Restricted accessResearch articleFirst published online 2026
Feasibility,safety,and preliminary efficacy of intermittent theta burst stimulation combined with task-oriented training in subacute stroke: A pilot randomized controlled trial
Upper limb motor impairment after stroke is a leading cause of long-term disability. This single-center pilot randomized controlled trial (RCT) evaluated the safety, feasibility, and preliminary efficacy of intermittent theta-burst stimulation (iTBS) combined with task-oriented training (TOT) for upper limb rehabilitation. iTBS, a non-invasive brain stimulation technique, may enhance recovery when paired with task-oriented training (TOT), particularly in the subacute phase of heightened neuroplasticity.
Methods
Twenty-nine patients with subacute stroke were randomized into three groups: (1) iTBS + TOT (n = 10), (2) sham iTBS + TOT (n = 9), and (3) traditional physiotherapy (n = 10). All underwent a 4-week intervention. Primary outcomes were safety and feasibility. Secondary outcomes included motor impairment (Fugl-Meyer Assessment for Upper Extremity, FMA-UE), functional independence (Modified Barthel Index, MBI), and neurological deficit (National Institutes of Health Stroke Scale, NIHSS), assessed at baseline, week 2, and week 4.
Results
Twenty-nine participants completed the trial without any adverse events, and one participant from Group 2 discontinued early due to discharge. At week 4, the iTBS + TOT group showed greater improvements in FMA-UE (22.9 points vs. 3.6 and 10.2; p = 0.013; p = 0.013), NIHSS (3.0 vs 6.6; p = 0.009), and MBI (90.7 vs 51.4; p < 0.001) compared with controls, indicating potential functional benefits.
Conclusions
This exploratory pilot RCT suggests that combining iTBS with TOT is safe and feasible, with preliminary evidence supporting its potential to improve upper limb recovery in subacute stroke. However, these findings should be interpreted with caution and validated in larger, adequately powered trials.
MartinSSAdayAWAlmarzooqZI. 2024 Heart disease and stroke statistics: a report of US and global data from the American Heart Association. Circulation2024; 149: e347–e913.
2.
AboMKakudaWMomosakiR. Randomized, multicenter, comparative study of NEURO versus CIMT in poststroke patients with upper limb hemiparesis: the NEURO-VERIFY study. Int J Stroke2014; 9: 607–612.
3.
RoseDKPattenCMcGuirkTE. Does inhibitory repetitive transcranial magnetic stimulation augment functional task practice to improve arm recovery in chronic stroke?Stroke Res Treat2014; 2014: 305236.
4.
WangCPTsaiPYYangTF. Differential effect of conditioning sequences in coupling inhibitory/facilitatory repetitive transcranial magnetic stimulation for poststroke motor recovery. CNS Neurosci Ther2014; 20: 355–363.
5.
KwakkelGKollenBTwiskJ. Impact of time on improvement of outcome after stroke. Stroke2006; 37: 2348–2353.
6.
KwakkelG. Impact of intensity of practice after stroke: issues for consideration. Disabil Rehabil2006; 28: 823–830.
7.
MuraseNDuqueJMazzocchioR. Influence of interhemispheric interactions on motor function in chronic stroke. Ann Neurol2004; 55: 400–409.
8.
VallejoPCuevaEMartínez-LozadaP. Repetitive transcranial magnetic stimulation in stroke: a literature review of the current role and controversies of neurorehabilitation through electromagnetic pulses. Cureus2023; 15: e0000.
9.
WinsteinCJSteinJArenaR. Guidelines for adult stroke rehabilitation and recovery: a guideline for healthcare professionals from the American Heart Association/American stroke association. Stroke2016; 47: e98–e169.
10.
KwakkelGKollenB. Predicting activities after stroke: what is clinically relevant?Int J Stroke2013; 8: 25–32.
11.
BoydLAHaywardKSWardNS. Biomarkers of stroke recovery: consensus-based core recommendations from the stroke recovery and rehabilitation roundtable. Int J Stroke2017; 12: 480–493.
12.
RiddingMCRothwellJC. Is there a future for therapeutic use of transcranial magnetic stimulation?Nat Rev Neurosci2007; 8: 559–567.
13.
AvenantiACocciaMLadavasE. Low-frequency rTMS promotes use-dependent motor plasticity in chronic stroke: a randomized trial. Neurology2012; 78: 256–264.
14.
KakudaWAboMSasanumaJ. Combination protocol of low-frequency rTMS and intensive occupational therapy for post-stroke upper limb hemiparesis: a 6-year experience of more than 1700 Japanese patients. Transl Stroke Res2016; 7: 172–179.
15.
HuangYXiaXMengX. Single session of intermittent theta burst stimulation alters brain activity of patients in vegetative state. Aging (Albany NY)2024; 16: 7119–7128.
16.
KanRLZhangBBLinTT. Sex differences in brain excitability revealed by concurrent iTBS/fNIRS. Asian J Psychiatry2024; 96: 104043.
17.
CirsteaCMPtitoALevinMF. Feedback and cognition in arm motor skill reacquisition after stroke. Stroke2006; 37: 1237–1242.
18.
KleimJAJonesTA. Principles of experience-dependent neural plasticity: implications for rehabilitation after brain damage. J Speech Lang Hear Res2008; 51: S225–S239.
19.
TakeuchiNIzumiS. Rehabilitation with poststroke motor recovery: a review with a focus on neural plasticity. Stroke Res Treat2013; 2013: 128641.
20.
RensinkMSchuurmansMLindemanE. Task-oriented training in rehabilitation after stroke: systematic review. J Adv Nurs2009; 65: 737–754.
21.
TimmermansAASpoorenAIKingmaH. Influence of task-oriented training content on skilled arm-hand performance in stroke: a systematic review. Neurorehabil Neural Repair2010; 24: 858–870.
22.
BowdenMGWoodburyMLDuncanPW. Promoting neuroplasticity and recovery after stroke: future directions for rehabilitation clinical trials. Curr Opin Neurol2013; 26: 37–42.
23.
BoschJO’DonnellMJBarrecaS. Does task-oriented practice improve upper extremity motor recovery after stroke? A systematic review. Int Sch Res Notices2014; 2014: 504910.
24.
BologniniNPascual-LeoneAFregniF. Using non-invasive brain stimulation to augment motor training-induced plasticity. J Neuroeng Rehabil2009; 6. doi:10.1186/1743-0003-6-8
25.
AderintoNOlatunjiGKokoriE. Clinical applications of non-invasive brain stimulation in stroke recovery: a review of current evidence and therapeutic strategies. Curr Treat Options Neurol2025; 27: 8.
26.
StraudiSAhmedIVallinE. The effectiveness of noninvasive brain stimulation techniques combined with motor interventions in adult patients after stroke: an overview of systematic reviews. Neuromodulation Technol Neural Interface2025; 28: 1104–1117.
27.
SchulzKFAltmanDGMoherD. CONSORT 2010 Statement: updated guidelines for reporting parallel group randomized trials. BMC Med2010; 8: 18.
28.
HuangYZEdwardsMJRounisE. Theta burst stimulation of the human motor cortex. Neuron2005; 45: 201–206.
29.
HuangYZLuCSRothwellJC. Modulation of the disturbed motor network in dystonia by multisession suppression of premotor cortex. PLoS One2012; 7: e47574.
30.
TalelliPGreenwoodRJRothwellJC. Exploring theta burst stimulation as an intervention to improve motor recovery in chronic stroke. Clin Neurophysiol2007; 118: 333–342.
31.
AckerleySJStinearCMBarberPA. Combining theta burst stimulation with training after subcortical stroke. Stroke2010; 41: 1568–1572.
32.
FengYZhangJJZhuJ. Does intermittent theta burst stimulation improve working memory capacity? A randomized controlled cross-over experiment. Behav Brain Res2023; 436: 114086.
33.
LisanbySHGutmanDLuberB. Sham TMS: intracerebral measurement of the induced electrical field and the induction of motor-evoked potentials. Biol Psychiatry2001; 49: 460–463.
34.
BirkenmeierRLLangCE. Upper-extremity task-specific training after stroke or disability. Bethesda: AOTA Press, 2013, pp.1–200.
35.
ThantAAWanpenSNualnetrN. Effects of task-oriented training on upper extremity functional performance in patients with subacute stroke: a randomized controlled trial. J Phys Ther Sci2019; 31: 82–87.
36.
KhanFRathoreCKateM. The comparative efficacy of theta burst stimulation or functional electrical stimulation when combined with physical therapy after stroke: a randomized controlled trial. Clin Rehabil2019; 33: 693–703.
37.
PollockABaerGCampbellP. Physical rehabilitation approaches for the recovery of function and mobility following stroke. Cochrane Database Syst Rev2014; 2014: CD001920.
38.
ICH Harmonisation. Guideline for good clinical practice E6 (R1). ICH Harmon Tripart Guidel1996; 4: 1–30.
39.
KimWSPaikNJ. Safety review for clinical application of repetitive transcranial magnetic stimulation. Brain Neurorehabil2021; 14: e1–e8.
40.
Fugl-MeyerARJääsköLLeymanI. A method for evaluation of physical performance. Scand J Rehabil Med1975; 7: 13–31.
41.
SullivanKJTilsonJKSYC. Fugl-Meyer assessment of sensorimotor function after stroke: standardized training procedure for clinical practice and clinical trials. Stroke2011; 42: 427–432.
42.
SeeJDodakianLChouC. A standardized approach to the Fugl-Meyer assessment and its implications for clinical trials. Neurorehabil Neural Repair2013; 27: 732–741.
43.
PlatzTPinkowskiCvan WijckF. Reliability and validity of arm function assessment with standardized guidelines for the Fugl-Meyer test, action research arm test and box and block test: a multicentre study. Clin Rehabil2005; 19: 404–411.
44.
WoodburyMLVelozoCARichardsLG. Longitudinal stability of the Fugl-Meyer assessment of the upper extremity. Arch Phys Med Rehabil2008; 89: 1563–1569.
45.
HiragamiSInoueYHaradaK. Minimal clinically important difference for the Fugl-Meyer assessment of the upper extremity in convalescent stroke patients with moderate to severe hemiparesis. J Phys Ther Sci2019; 31: 917–921.
46.
ShahSVanclayFCooperB. Improving the sensitivity of the Barthel Index for stroke rehabilitation. J Clin Epidemiol1989; 42: 703–709.
47.
HsiehYWWangCHWuSC. Establishing the minimal clinically important difference of the Barthel Index in stroke patients. Neurorehabil Neural Repair2007; 21: 233–238.
48.
BrottTAdamsHPOlingerCP. Measurements of acute cerebral infarction: a clinical examination scale. Stroke1989; 20: 864–870.
49.
LydenPBrottTTilleyB. Improved reliability of the NIH stroke scale using video training. Stroke1994; 25: 2220–2226.
50.
SucharewHKhouryJMoomawCJ. Profiles of the national institutes of health stroke scale items as a predictor of patient outcome. Stroke2013; 44: 2182–2187.
51.
YuanRQiaoXTangC. Effects of uni- vs. bilateral upper limb robot-assisted rehabilitation on motor function, activities of daily living, and electromyography in hemiplegic stroke: a single-blinded three-arm randomized controlled trial. J Clin Med2023; 12: 2950.
52.
DoddKCNairVAPrabhakaranV. Role of the contralesional vs. ipsilesional hemisphere in stroke recovery. Front Hum Neurosci2017; 11: 69.
53.
DingQZhangSChenS. The effects of intermittent theta burst stimulation on functional brain network following stroke: an electroencephalography study. Front Neurosci2021; 15: 755709.
54.
SilversteinJCortesMTsagarisKZ. Paired associative stimulation as a tool to assess plasticity enhancers in chronic stroke. Front Neurosci2019; 13: 92.
55.
BjørndalJRBeckMMJespersenL. Hebbian priming of human motor learning. Nat Commun2024; 15: 5126.
56.
BallesterBRMaierMDuffA. A critical time window for recovery extends beyond one-year post-stroke. J Neurophysiol2019; 122: 350–357.
57.
ChenYJHuangYZChenCY. Intermittent theta burst stimulation enhances upper limb motor function in patients with chronic stroke: a pilot randomized controlled trial. BMC Neurol2019; 19: 69.
58.
GaoBWangYZhangD. Intermittent theta-burst stimulation with physical exercise improves poststroke motor function: a systematic review and meta-analysis. Front Neurol2022; 13: 964627.
59.
LefaucheurJPAlemanABaekenC. Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS): an update (2014–2018). Clin Neurophysiol2020; 131: 474–528.
60.
LiewSLSantarnecchiEBuchER, et al.Non-invasive brain stimulation in neurorehabilitation: local and distant effects for motor recovery. Front Hum Neurosci2014; 8: 78.
61.
ChenYHChenCLHuangYZ. Augmented efficacy of intermittent theta burst stimulation on the virtual reality-based cycling training for upper limb function in patients with stroke: a double-blinded randomized controlled trial. J Neuroeng Rehabil2021; 18: 91.
62.
ZhangJJBaiZFongKNK. Priming intermittent theta burst stimulation for hemiparetic upper limb after stroke: a randomized controlled trial. Stroke2022; 53: 2171–2181.
63.
HsuYFHuangYZLinYY. Intermittent theta burst stimulation over ipsilesional primary motor cortex of subacute ischemic stroke patients: a pilot study. Brain Stimul2013; 6: 166–174.
64.
ChenSZhangSYangW. The effectiveness of intermittent theta burst stimulation for upper limb motor recovery after stroke: a systematic review and meta-analysis of randomized controlled trials. Front Neurosci2023; 17: 1272003.
