Brain‐oscillation-synchronized stimulation to enhance motor recovery in early subacute stroke: a randomized controlled double‐blind three‐ arm parallel‐group exploratory trial comparing personalized, non‐ personalized and sham repetitive transcranial magnetic stimulation (Acronym: BOSS-STROKE)

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Abstract

Background

Stroke is a major cause of death and the most frequent cause of permanent disability in western countries. Repetitive transcranial brain stimulation (rTMS) has been used to enhance neuronal plasticity after stroke, yet with only moderate effect sizes. Here we will apply a highly innovative technology that synchronizes rTMS to specific brain states identified by real-time analysis of electroencephalography.

Methods

One hundred forty-four patients with early subacute ischemic motor stroke will be included in a multicenter 3-arm parallel, randomized, double-blind, standard rTMS and sham rTMS-controlled exploratory trial in Germany. In the experimental condition, rTMS will be synchronized to the trough of the sensorimotor µ-oscillation, a high-excitability state, over ipsilesional motor cortex. In the standard rTMS control condition the identical protocol will be applied, but non-synchronized to the ongoing µ-oscillation. In the sham condition, the same µ-oscillation-synchronized protocol as in experimental condition will be applied, but with ineffective rTMS, using the sham side of an active/placebo TMS coil. The treatment will be performed over five consecutive work days (1,200 pulses per day, 6,000 pulses total). The primary endpoint will be motor performance after the last treatment session as measured by the Fugl-Meyer Assessment Upper Extremity.

Discussion

This study investigates, for the first time, the therapeutic efficacy of personalized, brain-state-dependent rTMS. We hypothesize that synchronization of rTMS with a high-excitability state will lead to significantly stronger improvement of paretic upper extremity motor function than standard or sham rTMS. Positive results may catalyze a paradigm-shift towards personalized brain-state-dependent stimulation therapies.

Trial registration

This study was registered at ClinicalTrials.gov (NCT05600374) on 10–21-2022.

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Most cited references 30

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Global, regional, and national burden of neurological disorders, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016

Valery L. Feigin, Emma Nichols, Tahiya Alam … (2020)

Summary Background Neurological disorders are increasingly recognised as major causes of death and disability worldwide. The aim of this analysis from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2016 is to provide the most comprehensive and up-to-date estimates of the global, regional, and national burden from neurological disorders. Methods We estimated prevalence, incidence, deaths, and disability-adjusted life-years (DALYs; the sum of years of life lost [YLLs] and years lived with disability [YLDs]) by age and sex for 15 neurological disorder categories (tetanus, meningitis, encephalitis, stroke, brain and other CNS cancers, traumatic brain injury, spinal cord injury, Alzheimer's disease and other dementias, Parkinson's disease, multiple sclerosis, motor neuron diseases, idiopathic epilepsy, migraine, tension-type headache, and a residual category for other less common neurological disorders) in 195 countries from 1990 to 2016. DisMod-MR 2.1, a Bayesian meta-regression tool, was the main method of estimation of prevalence and incidence, and the Cause of Death Ensemble model (CODEm) was used for mortality estimation. We quantified the contribution of 84 risks and combinations of risk to the disease estimates for the 15 neurological disorder categories using the GBD comparative risk assessment approach. Findings Globally, in 2016, neurological disorders were the leading cause of DALYs (276 million [95% UI 247–308]) and second leading cause of deaths (9·0 million [8·8–9·4]). The absolute number of deaths and DALYs from all neurological disorders combined increased (deaths by 39% [34–44] and DALYs by 15% [9–21]) whereas their age-standardised rates decreased (deaths by 28% [26–30] and DALYs by 27% [24–31]) between 1990 and 2016. The only neurological disorders that had a decrease in rates and absolute numbers of deaths and DALYs were tetanus, meningitis, and encephalitis. The four largest contributors of neurological DALYs were stroke (42·2% [38·6–46·1]), migraine (16·3% [11·7–20·8]), Alzheimer's and other dementias (10·4% [9·0–12·1]), and meningitis (7·9% [6·6–10·4]). For the combined neurological disorders, age-standardised DALY rates were significantly higher in males than in females (male-to-female ratio 1·12 [1·05–1·20]), but migraine, multiple sclerosis, and tension-type headache were more common and caused more burden in females, with male-to-female ratios of less than 0·7. The 84 risks quantified in GBD explain less than 10% of neurological disorder DALY burdens, except stroke, for which 88·8% (86·5–90·9) of DALYs are attributable to risk factors, and to a lesser extent Alzheimer's disease and other dementias (22·3% [11·8–35·1] of DALYs are risk attributable) and idiopathic epilepsy (14·1% [10·8–17·5] of DALYs are risk attributable). Interpretation Globally, the burden of neurological disorders, as measured by the absolute number of DALYs, continues to increase. As populations are growing and ageing, and the prevalence of major disabling neurological disorders steeply increases with age, governments will face increasing demand for treatment, rehabilitation, and support services for neurological disorders. The scarcity of established modifiable risks for most of the neurological burden demonstrates that new knowledge is required to develop effective prevention and treatment strategies. Funding Bill & Melinda Gates Foundation.

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The post-stroke hemiplegic patient. 1. a method for evaluation of physical performance.

A. R Fugl-Meyer, L Jääskö, I Leyman … (1975)

A system for evaluation of motor function, balance, some sensation qualities and joint function in hemiplegic patients is described in detail. The system applies a cumulative numerical score. A series of hemiplegic patients has been followed from within one week post-stroke and throughout one year. When initially nearly flaccid hemiparalysis prevails, the motor recovery, if any occur, follows a definable course. The findings in this study substantiate the validity of ontogenetic principles as applicable to the assessment of motor behaviour in hemiplegic patients, and foocus the importance of early therapeutic measures against contractures.

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Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS): An update (2014–2018)

Jean-Pascal Lefaucheur, André Aleman, Chris Baeken … (2020)

A group of European experts reappraised the guidelines on the therapeutic efficacy of repetitive transcranial magnetic stimulation (rTMS) previously published in 2014 [Lefaucheur et al., Clin Neurophysiol 2014;125:2150-206]. These updated recommendations take into account all rTMS publications, including data prior to 2014, as well as currently reviewed literature until the end of 2018. Level A evidence (definite efficacy) was reached for: high-frequency (HF) rTMS of the primary motor cortex (M1) contralateral to the painful side for neuropathic pain; HF-rTMS of the left dorsolateral prefrontal cortex (DLPFC) using a figure-of-8 or a H1-coil for depression; low-frequency (LF) rTMS of contralesional M1 for hand motor recovery in the post-acute stage of stroke. Level B evidence (probable efficacy) was reached for: HF-rTMS of the left M1 or DLPFC for improving quality of life or pain, respectively, in fibromyalgia; HF-rTMS of bilateral M1 regions or the left DLPFC for improving motor impairment or depression, respectively, in Parkinson's disease; HF-rTMS of ipsilesional M1 for promoting motor recovery at the post-acute stage of stroke; intermittent theta burst stimulation targeted to the leg motor cortex for lower limb spasticity in multiple sclerosis; HF-rTMS of the right DLPFC in posttraumatic stress disorder; LF-rTMS of the right inferior frontal gyrus in chronic post-stroke non-fluent aphasia; LF-rTMS of the right DLPFC in depression; and bihemispheric stimulation of the DLPFC combining right-sided LF-rTMS (or continuous theta burst stimulation) and left-sided HF-rTMS (or intermittent theta burst stimulation) in depression. Level A/B evidence is not reached concerning efficacy of rTMS in any other condition. The current recommendations are based on the differences reached in therapeutic efficacy of real vs. sham rTMS protocols, replicated in a sufficient number of independent studies. This does not mean that the benefit produced by rTMS inevitably reaches a level of clinical relevance.

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Author and article information

Contributors

Anne Lieb: anne.lieb@uni-tuebingen.de

Brigitte Zrenner: brigitte.zrenner@uni-tuebingen.de

Christoph Zrenner: christoph.zrenner@utoronto.ca

Gábor Kozák: Gabor.Kozak@med.uni-tuebingen.de

Peter Martus: peter.martus@unituebingen.de

Christian Grefkes: Christian.Grefkes-Hermann@kgu.de

Ulf Ziemann: ulf.ziemann@uni-tuebingen.de

Journal

Journal ID (nlm-ta): BMC Neurol

Journal ID (iso-abbrev): BMC Neurol

Title: BMC Neurology

Publisher: BioMed Central (London )

ISSN (Electronic): 1471-2377

Publication date (Electronic): 25 May 2023

Publication date PMC-release: 25 May 2023

Publication date Collection: 2023

Volume: 23

Electronic Location Identifier: 204

Affiliations

[1 ]GRID grid.10392.39, ISNI 0000 0001 2190 1447, Department of Neurology and Stroke, and Hertie-Institute for Clinical Brain Research, , University of Tübingen, ; Tübingen, Germany

[2 ]GRID grid.155956.b, ISNI 0000 0000 8793 5925, Temerty Centre for Therapeutic Brain Intervention, Centre for Addiction and Mental Health, ; Toronto, ON Canada

[3 ]GRID grid.17063.33, ISNI 0000 0001 2157 2938, Department of Psychiatry, , University of Toronto, ; Toronto, ON Canada

[4 ]GRID grid.17063.33, ISNI 0000 0001 2157 2938, Institute for Biomedical Engineering, , University of Toronto, ; Toronto, ON Canada

[5 ]GRID grid.10392.39, ISNI 0000 0001 2190 1447, Institute for Clinical Epidemiology and Applied Statistics, , University of Tübingen, ; Tübingen, Germany

[6 ]GRID grid.7839.5, ISNI 0000 0004 1936 9721, Department of Neurology, , Goethe University Frankfurt, ; Frankfurt am Main, Germany

Article

Publisher ID: 3235

DOI: 10.1186/s12883-023-03235-1

PMC ID: 10210305

SO-VID: a8dc4edc-d9f3-464b-8647-54b252ca0d98

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 1 February 2023

Date accepted : 29 April 2023

Funding

Funded by: Universitätsklinikum Tübingen (8868)

Open Access :

Open Access funding enabled and organized by Projekt DEAL.

Custom metadata

ScienceOpen disciplines: Neurology

Keywords: transcranial magnetic stimulation (tms),brain oscillation,brain-state-dependent stimulation,sensorimotor µ-oscillation,tms-eeg,personalized treatment

Data availability:

ScienceOpen disciplines: Neurology

Keywords: transcranial magnetic stimulation (tms), brain oscillation, brain-state-dependent stimulation, sensorimotor µ-oscillation, tms-eeg, personalized treatment

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Abstract

Background

Methods

Discussion

Trial registration

Related collections

Stroke MRI

Most cited references 30

Global, regional, and national burden of neurological disorders, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016

The post-stroke hemiplegic patient. 1. a method for evaluation of physical performance.

Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS): An update (2014–2018)

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