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• tSMS is a portable, inhibitory, non-invasive brain stimulation technique. • Repeated sessions of home-based tSMS of the motor cortex are feasible and safe. • tSMS may provide subjective benefit for the treatment of levodopa-induced dyskinesias. [ABSTRACT FROM AUTHOR]

Background Transcranial static magnetic field stimulation (tSMS) was recently added to the family of inhibitory non-invasive brain stimulation techniques. However, the application of tSMS for 10–20 min over the motor cortex (M1) induces only short-lasting effects that revert within few minutes. Objective We examined whether increasing the duration of tSMS to 30 min leads to long-lasting changes in cortical excitability, which is critical for translating tSMS toward clinical applications. Methods The study comprised 5 experiments in 45 healthy subjects. We assessed the impact of 30-min-tSMS over M1 on corticospinal excitability, as measured by the amplitude of motor evoked potentials (MEPs) and resting motor thresholds (RMTs) to single-pulse transcranial magnetic stimulation (TMS) (experiments 1–2). We then assessed the impact of 30-min-tSMS on intracortical excitability, as measured by short-interval intracortical facilitation (SICF) and short-interval intracortical inhibition (SICI) using paired-pulse TMS protocols (experiments 2–4). We finally assessed the impact of 10-min-tSMS on SICF and SICI (experiment 5). Results 30-min-tSMS decreased MEP amplitude compared to sham for at least 30 min after the end of the stimulation. This long-lasting effect was associated with increased SICF and reduced SICI. 10-min-tSMS –previously reported to induce a short-lasting decrease in MEP amplitude– produced the opposite changes in intracortical excitability, decreasing SICF while increasing SICI. Conclusions These results suggest a dissociation of intracortical changes in the consolidation from short-lasting to long-lasting decrease of corticospinal excitability induced by tSMS. The long-lasting effects of 30-min-tSMS open the way to the translation of this simple, portable and low-cost technique toward clinical trials. [ABSTRACT FROM AUTHOR]

Background Costello syndrome (CS) is a rare congenital disorder due to a G12S amino acid substitution in HRAS protoncogene. Previous studies have shown that Paired Associative Stimulation (PAS), a repetitive brain stimulation protocol inducing motor cortex plasticity by coupling peripheral nerve stimulation with brain stimulation, leads to an extremely pronounced motor cortex excitability increase in CS patients. Intermittent Theta Burst Stimulation (iTBS) represents a protocol able to induce motor cortex plasticity by trains of stimuli at 50 Hz. In healthy subjects PAS and iTBS produce similar after-effects in motor cortex excitability. Experimental models showed that HRAS-dependent signalling pathways differently affect LTP induced by different patterns of repetitive synaptic stimulation. Objective We aimed to compare iTBS-induced after-effects on motor cortex excitability with those produced by PAS in CS patients and to observe whether HRAS mutation differentially affects two different forms of neuromodulation protocols. Methods We evaluated in vivo after-effects induced by PAS and iTBS applied over the right motor cortex in 4 CS patients and in 21 healthy age-matched controls. Results Our findings confirmed HRAS-dependent extremely pronounced PAS-induced after-effects and showed for the first time that iTBS induces no change in MEP amplitude in CS patients whereas both protocols lead to an increase of about 50% in controls. Conclusions CS patients are characterized by an impairment of iTBS-related LTP-like phenomena besides enhanced PAS-induced after-effects, suggesting that HRAS-dependent signalling pathways have a differential influence on PAS- and iTBS-induced plasticity in humans. [ABSTRACT FROM AUTHOR]

Background Significant changes in neurophysiological and clinical outcomes in chronic stroke had been reported after tDCS; but there is a paucity of data in acute stroke. Objective We aimed to evaluate whether a tDCS-induced modulation of primary motor cortex excitability in patients with acute stroke enhances motor recovery associated with rehabilitation and induces differential neuroplasticity. Methods We conducted two experiments in acute stroke patients. In experiment 1 (14 patients), we tested the immediate effects of bilateral tDCS alone as compared to sham tDCS on recovery. Experiment 2 (20 patients) was designed to assess effects of bilateral tDCS delivered together with constraint-induced movement therapy (CIMT). In this experiment, we included a longer follow-up (3 months) and measured, in addition to the same clinical outcomes of experiment 1, changes of motor cortex excitability and the amount of promoted LTP-like activity. Results Despite the expected improvement at 1 week, none of the clinical measures showed any different modulation in dependence of CIMT and tDCS . On the neurophysiological assessments, on the other hand, the Real_tDCS group, compared to Sham_tDCS group, showed a reduction of inter-hemispheric imbalance when considering the differences of motor evoked potential between both 3-month and 1 week follow up ( P = 0.007) and three month and baseline ( P = 0.015). Conclusions Despite the lack of additional clinical changes, real bilateral tDCS, together with CIMT, significantly reduces inter-hemispheric imbalance between affected and unaffected hemispheres. These findings may shed light on plasticity changes in acute stroke and its potential impact in chronic phases. [ABSTRACT FROM AUTHOR]

Background: Motor cortex stimulation has been proposed for treatment of amyotrophic lateral sclerosis (ALS) and preliminary studies have reported a slight reduction of disease progression using both invasive and noninvasive repetitive stimulation of the motor cortex. Objective: The aim of this proof of principle study was to investigate the effects of motor cortex stimulation performed for a prolonged period (about 2 years) on ALS progression. Methods: Two patients were included in the study; the first patient was treated with monthly cycles of repetitive transcranial magnetic stimulation (rTMS) and the second one was treated with chronic epidural motor cortex stimulation. The rate of progression of the disease before and during treatment was compared. Results: The treatments were well tolerated by the patients. Both patients deteriorated during treatment; however, the patient treated with rTMS showed a slight reduction in deterioration rate. Conclusions: Although we cannot be sure whether the effects observed in the patient treated with rTMS can be attributed to this form of stimulation, our study set the groundwork for possible future studies investigating the effects of rTMS, for a prolonged period, on a larger group of ALS patients. [Copyright &y& Elsevier]

Abstract: Repetitive transcranial magnetic stimulation (rTMS) of brain can modulate cortical neurotransmission, a novel paradigm of repetitive stimulation termed continuous theta-burst stimulation (cTBS) produces a pronounced and prolonged suppression of motor cortex excitability. The aim of this preliminary study was to investigate whether cTBS of motor cortex could have any beneficial effect in patients with amyotrophic lateral sclerosis (ALS). We performed a double-blind, placebo-controlled trial. Twenty patients with definite ALS were randomly allocated to blinded active or placebo stimulation. Repetitive stimulation of the motor cortex was performed for five consecutive days every month for six consecutive months. The primary outcome was the rate of decline as evaluated with the ALS functional rating scale. The treatment was well tolerated by the patients. Fifteen patients (seven active and eight sham) completed the study and were included in the 6-months analysis. Both active and sham patients deteriorated during treatment, however, active patients showed a modest but significant slowing of the deterioration rate. Though we cannot be sure whether the effects observed can be attributed to cTBS, because of the restricted number of patients studied, further investigation on a larger group of ALS patients is warranted. The results of the pilot study might open up a new therapeutic perspective in ALS based on neuromodulation. [Copyright &y& Elsevier]

Summary Background Ablative neurosurgery has been used to treat Parkinson's disease for many decades. MRI-guided focused ultrasound allows focal lesions to be made in deep brain structures without skull incision. We investigated the safety and preliminary efficacy of unilateral subthalamotomy by focused ultrasound in Parkinson's disease. Methods This prospective, open-label pilot study was done at CINAC (Centro Integral de Neurociencias), University Hospital HM Puerta del Sur in Madrid, Spain. Eligible participants had Parkinson's disease with markedly asymmetric parkinsonism. Patients with severe dyskinesia, history of stereotactic surgery or brain haemorrhage, a diagnosis of an unstable cardiac or psychiatric disease, or a skull density ratio of 0·3 or less were excluded. Enrolled patients underwent focused ultrasound unilateral subthalamotomy. The subthalamic nucleus was targeted by means of brain images acquired with a 3-Tesla MRI apparatus. Several sonications above the definitive ablation temperature of 55°C were delivered and adjusted according to clinical response. The primary outcomes were safety and a change in the motor status of the treated hemibody as assessed with part III of the Movement Disorders Society–Unified Parkinson's Disease Rating Scale (MDS–UPDRS III) in both off-medication and on-medication states at 6 months. Adverse events were monitored up to 48 h after treatment and at scheduled clinic visits at 1, 3, and 6 months after treatment. The study is registered with ClinicalTrials.gov , number NCT02912871 . Findings Between April 26 and June 14, 2016, ten patients with markedly asymmetric parkinsonism that was poorly controlled pharmacologically were enrolled for focused ultrasound unilateral subthalamotomy. By 6 months follow-up, 38 incidents of adverse events had been recorded, none of which were serious or severe. Seven adverse events were present at 6 months. Three of these adverse events were directly related to subthalamotomy: off-medication dyskinesia in the treated arm (one patient, almost resolved by 6 months); on-medication dyskinesia in the treated arm (one patient, resolved after levodopa dose reduction); and subjective speech disturbance (one patient). Four of the adverse events present at 6 months were related to medical management (anxiety and fatigue [one patient each] and weight gain [two patients]). The most frequent adverse events were transient gait ataxia (related to subthalamotomy, six patients), transient pin-site head pain (related to the head frame, six patients), and transient high blood pressure (during the procedure, five patients). Transient facial asymmetry (one patient) and moderate impulsivity (two patients) were also recorded. The mean MDS–UPDRS III score in the treated hemibody improved by 53% from baseline to 6 months in the off-medication state (16·6 [SD 2·9] vs 7·5 [3·9]) and by 47% in the on-medication state (11·9 [3·1] vs 5·8 [3·5]). Interpretation MRI-guided focused ultrasound unilateral subthalamotomy was well tolerated and seemed to improve motor features of Parkinson's disease in patients with noticeably asymmetric parkinsonism. Large randomised controlled trials are necessary to corroborate these preliminary findings and to assess the potential of such an approach to treat Parkinson's disease. Funding Fundación de investigación HM Hospitales and Insightec. [ABSTRACT FROM AUTHOR]

Highlights: [•] We evaluated if inhibitory modulation of stroke hemisphere can enhance recovery. [•] We found no deleterious effects of inhibitory stimulation on recovery. [•] All patients showed some improvement from a retraining protocol for the upper limb. [•] Inhibition of stroke hemisphere is safe and has the potential to enhance recovery. [ABSTRACT FROM AUTHOR]

Abstract: Preliminary data suggest that repetitive transcranial magnetic stimulation (rTMS) of the brain may produce a modest slowing of disease progression in amyotrophic lateral sclerosis (ALS). The present study was designed to test the hypothesis that rTMS given as continuous theta burst stimulation (cTBS), repeated monthly for one year, would affect ALS progression. We performed a double blind, placebo-controlled trial. Twenty patients with ALS were randomly allocated to blinded real or placebo stimulation. cTBS of the motor cortex was performed for five consecutive days every month for one year. Primary outcome was the rate of decline as evaluated with the revised ALS functional rating scale (ALSFRS-R). Treatment was well tolerated. There was no significant difference in the ALSFRS-R score deterioration between patients treated with real or placebo stimulation. ALSFRS-R mean scores declined from 32.0 (SD 7.1) at study entry to 23.1 (SD 6.3) at 12 months in patients receiving real cTBS and from 31.3 (SD 6.9) to 21.2 (SD 6.0) in those receiving placebo stimulation. Although cTBS proved a safe procedure, on the basis of the present findings a larger randomized confirmatory trial seems unjustified in ALS patients, at least in advanced stage of the disease. [Copyright &y& Elsevier]

Objective: Repetitive transcranial magnetic stimulation (rTMS) of the brain can modulate neurotransmission. The aim of this preliminary study was to investigate whether rTMS of the motor cortex at low (1 Hz) or high (20 Hz) frequencies can have any beneficial effect in a transgenic rat model of amyotrophic lateral sclerosis (ALS) and in a few patients with ALS.Methods: The effects of chronic rTMS were evaluated in 20 transgenic rats overexpressing the human G93A mutant superoxide dismutase 1 gene. Several cycles of rTMS were also performed in 4 ALS patients and the rate of progression of the disease before and during rTMS treatment was compared.Results: No effects of rTMS was observed in transgenic rats. The rTMS treatment was well tolerated by the patients. All ALS patients continued to deteriorate. However, in the patients exposed to low-frequency rTMS the rate of progression during treatment was slightly slower than that evaluated before treatment; an opposite tendency was observed in patients exposed to high frequencies.Conclusions: Though we cannot be sure whether the effects observed in the patients can be attributed to rTMS, further investigation using low-frequency motor cortex stimulation on a larger group of ALS patients is warranted.Significance: The results of the pilot study in humans might open up a new therapeutic perspective in ALS based on neuromodulation. [Copyright &y& Elsevier]

Background: Ablative neurosurgery has been used to treat Parkinson's disease for many decades. MRI-guided focused ultrasound allows focal lesions to be made in deep brain structures without skull incision. We investigated the safety and preliminary efficacy of unilateral subthalamotomy by focused ultrasound in Parkinson's disease.Methods: This prospective, open-label pilot study was done at CINAC (Centro Integral de Neurociencias), University Hospital HM Puerta del Sur in Madrid, Spain. Eligible participants had Parkinson's disease with markedly asymmetric parkinsonism. Patients with severe dyskinesia, history of stereotactic surgery or brain haemorrhage, a diagnosis of an unstable cardiac or psychiatric disease, or a skull density ratio of 0·3 or less were excluded. Enrolled patients underwent focused ultrasound unilateral subthalamotomy. The subthalamic nucleus was targeted by means of brain images acquired with a 3-Tesla MRI apparatus. Several sonications above the definitive ablation temperature of 55°C were delivered and adjusted according to clinical response. The primary outcomes were safety and a change in the motor status of the treated hemibody as assessed with part III of the Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS III) in both off-medication and on-medication states at 6 months. Adverse events were monitored up to 48 h after treatment and at scheduled clinic visits at 1, 3, and 6 months after treatment. The study is registered with ClinicalTrials.gov, number NCT02912871.Findings: Between April 26 and June 14, 2016, ten patients with markedly asymmetric parkinsonism that was poorly controlled pharmacologically were enrolled for focused ultrasound unilateral subthalamotomy. By 6 months follow-up, 38 incidents of adverse events had been recorded, none of which were serious or severe. Seven adverse events were present at 6 months. Three of these adverse events were directly related to subthalamotomy: off-medication dyskinesia in the treated arm (one patient, almost resolved by 6 months); on-medication dyskinesia in the treated arm (one patient, resolved after levodopa dose reduction); and subjective speech disturbance (one patient). Four of the adverse events present at 6 months were related to medical management (anxiety and fatigue [one patient each] and weight gain [two patients]). The most frequent adverse events were transient gait ataxia (related to subthalamotomy, six patients), transient pin-site head pain (related to the head frame, six patients), and transient high blood pressure (during the procedure, five patients). Transient facial asymmetry (one patient) and moderate impulsivity (two patients) were also recorded. The mean MDS-UPDRS III score in the treated hemibody improved by 53% from baseline to 6 months in the off-medication state (16·6 [SD 2·9] vs 7·5 [3·9]) and by 47% in the on-medication state (11·9 [3·1] vs 5·8 [3·5]).Interpretation: MRI-guided focused ultrasound unilateral subthalamotomy was well tolerated and seemed to improve motor features of Parkinson's disease in patients with noticeably asymmetric parkinsonism. Large randomised controlled trials are necessary to corroborate these preliminary findings and to assess the potential of such an approach to treat Parkinson's disease.Funding: Fundación de investigación HM Hospitales and Insightec. [ABSTRACT FROM AUTHOR]