery after stroke. However, its clinical value, including anticipated size and duration of the treatment effects, remains largely unknown.
Objective
The authors designed a small semi-randomized clinical trial to explore whether long-lasting clinically important gains can be achieved by adding theta burst stimulation (TBS), a form of repetitive transcranial magnetic stimulation (TMS), to a rehabilitation program for the hand.
Methods
A total of 41 chronic stroke patients received excitatory TBS to the ipsilesional hemisphere or inhibitory TBS to the contralesional hemisphere in 2 centers; each active group was compared with a group receiving sham TBS. TBS was followed by physical therapy for 10 working days. Patients and therapists were blinded to the type of TBS. Primary outcome measures (9-hole Peg Test [9HPT], Jebsen Taylor Test [JTT], and grip and pinch-grip dynamometry) were assessed 4, 30, and 90 days post treatment. The clinically important difference was defined as 10% of the maximum score.
Results
There were no differences between the active treatment and sham groups in any of the outcome measures. All patients achieved small sustainable improvements—9HPT, 5% of maximum (confidence interval [CI] = 3%-7%); JTT, 5.7% (CI = 3%-8%); and grip strength, 6% (CI = 2%-10%)—all below the defined clinically important level.
Conclusions
Cortical stimulation did not augment the gains from a late rehabilitation program. The effect size anticipated by the authors was overestimated. These results can improve the design of future work on therapeutic uses of TMS.
doi:10.1177/1545968312437940
PMCID: PMC3719964  PMID: 22412171
transcranial magnetic stimulation; stroke rehabilitation; theta burst stimulation; upper extremity; motor control
21.  Modulation of cerebellar excitability by polarity-specific non-invasive direct current stimulation 
The cerebellum is a crucial structure involved in movement control and cognitive processing. Non-invasive stimulation of the cerebellum results in neurophysiological and behavioral changes, an effect that has been attributed to modulation of cerebello–brain connectivity. At rest, the cerebellum exerts an overall inhibitory tone over the primary motor cortex (M1), cerebello-brain inhibition (CBI), likely through dentate-thalamo-cortical connections. The level of excitability of this pathway before and after stimulation of the cerebellum, however, has not been directly investigated. In this study we used transcranial magnetic stimulation (TMS) to determine changes in M1, brainstem and CBI before and after 25 minutes of anodal, cathodal or sham transcranial direct current stimulation (tDCS) applied over the right cerebellar cortex. We hypothesized that anodal tDCS would result in an enhancement of CBI and cathodal would decrease it, relative to sham stimulation. We found that cathodal tDCS resulted in a clear decrease of CBI, whereas anodal tDCS increased it, in the absence of changes after sham stimulation. These effects were specific to the cerebello-cortical connections with no changes in other M1 or brainstem excitability measures. The cathodal effect on CBI was found to be dependent on stimulation intensity and lasted up to 30 minutes after the cessation of tDCS. These results suggest that tDCS can modulate in a focal and polarity-specific manner cerebellar excitability, likely through changes in Purkinje cell activity. Therefore, direct current stimulation of the cerebellum may have significant potential implications for patients with cerebellar dysfunction as well as to motor control studies.
doi:10.1523/JNEUROSCI.2184-09.2009
PMCID: PMC2760225  PMID: 19605648
brainstem; cerebellum; motor cortex; plasticity; Purkinje cell; reticular
22.  Chronic electrical stimulation of the contralesional lateral cerebellar nucleus enhances recovery of motor function after cerebral ischemia in rats 
Brain research  2009;1280:107-116.
Novel neurorehabilitative strategies are needed to improve motor outcomes following stroke. Based on the disynaptic excitatory projections of the dentatothalamocortical pathway to the motor cortex as well as anterior and posterior cortical areas, we hypothesize that chronic electrical stimulation of the contralesional dentate (lateral cerebellar) nucleus output can enhance motor recovery after ischemia via augmentation of perilesional cortical excitability. Seventy five Wistar rats were pre-trained in the Montoya staircase task and subsequently suffered left cerebral ischemia with the 3-vessel occlusion model. All survivors underwent stereotactic right lateral cerebellar nucleus (LCN) implantation of bipolar electrodes. Rats were then randomized to 4 groups: LCN stimulation at 10 pps, 20 pps, 50 pps or sham stimulation, which was delivered for a period of six weeks. Performance on the Montoya task was re-assessed over the last four weeks of the stimulation period. On the right (contralesional) side, motor performance of the groups undergoing sham, 10 pps, 20 pps and 50 pps stimulation was, respectively, 2.5± 2.7; 2.1 ± 2.5; 6.0 ± 3.9 (p<0.01) and 4.5 ± 3.5 pellets. There was no difference on the left (ipsilesional) side motor performance among the sham or stimulation groups, varying from 15.9 ± 6.7 to 17.2 ± 2.1 pellets. We conclude that contralesional chronic electrical stimulation of the lateral cerebellar nucleus at 20 pps but not at 10 or 50 pps improves motor recovery in rats following ischemic strokes. This effect is likely to be mediated by increased perilesional cortical excitability via chronic activation of the dentatothalamocortical pathway.
doi:10.1016/j.brainres.2009.05.007
PMCID: PMC2709491  PMID: 19445910
Stroke; Ischemia; Cerebellum; Dentate Nucleus; Electrical Stimulation; Plasticity; Deep Brain Stimulation
23.  Remote Brain Network Changes after Unilateral Cortical Impact Injury and Their Modulation by Acetylcholinesterase Inhibition 
Journal of Neurotrauma  2013;30(11):907-919.
Abstract
We explored whether cerebral cortical impact injury (CCI) effects extend beyond direct lesion sites to affect remote brain networks, and whether acetylcholinesterase (AChE) inhibition elicits discrete changes in functional activation of motor circuits following CCI. Adult male rats underwent unilateral motor-sensory CCI or sham injury. Physostigmine (AChE inhibitor) or saline were administered subcutaneously continuously via implanted minipumps (1.6 micromoles/kg/day) for 3 weeks, followed by cerebral perfusion mapping during treadmill walking using [14C]-iodoantipyrine. Quantitative autoradiographs were analyzed by statistical parametric mapping and functional connectivity (FC) analysis. CCI resulted in functional deficits in the ipsilesional basal ganglia, with increased activation contralesionally. Recruitment was also observed, especially contralesionally, of the red nucleus, superior colliculus, pedunculopontine tegmental nucleus, thalamus (ventrolateral n., central medial n.), cerebellum, and sensory cortex. FC decreased significantly within ipsi- and contralesional motor circuits and between hemispheres, but increased between midline cerebellum and select regions of the basal ganglia within each hemisphere. Physostigmine significantly increased functional brain activation in the cerebellar thalamocortical pathway (midline cerebellum→ventrolateral thalamus→motor cortex), subthalamic nucleus/zona incerta, and red nucleus and bilateral sensory cortex. In conclusion, CCI resulted in increased functional recruitment of contralesional motor cortex and bilateral subcortical motor regions, as well as recruitment of the cerebellar–thalamocortical circuit and contralesional sensory cortex. This phenomenon, augmented by physostigmine, may partially compensate motor deficits. FC decreased inter-hemispherically and in negative, but not positive, intra-hemispherical FC, and it was not affected by physostigmine. Circuit-based approaches into functional brain reorganization may inform future behavioral or molecular strategies to augment targeted neurorehabilitation.
doi:10.1089/neu.2012.2657
PMCID: PMC3684212  PMID: 23343118
cholinergic; diaschisis; functional brain mapping; functional connectivity; traumatic brain injury
24.  Longitudinal Changes of Resting-State Functional Connectivity during Motor Recovery after Stroke 
Background and Purpose
Functional magnetic resonance imaging (fMRI) studies could provide crucial information on the neural mechanisms of motor recovery in stroke patients. Resting-state fMRI is applicable to stroke patients who are not capable of proper performance of the motor task. In this study, we explored neural correlates of motor recovery in stroke patients by investigating longitudinal changes in resting-state functional connectivity of the ipsilesional primary motor cortex (M1).
Methods
A longitudinal observational study using repeated fMRI experiments was conducted in 12 patients with stroke. Resting-state fMRI data were acquired four times over a period of 6 months. Patients participated in the first session of fMRI shortly after onset, and thereafter in subsequent sessions at 1, 3, and 6 months after onset. Resting-state functional connectivity of the ipsilesional M1 was assessed and compared with that of healthy subjects.
Results
Compared with healthy subjects, patients demonstrated higher functional connectivity with the ipsilesional frontal and parietal cortices, bilateral thalamus, and cerebellum. Instead, functional connectivity with the contralesional M1 and occipital cortex were decreased in stroke patients. Functional connectivity between the ipsilesional and contralesional M1 showed the most asymmetry at 1 month after onset to the ipsilesional side. Functional connectivity of the ipsilesional M1 with the contralesional thalamus, supplementary motor area, and middle frontal gyrus at onset was positively correlated with motor recovery at 6 months after stroke.
Conclusions
Resting-state fMRI elicited distinctive but comparable results with previous task-based fMRI, presenting complementary and practical values for use in the study of stroke patients.
doi:10.1161/STROKEAHA.110.596155
PMCID: PMC3589816  PMID: 21441147
Resting-state fMRI; Stroke; Motor recovery; Functional connectivity
25.  Motor and premotor cortices in subcortical stroke: proton magnetic resonance spectroscopy measures and arm motor impairment 
Background
Although functional imaging and neurophysiological approaches reveal alterations in motor and premotor areas after stroke, insights into neurobiological events underlying these alterations are limited in human studies.
Objective
We tested whether cerebral metabolites related to neuronal and glial compartments are altered in the hand representation in bilateral motor and premotor areas and correlated with distal and proximal arm motor impairment in hemiparetic persons.
Methods
In twenty participants at >6 months post-onset of a subcortical ischemic stroke and sixteen age and sex-matched healthy controls, the concentrations of N-acetylaspartate and myoinositol were quantified by proton magnetic resonance spectroscopy (1H-MRS). Regions of interest, identified by functional MRI, included primary (M1), dorsal premotor (PMd), and supplementary (SMA) motor areas. Relationships between metabolite concentrations and distal (hand) and proximal (shoulder/elbow) motor impairment using Fugl-Meyer Upper Extremity (FMUE) subscores were explored.
Results
N-acetylaspartate was lower in M1 (p=0.04) and SMA (p=0.004) and myo-inositol was higher in M1 (p=0.003) and PMd (p=0.03) in the injured (ipsilesional) hemisphere after stroke compared to the left hemisphere in controls. N-acetylaspartate in ipsilesional M1 was positively correlated with hand FMUE subscores (p=0.04). Significant positive correlations were also found between N-acetylaspartate in ipsilesional M1, PMd, and SMA and in contralesional M1 and shoulder/elbow FMUE subscores (p=0.02, 0.01, 0.02 and 0.02 respectively).
Conclusions
Our preliminary results demonstrated that 1H-MRS is a sensitive method to quantify relevant neuronal changes in spared motor cortex after stroke, and consequently increase our knowledge of the factors leading from these changes to arm motor impairment.
doi:10.1177/1545968312469835
PMCID: PMC3943339  PMID: 23300210
subcortical stroke; motor and premotor cortices; proton magnetic resonance spectroscopy; distal and proximal arm motor impairment

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