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Additional stimulation parameters outside of standard of care during intraoperative brain stimulation to aid in motor mapping.

Intraoperative Brain Simulation - Alternate Stimulation Parameters

Sarah Cornell

The neurosurgical standard of care for treating a patient with a tumor invading hand primary motor cortex (M1) includes performing a craniotomy with intraoperative direct electrical stimulation (DES) mapping and to resect as much tumor as possible without a resultant permanent neurological deficit. However, the subjective nature of current intraoperative hand motor assessments do not offer a comprehensive understanding of how hand strength and function may be impacted by resection. Additionally, there is a paucity of data to inform how altering DES parameters may effect motor mapping. Here, the investigators seek to demonstrate a feasible, standardized protocol to quantitatively assess hand strength and function and systematically assess several stimulation parameters to improve intraoperative measurements and better understand how cortical stimulation interacts with underlying neural function.

A Study to Measure the Effect of Brain Stimulation on Hand Strength and Function in Patients With Brain Tumors

The Effect of Intraoperative Cortical Stimulation on Hand Strength and Function During Awake Craniotomies

Quantitative assessment on a scale of 0 - 5 5 - normal strength 4 - give away weakness 3 - movement against gravity 2 - movement in anti-gravity position 1 - muscle twitch 0 - no movement

Scored using force production in kilograms (0-90) Standardized procedure for positioning

The Cyberglove III collects data on the movement of the joints in the hand. Subjects will be asked to wear the Cyberglove III while doing various tasks. Velocity will be measured in degrees per second.

The Cyberglove III collects data on the movement of the joints in the hand. Subjects will be asked to wear the Cyberglove III while doing various tasks. Finger individuation will be calculated using joint angles.

The Cyberglove III collects data on the movement of the joints in the hand. Subjects will be asked to wear the Cyberglove III while doing various tasks. Smoothness will be calculated using joint angles.

Medical College of Wisconsin

Assistant Professor of Neurological Surgery

Rare Diseases

Glioma

Neoplasms, Neuroepithelial

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Neuroepithelioma

This is a device feasibility study, therefore participants will only be enrolled into the investigational arm and will receive the 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.

RNS System Implantation

Max Krucoff, MD

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 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

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

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.

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

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.

Reported as number of unintended stimulation effects, such as myoclonus, tonus, seizures, or unpleasant sensations

Reported as number of stimulation- or physiotherapy related ER visits, readmissions, or serious adverse events

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

Any new, permanent neurological deficits resulting from the second surgery

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
A Study to Measure the Effect of Brain Stimulation on Hand Strength and Function in Patients With Brain Tumors	NCT05023434	Brain Tumor Brain Cancer Motor Cortex; L...	Intraoperative ...	18 Years - 75 Years	Medical College of Wisconsin
A Study Using Brain Stimulation and Behavioral Therapy to Increase Extent of Resection in Low-Grade Gliomas	NCT04745156	Glioma Glioma Intracra... Gliomas Benign Brain Tumor Brain Cancer Motor Cortex; L...	RNS System Impl...	18 Years - 65 Years	Medical College of Wisconsin

Spots Global Cancer Trial Database for cortex stimulation