Low-frequency repetitive transcranial magnetic stimulation (rTMS) of the unaffected hemisphere can enhance function of the paretic hand in patients with mild motor impairment. Effects of low-frequency rTMS to the contralesional motor cortex at an early stage of mild to severe hemiparesis after stroke are unknown. In this pilot, randomized, double-blind clinical trial we compared the effects of low-frequency rTMS or sham rTMS as add-on therapies to outpatient customary rehabilitation, in 30 patients within 5–45 days after ischemic stroke, and mild to severe hand paresis. The primary feasibility outcome was compliance with the interventions. The primary safety outcome was the proportion of intervention-related adverse events. Performance of the paretic hand in the Jebsen–Taylor test and pinch strength were secondary outcomes. Outcomes were assessed at baseline, after ten sessions of treatment administered over 2 weeks and at 1 month after end of treatment. Baseline clinical features were comparable across groups. For the primary feasibility outcome, compliance with treatment was 100% in the active group and 94% in the sham group. There were no serious intervention-related adverse events. There were significant improvements in performance in the Jebsen–Taylor test (mean, 12.3% 1 month after treatment) and pinch force (mean, 0.5 Newtons) in the active group, but not in the sham group. Low-frequency rTMS to the contralesional motor cortex early after stroke is feasible, safe and potentially effective to improve function of the paretic hand, in patients with mild to severe hemiparesis. These promising results will be valuable to design larger randomized clinical trials.

Single sessions of PSS + tDCS, tDCS alone, or RPSS alone did not improve training effects in chronic stroke patients with moderate to severe impairment.

Low-frequency repetitive transcranial magnetic stimulation of the unaffected hemisphere (UH-LF-rTMS) in patients with stroke can decrease interhemispheric inhibition from the unaffected to the affected hemisphere and improve hand dexterity and strength of the paretic hand. The objective of this proof-of-principle study was to explore, for the first time, effects of UH-LF-rTMS as add-on therapy to motor rehabilitation on short-term intracortical inhibition (SICI) and intracortical facilitation (ICF) of the motor cortex of the unaffected hemisphere (M1UH) in patients with ischemic stroke. Eighteen patients were randomized to receive, immediately before rehabilitation treatment, either active or sham UH-LF-rTMS, during two weeks. Resting motor threshold (rMT), SICI, and ICF were measured in M1UH before the first session and after the last session of treatment. There was a significant increase in ICF in the active group compared to the sham group after treatment, and there was no significant differences in changes in rMT or SICI. ICF is a measure of intracortical synaptic excitability, with a relative contribution of spinal mechanisms. ICF is typically upregulated by glutamatergic agonists and downregulated by gabaergic antagonists. The observed increase in ICF in the active group, in this hypothesis-generating study, may be related to M1UH reorganization induced by UH-LF-rTMS.

Introduction: Transcranial direct current stimulation (tDCS) and somatosensory stimulation in the form of peripheral sensory stimulation (PSS) have emerged as potential powerful tools to enhance motor performance or increase effects of motor training in stroke victims. Objectives: To compare effects of active PSS+tDCS, tDCS alone, PSS alone and sham PSS+tDCS as add-on interventions to motor training in patients with stroke and moderate to severe upper limb impairments. Methods: Patients > 6 months post-stroke underwent four different interventions, in a cross-over design: repetitive training of wrist extension of the paretic arm preceded by either active PSS (median, ulnar and radial nerves), active anodal tDCS of the affected hemisphere, sham PSS+tDCS or active PSS+tDCS. Before and after each session, the following outcomes were blindly evaluated in the paretic upper limb: range of movement (ROM) of wrist extension (primary outcome); ROM of wrist flexion, grasp and pinch strength. Measures were compared with analysis of variance with repeated measures (ANOVARM) with factors “session” and “time”. Results: After screening 2499 patients, 22 subjects were included in the study (14 men). The mean age (± standard deviation) was 55.2±12.9 years and the mean time from stroke, 5.3±5.6 years. The mean Fugl-Meyer score for the paretic upper limb was 37±7.9. Two patients were excluded (one dropped out and one received botulinum toxin treatment). There was a significant effect of “time” (F=4.6, p=0.046), but no effects of “session” or interaction “session x time” in regard to grasp force. There were no significant effects of “session”, “time” or interaction “session x time” in regard to ROM of wrist extension, wrist flexion, or pinch force. Conclusions: Repetitive training of wrist extension specifically improved grasp force and did not influence other outcomes. PSS+tDCS, tDCS alone or PSS alone did not potentiate the effect of training.

Introduction: Peripheral sensory stimulation (PSS) administered for 2 hours prior to intensive task-oriented motor training delivered for 4 hours, over 10 days, leads to clinically significant benefits in subjects with stroke and moderate to severe upper limb motor impairment, compared to sham PSS. Whether similar results can be obtained with less intensive training programs remains to be determined. Methods: Twenty subjects with stroke in the chronic phase (>6m) and moderate to severe upper limb motor impairments were randomized to treatment with either 1.5h active PSS or sham, followed by functional electrical stimulation (FES) and task-specific training (TST) in sessions administered three times per week over six weeks. FES lasted for 30 minutes and TST, for 45 minutes. The primary outcome was the difference in performance in the Wolf Motor Function Test. The data were analyzed with a generalized estimating equations model with factors “group” (active or sham) and “time” (baseline, three and six weeks after starting treatment). Results: There were significant effects of “time” (Wald Chi-square = 16.5, p<0.001) and interaction between “group” and “time” (Wald Chi-square = 10.4, p=0.005) for the Wolf Motor Function Test, Functional Ability Scale. Post-hoc Bonferroni-corrected analyses showed a statistically significant improvement in performance between baseline and three weeks after beginning of treatment in the active (p=0.001) but not in the sham group (p=0.912). The difference between performance at baseline and six weeks after beginning of treatment almost reached statistically significance in the active (p=0.058) but not in the sham (p>0.999) group. Conclusions: These results are relevant for the design of larger clinical trials involving durations of interventions that are more easily implemented in clinical practice than rehabilitation protocols lasting for 6 hours per day. The study is ongoing.