Sensori-motor Network Pre-habilitation by Low-Frequency Repetitive Transcranial Magnetic Stimulation. A Proof-of-Concept

Sensori-motor Network Pre-habilitation by Low-Frequency Repetitive Transcranial Magnetic Stimulation. 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A Proof-of-Concept Noa Ben Dor Ziv, Giovanni Raffa, Antonino Scibilia, Shervin Espahbodinea, and 15 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6361679/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 01 Jul, 2025 Read the published version in Acta Neurochirurgica → Version 1 posted 11 You are reading this latest preprint version 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 prior to 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. Glioma Plasticity Transcranial magnetic stimulation Accelerated rTMS Functional connectivity Sensorimotor Network Prehabilitation Neuromodulation Neurorehabilitation Neurosurgery Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 Figure 11 1. Introduction Brain tumors remain among the leading causes of cancer-related death in individuals under 50, with a five-year survival rate of just 33 [1–3]. Beyond histological grade, the extent of resection (EOR) is the most important prognostic factor. However, when tumors are located in or near eloquent brain regions, achieving maximal resection is often limited by the need to preserve neurological function [4,5]. In motor-eloquent tumors—such as those involving the primary motor cortex or corticospinal tract—disruption of sensorimotor connectivity increases the risk of postoperative deficits [6,7]. The capacity of the brain to adapt—termed neuroplasticity—is an intrinsic feature of neural systems. It enables structural and functional reorganization in response to injury, experience, or environmental changes [8–11]. Importantly, neuroplasticity can be enhanced through external interventions, including neuromodulation. Both invasive and non-invasive techniques have demonstrated the ability to alter cortical excitability and reinforce connectivity within and between networks [12–15]. Building on this concept, neuromodulation-induced cortical prehabilitation (NICP) has emerged as a promising strategy for patients with tumors near eloquent areas. The goal of NICP is to preoperatively induce a reshaping of at-risk functional networks—specifically, to facilitate a shift of function from tumor-adjacent regions to distant, but connected, nodes within the same network [16–18]. Such reorganization could expand the functional margins of safe resection, potentially improving outcomes without increasing postoperative morbidity. Transcranial magnetic stimulation (TMS), the most extensively studied non-invasive neuromodulation technique, has demonstrated therapeutic potential and reasonable safety across a range of neurological and psychiatric disorders [13,19–26]. TMS modulates neural activity by delivering targeted magnetic pulses to the cortex, and depending on stimulation parameters, it can either excite or inhibit cortical regions. Inhibitory protocols, such as low-frequency repetitive TMS (rTMS), have shown particular promise in facilitating adaptive plasticity. Each session of NICP typically involves inhibitory stimulation of the tumor-adjacent eloquent area, followed by functional training to promote engagement of alternative circuits. Over repeated sessions, this process may increase the spatial separation between the tumor and essential functional areas, thereby enabling safer and more extensive resection [17,27,28]. In this exploratory, multimodal pilot study, we investigated whether inhibitory rTMS targeting the right primary motor cortex (M1) could induce functional and structural changes within the motor network in two healthy volunteers. Resting-state functional MRI (rs-fMRI) was used to evaluate changes in network connectivity, while diffusion tensor imaging (DTI) assessed microstructural adaptations. Our goal was to determine whether this intervention could promote measurable reorganization of the motor system—supporting its potential utility as a prehabilitation strategy for neurosurgical patients with motor-eloquent tumors. 2. Materials and Methods Subjects Two healthy volunteers participated in this study (30 years old female, and 28 years old male). Both participants were naive to rTMS and provided written informed consent and completed screening forms for contraindications to MRI and TMS. TMS exclusion criteria were history of epilepsy (also within the family), migraine, tinnitus, history of neurological or psychiatric illness, pregnancy and intake of prescription drugs within the past 14 days. MRI exclusion criteria included claustrophobia, implanted ferromagnetic devices and pregnancy). The study was designed as single-blind, approved by our ethics committee [prot. 88612 July 22nd, 2024] and conducted in accordance with the Declaration of Helsinki. MRI Acquisition The MR study was performed using a 1.5 T scanner (Philips, Ingenia, Netherlands) with the following specifications: T1-weighted, Gradient-Echo multiplanar reconstruction (MPR), echo time (TE) = 3.4 ms, repetition time (TR) = 7.4 ms; T2 weighted echo planar imaging (EPI) sensitized to blood oxygenation level-dependent imaging (BOLD) contrast, TE = 50 ms, TR = 2000 ms, Flip angle = 90°, 22 axial slices, Acquisition matrix (M × P) = 84 × 80, (resting-state fMRI). For resting-state fMRI acquisition (eight minutes), the subjects were trained to hold their eyes closed, trying not to think about anything and to remain awake. Diffusion MRI data were acquired with a single-shell DTI protocol: 32 diffusion directions, b-value of 1000 s/mm², in-plane resolution of 1.953 mm, and slice thickness of 2.0 mm. Acquisition parameters included TR = 4836 ms, TE = 90.7 ms, and parallel imaging using SENSE. Navigated repetitive TMS Procedure A T1-weighted structural MRI (TR = 2,500 ms; TE = 2.22 ms; TI = 1,000 ms; flip angle = 8°; voxel size = 0.8 × 0.8 × 0.8 mm; 208 slices) was used as the subject-specific navigation dataset for TMS. A Nexstim NBS 5 stimulator (Nexstim, Helsinki, Finland) with a figure-of-eight coil (70 mm outer diameter) was used for neuro-navigated TMS. Motor evoked potentials were recorded from the first dorsal interosseous muscle of the contralateral hand using disposable Ag/AgCl surface electrodes (Neuoline 700; Ambu, Ballerup, Denmark). The reference electrode was placed at the left wrist. Muscle activity of the target muscle was monitored to remain below a maximally tolerated baseline activity of 10 µV. Additionally, muscle activity was monitored throughout the session to identify any signs of epileptic activity. The motor hotspot was recorded for each subject as well as the direction of the electric field and the angle that consistently elicits the largest amplitude motor evoked potentials. Resting motor threshold (RMT) was determined before the first rTMS session using the automatic threshold-finding algorithm integrated into the system. The accelerated rTMS intervention (a-rTMS) consisted of 14 sessions, spread over seven consecutive days (two sessions a day). In each session, the subjects were submitted to 30 minutes of low frequency rTMS set at 110% RMT (1Hz, 1800 pulses) to the right primary motor cortex (precentral gyrus, M1), at the level of the area corresponding to the left hand (“omega sign” on the cortical surface). Between sessions, a 90-minute break was applied, and the subjects performed a short 10-minute motor training (left hand movement). Sessions of rTMS were well tolerated and there were no adverse effects observed. During the session, minor tingling sensation was reported, consistent with the rTMS safety literature [28]. Functional MRI Analysis Resting-state fMRI data were preprocessed and analyzed using the CONN toolbox (v22.v2407) and SPM12 [29–33]. Preprocessing included realignment with susceptibility distortion correction, outlier detection, segmentation, MNI normalization, and smoothing. Data were denoised by regressing out white matter and CSF signals, motion parameters and their derivatives, outlier scans, session effects, and linear trends, followed by band-pass filtering (0.008–0.09 Hz) [34]. Functional connectivity was assessed using: Seed-based Connectivity (SBC): The right primary motor cortex (M1; precentral gyrus) was used as a seed to compute whole-brain voxelwise correlations. ROI-to-ROI Connectivity (RRC): Fisher-transformed correlations were calculated between predefined sensorimotor network ROIs in both hemispheres. Interhemispheric Correlation (IHC): Connectivity was evaluated between homologous voxel pairs across hemispheres, using mirrored MNI coordinates. Second-level analysis used CONN’s GLM framework to descriptively compare pre- and post-intervention connectivity patterns within each subject. These voxelwise changes are exploratory and hypothesis-generating rather than statistically powered group-level results. Diffusion MRI Analysis In the current study, we used the DSI Studio ( http://dsi-studio.labsolver.org ) software package to perform a DTI-based connectometry analysis comparing pre- and post-rTMS scans in two healthy subjects, focusing on the potential for structural adaptation within the motor system. Generalized q-sampling imaging (GQI) was applied with a diffusion sampling length ratio of 1.25 [35]. Tensor metrics were derived from volumes with b-values < 1750 s/mm². The primary outcome measure was fractional anisotropy (FA). Tractography was performed using a deterministic algorithm with augmented tracking strategies [36]. A seeding region was placed in the right primary motor cortex, as delineated by the Julich Brain Atlas (Area 4a-R; MNI coordinates 88, 130, 140) [37]. One million seeds were generated. Tracking parameters included an anisotropy threshold between 0.5–0.7 (Otsu method), angular threshold 45–90°, step size equal to voxel spacing, and track length between 30–200 mm. FA values were extracted from regions of interest (ROIs) including bilateral M1 (Area 4a), pre-SMA and SMA proper (Area 6ma and 6mp), corpus callosum, right corticospinal tract, right superior longitudinal fasciculus, and right thalamocortical sensory pathways. 3. Results Resting-State fMRI Given the single-subject design of this exploratory study, all fMRI results are presented descriptively. Post-intervention scans revealed patterns of altered connectivity consistent with short-term reorganization of the motor network. In Subject 1 , seed-based connectivity (SBC) analysis of the right M1 revealed increased connectivity with the contralateral precentral gyrus, bilateral postcentral gyri, the right temporal pole, and anterior inferior temporal regions. A corresponding decrease in connectivity was observed in the right superior and middle frontal gyri, frontal pole, precuneus, and left cerebellum. ROI-to-ROI analysis confirmed these findings, showing enhanced coupling between the right precentral gyrus and bilateral SMAs. When the right SMA was used as a seed, increased connectivity was also observed with bilateral precentral gyri, the right postcentral gyrus, and the contralateral SMA. Interhemispheric correlation (IHC) maps demonstrated increased connectivity between homologous regions, notably in the cingulate cortex, precuneus, bilateral intracalcarine cortices, and precentral gyri. Table 1 ROI−to−ROI analysis with seed on the right precentral gyrus. Note: Values reported represent descriptive connectivity strength between ROIs, based on within−subject analysis. T−scores and p−values are thresholded for visualization purposes and do not indicate statistical significance in the inferential sense. Targets beta (Z) T-score p- uncorrected p-FDR Right SMA 0.61 302.48 0.002105 0.014733 Left SMA 0.42 58.44 0.010893 0.038127 Right postcentral gyrus 0.86 5.9 0.106816 0.249238 Right Frontal Pole -0.22 -3.17 0.194788 0.340879 Left precentral gyrus 0.66 2.41 0.250461 0.350646 Left postcentral gyrus 0.43 1.73 0.33344 0.389014 Left Frontal Pole -0.08 -0.46 0.723792 0.723792 Subject 2 exhibited a more focal pattern of change. SBC maps revealed increased connectivity between right M1 and the left postcentral gyrus, left superior temporal gyrus, and right postcentral gyrus. Reductions in connectivity were found in left frontal regions, including the frontal pole and middle frontal gyrus. ROI-to-ROI analysis identified the strongest increase in connectivity between the right precentral gyrus and left postcentral gyrus, with moderate increases in connectivity to the left precentral gyrus. A marginal increase in connectivity was also observed between right M1 and the SMAs. IHC analysis showed enhanced interhemispheric coherence in the pre central gyri, postcentral gyri, paracingulate gyri, cingulate cortex, medial frontal cortex and frontal poles. Table 2 ROI-to-ROI analysis with seed on the right precentral gyrus. Significant connections (p-uncorrected < 0.05) are seen with the right postcentral gyrus, left postcentral gyrus, and left precentral gyrus. Note: Reported values reflect connectivity changes from ROI-to-ROI analysis using the right precentral gyrus as seed. T-scores and p-values are shown for descriptive purposes only; no group-level or inferential statistical analysis was performed. Targets beta (Z) T-score p-unc p-FDR Right Postcentral gyrus 0.730168 38.145928 0.016685 0.116797 Left postcentral gyrus 0.342003 23.078077 0.027568 0.128652 Left precentral gyrus 0.770908 12.56644 0.050554 0.176938 Left SMA 0.401695 6.47518 0.097546 0.227608 Right SMA 0.526945 3.117117 0.19763 0.338273 Diffusion Tensor Imaging (DTI) DTI analyses revealed tract-specific changes in fractional anisotropy (FA) following the intervention. In Subject 1 , FA increased bilaterally in the SMA (pre-SMA and SMA proper), most prominently in the left hemisphere. Increases were also noted in the left M1 (Area 4a) and the corpus callosum. These changes may reflect compensatory recruitment of higher-order motor regions and increased interhemispheric communication. In contrast, FA decreased in right-hemispheric sensorimotor tracts, including the right corticospinal tract, superior longitudinal fasciculus/cingulum, medial lemniscus, and thalamic radiation, potentially indicating reduced reliance on the stimulated hemisphere’s output pathways. Table 3 A summary of mean FA values across selected motor-related regions and tracts. Region/Tract FA Pre FA Post Δ FA (Post – Pre) Area 4a – Right (M1) 0.253634 0.237745 –0.0159 Area 4a – Left 0.493147 0.499099 0.0059 Area 6ma – Left (pre-SMA) 0.219084 0.238697 0.0196 Area 6mp – Left (SMA proper) 0.188042 0.207331 0.0193 Area 6ma – Right (pre-SMA) 0.223259 0.23434 0.0111 Area 6mp – Right (SMA proper) 0.20712 0.218388 0.0113 Corpus Callosum 0.500761 0.504344 0.0036 Corticospinal Tract – Right 0.559721 0.556508 –0.0032 R. SLF / Cingulum 0.404407 0.40085 –0.0036 Medial Lemniscus – Right 0.493402 0.487191 –0.0062 Thalamic Radiation – Right 0.439626 0.436611 –0.0030 In Subject 2 , the post-intervention scans exhibited a marked reduction of FA in the left SMA proper (Area 6mp-L). Subtle reductions in FA were observed in the right M1, right pre-SMA, and left pre-SMA. FA increased modestly in the right SMA proper and right thalamic radiation, while values remained stable in the corpus callosum, right CST, and right SLF/cingulum. A slight decrease was noted in the right medial lemniscus. Table 4 A summary of mean FA values across selected motor-related regions and tracts. Region/Tract FA Pre FA Post Δ FA (Post – Pre) Area 4a – Right (M1) 0.50676 0.505561 -0.001199 Area 4a – Left 0.489557 0.486547 -0.00301 Area 6ma – Left (pre-SMA) 0.520421 0.505975 -0.014446 Area 6mp – Left (SMA proper) 0.539573 0.207331 -0.014446 Area 6ma – Right (pre-SMA) 0.491937 0.480468 -0.011469 Area 6mp – Right (SMA proper) 0.463579 0.471293 0.007714 Corpus Callosum 0.523754 0.523197 -0.000557 Corticospinal Tract – Right 0.518193 0.517382 -0.000811 R. SLF / Cingulum 0.403649 0.40361 –0.000039 Medial Lemniscus – Right 0.486809 0.481385 -0.005424 Thalamic Radiation – Right 0.460806 0.465018 0.004212 4. Discussion This exploratory study investigated whether accelerated low-frequency rTMS targeting the right primary motor cortex (M1) could induce short-term reorganization within the motor network in healthy individuals. Using resting-state fMRI and diffusion tensor imaging (DTI), we identified descriptive changes in functional connectivity and white matter microstructure, consistent with early neuromodulatory effects on motor system architecture. In both subjects, post-intervention imaging revealed increased interhemispheric functional connectivity, particularly between homologous sensorimotor regions. Connectivity between the right M1 and supplementary motor areas (SMAs) was also strengthened, especially in Subject 1, who showed a broader pattern of bilateral engagement. Subject 2 exhibited a more localized and lateralized response, with enhanced coupling between right M1 and contralateral somatosensory regions, but more limited SMA involvement. These functional changes were mirrored, to varying degrees, in DTI-based measures of microstructure. Subject 1 showed increased FA in bilateral SMA regions, left M1, and the corpus callosum, alongside decreased FA in right-hemispheric tracts, including the corticospinal tract and medial lemniscus—suggesting a potential shift in network balance from the stimulated to the contralateral hemisphere. In contrast, Subject 2 demonstrated a more focal structural response, with prominent FA reduction in the left SMA and more stable values in other tracts. The heterogeneity between subjects underscores the individual variability in plastic responses to neuromodulation. Table 5 Descriptive changes in fractional anisotropy (ΔFA) following inhibitory rTMS across selected motor-related tracts. Region/Tract ΔFA Subject 1 ΔFA Subject 2 Interpretation Area 4a – Right (M1) 0.0005 –0.0012 Opposite trend; S1 ↑, S2 ↓ Area 6ma – Right (pre-SMA) 0.011 –0.0115 Opposite trend Area 6mp – Right (SMA) 0.0113 0.0077 ↑ in both (plasticity) Area 6ma – Left (pre-SMA) 0.0196 –0.0144 Strong opposite pattern Area 6mp – Left (SMA proper) 0.0193 –0.3322 S1 ↑ vs. strong ↓ in S2 Corpus Callosum 0.0036 –0.0006 S1 ↑, S2 ~ stable ↓ Corticospinal Tract – Right –0.0032 –0.0008 Mild ↓ in both SLF / Cingulum – Right –0.0036 –0.0000 Nearly no change Medial Lemniscus – Right –0.0062 –0.0054 Consistent mild ↓ Thalamic Radiation – Right –0.0030 0.0042 Opposite trend Theoretically, the evidence of sensory-motor TMS-induced potentiation might have important clinical implications for neurosurgery, such as in the management of brain tumors, where motor network connectivity has been demonstrated to be involved in tolerance and recovery to surgical manipulation. Specifically, strong connectivity, especially between M1 and SMA, intra- and interhemispheric, was associated with reduced risk of post-operative deficits and with better motor performance, where increased connectivity of the sensorimotor network has been shown to be related to better motor performance and lower risk of post-operative deficits [6,7,38–40]. The use of rTMS to elicit sensorimotor network re-organization has been studied extensively in both healthy volunteers [41–44], and in patient population, mainly in the motor rehabilitation literature [43,45–47]. The highest volume of data comes from adult stroke rehabilitation, where rTMS was shown to facilitate post-lesional neuroplasticity with consequent beneficial motor effects [20,38,39]. The same concept has been recently utilized for rehabilitation after glioma surgery, where rTMS treatment with theta burst stimulation (TBS) protocol was associated with a significant improvement [48]. These treatments often require long stimulation protocols lasting several weeks [20]. To overcome this limitation, we have recently demonstrated preliminary evidence for the safety and feasibility of an accelerated protocol, where low frequency rTMS was applied over the primary motor cortex (M1) for 7 days, twice daily (1Hz, 30 min, 110% RMT) [28]. Our study provides the proof-of-concept that sensory-motor connectivity can be modulated by performing accelerated low frequency rTMS in 7 days. This short-lasting prehabilitation protocol is potentially suitable for almost any neurosurgical patient harboring brain tumors at risk of postoperative motor deficit. For those patients, non-invasive individual functional reorganization might lead to larger resection while preserving neurological function and quality of life. This concept of non-invasive “neuromodulation-induced cortical prehabilitation” (NICP) has been recently proposed in the literature as a novel strategy to increase the safety of surgical resection of brain tumors [16–18,49–54]. Pioneering efforts have been made in the field, with the publications of five studies: Barcia et al. and Dadario et al. performed theta-burst rTMS in patients with relapsed tumors affecting Broca’s area and the right motor area respectively. However, in the first case [51], follow-up fMRI showed no discernible change; in the second case [52], a gross-total resection was obtained, but the patient woke up with left-sided hemiparesis. In a proof-of-concept pilot study, Lang et al. investigated preoperative tDCS in eight patients with left-sided glioma [49]. In an attempt to modulate the sensorimotor network, patients underwent four consecutive days of motor training combined with tDCS (the anode positioned over the left primary motor cortex and the cathode over the contralateral supraorbital area). Following the intervention, M1 had increased global and local connectivity, though the seed-to-whole-brain analysis did not show significant clusters, suggesting the increased global and local connectivity observed in M1 was not due to any particular connection. Moreover, interhemispheric connectivity did not change significantly and SMA seemed to be decreased in connectivity. Very recently, Boccuni et al. described a case series of ten patients who underwent a prehabilitation protocol consisting of daily neuromodulation coupled with intensive functional training, for a period of two to four weeks [17,18,55]. Neuromodulation was performed by means of low frequency rTMS set at 90% RMT (eight patients), multichannel tDCS (one patient), or both rTMS and tDCS (one patient). Patients were classified as “motor” or “cognitive” depending on the location of the tumor and the potential compromised function (motor or language). Relevant plasticity changes (increase in the distance between tumor and critical area) were observed in only two cases, when the rTMS was applied on the peak fMRI (main cluster of activation). 5. Conclusions This small-scale pilot study provides proof of concept that accelerated, low-frequency rTMS over the primary motor cortex can induce functional and structural reorganization of the sensorimotor network. In both subjects, resting-state fMRI revealed changes in intra- and interhemispheric connectivity involving M1, SMA, and sensorimotor regions, while diffusion tensor imaging (DTI) identified tract-specific alterations in white matter microstructure. Overall, this research supports the potential of rTMS-based prehabilitation to inform novel strategies for the treatment of eloquent brain tumors, particularly in enhancing functional resilience prior to surgery. Although the results remain descriptive and limited to healthy individuals, they align with compelling findings from other studies and underscore the clinical relevance of early network reorganization. To validate and extend these observations, further studies are needed to assess the safety, feasibility, and efficacy of this protocol in larger samples, including both healthy volunteers and patient populations. In our view, these efforts are fully warranted by the results presented here and by the growing body of evidence supporting neuromodulation as a promising adjunct to neurosurgical planning. Declarations Author Contributions: Conceptualization, A.C.; methodology, A.C., G.R..; validation, C.T., R.L., S.C., S.V., F.G.; formal analysis, N.B.D., G. Ga., G.Z.; investigation, N.B.D., A.C., A.R., L.C.; resources, S.E., C.G.G.M, F.F..; data curation, X.X.; writing—original draft preparation, N.B.D., A.C. , A.S.; writing—review and editing, M..M, M.Z., G.G..; supervision, A.C..; project administration, A.C.; funding acquisition, A.C., M.Z.., S.C., G.R..Y. All authors have read and agreed to the published version of the manuscript. Funding: This research was funded by Next Generation EU – PNRR M6C2, project number: PNRR-TR1-2023-12377246 Institutional Review Board Statement: The study was conducted in accordance with the Declaration of Helsinki, and approved by the Institutional Ethics Committee of CE-AVEC Azienda USL Bologna and Azienda USL Imola (protocol code N° 362-2024-OSS-AUSLBO approved on July 18 th 2024) Informed Consent Statement: Written informed consent has been obtained from the patient to publish this paper Conflicts of Interest: The authors declare no conflicts of interest References Rasmussen, B.K.; Hansen, S.; Laursen, R.J.; Kosteljanetz, M.; Schultz, H.; Nørgård, B.M.; Guldberg, R.; Gradel, K.O. Epidemiology of Glioma: Clinical Characteristics, Symptoms, and Predictors of Glioma Patients Grade I–IV in the the Danish Neuro-Oncology Registry. J Neurooncol 2017 , 135 , 571–579, doi:10.1007/s11060-017-2607-5. 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Cite Share Download PDF Status: Published Journal Publication published 01 Jul, 2025 Read the published version in Acta Neurochirurgica → Version 1 posted Editorial decision: Revision requested 19 May, 2025 Reviews received at journal 19 May, 2025 Reviews received at journal 07 May, 2025 Reviewers agreed at journal 04 May, 2025 Reviewers agreed at journal 28 Apr, 2025 Reviews received at journal 08 Apr, 2025 Reviewers agreed at journal 08 Apr, 2025 Reviewers invited by journal 08 Apr, 2025 Editor assigned by journal 07 Apr, 2025 Submission checks completed at journal 07 Apr, 2025 First submitted to journal 02 Apr, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6361679","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":440272802,"identity":"c336a6b8-0b41-4778-a222-86b9eddf9f9e","order_by":0,"name":"Noa Ben Dor Ziv","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABFElEQVRIie2RsWrDMBBAJQT1YrerQ5t/EGQImforMhmydPBUPASjElAW06wRlH5Du2SWObAX0TlDBptAZvUHSqUECiUOSbcOeqDjdOJxOgkhj+efQuzC3AaFMrdPXI5Cuq+cVTSKfysnnB8FYeEUdig7pavNMJg1JM02/cVt3UL0mue0Hj81WGzuhgHHYI6VUVFRstS7gXxmDKIVxFS3M4rFLhwVqvNidM0oiQQkbxqpUq5UTNeJiLGA0B6dUCaGRF9OwbyUL/klyoPtwp1CkPrk5AJF6xSWFQxkcYWUqaAn3SzsA+wsJVe6Q6nn79t0Cv1FGGwNm+Y31/Wkbcwj3NvHBJMdK46O5mwfD5/l8Xg8nr/zDWCPedRV/IbyAAAAAElFTkSuQmCC","orcid":"","institution":"University of Bologna","correspondingAuthor":true,"prefix":"","firstName":"Noa","middleName":"Ben Dor","lastName":"Ziv","suffix":""},{"id":440272804,"identity":"b5a5c96b-2d07-4591-bc96-df3fa2f8c119","order_by":1,"name":"Giovanni Raffa","email":"","orcid":"","institution":"University of Messina","correspondingAuthor":false,"prefix":"","firstName":"Giovanni","middleName":"","lastName":"Raffa","suffix":""},{"id":440272806,"identity":"d1e4c722-e386-42ba-870a-cf53151d0708","order_by":2,"name":"Antonino Scibilia","email":"","orcid":"","institution":"IRCCS Istituto delle Scienze Neurologiche di Bologna","correspondingAuthor":false,"prefix":"","firstName":"Antonino","middleName":"","lastName":"Scibilia","suffix":""},{"id":440272809,"identity":"be244e94-32af-4c86-9459-3cdaa393c8b5","order_by":3,"name":"Shervin Espahbodinea","email":"","orcid":"","institution":"University of Messina","correspondingAuthor":false,"prefix":"","firstName":"Shervin","middleName":"","lastName":"Espahbodinea","suffix":""},{"id":440272811,"identity":"fc4fa615-1ddd-4489-8aeb-9410db9d22f2","order_by":4,"name":"Cristofer Gonzalo Garcia Moreira","email":"","orcid":"","institution":"University of Messina","correspondingAuthor":false,"prefix":"","firstName":"Cristofer","middleName":"Gonzalo Garcia","lastName":"Moreira","suffix":""},{"id":440272812,"identity":"d6baab15-7210-42c2-910f-d0d8525dc413","order_by":5,"name":"Domenico La Torre","email":"","orcid":"","institution":"Università degli Studi Magna Graecia di Catanzaro","correspondingAuthor":false,"prefix":"","firstName":"Domenico","middleName":"La","lastName":"Torre","suffix":""},{"id":440272816,"identity":"7c4d217a-8989-4309-a24c-79a87c63b10a","order_by":6,"name":"Filippo Friso","email":"","orcid":"","institution":"IRCCS Istituto delle Scienze Neurologiche di Bologna, Alma Mater Studiorum Università di Bologna","correspondingAuthor":false,"prefix":"","firstName":"Filippo","middleName":"","lastName":"Friso","suffix":""},{"id":440272823,"identity":"853bab05-3159-48d7-bd04-70eb0595bb51","order_by":7,"name":"Francesca Granata","email":"","orcid":"","institution":"University of Messina","correspondingAuthor":false,"prefix":"","firstName":"Francesca","middleName":"","lastName":"Granata","suffix":""},{"id":440272827,"identity":"954a76d5-bf50-476c-9fe5-5072a82a748a","order_by":8,"name":"Sergio Vinci","email":"","orcid":"","institution":"University of Messina","correspondingAuthor":false,"prefix":"","firstName":"Sergio","middleName":"","lastName":"Vinci","suffix":""},{"id":440272831,"identity":"d8e4da5a-e52a-422f-8d76-e7dce8fc9dc8","order_by":9,"name":"Arianna Rustici","email":"","orcid":"","institution":"IRCCS Istituto delle Scienze Neurologiche di Bologna, Alma Mater Studiorum Università di Bologna","correspondingAuthor":false,"prefix":"","firstName":"Arianna","middleName":"","lastName":"Rustici","suffix":""},{"id":440272833,"identity":"a959018f-d6af-4c34-84ea-b9ac3bb938ff","order_by":10,"name":"Salvatore M. 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Before (A) and after (B) rTMS stimulation. Color scale reflects Fisher-transformed correlation coefficients.\u003c/p\u003e","description":"","filename":"image1.png","url":"https://assets-eu.researchsquare.com/files/rs-6361679/v1/4e511cbad074d006926ef310.png"},{"id":80293376,"identity":"860694fe-9933-4204-a418-f22d5e6b82ad","added_by":"auto","created_at":"2025-04-10 08:17:44","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":34935,"visible":true,"origin":"","legend":"\u003cp\u003eAnatomical 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. \u003cem\u003eNote: These T-values reflect descriptive thresholds applied within a single-subject analysis; no group-level inference was performed.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"image2.png","url":"https://assets-eu.researchsquare.com/files/rs-6361679/v1/5fb186b52a0dd60adf40f192.png"},{"id":80293377,"identity":"e6279433-1dde-4c87-8dcd-ec8520827c11","added_by":"auto","created_at":"2025-04-10 08:17:44","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":99910,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eROI-to-ROI analysis with seed on the right precentral gyrus.\u003c/strong\u003e 3D brain reconstruction showing the above threshold connections (p-uncorrected \u0026lt; 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.\u003c/p\u003e","description":"","filename":"image3.png","url":"https://assets-eu.researchsquare.com/files/rs-6361679/v1/105f70472af439bb365cd3da.png"},{"id":80294477,"identity":"8b8eaf4c-4b05-4867-896d-d893b2f48363","added_by":"auto","created_at":"2025-04-10 08:25:44","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":209856,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eInterhemispheric connectivity.\u003c/strong\u003e Before (A) and after (B) stimulation. Color bar represents the Z-score of Fisher-transformed correlation coefficients.\u003c/p\u003e","description":"","filename":"image4.png","url":"https://assets-eu.researchsquare.com/files/rs-6361679/v1/f15534763e87df0b44e3f524.png"},{"id":80293379,"identity":"8769f0c1-43a1-4e05-8129-5e3f933a669f","added_by":"auto","created_at":"2025-04-10 08:17:44","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":429969,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSeed-based connectivity (SBC) maps with the right precentral gyrus as seed\u003c/strong\u003e. Before (A) and after (B) rTMS stimulation. Color scale reflects Fisher-transformed correlation coefficients.\u003c/p\u003e","description":"","filename":"image5.png","url":"https://assets-eu.researchsquare.com/files/rs-6361679/v1/ad1c3b163535761eaafff783.png"},{"id":80292718,"identity":"f7493daf-fa74-4d7c-8c0a-b9c0f7b503da","added_by":"auto","created_at":"2025-04-10 08:09:44","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":47382,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eROI-to-ROI connectivity after rTMS with seed in the right precentral gyrus.\u003c/strong\u003e Yellow bars indicate observed increases above descriptive threshold (p-uncorrected \u0026lt; 0.05). \u003cem\u003eNote: All connectivity changes are descriptive and based on single-subject analysis.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"image6.png","url":"https://assets-eu.researchsquare.com/files/rs-6361679/v1/6a579d41b43790a6cb59cf4a.png"},{"id":80292727,"identity":"0349e2cd-8489-404e-ad33-5f95e6a5ff62","added_by":"auto","created_at":"2025-04-10 08:09:44","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":318077,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eInterhemispheric connectivity maps\u003c/strong\u003e. Before (A) and after (B) rTMS, showing Z-score differences in correlation strength. \u003cem\u003eNote: Results are visualized using descriptive voxelwise thresholds; no inferential statistical conclusions are drawn.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"image7.png","url":"https://assets-eu.researchsquare.com/files/rs-6361679/v1/005b4e6e0dbaabe59388bfc8.png"},{"id":80292728,"identity":"2904f451-4cb8-4076-b1c8-1b676ffd2a14","added_by":"auto","created_at":"2025-04-10 08:09:44","extension":"png","order_by":8,"title":"Figure 8","display":"","copyAsset":false,"role":"figure","size":84762,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFractional anisotropy (FA) values pre- and post-rTMS in Subject 1 across selected motor-related white matter regions. \u003c/strong\u003eEach bar represents the FA value before (gray) and after (blue) the rTMS intervention\u003cem\u003e. Note: Quantitative analysis is reported in table 4.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"image8.png","url":"https://assets-eu.researchsquare.com/files/rs-6361679/v1/739132c7db64483a7068f376.png"},{"id":80293381,"identity":"a894bbfb-003e-46c4-861d-f432c2d457b7","added_by":"auto","created_at":"2025-04-10 08:17:44","extension":"png","order_by":9,"title":"Figure 9","display":"","copyAsset":false,"role":"figure","size":95979,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFractional anisotropy (FA) values pre- and post-rTMS in Subject 2 across selected motor-related white matter regions. \u003c/strong\u003eEach bar represents the FA value before (gray) and after (red) the rTMS intervention\u003cem\u003e. Note: Quantitative analysis is reported in table 5.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"image9.png","url":"https://assets-eu.researchsquare.com/files/rs-6361679/v1/94243536966ec801c4a4f451.png"},{"id":80297317,"identity":"bc731f77-c2da-4c4c-b579-ef564552436a","added_by":"auto","created_at":"2025-04-10 08:41:44","extension":"png","order_by":10,"title":"Figure 10","display":"","copyAsset":false,"role":"figure","size":108721,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eDescriptive comparison of fMRI connectivity changes (post vs. pre rTMS) in Subject 1 and Subject 2.\u003c/strong\u003e 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.\u003c/p\u003e","description":"","filename":"image10.png","url":"https://assets-eu.researchsquare.com/files/rs-6361679/v1/7531427a07bcd57d7fe60934.png"},{"id":80295322,"identity":"dd1ee30d-ae42-4fad-af2e-fadbafbe6055","added_by":"auto","created_at":"2025-04-10 08:33:44","extension":"png","order_by":11,"title":"Figure 11","display":"","copyAsset":false,"role":"figure","size":107996,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eChange in fractional anisotropy (ΔFA) across motor-related white matter regions and tracts following rTMS intervention.\u003c/strong\u003e 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. Note: Quantitative analysis is reported in table 6.\u003c/p\u003e","description":"","filename":"image11.png","url":"https://assets-eu.researchsquare.com/files/rs-6361679/v1/2b08745bcbd2cf27d9ed9f41.png"},{"id":86178988,"identity":"7d67a0b4-2a76-4fd9-9402-59aae93699e5","added_by":"auto","created_at":"2025-07-07 16:14:11","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3509922,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6361679/v1/41547e70-7b42-4032-8f80-f17ff94c3e87.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Sensori-motor Network Pre-habilitation by Low-Frequency Repetitive Transcranial Magnetic Stimulation. A Proof-of-Concept","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eBrain tumors remain among the leading causes of cancer-related death in individuals under 50, with a five-year survival rate of just 33 [1\u0026ndash;3]. Beyond histological grade, the extent of resection (EOR) is the most important prognostic factor. However, when tumors are located in or near eloquent brain regions, achieving maximal resection is often limited by the need to preserve neurological function [4,5]. In motor-eloquent tumors\u0026mdash;such as those involving the primary motor cortex or corticospinal tract\u0026mdash;disruption of sensorimotor connectivity increases the risk of postoperative deficits [6,7].\u003c/p\u003e \u003cp\u003eThe capacity of the brain to adapt\u0026mdash;termed neuroplasticity\u0026mdash;is an intrinsic feature of neural systems. It enables structural and functional reorganization in response to injury, experience, or environmental changes [8\u0026ndash;11]. Importantly, neuroplasticity can be enhanced through external interventions, including neuromodulation. Both invasive and non-invasive techniques have demonstrated the ability to alter cortical excitability and reinforce connectivity within and between networks [12\u0026ndash;15].\u003c/p\u003e \u003cp\u003eBuilding on this concept, neuromodulation-induced cortical prehabilitation (NICP) has emerged as a promising strategy for patients with tumors near eloquent areas. The goal of NICP is to preoperatively induce a reshaping of at-risk functional networks\u0026mdash;specifically, to facilitate a shift of function from tumor-adjacent regions to distant, but connected, nodes within the same network [16\u0026ndash;18]. Such reorganization could expand the functional margins of safe resection, potentially improving outcomes without increasing postoperative morbidity.\u003c/p\u003e \u003cp\u003eTranscranial magnetic stimulation (TMS), the most extensively studied non-invasive neuromodulation technique, has demonstrated therapeutic potential and reasonable safety across a range of neurological and psychiatric disorders [13,19\u0026ndash;26]. TMS modulates neural activity by delivering targeted magnetic pulses to the cortex, and depending on stimulation parameters, it can either excite or inhibit cortical regions. Inhibitory protocols, such as low-frequency repetitive TMS (rTMS), have shown particular promise in facilitating adaptive plasticity. Each session of NICP typically involves inhibitory stimulation of the tumor-adjacent eloquent area, followed by functional training to promote engagement of alternative circuits. Over repeated sessions, this process may increase the spatial separation between the tumor and essential functional areas, thereby enabling safer and more extensive resection [17,27,28].\u003c/p\u003e \u003cp\u003eIn this exploratory, multimodal pilot study, we investigated whether inhibitory rTMS targeting the right primary motor cortex (M1) could induce functional and structural changes within the motor network in two healthy volunteers. Resting-state functional MRI (rs-fMRI) was used to evaluate changes in network connectivity, while diffusion tensor imaging (DTI) assessed microstructural adaptations. Our goal was to determine whether this intervention could promote measurable reorganization of the motor system\u0026mdash;supporting its potential utility as a prehabilitation strategy for neurosurgical patients with motor-eloquent tumors.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e"},{"header":"2. Materials and Methods","content":"\u003cp\u003e\u003cb\u003eSubjects\u003c/b\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eTwo healthy volunteers participated in this study (30 years old female, and 28 years old male). Both participants were naive to rTMS and provided written informed consent and completed screening forms for contraindications to MRI and TMS. TMS exclusion criteria were history of epilepsy (also within the family), migraine, tinnitus, history of neurological or psychiatric illness, pregnancy and intake of prescription drugs within the past 14 days. MRI exclusion criteria included claustrophobia, implanted ferromagnetic devices and pregnancy).\u003c/p\u003e\u003cp\u003e The study was designed as single-blind, approved by our ethics committee [prot. 88612 July 22nd, 2024] and conducted in accordance with the Declaration of Helsinki.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e \u003cp\u003e \u003cb\u003eMRI Acquisition\u003c/b\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eThe MR study was performed using a 1.5 T scanner (Philips, Ingenia, Netherlands) with the following specifications: T1-weighted, Gradient-Echo multiplanar reconstruction (MPR), echo time (TE)\u0026thinsp;=\u0026thinsp;3.4 ms, repetition time (TR)\u0026thinsp;=\u0026thinsp;7.4 ms; T2 weighted echo planar imaging (EPI) sensitized to blood oxygenation level-dependent imaging (BOLD) contrast, TE\u0026thinsp;=\u0026thinsp;50 ms, TR\u0026thinsp;=\u0026thinsp;2000 ms, Flip angle\u0026thinsp;=\u0026thinsp;90\u0026deg;, 22 axial slices, Acquisition matrix (M \u0026times; P)\u0026thinsp;=\u0026thinsp;84 \u0026times; 80, (resting-state fMRI). For resting-state fMRI acquisition (eight minutes), the subjects were trained to hold their eyes closed, trying not to think about anything and to remain awake. Diffusion MRI data were acquired with a single-shell DTI protocol: 32 diffusion directions, b-value of 1000 s/mm\u0026sup2;, in-plane resolution of 1.953 mm, and slice thickness of 2.0 mm. Acquisition parameters included TR\u0026thinsp;=\u0026thinsp;4836 ms, TE\u0026thinsp;=\u0026thinsp;90.7 ms, and parallel imaging using SENSE.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eNavigated repetitive TMS Procedure\u003c/b\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eA T1-weighted structural MRI (TR\u0026thinsp;=\u0026thinsp;2,500 ms; TE\u0026thinsp;=\u0026thinsp;2.22 ms; TI\u0026thinsp;=\u0026thinsp;1,000 ms; flip angle\u0026thinsp;=\u0026thinsp;8\u0026deg;; voxel size\u0026thinsp;=\u0026thinsp;0.8 \u0026times; 0.8 \u0026times; 0.8 mm; 208 slices) was used as the subject-specific navigation dataset for TMS. A Nexstim NBS 5 stimulator (Nexstim, Helsinki, Finland) with a figure-of-eight coil (70 mm outer diameter) was used for neuro-navigated TMS.\u003c/p\u003e \u003cp\u003eMotor evoked potentials were recorded from the first dorsal interosseous muscle of the contralateral hand using disposable Ag/AgCl surface electrodes (Neuoline 700; Ambu, Ballerup, Denmark). The reference electrode was placed at the left wrist. Muscle activity of the target muscle was monitored to remain below a maximally tolerated baseline activity of 10 \u0026micro;V. Additionally, muscle activity was monitored throughout the session to identify any signs of epileptic activity. The motor hotspot was recorded for each subject as well as the direction of the electric field and the angle that consistently elicits the largest amplitude motor evoked potentials. Resting motor threshold (RMT) was determined before the first rTMS session using the automatic threshold-finding algorithm integrated into the system.\u003c/p\u003e \u003cp\u003eThe accelerated rTMS intervention (a-rTMS) consisted of 14 sessions, spread over seven consecutive days (two sessions a day). In each session, the subjects were submitted to 30 minutes of low frequency rTMS set at 110% RMT (1Hz, 1800 pulses) to the right primary motor cortex (precentral gyrus, M1), at the level of the area corresponding to the left hand (\u0026ldquo;omega sign\u0026rdquo; on the cortical surface). Between sessions, a 90-minute break was applied, and the subjects performed a short 10-minute motor training (left hand movement).\u003c/p\u003e \u003cp\u003eSessions of rTMS were well tolerated and there were no adverse effects observed. During the session, minor tingling sensation was reported, consistent with the rTMS safety literature [28].\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eFunctional MRI Analysis\u003c/b\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eResting-state fMRI data were preprocessed and analyzed using the CONN toolbox (v22.v2407) and SPM12 [29\u0026ndash;33]. Preprocessing included realignment with susceptibility distortion correction, outlier detection, segmentation, MNI normalization, and smoothing. Data were denoised by regressing out white matter and CSF signals, motion parameters and their derivatives, outlier scans, session effects, and linear trends, followed by band-pass filtering (0.008\u0026ndash;0.09 Hz) [34].\u003c/p\u003e \u003cp\u003eFunctional connectivity was assessed using:\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eSeed-based Connectivity (SBC): The right primary motor cortex (M1; precentral gyrus) was used as a seed to compute whole-brain voxelwise correlations.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eROI-to-ROI Connectivity (RRC): Fisher-transformed correlations were calculated between predefined sensorimotor network ROIs in both hemispheres.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eInterhemispheric Correlation (IHC): Connectivity was evaluated between homologous voxel pairs across hemispheres, using mirrored MNI coordinates.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eSecond-level analysis used CONN\u0026rsquo;s GLM framework to descriptively compare pre- and post-intervention connectivity patterns within each subject. These voxelwise changes are exploratory and hypothesis-generating rather than statistically powered group-level results.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eDiffusion MRI Analysis\u003c/b\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eIn the current study, we used the DSI Studio (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://dsi-studio.labsolver.org\u003c/span\u003e\u003cspan address=\"http://dsi-studio.labsolver.org\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) software package to perform a DTI-based connectometry analysis comparing pre- and post-rTMS scans in two healthy subjects, focusing on the potential for structural adaptation within the motor system.\u003c/p\u003e \u003cp\u003eGeneralized q-sampling imaging (GQI) was applied with a diffusion sampling length ratio of 1.25 [35]. Tensor metrics were derived from volumes with b-values\u0026thinsp;\u0026lt;\u0026thinsp;1750 s/mm\u0026sup2;. The primary outcome measure was fractional anisotropy (FA). Tractography was performed using a deterministic algorithm with augmented tracking strategies [36]. A seeding region was placed in the right primary motor cortex, as delineated by the Julich Brain Atlas (Area 4a-R; MNI coordinates 88, 130, 140) [37]. One million seeds were generated. Tracking parameters included an anisotropy threshold between 0.5\u0026ndash;0.7 (Otsu method), angular threshold 45\u0026ndash;90\u0026deg;, step size equal to voxel spacing, and track length between 30\u0026ndash;200 mm.\u003c/p\u003e \u003cp\u003eFA values were extracted from regions of interest (ROIs) including bilateral M1 (Area 4a), pre-SMA and SMA proper (Area 6ma and 6mp), corpus callosum, right corticospinal tract, right superior longitudinal fasciculus, and right thalamocortical sensory pathways.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e"},{"header":"3. Results","content":"\u003cp\u003e \u003cb\u003eResting-State fMRI\u003c/b\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eGiven the single-subject design of this exploratory study, all fMRI results are presented descriptively. Post-intervention scans revealed patterns of altered connectivity consistent with short-term reorganization of the motor network.\u003c/p\u003e \u003cp\u003eIn \u003cb\u003eSubject 1\u003c/b\u003e, seed-based connectivity (SBC) analysis of the right M1 revealed increased connectivity with the contralateral precentral gyrus, bilateral postcentral gyri, the right temporal pole, and anterior inferior temporal regions. A corresponding decrease in connectivity was observed in the right superior and middle frontal gyri, frontal pole, precuneus, and left cerebellum. ROI-to-ROI analysis confirmed these findings, showing enhanced coupling between the right precentral gyrus and bilateral SMAs. When the right SMA was used as a seed, increased connectivity was also observed with bilateral precentral gyri, the right postcentral gyrus, and the contralateral SMA. Interhemispheric correlation (IHC) maps demonstrated increased connectivity between homologous regions, notably in the cingulate cortex, precuneus, bilateral intracalcarine cortices, and precentral gyri.\u003c/p\u003e \u003c/div\u003e\u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e\u003cb\u003eROI\u0026minus;to\u0026minus;ROI analysis with seed on the right precentral gyrus.\u003c/b\u003e \u003cem\u003eNote: Values reported represent descriptive connectivity strength between ROIs, based on within\u0026minus;subject analysis. T\u0026minus;scores and p\u0026minus;values are thresholded for visualization purposes and do not indicate statistical significance in the inferential sense.\u003c/em\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTargets\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ebeta (Z)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eT-score\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep- uncorrected\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003ep-FDR\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRight SMA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e302.48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.002105\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.014733\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLeft SMA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e58.44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.010893\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.038127\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRight postcentral gyrus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.86\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.106816\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.249238\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRight Frontal Pole\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-0.22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-3.17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.194788\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.340879\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLeft precentral gyrus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.250461\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.350646\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLeft postcentral gyrus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.73\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.33344\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.389014\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLeft Frontal Pole\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-0.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-0.46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.723792\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.723792\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003e \u003cb\u003eSubject 2\u003c/b\u003e exhibited a more focal pattern of change. SBC maps revealed increased connectivity between right M1 and the left postcentral gyrus, left superior temporal gyrus, and right postcentral gyrus. Reductions in connectivity were found in left frontal regions, including the frontal pole and middle frontal gyrus. ROI-to-ROI analysis identified the strongest increase in connectivity between the right precentral gyrus and left postcentral gyrus, with moderate increases in connectivity to the left precentral gyrus. A marginal increase in connectivity was also observed between right M1 and the SMAs. IHC analysis showed enhanced interhemispheric coherence in the pre central gyri, postcentral gyri, paracingulate gyri, cingulate cortex, medial frontal cortex and frontal poles.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e\u003cb\u003eROI-to-ROI analysis with seed on the right precentral gyrus.\u003c/b\u003e Significant connections (p-uncorrected\u0026thinsp;\u0026lt;\u0026thinsp;0.05) are seen with the right postcentral gyrus, left postcentral gyrus, and left precentral gyrus. \u003cem\u003eNote: Reported values reflect connectivity changes from ROI-to-ROI analysis using the right precentral gyrus as seed. T-scores and p-values are shown for descriptive purposes only; no group-level or inferential statistical analysis was performed.\u003c/em\u003e\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTargets\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ebeta (Z)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eT-score\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep-unc\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep-FDR\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRight Postcentral gyrus\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.730168\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e38.145928\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.016685\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.116797\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLeft postcentral gyrus\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.342003\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e23.078077\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.027568\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.128652\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLeft precentral gyrus\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.770908\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e12.56644\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.050554\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.176938\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLeft SMA\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.401695\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6.47518\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.097546\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.227608\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRight SMA\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.526945\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3.117117\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.19763\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.338273\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eDiffusion Tensor Imaging (DTI)\u003c/b\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eDTI analyses revealed tract-specific changes in fractional anisotropy (FA) following the intervention.\u003c/p\u003e \u003cp\u003eIn \u003cb\u003eSubject 1\u003c/b\u003e, FA increased bilaterally in the SMA (pre-SMA and SMA proper), most prominently in the left hemisphere. Increases were also noted in the left M1 (Area 4a) and the corpus callosum. These changes may reflect compensatory recruitment of higher-order motor regions and increased interhemispheric communication. In contrast, FA decreased in right-hemispheric sensorimotor tracts, including the right corticospinal tract, superior longitudinal fasciculus/cingulum, medial lemniscus, and thalamic radiation, potentially indicating reduced reliance on the stimulated hemisphere\u0026rsquo;s output pathways.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eA summary of mean FA values across selected motor-related regions and tracts.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRegion/Tract\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFA Pre\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFA Post\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eΔ FA (Post \u0026ndash; Pre)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eArea 4a \u0026ndash; Right (M1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.253634\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.237745\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026ndash;0.0159\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eArea 4a \u0026ndash; Left\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.493147\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.499099\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.0059\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eArea 6ma \u0026ndash; Left (pre-SMA)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.219084\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.238697\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.0196\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eArea 6mp \u0026ndash; Left (SMA proper)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.188042\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.207331\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.0193\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eArea 6ma \u0026ndash; Right (pre-SMA)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.223259\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.23434\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.0111\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eArea 6mp \u0026ndash; Right (SMA proper)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.20712\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.218388\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.0113\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCorpus Callosum\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.500761\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.504344\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.0036\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCorticospinal Tract \u0026ndash; Right\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.559721\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.556508\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026ndash;0.0032\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eR. SLF / Cingulum\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.404407\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.40085\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026ndash;0.0036\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedial Lemniscus \u0026ndash; Right\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.493402\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.487191\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026ndash;0.0062\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThalamic Radiation \u0026ndash; Right\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.439626\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.436611\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026ndash;0.0030\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eIn \u003cb\u003eSubject 2\u003c/b\u003e, the post-intervention scans exhibited a marked reduction of FA in the left SMA proper (Area 6mp-L). Subtle reductions in FA were observed in the right M1, right pre-SMA, and left pre-SMA. FA increased modestly in the right SMA proper and right thalamic radiation, while values remained stable in the corpus callosum, right CST, and right SLF/cingulum. A slight decrease was noted in the right medial lemniscus.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eA summary of mean FA values across selected motor-related regions and tracts.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRegion/Tract\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFA Pre\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFA Post\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eΔ FA (Post \u0026ndash; Pre)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eArea 4a \u0026ndash; Right (M1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.50676\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.505561\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-0.001199\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eArea 4a \u0026ndash; Left\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.489557\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.486547\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-0.00301\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eArea 6ma \u0026ndash; Left (pre-SMA)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.520421\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.505975\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-0.014446\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eArea 6mp \u0026ndash; Left (SMA proper)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.539573\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.207331\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-0.014446\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eArea 6ma \u0026ndash; Right (pre-SMA)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.491937\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.480468\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-0.011469\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eArea 6mp \u0026ndash; Right (SMA proper)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.463579\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.471293\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.007714\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCorpus Callosum\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.523754\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.523197\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-0.000557\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCorticospinal Tract \u0026ndash; Right\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.518193\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.517382\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-0.000811\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eR. SLF / Cingulum\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.403649\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.40361\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026ndash;0.000039\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedial Lemniscus \u0026ndash; Right\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.486809\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.481385\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-0.005424\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThalamic Radiation \u0026ndash; Right\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.460806\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.465018\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.004212\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"4. Discussion","content":"\u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eThis exploratory study investigated whether accelerated low-frequency rTMS targeting the right primary motor cortex (M1) could induce short-term reorganization within the motor network in healthy individuals. Using resting-state fMRI and diffusion tensor imaging (DTI), we identified descriptive changes in functional connectivity and white matter microstructure, consistent with early neuromodulatory effects on motor system architecture.\u003c/p\u003e \u003cp\u003eIn both subjects, post-intervention imaging revealed increased interhemispheric functional connectivity, particularly between homologous sensorimotor regions. Connectivity between the right M1 and supplementary motor areas (SMAs) was also strengthened, especially in Subject 1, who showed a broader pattern of bilateral engagement. Subject 2 exhibited a more localized and lateralized response, with enhanced coupling between right M1 and contralateral somatosensory regions, but more limited SMA involvement.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eThese functional changes were mirrored, to varying degrees, in DTI-based measures of microstructure. Subject 1 showed increased FA in bilateral SMA regions, left M1, and the corpus callosum, alongside decreased FA in right-hemispheric tracts, including the corticospinal tract and medial lemniscus\u0026mdash;suggesting a potential shift in network balance from the stimulated to the contralateral hemisphere. In contrast, Subject 2 demonstrated a more focal structural response, with prominent FA reduction in the left SMA and more stable values in other tracts. The heterogeneity between subjects underscores the individual variability in plastic responses to neuromodulation.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDescriptive changes in fractional anisotropy (ΔFA) following inhibitory rTMS across selected motor-related tracts.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRegion/Tract\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eΔFA Subject 1\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eΔFA Subject 2\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eInterpretation\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eArea 4a \u0026ndash; Right (M1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.0005\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026ndash;0.0012\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eOpposite trend; S1 \u0026uarr;, S2 \u0026darr;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eArea 6ma \u0026ndash; Right (pre-SMA)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.011\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026ndash;0.0115\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eOpposite trend\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eArea 6mp \u0026ndash; Right (SMA)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.0113\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.0077\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026uarr; in both (plasticity)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eArea 6ma \u0026ndash; Left (pre-SMA)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.0196\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026ndash;0.0144\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eStrong opposite pattern\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eArea 6mp \u0026ndash; Left (SMA proper)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.0193\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026ndash;0.3322\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eS1 \u0026uarr; vs. strong \u0026darr; in S2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCorpus Callosum\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.0036\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026ndash;0.0006\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eS1 \u0026uarr;, S2\u0026thinsp;~\u0026thinsp;stable \u0026darr;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCorticospinal Tract \u0026ndash; Right\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e\u0026ndash;0.0032\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026ndash;0.0008\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMild \u0026darr; in both\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSLF / Cingulum \u0026ndash; Right\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e\u0026ndash;0.0036\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026ndash;0.0000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNearly no change\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedial Lemniscus \u0026ndash; Right\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e\u0026ndash;0.0062\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026ndash;0.0054\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eConsistent mild \u0026darr;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThalamic Radiation \u0026ndash; Right\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e\u0026ndash;0.0030\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.0042\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eOpposite trend\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eTheoretically, the evidence of sensory-motor TMS-induced potentiation might have important clinical implications for neurosurgery, such as in the management of brain tumors, where motor network connectivity has been demonstrated to be involved in tolerance and recovery to surgical manipulation. Specifically, strong connectivity, especially between M1 and SMA, intra- and interhemispheric, was associated with reduced risk of post-operative deficits and with better motor performance, where increased connectivity of the sensorimotor network has been shown to be related to better motor performance and lower risk of post-operative deficits [6,7,38\u0026ndash;40].\u003c/p\u003e \u003cp\u003eThe use of rTMS to elicit sensorimotor network re-organization has been studied extensively in both healthy volunteers [41\u0026ndash;44], and in patient population, mainly in the motor rehabilitation literature [43,45\u0026ndash;47]. The highest volume of data comes from adult stroke rehabilitation, where rTMS was shown to facilitate post-lesional neuroplasticity with consequent beneficial motor effects [20,38,39]. The same concept has been recently utilized for rehabilitation after glioma surgery, where rTMS treatment with theta burst stimulation (TBS) protocol was associated with a significant improvement [48].\u003c/p\u003e \u003cp\u003eThese treatments often require long stimulation protocols lasting several weeks [20]. To overcome this limitation, we have recently demonstrated preliminary evidence for the safety and feasibility of an accelerated protocol, where low frequency rTMS was applied over the primary motor cortex (M1) for 7 days, twice daily (1Hz, 30 min, 110% RMT) [28]. Our study provides the proof-of-concept that sensory-motor connectivity can be modulated by performing accelerated low frequency rTMS in 7 days. This short-lasting prehabilitation protocol is potentially suitable for almost any neurosurgical patient harboring brain tumors at risk of postoperative motor deficit. For those patients, non-invasive individual functional reorganization might lead to larger resection while preserving neurological function and quality of life.\u003c/p\u003e \u003cp\u003eThis concept of non-invasive \u0026ldquo;neuromodulation-induced cortical prehabilitation\u0026rdquo; (NICP) has been recently proposed in the literature as a novel strategy to increase the safety of surgical resection of brain tumors [16\u0026ndash;18,49\u0026ndash;54]. Pioneering efforts have been made in the field, with the publications of five studies: Barcia et al. and Dadario et al. performed theta-burst rTMS in patients with relapsed tumors affecting Broca\u0026rsquo;s area and the right motor area respectively. However, in the first case [51], follow-up fMRI showed no discernible change; in the second case [52], a gross-total resection was obtained, but the patient woke up with left-sided hemiparesis.\u003c/p\u003e \u003cp\u003eIn a proof-of-concept pilot study, Lang et al. investigated preoperative tDCS in eight patients with left-sided glioma [49]. In an attempt to modulate the sensorimotor network, patients underwent four consecutive days of motor training combined with tDCS (the anode positioned over the left primary motor cortex and the cathode over the contralateral supraorbital area). Following the intervention, M1 had increased global and local connectivity, though the seed-to-whole-brain analysis did not show significant clusters, suggesting the increased global and local connectivity observed in M1 was not due to any particular connection. Moreover, interhemispheric connectivity did not change significantly and SMA seemed to be decreased in connectivity.\u003c/p\u003e \u003cp\u003eVery recently, Boccuni et al. described a case series of ten patients who underwent a prehabilitation protocol consisting of daily neuromodulation coupled with intensive functional training, for a period of two to four weeks [17,18,55]. Neuromodulation was performed by means of low frequency rTMS set at 90% RMT (eight patients), multichannel tDCS (one patient), or both rTMS and tDCS (one patient). Patients were classified as \u0026ldquo;motor\u0026rdquo; or \u0026ldquo;cognitive\u0026rdquo; depending on the location of the tumor and the potential compromised function (motor or language). Relevant plasticity changes (increase in the distance between tumor and critical area) were observed in only two cases, when the rTMS was applied on the peak fMRI (main cluster of activation).\u003c/p\u003e"},{"header":"5. Conclusions","content":"\u003cp\u003eThis small-scale pilot study provides proof of concept that accelerated, low-frequency rTMS over the primary motor cortex can induce functional and structural reorganization of the sensorimotor network. In both subjects, resting-state fMRI revealed changes in intra- and interhemispheric connectivity involving M1, SMA, and sensorimotor regions, while diffusion tensor imaging (DTI) identified tract-specific alterations in white matter microstructure.\u003c/p\u003e \u003cp\u003eOverall, this research supports the potential of rTMS-based prehabilitation to inform novel strategies for the treatment of eloquent brain tumors, particularly in enhancing functional resilience prior to surgery. Although the results remain descriptive and limited to healthy individuals, they align with compelling findings from other studies and underscore the clinical relevance of early network reorganization.\u003c/p\u003e \u003cp\u003eTo validate and extend these observations, further studies are needed to assess the safety, feasibility, and efficacy of this protocol in larger samples, including both healthy volunteers and patient populations. In our view, these efforts are fully warranted by the results presented here and by the growing body of evidence supporting neuromodulation as a promising adjunct to neurosurgical planning.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor Contributions:\u003c/strong\u003e Conceptualization, A.C.; methodology, A.C., G.R..; validation, C.T., R.L., S.C., S.V., F.G.; formal analysis, N.B.D., G. Ga., G.Z.; investigation, N.B.D., A.C., A.R., L.C.; resources, S.E., C.G.G.M, F.F..; data curation, X.X.; writing\u0026mdash;original draft preparation, N.B.D., A.C. , A.S.; writing\u0026mdash;review and editing, M..M, M.Z., G.G..; supervision, A.C..; project administration, A.C.; funding acquisition, A.C., \u0026nbsp;M.Z.., \u0026nbsp; S.C., G.R..Y. All authors have read and agreed to the published version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e This research was funded by Next Generation EU \u0026ndash; PNRR M6C2, project number: PNRR-TR1-2023-12377246\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInstitutional Review Board Statement:\u0026nbsp;\u003c/strong\u003eThe study was conducted in accordance with the Declaration of Helsinki, and approved by the Institutional Ethics Committee of CE-AVEC Azienda USL Bologna and Azienda USL Imola (protocol code N\u0026deg; 362-2024-OSS-AUSLBO approved on July 18\u003csup\u003eth\u003c/sup\u003e 2024)\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInformed Consent Statement:\u0026nbsp;\u003c/strong\u003eWritten informed consent has been obtained from the patient to publish this paper\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of Interest:\u003c/strong\u003e The authors declare no conflicts of interest\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eRasmussen, B.K.; Hansen, S.; Laursen, R.J.; Kosteljanetz, M.; Schultz, H.; N\u0026oslash;rg\u0026aring;rd, B.M.; Guldberg, R.; Gradel, K.O. Epidemiology of Glioma: Clinical Characteristics, Symptoms, and Predictors of Glioma Patients Grade I\u0026ndash;IV in the the Danish Neuro-Oncology Registry. \u003cem\u003eJ Neurooncol\u003c/em\u003e \u003cb\u003e2017\u003c/b\u003e, \u003cem\u003e135\u003c/em\u003e, 571\u0026ndash;579, doi:10.1007/s11060-017-2607-5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVan Den Bent, M.J.; Geurts, M.; French, P.J.; Smits, M.; Capper, D.; Bromberg, J.E.C.; Chang, S.M. Primary Brain Tumours in Adults. \u003cem\u003eThe Lancet\u003c/em\u003e \u003cb\u003e2023\u003c/b\u003e, \u003cem\u003e402\u003c/em\u003e, 1564\u0026ndash;1579, doi:10.1016/S0140-6736(23)01054-1.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchaff, L.R.; Mellinghoff, I.K. 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Preconditioning of the Motor Network with Repetitive Navigated Transcranial Magnetic Stimulation (rnTMS) to Improve Oncological and Functional Outcome in Brain Tumor Surgery: A Study Protocol for a Randomized, Sham-Controlled, Triple-Blind Clinical Trial. \u003cem\u003eTrials\u003c/em\u003e \u003cb\u003e2023\u003c/b\u003e, \u003cem\u003e24\u003c/em\u003e, 638, doi:10.1186/s13063-023-07640-2.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHamer, R.P.; Yeo, T.T. Current Status of Neuromodulation-Induced Cortical Prehabilitation and Considerations for Treatment Pathways in Lower-Grade Glioma Surgery. \u003cem\u003eLife\u003c/em\u003e \u003cb\u003e2022\u003c/b\u003e, \u003cem\u003e12\u003c/em\u003e, 466, doi:10.3390/life12040466.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBoccuni, L.; Roca-Ventura, A.; Buloz-Osorio, E.; Leno-Colorado, D.; Mart\u0026iacute;n-Fern\u0026aacute;ndez, J.; Cabello-Toscano, M.; Perell\u0026oacute;n-Alfonso, R.; Pariente Zorrilla, J.C.; Laredo, C.; Garrido, C.; et al. Exploring the Neural Basis of Non-Invasive Prehabilitation in Brain Tumour Patients: An fMRI-Based Case Report of Language Network Plasticity. \u003cem\u003eFront. Oncol.\u003c/em\u003e \u003cb\u003e2024\u003c/b\u003e, \u003cem\u003e14\u003c/em\u003e, 1390542, doi:10.3389/fonc.2024.1390542.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"acta-neurochirurgica","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"anch","sideBox":"Learn more about [Acta Neurochirurgica](http://link.springer.com/journal/701)","snPcode":"701","submissionUrl":"https://submission.springernature.com/new-submission/701/3","title":"Acta Neurochirurgica","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Glioma, Plasticity, Transcranial magnetic stimulation, Accelerated rTMS, Functional connectivity, Sensorimotor Network, Prehabilitation, Neuromodulation, Neurorehabilitation, Neurosurgery","lastPublishedDoi":"10.21203/rs.3.rs-6361679/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6361679/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eTumors 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 prior to surgery, potentially expanding the margins of safe resection.\u003c/p\u003e\u003ch2\u003eObjective\u003c/h2\u003e \u003cp\u003eThis 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.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eTwo 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).\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eBoth 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.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eThese 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.\u003c/p\u003e","manuscriptTitle":"Sensori-motor Network Pre-habilitation by Low-Frequency Repetitive Transcranial Magnetic Stimulation. 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