Effectiveness and mechanism of action of rTMS combined with quadriceps strength training in individuals with knee osteoarthritis: study protocol for a randomized controlled trial.

BACKGROUND: Quadriceps training is necessary in function and activity of daily living for patients with knee osteoarthritis (KOA). However, it did not reduce the rate of surgical treatment for end-stage KOA in the long term. This may be related to brain structure changes and maladaptive plasticity in KOA patients. Transcranial Magnetic Stimulation (TMS) could enhance the functional connectivity of brain regions and improves maladaptive plasticity. However, the synergistic effect of the combination of the two for treat KOA is still unclear. Therefore, the purpose of this study is to investigate whether the High-Frequency rTMS combined with quadriceps strength training can improve the pain and function in KOA more effectively than quadriceps training alone and explore the mechanism of action. METHODS: This study is an assessor-blind, sham-controlled, randomized controlled trial involving 12 weeks of intervention and 6 months follow-up. 148 participants with KOA will receive usual care management and be randomized into four subgroups equally, including quadriceps strength training, high-frequency rTMS training, sham rTMS and quadriceps strength training, high-frequency rTMS and quadriceps strength training. The rehabilitation interventions will be carried out 5 days per week for a total of 12 weeks. All outcomes will be measured at baseline, 4 weeks, 8 weeks, and 12 weeks during the intervention and 1 month, 3 months and 6 months during the follow-up period. The effectiveness outcomes will be included visual analog scale, isokinetic knee muscle strength, Knee Injury and Osteoarthritis Outcome score and 36-Item Short-Form Health Survey score; The act mechanism outcomes will be included motor evoked potential, grey matter density, white matter, subcortical nuclei volumes, cortical thickness and functional connectivity by MRI. Two-way of variance with repeated measures will be used to test the group and time effect for outcome measures. DISCUSSION: The study will be the first protocol to examine whether there are synergistic effects following high-frequency rTMS combined with quadriceps strength training for treat KOA and clarify the mechanism of action. High-frequency rTMS can be added into the training program for KOA patients if it is proven effective. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2300067617. Registered on Jan.13,2023.

Chronic high-frequency repetitive transcranial magnetic stimulation improves age-related cognitive impairment in parallel with alterations in neuronal excitability and the voltage-dependent Ca2+ current in female mice.

Chronic high-frequency repetitive transcranial magnetic stimulation (rTMS) is a noninvasive method to increase the excitability of neurons, and it induces long-term effects that can improve symptoms related to neurodegenerative diseases, including cognitive ability. The present study was undertaken to identify the mechanism by which rTMS improves cognitive impairments in mice. The novel object recognition test in vivo was used to evaluate the cognitive function of the mice. Whole-cell patch-clamp recordings were used to evaluate the neuronal excitability, including the resting membrane potential, the number of action potentials induced by depolarized current, after-hyperpolarization, and the voltage-dependent Ca(2+) current in hippocampal slices. We found that the aged mice showed impairments in cognitive function, and high-frequency (25Hz) rTMS for 14 consecutive-days ameliorated the impairments. Whole-cell patch-clamp recordings showed that, compared to matured mice, the hippocampal CA1 pyramidal neurons of aged mice showed significantly hyperpolarized resting membrane potential, significantly decreased numbers of action potentials after injection of depolarizing current, and significantly increased after-hyperpolarization after an action potential. The exposure to high-frequency rTMS significantly improved the above deficits in the neuronal excitability in the aged rTMS mice. Consistent with the above changes, the exposure to high-frequency rTMS also significantly decreased the voltage-dependent Ca(2+) current of the neurons compared with the aged sham mice. These data suggested that the rTMS could improve the age-related cognitive impairment in parallel with regulating the neuronal excitability and modifying the voltage-dependent Ca(2+) channels.

Effects of high-frequency transcranial magnetic stimulation on theta-gamma oscillations and coupling in the prefrontal cortex of rats during working memory task.

High-frequency rTMS has been widely used to improve working memory (WM) impairment; however, the underlying neurophysiological mechanisms are unclear. We evaluated the effect of high-frequency rTMS on behaviors relevant to WM as well as coupling between theta and gamma oscillations in the prefrontal cortex (PFC) of rats. Accordingly, Wistar rats received high-frequency rTMS daily for 14 days (5 Hz, 10 Hz, and 15 Hz stimulation; 600 pulses; n = 6 per group), whereas the control group received sham stimulation. Electrophysiological signals were recorded simultaneously to obtain the local field potential (LFP) from the PFC, while the rats performed T-maze tasks for the evaluation of WM. Phase-amplitude coupling (PAC) was utilized to determine the effect of high-frequency rTMS on the theta-gamma coupling of LFPs. We observed that rats in the rTMS groups needed a smaller number of training days to complete the WM task as compared to the control group. High-frequency rTMS reinforced the coupling connection strength in the PFC of rats. Notably, the effect of rTMS at 15 Hz was the most effective among the three frequencies, i.e., 5 Hz, 10 Hz, and 15 Hz. The results suggested that rTMS can improve WM impairment in rats by modulating the coupling of theta and gamma rhythms. Hence, the current study provides a scientific basis for the optimization of TMS models, which would be relevant for clinical application.

Efficacy and safety of intermittent theta burst stimulation versus high-frequency repetitive transcranial magnetic stimulation for patients with treatment-resistant depression: a systematic review.

Objective: Intermittent theta-burst stimulation (iTBS), which is a form of repetitive transcranial magnetic stimulation (rTMS), can produce 600 pulses to the left dorsolateral prefrontal cortex (DLPFC) in a stimulation time of just over 3 min. The objective of this systematic review was to compare the safety and efficacy of iTBS and high-frequency (≥ 5 Hz) rTMS (HF-rTMS) for patients with treatment-resistant depression (TRD). Methods: Randomized controlled trials (RCTs) comparing the efficacy and safety of iTBS and HF-rTMS were identified by searching English and Chinese databases. The primary outcomes were study-defined response and remission. Results: Two RCTs (n = 474) investigating the efficacy and safety of adjunctive iTBS (n = 239) versus HF-rTMS (n = 235) for adult patients with TRD met the inclusion criteria. Among the two included studies (Jadad score = 5), all were classified as high quality. No group differences were found regarding the overall rates of response (iTBS group: 48.0% versus HF-rTMS group: 45.5%) and remission (iTBS group: 30.0% versus HF-rTMS group: 25.2%; all Ps > 0.05). The rates of discontinuation and adverse events such as headache were similar between the two groups (all Ps > 0.05). Conclusion: The antidepressant effects and safety of iTBS and HF-rTMS appeared to be similar for patients with TRD, although additional RCTs with rigorous methodology are needed.

Preliminary findings on the role of high-frequency (5Hz) rTMS stimulation on M1 and pre-SMA regions in Parkinson's disease.

It has been already shown that the motor symptoms of the Parkinson's Disease (PD) have been improved with high frequency rTMS although there is no consensus on the most suitable target brain localization for a maximal therapeutic efficacy. Here, we aimed to compare the therapeutic effect of high frequency (5Hz) rTMS stimulation on primary motor cortex (M1) and pre-supplementary (pre SMA) regions in patients with PD who were still on pharmacological treatment. The study included right-hand dominant16 patients with PD (5 females, 11 males) with demographically and clinically similar characteristics which were randomly assigned to group 1 (n=8) and group 2 (n=8) and received left M1 and the left pre-SMA rTMS procedure, respectively. Total and sequential motor scores of the Unified Parkinson's Disease Rating Scale (UPDRSmotor) were applied to all patients at the baseline and the patients were re-evaluated under the same clinical conditions one week after the end of the sessions. Comparisons of the UPDRS-motor scores between two groups yielded significant improvements after the rTMS on pre-SMA compared to M1 (M1 p=0.14; pre-SMA p=0.01). which were especially significant for the bradykinesia (p=0.04) and axial score related items (p=0.01). This is the first study that shows the effect of rTMS on pre-SMA and it appears to be a promising option in the treatment of PD.

High-frequency repetitive transcranial magnetic stimulation enhanced treadmill training effects on gait performance in individuals with chronic stroke: A double-blinded randomized controlled pilot trial.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) combined with treadmill training has been suggested to modulate corticomotor activity and improve gait performance in people with Parkinson's disease. RESEARCH QUESTION: It is unclear whether this combination therapy has a similar effect in people with stroke. The current study aimed to investigate whether high-frequency rTMS enhances the effects of subsequent treadmill training in individuals with chronic stroke. METHODS: Fourteen participants meeting the selection criteria were randomly assigned to either the experimental (n = 8) or control (n = 6) group. The experimental group received 5 Hz rTMS prior to treadmill training three times per week for 3 weeks. The control group received sham rTMS before treadmill training. Walking speed, gait symmetry, corticomotor excitability, motor function of the lower extremities, and muscle activity during walking were measured before intervention, after intervention, and at 1-month follow-up. RESULTS: The walking speed, spatial asymmetry of gait, and motor function of the lower extremities improved significantly in the experimental group, and these improvements exhibited significant differences in between-group comparisons. However, there was no significant difference in corticomotor excitability or brain asymmetry ratio after the intervention in each group. SIGNIFICANCE: The current results revealed that applying 5 Hz high-frequency rTMS over the leg motor cortex in the affected hemisphere enhanced the effects of subsequent treadmill training on gait speed and spatial asymmetry in individuals with chronic stroke. Improvement in gait speed persisted for at least 1 month in individuals with chronic stroke.

Effectiveness and acceptability of accelerated repetitive transcranial magnetic stimulation (rTMS) for treatment-resistant major depressive disorder: an open label trial.

BACKGROUND: Major depressive disorder (MDD) is a significant cause of worldwide disability and treatment resistance is common. High-frequency repetitive transcranial magnetic stimulation (HF-rTMS) has emerged as a treatment for MDD, and while efficacious, the daily commitment for typical 4-6 weeks of treatment poses a significant challenge. We aimed to determine the effectiveness and acceptability of an accelerated rTMS protocol for MDD. METHODS: In this naturalistic trial, 27 patients with moderate to severe chronic and treatment-resistant MDD were treated with twice-daily HF-rTMS (10 Hz) applied over the left dorsolateral prefrontal cortex for 2 consecutive weeks (60,000 pulses). The primary outcomes were rates of clinical remission and response (16-item Quick Inventory of Depressive Symptomatology post-treatment score ≤ 6, and ≥ 50% reduction, respectively). Secondary outcomes were self-reported anxious symptoms, depressive symptoms and quality of life, and dropout rates as a proxy for acceptability. RESULTS: Ten (37.0%) patients met criteria for clinical remission and 15 (55.6%) were classified as responders, with comparable outcomes for both moderate and severe MDD. Clinician-rated improvements in depressive symptoms were paralleled in self-reported depressive and anxious symptoms, as well as quality of life. No patient discontinued treatment. LIMITATIONS: This study is limited by short treatment duration that might be lengthened with corresponding improvements in effectiveness, limited duration of follow-up, small sample size, and an open-label design requiring randomized controlled replication. CONCLUSION: An accelerated protocol involving twice-daily sessions of HF-rTMS over the left DLPFC for 2 weeks was effective in treatment-resistant MDD, and had excellent acceptability. Additional research is required to optimize accelerated rTMS treatment protocols and determine efficacy using sham-controlled trials.

Short-term efficacy of repetitive transcranial magnetic stimulation (rTMS) in depression- reanalysis of data from meta-analyses up to 2010.

BACKGROUND: According to a narrative review of 13 meta-analyses (published up to 2010), repetitive transcranial magnetic stimulation (rTMS) has a moderate, short-term antidepressant effect in the treatment of major depression. The aim of the current study was to reanalyse the data from these 13 meta-analyses with a uniform meta-analytical procedure and to investigate predictors of such an antidepressant response. METHODS: A total of 40 double-blind, randomised, sham-controlled trials with parallel designs, utilising rTMS of the dorsolateral prefrontal cortex in the treatment of major depression, was included in the current meta-analysis. The studies were conducted in 15 countries on 1583 patients and published between 1997-2008. Depression severity was measured using the Hamilton Depression Rating Scale, Beck Depression Inventory, or Montgomery Åsberg Depression Rating Scale at baseline and after the last rTMS. A random-effects model with the inverse-variance weights was used to compute the overall mean weighted effect size, Cohen's d. RESULTS: There was a significant and moderate reduction in depression scores from baseline to final, favouring rTMS over sham (overall d = -.54, 95% CI: -.68, -.41, N = 40 studies). Predictors of such a response were investigated in the largest group of studies (N = 32) with high-frequency (>1 Hz) left (HFL) rTMS. The antidepressant effect of HFL rTMS was present univariately in studies with patients receiving antidepressants (at stable doses or started concurrently with rTMS), with treatment-resistance, and with unipolar (or bipolar) depression without psychotic features. Univariate meta-regressions showed that depression scores were significantly lower after HFL rTMS in studies with higher proportion of female patients. There was little evidence for publication bias in the current analysis. CONCLUSIONS: Daily rTMS (with any parameters) has a moderate, short-term antidepressant effect in studies published up to 2008. The clinical efficacy of HFL rTMS may be better in female patients not controlling for any other study parameters.