A Study Using Brain Stimulation and Behavioral Therapy to Increase Extent of Resection in Low-Grade Gliomas

Inducing Functional Plasticity in Glioma-Involved Functional Cortex With Deficit-Inducing Cortical Stimulation and Targeted Behavioral Therapy to Increase Extent of Resection

This study uses a cranial implant to deliver cortical stimulation that, when paired with physiotherapy, will remap the brain so that critical brain functions can be protected during brain tumor surgery. This pilot study will provide initial evidence for the safety and feasibility of such a protocol which will lead to future pivotal trials that could radically change eloquent area brain surgery. For patients with otherwise incompletely resectable brain tumors, this could mean a longer life expectancy and a better quality of life.

Study Overview

• Status: Not yet recruiting
• Conditions: Glioma; Brain Cancer; Brain Tumor; Glioma Intracranial; Gliomas Benign; Motor Cortex; Lesion
• Intervention / Treatment: Device: RNS System Implantation

Detailed Description

Study Protocol: Participants will undergo a standard-of-care craniotomy for resection of low-grade glioma. If part of the lesion cannot be removed due to involvement of functional cortex, RNS (Responsive Neurostimulation System [RNS; NeuroPace, Inc.]) electrodes will be implanted over the tumor-invaded area(s) in five participants. Stimulation will then be optimized for each individual to disrupt the function of the invaded cortical node (e.g., hand motor area -> hand dysfunction) (Aim 1). Over the next two months, outpatient physiotherapy will work to overcome the stim-induced deficits through gradual increases in stimulation amplitude as other, non-stimulated brain regions begin to assume its function (Aim 2). Once complete, participants will return to the OR for device explantation, repeated intraoperative mapping, and extended resection (if safe) (Aim 3).

Aim 1: Optimize stimulation to maximize stim-induced deficits and minimize side effects Rationale: To induce plasticity, stimulation parameters must be individually tuned to maximize effect and minimize side effects. Approach: After device implantation and prior to hospital discharge, stimulus settings (frequency, pulse-width, and amplitude) will be optimized to the relevant clinical response while minimizing adverse effects (e.g., focal tonus, myoclonus, or seizures) while still in the safe, inpatient setting. Outcomes: Primary Endpoints: 1) stim-induced focal clinical deficit as measured on the relevant clinical scale (e.g., manual motor score [0-5], picture naming [x/10]), repetition [x/3]); 2) stim-induced side effects (e.g., seizures).

Aim 2: Evaluate extent of remapping and safety of outpatient stimulation-physiotherapy protocol. Rationale: The ability to deliver chronic, outpatient stimulation is vital for practical clinical translation, yet neither its safety nor efficacy has been demonstrated. Approach: After Aim 1, a physiotherapist will assign a personalized, outpatient therapy regimen aimed at overcoming stim-induced deficits. Participants will have daily virtual sessions and return to clinic 2x/week for amplitude increases to re-induce deficits that therapy has overcome. This will continue until stimulation no longer can induce a deficit, suggesting successful functional remapping and enabling a return to the OR for further resection. Outcomes: Primary Endpoints: 1) absence of stim-related ER visits, readmissions, or serious adverse events (safety), 2) changes in intraop stimulation maps from surgery 1 to surgery 2 (induced remapping).

Aim 3: Evaluate ability to extend surgical resections and associated neurological outcomes. Rationale: Any change in functional boundaries will only be useful if it results in a safe, extended resection. Approach: Each surgery will proceed with standard-of-care intraoperative functional mapping techniques and decision making. Neurological examinations will be performed preoperatively, daily while inpatient, then again at 2-weeks and 3-months postoperatively. Extent of resection will be evaluated as 3D residual tumor volume on postoperative MRI. Outcomes: Primary Endpoint: 1) Change in residual tumor volume after second versus first resection, 2) new neurological deficits 3-months after second resection compared to before second resection. Secondary Endpoint: 1) New, temporary neurological deficits after the second surgery

• Study Type: Interventional
• Enrollment (Estimated): 3
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Sarah Cornell; Phone Number: 414-955-0989; Email: scornell@mcw.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age 18-65 years old
2. Ability to understand a written informed consent document, and the willingness to sign it
3. Radiographic evidence of likely low-grade glioma on MRI (i.e. non-enhancing) invading primary motor cortex in the non-dominant hemisphere.
4. Karnofsky performance status (KPS) ≥ 75
5. Normal or near normal motor strength (i.e., at least 3/5 in relevant areas)
6. Normal or near normal speech (Can consistently name at least 4/5 cards)
7. No medical contraindication to surgery
8. Free of other illness that may shorten life expectancy

Exclusion Criteria:

1. Presence of other malignancy not in remission
2. Evidence of bi-hemispheric or widespread tumor involvement
3. Likely candidate to receive GTR on initial resection
4. Medically high-risk surgical candidate
5. History of recent scalp or systemic infection
6. Presence of other implants or foreign bodies in the head
7. Inability to receive an MRI for any reason
8. Inability to receive cortical stimulation for any reason
9. Coagulation disorders and/or use of anti-thrombotic therapies
10. Platelet count < 50
11. Diathermy procedures
12. Electroconvulsive Therapy (ECT)
13. Transcranial Magnetic Stimulation (TMS)
14. Presence of implanted cardiac device (such as a pacemaker or defibrillator)
15. Pregnant women

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Device Feasibility
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: RNS System Implantation; This is a device feasibility study, therefore participants will only be enrolled into the investigational arm and will receive the RNS System Implantation.

Device: RNS System Implantation; Following resection consistent with SoC, if there is evidence of residual tumor which cannot be resected due to invasion of hand-M1 but which is small enough to be covered by two four-electrode strips, these strips will be placed on the functional cortex of interest and secured to the dura. The location of the leads will be registered into the navigation software (either Medtronic Stealth or Brainlab). The dura will then be closed as watertight as possible, and the RNS System will be incorporated into the craniotomy on closure Prior to closure, four bone screws will be placed and registered to the intraoperative navigation system as internal fiducials to be retrieved for future procedures.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Extent of resection	Calculated as: Tumor volume after second surgery - tumor volume before second surgery. Determination of volumes will be made by an attending radiologist without knowledge of clinical outcome. Manual segmentation will be performed to measure tumor volumes based on fluid-attenuated inversion recovery (FLAIR) axial slices.	Within 1 week after second surgery
Stimulation-induced motor deficits	Calculated as manual muscle score (MMS) before stimulation - MMS after stimulation. MMS is a zero-to-five scale assessed as the following: 5 - normal strength 4 - give away weakness 3 - movement against gravity 2 - movement in anti-gravity position 1 - muscle twitch 0 - no movement	Within 2 weeks after first surgery
Stimulation-induced language deficits	3a. Calculated as picture naming score (x/10) before stimulation minus after stimulation. 3b. Calculated as sentence repitition score (x/3) before stimulation minus after stimulation.	Within 2 weeks after first surgery
Stimulation-induced side effects	Reported as number of unintended stimulation effects, such as myoclonus, tonus, seizures, or unpleasant sensations	Within 2 weeks after first surgery
Safety of outpatient stimulation-therapy protocol	Reported as number of stimulation- or physiotherapy related ER visits, readmissions, or serious adverse events	Up to 8 weeks
Stimulation-induced brain remapping	This outcome will be reported as a descriptive variable, calculated as changes in the intraoperative stimulation map obtained during surgery 2 compared to surgery 1	This data will be obtained intraoperatively during the second surgery
Number of participants with a new neurological deficit	Any new, permanent neurological deficits resulting from the second surgery	Assessed at 3-month postoperative visit after second surgery

Collaborators and Investigators

• Sponsor: Medical College of Wisconsin
• Investigators: Principal Investigator: Max Krucoff, MD, Medical College of Wisconsin

Study record dates

Study Major Dates

• Study Start (Estimated): August 1, 2026
• Primary Completion (Estimated): August 1, 2027
• Study Completion (Estimated): September 1, 2027

Study Registration Dates

• First Submitted: February 2, 2021
• First Submitted That Met QC Criteria: February 5, 2021
• First Posted (Actual): February 9, 2021

Study Record Updates

• Last Update Posted (Estimated): January 12, 2026
• Last Update Submitted That Met QC Criteria: January 9, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Keywords: Surgery; Neuroplasticity; Brain Stimulation; Prehabilitation; M1; Plasticity; Resection; Primary Motor Cortex; Motor Rehabilitation; NeuroPace; Cortex Stimulation; Hand Motor Cortex; Motor Mapping
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Nervous System Neoplasms; Central Nervous System Neoplasms; Glioma; Brain Neoplasms
• Other Study ID Numbers: PRO00039766

Drug and device information, study documents

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