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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
SINGLE
Enrollment
63
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)
Repetitive 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.
Time frame: From the date of randomization until the date of surgery, assessed up to 15 days
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)
Time frame: From the date of randomization until the date of surgery, assessed up to 15 days
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)
Time frame: At 1 month and 3 months after surgery
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)
Time frame: At 1 month and 3 months after surgery
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