Motor Eloquent Navigated Transcranial Magnetic Stimulation for Radiosurgery Planning

Background:

Radiation therapy is a cornerstone in the management of metastatic brain tumors. It is applied either as a first-line treatment or postoperatively to the resected tumor bed. Delivering a sufficiently high radiation dose to the lesion or tumor bed while preventing neurological deficits due to radionecrosis from overexposure of vulnerable healthy brain tissue remains particularly challenging in eloquent brain regions such as the motor cortex.

According to international guidelines (ICRU Reports 50, 62, and 83), target volumes for radiation therapy must be carefully defined, while organs at risk (OARs), including the optic apparatus, cochlea, hippocampus, brainstem, and pituitary gland, must be spared. The motor cortex (M1) and corticospinal tract (CST) should likewise be preserved; however, they are not formally defined as OARs in current guidelines, and their precise delineation is technically demanding.

The anatomical precentral gyrus ("anatomical M1") does not exactly correspond to the functional location of motor control ("functional M1"). Conventional imaging techniques such as functional MRI (fMRI) and diffusion tensor imaging (DTI) provide limited spatial accuracy, with localization errors of up to 1 cm. In contrast, navigated transcranial magnetic stimulation (nTMS) is a noninvasive method that identifies motor-eloquent regions based on individual MRI data, offering more accurate functional mapping for radiation treatment planning. This raises the question of whether integrating postoperative, pre-radiotherapy nTMS maps could enable more tailored and precise radiation therapy plans.

Previous studies have shown that nTMS demonstrates a median deviation of only 5.2 mm compared with direct cortical stimulation (the gold standard), whereas fMRI may deviate even more than 1 cm. Especially in patients with tumors involving the motor cortex, nTMS has been shown to provide superior spatial accuracy. Preliminary data further suggest that incorporating nTMS into radiotherapy planning may reduce radiation exposure to the motor cortex and CST while maintaining optimal target coverage.

However, published studies so far have relied exclusively on preoperative imaging. Postoperative anatomical changes, due to brain shift and variations in the resection cavity, can render these maps inaccurate for postoperative planning. It therefore remains to be determined whether updating nTMS maps using postoperative MRI obtained immediately before radiotherapy can enhance treatment precision and clinical outcomes.

Objective:

The objective of this study is to address the following questions in patients with resected brain metastases involving or adjacent to the motor cortex:

• Is it possible to simultaneously maintain the sufficient radiation dose in the region of the lesion and keep the dose on the functional primary motor area (M1) as low as possible?
• Does the integration of nTMS mapping into radio-oncological treatment planning and the associated dose reduction to M1 affect clinical outcomes?
• Is there a correlation between the final dose received by the functional M1 and the clinical/oncological outcome (post-radiosurgery motor function, radionecrosis and local tumor control at 3, 6- and 12-months follow-up)?

Methods:

The planning of SRS will be performed by a team of radiation oncologists at the Inselspital, Bern University Hospital with extensive experience in brain metastases treatment. Manual segmentations of the target volume and nTMS points will be performed. The included cases will be reviewed for the extent/dose of the treatment plan and two treatment plans will be created: a "standard" and an "nTMS-adapted" treatment plan.

For the "nTMS-adapted" plan, the nTMS motor map will be fused with the planning MRI. The motor map of each patient (regions of interest defined by the positive MEP responses) will be used to define "functional M1". The treatment dose will be prescribed to the planning target volume (Planning target volume (PTV): resection cavity plus any contrast enhancement with a 2 mm safety margin in patients with surgery). This plan will be optimized according to nTMS motor maps by reducing the dose applied to the motor eloquent tissue as low as reasonably possible by constraining the dose prescription in this area to 15 Gy in single fraction. PTV overlap with the motor maps will not be spared. The radiation oncologist selects the nTMS-adapted plan if it covers at least 95% of the target volume; otherwise, the standard plan is chosen to ensure adequate dose coverage.

Inclusion criteria

• Informed consent
• Age ≥ 18 years
• Cerebral metastasis within or adjacent to the primary motor cortex (≤10 mm)
• Resection of tumor
• Eligible for and planned to undergo postresection radiosurgery at Inselspital Bern

Exclusion criteria

• Contraindication to TMS (e.g. Cochlear Implant, other metallic or electrical implants, excluding teeth and post craniotomy, Meniere's disease, pacemaker, deep brain stimulation electrodes, refractory convulsion, symptomatic tinnitus, depression diagnosed by a specialist, psychosis)
• Prior cerebral radiation therapy within the affected precentral gyrus/affecting the planned SRS plan
• Planned whole brain radiotherapy
• Second lesion within 2 cm ipsilateral in the primary motor cortex
• Infection or difficulties in wound healing within the last two weeks prior inclusion
• Pregnancy