Effects of High-Frequency rTMS on Cortical Motor Mapping in Stroke Patients With Severe Upper Limb Impairment (MAP2024SJD)

Background Upper limb recovery is a top research priority in stroke rehabilitation. Repetitive transcranial magnetic stimulation (rTMS) has emerged as a promising neuromodulation tool to enhance cortical excitability and promote motor recovery. However, most of the existing evidence is based on patients with detectable motor evoked potentials (MEP+) and mild-to-moderate impairment. Patients with MEP-negative status (MEP-) and severe upper limb deficits are systematically underrepresented in the literature, leaving a critical gap regarding the potential of rTMS in this subgroup.

The absence of MEP does not necessarily indicate complete structural damage to the corticospinal tract. Phenomena such as cerebral diaschisis - a transient suppression of cortical excitability in areas remote from the lesion - may render intact or partially intact pathways neurophysiologically silent. Cortical motor mapping with navigated TMS offers a more sensitive assessment than single-point MEP measurement, allowing evaluation of the spatial distribution and amplitude of cortical motor representations across a standardized grid.

Rationale High-frequency rTMS (10 Hz) applied over the ipsilesional primary motor cortex has been shown to increase cortical excitability and may reveal latent corticospinal tract activity in MEP-negative patients. This study proposes that a single session of high-frequency rTMS may shift some patients from MEP-negative to MEP-positive status, or increase the number of MEP-positive points in the cortical motor map, by transiently enhancing excitability in the affected hemisphere.

Study Design Prospective, single-centre, two-arm parallel-group randomized controlled trial conducted at the Neurorehabilitation Service of Hospital Sant Joan de Deu Palma (Mallorca, Spain). Participants are randomly assigned 1:1 to the intervention or control group using the REDCap randomisation module (simple randomisation). Analysis will be performed by intention-to-treat.

Intervention The intervention consists of a single session of high-frequency rTMS at 10 Hz applied using a Magstim Rapid2 stimulator (The Magstim Co. Ltd) with a D70mm Air Film figure-of-eight coil. A total of 600 pulses are delivered in trains of 15 pulses (1.5 s on, 10 s off) at an intensity of 80% of the motor threshold. The stimulation target is the optimal hotspot identified during the pre-intervention cortical motor mapping. In cases where no MEP-positive point is found, stimulation is applied at C3 or C4 (international 10-20 system), corresponding to the cortical motor representation of the affected hemisphere. The coil is placed at 45 degrees to the sagittal line with the handle pointing posteriorly. All parameters are within the safety guidelines established by the International Federation of Clinical Neurophysiology (IFCN).

The control group receives sham stimulation using the same coil rotated 90 degrees at the same position, producing comparable auditory and cutaneous sensations without effective cortical stimulation. This validated sham procedure controls for placebo and expectancy effects.

Cortical Motor Mapping Procedure Cortical motor mapping is performed before and immediately after the intervention in both groups. The procedure uses the Magstim Rapid2 stimulator with the D70mm Air Film coil and the Brainsight 2 neuronavigation software (Rogue Research Inc.), which reconstructs a 3D structural MRI brain model based on the MNI/Talairach standard space. A 5x5 grid with cells separated by 1 cm is centred on C3 or C4 of the affected hemisphere. Three biphasic pulses at 100% of the maximum stimulator output are delivered per grid point, with a 3-second inter-pulse interval.

Electromyographic responses are recorded using the UltraPro S100 system with Natus Elite Synergy software (Natus Medical Inc.) from the extensor carpi radialis muscle via bipolar surface Ag/AgCl electrodes placed according to SENIAM recommendations. Recording parameters: sampling frequency 5000 Hz, high-pass filter 1 Hz, low-pass filter 2000 Hz, notch filter 50 Hz, gain 1 mV/div, recording window -100 ms pre-stimulus to 300 ms post-stimulus. MEP amplitude is measured peak-to-peak; responses below 10 microvolts are assigned a value of 0.

Recruitment Participants are recruited from the Neurorehabilitation Service and referred by their rehabilitation physicians to the non-invasive brain neuromodulation unit. A neurophysiologist evaluates each candidate for contraindications and potential pharmacological interactions with TMS prior to enrolment. Written informed consent is obtained from all participants before any study procedure.

Safety Monitoring Immediately after completing the post-intervention mapping, participants complete an adverse events questionnaire based on IFCN safety guidelines, assessing pain, auditory changes, cutaneous sensations, muscle contractions, fatigue, drowsiness, mood changes, nausea, neck pain, anxiety, and concentration difficulties.

Statistical Analysis Sample size was calculated accepting an alpha risk of 0.05 and a statistical power above 0.80 in a bilateral contrast, requiring 27 subjects per group (54 total) to detect a statistically significant difference between two proportions (0 in the control group and 0.3 in the intervention group), using the Poisson approximation with an estimated 0% loss to follow-up.

The primary analysis will use repeated-measures ANOVA with group (intervention vs. control) and time (pre vs. post) as factors. Non-parametric tests (Wilcoxon, Friedman) will be applied where distributional assumptions are not met. Correlations between neurophysiological mapping variables and baseline clinical measures will be assessed using Pearson or Spearman coefficients depending on data distribution.

Inclusion criteria

• First-ever stroke confirmed by MRI or CT scan.
• Inability to voluntarily activate the hand musculature:

manual muscle testing score of 1 or less in finger extension.

• Time since stroke onset greater than 6 months.

Exclusion criteria

• History of craniotomy or metallic implants in the skull.
• Diagnosis of uncontrolled epilepsy.
• Diagnosis of other neurological diseases (dementia, Parkinson's disease, neuropathies, multiple sclerosis, or similar conditions).
• Low level of consciousness or significant cognitive impairment that prevents informed consent or study collaboration.
• Diagnosis of rheumatic disease or presence of hand deformities.
• Pregnancy.