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Background: Several patients with language-eloquent gliomas face language deterioration postoperatively. Persistent aphasia is frequently associated with damage to subcortical language pathways. Underlying mechanisms still need to be better understood, complicating preoperative risk assessment. This study compared qualitative and quantitative functionally relevant subcortical differences pre- and directly postoperatively in glioma patients with and without aphasia., Methods: Language-relevant cortical sites were defined using navigated transcranial magnetic stimulation (nTMS) language mapping in 74 patients between 07/2016 and 07/2019. Post-hoc nTMS-based diffusion tensor imaging tractography was used to compare a tract's pre- and postoperative visualization, volume and fractional anisotropy (FA), and the preoperative distance between tract and lesion and postoperative overlap with the resection cavity between the following groups: no aphasia (NoA), tumor- or previous resection induced aphasia persistent pre- and postoperatively (TIA&#95;P), and surgery-induced transient or permanent aphasia (SIA&#95;T or SIA&#95;P)., Results: Patients with NoA, TIA&#95;P, SIA&#95;T, and SIA&#95;P showed distinct fasciculus arcuatus (AF) and inferior-fronto-occipital fasciculus (IFOF) properties. The AF was more frequently reconstructable, and the FA of IFOF was higher in NoA than TIA&#95;P cases (all p ≤ 0.03). Simultaneously, SIA&#95;T cases showed higher IFOF fractional anisotropy than TIA&#95;P cases (p < 0.001) and the most considerable AF volume loss overall. While not statistically significant, the four SIA&#95;P cases showed complete loss of ventral language streams postoperatively, the highest resection-cavity-AF-overlap, and the shortest AF to tumor distance., Conclusion: Functionally relevant qualitative and quantitative differences in AF and IFOF provide a pre- and postoperative pathophysiological and clinically relevant diagnostic indicator that supports surgical risk stratification., Competing Interests: Declarations. Conflicts of interest: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. This trial was funded entirely by institutional grants from the Department of Neurosurgery, Technical University of Munich, Germany, School of Medicine, Klinikum rechts der Isar. BM received honoraria, consulting fees, and research grants from Medtronic (Meerbusch, Germany), Icotec AG (Altstätten, Switzerland), Nexstim Plc (Helsinki, Finland), and Relievant Medsystems Inc. (Sunnyvale, CA, USA), honoraria, and research grants from Ulrich Medical (Ulm, Germany), honoraria and consulting fees from Spineart Deutschland GmbH (Frankfurt, Germany) and DePuy Synthes (West Chester, PA, USA), and royalties from Spineart Deutschland GmbH (Frankfurt, Germany). SMK is consultant for Ulrich Medical (Ulm, Germany), and Need Inc. (Santa Monica, CA, USA), and received honoraria from Nexstim Plc (Helsinki, Finland), Spineart Deutschland GmbH (Frankfurt, Germany), Medtronic (Meerbusch, Germany) and Carl Zeiss Meditec (Oberkochen, Germany). SMK and BM received research grants and are consultants for Brainlab AG (Munich, Germany). SI is consultant for Brainlab AG (Munich, Germany) and received honoraria and consulting fees from Icotec AG (Altstätten, Switzerland), Carl Zeiss Meditec (Oberkochen, Germany), and Nexstim Plc (Helsinki, Finland). All authors declare that they have no conflict of interest regarding the materials used as well as the results presented in this study. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results. Institutional Review Board: The study was conducted in line with the Declaration of Helsinki and approved by the Institutional Review Board of the Technical University of Munich (reference number: 192/18S, date of approval: 09/20/2018). Informed consent: Informed consent for inclusion was obtained from all subjects before they participated in the study., (© 2024. The Author(s).)

Objective: Language-related networks have been recognized in functional maintenance, which has also been considered the mechanism of plasticity and reorganization in patients with cerebral malignant tumors. However, the role of interhemispheric connections (ICs) in language restoration remains unclear at the network level. Navigated transcranial magnetic stimulation (nTMS) and diffusion tensor imaging fiber tracking data were used to identify language-eloquent regions and their corresponding subcortical structures, respectively., Methods: Preoperative image-based IC networks and nTMS mapping data from 30 patients without preoperative and postoperative aphasia as the nonaphasia group, 30 patients with preoperative and postoperative aphasia as the glioma-induced aphasia (GIA) group, and 30 patients without preoperative aphasia but who developed aphasia after the operation as the surgery-related aphasia group were investigated using fully connected layer-based deep learning (FC-DL) analysis to weight ICs., Results: GIA patients had more weighted ICs than the patients in the other groups. Weighted ICs between the left precuneus and right paracentral lobule, and between the left and right cuneus, were significantly different among these three groups. The FC-DL approach for modeling functional and structural connectivity was also tested for its potential to predict postoperative language levels, and both the achieved sensitivity and specificity were greater than 70%. Weighted IC was reorganized more in GIA patients to compensate for language loss., Conclusions: The authors' method offers a new perspective to investigate brain structural organization and predict functional prognosis.

Glioma resection within language-eloquent regions poses a high risk of surgery-related aphasia (SRA). Preoperative functional mapping by navigated transcranial magnetic stimulation (nTMS) combined with diffusion tensor imaging (DTI) is increasingly used to localize cortical and subcortical language-eloquent areas. This study enrolled 60 nonaphasic patients with left hemispheric perisylvian gliomas to investigate the prediction of SRA based on function-specific connectome network properties under different fractional anisotropy (FA) thresholds. Moreover, we applied a machine learning model for training and cross-validation to predict SRA based on preoperative connectome parameters. Preoperative connectome analysis helps predict SRA development with an accuracy of 73.3% and sensitivity of 78.3%. The current study provides a new perspective of combining nTMS and function-specific connectome analysis applied in a machine learning model to investigate language in neurooncological patients and promises to advance our understanding of the intricate networks., (© 2022 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Objective: In adult patients, an increasing group of neurosurgeons specialize entirely in the treatment of highly eloquent tumors, particularly gliomas. In contrast, extensive perioperative neurophysiological workup for pediatric cases has been limited essentially to epilepsy surgery., Methods: The authors discuss radio-oncological and general oncological considerations based on the current literature and their personal experience., Results: While several functional mapping modalities facilitate preoperative identification of cortically and subcortically located eloquent areas, not all are suited for children. Direct cortical intraoperative stimulation is impractical in many young patients due to the reduced excitability of the immature cortex. Behavioral requirements also limit the utility of functional MRI and magnetoencephalography in children. In contrast, MRI-derived tractography and navigated transcranial magnetic stimulation are available across ages. Herein, the authors review the oncological rationale of function-guided resection in pediatric gliomas including technical implications such as personalized perioperative neurophysiology, surgical strategies, and limitations., Conclusions: Taken together, these techniques, despite the limitations of some, facilitate the identification of eloquent areas prior to tumor surgery and radiotherapy as well as during follow-up of residual tumors.

Background: Management of high-grade gliomas (HGGs) close to motor areas is challenging due to the risk of treatment-related morbidity. Thus, for resection, functional mapping of the corticospinal tract (CST) with navigated transcranial magnetic stimulation (nTMS) combined with diffusion tensor imaging (DTI)-based fiber tracking (DTI-FT TMS ) is increasingly used. This study investigated the application of DTI-FT TMS in adjuvant radiation therapy (RT) planning of HGGs for CST avoidance., Methods: The preoperative DTI-FT TMS -based CST reconstructions of 35 patients harboring HGGs were incorporated into the RT planning system and merged with planning imaging. The CST was delineated as the planning risk volume (PRV-FT TMS ). Intensity-modulated RT (IMRT) plans were optimized to preserve PRV-FT TMS . Segments within the planning target volume (PTV) were not spared (overlap)., Results: With plan optimization, mean dose (Dmean) of PRV-FT TMS can be reduced by 17.1% on average (range 0.1-37.9%), thus from 25.5 Gy to 21.2 Gy (p < 0.001). For PRV-FT TMS segments beyond the PTV dose, reduction is possible by 26.8% (range 0.1-43.9%, Dmean 17.4 Gy vs. 12.5 Gy, p < 0.001). Considering only portions within the 50% isodose level, Dmean is decreased by 46.7% from 38.6 Gy to 20.5 Gy (range 19.1-62.8%, p < 0.001). PTV coverage was not affected: V95% and V90% were 96.4 ± 3.1% and 98.0 ± 3.9% vs. 96.1 ± 3.5% (p = 0.34) and 98.3 ± 2.9% (p = 0.58). Dose constraints for organs at risk (OARs) were all met., Conclusion: This study demonstrates that DTI-FT TMS can be utilized in the RT planning of HGGs for CST sparing. However, the degree of dose reduction depends on the overlap with the PTV. The functional benefit needs to be investigated in future prospective clinical trials., Competing Interests: Conflict of interest statement NS received honoraria from Nexstim Plc (Helsinki, Finland). SK is consultant for Nexstim Plc (Helsinki, Finland) and received honoraria from Medtronic (Meerbusch, Germany) and Carl Zeiss Meditec (Oberkochen, Germany). SK and BM received research grants and are consultants for Brainlab AG (Munich, Germany). BM received honoraria, consulting fees, and research grants from Medtronic (Meerbusch, Germany), icotec ag (Altstätten, Switzerland), and Relievant Medsystemy Inc. (Sunnyvale, CA, USA), honoraria and research grants from Ulrich Medical (Ulm, Germany), honoraria and consulting fees from Spineart Deutschland GmbH (Frankfurt, Germany) and DePuy Synthes (West Chester, PA, USA), and royalties from Spineart Deutschland GmbH (Frankfurt, Germany). However, all authors declare that they have no conflict of interest regarding the materials used or the results presented in this study., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Glioma-induced aphasia (GIA) is frequently observed in patients with newly diagnosed gliomas. Previous studies showed an impact of gliomas not only on local brain regions but also on the functionality and structure of brain networks. The current study used navigated transcranial magnetic stimulation (nTMS) to localize language-related regions and to explore language function at the network level in combination with connectome analysis. Thirty glioma patients without aphasia (NA) and 30 patients with GIA were prospectively enrolled. Tumors were located in the vicinity of arcuate fasciculus-related cortical and subcortical regions. The visualized ratio (VR) of each tract was calculated based on their respective fractional anisotropy (FA) and maximal FA. Using a thresholding method of each tract at 25% VR and 50% VR, DTI-based tractography was performed to construct structural brain networks for graph-based connectome analysis, containing functional data acquired by nTMS. The average degree of left hemispheric networks (M left ) was higher in the NA group than in the GIA group for both VR thresholds. Differences of global and local efficiency between 25% and 50% VR thresholds were significantly lower in the NA group than in the GIA group. Aphasia levels correlated with connectome properties in M left and networks based on positive nTMS mapping regions (M pos ). A more substantial relation to language performance was found in M pos and M left compared to the network of negative mapping regions (M neg ). Gliomas causing deterioration of language are related to various cerebral networks. In NA patients, mainly M neg was impacted, while M pos was impacted in GIA patients., (© 2021 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Background: Navigated repetitive transcranial magnetic stimulation (nrTMS) is effective therapy for stroke patients. Neurorehabilitation could be supported by low-frequency stimulation of the non-damaged hemisphere to reduce transcallosal inhibition., Objective: The present study examines the effect of postoperative nrTMS therapy of the unaffected hemisphere in glioma patients suffering from acute surgery-related paresis of the upper extremity (UE) due to subcortical ischemia., Methods: We performed a randomized, sham-controlled, double-blinded trial on patients suffering from acute surgery-related paresis of the UE after glioma resection. Patients were randomly assigned to receive either low frequency nrTMS (1 Hz, 15 min) or sham stimulation directly before physical therapy for 7 consecutive days. We performed primary and secondary outcome measures on day 1, on day 7, and at a 3-month follow-up (FU). The primary endpoint was the change in Fugl-Meyer Assessment (FMA) at FU compared to day 1 after surgery., Results: Compared to the sham stimulation, nrTMS significantly improved outcomes between day 1 and FU based on the FMA (mean [95% CI] +31.9 [22.6, 41.3] vs. +4.2 [-4.1, 12.5]; P = .001) and the National Institutes of Health Stroke Scale (NIHSS) (-5.6 [-7.5, -3.6] vs. -2.4 [-3.6, -1.2]; P = .02). To achieve a minimal clinically important difference of 10 points on the FMA scale, the number needed to treat is 2.19., Conclusion: The present results show that patients suffering from acute surgery-related paresis of the UE due to subcortical ischemia after glioma resection significantly benefit from low-frequency nrTMS stimulation therapy of the unaffected hemisphere., Clinical Trial Registration: Local institutional registration: 12/15; ClinicalTrials.gov number: NCT03982329., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The human white matter pathway network is complex and of critical importance for functionality. Thus, learning and understanding white matter tract anatomy is important for the training of neuroscientists and neurosurgeons. The study aims to test and evaluate a new method for fiber dissection using augmented reality (AR) in a group which is experienced in cadaver white matter dissection courses and in vivo tractography., Methods: Fifteen neurosurgeons, neurolinguists, and neuroscientists participated in this questionnaire-based study. We presented five cases of patients with left-sided perisylvian gliomas who underwent awake craniotomy. Diffusion tensor imaging fiber tracking (DTI FT) was performed and the language-related networks were visualized separated in different tracts by color. Participants were able to virtually dissect the prepared DTI FTs using a spatial computer and AR goggles. The application was evaluated through a questionnaire with answers from 0 (minimum) to 10 (maximum)., Results: Participants rated the overall experience of AR fiber dissection with a median of 8 points (mean ± standard deviation 8.5 ± 1.4). Usefulness for fiber dissection courses and education in general was rated with 8 (8.3 ± 1.4) and 8 (8.1 ± 1.5) points, respectively. Educational value was expected to be high for several target audiences (student: median 9, 8.6 ± 1.4; resident: 9, 8.5 ± 1.8; surgeon: 9, 8.2 ± 2.4; scientist: 8.5, 8.0 ± 2.4). Even clinical application of AR fiber dissection was expected to be of value with a median of 7 points (7.0 ± 2.5)., Conclusion: The present evaluation of this first application of AR for fiber dissection shows a throughout positive evaluation for educational purposes.

Although intraoperative mapping of brain areas was shown to promote greater extent of resection and reduce functional deficits, this was shown only recently for some noninvasive techniques. Yet, proper surgical planning, indication, and patient consultation require reliable noninvasive techniques. Because functional magnetic resonance imaging, tractography, and neurophysiologic methods like navigated transcranial magnetic stimulation and magnetoencephalography allow identifying eloquent areas prior to resective surgery and tailor the surgical approach, this article provides an overview on the individual strengths and limitations of each modality., Competing Interests: Disclosure S.M. Krieg is consultant for Nexstim Plc (Helsinki, Finland), Brainlab AG (Munich, Germany), and Spineart Deutschland GmbH (Frankfurt, Germany) and received honoraria from Medtronic (Meerbusch, Germany) and Carl Zeiss Meditec (Oberkochen, Germany). S. Ille is consultant for Brainlab AG (Munich, Germany). Both authors, however, declare that they have no conflict of interest regarding the materials used or the results presented in this article. Both authors declare no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Navigated transcranial magnetic stimulation (nTMS) allows for preoperative mapping for eloquent gliomas. Besides surgical planning, it also guides intraoperative stimulation mapping. The authors' routine includes preoperative nTMS plus nTMS-based tractography for motor and language to consult patients, plan surgery, craniotomy, and guide cortical and subcortical stimulation. Here, the authors present this routine in a 48-year-old woman with a glioma of the left middle and superior frontal gyrus reaching the precentral gyrus and superior longitudinal fascicle. Gross-total resection via awake surgery was achieved without deficit. The nTMS data and nTMS-based tractography augment eloquent glioma management far beyond its current application. The video can be found here: https://youtu.be/h4ldgMXL1ys .

OBJECTIVE Navigated transcranial magnetic stimulation (nTMS) is used to identify the motor cortex prior to surgery. Yet, there has, until now, been no published evidence on the economic impact of nTMS. This study aims to analyze the cost-effectiveness of nTMS, evaluating the incremental costs of nTMS motor mapping per additional quality-adjusted life year (QALY). By doing so, this study also provides a model allowing for future analysis of general cost-effectiveness of new neuro-oncological treatment options. METHODS The authors used a microsimulation model based on their cohort population sampled for 1000 patients over the time horizon of 2 years. A health care provider perspective was used to assemble direct costs of total treatment. Transition probabilities and health utilities were based on published literature. Effects were stated in QALYs and established for health state subgroups. RESULTS In all scenarios, preoperative mapping was considered cost-effective with a willingness-to-pay threshold < 3*per capita GDP (gross domestic product). The incremental cost-effectiveness ratio (ICER) of nTMS versus no nTMS was 45,086 Euros/QALY. Sensitivity analyses showed robust results with a high impact of total treatment costs and utility of progression-free survival. Comparing the incremental costs caused by nTMS implementation only, the ICER decreased to 1967 Euros/QALY. CONCLUSIONS Motor mapping prior to surgery provides a cost-effective tool to improve the clinical outcome and overall survival of high-grade glioma patients in a resource-limited setting. Moreover, the model used in this study can be used in the future to analyze new treatment options in neuro-oncology in terms of their general cost-effectiveness.

OBJECTIVE Awake surgery combined with intraoperative direct electrical stimulation (DES) and intraoperative neuromonitoring (IONM) is considered the gold standard for the resection of highly language-eloquent brain tumors. Different modalities, such as functional magnetic resonance imaging (fMRI) or magnetoencephalography (MEG), are commonly added as adjuncts for preoperative language mapping but have been shown to have relevant limitations. Thus, this study presents a novel multimodal setup consisting of preoperative navigated transcranial magnetic stimulation (nTMS) and nTMS-based diffusion tensor imaging fiber tracking (DTI FT) as an adjunct to awake surgery. METHODS Sixty consecutive patients (63.3% men, mean age 47.6 ± 13.3 years) suffering from highly language-eloquent left-hemispheric low- or high-grade glioma underwent preoperative nTMS language mapping and nTMS-based DTI FT, followed by awake surgery for tumor resection. Both nTMS language mapping and DTI FT data were available for resection planning and intraoperative guidance. Clinical outcome parameters, including craniotomy size, extent of resection (EOR), language deficits at different time points, Karnofsky Performance Scale (KPS) score, duration of surgery, and inpatient stay, were assessed. RESULTS According to postoperative evaluation, 28.3% of patients showed tumor residuals, whereas new surgery-related permanent language deficits occurred in 8.3% of patients. KPS scores remained unchanged (median preoperative score 90, median follow-up score 90). CONCLUSIONS This is the first study to present a clinical outcome analysis of this very modern approach, which is increasingly applied in neurooncological centers worldwide. Although human language function is a highly complex and dynamic cortico-subcortical network, the presented approach offers excellent functional and oncological outcomes in patients undergoing surgery of lesions affecting this network.