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.
Age 18-80
Suspect of High Grade Glioma in MRI
Any case of cortical/subcortical HGG radiologically close to Motor Pathway and, thus, where intraoperative monitoring assistance is usually required
Preservation of motor function (at least ≥ 3 according to Medical Research Council classification)
Refusal to Study participation
Multifocal/Bilateral Disease
Parallel
Physical Therapy
Procedure/SurgeryPhysical Therapy protocol for the 10 days preceding surgery: 6h/day Constraint Induced Movement - CIM (immobilization of the ipsilesional hand - unaffected side) + 1h twice a day of fine motor skills focused exercises (e.g. 9-hole peg test) on the controlateral hand (affected side)
Combined Therapy Group
Procedure/SurgeryRepetitive Transcranial Magnetic Stimulation protocol for the 10 days preceding surgery: This will be done following standard protocols mediated from the protocols for motor and language function in stroke, i.e, daily sessions of 1Hz rTMS for 20 minutes applied to the contralesional hemisphere. • Physical Therapy protocol for the 10 days preceding surgery: 6h/day Constraint Induced Movement - CIM (immobilization of the ipsilesional hand - unaffected side) + 1h twice a day of fine motor skills focused exercises (e.g. 9-hole peg test) on the controlateral hand (affected side)
Measurement of neuroplasticity with nTMS
Cortical changes in motor representations will be addressed with Neuronavigated TMS mapping of the motor representations (MEP amplitude and waveforms) of the cortical surface of the peri-Rolandic region on individual anatomical images (Nextim NBS System 5 in Bolzano/EbNeruo STM9000 in Verona). We will consider as primary outcome variable the extension of the cortical surface from which MEPs can be obtained by neuronavigated TMS on the affected hemisphere during the procedure of neuronavigation. This index will be calculated quantitatively as surface area, on the flattened cortical surface, and on the "density" of MEP amplitude on such surface. In addition, we will carry out a quantitative analysis of how many excitable points are present in different cortical regions, by applying the cortical atlas by Glasser et al. (2016) to the patient's brain. In this way we will also be able to quantify the extension of excitable points to the premotor or even non-motor cortical regions.
Measurement of neuroplasticity with TMS
1. Single-pulse indexes of motor cortical excitability (unit of measure milli Volt - mV): * Cortical Silent Period (CSP) * Recruitment (input-output) Curve (RC) * Resting Motor Threshold (rMT) and intehemispheric rMT ratio (rMT ratio) 2. Dual-pulse measures of cortical excitability (Adimensional; they are MEP-derived ratios . MEP amplitudes are measured in mV).): * Short-latency intracortical inhibition/facilitation (SICI and SICF) * Short-latency afferent inhibition (SAI)
Measurement of neuroplasticity with TMS (after surgery)
Cortical changes in motor representations will be addressed with: Neuronavigated TMS mapping of the motor representations (MEP amplitude and waveforms) of the cortical surface of the peri-Rolandic region on individual anatomical images (Nextim NBS System 5 in Bolzano/EbNeruo STM9000 in Verona)
Measurement of neuroplasticity with TMS
1. Single-pulse indexes of motor cortical excitability (measured in mV): Cortical Silent Period (CSP) Recruitment (input-output) Curve (RC) Resting Motor Threshold (rMT) and intehemispheric rMT ratio (rMT ratio) 2. Dual-pulse measures of cortical excitability (Adimensional; they are MEP-derived ratios - MEP amplitudes are measured in mV): Short-latency intracortical inhibition/facilitation (SICI and SICF) Short-latency afferent inhibition (SAI)
Radiological outcome
Initial Tumor Volume (ITV), Gross Total vs Subtotal Resection (GTR vs STR), Residual Tumor Volume (RTV) These volumes will be measured in mL.
Clinical Outcome
Muscular Strenght Evaluation according to Medical Research Council (1-5)
Clinical Outcome
Apraxia Network evaluation: 10-ideomotor apraxia task (score from 0 to 20)
Clinical Outcome
9-hole peg test (seconds)
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Azienda Sanitaria dell'Alto Adige
Lead sponsor
Università degli Studi di Trento
Collaborator
Azienda Ospedaliera Universitaria Integrata Verona
Collaborator
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