Motor network pre-habilitation by low-frequency repetitive transcranial magnetic stimulation. A proof-of-concept

Abstract

Background: Tumors involving motor-eloquent brain regions pose a significant surgical challenge, as maximizing resection while preserving motor function requires a delicate balance. Neuromodulation-induced cortical prehabilitation (NICP) has emerged as a potential strategy to promote functional reorganization before surgery, potentially expanding the margins of safe resection.

Objective: This pilot study aimed to investigate whether accelerated, low-frequency repetitive transcranial magnetic stimulation (rTMS) targeting the right primary motor cortex (M1) could induce functional and microstructural changes in the motor network.

Methods: Two healthy subjects underwent a seven-day intervention consisting of twice-daily sessions of inhibitory rTMS over the right M1 (14 sessions in total). Pre- and post-intervention imaging included resting-state functional MRI (rs-fMRI) and diffusion tensor imaging (DTI). Functional changes were assessed descriptively using seed-based and ROI-to-ROI connectivity analyses. Microstructural changes were evaluated through tract-specific comparisons of fractional anisotropy (FA).

Results: Both subjects exhibited increased interhemispheric functional connectivity and strengthening of compensatory motor pathways, including the supplementary motor areas and bilateral precentral and postcentral gyri. DTI revealed tract-specific changes in FA, with evidence of microstructural modulation in regions such as the SMA, corpus callosum, and corticospinal tract. The magnitude and spatial distribution of changes varied between individuals.

Conclusion: These preliminary findings provide exploratory support for the hypothesis that inhibitory rTMS can induce functional and structural reorganization of the motor network. The combined use of rs-fMRI and DTI highlights the potential of NICP as a prehabilitation strategy in neurosurgical contexts. Further studies in clinical populations are warranted.

Keywords: Accelerated rTMS; Functional connectivity; Glioma; Neuromodulation; Neurorehabilitation; Neurosurgery; Plasticity; Prehabilitation; Sensorimotor Network; Transcranial magnetic stimulation.

Fig. 1

Seed-based connectivity (SBC) maps with the right precentral gyrus as seed. Before (A) and after (B) rTMS stimulation. The color scale reflects Fisher-transformed correlation coefficients

Fig. 2

Anatomical location, MNI coordinates, and T-values of peak clusters identified in the Seed-Based analysis of the right primary motor cortex. Red clusters represent increased connectivity post-stimulation; blue clusters represent reduced connectivity. Note: These T-values reflect descriptive thresholds applied within a single-subject analysis; no group-level inference was performed

Fig. 3

ROI-to-ROI analysis with seed on the right precentral gyrus. 3D brain reconstruction showing the above threshold connections (p-uncorrected < 0.05). Following the intervention, resting state fMRI unveiled a significant correlation between the right precentral gyrus (stimulated area) and both right and left supplementary motor areas (p-uncorrected = 0.0022 and 0.010 respectively). Note: Quantitative analysis is reported in Table 1

Fig. 4

Interhemispheric connectivity. Before (A) and after (B) stimulation. The color bar represents the Z-score of Fisher-transformed correlation coefficients

Fig. 5

Seed-Based connectivity (SBC) maps with the right precentral gyrus as seed. Before (A) and after (B) rTMS stimulation. The color scale reflects Fisher-transformed correlation coefficients

Fig. 6

ROI-to-ROI connectivity after rTMS with seed in the right precentral gyrus. Yellow bars indicate observed increases above the descriptive threshold (p-uncorrected < 0.05). Note: All connectivity changes are descriptive and based on single-subject analysis

Fig. 7

Interhemispheric connectivity maps. Before (A) and after (B) rTMS, showing Z-score differences in correlation strength. Note: Results are visualized using descriptive voxel-wise thresholds; no inferential statistical conclusions are drawn

Fig. 8

Fractional anisotropy (FA) values pre- and post-rTMS in Subject 1 across selected motor-related white matter regions. Each bar represents the FA value before (gray) and after (blue) the rTMS intervention. Note: Quantitative analysis is reported in Table 3

Fig. 9

Fractional anisotropy (FA) values pre- and post-rTMS in Subject 2 across selected motor-related white matter regions. Each bar represents the FA value before (gray) and after (red) the rTMS intervention

Fig. 10

Descriptive comparison of fMRI connectivity changes (post vs. pre rTMS) in Subject 1 and Subject 2. The bar graph represents qualitative changes in functional connectivity between the right M1 and various motor and associative regions following inhibitory rTMS. Ratings were derived from Seed-Based and ROI-to-ROI analyses, interpreted on a qualitative scale: − 2 = marked decrease, − 1 = mild decrease, 0 = no change, 1 = mild increase, 2 = strong increase. Both subjects exhibited increased connectivity in core sensorimotor areas (e.g., precentral and postcentral gyri, SMA), while reductions were observed in frontal associative regions, with notable inter-subject differences in the extent and direction of changes

Fig. 11

Change in fractional anisotropy (ΔFA) across motor-related white matter regions and tracts following rTMS intervention. Bar graph showing the difference in FA values (post – pre) for Subject 1 (blue) and Subject 2 (red) across ten selected regions of interest (ROIs), including primary motor and premotor areas, the corpus callosum, and key projection and association tracts. Positive values indicate increased FA post-intervention; negative values reflect reductions. Notable variability was observed between subjects, with some tracts (e.g., right SMA, right CST) showing similar trends, and others (e.g., left SMA proper) displaying opposite patterns. These results are presented descriptively and should be interpreted as exploratory, given the single-subject design