A Study Using Brain Stimulation and Behavioral Therapy to Increase Extent of Resection in Low-Grade Gliomas
A Study Using Brain Stimulation and Behavioral Therapy to Increase Extent of Resection in Low-Grade Gliomas
This project is being done to induce remapping of functional cortex in patients with invasive
 gliomas to enable a greater extent of resection of invasive gliomas while minimizing the risk
 of a permanent neurological deficit. Adult diffuse gliomas, or the type of gliomas that are
 being targeted in this study, are not generally curable by surgery; however, life expectancy
 is generally believed to be increased by resecting more of the tumor. Because surgeons cannot
 resect all the tumor when it invades certain parts of the brain that are primarily
 responsible for language or movement, the investigators are attempting to see if they can
 electrically inactivate those parts of the brain with tumor in it so it can be resected in a
 subsequent surgery.
Specific Aim 1: To induce a remapping of primary motor function by pairing deficit-inducing
 cortical stimulation with targeted physiotherapy after an initial maximal safe, but subtotal,
 resection (i.e. standard of care).

 Introduction. The objective for this aim is to demonstrate the ability to induce
 glioma-involved hand M1 remapping with an ICS-TBT protocol using the RNS System (responsive
 neurostimulation device) to enable an extended EoR (extent of resection) upon a second
 surgery before the tumor has significantly grown. The working hypothesis is that the proposed
 protocol will mobilize motor function enough to allow extended resection during a second
 surgery without an associated permanent loss of function. My approach involves implanting the
 RNS System in 3 patients with M1-involved gliomas after they undergo a maximal safe, but
 subtotal, resection (i.e. current SoC (standard of care)). An outpatient ICS-TBT (inhibitory
 cortical stimulation-targeted behavioral therapy) protocol will then be initiated based on
 the previously demonstrated principles with our newly proposed techniques. The rationale for
 this aim is to provide initial evidence for the ability of this technique to safely induce
 plasticity in this anatomical location and patient population. The expected outcome will be a
 demonstration of the remapping of hand M1 function and a corresponding extended resection
 without permanent neurological deficit upon a second surgery.

 Preliminary Evidence. It is well established that the function inherent to certain critical
 cortical nodes, i.e. movement and speech generation, can remap to new areas after years of
 slow tumor invasion. Recently, however, such plasticity was accelerated by delivering
 deficit-inducing cortical stimulation (130 Hz) with implanted subdural grids. While this
 protocol generated remapping that enabled further resection in 5 patients, it also required
 an average inpatient stay of 33 days and unacceptable infectious morbidity, making it not a
 widely applicable protocol. The FDA-approved NeuroPace RNS device is fully implantable and
 can deliver similar stimulation in the outpatient. In fellowship, the investigator became
 well trained in the implantation of this device, and wrote a review of 57 consecutive cases
 at their institution without a single reported infection, lead migration, or hemorrhage.
 Similar technique will be applied to the proposed study.

 Research Design. This is a proof-of-concept study to be performed on 3 patients over
 approximately 3 years.

 Participants: Patients with radiographical evidence of lesions consistent with WHO grade II
 gliomas (i.e. non-enhancing lesions) involving hand M1 will be eligible for this study. WHO
 grade IV gliomas (glioblastomas) will not be considered due to their shorter life
 expectancy4, and WHO grade I gliomas will also not be included because they are more likely
 to receive a GTR (gross total resection). Patients with tumors invading or abutting primary
 motor cortices on structural and functional MRIs such that GTR is anticipated to be unlikely
 during initial resection as SoC will be targeted. Outside of active pregnancy, Neither sex
 nor gender will be considered inclusionary nor exclusionary as it is not expected to affect
 outcome and due to the small study N.

 Initial Surgery: Subjects will undergo an awake craniotomy for maximal safe tumor resection
 with DES (direct electrical simulation) motor mapping and continuous motor monitoring
 consistent with SoC and the anatomy of their lesion. Upon completion of the resection, a
 final DES map will be obtained, and an intraoperative MRI will be taken. If a GTR has been
 achieved, there is evidence of tumor widespread beyond the intraoperative functional map, or
 the final DES suggested new injury to motor pathways, the case will be concluded, consistent
 with SoC, and the patient will exit the study. Otherwise, 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.
 Despite the newly proposed indication, the surgical technique used to implant the device is
 similar to those in combined subtotal resection epilepsy cases. Therefore, the device-related
 risk profile is expected to be similar.

 ICS-TBT Protocol: When the patient is clinically ready for discharge, prior to leaving the
 hospital and removing any intravenous lines, the patient will undergo another complete
 neurological examination and measurement of grip and pinch strength on a dynamometer. An
 extra-operative cortical stimulation map (ECSM) will be performed through the implanted
 electrodes using parameters similar to intraoperative mapping.

 After the ECSM is obtained, ICS will begin. Initial stimulation parameters will be chosen to
 closely approximate previously published parameters of 130 Hz and 1 ms pulse width, and they
 will be adjusted to clinical effect (i.e. a measurable decrease in strength on the Manual
 Motor Scale and/or dynamometer). The stimulation intensity at each electrode contact (or
 pair) will be increased by approximately 0.5 V increments every 3 minutes until the threshold
 for induction of weakness is discovered. Grip and pinch strength will be remeasured, and
 stimulation will be set at this threshold so that the patient might recover the corresponding
 disrupted function through daily intensive TBT practice. If this threshold is set without
 incident, ICS will remain on and the patient can be discharged after 1 hour of observation.
 Further sessions can be conducted on an outpatient basis. If stimulation induces a seizure,
 the stimulation will be paused and the patient will be treated as clinically necessary. If a
 seizure occurs that requires medical intervention, the stimulation will be paused and may be
 turned back on the following day with lower settings up to three more times. If it is
 determined that stimulation cannot be tolerated without seizure induction, no further ICS
 attempts will be made for that patient.

 Once a mild deficit is induced, a TBT regimen of movements focused on rehabilitating the
 affected area will be established. Supervised sessions will be conducted 5 days per week for
 1 hour per session, and patients will be encouraged to continue unsupervised practice
 (self-applied training) at home. Such sessions will continue until an increase of 1.0 V from
 the previous session no longer induces any measurable deficit, at which point the patient
 will undergo another ECSM and may be considered a candidate for a second surgery. Previous
 patients received stimulation for an average of 16 days as inpatients; a similar timeline is
 anticipated here, with the possibility of extending up to 2 months if continued deficits are
 seen. If no improvements change is seen at 2 months, the patient will be offered a second
 surgery at that time to retest the DES map and explant the device.

 As the RNS System is designed to deliver stimulation in response to a detection algorithm (as
 opposed to continuous stimulation), the device will be set to its longest stimulation
 duration of 10-seconds and the lowest possible threshold for triggering. This will
 essentially trigger a responsive stimulation therapy constantly with a downtime of about
 100-300ms between stimulations (i.e. 97-99% continuous stimulation). It is anticipated that
 this is to be essentially equivalent to 100% continuous stimulation. Battery life is expected
 to be sufficient for the proposed trial period, with the option of replacing the battery in
 case of longer-than-expected stimulation requirements with evidence of progress.

 Second Surgery: After opening the previous wound, the bone screw fiducials will be
 re-registered to the neuro-navigation system and lead locations will be reconfirmed. The RNS
 System will then be explanted. An intraoperative MRI with and without contrast will be
 obtained at this point to re-assess the tumor status (note that the RNS System precludes MRIs
 on magnets over 1.5T and with a head coil), and another intraoperative DES map will be
 obtained. Two attending neurosurgeons will discuss the results, and, if it agreed to be safe
 to proceed, an extended resection will be performed with continuous motor monitoring. Once
 the extended resection is completed based on functional constraints and tumor location,
 stable monitoring will be confirmed, and a final intraoperative MRI will be obtained. The
 wound will then be closed in the standard fashion, repairing the skull defect from the device
 with a titanium mesh plate. Standard post-craniotomy clinical care will be followed.

 Outcome Measures, Analyses, and Expected Outcome: Hand strength will be assessed by the
 Manual Motor Scale and dynamometer grip and pinch strength. Upper extremity function will be
 assessed with the Nine-Hole Peg Test (NHPT) and Duruoz Hand Index survey. Formal assessments
 will occur preoperatively, after the first surgery, before the second surgery, after the
 second surgery, and then weekly until the results return to within baseline (i.e. within the
 previously validated minimal clinically important difference [MCID]) or at 3 months. Extent
 of resection will be calculated as: (preoperative tumor volume - postoperative tumor
 volume)/preoperative tumor volume. 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. The
 expected outcome is that all assessments of hand strength and function in all three patients
 will return to within the MCID for their respective scales by 3-months postoperatively with a
 radiographically measurable increase in EoR from the first to second surgery, thereby
 demonstrating the first safe resections into previously unresectable hand M1 enabled by ICS
 delivered through a fully implanted device.
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