Transcranial Magnetic Stimulation for Poststroke Motor Recovery: What We Have Learned.

HomeStrokeVol. 54, No. 8Transcranial Magnetic Stimulation for Poststroke Motor Recovery: What We Have Learned Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBTranscranial Magnetic Stimulation for Poststroke Motor Recovery: What We Have Learned Wuwei Feng, Ela B. Plow and Nam-Jong Paik Wuwei FengWuwei Feng Correspondence to: Wuwei “Wayne” Feng, MD, MS, Department of Neurology, Duke University School of Medicine, Durham, NC, 27710. Email E-mail Address: [email protected] https://orcid.org/0000-0001-6230-4905 Department of Neurology, Duke University School of Medicine, Durham, NC (W.F.). Search for more papers by this author , Ela B. PlowEla B. Plow Lerner Research Institute, Cleveland Clinic, Cleveland Clinic Rehabilitation Hospitals, OH (E.B.P.). Search for more papers by this author and Nam-Jong PaikNam-Jong Paik https://orcid.org/0000-0002-5193-8678 Department of Rehabilitation Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Korea (N.-J.P.). Search for more papers by this author Originally published22 Jun 2023https://doi.org/10.1161/STROKEAHA.123.043536Stroke. 2023;54:1972–1973This article is a commentary on the followingContinuous Theta-Burst Stimulation of the Contralesional Primary Motor Cortex for Promotion of Upper Limb Recovery After Stroke: A Randomized Controlled TrialOther version(s) of this articleYou are viewing the most recent version of this article. Previous versions: June 22, 2023: Ahead of Print See related article, p 1962Motor impairment is the most common complication after stroke that negatively affects the quality of life of stroke survivors. Based on the poststroke interhemispheric imbalance model, using repetitive transcranial magnetic stimulation, a noninvasive brain stimulation tool to either stimulate the ipsilesional hemisphere with excitatory paradigm or stimulate the contralesional hemisphere with inhibitory paradigm has been attempted in the last 2 decades with variable results.1,2We have a win this time. Vink et al3 conducted a single-center phase II clinical trial in the Netherlands that randomized 60 stroke patients (including both ischemic and hemorrhagic stroke types) into sham stimulation (10% of resting motor threshold) versus active continuous theta burst stimulation (70% of resting motor threshold) over the contralesional motor cortex, along with regular rehabilitation therapy over 10 sessions in the subacute phase (about 2 weeks after stroke onset). Although included stroke patients were at moderate-to-severe impairment level (average baseline Fugl-Meyer Upper-Extremity score is 25.6), it was not clear to us whether those patients had preserved corticospinal tract (descending motor pathway) or not, because, per inclusion criteria, not everyone could extend one or more fingers. The stimulation to the contralesional motor cortex was only 40 seconds followed by a subsequent 60-minute rehabilitation therapy.The study results are quite exciting and robust. The mean difference of changes score between the 2 groups for the Action Research Arm Test (a measure of motor function) is 9.6 (95% CI, 1.2–17.9; P=0.0244), which exceeds the typical minimal clinically important difference of 5.7 points.4 Furthermore, the mean difference of changes score between the 2 groups for the Fugl-Meyer Upper-Extremity score (a measure of motor impairment) at 3 months is 9.1 points (95% CI, 1.5–16.7; P=0.0196), which also beats the typical minimal clinically important difference ranging from 4.25 to 7.25.5 It also leads to a significant difference in Stroke-Impact Scale-Upper Extremity (a measure of quality of life) of 4.3 (95% CI, 1.4–7.2; P=0.0041). In addition, there is a significant statistical separation in global function improvement between the 2 groups: the mean difference of modified Rankin Scale score at day 90 is 0.2 (95% CI, 0.05–0.79; P=00225). It has been demonstrated that a change of ≥9 points on Fugl-Meyer Upper-Extremity score is correlated with perceived improvement on the disability level by stroke patients.6 It is worthy to note that 40 seconds of theta burst stimulation not only is inexpensive but also is safe and tolerable, except the active stimulation incurs relatively more headache, which is expected and not surprising (3.58% versus 0.98%; P=0.03).This is the only repetitive transcranial magnetic stimulation stroke motor recovery study to demonstrate that active stimulation exceeds sham stimulation in all outcome domains both statistically and clinically, with meaningful improvements in motor impairment, motor function, and quality of life—all positive signs that stroke patients truly improve with such brain stimulation treatment. It is important to point out that future stroke recovery studies should have end points measuring all 3 aspects of motor recovery, such as those used in this study. Other strengths of the study include conducting the trial in the inpatient rehabilitation setting, having outcome measures extended to 1-year postintervention, providing evidence of dissociation of improvement across a variety of functional and participation scales recommended by the World Health Organization.We have learned a few things from this positive study as well as other brain stimulation and nonstimulation stroke recovery studies in the past. Contralesional hemispheric overactivation is likely compensational, rather than a consequence of poor recovery after stroke; and it likely occurs in the acute and subacute phase, then normalizes in the chronic phase.7 If we also consider that the sensitive recovery window and dynamic plasticity in human stroke likely are in the subacute phase,8 then brain stimulation studies should be implemented in the subacute phase. This study is indeed conducted in the subacute phase. Two transcranial magnetic stimulation studies demonstrated that patients with subcortical infarct in the subacute phase appeared are more likely to respond to the stimulation.9,10 This study provides further support for the interhemispheric imbalance theory or rivalry theory, indicating that inhibitory stimulation over the contralesional hemisphere is a reasonable approach. The time window during which this inhibitory effect should be targeted and harnessed is another critical factor.11,12Although the authors fully acknowledge the limitations of this exciting study, several deserve further attention and discussion. One major lost opportunity is that the authors did not evaluate the interhemispheric balance before or after the intervention. Single-center proof-of-concept study typically is embedded with mechanistic aims to better understand the underlying recovery process; however, the study team collected comprehensive behavioral and clinical outcomes without collecting any neuroimaging or neurophysiological data (ie, presence of motor-evoked potentials or not measured by single-pulse transcranial magnetic stimulation). A contemporary theory of stroke motor recovery and related evidence indicates that an inhibitory or a compensatory tone is also dependent on the degree of the structural reserve available. This can have a major implication in patient selection and identifying responders for future brain stimulation studies. In addition, it is not clear whether the group has established outcome assessment standardization through this study, which is another critical factor for the success of future multicenter studies to confirm the positive results from this single-center study.13 Reproducibility of therapeutic effects is as important (if not more important) as milestones for evidence of a positive therapeutic effect. Frequently, a positive effect witnessed in 1 study can be difficult to replicate in a multisite trial setting; therefore, rigor-based standardization of outcome assessments and double blinding are critical to advance the stroke recovery field. We hope the authors take into consideration these factors outlined above when designing the next study.Disclosures Dr Paik receives a grant from REMED and is currently leading a clinical trial (URL: https://www.clinicaltrials.gov; Unique identifier: NCT05535504) to obtain Korean Food Drug and Administration approval for the use of repetitive transcranial magnetic stimulation in subacute stroke patients with subcortical lesions. The other authors report no conflicts.FootnotesFor Disclosures, see page 1972.The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to: Wuwei “Wayne” Feng, MD, MS, Department of Neurology, Duke University School of Medicine, Durham, NC, 27710. Email wayne.feng@duke.eduREFERENCES1. Nowak DA, Grefkes C, Ameli M, Fink GR. Interhemispheric competition after stroke: brain stimulation to enhance recovery of function of the affected hand.Neurorehabil Neural Repair. 2009; 23:641–656. doi: 10.1177/1545968309336661CrossrefMedlineGoogle Scholar2. Bai Z, Zhang J, Fong KNK. Effects of transcranial magnetic stimulation in modulating cortical excitability in patients with stroke: a systematic review and meta-analysis.J Neuroeng Rehabil. 2022; 19:24. doi: 10.1186/s12984-022-00999-4CrossrefGoogle Scholar3. Vink JJT, van Lieshout ECC, Ottea WM, van Eijk RPA, Kouwenhoven M, Neggers SFW, van der Worp HB, Visser-Meily JMA, Dijkhuizen RM. Continuous theta-burst stimulation of the contralesional primary motor cortex for promotion of upper limb recovery after stroke: an randomized controlled trial.Stroke. 2023; 54:1962–1971. doi: 10.1161/STROKEAHA.123.042924LinkGoogle Scholar4. Van der Lee JH, De Groot V, Beckerman H, Wagenaar RC, Lankhorst GJ, Bouter LM. The intra- and interrater reliability of the action research arm test: a practical test of upper extremity function in patients with stroke.Arch Phys Med Rehabil. 2001; 82:14–19. doi: 10.1053/apmr.2001.18668CrossrefMedlineGoogle Scholar5. Page SJ, Fulk GD, Boyne P. Clinically important differences for the upper-extremity Fugl-Meyer Scale in people with minimal to moderate impairment due to chronic stroke.Phys Ther. 2012; 92:791–798. doi: 10.2522/ptj.20110009CrossrefMedlineGoogle Scholar6. Arya KN, Verma R, Garg RK. Estimating the minimal clinically important difference of an upper extremity recovery measure in subacute stroke patients.Top Stroke Rehabil. 2011; 18(Suppl 1):599–610. doi: 10.1310/tsr18s01-599CrossrefMedlineGoogle Scholar7. Xu J, Branscheidt M, Schambra H, Steiner L, Widmer M, Diedrichsen J, Goldsmith J, Lindquist M, Kitago T, Luft AR, et al; SMARTS Study Group. Rethinking interhemispheric imbalance as a target for stroke neurorehabilitation.Ann Neurol. 2019; 85:502–513. doi: 10.1002/ana.25452CrossrefGoogle Scholar8. Dromerick AW, Geed S, Barth J, Brady K, Giannetti ML, Mitchell A, Edwardson MA, Tan MT, Zhou Y, Newport EL, et al. Critical Period After Stroke Study (CPASS): a phase II clinical trial testing an optimal time for motor recovery after stroke in humans.Proc Natl Acad Sci U S A. 2021; 118:e2026676118. doi: 10.1073/pnas.2026676118CrossrefGoogle Scholar9. Harvey RL, Edwards D, Dunning K, Fregni F, Stein J, Laine J, Rogers LM, Vox F, Durand-Sanchez A, Bockbrader M, et al; NICHE Trial Investigators *. Randomized sham-controlled trial of navigated repetitive transcranial magnetic stimulation for motor recovery in stroke.Stroke. 2018; 49:2138–2146. doi: 10.1161/STROKEAHA.117.020607LinkGoogle Scholar10. Kim WS, Kwon BS, Seo HG, Park J, Paik NJ. Low-frequency repetitive transcranial magnetic stimulation over contralesional motor cortex for motor recovery in subacute ischemic stroke: a randomized sham-controlled trial.Neurorehabil Neural Repair. 2020; 34:856–867. doi: 10.1177/1545968320948610CrossrefGoogle Scholar11. Di Pino G, Pellegrino G, Assenza G, Capone F, Ferreri F, Formica D, Ranieri F, Tombini M, Ziemann U, Rothwell JC, et al. Modulation of brain plasticity in stroke: a novel model for neurorehabilitation.Nat Rev Neurol. 2014; 10:597–608. doi: 10.1038/nrneurol.2014.162CrossrefMedlineGoogle Scholar12. Lin YL, Potter-Baker KA, Cunningham DA, Li M, Sankarasubramanian V, Lee J, Jones S, Sakaie K, Wang X, Machado AG, et al. Stratifying chronic stroke patients based on the influence of contralesional motor cortices: an inter-hemispheric inhibition study.Clin Neurophysiol. 2020; 131:2516–2525. doi: 10.1016/j.clinph.2020.06.016CrossrefGoogle Scholar13. See J, Dodakian L, Chou C, Chan V, McKenzie A, Reinkensmeyer DJ, Cramer SC. A standardized approach to the Fugl-Meyer assessment and its implications for clinical trials.Neurorehabil Neural Repair. 2013; 27:732–741. doi: 10.1177/1545968313491000CrossrefMedlineGoogle Scholar eLetters(0)eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. 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