Multifocal Theta-Burst Stimulation to Enhance Upper Limb Motor Recovery After Stroke (INSPIRE)

Official title

Advancing Stroke Rehabilitation Through Multifocal Network-based Theta-burst Stimulation and Assistive Technology: Enhancing Upper Limb Motor Learning: A Single-center, Randomized, Sham-controlled Study With Parallel Groups.

Overview

Stroke is one of the leading causes of long-term disability worldwide. Many individuals who survive a stroke continue to experience weakness and reduced control of one arm, even months or years after the event. These motor impairments significantly affect independence, daily activities, and quality of life. Despite rehabilitation efforts, recovery of upper limb function remains incomplete for many patients. Motor recovery after stroke depends on the brain's ability to reorganize itself, a process known as neuroplasticity. Recent research suggests that motor learning and brain recovery are influenced not only by activity in the primary motor cortex (M1), but also by its functional connectivity with other brain regions, particularly the parietal cortex (PC). Strengthening communication between these regions may enhance motor recovery. This study aims to investigate a novel, non-invasive brain stimulation approach called intermittent theta-burst stimulation (iTBS). Unlike traditional stimulation methods that target a single brain region, this study uses a multifocal stimulation protocol targeting both the primary motor cortex and the parietal cortex. The stimulation is combined with structured motor training using an interactive tablet-based rehabilitation device (REAtouch®Lite 2), designed to improve arm movement through goal-directed reaching tasks. The study is a single-center, randomized, sham-controlled, triple-blind clinical trial with parallel groups. Thirty-six individuals with chronic stroke-related upper limb impairment will be randomly assigned to receive either active multifocal iTBS or sham (placebo) stimulation. Both groups will complete identical motor training sessions. In addition, ten healthy participants will complete the same motor training protocol (without brain stimulation) to provide reference data. Participants will attend six visits over approximately 10 days. Assessments will include motor performance tests using the interactive tablet, a standardized clinical motor scale (Fugl-Meyer Assessment for Upper Extremity), and resting-state electroencephalography (EEG) to measure brain connectivity changes. The primary outcome is improvement in motor performance between baseline and one week after the intervention. Secondary outcomes include short-term motor improvements, retention of learning, changes in movement quality, and changes in brain functional connectivity. This study seeks to determine whether combining multifocal brain stimulation with targeted motor training can enhance motor learning and promote better recovery of arm function after stroke. If effective, this approach could contribute to the development of more precise, network-based neurorehabilitation strategies.

Detailed description

Stroke is a leading cause of long-term motor disability, with persistent upper limb impairment affecting a large proportion of individuals in the chronic phase. Despite advances in rehabilitation, recovery of arm function remains limited for many patients. Motor recovery after stroke depends on neuroplastic reorganization within distributed brain networks. While most neuromodulation studies have focused on stimulating the primary motor cortex (M1) alone, growing evidence indicates that motor learning relies on coordinated interactions between multiple cortical regions, particularly the functional connectivity between the parietal cortex (PC) and M1.

Resting-state functional connectivity between parietal and motor areas has been identified as a neurophysiological marker associated with motor performance and recovery potential. Enhancing this network-level connectivity may therefore represent a promising strategy to improve motor learning and functional outcomes after stroke.

The INSPIRE project investigates a novel multifocal intermittent theta-burst stimulation (iTBS) paradigm targeting both M1 and PC. Intermittent theta-burst stimulation is a patterned form of repetitive transcranial magnetic stimulation (rTMS) capable of inducing lasting modulation of cortical excitability. In contrast to conventional monofocal approaches, this study applies neuronavigated iTBS sequentially over M1 and the superior parietal lobule within the affected hemisphere, with the objective of modulating network-level interactions rather than isolated cortical excitability.

The stimulation protocol is combined with structured motor training delivered through a tablet-based interactive device (REAtouch®Lite 2). This system implements a standardized two-dimensional reaching task that allows precise quantification of motor performance and spatio-temporal movement parameters. The combination of neuromodulation and task-specific training is designed to engage Hebbian plasticity mechanisms, whereby stimulation-induced network modulation may facilitate motor learning processes during training.

This study is designed as a single-center, randomized, sham-controlled, triple-blind, parallel-group clinical trial. Thirty-six individuals in the chronic phase after a first stroke (≥6 months) with moderate upper limb impairment will be randomized in a 1:1 ratio to receive either active multifocal iTBS or sham stimulation. Both groups will undergo identical motor training sessions. A group of ten age- and sex-matched healthy participants will complete the same motor training protocol without brain stimulation to provide normative reference data for behavioral and neurophysiological measures.

The intervention consists of two consecutive days of stimulation combined with motor training. Each session includes neuronavigated iTBS delivered over M1 and PC (600 pulses per target at 70% resting motor threshold), followed by 45 minutes of structured motor training. Sham stimulation reproduces auditory and sensory aspects of active stimulation without inducing a cortical electric field.

Motor performance is assessed using a composite motor performance index derived from reaching accuracy and movement time during a standardized visuo-motor task. Secondary behavioral measures include short-term learning indices, offline consolidation effects, detailed spatio-temporal movement parameters, and clinical motor impairment assessed with the Fugl-Meyer Assessment for Upper Extremity (FMA-UE).

Neurophysiological outcomes include resting-state electroencephalography (EEG) recorded before and after the intervention. Functional connectivity between parietal and motor regions is quantified using frequency-specific coherence measures and graph-theoretical metrics. These analyses aim to determine whether multifocal iTBS enhances cortico-cortical connectivity and whether changes in connectivity are associated with behavioral improvements.

The primary hypothesis is that multifocal iTBS combined with motor training will lead to greater improvements in motor performance compared with sham stimulation. Secondary hypotheses include enhanced short-term motor learning, improved retention of learned motor skills, and increased parieto-motor functional connectivity in the active stimulation group.

This project integrates behavioral, clinical, and neurophysiological measures to evaluate a network-based neuromodulation approach in chronic stroke rehabilitation. By targeting distributed cortical interactions rather than a single cortical region, the study aims to advance precision neurorehabilitation strategies grounded in contemporary models of motor learning and brain network plasticity.

If successful, this intervention paradigm could inform future rehabilitation protocols and support the development of individualized, connectivity-driven therapeutic approaches for stroke recovery.

Interventions

• Device Active iTBS
  Standard 600-pulse intermittent theta burst stimulation (iTBS) can increase corticomotor excitability. The iTBS will be delivered with an intensity of 70% of the individual resting motor threshold (RMT) over the ipsilesional primary motor cortex (M1) and superior parietal lobule using a Magstim Rapid2 stimulator equipped with a figure-of-eight coil. Stimulation will follow the standard iTBS pattern consisting of bursts of 3 pulses at 50 Hz repeated at 5 Hz.
• Device Tablet-based upper limb training
  REAtouch® Lite 2 interactive rehabilitation device will be used for upper limb motor training. REAtouch® Lite 2 is a touchscreen-based, task-oriented rehabilitation device designed to train upper limb movements through interactive exercises. The device targets (1) goal-directed reaching movements, (2) hand transport toward visual targets, (3) grasp and release coordination in a two-dimensional workspace, and (4) movement accuracy and speed. Training is supported by customizable visual feedback
• Device Sham iTBS
  Sham intermittent theta burst stimulation (iTBS) mimics the auditory and somatosensory characteristics of active stimulation without inducing a biologically effective cortical electric field. Sham stimulation will be delivered over the ipsilesional primary motor cortex (M1) and superior parietal lobule using a placebo coil identical in appearance, sound, and positioning to the active coil. Stimulation procedures, session duration, neuronavigation, and device setup are identical to the active i

Primary outcome measures

• Change in Global Motor Performance Index (Baseline to Day 10) [Time frame: Baseline (Day 0) to Day 10]

Secondary outcome measures (10)

• Change in Short-Term Motor Performance Index (Baseline to Day 3) [Time frame: Baseline (Day 0) to Day 3]
• Offline Motor Consolidation Index (Day 3 to Day 10) [Time frame: Day 3 to Day 10]
• Change in Upper Limb Motor Impairment (Fugl-Meyer Assessment - Upper Extremity) [Time frame: Baseline (Day 0), Day 3, and Day 10]
• Change in Mean Number of Reaching Errors [Time frame: Baseline (Day 0), Day 3, and Day 10]
• Change in Mean Movement Speed (cm/s) [Time frame: Baseline (Day 0), Day 3, and Day 10]
• Change in Mean Movement Smoothness (cm/s³) [Time frame: Baseline (Day 0), Day 3, and Day 10]
• Change in Mean Maximum Lateral Deviation (cm) [Time frame: Baseline (Day 0), Day 3, and Day 10]
• Change in Mean Directional Error at 100 ms (degrees) [Time frame: Baseline (Day 0), Day 3, and Day 10]
• Change in Mean Reaction Time (seconds) [Time frame: Baseline (Day 0), Day 3, and Day 10]
• Change in Parieto-Motor Functional Connectivity Measured by Resting-State EEG [Time frame: Baseline (Day 0) and Day 3]

Eligibility criteria

Inclusion criteria

For Stroke Participants:

• Age ≥ 18 years
• First-ever ischemic or hemorrhagic stroke
• Time since stroke ≥ 6 months
• Unilateral upper limb hemiparesis
• Fugl-Meyer Assessment Upper Extremity (FMA-UE) score between 29 and 57
• Modified Ashworth Scale score < 2 at elbow, wrist, or finger flexors
• Manual muscle testing ≥ 3/5 in proximal upper limb muscles (deltoid, biceps, triceps, wrist pronators/supinators)
• Ability to understand and follow study procedures
• Provided written informed consent

For Healthy Participants:

• Age ≥ 18 years
• No history of neurological disease
• Ability to understand and follow study procedures
• Provided written informed consent

Exclusion criteria

For Stroke Participants:

• Second stroke occurring during the study period
• Botulinum toxin injection within 3 months prior to study start
• History of one or more epileptic seizures
• Metallic object near the stimulation site
• Implanted electronic or metallic devices (e.g., pacemaker, neurostimulator) incompatible with TMS
• Severe comorbid conditions affecting the upper limb (traumatic, rheumatologic, osteoarticular, or neurodegenerative disorders)
• Pregnancy
• Delirium or impaired vigilance
• Inability to participate in one-hour treatment sessions
• Inability to comply with study procedures (e.g., language barrier, psychological disorder, dementia)
• Current or past substance abuse, including excessive alcohol consumption
• Participation in another interventional clinical trial within 30 days prior to enrollment

For Healthy Participants:

• Severe musculoskeletal or neurological condition affecting the non-dominant upper limb
• Pregnancy
• Delirium or impaired vigilance
• Inability to participate in one-hour treatment sessions
• Inability to comply with study procedures
• Current or past substance abuse, including excessive alcohol consumption
• Participation in another interventional clinical trial within 30 days prior to enrollment

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

Switzerland · 1 center

• University School of Health ▪ HES-SO Genève — Carouge

Publications

• Fugl-Meyer AR, Jaasko L, Leyman I, Olsson S, Steglind S. The post-stroke hemiplegic patient. 1. a method for evaluation of physical performance. Scand J Rehabil Med. 1975;7(1):13-31. PMID 1135616
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• El-Hoss J, Sullivan K, Cheng T, Yu NY, Bobyn JD, Peacock L, Mikulec K, Baldock P, Alexander IE, Schindeler A, Little DG. A murine model of neurofibromatosis type 1 tibial pseudarthrosis featuring proliferative fibrous tissue and osteoclast-like cells. J Bone Miner Res. 2012 Jan;27(1):68-78. doi: 10.1002/jbmr.528. PMID 21956219
• Van Moerbeke M, Kasim A, Shkedy Z. The Usage of Exon-Exon Splice Junctions for the Detection of Alternative Splicing using the REIDS model. Sci Rep. 2018 May 29;8(1):8331. doi: 10.1038/s41598-018-26695-9. PMID 29844567
• Sobczyk O, Battisti-Charbonney A, Fierstra J, Mandell DM, Poublanc J, Crawley AP, Mikulis DJ, Duffin J, Fisher JA. A conceptual model for CO(2)-induced redistribution of cerebral blood flow with experimental confirmation using BOLD MRI. Neuroimage. 2014 May 15;92:56-68. doi: 10.1016/j.neuroimage.2014.01.051. Epub 2014 Feb 5. PMID 24508647
• Papaleonidopoulos V, Papatheodoropoulos C. beta-adrenergic receptors reduce the threshold for induction and stabilization of LTP and enhance its magnitude via multiple mechanisms in the ventral but not the dorsal hippocampus. Neurobiol Learn Mem. 2018 May;151:71-84. doi: 10.1016/j.nlm.2018.04.010. Epub 2018 Apr 10. PMID 29653257

Identifiers

NCT: NCT07439367 · 2025-D0020

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗