rTMS Of M1 Research Articles

Effects of rTMS to primary motor cortex and cerebellum on balance control in healthy adults.

Both the primary motor cortex (M1) and the cerebellum are crucial for postural stability and deemed as potential targets for non-invasive brain stimulation (NIBS) to enhance balance performance. However, the optimal target remains unknown. The purpose of this study was to compare the role of M1 and the cerebellum in modulating balance performance in young healthy adults using facilitatory 5Hz repetitive transcranial magnetic stimulation (rTMS). Twenty-one healthy young adults (mean age = 27.95 ±1.15 years) received a single session of 5Hz rTMS on M1 and the cerebellum in a cross-over order with a 7-day washout period between the two sessions. Three balance assessments were performed on the Biodex Balance system SD: Limits of Stability (LOS), modified Clinical Test of Sensory Interaction on Balance (mCTSIB), and Balance Error Scoring System (BESS). No significant effect of rTMS was found on the LOS. The effect of rTMS on the mCTSIB was mediated by stimulation target, proprioception, and vision (p = .003, ηp 2 = 0.37). Cerebellar rTMS improved the mCTSIB sway index under eyes closed-foam surface condition (p = .02), whereas M1 rTMS did not result in improvement on the mCTSIB. The effect of rTMS on the BESS was mediated by stimulation target, posture, and proprioception (p = .049, ηp 2 = 0.14). Cerebellar rTMS enhanced reactive balance performance during most sensory deprived conditions.

Repetitive Transcranial Magnetic Stimulation of the Human Motor Cortex Modulates Processing of Heat Pain Sensation as Assessed by the Offset Analgesia Paradigm.

Offset analgesia (OA), which is defined as a disproportionately large reduction in pain perception following a small decrease in a heat stimulus, quantifies temporal aspects of endogenous pain modulation. In this study on healthy subjects, we aimed to (i) determine the Heat Pain Threshold (HPT) and the response to constant and dynamic heat stimuli assessing sensitization, adaptation and OA phenomena at the thenar eminence; (ii) evaluate the effects of high-frequency repetitive Transcranial Magnetic Stimulation (rTMS) of the primary motor cortex (M1) on these measures. Twenty-four healthy subjects underwent quantitative sensory testing before and after active or sham 10 Hz rTMS (1200 stimuli) of the left M1, during separate sessions. We did not observe any rTMS-related changes in the HPT or visual analogue scale (VAS) values recorded during the constant trial. Of note, at baseline, we did not find OA at the thenar eminence. Only after active rTMS did we detect significantly reduced VAS values during dynamic heat stimuli, indicating a delayed and attenuated OA phenomenon. rTMS of the left M1 may activate remote brain areas that belong to the descending pain modulatory and reward systems involved in the OA phenomenon. Our findings provide insights into the mechanisms by which rTMS of M1 could exert its analgesic effects.

Feasibility and safety of combining repetitive transcranial magnetic stimulation and quadriceps strengthening exercise for chronic pain in knee osteoarthritis: a study protocol for a pilot randomised controlled trial

IntroductionKnee osteoarthritis is a leading cause of disability, resulting in pain and reduced quality of life. Exercise is the cornerstone of conservative management but effects are, at best, moderate. Early...

Offline low-frequency rTMS of the primary and premotor cortices does not impact motor sequence memory consolidation despite modulation of corticospinal excitability

Motor skills are acquired and refined across alternating phases of practice (online) and subsequent consolidation in the absence of further skill execution (offline). Both stages of learning are sustained by dynamic interactions within a widespread motor learning network including the premotor and primary motor cortices. Here, we aimed to investigate the role of the dorsal premotor cortex (dPMC) and its interaction with the primary motor cortex (M1) during motor memory consolidation. Forty-eight healthy human participants (age 22.1 ± 3.1 years) were assigned to three different groups corresponding to either low-frequency (1 Hz) repetitive transcranial magnetic stimulation (rTMS) of left dPMC, rTMS of left M1, or sham rTMS. rTMS was applied immediately after explicit motor sequence training with the right hand. Motor evoked potentials were recorded before training and after rTMS to assess potential stimulation-induced changes in corticospinal excitability (CSE). Participants were retested on motor sequence performance after eight hours to assess consolidation. While rTMS of dPMC significantly increased CSE and rTMS of M1 significantly decreased CSE, no CSE modulation was induced by sham rTMS. However, all groups demonstrated similar significant offline learning indicating that consolidation was not modulated by the post-training low-frequency rTMS intervention despite evidence of an interaction of dPMC and M1 at the level of CSE. Motor memory consolidation ensuing explicit motor sequence training seems to be a rather robust process that is not affected by low-frequency rTMS-induced perturbations of dPMC or M1. Findings further indicate that consolidation of explicitly acquired motor skills is neither mediated nor reflected by post-training CSE.

P 36. rTMS-induced offline-modulation of premotor-motor interaction after motor sequence learning does not affect consolidation

Introduction. The acquisition of novel motor skills depends on active training and further offline processing of the motor engram (i.e., consolidation). Previous studies suggest an essential role of post-training corticospinal excitability (CSE) for the induction of offline motor memory consolidation. Furthermore, it was shown that the interaction of the primary motor cortex (M1) and the premotor cortex (PMC) after training affects the consolidation process. In this study, we modulated the post-training interaction of M1 and PMC by applying inhibitory repetitive transcranial magnetic stimulation (rTMS) and investigated the effects on CSE and consolidation. Methods. 48 healthy, right-handed subjects (age 22.13 ± 3.2 a) were assigned to 3 groups. All participants practiced an explicit motor sequence learning task with their right hand. Immediately after training, participants received 1 Hz rTMS to either left M1, left PMC, or sham stimulation. Motor evoked potentials (MEP) were recorded before training and after rTMS. Task performance was retested eight hours after the end of stimulation to assess offline performance changes. Task performance was assessed using a performance index (PI) that integrated speed and accuracy of sequence execution. Consolidation was quantified as the difference of task performance at the end of the training session compared to the beginning of the retest (mean PI of 4 blocks each). Results. In terms of changes of MEP amplitudes, rmANOVA revealed an interaction of factors group*time ( p = 0.001). When applied to M1, rTMS induced a decrease of CSE compared to the pre-training assessments ( p = 0.007), whereas stimulation of the PMC led to an increase of MEP amplitudes ( p = 0.009). No relevant change of corticospinal excitability was seen after sham stimulation ( p = 0.862). Training performance did not differ between groups (group*block, p = 0.781) and all groups demonstrated significant offline-improvements at delayed retesting. However, there were no significant differences of consolidation between groups ( p = 0.456). Furthermore, correlation analysis revealed no significant association of CSE modulation and offline performance changes ( r = 0.101, p = 0.493). Discussion. The increase of CSE induced by post-training PMC demonstrated here differs from results of previous studies that applied inhibitory PMC stimulation at rest or before a training intervention, which resulted in decreased CSE. We, therefore, interpret our findings as further evidence of a state-dependent function of the PMC. Despite significant modulation of CSE by post-training rTMS of M1 and PMC, there was no behavioral effect on consolidation. This challenges the relevance of immediate post-training CSE changes as a key mechanism in terms of the induction of consolidation. Although proximal intracortical physiological mechanisms are still not excluded, they are not detected by changes in post-training corticospinal excitability.

Systematic review and quantitative meta-analysis demonstrates analgesic effect of excitatory motor cortex non-invasive brain stimulation, which is inflated by small study and publication bias

This systematic meta-analysis evaluated the analgesic effect of excitatory motor cortex (M1) non-invasive brain stimulation (NIBS) in patients experiencing chronic neuropathic pain (CNP). Considering intervention groups with a median sample of 16.5 patients, we expected small-study and publication bias. We searched randomized controlled trials (RCTs) of high frequency (HF) (≥5 Hz) M1 rTMS and anodal M1 tDCS in patients with CNP, using PubMed and Web of Science, covering 1990 to 2019. Our search yielded 58 eligible studies. We calculated random effects models to obtain confidence and prediction intervals (PIs) of mean differences (MD) of analgesic effect. To assess small-study and publication bias, we created funnel plots, and trim-and-fill and Copas models. Excitatory M1 NIBS RCTs included 1246 patients in intervention and 1202 patients in sham groups across 58 studies. The MD was 0.92 with 95% confidence interval (CI) [0.70;1.14] and PI [−0.59;2.44]. Considering HF M1 rTMS studies, MD was 0.99 with 95%CI of [0.71;1.27] and 95%PI of [-0.61;2.58]. In anodal M1 tDCS, MD was 0.86 with 95%CI [0.48;1.25] and 95%PI of [-0.73;2.46]. In funnel plot analysis, 18/58 excitatory NIBS reports fell outside the funnel bounds. After trim-and-fill model imputation of missing studies, MD was 0.44 with 95%CI of [0.18;0.70]. The Copas model revealed, at a 0.5 probability of largest standard error study publication, MD was 0.535. Probability of 0.1 residual selection bias occurred at 0.52 probability of largest SE study publication. Copas model MD was 0.6 with 95%CI [0.46;0.75]. We found significant analgesia following excitatory M1 NIBS in patients with CNP. PIs encompass zero, indicating significant analgesia is not probable in 0.95 of future studies. Results support small-study and publication bias. Future studies should include larger sample sizes. Emphasis on null result publication and pre-publication registration is warranted. Neurosurgery Pain Research Institute, Postdoctoral Scholarship and other funds (TJM and FAL) NIH - National Institute of Neurological Disorders and Stroke - R01NS107602 (FAL).

Repetitive transcranial magnetic stimulation of the primary motor cortex in management of chronic neuropathic pain: a systematic review.

Repetitive transcranial magnetic stimulation (rTMS) of the primary motor cortex (M1) with frequencies 5-20Hz is an expanding non-invasive treatment for chronic neuropathic pain (NP). Outcome data, however, show considerable inhomogeneity with concern to the levels of effect due to the great diversity of treated conditions. The aim of this review was to survey the literature regarding the efficacy and safety of M1 rTMS, and the accuracy to predict a positive response to epidural motor cortex stimulation (MCS) which is supposed to give a more longstanding pain relief. A systematic literature search was conducted up to June 2019 in accordance with the PRISMA guidelines. We used the PICO Model to define two specific clinical questions: (1) Does rTMS of M1 relieve NP better than sham treatment? (2) Can the response to rTMS be used to predict the effect of epidural MCS? After article selection, data extraction, and study quality assessment, the certainty of evidence of treatment effect was defined using the GRADE system. Data on 5-20Hz (high-frequency) rTMS vs. sham was extracted from 24 blinded randomised controlled trials which were of varying quality, investigated highly heterogeneous pain conditions, and used excessively variable stimulation parameters. The difference in pain relief between active and sham stimulation was statistically significant in 9 of 11 studies using single-session rTMS, and in 9 of 13 studies using multiple sessions. Baseline data could be extracted from 6 single and 12 multiple session trials with a weighted mean pain reduction induced by active rTMS, compared to baseline, of-19% for single sessions,-32% for multiple sessions with follow-up <30days, and-24% for multiple sessions with follow-up≥30days after the last stimulation session. For single sessions the weighted mean difference in pain reduction between active rTMS and sham was 15 percentage points, for multiple sessions the difference was 22 percentage points for follow-ups <30days, and 15 percentage points for follow-ups≥30days. Four studies reported data that could be used to evaluate the accuracy of rTMS to predict response to MCS, showing a specificity of 60-100%, and a positive predictive value of 75-100%. No serious adverse events were reported. rTMS targeting M1 can result in significant reduction of chronic NP which, however, is transient and shows a great heterogeneity between studies; very low certainty of evidence for single sessions and low for multiple sessions. Multiple sessions of rTMS can maintain a more longstanding effect. rTMS seems to be a fairly good predictor of a positive response to epidural MCS and may be used to select patients for implantation of permanent epidural electrodes. More studies are needed to manifest the use of rTMS for this purpose. Pain relief outcomes in a longer perspective, and outcome variables other than pain reduction need to be addressed more consistently in future studies to consolidate the applicability of rTMS in routine clinical practice.

New procedure of high-frequency repetitive transcranial magnetic stimulation for central neuropathic pain: a placebo-controlled randomized crossover study.

Repetitive transcranial magnetic stimulation (rTMS) is a procedure increasingly used to treat patients with central neuropathic pain, but its efficacy is still under debate. Patients with medically refractory chronic central neuropathic pain were included in 2 randomized phases (active/sham), separated by a wash-out period of 8 weeks. Each phase consisted of 4 consecutive rTMS sessions and a final evaluation session, all separated from one another by 3 weeks. High-frequency (20 Hz) rTMS was delivered over the primary motor cortex (M1) contralateral to the patient's pain using a neuronavigated robotic system. Patients and clinicians assessing outcomes were blinded to treatment allocation during the trial. The primary outcome measured the percentage of pain relief (%R) from baseline. Secondary outcomes were VAS score, Neuropathic Pain Symptom Inventory, analgesic drug consumption, and quality of life (EQ-5D). Thirty-six patients performed the entire study with no adverse effects. The analgesic effect for the main criterion (%R) was significantly higher in the active (33.8% confidence interval [CI]: [23.88-43.74]) than in the sham phase (13.02% CI: [6.64-19.76]). This was also the case for the secondary outcome VAS (-19.34% CI: [14.31-25.27] vs -4.83% CI: [1.96-8.18]). No difference was observed for quality of life or analgesic drug consumption. Seventeen patients (47%) were identified as responders, but no significant interaction was found between clinical and technical factors considered here and the analgesic response. These results provide strong evidence that 3 weeks spaced high-frequency rTMS of M1 results in a sustained analgesic effect and support the clinical interest of this stimulation paradigm to treat refractory chronic pain.

A randomized controlled trial of 5 daily sessions and continuous trial of 4 weekly sessions of repetitive transcranial magnetic stimulation for neuropathic pain.

We conducted a multicenter, randomized, patient- and assessor-blinded, sham-controlled trial to investigate the efficacy of repetitive transcranial magnetic stimulation (rTMS) of the primary motor cortex (M1) in patients with neuropathic pain (NP). Patients were randomly assigned to receive 5 daily sessions of active or sham rTMS of M1 corresponding to the part of the body experiencing the worst pain (500 pulses per session at 5 Hz). Responders were invited to enroll in an open-label continuous trial involving 4 weekly sessions of active rTMS. The primary outcome was a mean decrease in a visual analogue scale of pain intensity (scaled 0-100 mm) measured daily during the daily sessions in an intention-to-treat population. Secondary outcomes were other pain scores, quality-of-life measures, and depression score. One hundred forty-four patients were assigned to the active or sham stimulation groups. The primary outcome, mean visual analogue scale decreases, was not significantly different (P = 0.58) between the active stimulation group (mean, 8.0) and the sham group (9.2) during the daily sessions. The secondary outcomes were not significantly different between 2 groups. The patients enrolled in the continuous weekly rTMS achieved more pain relief in the active stimulation group compared with the sham (P < 0.01). No serious adverse events were observed. Five daily sessions of rTMS with stimulus conditions used in this trial were ineffective in short-term pain relief in the whole study population with various NP. Long-term administration to the responders should be investigated for the clinical use of rTMS on NP in the future trials.

Repetitive transcranial magnetic stimulation of the primary motor cortex expedites recovery in the transition from acute to sustained experimental pain: a randomised, controlled study.

Repetitive transcranial magnetic stimulation (rTMS) of the primary motor cortex (M1) is increasingly being investigated as a means of alleviating chronic pain. However, rTMS interventions are typically initiated once pain has already become chronic and maladaptive patterns of neural activity are likely to have been established. A critical question is whether M1 rTMS applied soon after pain onset can prevent the development of maladaptive neural activity and promote recovery. This study investigated the effect of 5 consecutive days of excitatory M1 rTMS on pain, functional limitation, mechanical hyperalgesia, descending inhibitory pain control, and M1 organisation in the transition from acute to sustained pain. Thirty healthy participants attended 8 sessions over a 16-day period. On days 0, 2, and 4, nerve growth factor was injected into the right forearm to induce progressively developing muscle soreness and mechanical hyperalgesia. Active or sham excitatory rTMS was delivered on days 4 to 8. Clinical and neurophysiological outcomes were recorded on days 0, 2, 4, 6, 8, 11, and 14. Active rTMS promoted recovery of muscle soreness, pain, and mechanical hyperalgesia when compared with sham rTMS (all between-group P < 0.05). Corticomotor excitability and descending inhibitory pain control did not differ between groups. These findings suggest that active excitatory M1 rTMS promotes recovery of muscle soreness, pain, and mechanical hyperalgesia in the transition from acute to sustained experimental pain. The analgesic effects of M1 rTMS do not seem to be modulated by descending inhibitory pain control or local changes in corticomotor excitability.

The analgesic effect of therapeutic rTMS is not mediated or predicted by comorbid psychiatric or sleep disorders.

Background:Mechanisms underlying alleviation of neuropathic pain by repetitive transcranial magnetic stimulation (rTMS) of primary motor cortex (M1) and right secondary somatosensory cortex (S2) are only partly known. Patients with chronic neuropathic pain often have comorbidities like depression and sleep problems. Through functional connectivity, rTMS of M1 and S2 may activate dorsolateral prefrontal cortex, the target for treating depression with rTMS. Thus, the analgesic effect of rTMS could be mediated indirectly via improvement of psychiatric comorbidities or sleep. We examined whether rTMS has an independent analgesic effect or whether its clinical benefits depend on effects on mood or sleep. We also evaluated if comorbid psychiatric or sleep disorders predict the treatment outcome.Methods:Sixteen patients with chronic drug-resistant neuropathic orofacial pain participated in this randomized controlled crossover rTMS study. Patients’ psychiatric history was evaluated by a specialist in psychiatry. Intensity and interference of pain, mood, and the quality of sleep and life were evaluated at baseline and after 2 active (primary somatosensory cortex [S1]/M1 and S2) and placebo rTMS treatments. A logistic regression analysis was done to investigate predictors of treatment outcome.Results:The analgesic effect of the right S2 stimulation was not associated with improvement of psychiatric conditions or sleep, whereas S1/M1 stimulation improved sleep without significant analgesic effect (P = 0.013–0.046 in sleep scores). Psychiatric and sleep disorders were more common in patients than in the general population (P = 0.000–0.001 in sleep scores), but these comorbidities did not predict the rTMS treatment outcome.Conclusion:We conclude that rTMS to the right S2 does not exert its beneficial analgesic effects in chronic neuropathic orofacial pain via indirect improvement of comorbid psychiatric or sleep disorders.

Neuromodulatory effects of offline low-frequency repetitive transcranial magnetic stimulation of the motor cortex: A functional magnetic resonance imaging study.

Repetitive transcranial magnetic stimulation (rTMS) of the primary motor cortex (M1) can modulate cortical excitability and is thought to influence activity in other brain areas. In this study, we investigated the anatomical and functional effects of rTMS of M1 and the time course of after-effects from a 1-Hz subthreshold rTMS to M1. Using an “offline” functional magnetic resonance imaging (fMRI)-rTMS paradigm, neural activation was mapped during simple finger movements after 1-Hz rTMS over the left M1 in a within-subjects repeated measurement design, including rTMS and sham stimulation. A significant decrease in the blood oxygen level dependent (BOLD) signal due to right hand motor activity during a simple finger-tapping task was observed in areas remote to the stimulated motor cortex after rTMS stimulation. This decrease in BOLD signal suggests that low frequency subthreshold rTMS may be sufficiently strong to elicit inhibitory modulation of remote brain regions. In addition, the time course patterns of BOLD activity showed this inhibitory modulation was maximal approximately 20 minutes after rTMS stimulation.

Multifocal repetitive TMS for motor and mood symptoms of Parkinson disease: A randomized trial.

To assess whether multifocal, high-frequency repetitive transcranial magnetic stimulation (rTMS) of motor and prefrontal cortex benefits motor and mood symptoms in patients with Parkinson disease (PD). Patients with PD and depression were enrolled in this multicenter, double-blind, sham-controlled, parallel-group study of real or realistic (electric) sham rTMS. Patients were randomized to 1 of 4 groups: bilateral M1 ( + sham dorsolateral prefrontal cortex [DLPFC]), DLPFC ( + sham M1), M1 + DLPFC, or double sham. The TMS course consisted of 10 daily sessions of 2,000 stimuli for the left DLPFC and 1,000 stimuli for each M1 (50 × 4-second trains of 40 stimuli at 10 Hz). Patients were evaluated at baseline, at 1 week, and at 1, 3, and 6 months after treatment. Primary endpoints were changes in motor function assessed with the Unified Parkinson's Disease Rating Scale-III and in mood with the Hamilton Depression Rating Scale at 1 month. Of the 160 patients planned for recruitment, 85 were screened, 61 were randomized, and 50 completed all study visits. Real M1 rTMS resulted in greater improvement in motor function than sham at the primary endpoint (p < 0.05). There was no improvement in mood in the DLPFC group compared to the double-sham group, as well as no benefit to combining M1 and DLPFC stimulation for either motor or mood symptoms. In patients with PD with depression, M1 rTMS is an effective treatment of motor symptoms, while mood benefit after 2 weeks of DLPFC rTMS is not better than sham. Targeting both M1 and DLPFC in each rTMS session showed no evidence of synergistic effects. NCT01080794. This study provides Class I evidence that in patients with PD with depression, M1 rTMS leads to improvement in motor function while DLPFC rTMS does not lead to improvement in depression compared to sham rTMS.

EAN guidelines on central neurostimulation therapy in chronic pain conditions.

Our aim was to update previous European Federation of Neurological Societies guidelines on neurostimulation for neuropathic pain, expanding the search to new techniques and to chronic pain conditions other than neuropathic pain, and assessing the evidence with the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system. A systematic review and meta-analysis of trials published between 2006 and December 2014 was conducted. Pain conditions included neuropathic pain, fibromyalgia, complex regional pain syndrome (CRPS) type I and post-surgical chronic back and leg pain (CBLP). Spinal cord stimulation (SCS), deep brain stimulation (DBS), epidural motor cortex stimulation (MCS), repetitive transcranial magnetic stimulation (rTMS) and transcranial direct electrical stimulation (tDCS) of the primary motor cortex (M1) or dorsolateral prefrontal cortex (DLPFC) were assessed. The GRADE system was used to assess quality of evidence and propose recommendations. The following recommendations were reached: 'weak' for SCS added to conventional medical management in diabetic painful neuropathy, CBLP and CRPS, for SCS versus reoperation in CBLP, for MCS in neuropathic pain, for rTMS of M1 in neuropathic pain and fibromyalgia and for tDCS of M1 in neuropathic pain; 'inconclusive' for DBS in neuropathic pain, rTMS and tDCS of the DLPFC, and for motor cortex tDCS in fibromyalgia and spinal cord injury pain. Given the poor to moderate quality of evidence identified by this review, future large-scale multicentre studies of non-invasive and invasive neurostimulation are encouraged. The collection of higher quality evidence of the predictive factors for the efficacy of these techniques, such as the duration, quality and severity of pain, is also recommended.

High-Frequency Repetitive Transcranial Magnetic Stimulation Can Improve Depression in Parkinson's Disease: A Randomized, Double-Blind, Placebo-Controlled Study

Background: A recent evidence-based guideline demonstrated that bilateral repetitive transcranial magnetic stimulation (rTMS) over the motor cortex (M1) can improve motor symptoms of Parkinson's disease (PD). We conducted a randomized, double-blind, placebo-controlled study to evaluate the impact of bilateral M1 rTMS on depression in PD. Methods: Forty-six patients with PD and mild-to-moderate depression were randomly assigned to active (n = 23) and sham (n = 23) rTMS. Two patients in the sham group did not complete the protocol because of reasons unrelated to the study. High-frequency rTMS was applied over the primary motor cortex bilaterally for 10 days. An investigator blinded to the treatment performed three video-taped examinations on each patient: before stimulation (baseline), and 1 day (short-term effect) and 30 days after the treatment session ended (long-term effect). The primary end point was the changes in depression, while secondary end points included health-related quality of life scales and Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS). Results: In the actively treated group, not only did the severity of depression improve (from 17 to 7 points, Montgomery-Åsberg Depression Rating Scale, median values, p < 0.001), but also the health-related quality of life (from 25.4 to 16.9 points, PDQ-39 summary index, median values, p < 0.001). Besides, we could also demonstrate an improvement in MDS-UPDRS Motor Examination (from 26 to 20 points, median values, p < 0.05). In the sham-treated group, none of the examined tests and scales improved significantly after treatment. Conclusions: Our results demonstrate the beneficial effects of high-frequency bilateral M1 rTMS on depression and health-related quality of life in PD. However, this effect of rTMS should also be confirmed in patients with severe depression by further clinical trials.

一次運動野刺激による中枢性脳卒中後疼痛患者の機能的結合

We have previously reported the efficacy of 5 Hz repetitive transcranial magnetic stimulation (rTMS) of the primary motor cortex (M1) in relief of central post–stroke pain (CPSP). The objective of this study was to explore changes of functional connectivity related to CPSP condition, and to assess changes of functional connectivity induced by rTMS in patients with CPSP. In 14 patients with CPSP and 14 control subjects, resting–state functional MRI were taken. Twelve of these patients received 5 Hz–rTMS of M1, and underwent resting–state functional MRI before and after rTMS. Functional connectivity associated with motor and default mode networks increased in patients with CPSP compared with control subjects. Moreover, functional connectivity associated with default mode network and anterior cingulate cortex decreased after rTMS. These findings suggest that several functional networks are involved in pathophysiology of CPSP and mechanisms of action of rTMS.

Daily repetitive transcranial magnetic stimulation of primary motor cortex for neuropathic pain: A randomized, multicenter, double-blind, crossover, sham-controlled trial

There is little evidence for multisession repetitive transcranial magnetic stimulation (rTMS) on pain relief in patients with neuropathic pain (NP), although single-session rTMS was suggested to provide transient pain relief in NP patients. We aimed to assess the efficacy and safety of 10 daily rTMS in NP patients. We conducted a randomized, double-blind, sham-controlled, crossover study at 7 centers. Seventy NP patients were randomly assigned to 2 groups. A series of 10 daily 5-Hz rTMS (500 pulses/session) of primary motor cortex (M1) or sham stimulation was applied to each patient with a follow-up of 17days. The primary outcome was short-term pain relief assessed using a visual analogue scale (VAS). The secondary outcomes were short-term change in the short form of the McGill pain questionnaire (SF-MPQ), cumulative changes in the following scores (VAS, SF-MPQ, the Patient Global Impression of Change scale [PGIC], and the Beck Depression Inventory [BDI]), and the incidence of adverse events. Analysis was by intention to treat. This trial is registered with the University hospital Medical Information Network Clinical Trials Registry. Sixty-four NP patients were included in the intention-to-treat analysis. The real rTMS, compared with the sham, showed significant short-term improvements in VAS and SF-MPQ scores without a carry-over effect. PGIC scores were significantly better in real rTMS compared with sham during the period with daily rTMS. There were no significant cumulative improvements in VAS, SF-MPQ, and BDI. No serious adverse events were observed. Our findings demonstrate that daily high-frequency rTMS of M1 is tolerable and transiently provides modest pain relief in NP patients.

Changes in cerebrovascular reactivity following low-frequency repetitive transcranial magnetic stimulation

Objectives Repetitive Transcranial Magnetic Stimulation (rTMS) potential therapeutic uses have been explored in many conditions including stroke. However, its potential effects on cerebral hemodynamics have not been deeply considered. Transcranial Doppler ultrasonography (TCD) is a promising tool in detecting focal changes of cerebral blood flow velocity (CBFV) and cerebrovascular reactivity (CRV) induced by rTMS. We evaluated possible changes in CBFV and CVR in healthy volunteers. Methods Low-frequency (1 Hz) and Sham rTMS were applied over the motor cortex (M1) of the left hemisphere of healthy volunteers. CBFV and CVR were evaluated in the ipsilateral middle cerebral artery (MCA). CVR to hypercapnia was derived from the breath-holding index (BHI). Subjects were randomly assigned to real or sham stimulation. Results Maximal CBFV of MCA tended to decrease after 1 Hz M1 rTMS. Low-frequency 1 Hz M1 rTMS increased BHI (measured in MCA) immediately after rTMS, and the observed effect vanished after 15 min when applied over M1. We did not observe any significant change in Pulsatility Index (PI) and Resistance Index (RI) measures in all conditions. No significant changes of above mentioned parameters were observed in the sham stimulation group. Conclusions Low-frequency rTMS induces a significant modulation of CVR in healthy subjects. This effect should be relevant in acute stroke patients with impaired cerebral autoregulation.

Effect of slow repetitive TMS of the motor cortex on ipsilateral sequential simple finger movements and motor skill learning

Disruption of a cortical region can paradoxically improve behavior. After unilateral damage to the primary motor cortex (M1), increased excitability of the unaffected M1 has been shown. The M1 plays a critical role in motor performance and also early aspects of motor skill learning. Repetitive transcranial magnetic stimulation (rTMS) of one motor cortex can lead a temporary reduction in cortical excitability. We hypothesize that unilateral suppression of one M1 by rTMS may increase excitability of the unaffected motor cortex and thus improve motor performance and motor skill learning with the ipsilateral hand by releasing the contralateral motor cortex from transcallosal inhibition. Forty healthy volunteers participated in our study; 16 for the experiment I and 24 for the experiment II. In the experiment I, after practicing a sequential simple key-pressing task with the index finger, their motor performance was monitored before and after slow-frequency (1Hz) rTMS, applied on the M1 ipsilateral or contralateral to the hand, ipsilateral premotor area or vertex (Cz). In the experiment II, participants were randomly divided into three stimulation groups: i) ipsilateral M1; ii) contralateral M1; and iii) Cz. rTMS was applied before the initiation of practice and learning of a simple motor skill. Mean execution time and error rate were recorded in 4 sessions distributed over 2 days. In experiment I: rTMS of M1 shortened execution time of the motor task with the ipsilateral hand, without affecting performance with the contralateral hand. This effect outlasted rTMS by at least 10 min, and was most prominent for M1 stimulation. In experiment II, disruption of M1 with rTMS slowed down skill acquisition with the contralateral hand, but paradoxically accelerated learning with the ipsilateral hand. This effect was evident during the first of 2 days of practice in the group with rTMS over the ipsilateral M1 compared to the other two groups (Cz and contralateral M1). Our results support the notion of an interhemispheric competition, and demonstrate the utility of rTMS to explore the functional facilitation of the un-stimulated counterpart M1 with effects on motor execution and learning, which may have implications for neurorehabilitation.

Diffuse analgesic effects of unilateral repetitive transcranial magnetic stimulation (rTMS) in healthy volunteers

We investigated the analgesic effects of unilateral repetitive transcranial magnetic stimulation (rTMS) of the motor cortex (M1) or dorsolateral prefrontal cortex (DLPFC) in two models of experimental pain in healthy volunteers. Two studies were carried out in parallel in two groups of 26 paid healthy volunteers. The effects of active or sham rTMS (frequency, 10Hz; intensity, 80% resting motor threshold) applied to the right M1 or DLPFC were compared in a double-blind randomized cross-over design. In the first series of experiments, we analyzed the effects of rTMS on thermal (heat and cold) detection and pain thresholds measured on both hands and the left foot, by standardized quantitative sensory testing methods. In the second series of experiments, we measured the effects of M1 or DLPFC rTMS on the threshold and recruitment curves of the RIII nociceptive reflex evoked by ipsilateral electrical stimulation of the sural nerve and recorded on the biceps femoris of both lower limbs. In both studies, measurements were taken before and up to 60min after the end of rTMS. Active rTMS of both M1 and DLPFC significantly increased the thermal pain thresholds, measured for both hands and the left foot, this effect being most marked for cold pain. These effects, which lasted at least 1h after rTMS, were selective because they were not associated with changes in non-painful thermal sensations. By contrast, the second study showed that rTMS of M1 or DLPFC had no significant effect on the threshold or recruitment curve of the nociceptive flexion RIII reflex. Our findings demonstrate that unilateral rTMS of M1 or DLPFC induces diffuse and selective analgesic effects in healthy volunteers. The lack of effect on the RIII reflex suggests that such analgesic effects may not depend on the activation of descending inhibitory systems.