Long‐term progressive motor skill training enhances corticospinal excitability for the ipsilateral hemisphere and motor performance of the untrained hand

It is well established that unilateral motor practice can lead to increased performance in the opposite non‐trained hand. Here, we test the hypothesis that progressively increasing task difficulty during long‐term skill training with the dominant right hand increase performance and corticomotor excitability of the left non‐trained hand. Subjects practiced a visuomotor tracking task engaging right digit V for 6 weeks with either progressively increasing task difficulty (PT) or no progression (NPT). Corticospinal excitability (CSE) was evaluated from the resting motor threshold (rMT) and recruitment curve parameters following application of transcranial magnetic stimulation (TMS) to the ipsilateral primary motor cortex (iM1) hotspot of the left abductor digiti minimi muscle (ADM). PT led to significant improvements in left‐hand motor performance immediately after 6 weeks of training (63 ± 18%, P < 0.001) and 8 days later (76 ± 14%, P < 0.001). In addition, PT led to better task performance compared to NPT (19 ± 15%, P = 0.024 and 27 ± 15%, P = 0.016). Following the initial training session, CSE increased across all subjects. After 6 weeks of training and 8 days later, only PT was accompanied by increased CSE demonstrated by a left and upwards shift in the recruitment curves, e.g. indicated by increased MEP_max (P = 0.012). Eight days after training similar effects were observed, but 14 months later motor performance and CSE were similar between groups. We suggest that progressively adjusting demands for timing and accuracy to individual proficiency promotes motor skill learning and drives the iM1‐CSE resulting in enhanced performance of the non‐trained hand. The results underline the importance of increasing task difficulty progressively and individually in skill learning and rehabilitation training.     

Does transcranial electrical stimulation enhance corticospinal excitability of the motor cortex in healthy individuals? A systematic review and meta‐analysis

Numerous studies have explored the effects of transcranial electrical stimulation (tES) – including anodal transcranial direct current stimulation (a‐tDCS), cathodal transcranial direct current stimulation (c‐tDCS), transcranial alternative current stimulation (tACS), transcranial random noise stimulation (tRNS) and transcranial pulsed current stimulation (tPCS) – on corticospinal excitability (CSE) in healthy populations. However, the efficacy of these techniques and their optimal parameters for producing robust results has not been studied. Thus, the aim of this systematic review was to consolidate current knowledge about the effects of various parameters of a‐tDCS, c‐tDCS, tACS, tRNS and tPCS on the CSE of the primary motor cortex (M1) in healthy people. Leading electronic databases were searched for relevant studies published between January 1990 and February 2017; 126 articles were identified, and their results were extracted and analysed using RevMan software. The meta‐analysis showed that a‐tDCS application on the dominant side significantly increases CSE (P < 0.01) and that the efficacy of a‐tDCS is dependent on current density and duration of application. Similar results were obtained for stimulation of M1 on the non‐dominant side (P = 0.003). The effects of a‐tDCS reduce significantly after 24 h (P = 0.006). Meta‐analysis also revealed significant reduction in CSE following c‐tDCS (P < 0.001) and significant increases after tRNS (P = 0.03) and tPCS (P = 0.01). However, tACS effects on CSE were only significant when the stimulation frequency was ≥140 Hz. This review provides evidence that tES has substantial effects on CSE in healthy individuals for a range of stimulus parameters.     

Protection against stroke with glucagon‐like peptide 1 receptor agonists: a systematic review and meta‐analysis

In experimental stroke models pretreatment with the newly introduced antidiabetic agents, glucagon‐like peptide 1 receptor (GLP‐1R) agonists, has been shown to exert neuroprotective effects. Published evidence with regard to the effect of treatment with GLP‐1R agonists on the risk of stroke was evaluated. Data from prospective randomized placebo‐controlled trials up to October 2018 involving GLP‐1R agonists which reported cardiovascular outcomes as primary end‐points of efficacy and/or safety were meta‐analysed. Five eligible multicentre randomized placebo‐controlled trials (ELIXA, LEADER, SUSTAIN, EXSCEL and HARMONY) were included. The pooled analysis (n = 42 358) showed a significant reduction by 13% in the risk of total stroke from treatment with GLP‐1R agonists versus placebo (risk ratio 0.87, 95% confidence interval 0.78–0.98, P = 0.021) with no significant heterogeneity between trials (Q = 4.094, P = 0.393, I² = 2.307%). When only fatal stroke was included (this applied for the ELIXA, LEADER, EXSCEL and HARMONY trials), active treatment was associated with a non‐significant reduction by 16% compared with placebo (risk ratio 0.84, 95% confidence interval 0.60–1.17, P = 0.29). The findings of this meta‐analysis support the evidence from earlier experimental studies calling attention to potential ‘stroke protective’ effects from treatment with GLP‐1R.     

Resting state functional connectivity measures correlate with the response to anodal transcranial direct current stimulation

Responses to non‐invasive brain stimulation are highly variable between subjects. Resting state functional connectivity was investigated as a marker of plasticity induced by anodal transcranial direct current stimulation (tDCS). Twenty‐six healthy adults (15 male, 26.4 ± 6.5 years) were tested. Experiment 1 investigated whether functional connectivity could predict modulation of corticospinal excitability following anodal tDCS. Experiment 2 determined test – retest reliability of connectivity measures. Three minutes of electroencephalography was recorded and connectivity was quantified with the debiased weighted phase lag index. Anodal (1 mA, 20 min) or sham tDCS was applied to the left primary motor cortex (M1), with a change in motor evoked potential amplitude recorded from the right first dorsal interosseous used as a marker of tDCS response. Connectivity in the high beta frequency (20–30 Hz) between an electrode approximating the left M1 (C3) and electrodes overlying the left parietal cortex was a strong predictor of tDCS response (cross‐validated R² = 0.69). Similar relationships were observed for alpha (8–13 Hz; R² = 0.64), theta (4–7 Hz; R² = 0.53), and low beta (14–19 Hz; R² = 0.58) frequencies, however, test – retest reliability of connectivity measures was strongest for the high beta frequency model (ICC = 0.65; good reliability). Further investigation of the high beta model found that greater connectivity between C3 and a cluster of electrodes approximately overlying the left parietal cortex was associated with stronger responses to anodal (rho = 0.61, P = 0.03), but not sham tDCS (rho = 0.43, P = 0.14). Functional connectivity is a strong predictor of the neuroplastic response to tDCS and may be one important characteristic to assist targeted tDCS application.     

The Adjunct of Electric Neurostimulation to Rehabilitation Approaches in Upper Limb Stroke Rehabilitation: A Systematic Review With Network Meta-Analysis of Randomized Controlled Trials

ObjectiveThis review analyzed the current evidence and the potential for the application of electric neurostimulation such as transcranial direct current stimulation (tDCS) and vagus nerve stimulation (VNS) in upper limb stroke rehabilitation.Materials and MethodsWe performed a systematic review of randomized controlled trials (RCTs) using network meta-analysis (NMA), searching the following data bases: PubMed, Web of Science, Cochrane, and Google Scholar, using specific keywords, from January 2010 to April 2021, and assessing the effects of “tDCS” or “VNS” combined with other therapies on upper limb motor function and activities of daily living (ADL) after stroke.ResultsWe included 38 RCTs with 1261 participants. Pairwise NMA showed transcutaneous VNS (tVNS) and anodal tDCS were effective in improving upper limb motor function (tVNS: mean difference [MD]: 5.50; 95% CI [0.67–11.67]; p < 0.05; anodal tDCS: MD: 5.23; 95% CI [2.45–8.01]; p < 0.05). tVNS and tDCS (anodal and cathodal) were also effective in improving ADL performance after stroke (tVNS: standard MD [SMD]: 0.96; 95% CI [0.15–2.06]; p < 0.05; anodal tDCS: SMD: 3.78; 95% CI [0.0–7.56]; p < 0.05; cathodal tDCS: SMD: 5.38; 95% CI [0.22–10.54]; p < 0.05). Surface under the cumulative ranking curve analysis revealed that tVNS is the best ranked treatment in improving upper limb motor function and performance in ADL after stroke. There was no difference in safety between VNS and its control interventions, measured by reported adverse events (VNS: risk ratio = 1.02 [95% CI = 0.48–2.17; I² = 0; p = 0.96]).ConclusionModerate- to high-quality evidence suggests that tVNS and anodal tDCS were effective in improving upper limb motor function in both acute/subacute and chronic stroke. In addition to tVNS and anodal tDCS, cathodal tDCS is also effective in improving ADL performance after stroke.     

Online and offline effects of cerebellar transcranial direct current stimulation on motor learning in healthy older adults: a randomized double‐blind sham‐controlled study

The aim of this randomized double blinded sham‐controlled study was to determine the effect of cerebellar anodal transcranial direct current stimulation (a‐tDCS) on online and offline motor learning in healthy older individuals. Thirty participants were randomly assigned in experimental (n = 15) or sham tDCS (n = 15) groups. Participants in experimental group received 2 mA cerebellar a‐tDCS for 20 min. However, the tDCS was turned off after 30 seconds in sham group. Response time (RT) and error rate (ER) in serial RT test were assessed before, during 35 minutes and 48 h after the intervention. Reduction of RT and ER following the intervention session was considered as short‐term (35 min post intervention) and long‐term offline learning (48 h post intervention), respectively. Online RT and ER reduction were similar in both groups (P > 0.05). RT was significantly reduced 48 hours post intervention in cerebellar a‐tDCS group (P = 0.03). Moreover, RT was significantly increased after 35 minutes and 48 hours in sham tDCS group (P = 0.03, P = 0.007), which indicates a lack of short‐term and long‐term offline learning in older adults. A‐tDCS on cerebellar region produced more short‐term and long‐term offline improvement in RT (P = 0.014, P = 0.01) compared to sham tDCS. In addition, online, short‐term and long‐term (48 h) offline error reduced in cerebellar a‐tDCS as compared to sham‐control group, although this reduction was not significant (P > 0.05). A deficit suggests that a direct comparison to a younger group was made. The findings suggested that cerebellar a‐tDCS might be useful for improvement of offline motor learning in older individuals.     

Practice‐related reduction of electromyographic mirroring activity depends on basal levels of interhemispheric inhibition

Paired‐pulse transcranial magnetic stimulation (TMS) is used to measure the excitability of interhemispheric inhibition (IHI) between the hand areas of the two motor cortices. It varies from person to person, and is highly predictive of individual differences in callosal anatomy (fractional anisotropy) and even motor behaviour, e.g. the amount of involuntary electromyographic (EMG) ‘mirroring’ in one hand during rapid contraction of the other. The present experiments tested whether it also predicts how well individuals can improve motor performance in a task involving the two hands. Healthy participants were given 100 trials to maximize the initial acceleration of a ballistic finger movement made with one hand while trying to maintain a tonic low level of EMG activity in the other hand. Initially, each movement was accompanied by additional unwanted EMG mirroring in the other hand. However, after practice, participants had on average increased acceleration by approximately one‐third without changing the amount of EMG mirroring in the contralateral hand; indeed, in some individuals EMG mirroring activity declined. TMS measures showed that there was an increase in corticospinal excitability in the trained hemisphere, but there was no change in the excitability of short‐ or long‐latency IHI from the trained to non‐trained hemisphere. Nevertheless, in each individual, the baseline (pre‐practice) excitability of short‐latency IHI was highly predictive (r = 0.65; P = 0.0019) of the change in EMG mirroring. The implication is that a physiological measure of brain excitability at rest can predict behaviour in response to training.     

A meta-analysis of non-invasive brain stimulation and autonomic functioning: Implications for brain-heart pathways to cardiovascular disease

Given the intrinsic connection between the brain and the heart, a recent body of research emerged with the aim to influence cardiovascular system functioning by non-invasive brain stimulation (NIBS) methods such as repetitive transcranial magnetic stimulation and transcranial direct current stimulation. Despite the implications of cardiovascular activity modulation for therapeutic purposes, such effects of NIBS have not yet been quantified. The aim of this study was to meta-analyze studies on NIBS effects on blood pressure (BP), heart rate (HR) and its variability (HRV). PubMed and Scopus databases were searched for English language studies conducted in humans. Twenty-nine studies were eligible for the analyses. Pooled effect sizes (Hedges’ g) were compared. Random effect models were used. NIBS was effective in reducing HR (g = 0.17) and enhancing HRV (g = 0.30). A marginal effect emerged for BP (g = 0.21). Significant moderators were the stimulation technique and the site of stimulation. Results show that NIBS affects cardiovascular and autonomic nervous system activity, confirming a potential pathogenic brain-heart pathway to cardiovascular disease.     

Comparison of Rossini–Rothwell and adaptive threshold‐hunting methods on the stability of TMS induced motor evoked potentials amplitudes

Several methods can be used to determine the resting motor threshold (RMT) and by that recording transcranial magnetic stimulation (TMS) induced motor evoked potentials (MEPs). However, no research has compared the test retest reliability of these methods. Thus, the aim of this study was to determine intra‐ and inter‐session reliability of Rossini–Rothwell (R–R) and parameter estimation by sequential testing (PEST) methods on TMS‐induced MEPs and comparison of these two methods on RMT. Twelve healthy individuals participated in this study three times (T1, T2 and T3) over two days. TMS was applied using both R–R and PEST to estimate RMT and average of 25 MEPs were acquired at each of the three time points. The intra‐class correlation coefficient indicated high intra‐session reliability in the MEP amplitudes for both methods (0.79 and 0.88, R–R and PEST respectively). The RMT and MEP amplitudes had higher inter‐session reliability in both methods (0.99 and 0.998, R–R and PEST respectively; 0.84 and 0.76, R–R and PEST respectively). There was no significant difference between methods for RMT at both T1 (maximum stimulator output of R–R vs. PEST, 33.7% ± 7.7% vs. 33.8% ± 7.6%, p = 0.75) and T3 (maximum stimulator output of R–R vs. PEST, 33.5% ± 7.3% vs. 33.7% ± 7.3%, p = 0.19). There was a significant positive correlation between the methods' estimates of RMT, with PEST requiring significantly fewer stimuli. This study shows that the R–R and PEST methods have high intra‐and inter‐session reliability and the same precision, with PEST having the advantage over R–R in speed of estimation of RMT.     

Ipsilateral corticomotor excitability is associated with increased gait variability in unilateral transtibial amputees

Ipsilateral primary motor cortex (M1) reorganisation after unilateral lower‐limb amputation may degrade function of the amputated limb. We hypothesised unilateral lower‐limb amputees would have a bilateral increase in corticomotor excitability, and increased excitability of ipsilateral M1 would be associated with increased step‐time variability during gait. Twenty transtibial amputees (16 male) aged 60.1 years (range 45–80 years), and 20 age‐ and gender‐matched healthy adult controls were recruited. Single‐pulse transcranial magnetic stimulation assessed corticomotor excitability. Two indices of corticomotor excitability were calculated. An index of corticospinal excitability (ICE) determined relative excitability of ipsilateral and contralateral corticomotor projections to alpha‐motoneurons innervating the quadriceps muscle (QM) of the amputated limb. A laterality index (LI) assessed relative excitability of contralateral projections from each hemisphere. Spatial‐temporal gait analysis was performed to calculate step‐time variability. Amputees had lower ICE values, indicating relatively greater excitability of ipsilateral corticomotor projections than controls (P = 0.04). A lower ICE value was associated with increased step‐time variability for amputated (P = 0.04) and non‐amputated limbs (P = 0.02). This association suggests corticomotor projections from ipsilateral M1 to alpha‐motoneurons innervating the amputated limb QM may interfere with gait. Cortical excitability in amputees was not increased bilaterally, contrary to our hypothesis. There was no difference in excitability of contralateral M1 between amputees and controls (P = 0.10), and no difference in LI (P = 0.71). It appears both hemispheres control one QM, with predominance of contralateral corticomotor excitability in healthy adults. Following lower‐limb amputation, putative ipsilateral corticomotor excitability is relatively increased in some amputees and may negatively impact on function.     

Differential effects of cathodal transcranial direct current stimulation of prefrontal,motor and somatosensory cortices on cortical excitability and pain perception – a double‐blind randomised sham‐controlled study

The primary aim of this study was to assess the effects of cathodal transcranial direct current stimulation (c‐tDCS) over cortical regions of the pain neuromatrix, including the primary motor (M1), sensory (S1) and dorsolateral prefrontal (DLPFC) cortices on M1/S1 excitability, sensory (STh), and pain thresholds (PTh) in healthy adults. The secondary aim was to evaluate the placebo effects of c‐tDCS on induced cortical and behavioural changes. Before, immediately after and 30 min after c‐tDCS the amplitude of N20–P25 components of somatosensory evoked potentials (SEPs) and peak‐to‐peak amplitudes of motor evoked potentials (MEPs) were measured under four different experimental conditions. STh and PTh for peripheral electrical and mechanical stimulation were also evaluated. c‐tDCS of 0.3 mA was applied for 20 min. A blinded assessor evaluated all outcome measures. c‐tDCS of M1, S1 and DLPFC significantly decreased the corticospinal excitability of M1 (P < 0.05) for at least 30 min. Following the application of c‐tDCS over S1, M1 and DLPFC, the amplitude of the N20–P25 component of SEPs decreased for at least 30 min (P < 0.05). Compared with baseline values, significant STh and PTh increases were observed after c‐tDCS of these three sites. Decreasing the level of S1 and M1 excitability, following S1, M1 and DLPFC stimulation, confirmed the functional connectivities between these cortical sites involved in pain processing. Furthermore, increasing the level of STh/PTh after c‐tDCS of these sites indicated that stimulation of not only M1 but also S1 and DLPFC could be considered a technique to decrease the level of pain in patients.     

Unihemispheric concurrent dual‐site cathodal transcranial direct current stimulation: the effects on corticospinal excitability

We aimed to assess the effects of concurrent cathodal transcranial direct current stimulation (c‐tDCS) of two targets in a hemisphere, termed unihemispheric concurrent dual‐site cathodal tDCS (c‐tDCS_UHCDS), on the size of M1 corticospinal excitability and its lasting effect. Secondary aims were to identify the mechanisms behind the efficacy of c‐tDCS_UHCDS and to evaluate the side effects of this new technique. Twelve healthy volunteers received 20 min c‐tDCS under five conditions in a random order: M1 c‐tDCS, c‐tDCS_UHCDS of M1–dorsolateral prefrontal cortex (DLPFC), M1–primary sensory cortex (S1), M1–primary visual cortex (V1) and sham. The M1 corticospinal excitability of the first dorsal interossei muscle was assessed before, immediately after, and 30 min, 60 min and 24 h after the interventions. Short‐interval intracortical inhibition (SICI) and intracortical facilitation (ICF) were also assessed, using a paired‐pulse paradigm. Compared to conventional M1 c‐tDCS, corticospinal excitability significantly increased following c‐tDCS_UHCDS of M1‐DLPFC and M1‐V1 for up to 24 h (P = 0.001). Significant increases in ICF were observed following c‐tDCS_UHCDS of M1‐DLPFC (P = 0.005) and M1‐V1 (P = 0.002). Compared to baseline values, ICF and SICI increased significantly at T₆₀ (P < 0.001) and T_24 h (P < 0.001) following the concurrent c‐tDCS of M1 and V1. Sham c‐tDCS_UHCDS did not induce any significant alteration. The corticospinal excitability increase was mainly accompanied by ICF increase, which indirectly indicates the activity of glutamergic mechanisms. The findings may help us to more fully understand the brain function and develop future motor learning studies. No significant excitability change induced by sham c‐tDCS_UHCDS suggests that there is no placebo effect associated with this new tDCS technique.     

Motor cortical excitability and pre-supplementary motor area neurochemistry in healthy adults with substantia nigra hyperechogenicity

Substantia nigra (SN) hyperechogenicity, viewed with transcranial ultrasound, is a risk marker for Parkinson's disease. We hypothesized that SN hyperechogenicity in healthy adults aged 50–70 years is associated with reduced short-interval intracortical inhibition in primary motor cortex, and that the reduced intracortical inhibition is associated with neurochemical markers of activity in the pre-supplementary motor area (pre-SMA). Short-interval intracortical inhibition and intracortical facilitation in primary motor cortex was assessed with paired-pulse transcranial magnetic stimulation in 23 healthy adults with normal (n = 14; 61 ± 7 yrs) or abnormally enlarged (hyperechogenic; n = 9; 60 ± 6 yrs) area of SN echogenicity. Thirteen of these participants (7 SN− and 6 SN+) also underwent brain magnetic resonance spectroscopy to investigate pre-SMA neurochemistry. There was no relationship between area of SN echogenicity and short-interval intracortical inhibition in the ipsilateral primary motor cortex. There was a significant positive relationship, however, between area of echogenicity in the right SN and the magnitude of intracortical facilitation in the right (ipsilateral) primary motor cortex (p = .005; multivariate regression), evidenced by the amplitude of the conditioned motor evoked potential (MEP) at the 10–12 ms interstimulus interval. This relationship was not present on the left side. Pre-SMA glutamate did not predict primary motor cortex inhibition or facilitation. The results suggest that SN hyperechogenicity in healthy older adults may be associated with changes in excitability of motor cortical circuitry. The results advance understanding of brain changes in healthy older adults at risk of Parkinson's disease.     

Augmenting mirror visual feedback‐induced performance improvements in older adults

Previous studies have indicated that age‐related behavioral alterations are not irreversible but are subject to amelioration through specific training interventions. Both training paradigms and non‐invasive brain stimulation (NIBS) can be used to modulate age‐related brain alterations and thereby influence behavior. It has been shown that mirror visual feedback (MVF) during motor skill training improves performance of the trained and untrained hands in young adults. The question remains of whether MVF also improves motor performance in older adults and how performance improvements can be optimised via NIBS. Here, we sought to determine whether anodal transcranial direct current stimulation (a‐tDCS) can be used to augment MVF‐induced performance improvements in manual dexterity. We found that older adults receiving a‐tDCS over the right primary motor cortex (M1) during MVF showed superior performance improvements of the (left) untrained hand relative to sham stimulation. An additional control experiment in participants receiving a‐tDCS over the right M1 only (without MVF/motor training of the right hand) revealed no significant behavioral gains in the left (untrained) hand. On the basis of these findings, we propose that combining a‐tDCS with MVF might be relevant for future clinical studies that aim to optimise the outcome of neurorehabilitation.     

The effect of 5Hz high‐frequency rTMS over contralesional pharyngeal motor cortex in post‐stroke oropharyngeal dysphagia: a randomized controlled study

Background We sought to find the therapeutic effect of 5Hz high‐frequency repetitive transcranial magnetic stimulation (rTMS) over the unaffected pharyngeal motor cortex in post‐stroke dysphagic patients. Methods Eighteen patients with unilateral hemispheric stroke oropharyngeal dysphagia that lasted more than 1 month were randomly divided into two groups. They all performed videofluoroscopic swallowing study (VFSS) before rTMS intervention. The experimental group (EG) received 5Hz rTMS over contra‐lesional pharyngeal motor cortex for 10 min per day for 2 weeks. The control group (CG) received sham stimulation under the same condition. Videofluoroscopic swallowing study were performed again just after treatment cessation and 2 weeks afterward. The evaluation was performed using videofluoroscopic dysphagia scale (VDS) and penetration‐aspiration scale (PAS). Key Results Mean baseline VDS and PAS of EG was 33.6 ± 12.1 and 3.41 ± 2.32 respectively and the scores were reduced to 25.3 ± 9.8 and 1.93 ± 1.52 just after 2 weeks intervention (P < 0.05). This effect lasted for up to 2 weeks after treatment. However, there was no change in the CG. Baseline prevalence of aspiration, pharyngeal residue, delayed triggering of pharyngeal swallowing and abnormal pharyngeal transit time (PTT) in EG was 66.7%, 66.7%, 33.3%, and 44.4%, respectively. After rTMS, the prevalence of aspiration and pharyngeal residue was reduced to 33.3% and 33.3%, respectively. However, the prevalence of delayed triggering and abnormal PTT was not changed. Conclusions & Inferences A 5Hz high‐frequency rTMS on contra‐lesional pharyngeal motor cortex might be beneficial for post‐stroke dysphagic patients. This intervention can be used as a new treatment method in post‐stroke patients with dysphagia.     

Functional MRI-navigated Repetitive Transcranial Magnetic Stimulation Over Supplementary Motor Area in Chronic Tic Disorders

BackgroundOpen label studies have shown repetitive transcranial magnetic stimulation to be effective in reducing tics.ObjectivesTo determine whether 8 sessions of continuous theta burst stimulation (cTBS) over supplementary motor area (SMA) given over 2 days may reduce tics and motor cortical network activity in Tourette syndrome/chronic tic disorders.MethodsThis was a randomized (1:1), double-blind, sham-controlled trial of functional MRI (fMRI)-navigated, 30 Hz cTBS at 90% of resting motor threshold (RMT) over SMA in 12 patients ages 10–22 years. Comorbid ADHD (n = 8), OCD (n = 8), and stable concurrent medications (n = 9) were permitted. Neuro-navigation utilized each individual's event-related fMRI signal. Primary clinical and cortical outcomes were: 1) Yale Global Tic Severity Scale (YGTSS) at one week; 2) fMRI event-related signal in SMA and primary motor cortex (M1) during a finger-tapping motor task.ResultBaseline characteristics were not statistically different between groups (age, current tic/OCD/ADHD severities, tic-years, number of prior medication trials, RMT). Mean YGTSS scores decreased in both active (27.5 ± 7.4 to 23.2 ± 9.8) and sham (26.8 ± 4.8 to 21.7 ± 7.7) groups. However, no significant difference in video-based tic severity rating was detected between the two groups. Two-day post-treatment fMRI activation during finger tapping decreased significantly in active vs. sham groups for SMA (P = 0.02), left M1 (P = 0.0004), and right M1 (P < 0.0001). No serious adverse events occurred.ConclusionActive, fMRI-navigated cTBS administered in 8 sessions over 2 days to the SMA induced significant inhibition in the motor network (SMA, bilateral M1). However, both groups on average experienced tic reduction at 7 days. Larger sample size and protocol modifications may be needed to produce clinically significant tic reduction beyond placebo effect.     

Effects of anodal transcranial direct current stimulation over lower limb primary motor cortex on motor learning in healthy individuals

Transcranial direct current stimulation (tDCS) is a neuromodulatory technique which alters motor functions in healthy humans and in neurological patients. Most studies so far investigated the effects of tDCS on mechanisms underlying improvements in upper limb performance. To investigate the effect of anodal tDCS over the lower limb motor cortex (M1) on lower limb motor learning in healthy volunteers, we conducted a randomized, single‐blind and sham‐controlled study. Thirty‐three (25.81 ± 3.85, 14 female) volunteers were included, and received anodal or sham tDCS over the left M1 (M1‐tDCS); 0.0625 mA/cm² anodal tDCS was applied for 15 min during performance of a visuo‐motor task (VMT) with the right leg. Motor learning was monitored for performance speed and accuracy based on electromyographic recordings. We also investigated the influence of electrode size and baseline responsivity to transcranial magnetic stimulation (TMS) on the stimulation effects. Relative to baseline measures, only M1‐tDCS applied with small electrodes and in volunteers with high baseline sensitivity to TMS significantly improved VMT performance. The computational analysis showed that the small anode was more specific to the targeted leg motor cortex volume when compared to the large anode. We conclude that anodal M1‐tDCS modulates VMT performance in healthy subjects. As these effects critically depend on sensitivity to TMS and electrode size, future studies should investigate the effects of intensified tDCS and/or model‐based different electrode positions in low‐sensitivity TMS individuals.     

Alterations of motor cortical excitability and anatomy in Unverricht‐Lundborg disease

Unverricht‐Lundborg disease is the most common form of progressive myoclonus epilepsies. In addition to generalized seizures, it is characterized by myoclonus, which usually is the most disabling feature of the disease. Classically, the myoclonus has been attributed to increased excitability of the primary motor cortex. However, inhibitory cortical phenomena have also been described along with anatomical alterations. We aimed to characterize the relationship between the excitability and anatomy of the motor cortex and their association with the severity of the clinical symptoms. Seventy genetically verified patients were compared with forty healthy controls. The symptoms were evaluated with the Unified Myoclonus Rating Scale. Navigated transcranial magnetic stimulation was applied to characterize the excitability of the primary motor cortex by determining the motor thresholds and cortical silent periods. In addition, the induced cortical electric fields were estimated using individual scalp‐to‐cortex distances measured from MRIs. A cortical thickness analysis was performed to elucidate possible disease‐related anatomical alterations. The motor thresholds, cortical electric fields, and silent periods were significantly increased in the patients (P < 0.01). The silent periods correlated with the myoclonus scores (r = 0.48 to r = 0.49, P < 0.001). The scalp‐to‐cortex distance increased significantly with disease duration (r = 0.56, P < 0.001) and correlated inversely with cortical thickness. The results may reflect the refractory nature of the myoclonus and indicate a possible reactive cortical inhibitory mechanism to the underlying disease process. This is the largest clinical series on Unverricht‐Lundborg disease and the first study describing parallel pathophysiological and structural alterations associated with the severity of the symptoms. © 2013 International Parkinson and Movement Disorder Society     

rTMS over human motor cortex can modulate tremor during movement

Abnormally large tremor during movement is a symptom of many movement disorders and significantly impairs activities of daily living. The aim of this study was to investigate whether repetitive magnetic brain stimulation (rTMS) can reduce tremor size during human movement. We hypothesised that inhibitory rTMS over motor cortex would reduce tremor size during subsequent movement. The study involved 26 healthy young adults (21 ± 2 years) and began with application of single TMS stimuli to measure baseline corticospinal excitability. The response to stimulation was recorded in hand muscles with electromyography. Subjects then performed a 3‐min task to measure baseline tremor during movement. This involved matching index finger position with a moving target on a computer screen. Tremor was recorded with an accelerometer on the fingernail. Finger acceleration was analysed with fast‐Fourier transform to quantify tremor in the physiological range (7.8–12.2 Hz). Subjects then received 10 min of real (n = 13) or sham (n = 13) inhibitory rTMS. Tremor and corticospinal excitability were then remeasured. Real rTMS significantly decreased corticospinal excitability by ~30% (P = 0.022) and increased tremor size during movement by ~120% (P = 0.047) relative to sham rTMS. However, the direction of tremor change was opposite to that hypothesised for inhibitory rTMS. The results suggest that rTMS over human motor cortex can modulate action tremor and the level of corticospinal excitability may be important for setting the amplitude of action tremor in healthy young adults.     

Inter-individual Variability in Response to Non-invasive Brain Stimulation Paradigms

BackgroundNon-invasive Brain Stimulation (NIBS) paradigms are unique in their ability to safely modulate cortical plasticity for experimental or therapeutic applications. However, increasingly, there is concern regarding inter-individual variability in the efficacy and reliability of these paradigms.HypothesisInter-individual variability in response to NIBS paradigms would be better explained if a multimodal distribution was assumed.MethodsIn three different sessions for each subject (n = 56), we studied the Paired Associative Stimulation (PAS₂₅), Anodal transcranial DC stimulation (AtDCS) and intermittent theta burst stimulation (iTBS) protocols. We applied cluster analysis to detect distinct patterns of response between individuals. Furthermore, we tested whether baseline TMS measures (such as short intracortical inhibition (SICI), resting motor threshold (RMT)) or factors such as time of day could predict each individual's response pattern.ResultsAll three paradigms show similar efficacy over the first hour post stimulation – there is no significant effect on excitatory or inhibitory circuits for the whole sample, and AtDCS fares no better than iTBS or PAS₂₅. Cluster analysis reveals a bimodal response pattern – but only 39%, 45% and 43% of subjects responded as expected to PAS₂₅, AtDCS, and iTBS respectively. Pre-stimulation SICI accounted for 10% of the variability in response to PAS₂₅, but no other baseline measures were predictive of response. Finally, we report implications for sample size calculation and the remarkable effect of sample enrichment.ConclusionThe implications of the high rate of ‘dose-failure’ for experimental and therapeutic applications of NIBS lead us to conclude that addressing inter-individual variability is a key area of concern for the field.