To compare the therapeutic effect of intermittent theta burst stimulation (iTBS) and repetitive transcranial magnetic stimulation (rTMS) on cognitive function in patients with post-stroke cognitive impairment (PSCI) and investigate underlying neuroelectrophysiological mechanisms using microstate analysis.
Methods:
In this randomized, double-blind, sham-controlled trial, 45 patients with PSCI were assigned 2:2:1 to iTBS, rTMS, and sham groups, with stimulation targeting the left dorsolateral prefrontal cortex. All participants also received therapist-delivered cognitive training in addition to stimulation. Outcomes were evaluated before (T0) and 10 days after (T1). The primary outcome measure was Montreal Cognitive Assessment (MoCA) score. Secondary outcomes were auditory verbal learning test, Wechsler Adult Intelligence Scale-Ⅲ digit symbol coding test and digit span test scores as well as microstate indices.
Results:
ΔMoCA(T1-T0) scores were significantly improved in both the iTBS (median [interquartile range]: 2.00 [1.00, 4.00]) and rTMS groups (2.00 [1.00, 3.00]) compared with sham group (P < .05). There was no significant difference in ΔMoCA between the 2 active protocols. Significant within-group improvements in memory and working memory were observed in the iTBS group (P < .05). Both iTBS and rTMS group showed significantly increased microstate C parameters between T0 and T1 (P < .05). Furthermore, the transition probabilities in the iTBS group showed more diversity between microstates, while the other groups showed no significant transformation.
Conclusion:
iTBS and 5-Hz rTMS were effective in improving overall cognitive ability in PSCI, and iTBS may represent a practical, time-efficient alternative to 5-Hz rTMS. EEG microstate suggested distinct modulation patterns, serving as a useful exploratory tool.
Clinical Trial Registry Name:
Effect of different transcranial magnetic stimulation protocols on cognitive function in patients with post-stroke cognitive impairment.
DingMYXuYWangYZ, et al. Predictors of cognitive impairment after stroke: a prospective stroke cohort study. J Alzheimers Dis. 2019;71(4):1139-1151. doi:10.3233/jad-190382
2.
CarlsonMCXueQLZhouJFriedLP.Executive decline and dysfunction precedes declines in memory: the Women’s Health and Aging Study II. J Gerontol A Biol Sci Med Sci. 2009;64(1):110-117. doi:10.1093/gerona/gln008
3.
ObaidMFlachCMarshallIDAWCDouiriA.Long-term outcomes in stroke patients with cognitive impairment: a population-based study. Geriatrics. 2020;5(2):32. doi:10.3390/geriatrics5020032
4.
KobayashiMPascual-LeoneA.Transcranial magnetic stimulation in neurology. Lancet Neurol. 2003;2(3):145-156. doi:10.1016/s1474-4422(03)00321-1
5.
FitzsimmonsSOostraEPostmaTSvan der WerfYDvan den HeuvelOA.Repetitive transcranial magnetic stimulation-induced neuroplasticity and the treatment of psychiatric disorders: state of the evidence and future opportunities. Biol Psychiatry. 2024;95(6):592-600. doi:10.1016/j.biopsych.2023.11.016
6.
HaraTShanmugalingamAMcIntyreABurhanAM.The effect of non-invasive brain stimulation (NIBS) on attention and memory function in stroke rehabilitation patients: a systematic review and meta-analysis. Diagnostics. 2021;11(2):227. doi:10.3390/diagnostics11020227
7.
WuXJiGJGengZ, et al. Accelerated intermittent theta-burst stimulation broadly ameliorates symptoms and cognition in Alzheimer’s disease: a randomized controlled trial. Brain Stimul. 2022;15(1):35-45. doi:10.1016/j.brs.2021.11.007
8.
AghamoosaSLopezJRbeizK, et al. A phase I trial of accelerated intermittent theta burst rTMS for amnestic MCI. J Neurol Neurosurg Psychiatry. 2024;95(11):1036-1045. doi:10.1136/jnnp-2023-332680
9.
HeWWangJCTsaiPY.Theta burst magnetic stimulation improves Parkinson’s-related cognitive impairment: a randomised controlled study. Neurorehabil Neural Repair. 2021;35(11):986-995. doi:10.1177/1545968321104131
10.
LefaucheurJPAlemanABaekenC, et al. Corrigendum to “evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS): an update (2014-2018)” [Clin. Neurophysiol. 131 (2020) 474-528]. Clin Neurophysiol. 2020;131(5):1168-1169. doi:10.1016/j.clinph.2020.02.003
11.
NowakDABöslKPodubeckàJCareyJR.Noninvasive brain stimulation and motor recovery after stroke. Restor Neurol Neurosci. 2010;28(4):531-544. doi:10.3233/rnn-2010-0552
12.
DaoudAElsayedMAlnajjarAZ, et al. Efficacy of intermittent theta burst stimulation (iTBS) on post-stroke cognitive impairment (PSCI): a systematic review and meta-analysis. Neurol Sci. 2024;45(5):2107-2118. doi:10.1007/s10072-023-07267-w
13.
WuXWangLGengZ, et al. Improved cognitive promotion through accelerated magnetic stimulation. eNeuro. 2021;8(1):ENEURO.0392-20.2020. doi:10.1523/eneuro.0392-20.2020
14.
YanYTianMWangTWangXWangYShiJ.Transcranial magnetic stimulation effects on cognitive enhancement in mild cognitive impairment and Alzheimer’s disease: a systematic review and meta-analysis. Front Neurol. 2023;14:1209205. doi:10.3389/fneur.2023.1209205
15.
KhannaAPascual-LeoneAFarzanF.Reliability of resting-state microstate features in electroencephalography. PLoS ONE. 2014;9(12):e114163. doi:10.1371/journal.pone.0114163
16.
KleinertTKoenigTNashKWascherE.On the reliability of the EEG microstate approach. Brain Topogr. 2024;37(2):271-286. doi:10.1007/s10548-023-00982-9
17.
MoherDHopewellSSchulzKF, et al. CONSORT 2010 explanation and elaboration: updated guidelines for reporting parallel group randomised trials. Int J Surg. 2012;10(1):28-55. doi:10.1016/j.ijsu.2011.10.001
18.
EinstadMSSaltvedtILydersenS, et al. Associations between post-stroke motor and cognitive function: a cross-sectional study. BMC Geriatr. 2021;21(1):103. doi:10.1186/s12877-021-02055-7
19.
PagaliSRKumarRLeMahieuAM, et al. Efficacy and safety of transcranial magnetic stimulation on cognition in mild cognitive impairment, Alzheimer’s disease, Alzheimer’s disease-related dementias, and other cognitive disorders: a systematic review and meta-analysis. Int Psychogeriatr. 2024;36(10):880-928. doi:10.1017/s1041610224000085
20.
TorresIJGeRMcGirrA, et al. Effects of intermittent theta-burst transcranial magnetic stimulation on cognition and hippocampal volumes in bipolar depression. Dialogues Clin Neurosci. 2023;25(1):24-32. doi:10.1080/19585969.2023.2186189
21.
RossiniPMBurkeDChenR, et al. Non-invasive electrical and magnetic stimulation of the brain, spinal cord, roots and peripheral nerves: basic principles and procedures for routine clinical and research application. An updated report from an I.F.C.N. Committee. Clin Neurophysiol. 2015;126(6):1071-1107. doi:10.1016/j.clinph.2015.02.001
22.
KimBRKimDYChunMHYiJHKwonJS.Effect of repetitive transcranial magnetic stimulation on cognition and mood in stroke patients: a double-blind, sham-controlled trial. Am J Phys Med Rehabil. 2010;89(5):362-368. doi:10.1097/PHM.0b013e3181d8a5b1
23.
Whitfield-GabrieliSWendelkenCNieto-CastañónA, et al. Association of intrinsic brain architecture with changes in attentional and mood symptoms during development. JAMA Psychiatry. 2020;77(4):378-386. doi:10.1001/jamapsychiatry.2019.4208
24.
GaoYQiuYYangQ, et al. Repetitive transcranial magnetic stimulation combined with cognitive training for cognitive function and activities of daily living in patients with post-stroke cognitive impairment: a systematic review and meta-analysis. Ageing Res Rev. 2023;87:101919. doi:10.1016/j.arr.2023.101919
25.
RossiSAntalABestmannS, et al. Safety and recommendations for TMS use in healthy subjects and patient populations, with updates on training, ethical and regulatory issues: expert Guidelines. Clin Neurophysiol. 2021;132(1):269-306. doi:10.1016/j.clinph.2020.10.003
26.
YuJLiJHuangX.The Beijing version of the Montreal Cognitive Assessment as a brief screening tool for mild cognitive impairment: a community-based study. BMC Psychiatry. 2012;12:156. doi:10.1186/1471-244x-12-156
27.
HawkinsKADeanDPearlsonGD.Alternative forms of the rey auditory verbal learning test: a review. Behav Neurol. 2004;15(3-4):99-107. doi:10.1155/2004/940191
28.
SilvaPHRCTSpedoBarreiraAALeoniRF. Symbol digit modalities test adaptation for magnetic resonance imaging environment: a systematic review and meta-analysis. Mult Scler Relat Disord. 2018;20:136-143. doi:10.1016/j.msard.2018.01.014
29.
JahanshahiMSaleemTHoAKFullerRDirnbergerG.A preliminary investigation of the running digit span as a test of working memory. Behav Neurol. 2008;20(1-2):17-25. doi:10.3233/ben-2008-0212
30.
TamburroGdi FronsoSRobazzaCBertolloMComaniS.Modulation of brain functional connectivity and efficiency during an endurance cycling task: a source-level EEG and graph theory approach. Front Hum Neurosci. 2020;14:243. doi:10.3389/fnhum.2020.00243
31.
MichelCMKoenigT.EEG microstates as a tool for studying the temporal dynamics of whole-brain neuronal networks: a review. Neuroimage. 2018;180(Pt B):577-593. doi:10.1016/j.neuroimage.2017.11.062
32.
LiYGaoJYangY, et al. Temporal and spatial variability of dynamic microstate brain network in disorders of consciousness. CNS Neurosci Ther. 2024;30(2):e14641. doi:10.1111/cns.14641
33.
LindvallEAbzhandadzeTQuinnTJSunnerhagenKSLundströmE.Is the difference real, is the difference relevant: the minimal detectable and clinically important changes in the Montreal Cognitive Assessment. Cereb Circ Cogn Behav. 2024;6:100222. doi:10.1016/j.cccb.2024.100222
34.
MurphyKKhanABachuATampiR.Treatment of behavioral and psychological symptoms of dementia using transcranial magnetic stimulation: a systematic review. Int Psychogeriatr. 2023;35(11):611-622. doi:10.1017/s1041610223000091
35.
ChaBKimJKimJM, et al. Therapeutic effect of repetitive transcranial magnetic stimulation for post-stroke vascular cognitive impairment: a prospective pilot study. Front Neurol. 2022;13:813597. doi:10.3389/fneur.2022.813597
36.
MilzPFaberPLLehmannDKoenigTKochiKPascual-MarquiRD.The functional significance of EEG microstates–associations with modalities of thinking. Neuroimage. 2016;125:643-656. doi:10.1016/j.neuroimage.2015.08.023
37.
SantarnecchiEKhannaARMusaeusCS, et al. EEG microstate correlates of fluid intelligence and response to cognitive training. Brain Topogr. 2017;30(4):502-520. doi:10.1007/s10548-017-0565-z
38.
SmailovicUKoenigTLaukkaEJ, et al. EEG time signature in Alzheimer’s disease: functional brain networks falling apart. Neuroimage Clin. 2019;24:102046. doi:10.1016/j.nicl.2019.102046
39.
TaitLTamagniniFStothartG, et al. EEG microstate complexity for aiding early diagnosis of Alzheimer’s disease. Sci Rep. 2020;10(1):17627. doi:10.1038/s41598-020-74790-7
40.
ZappasodiFCrocePGiordaniA, et al. Prognostic value of EEG microstates in acute stroke. Brain Topogr. Sep2017;30(5):698-710. doi:10.1007/s10548-017-0572-0
41.
HaoZZhaiXChengDPanYDouW.EEG microstate-specific functional connectivity and stroke-related alterations in brain dynamics. Front Neurosci. 2022;16:848737. doi:10.3389/fnins.2022.848737
42.
WangZLiuZChenL, et al. Resting-state electroencephalogram microstate to evaluate post-stroke rehabilitation and associate with clinical scales. Front Neurosci. 2022;16:1032696. doi:10.3389/fnins.2022.1032696
43.
WackermannJLehmannDMichelCMStrikWK.Adaptive segmentation of spontaneous EEG map series into spatially defined microstates. Int J Psychophysiol. 1993;14(3):269-283. doi:10.1016/0167-8760(93)90041-m
44.
KoenigTPrichepLLehmannD, et al. Millisecond by millisecond, year by year: normative EEG microstates and developmental stages. Neuroimage. 2002;16(1):41-48. doi:10.1006/nimg.2002.1070
45.
BritzJVan De VilleDMichelCM.BOLD correlates of EEG topography reveal rapid resting-state network dynamics. Neuroimage. 2010;52(4):1162-1170. doi:10.1016/j.neuroimage.2010.02.052
46.
CustoAVan De VilleDWellsWMTomescuMIBrunetDMichelCM.Electroencephalographic resting-state networks: source localization of microstates. Brain Connect. 2017;7(10):671-682. doi:10.1089/brain.2016.0476
47.
ChuCWangXCaiL, et al. Spatiotemporal EEG microstate analysis in drug-free patients with Parkinson's disease. Neuroimage Clin. 2020;25:102132. doi:10.1016/j.nicl.2019.102132
48.
YanYGaoMGengZ, et al. Abnormal EEG microstates in Alzheimer’s disease: predictors of β-amyloid deposition degree and disease classification. Geroscience. 2024;46(5):4779-4792. doi:10.1007/s11357-024-01181-5
49.
RainerG.Allocating attention in rank-ordered groups. Neuron. 2011;70(1):5-7. doi:10.1016/j.neuron.2011.03.016
50.
CoolsRArnstenAFT. Neuromodulation of prefrontal cortex cognitive function in primates: the powerful roles of monoamines and acetylcholine. Neuropsychopharmacology. 2022;47(1):309-328. doi:10.1038/s41386-021-01100-8
51.
ChenACOathesDJChangC, et al. Causal interactions between fronto-parietal central executive and default-mode networks in humans. Proc Natl Acad Sci USA. 2013;110(49):19944-19949. doi:10.1073/pnas.1311772110
52.
DenkovaENomiJSUddinLQJhaAP.Dynamic brain network configurations during rest and an attention task with frequent occurrence of mind wandering. Hum Brain Mapp. 2019;40(15):4564-4576. doi:10.1002/hbm.24721
53.
PhilipNSBarredoJvan’t Wout-FrankMTyrkaARPriceLHCarpenterLL.Network mechanisms of clinical response to transcranial magnetic stimulation in posttraumatic stress disorder and major depressive disorder. Biol Psychiatry. 2018;83(3):263-272. doi:10.1016/j.biopsych.2017.07.021
54.
ShangYChangDZhangJ, et al. Theta-burst transcranial magnetic stimulation induced functional connectivity changes between dorsolateral prefrontal cortex and default-mode-network. Brain Imaging Behav. 2020;14(5):1955-1963. doi:10.1007/s11682-019-00139-y
55.
HausmanHKO’SheaAKraftJN, et al. The role of resting-state network functional connectivity in cognitive aging. Front Aging Neurosci. 2020;12:177. doi:10.3389/fnagi.2020.00177
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
