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

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.

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