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 promisingneuromodulation tool to enhance cortical excitability and promote motor recovery.However, most of the existing evidence is based on patients with detectable motor evokedpotentials (MEP+) and mild‐to‐moderate impairment. Patients with MEP‐negative status(MEP‐) and severe upper limb deficits are systematically underrepresented in theliterature, leaving a critical gap regarding the potential of rTMS in this subgroup.The absence of MEP does not necessarily indicate complete structural damage to thecorticospinal tract. Phenomena such as cerebral diaschisis ‐ a transient suppression ofcortical excitability in areas remote from the lesion ‐ may render intact or partiallyintact pathways neurophysiologically silent. Cortical motor mapping with navigated TMSoffers a more sensitive assessment than single‐point MEP measurement, allowing evaluationof the spatial distribution and amplitude of cortical motor representations across astandardized grid.Rationale High‐frequency rTMS (10 Hz) applied over the ipsilesional primary motor cortexhas been shown to increase cortical excitability and may reveal latent corticospinaltract activity in MEP‐negative patients. This study proposes that a single session ofhigh‐frequency rTMS may shift some patients from MEP‐negative to MEP‐positive status, orincrease the number of MEP‐positive points in the cortical motor map, by transientlyenhancing excitability in the affected hemisphere.Study Design Prospective, single‐centre, two‐arm parallel‐group randomized controlledtrial conducted at the Neurorehabilitation Service of Hospital Sant Joan de Deu Palma(Mallorca, Spain). Participants are randomly assigned 1:1 to the intervention or controlgroup using the REDCap randomisation module (simple randomisation). Analysis will beperformed by intention‐to‐treat.Intervention The intervention consists of a single session of high‐frequency rTMS at 10Hz applied using a Magstim Rapid2 stimulator (The Magstim Co. Ltd) with a D70mm Air Filmfigure‐of‐eight coil. A total of 600 pulses are delivered in trains of 15 pulses (1.5 son, 10 s off) at an intensity of 80% of the motor threshold. The stimulation target isthe optimal hotspot identified during the pre‐intervention cortical motor mapping. Incases 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 theaffected hemisphere. The coil is placed at 45 degrees to the sagittal line with thehandle pointing posteriorly. All parameters are within the safety guidelines establishedby the International Federation of Clinical Neurophysiology (IFCN).The control group receives sham stimulation using the same coil rotated 90 degrees at thesame position, producing comparable auditory and cutaneous sensations without effectivecortical stimulation. This validated sham procedure controls for placebo and expectancyeffects.Cortical Motor Mapping Procedure Cortical motor mapping is performed before andimmediately after the intervention in both groups. The procedure uses the Magstim Rapid2stimulator 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 theMNI/Talairach standard space. A 5x5 grid with cells separated by 1 cm is centred on C3 orC4 of the affected hemisphere. Three biphasic pulses at 100% of the maximum stimulatoroutput are delivered per grid point, with a 3‐second inter‐pulse interval.Electromyographic responses are recorded using the UltraPro S100 system with Natus EliteSynergy software (Natus Medical Inc.) from the extensor carpi radialis muscle via bipolarsurface Ag/AgCl electrodes placed according to SENIAM recommendations. Recordingparameters: 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 mspost‐stimulus. MEP amplitude is measured peak‐to‐peak; responses below 10 microvolts areassigned a value of 0.Recruitment Participants are recruited from the Neurorehabilitation Service and referredby their rehabilitation physicians to the non‐invasive brain neuromodulation unit. Aneurophysiologist evaluates each candidate for contraindications and potentialpharmacological interactions with TMS prior to enrolment. Written informed consent isobtained 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 astatistical power above 0.80 in a bilateral contrast, requiring 27 subjects per group (54total) to detect a statistically significant difference between two proportions (0 in thecontrol group and 0.3 in the intervention group), using the Poisson approximation with anestimated 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 betweenneurophysiological mapping variables and baseline clinical measures will be assessedusing Pearson or Spearman coefficients depending on data distribution.