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

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.

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.

Study Overview

• Status: Recruiting
• Conditions: Neurorehabilitation; Motor Impairment; Theta Burst Stimulation; Chronic Stroke Patient
• Intervention / Treatment: Device: Active iTBS; Device: Tablet-based upper limb training; Device: Sham iTBS

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.

• Study Type: Interventional
• Enrollment (Estimated): 46
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Pierre Nicolo, PhD; Phone Number: +41 22 558 64 +41792633543; Email: pierre.nicolo@hesge.ch
• Study Contact Backup: Name: Nicolas Nicastro, MD; Phone Number: +41 +41 22 372 36 24; Email: nicolas.nicastro@hug.ch

Study Locations

• Switzerland
  • Canton of Geneva
    • Carouge, Canton of Geneva, Switzerland, 1227
      • Recruiting
      • University School of Health ▪ HES-SO Genève
      • Contact: Pierre Nicolo, PhD; Phone Number: +41 22 558 64 0792633543; Email: pierre.nicolo@hesge.ch

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Active iTBS + motor training; active iTBS stimulation prior to tablet-based motor training	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 and task-specific interactive exercises integrated into the device.
Sham Comparator: Sham iTBS + motor training; sham iTBS stimulation prior to tablet-based motor training	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 and task-specific interactive exercises integrated into the device.; 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 iTBS condition to ensure participant and assessor blinding.
Other: No iTBS + motor training (healthy controls); no brain stimulation; tablet-based motor training only	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 and task-specific interactive exercises integrated into the device.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Global Motor Performance Index (Baseline to Day 10)	The primary outcome is the change in the Global Motor Performance Index score between baseline (Day 0) and post-intervention follow-up (Day 10). The Global Motor Performance Index is a composite performance score derived from a standardized two-dimensional reaching task performed using the REAtouch® Lite 2 interactive rehabilitation device. The index integrates movement accuracy (number of errors) and movement time into a single continuous score. The score ranges from -100 to +100, with lower (more negative) values indicating better motor performance and improvement over time, and higher values indicating worse performance.	Baseline (Day 0) to Day 10

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Short-Term Motor Performance Index (Baseline to Day 3)	This outcome evaluates short-term motor learning effects by measuring the change in the Short-Term Motor Performance Index score between Baseline (Day 0) and immediate post-intervention (Day 3). The Short-Term Motor Performance Index is a composite continuous score derived from a standardized two-dimensional reaching task performed using the REAtouch® Lite 2 interactive rehabilitation device. The index integrates movement accuracy (number of errors) and movement time into a single performance metric. The score ranges from -100 (best motor performance) to +100 (worst motor performance). Lower (more negative) scores indicate better motor performance, and a decrease in the score over time reflects motor improvement.	Baseline (Day 0) to Day 3
Offline Motor Consolidation Index (Day 3 to Day 10)	This outcome assesses motor memory consolidation by measuring the change in the Offline Motor Consolidation Index score between immediate post-intervention (Day 3) and follow-up (Day 10). The Offline Motor Consolidation Index is a continuous composite score derived from the same standardized two-dimensional reaching task performed using the REAtouch® Lite 2 interactive rehabilitation device. The index reflects performance retention or change after completion of the stimulation and training sessions. The score ranges from -100 (best motor performance) to +100 (worst motor performance). Lower (more negative) scores indicate better motor performance. A decrease in the score between Day 3 and Day 10 reflects performance improvement, whereas stable scores indicate retention and an increase indicates performance deterioration.	Day 3 to Day 10
Change in Upper Limb Motor Impairment (Fugl-Meyer Assessment - Upper Extremity)	Upper limb motor impairment will be assessed using the Fugl-Meyer Assessment - Upper Extremity (FMA-UE), a validated clinical scale measuring motor function of the upper limb after stroke. The FMA-UE total score ranges from 0 to 66, where 0 indicates severe motor impairment and 66 indicates normal motor function. Higher scores represent better motor function. Change in FMA-UE scores over time will be analyzed to evaluate clinical motor recovery.	Baseline (Day 0), Day 3, and Day 10
Change in Mean Number of Reaching Errors	The mean number of reaching errors will be measured during a standardized two-dimensional reaching task performed using the REAtouch® Lite 2 interactive rehabilitation device. An error is defined as failure to reach or stabilize within the predefined target area during a trial. The outcome is a continuous variable representing the average number of errors per session. The minimum possible value is 0 (no errors), with no predefined upper limit. Higher values indicate worse motor performance. Changes in the mean number of errors over time will be analyzed.	Baseline (Day 0), Day 3, and Day 10
Change in Mean Movement Speed (cm/s)	Mean movement speed will be measured during a standardized two-dimensional reaching task performed using the REAtouch® Lite 2 interactive rehabilitation device. Movement speed (cm/s) is calculated as the displacement divided by the time between movement initiation (defined as >5 mm displacement from the starting position) and movement stabilization within the target area. This is a continuous variable with a minimum possible value of 0 cm/s and no predefined upper limit. Higher values indicate faster movement performance. Changes in mean movement speed over time will be analyzed.	Baseline (Day 0), Day 3, and Day 10
Change in Mean Movement Smoothness (cm/s³)	Mean movement smoothness will be measured during a standardized two-dimensional reaching task performed using the REAtouch® Lite 2 interactive rehabilitation device. Movement smoothness is quantified using a jerk-based metric (third derivative of position with respect to time), expressed in centimeters per second cubed (cm/s³). The metric reflects the magnitude of trajectory corrections during movement execution. This is a continuous variable with a minimum possible value of 0 cm/s³ and no predefined upper limit. Lower values indicate smoother movements and better motor control, whereas higher values indicate greater movement irregularity. Changes in mean movement smoothness over time will be analyzed.	Baseline (Day 0), Day 3, and Day 10
Change in Mean Maximum Lateral Deviation (cm)	Mean maximum lateral deviation will be measured during a standardized two-dimensional reaching task performed using the REAtouch® Lite 2 interactive rehabilitation device. Maximum lateral deviation (cm) is defined as the greatest perpendicular distance between the participant's actual movement trajectory and the optimal straight-line trajectory from the start position to the target. This is a continuous variable with a minimum possible value of 0 cm (perfectly straight trajectory) and no predefined upper limit. Lower values indicate better trajectory control and movement accuracy, whereas higher values indicate greater deviation from the optimal path. Changes in mean maximum lateral deviation over time will be analyzed.	Baseline (Day 0), Day 3, and Day 10
Change in Mean Directional Error at 100 ms (degrees)	Mean directional error at 100 milliseconds will be measured during a standardized two-dimensional reaching task performed using the REAtouch® Lite 2 interactive rehabilitation device. Directional error (degrees) is defined as the angular deviation between the initial movement direction and the straight-line direction to the target, calculated 100 milliseconds after movement onset. Movement onset is defined as displacement exceeding 5 mm from the starting position. This is a continuous variable expressed in degrees, with a minimum possible value of 0° (perfect alignment with the target direction) and no predefined upper limit. Lower values indicate greater motor planning accuracy, whereas higher values indicate greater deviation from the intended direction. Changes in mean directional error over time will be analyzed.	Baseline (Day 0), Day 3, and Day 10
Change in Mean Reaction Time (seconds)	Mean reaction time will be measured during a standardized two-dimensional reaching task performed using the REAtouch® Lite 2 interactive rehabilitation device. Reaction time (seconds) is defined as the time elapsed between target appearance and movement initiation in the correct direction, defined as an initial movement trajectory within ≤15° of the straight-line direction to the target. Movement initiation is defined as displacement exceeding 5 mm from the starting position. This is a continuous variable expressed in seconds, with a minimum possible value of 0 seconds and no predefined upper limit. Lower values indicate faster response initiation and better motor preparation, whereas higher values indicate slower response initiation. Changes in mean reaction time over time will be analyzed.	Baseline (Day 0), Day 3, and Day 10
Change in Parieto-Motor Functional Connectivity Measured by Resting-State EEG	Resting-state electroencephalography (EEG) will be used to assess functional connectivity between parietal and motor cortical regions. Functional connectivity will be quantified using frequency-specific coherence values and graph-theoretical network metrics derived from EEG signals. Coherence values range from 0 to 1, with higher values indicating stronger functional connectivity between cortical regions. Graph-based metrics (e.g., global efficiency, clustering coefficient) are continuous measures without fixed theoretical minimum or maximum values; higher values indicate greater network integration or segregation depending on the specific metric analyzed. Change in these connectivity measures between Baseline (Day 0) and Day 3 will be analyzed to evaluate neurophysiological effects of stimulation.	Baseline (Day 0) and Day 3

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Upper Limb Active Duration (minutes)	Upper limb activity during motor training sessions will be quantified using a wrist-worn ActiGraph® device. Active duration (minutes) is defined as the total time during each training session in which wrist acceleration exceeds the predefined activity threshold. This is a continuous variable expressed in minutes, with a minimum possible value of 0 minutes and a maximum corresponding to the total session duration. Higher values indicate greater active training time. These values will be used to verify equivalence of training dose across study groups.	During Intervention Sessions (Day 1 and Day 2)
Mean Movement Intensity (vector magnitude counts)	Upper limb movement intensity during motor training sessions will be quantified using a wrist-worn ActiGraph® device. Mean movement intensity is calculated as the average vector magnitude of triaxial acceleration signals recorded during each training session. This is a continuous variable expressed in activity counts (vector magnitude units) with no predefined theoretical maximum. Higher values indicate greater movement intensity. These values will be used to verify equivalence of training intensity across study groups.	During Intervention Sessions (Day 1 and Day 2)
Percentage of Active Time (%)	Upper limb activity during motor training sessions will be quantified using a wrist-worn ActiGraph® device. Percentage of active time (%) is defined as the proportion of total session time during which wrist acceleration exceeds the predefined activity threshold. This is a continuous variable expressed as a percentage ranging from 0% to 100%. Higher values indicate greater proportion of active training time. These values will be used to verify equivalence of training exposure across study groups.	During Intervention Sessions (Day 1 and Day 2)

Collaborators and Investigators

• Sponsor: School of Health Sciences Geneva
• Collaborators: University Hospital, Geneva

Publications and helpful links

General Publications

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• 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.
• Haziza C, de La Bourdonnaye G, Merlet S, Benzimra M, Ancerewicz J, Donelli A, Baker G, Picavet P, Ludicke F. Assessment of the reduction in levels of exposure to harmful and potentially harmful constituents in Japanese subjects using a novel tobacco heating system compared with conventional cigarettes and smoking abstinence: A randomized controlled study in confinement. Regul Toxicol Pharmacol. 2016 Nov;81:489-499. doi: 10.1016/j.yrtph.2016.09.014. Epub 2016 Sep 29.
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Helpful Links

• Advancing Upper Limb Stroke Rehab & Assistive Technology
• Advancing Upper Limb Stroke Rehab & Assistive Technology

Study record dates

Study Major Dates

• Study Start (Actual): September 5, 2025
• Primary Completion (Estimated): August 31, 2026
• Study Completion (Estimated): August 31, 2026

Study Registration Dates

• First Submitted: February 16, 2026
• First Submitted That Met QC Criteria: February 23, 2026
• First Posted (Actual): February 27, 2026

Study Record Updates

• Last Update Posted (Actual): February 27, 2026
• Last Update Submitted That Met QC Criteria: February 23, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: Neuroplasticity; Motor Learning; Intermittent Theta Burst Stimulation; Chronic Stroke; Upper Limb Rehabilitation; Tablet-Based Rehabilitation
• Other Study ID Numbers: 2025-D0020

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

De-identified individual participant data (IPD) underlying the results reported in publications will be shared. This includes behavioral motor performance data, spatio-temporal movement parameters, Fugl-Meyer Assessment scores (for stroke participants), resting-state EEG-derived functional connectivity measures, and relevant demographic and clinical variables necessary to reproduce the analyses.

All shared datasets will be fully anonymized and stripped of direct and indirect identifiers in accordance with applicable data protection regulations. Data will be made available to qualified researchers upon reasonable request and after approval of a methodologically sound research proposal. A data-sharing agreement will be required to ensure appropriate use of the data.

• IPD Sharing Time Frame: Individual participant data (IPD) and supporting information will be available beginning 6 months after publication of the primary results and will remain available for a period of 5 years following publication.

IPD Sharing Access Criteria

De-identified individual participant data (IPD) and supporting documents (study protocol, statistical analysis plan, and analytic code) will be available to qualified researchers whose proposed use of the data has been approved by the study investigators.

Access will be granted upon submission of a methodologically sound research proposal that is aligned with the scientific objectives of the original study. Requests must include a research plan, statistical analysis outline, and evidence of institutional affiliation.

Data will be shared under a formal data-sharing agreement to ensure appropriate use, confidentiality, and compliance with applicable data protection regulations. Data will be transferred securely via encrypted electronic files or through a controlled-access institutional data repository.

• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ANALYTIC_CODE

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No