Neuromodulation-Induced Cortical Prehabilitation in High Grade Glioma Near the Motor Pathway: Cortical Plasticity Assessed by Navigated Transcranial Magnetic Stimulation (nTMS)

Neuromodulation-Induced-Cortical-Prehabilitation In High Grade Glioma Close To The Motor Pathway: Analysis Of The Cortical Brain Plasticity Through Navigated Transacranial Magnetic Stimulation

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Glioma; Glioma, High Grade; Brain Tumor Adult
• Intervention / Treatment: Procedure: Physical Therapy; Procedure: Combined Therapy Group

Detailed Description

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
• Enrollment (Estimated): 63
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Pier Paolo Berti, MD, PhD(c); Phone Number: +39 0471439716; Email: pierpaolo.berti@sabes.it
• Study Contact Backup: Name: Luigi Cattaneo, Associate professor; Phone Number: +39 0464 808773; Email: luigi.cattaneo@unitn.it

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Control (no NICP); Physical Therapy Group
Experimental: Physical Therapy Group: patients who undergo only physical therapy; 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)	Procedure: Physical Therapy; 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)
Experimental: Combined Therapy Group: patients who undergo physical therapy + rTMS; 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)	Procedure: Combined Therapy Group; 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)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	From the date of randomization until the date of surgery, assessed up to 15 days
Measurement of neuroplasticity with TMS	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); 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)	From the date of randomization until the date of surgery, assessed up to 15 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)	At 1 month and 3 months after surgery
Measurement of neuroplasticity with TMS	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); 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)	At 1 month and 3 months after surgery

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	From date of randomization until 3 months after surgery
Clinical Outcome	Muscular Strenght Evaluation according to Medical Research Council (1-5)	From date of randomization until 3 months after surgery
Clinical Outcome	Apraxia Network evaluation: 10-ideomotor apraxia task (score from 0 to 20)	From date of randomization until 3 months after surgery
Clinical Outcome	9-hole peg test (seconds)	From date of randomization until 3 months after surgery
Clinical Outcome	Function scale for upper limb: ARAT, Action Research Arm Test (score 0-57)	From date of randomization until 3 months after surgery
Clinical Outcome	Function scale for upper limb: FM-UE, Fugl-Meyer Upper Extremity scale (score 0-66)	From date of randomization until 3 months after surgery

Collaborators and Investigators

• Sponsor: Azienda Sanitaria dell'Alto Adige
• Collaborators: Azienda Ospedaliera Universitaria Integrata Verona; Università degli Studi di Trento
• Investigators: Principal Investigator: Pier Paolo Berti, MD, Department of Neurosurgery, Hospital of Bolzano (SABES-ASDAA) - L. Boehler street n5 Bolzano, BZ, Italy 39100

Publications and helpful links

General Publications

• Boccuni L,Roca-Ventura A,Buloz-Osorio E,Leno-Colorado D,Delgado-Gallén S,Cabello-Toscano M,Perellón-Alfonso R,Villalba-Martínez G,Martínez-Ricarte F,Martín-Fernández J,Buxeda-Rodriguez M,Conesa-Bertrán G,Illueca-Moreno M,Lladó-Carbó E,Perla Y Perla C,Garrido C,Pariente JC,Laredo C,Muñoz-Moreno E,Bargalló N,Trompetto C,Marinelli L,Bartrés-Faz D,Abellaneda-Pérez K,Pascual-Leone A,Tormos-Muñoz JM
• Gulrandhe P,Acharya S,Patel M,Shukla S,Kumar S
• Sheng R,Chen C,Chen H,Yu P
• de Almeida CC,Neville IS,Hayashi CY,Gomes Dos Santos A,Brunoni AR,Teixeira MJ,Paiva WS
• Hamer RP,Yeo TT
• Cargnelutti E,Ius T,Skrap M,Tomasino B

Study record dates

Study Major Dates

• Study Start (Estimated): April 1, 2026
• Primary Completion (Estimated): March 31, 2028
• Study Completion (Estimated): March 31, 2030

Study Registration Dates

• First Submitted: March 2, 2026
• First Submitted That Met QC Criteria: March 11, 2026
• First Posted (Actual): March 13, 2026

Study Record Updates

• Last Update Posted (Actual): March 13, 2026
• Last Update Submitted That Met QC Criteria: March 11, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: rTMS; prehabilitation; neuromodulation; physical therapy; nTMS; brain plasticity; cortical plasticity
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioma; Therapeutics; Rehabilitation; Physical Therapy Modalities
• Other Study ID Numbers: Protocol n.4/2024 bis

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: 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.
• IPD Sharing Time Frame: Beginning 3 months and ending 3 years after the publication of results
• IPD Sharing Access Criteria: 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.
• IPD Sharing Supporting Information Type: SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No