The goal of this clinical trial is to learn whether Neuromodulation-Induced-Cortical-Prehabilitation (NICP)-using physical therapy (constraint-induced movement training, CIM) alone or combined with repetitive transcranial magnetic stimulation (rTMS)-can promote motor-cortex neuroplasticity before surgery in adults with high-grade gliomas near the motor pathway. It will also learn about the feasibility and safety of these prehabilitation strategies around the time of surgery. The main questions it aims to answer are:

1. Does CIM (with or without rTMS) produce measurable motor-cortex plasticity from baseline to pre-surgery as assessed by neuronavigated TMS (nTMS)?
2. Does adding rTMS to CIM lead to greater neuroplastic changes than CIM alone?
3. What clinical, radiological, and neurophysiological outcomes are observed after surgery in participants who receive prehabilitation compared with controls?

Researchers will compare standard care (control) vs CIM-based physical therapy vs CIM plus rTMS to see if these approaches induce preoperative neuroplastic changes that may support better surgical outcomes. Participants will:

1. Be randomized to one of three groups: control, CIM physical therapy, or CIM + rTMS• Undergo nTMS motor mapping and excitability testing at baseline (T0) and the day before surgery (T1)
2. Undergo planned tumor surgery (according to standard methods of care) and complete postoperative clinical, imaging, and neurophysiological follow-up assessments.

Background. The Neuromodulation-Induced-Cortical-Prehabilitation (NICP) is a groundbreaking idea to promote plastic brain changes and, theoretically, to increase the Extent of Resection in brain gliomas improving the surgical outcomes. Moreover, given the infiltrative nature of brain gliomas, NICP could be consistently worthwhile for the patient's clinical outcome, reducing the likelihood of premeditated neurologic sequelae and/or the time-to-recovery during the post-surgical rehabilitation.

Hypothesis, Research Need. Up to date only small case series have analysed NICP-induced neuroplasticity, complicating data interpretation. Our study aims to thoroughly measure through neuronavigated Transcranial-Magnetic-Stimulation (nTMS) the plastic brain changes of Physical Therapy (in particular Constraint-Induced-Movements - CIM), repetitive-TMS (rTMS) and the combination of these two techniques in high-grade gliomas (HGGs) close to the motor pathway before surgery to improve surgical outcomes for the benefit of the patient.

Methodology. This is a multi-center, prospective, randomized pilot trial. The patients are randomized in 3 groups (A. Control Group, B. Physical Therapy Group, C. Physical Therapy+rTMS Group; randomization 1:2:2). The participants undergo motor cortex analysis through nTMS at the baseline - T0 - and the day before surgery - T1. Postoperative clinical, radiological and neurophyisiological outcomes are also gathered.

Patient Enrolment:

• Department of Neurosurgery, Hospital of Bolzano (SABES-ASDAA), Bolzano, Italy
• Department of Neurosurgery, Azienda Ospedaliera Universitaria Integrata (AOUI) di Verona, Italy

Data analysis:

• Department of Neurosurgery, Hospital of Bolzano (SABES-ASDAA), Bolzano, Italy
• Center for Mind/Brain Sciences - CIMEC, University of Trento, Italy
• Department of Neurorehabilitation, Hospital of Vipiteno, SABES-ASDAA), Vipiteno, Italy

Analysis Tools:

1. Measurement of neuroplasticity with TMS(Nextim NBS System 5 in Bolzano/EbNeruo STM9000 in Verona). Cortical changes in motor representations will be addressed with:a) nTMS mapping of the motor cortex representations (MEP amplitude and waveforms) on individual anatomical imagesb)

2. Single-pulse indexes of motor cortical excitability:

   • Cortical Silent Period
   • Recruitment Curve
   • Resting Motor Threshold (and intehemispheric ratio)

3. Dual-pulse measures of cortical excitability:

   • Short-latency intracortical inhibition/facilitation
   • Short-latency afferent inhibition

Expected Outcomes. The investigators don't expect any variation in cortical neuroplasticity between T0 and T1 in group A. On the contrary, The investigators expect a variation in group B, in group C and in group B vs. C.

Inclusion Criteria:

1. Age 18-80
2. Suspect of High Grade Glioma in MRI
3. Any case of cortical/subcortical HGG radiologically close to Motor Pathway and, thus, where intraoperative monitoring assistance is usually required
4. Preservation of motor function (at least ≥ 3 according to Medical Research Council classification)
5. Signed informed Consent

Exclusion Criteria:

1. Refusal to Study participation
2. Multifocal/Bilateral Disease

De-identified IPD necessary to reproduce the primary and secondary analyses, including variables used in the statistical models (baseline characteristics, key covariates, endpoints, and safety outcomes), together with the data dictionary and statistical code. Data not required for the planned analyses and variables posing an increased re-identification risk will not be shared.

Beginning 3 months and ending 3 years after the publication of results

Access will be provided to qualified researchers who submit a methodologically sound proposal. Approved requestors will be granted access to de-identified IPD underlying the published results, the data dictionary/codebook, and the statistical analysis code. Requests should be sent by email to the study sponsor/principal investigator and will be reviewed by a data access committee (or the study team). Access will be provided after signing a data use agreement and only for the purpose approved in the proposal.