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Role of Brain-Derived Neurotrophic Factor in Beneficial Effects of Repetitive Transcranial Magnetic Stimulation for Upper Limb Hemiparesis after Stroke.

ABSTRACT: BACKGROUND:Repetitive transcranial magnetic stimulation (rTMS) can improve upper limb hemiparesis after stroke but the mechanism underlying its efficacy remains elusive. rTMS seems to alter brain-derived neurotrophic factor (BDNF) and such effect is influenced by BDNF gene polymorphism. OBJECTIVES:To investigate the molecular effects of rTMS on serum levels of BDNF, its precursor proBDNF and matrix metalloproteinase-9 (MMP-9) in poststroke patients with upper limb hemiparesis. METHODS:Poststroke patients with upper limb hemiparesis were studied. Sixty-two patients underwent rehabilitation plus rTMS combination therapy and 33 patients underwent rehabilitation monotherapy without rTMS for 14 days at our hospital. One Hz rTMS was applied over the motor representation of the first dorsal interosseous muscle on the non-lesional hemisphere. Fugl-Meyer Assessment and Wolf Motor Function (WMFT) were used to evaluate motor function on the affected upper limb before and after intervention. Blood samples were collected for analysis of BDNF polymorphism and measurement of BDNF, proBDNF and MMP-9 levels. RESULTS:Two-week combination therapy increased BDNF and MMP-9 serum levels, but not serum proBDNF. Serum BDNF and MMP-9 levels did not correlate with motor function improvement, though baseline serum proBDNF levels correlated negatively and significantly with improvement in WMFT (? = -0.422, p = 0.002). The outcome of rTMS therapy was not altered by BDNF gene polymorphism. CONCLUSIONS:The combination therapy of rehabilitation plus low-frequency rTMS seems to improve motor function in the affected limb, by activating BDNF processing. BDNF and its precursor proBDNF could be potentially suitable biomarkers for poststroke motor recovery.

SUBMITTER: Niimi M

PROVIDER: S-EPMC4805302 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Role of Brain-Derived Neurotrophic Factor in Beneficial Effects of Repetitive Transcranial Magnetic Stimulation for Upper Limb Hemiparesis after Stroke.

Niimi Masachika M Hashimoto Kenji K Kakuda Wataru W Miyano Satoshi S Momosaki Ryo R Ishima Tamaki T Abo Masahiro M

PloS one 20160323 3

<h4>Background</h4>Repetitive transcranial magnetic stimulation (rTMS) can improve upper limb hemiparesis after stroke but the mechanism underlying its efficacy remains elusive. rTMS seems to alter brain-derived neurotrophic factor (BDNF) and such effect is influenced by BDNF gene polymorphism.<h4>Objectives</h4>To investigate the molecular effects of rTMS on serum levels of BDNF, its precursor proBDNF and matrix metalloproteinase-9 (MMP-9) in poststroke patients with upper limb hemiparesis.<h4> ...[more]

PMID: 27007747

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Project description:Background: Repetitive transcranial magnetic stimulation (rTMS) is a promising intervention to promote upper limb recovery after stroke. We aimed to identify differences in the efficacy of rTMS treatment on upper limb function depending on the onset time post-stroke. Methods: We searched PubMed, Embase, and the Cochrane Library to identify relevant RCTs from their inception to February 2018. RCTs on the effects of rTMS on upper limb function in adult patients with stroke were included. Study quality and risk of bias were assessed independently by two authors. Meta-analyses were performed for outcomes on individual upper limb outcome measures (function or activity) and for function and activity measures jointly, categorized by timing of treatment initiation. Timing of treatment initiation post-stroke was categorized as follows: acute to early subacute (<1 month), early subacute (1-3 months), late subacute (3-6 months), and chronic (>6 months). Results: We included 38 studies involving 1,074 stroke patients. Subgroup analysis demonstrated benefit of rTMS applied within the first month post-stroke [MD = 9.31; 95% confidence interval (6.27-12.34); P < 0.0001], but not in the early subacute phase (1-3 months post-stroke) [MD = 1.14; 95% confidence interval (-5.32 to 7.59), P = 0.73) or chronic phase (>6 months post-stroke) [MD = 1.79; 95% confidence interval (-2.00 to 5.59]; P = 0.35), when assessed with a function test [Fugl-Meyer Arm test (FMA)]. There were no studies within the late subacute phase (3-6 months post-stroke) that used the FMA. Tests at the level of function revealed improved upper limb function after rTMS [SMD = 0.43; 95% confidence interval (0.02-0.75); P = 0.0001], but tests at the level of activity did not, independent of rTMS onset post-stroke [SMD = 0.17; 95% confidence interval (-0.09 to 0.44); P = 0.19]. Heterogeneities in the results of the individual studies included in the main analyses were large, as suggested by funnel plot asymmetry. Conclusions: Based on the FMA, rTMS seems more beneficial only when started in the first month post-stroke. Tests at the level of function are likely more sensitive to detect beneficial rTMS effects on upper limb function than tests at the level of activity. However, heterogeneities in treatment designs and outcomes are high. Future rTMS trials should include the FMA and work toward a core set of outcome measures.

Project description:BackgroundThe recovery of upper extremity motor impairment after stroke remains a challenging task. The clinical effectiveness of repetitive transcranial magnetic stimulation (rTMS), which is believed to aid in the recovery process, is still uncertain.MethodsA systematic search was conducted in Medline (Ovid), Cochrane and Embase electronic databases from March 28, 2014, to March 28, 2023. The inclusion criteria consisted of randomized controlled trials that assessed the effects of rTMS on the recovery of upper limb motor impairment among stroke patients. Various measurements, including the Fugl Meyer Assessment Upper Extremity Scale (FMA-UE), Brunnstrom recovery stage, Action Research Arm Test (ARAT), and Barthel index, were evaluated both before and after the intervention.ResultsNineteen articles with 865 patients were included. When considering only the rTMS parameters, both inhibitory and excitatory rTMS improved FMA-UE (MD = 1.87, 95% CI = [0.88]-[2.86], p < 0.001) and Barthel index (MD = 9.73, 95% CI = [4.57]-[14.89], p < 0.001). When considering only the severity of upper limb hemiplegia, both less severe (MD = 1.56, 95% CI = [0.64]-[2.49], p < 0.001) and severe (MD = 2.05, 95% CI = [1.09]-[3.00], p < 0.001) hemiplegia benefited from rTMS based on FMA-UE. However, when considering the rTMS parameters, severity of hemiplegia and stroke stages simultaneously, inhibitory rTMS was found to be significantly effective for less severe hemiplegia in the acute and subacute phases (MD = 4.55, 95% CI = [2.49]-[6.60], p < 0.001), but not in the chronic phase based on FMA-UE. For severe hemiplegia, inhibitory rTMS was not significantly effective in the acute and subacute phases, but significantly effective in the chronic phase (MD = 2.10, 95% CI = [0.75]-[3.45], p = 0.002) based on FMA-UE. Excitatory rTMS was found to be significantly effective for less severe hemiplegia in the acute and subacute phases (MD = 1.93, 95% CI = [0.58]-[3.28], p = 0.005) based on FMA-UE. The improvements in Brunnstrom recovery stage and ARAT need further research.ConclusionThe effectiveness of rTMS depends on its parameters, severity of hemiplegia, and stroke stages. It is important to consider all these factors together, as any single grouping method is incomplete.

Project description:BackgroundRepetitive transcranial magnetic stimulation (rTMS) is a promising therapy to promote recovery of the upper limb after stroke. According to the regulation of cortical excitability, rTMS can be divided into excitatory rTMS and inhibitory rTMS, and excitatory rTMS includes high-frequency rTMS (HF-rTMS) or intermittent theta-burst stimulation (iTBS). We aimed to evaluate the effects of excitatory rTMS over the ipsilesional hemisphere on upper limb motor recovery after stroke.MethodsDatabases of PubMed, Embase, ISI Web of Science, and the Cochrane Library were searched for randomized controlled trials published before 31 December 2021. RCTs on the effects of HF-rTMS or iTBS on upper limb function in patients diagnosed with stroke were included. Two researchers independently screened the literature, extracted the data, and assessed quality. The meta-analysis was performed by using Review Manager Version 5.4 software.ResultsFifteen studies with 449 participants were included in this meta-analysis. This meta-analysis found that excitatory rTMS had significant efficacy on upper limb motor function (MD = 5.88, 95% CI, 3.32-8.43, P < 0.001), hand strength (SMD = 0.53, 95% CI, 0.04-1.01, P = 0.03), and hand dexterity (SMD = 0.76, 95% CI, 0.39-1.14, P < 0.001). Subgroup analyses based on different types of rTMS showed that both iTBS and HF-rTMS significantly promoted upper limb motor function (iTBS, P < 0.001; HF-rTMS, P < 0.001) and hand dexterity (iTBS, P = 0.01; HF-rTMS, P < 0.001) but not hand strength (iTBS, P = 0.07; HF-rTMS, P = 0.12). Further subgroup analysis based on the duration of illness demonstrated that applying excitatory rTMS during the first 3 months (<1 month, P = 0.01; 1-3 months, P = 0.001) after stroke brought significant improvement in upper limb motor function but not in the patients with a duration longer than 3 months (P = 0.06). We found that HF-rTMS significantly enhanced the motor evoked potential (MEP) amplitude of affected hemisphere (SMD = 0.82, 95% CI, 0.32-1.33, P = 0.001).ConclusionOur study demonstrated that excitatory rTMS over the ipsilesional hemisphere could significantly improve upper limb motor function, hand strength, and hand dexterity in patients diagnosed with stroke. Both iTBS and HF-rTMS which could significantly promote upper limb motor function and hand dexterity, and excitatory rTMS were beneficial to upper limb motor function recovery only when applied in the first 3 months after stroke. HF-rTMS could significantly enhance the MEP amplitude of the affected hemisphere. High-quality and large-scale randomized controlled trials in the future are required to confirm our conclusions.Clinical trial registrationwww.crd.york.ac.uk/prospero/, identifier: CRD42022312288.

Project description:BackgroundIt had been assumed that suppressing the undamaged contralesional motor cortex by repetitive low-frequency transcranial magnetic stimulation (rTMS) or increasing the excitability of the damaged hemisphere cortex by high-frequency rTMS will promote function recovery after stroke.ObjectivesTo assess the efficacy and safety of rTMS for improving function in people with stroke.Search methodsWe searched the Cochrane Stroke Group Trials Register (April 2012), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 4), the Chinese Stroke Trials Register (April 2012), MEDLINE (1950 to May 2012), EMBASE (1980 to May 2012), Science Citation Index (1981 to April 2012), Conference Proceedings Citation Index-Science (1990 to April 2012), CINAHL (1982 to May 2012), AMED (1985 to May 2012), PEDro (April 2012), REHABDATA (April 2012) and CIRRIE Database of International Rehabilitation Research (April 2012). In addition, we searched five Chinese databases, ongoing trials registers and relevant reference lists.Selection criteriaWe included randomised controlled trials comparing rTMS therapy with sham therapy or no therapy. We excluded trials that reported only laboratory parameters.Data collection and analysisTwo review authors independently selected trials, assessed trial quality and extracted the data. We resolved disagreements by discussion.Main resultsWe included 19 trials involving a total of 588 participants in this review. Two heterogenous trials with a total of 183 participants showed that rTMS treatment was not associated with a significant increase in the Barthel Index score (mean difference (MD) 15.92, 95% CI -2.11 to 33.95). Four trials with a total of 73 participants were not found to have a statistically significant effect on motor function (standardised mean difference (SMD) 0.51, 95% CI -0.99 to 2.01). Subgroup analyses of different stimulation frequencies or duration of illness also showed no significant difference. Few mild adverse events were observed in the rTMS groups, with the most common events being transient or mild headaches (2.4%, 8/327) and local discomfort at the site of the stimulation.Authors' conclusionsCurrent evidence does not support the routine use of rTMS for the treatment of stroke. Further trials with larger sample sizes are needed to determine a suitable rTMS protocol and the long-term functional outcome.

Project description:Background Repetitive transcranial magnetic stimulation (rTMS) is a promising intervention for stroke rehabilitation. Several studies have demonstrated the effectiveness of rTMS in restoring motor function. This meta-analysis aimed to summarize the current evidence of the effect of rTMS in improving upper limb function and fine motor recovery in stroke patients. Methods Three online databases (Web of Science, PubMed, and Embase) were searched for relevant randomized controlled trials. A total of 45 studies (combined n = 2064) were included. Random effects model was used for meta-analysis and effect size was reported as standardized mean difference (SMD). Results rTMS was effective in improving fine motor function in stroke patients (SMD, 0.38; 95% CI 0.19–0.58; P = 0). On subgroup analyses, for post-stroke functional improvement of the upper extremity, bilateral hemisphere stimulation was more effective than unilateral stimulation during the acute phase of stroke, and a regimen of 20 rTMS sessions produced greater improvement than <20 sessions. In the subacute phase of stroke, affected hemispheric stimulation with a 40-session rTMS regimen was superior to unaffected hemispheric stimulation or bilateral hemispheric stimulation with <40 sessions. Unaffected site stimulation with a 10-session rTMS regimen produced significant improvement in the chronic phase compared to affected side stimulation and bilateral stimulation with >10 rTMS sessions. For the rTMS stimulation method, both TBS and rTMS were found to be significantly more effective in the acute phase of stroke, but TBS was more effective than rTMS. However, rTMS was found to be more effective than TBS stimulation in patients in the subacute and chronic phases of stroke. rTMS significantly improved upper limb and fine function in the short term (0–1-month post-intervention) and medium term (2–5 months), but not for upper limb function in the long term (6 months+). The results should be interpreted with caution due to significant heterogeneity. Conclusions This updated meta-analysis provides robust evidence of the efficacy of rTMS treatment in improving upper extremity and fine function during various phases of stroke. Systematic Review Registration https://inplasy.com/inplasy-2022-5-0121/, identifier: INPLASY202250121.

Project description:ObjectiveThe purpose of this study was to examine long-term outcomes of nonpharmacological intervention in children and adolescents with stroke utilizing repetitive transcranial magnetic stimulation (rTMS) to the primary motor cortex combined with constraint- induced movement therapy (CIMT) to improve motor function in the paretic hand. Outcome measures included function, satisfaction, and medical status review.MethodsFourteen of the original 19 participants (74%) from our rTMS/CIMT clinical trial (real rTMS+CIMT, n = 8; and sham rTMS+CIMT, n = 6) were evaluated. The median age of the subjects at follow up was 13.4 years (range 11-20 years old, 50% male). Median time to follow-up was 47.5 months (range 21-57 months). Descriptive statistics were conducted using frequencies and counts. Motor performance was measured using the Assisting Hand Assessment (AHA) and Canadian Occupational Performance Measure (COPM). Satisfaction was reported with use of the COPM and TMS Tolerance Survey. Open-ended interview was conducted for feedback on study experience and subjective perspectives of current functional status.ResultsOverall, seven of eight individuals who received real rTMS and five of six individuals who received sham rTMS maintained or improved AHA scores. Six of 14 participants reported new onset of co-occurring conditions (four individuals in the real rTMS group, two individuals in the sham rTMS group). The majority (86%) of participants reported study satisfaction. Review of medical status revealed co-occurring conditions including: Epilepsy, obsessive-compulsive disorder, anxiety, depression, unspecified mood disorder, and undiagnosed inattentiveness.ConclusionsLong-term outcomes of rTMS/CIMT in pediatric stroke were investigated. Variability in performance and unattributed symptoms were noted. Considering the prevalence of co-occurring conditions in children and adolescents with stroke, new-onset symptoms were not attributed to original intervention. With the small sample size, the impact of rTMS on long-term outcomes cannot be fully determined from these data. Characterizing long-term outcomes through performance, participant perspectives, and medical status allows comprehensive assessment of rTMS/CIMT intervention efficacy.

Project description:Background Transcranial magnetic stimulation (TMS) treatments have shown promise in improving arm recovery in stroke patients. Currently, little is known about patients’ experiences with repetitive TMS treatment, and this lack of knowledge may affect optimal implementation in clinical practice. The aim of this explorative study was to gain insight in the perceived effects and experiences of the design and delivery of a rTMS treatment for upper limb recovery from the perspectives of stroke patients. Methods This qualitative study was conducted as part of a randomized controlled trial (RCT) in a specialized rehabilitation center. Data were collected through face-to-face semi-structured interviews with 13 stroke patients who completed a 10-day rTMS intervention for upper limb recovery. The interviews were recorded, transcribed verbatim and analyzed using thematic analysis. Results The major themes that emerged from the patients’ feedback were the following: positive experiences of the treatment (experienced physical effects, comfort, therapeutic relationship, receiving information, learning about the brain, no burden of added rTMS treatment session, no unpleasant aspects), concerns (effects of stimulation of the brain, equipment, logistics), general experience of recovery, experienced psychological effects (grateful, sense of purpose, recovery as extra motivation to exercise, disappointment and hope of group allocation), and motivation to participate (personal benefit and cognitions, altruism). Important components related to the positive experience of the design and delivery of the treatment included comfort (i.e. moment of relaxation) and the sensation of a painless treatment without side-effects. Key concerns included uncertainty and anxiety about possible negative consequences and group allocation. Conclusions This study demonstrates that rTMS is well accepted by stroke patients with an upper limb paresis. Besides the expectation of a therapeutic benefit, the patients reported various psychological effects. Positive experiences, such as the provision of a short moment of relaxation each day, could have practical implications for clinical stroke rehabilitation settings aimed at improving patient satisfaction. Explanation about and feedback from routine motor recovery progression monitoring at fixed times post-stroke is also valued by patients. Negative emotions may be limited or avoided by transparent and recurrent information delivery in future trials.

Project description:IntroductionRepetitive transcranial magnetic stimulation (rTMS) is an evidence-based treatment widely recommended to promote hand motor recovery after ischaemic stroke. However, the therapeutic efficacy of rTMS over the motor cortex in stroke patients is currently restricted and heterogeneous. This study aimed to determine whether excitatory rTMS over the contralesional dorsal premotor cortex (cPMd) facilitates the functional recovery of the upper limbs during the postacute stage of severe ischaemic stroke.Methods and analysisThis study will be conducted as a single-blind, controlled, randomised study, in which 44 patients with poststroke hemiplegia with a course of disease ranging from 1 week to 3 months and Fugl-Meyer upper limb score ≤22 will be enrolled. The study participants will be randomly assigned to groups A (n=22) and B (n=22). The two groups are based on routine rehabilitation training and drug treatment; group A will be treated with low-frequency (1 Hz) rTMS over the contralesional primary motor cortex (cM1), and group B will be treated with high-frequency (10 Hz) rTMS over cPMd. For 2 weeks, rTMS will be administered once a day, 5 days a week. The primary outcome is the Fugl-Meyer assessment of the upper limb. The secondary outcomes include the Arm Subscore of the Motricity Index, Hong Kong edition of Functional Test for the Hemiplegic Upper Extremity, Modified Barthel Index and Modified Ashworth Scale score of the paralysed pectoralis major and biceps brachii. Furthermore, data of diffusion tensor imaging and functional MRI will be collected. These outcomes will be assessed before and after the completion of the intervention.Ethics and disseminationThis study has been approved by the Ethics Committee of the First Affiliated Hospital of Nanjing Medical University (2020 SR-266). The findings of this study will be spread through networks of scientists, professionals and the general public as well as peer-reviewed scientific papers and presentations at pertinent conferences.Trial registration numberChiCTR2000038049.

Dataset Information

Role of Brain-Derived Neurotrophic Factor in Beneficial Effects of Repetitive Transcranial Magnetic Stimulation for Upper Limb Hemiparesis after Stroke.

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Role of Brain-Derived Neurotrophic Factor in Beneficial Effects of Repetitive Transcranial Magnetic Stimulation for Upper Limb Hemiparesis after Stroke.

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