Neurosurgery

Abstract:
Background: Lesions within the primary motor cortex (M1) and the corticospinal tract (CST) represent a significant surgical challenge with a delicate functional trade-off that should be integrated in the overall patient-centered treatment plan.
Methods: Patients with lesions within the M1 and CST with preoperative cortical and subcortical mapping (navigated transcranial magnetic stimulation [nTMS] and tractography), intraoperative mapping, and intraoperative provisional histologic information (smear with and without 5-aminolevulinic acid [5-ALA]) were included. This independently acquired information was integrated in a decision-making process model to determine the intraoperative extent of resection.
Results: A total of 10 patients (6 patients with metastatic precentral tumor; 1 patient with grade III and 2 patients with grade IV gliomas; 1 patient with precentral cavernoma) were included in the study. Most of the patients (60%) had a preoperative motor deficit. The nTMS documented M1 invasion in all cases, and in eight patients, the lesions were embedded within the CST. Overall, 70% of patients underwent gross total resection; 20% of patients underwent near-total resection of the lesions. In only one patient was no surgical resection possible after both preoperative and intraoperative mapping. Overall, 70% of patients remained stable postoperatively, and previous motor weakness improved in 20%.
Conclusion: The independently acquired anatomical (anatomical MRI) and functional (nTMS and tractography) tests in patients with CST lesions provide a useful guide for resection. The inclusion of histologic information (smear with or without 5-ALA) further allows the surgical team to balance the potential functional risks within the global treatment plan. Therefore, the patient is kept at the center of the informed decision-making process.

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Abstract:
BACKGROUND: Navigated transcranial magnetic stimulation (nTMS) is an established, noninvasive tool to preoperatively map the motor cortex. Despite encouraging reports from few academic centers with vast nTMS experience, its value for motor-eloquent brain surgery still requires further exploration.
OBJECTIVE: To further elucidate the role of preoperative nTMS in motor-eloquent brain surgery.
METHODS: Patients who underwent surgery for a motor-eloquent supratentorial glioma or metastasis guided by preoperative nTMS were retrospectively reviewed. The nTMS group (n = 105) was pair-matched to controls (non-nTMS group, n = 105). Gross total resection (GTR) and motor outcome were evaluated. Subgroup analyses including survival analysis for WHO III/IV glioma were performed.
RESULTS: GTR was significantly more frequently achieved in the entire nTMS group compared to the non-nTMS group (P = .02). Motor outcome did not differ (P = .344). Bootstrap analysis confirmed these findings. In the metastases subgroup, GTR rates and motor outcomes were equal. In the WHO III/IV glioma subgroup, however, GTR was achieved more frequently in the nTMS group (72.3%) compared to non-nTMS group (53.2%) (P = .049), whereas motor outcomes did not differ (P = .521). In multivariable Cox-regression analysis, prolonged survival in WHO III/IV glioma was significantly associated with achievement of GTR and younger patient age but not nTMS mapping.
CONCLUSION: Preoperative nTMS improves GTR rates without jeopardizing neurological function. In WHO III/IV glioma surgery, nTMS increases GTR rates that might translate into a beneficial overall survival. The value of nTMS in the setting of a potential survival benefit remains to be determined.

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Abstract:
Background: The surgical strategy for brain glioma has changed, shifting from tumor debulking to a more careful tumor dissection with the aim of a gross-total resection, extended beyond the contrast-enhancement MRI, including the hyperintensity on FLAIR MR images and defined as supratotal resection. It is possible to pursue this goal thanks to the refinement of several technological tools for pre and intraoperative planning including intraoperative neurophysiological monitoring (IONM), cortico-subcortical mapping, functional MRI (fMRI), navigated transcranial magnetic stimulation (nTMS), intraoperative CT or MRI (iCT, iMR), and intraoperative contrast-enhanced ultrasound. This systematic review provides an overview of the state of the art techniques in the application of nTMS and nTMS-based DTI-FT during brain tumor surgery.
Materials and Methods: A systematic literature review was performed according to the PRISMA statement. The authors searched the PubMed and Scopus databases until July 2020 for published articles with the following Mesh terms: (Brain surgery OR surgery OR craniotomy) AND (brain mapping OR functional planning) AND (TMS OR transcranial magnetic stimulation OR rTMS OR repetitive transcranial stimulation). We only included studies regarding motor mapping in craniotomy for brain tumors, which reported data about CTS sparing.
Results: A total of 335 published studies were identified through the PubMed and Scopus databases. After a detailed examination of these studies, 325 were excluded from our review because of a lack of data object in this search. TMS reported an accuracy range of 0.4–14.8 mm between the APB hotspot (n1/4 8) in nTMS and DES from the DES spot; nTMS influenced the surgical indications in 34.3–68.5%.
Conclusion: We found that nTMS can be defined as a safe and non-invasive technique and in association with DES, fMRI, and IONM, improves brain mapping and the extent of resection favoring a better postoperative outcome.

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Abstract:
Background: The resection of a motor-eloquent glioma should be guided by intraoperative neurophysiological monitoring (IOM) but its interpretation is often difficult and may (unnecessarily) lead to subtotal resection. Navigated transcranial magnetic stimulation (nTMS) combined with diffusion-tensor-imaging (DTI) is able to stratify patients with motor-eloquent lesion preoperatively into high- and low-risk cases with respect to a new motor deficit.
Objective: To analyze to what extent preoperative nTMS motor risk stratification can improve the interpretation of IOM phenomena.
Methods: In this monocentric observational study, nTMS motor mapping with DTI fiber tracking of the corticospinal tract was performed before IOM-guided surgery for motor-eloquent gliomas in a prospectively collected cohort from January 2017 to October 2020. Descriptive analyses were performed considering nTMS data (motor cortex infiltration, resting motor threshold (RMT), motor evoked potential (MEP) amplitude, latency) and IOM data (transcranial MEP monitoring, intensity of monopolar subcortical stimulation (SCS), somatosensory evoked potentials) to examine the association with the postoperative motor outcome (assessed at day of discharge and at 3 months).
Results: Thirty-seven (56.1%) of 66 patients (27 female) with a median age of 48 years had tumors located in the right hemisphere, with glioblastoma being the most common diagnosis with 39 cases (59.1%). Three patients (4.9%) had a new motor deficit that recovered partially within 3 months and 6 patients had a persistent deterioration (9.8%). The more risk factors of the nTMS risk stratification model (motor cortex infiltration, tumor-tract distance (TTD) ≤8mm, RMTratio <90%/>110%) were detected, the higher was the risk for developing a new postoperative motor deficit, whereas no patient with a TTD >8mm deteriorated. Irreversible MEP amplitude decrease >50% was associated with worse motor outcome in all patients, while a MEP amplitude decrease ≤50% or lower SCS intensities ≤4mA were particularly correlated with a postoperative worsened motor status in nTMS-stratified high-risk cases. No patient had postoperative deterioration of motor function (except one with partial recovery) when intraoperative MEPs remained stable or showed only reversible alterations.
Conclusions: The preoperative nTMS-based risk assessment can help to interpret ambiguous IOM phenomena (such as irreversible MEP amplitude decrease ≤50%) and adjustment of SCS stimulation intensity.

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Abstract:
Navigated transcranial magnetic stimulation (nTMS) has developed into a reliable non-invasive clinical and scientific tool over the past decade. Specifically, it has undergone several validating clinical trials that demonstrated high agreement with intraoperative direct electrical stimulation (DES), which paved the way for increasing application for the purpose of motor mapping in patients harboring motor-eloquent intracranial neoplasms. Based on this clinical use case of the technique, in this article we review the evidence for the feasibility of motor mapping and derived models (risk stratification and prediction, nTMS-based fiber tracking, improvement of clinical outcome, and assessment of functional plasticity), and provide collected sets of evidence for the applicability of quantitative mapping with nTMS. In addition, we provide evidence-based demonstrations on factors that ensure methodological feasibility and accuracy of the motor mapping procedure. We demonstrate that selection of the stimulation intensity (SI) for nTMS and spatial density of stimuli are crucial factors for applying motor mapping accurately, while also demonstrating the effect on the motor maps. We conclude that while the application of nTMS motor mapping has been impressively spread over the past decade, there are still variations in the applied protocols and parameters, which could be optimized for the purpose of reliable quantitative mapping.

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Abstract:

OBJECTIVE: The authors sought to validate the navigated transcranial magnetic stimulation (nTMS)–based risk stratification model. The postoperative motor outcome in glioma surgery may be preoperatively predicted based on data derived by nTMS. The tumor-to-tract distance (TTD) and the interhemispheric resting motor threshold (RMT) ratio (as a surrogate parameter for cortical excitability) emerged as major factors related to a new postoperative deficit.
METHODS: In this bicentric study, a consecutive prospectively collected cohort underwent nTMS mapping with diffusion tensor imaging (DTI) fiber tracking of the corticospinal tract prior to surgery of motor eloquent gliomas. The authors analyzed whether the following items were associated with the patient’s outcome: patient characteristics, TTD, RMT value, and diffusivity parameters (fractional anisotropy [FA] and apparent diffusion coefficient [ADC]). The authors assessed the validity of the published risk stratification model and derived a new model.
RESULTS: A new postoperative motor deficit occurred in 36 of 165 patients (22%), of whom 20 patients still had a deficit after 3 months (13%; n3 months = 152). nTMS-verified infiltration of the motor cortex as well as a TTD ≤ 8 mm were confirmed as risk factors. No new postoperative motor deficit occurred in patients with TTD > 8 mm. In contrast to the previous risk stratification, the RMT ratio was not substantially correlated with the motor outcome, but high RMT values of both the tumorous and healthy hemisphere were associated with worse motor outcome. The FA value was negatively associated with worsening of motor outcome. Accuracy analysis of the final model showed a high negative predictive value (NPV), so the preoperative application may accurately predict the preservation of motor function in particular (day of discharge: sensitivity 47.2%, specificity 90.7%, positive predictive value [PPV] 58.6%, NPV 86.0%; 3 months: sensitivity 85.0%, specificity 78.8%, PPV 37.8%, NPV 97.2%).
CONCLUSIONS: This bicentric validation analysis further improved the model by adding the FA value of the corticospinal tract, demonstrating the relevance of nTMS/nTMS-based DTI fiber tracking for clinical decision making.

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Abstract:

Navigated transcranial magnetic stimulation (nTMS) is a modality for noninvasive cortical mapping. Specifically, nTMS motor mapping is an objective measure of motor function, offering quantitative diagnostic information regardless of subject cooperation or consciousness. Thus far, it has mostly been restricted to the outpatient setting. This study evaluates the feasibility of nTMS motor mapping in the intensive care unit (ICU) setting and solves the challenges encountered in this special environment. We compared neuronavigation based on computed tomography (CT) and magnetic resonance imaging (MRI). We performed motor mappings in neurocritical patients under varying conditions (e.g., sedation or hemicraniectomy). Furthermore, we identified ways of minimizing electromyography (EMG) noise in the interference-rich ICU environment. Motor mapping was performed in 21 patients (six females, median age: 69 years). In 18 patients, motor evoked potentials (MEPs) were obtained. In three patients, MEPs could not be evoked. No adverse reactions occurred. We found CT to offer a comparable neuronavigation to MRI (CT maximum e-field 52 ± 14 V/m vs. MRI maximum e-field 52 ± 11 V/m; p = 0.6574). We detailed EMG noise reduction methods and found that propofol sedation of up to 80 mcg/kg/h did not inhibit MEPs. Yet, nTMS equipment interfered with exposed pulse oximetry. nTMS motor mapping application and use was illustrated in three clinical cases. In conclusion, we present an approach for the safe and reliable use of nTMS motor mapping in the ICU setting and outline possible benefits. Our findings support further studies regarding the clinical value of nTMS in critical care settings.

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Abstract:

Background: Navigated transcranial magnetic stimulation (nTMS) is an established, noninvasive tool to preoperatively map the motor cortex. Despite encouraging reports from few academic centers with vast nTMS experience, its value for motor-eloquent brain surgery still requires further exploration.

Objective: To further elucidate the role of preoperative nTMS in motor-eloquent brain surgery.

Methods: Patients who underwent surgery for a motor-eloquent supratentorial glioma or metastasis guided by preoperative nTMS were retrospectively reviewed. The nTMS group (n = 105) was pair-matched to controls (non-nTMS group, n = 105). Gross total resection (GTR) and motor outcome were evaluated. Subgroup analyses including survival analysis for WHO III/IV glioma were performed.

Results: GTR was significantly more frequently achieved in the entire nTMS group compared to the non-nTMS group (P = .02). Motor outcome did not differ (P = .344). Bootstrap analysis confirmed these findings. In the metastases subgroup, GTR rates and motor outcomes were equal. In the WHO III/IV glioma subgroup, however, GTR was achieved more frequently in the nTMS group (72.3%) compared to non-nTMS group (53.2%) (P = .049), whereas motor outcomes did not differ (P = .521). In multivariable Cox-regression analysis, prolonged survival in WHO III/IV glioma was significantly associated with achievement of GTR and younger patient age but not nTMS mapping.

Conclusion: Preoperative nTMS improves GTR rates without jeopardizing neurological function. In WHO III/IV glioma surgery, nTMS increases GTR rates that might translate into a beneficial overall survival. The value of nTMS in the setting of a potential survival benefit remains to be determined.

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BACKGROUND

Diffuse gliomas have an increased biological aggressiveness across the World Health Organization (WHO) grading system. The implications of glioma grading on the primary motor cortex (M1)-corticospinal tract (CST) excitability is unknown.

OBJECTIVE

To assess the excitability of the motor pathway with navigated transcranial magnetic stimulation (nTMS).

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Abstract

Patients with functionally eloquent brain lesions are at risk of functional decline in the course of resection. Given tumor-related plastic reshaping and reallocation of function, individual data are needed for patient counseling and risk assessment prior to surgery. This study evaluates the utility of mapping by navigated transcranial magnetic stimulation (nTMS) and nTMS-based diffusion tensor imaging fiber tracking (DTI FT) for individual risk evaluation of surgery-related decline of motor or language function in the clinical setting. In total, 250 preoperative nTMS mappings (100 language and 150 motor mappings) derived from 216 patients (mean age: 57.0 ± 15.5 years, 58.8% males; glioma World Health Organization (WHO) grade I & II: 4.2%, glioma WHO grade III & IV: 83.4%, arteriovenous malformations: 1.9%, cavernoma: 2.3%, metastasis: 8.2%) were included. Deterministic tractography based on nTMS motor or language maps as seed regions was performed with 25%, 50%, and 75% of the individual fractional anisotropy threshold (FAT). Lesion-to-tract distances (LTDs) were measured between the tumor mass and the corticospinal tract (CST), arcuate fascicle (AF), or other closest language-related tracts. LTDs were compared between patients and correlated to the functional status (no/transient/permanent surgery-related paresis or aphasia). Significant differences were found between patients with no or transient surgery-related deficits and patients with permanent surgery-related deficits regarding LTDs in relation to the CST (p < 0.0001), AF (p ≤ 0.0491), or other closest language-related tracts (p ≤ 0.0435). The cut-off values for surgery-related paresis or aphasia were ≤ 12 mm (LTD—CST) and ≤ 16 mm (LTD—AF) or ≤25 mm (LTD—other closest language-related tract), respectively. Moreover, there were significant associations between the status of surgery-related deficits and the LTD when considering the CST (range r: −0.3994 to −0.3910, p < 0.0001) or AF (range r: −0.2918 to −0.2592, p = 0.0135 and p = 0.0473 for 25% and 50% FAT). In conclusion, this is the largest study evaluating the application of both preoperative functional mapping and function-based tractography for motor and language function for risk stratification in patients with functionally eloquent tumors. The LTD may qualify as a viable marker that can be seamlessly assessed in the clinical neurooncological setup.

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Meta-analysis

Navigated transcranial magnetic stimulation (nTMS) is an emerging tool for surgery of motor-eloquent intrinsic brain tumors, but a critical reappraisal of the literature evidence has never been performed, so far. A systematic review and meta-analysis was performed searching on PubMed/MEDLINE, and the Cochrane Central Register of Controlled Trials for studies that analyzed the impact of nTMS-based motor mapping on surgery of patients affected by motor-eloquent intrinsic brain tumors, in comparison with series of patients operated without using nTMS. The impact of nTMS mapping was assessed analyzing the occurrence of postoperative new permanent motor deficits, the gross total resection rate (GTR), the size of craniotomy and the length of surgery. Only eight studies were considered eligible and were included in the quantitative review and meta-analysis. The pooled analysis showed that nTMS motor mapping significantly reduced the risk of postoperative new permanent motor deficits (OR = 0.54, p = 0.001, data available from eight studies) and increased the GTR rate (OR = 2.32, p < 0.001, data from seven studies). Moreover, data from four studies documented the craniotomy size was reduced in the nTMS group (-6.24 cm², p < 0.001), whereas a trend towards a reduction, even if non significant, was observed for the length of surgery (-10.30 min, p = 0.38) in three studies. Collectively, currently available literature provides data in favor of the use of nTMS motor mapping: its use seems to be associated with a reduced occurrence of postoperative permanent motor deficits, an increased GTR rate, and a tailored surgical approach compared to standard surgery without using preoperative nTMS mapping. Nonetheless, a growing need of high-level evidence about the use of nTMS motor mapping in brain tumor surgery is perceived. Well-designed randomized controlled studies from multiple Institutions are clearly advocated to continue to shed a light on this emerging topic.

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(Level of Evidence IIb)

A multi-center study at Departments of Neurosurgery at Charite Univärsitetsmedizin, Berlin, Teknische Universität Munchen and University of California San Francisco.

In the study outcomes of brain surgery performed because of tumor metastases in the central brain areas were compared between two observational patient cohorts. Cohort 1 included 120 consecutive patients in whom preoperative localization of the motor cortex in relation to the metastasis was performed with Nexstim NBS device. Cohort 2 included 130 consecutive patients in whom NBS motor mapping was not performed because of organizational issues.

Results in Cohort 1 were significantly better than those in Cohort 2 both in regard to complete tumor removal and likelihood of poor post-operative motor function. Specifically, the NBS mapped patients had a lower rate of residual tumor on postoperative magnetic resonance imaging (odds ratio 0.3025; 95% confidence interval 0.1356-0.6749). Further, surgery-related paresis was less likely in the NBS group (Cohort 1 vs. Cohort 2; patients improved in long-term follow-up: 30.8 vs. 13.1%, unchanged: 65.8 vs. 73.8%, worse: 3.4 vs. 13.1%; p = 0.0002).

In the operating room, the duration of surgery was approximately 30 minutes shorter (Cohort 1: 128.8 ± 49.4 min vs. Cohort 2: 158.0 ± 65.8 min; p = 0.0002) and the surgical skull opening (craniotomy size) 33% smaller (Cohort 1: 16.7 ± 8.6 cm2 vs. Cohort 2: 25.0 ± 17.1 cm2; p < 0.0001) in the NBS mapped patients.

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(Level of Evidence IIb)

A large scale study comparing clinical outcomes of patients with brain tumors near motor eloquent cortex in whom preoperative NBS motor mapping (n=93) was done to outcomes of similar patients in whom NBS mapping could not be done due to logistic/organizational issues (n=34). According to the routine clinical practice at the study institution NBS mapping should have been done to all subjects but due to the institution having its neurosurgical department on two campuses 15km apart from each other and only one NBS system, all patients were not mapped. In other respects patients in both groups received the same medical care (same surgical team and the same operating surgeons, MRI and DTI imaging, the same intraoperative monitoring (IOM) team and practice etc.). The patients in both groups were from the same 3-year time period (2011-2014) ruling out effects of changing clinical practice on any potential differences in outcomes between the groups.

In the group comparison, gross total tumor resection rate was significantly higher in the NBS + IOM group compared to IOM only (61% vs 45%, p<0.05). Further, the degree of tumor resection was also significantly higher in the NBS + IOM group compared to IOM only (85.4% vs 75.9%, p<0.05). In addition, in the NBS+IOM group there were 9 patients (10%) in whom prior to the NBS mapping the surgical plan had been biopsy only (n=3) or tumor debulking only (n=6) due to suspected tumor invasion of motor cortex or pyramidal tracts. NBS mapping and NBS based DTI disproved the suspected invasion and changed the surgical plan to total or subtotal resection.

The mean surgical time tended to be shorter in the NBS + IOM group compared to IOM only (22 min or 9.6%) but the difference between groups was not statistically significant.

There were no differences in motor functional outcomes between the groups indicating that the more extensive resections in the NBS + IOM group compared to IOM only did not come at the expense of increasing adverse events.

The authors state: “This study is the first to prove that the improved surgical outcomes observed in previous studies after the implementation of nTMS to presurgical work-up are not caused by any overall improvement in patient care or a paradigm shift toward more aggressive resection but by the additional functional data provided by nTMS”.

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(Level of evidence III)

A large-scale comparative study on patient outcomes following neurosurgery guided by Navigated Brain Stimulation (NBS) in patients with high-grade glioma. A prospectively enrolled cohort of 70 patients with lesions located in motor eloquent areas were preoperatively mapped by NBS following adoption of the NBS System in 2010. The 70 patients were matched with a control group of 70 patients who had been operated on in 2007- 2010.

On average, the overall size of the craniotomy was significantly smaller for NBS mapped patients when compared to the non-NBS group (25.3 ± 9.7 cm(2) vs. 30.8 ± 13.2 cm(2); p = 0.0058). Furthermore, residual tumor tissue (NBS: 34.3%; non-NBS: 54.3%; p = 0.0172) and unexpected tumor residuals (NBS: 15.7%; non-NBS: 32.9%; p = 0.0180) were less frequent in NBS patients.

Further median inpatient stay was shorter in the NBS group with 12 days for the NBS and 14 days for the non-NBS group (NBS: CI 10.5 - 13.5 days; non-NBS: CI 11.6 - 16.4 days; p = 0.0446). 60.0% of patients of the NBS group and 54.3% of patients of the non-NBS group were eligible for postoperative chemotherapy (OR 1.2630, CI 0.6458 - 2.4710, p = 0.4945), while 67.1% of NBS patients and 48.6% of non-NBS patients received radiotherapy (OR 2.1640, CI 1.0910 - 4.2910, p = 0.0261). Moreover, 3, 6, and 9 months survival was significantly better in the NBS group (p = 0.0298, p = 0.0015, and p = 0.0167).

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(Level of evidence III)

A large-scale comparative study comparing patient outcomes following brain tumor surgery guided by Navigated Brain Stimulation (NBS) to outcomes in patients without NBS functional mapping. A prospectively enrolled cohort of all 250 patients evaluated for surgery for a tumor in a motor eloquent location between May 2007 and October 2012 were preoperatively mapped with NBS following adoption of the NBS System in 2007. The 250 patients were compared with a control group of all 115 patients who met the same in- and exclusion criteria from January 2005 through April 2007, before the availability of NBS mapping at Charité, Berlin.

In the patients mapped with NBS, the mapping results disproved suspected involvement of primary motor cortex in 25.1% of cases, expanded surgical indication in 14.8%, and led to planning of more extensive resection in 35.2% of cases and more restrictive resection in 3.5%. In comparison with the control group, the rate of gross total resections increased significantly from 42% to 59% (P <0.05). Progression-free survival for low grade glioma was significantly better in the nTMS group at 22.4 months than in control group at 15.4 months (P<0.05).

There was no significant difference in postoperative deficits between the groups despite the more extensive resections performed in the NBS mapped patients (rate of postoperative deficits was 8.5% in the control group and 6.1% in the NBS group.

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(Level of evidence III)

A large-scale comparative study on patient outcomes following neurosurgery guided by Navigated Brain Stimulation (NBS) in challenging cases. A prospectively enrolled cohort of 100 patients with lesions located in motor eloquent areas were preoperatively mapped by NBS following adoption of the NBS System in 2010. The 100 patients were matched with a control group of 100 patients who had been operated on in the 3 years prior to 2010 – before the availability of NBS mapping at TUM.

The group of patients benefiting from NBS mapping showed a statistically significantly lower rate of residual tumor, as determined by postoperative MRI scanning. On long-term follow-up, 12% of the patients in the NBS group had improved motor function, compared to only 1% of the patients in the control group. Moreover, fewer patients mapped by NBS showed deteriorated motor function postoperatively compared to the control group. With regard to surgical technique, NBS mapping enabled significantly smaller craniotomies.

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Sollmann N, et al. Associations between clinical outcome and navigated transcranial magnetic stimulation characteristics in patients with motor-eloquent brain lesions: a combined navigated transcranial magnetic stimulation-diffusion tensor imaging fiber tracking approach.

(Level of evidence III)

Data derived from preoperative nTMS motor mapping and subsequent nTMS-based tractography in 86 patients were analyzed. All patients suffered from high-grade glioma (HGG), low-grade glioma (LGG), or intracranial metastasis (MET). In this context, nTMS-based DTI FT of the corticospinal tract (CST) was performed at a range of fractional anisotropy (FA) levels based on an individualized FA threshold ([FAT]; tracking with 50%, 75%, and 100% FAT), which was defined as the highest FA value allowing for visualization of fibers (100% FAT). Minimum lesion-to-CST distances were measured, and fiber numbers of the reconstructed CST were assessed. These data were then correlated with the preoperative, postoperative, and follow-up status of motor function and the resting motor threshold (rMT). RESULTS At certain FA levels, a statistically significant difference in lesion-to-CST distances was observed between patients with HGG who had no impairment and those who developed surgery-related transient or permanent motor deficits (75% FAT: p = 0.0149; 100% FAT: p = 0.0233). In this context, no patient with a lesion-to-CST distance ≥ 12 mm suffered from any new surgery-related permanent paresis (50% FAT and 75% FAT). Furthermore, comparatively strong negative correlations were observed between the rMT and lesion-to-CST distances of patients with surgery-related transient paresis (Spearman correlation coefficient [rs]; 50% FAT: rs = -0.8660; 75% FAT: rs = -0.8660) or surgery-related permanent paresis (50% FAT: rs = -0.7656; 75% FAT: rs = -0.6763). CONCLUSIONS This is one of the first studies to show a direct correlation between imaging, clinical status, and neurophysiological markers for the integrity of the motor system in patients with brain tumors. The findings suggest that nTMS-based DTI FT might be suitable for individual risk assessment in patients with HGG, in addition to being a surgery-planning tool. Importantly, necessary data for risk assessment were obtained without significant additional efforts, making this approach potentially valuable for direct clinical use.

Pubished in: J Neurosurg. 2017 Mar 31:1-11. doi: 10.3171/2016.11.JNS162322. [Epub ahead of print]

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(Level of evidence III)

OBJECTIVE: To investigate the resection of nTMS-positive prerolandic motor areas and its correlation with postsurgical impairment of motor function. METHODS: Forty-three patients with rolandic or prerolandic gliomas (WHO grade I-IV) underwent nTMS prior to surgery. Only patients without ischemia within the motor system in postoperative MRI diffusion sequences were enrolled. Based on the 3- dimensional fusion of preoperative nTMS motor mapping data with postsurgical MRI scans, we identified nTMS points that were resected in the infiltration zone of the tumor. We then classified the resected points according to the localization and latency of their motor evoked potentials. Surgery-related paresis was graded as transient (≤6 weeks) or permanent (>6 weeks). RESULTS: Out of 43, 31 patients (72%) showed nTMS-positive motor points in the prerolandic gyri. In general, 13 out of 43 patients (30%) underwent resection of nTMS points. Ten out of these patients showed postoperative paresis. There were 2 (15%) patients with a transient and 8 (62%) with a permanent surgery-related paresis. In 3 cases (23%), motor function remained unimpaired.

CONCLUSION: After resection of nTMS-positive motor points, 62% of patients suffered from a new permanent paresis. Thus, even though they are located in the superior or middle frontal gyrus, these cortical areas must undergo intraoperative mapping.

(Review)

A systematic search was used to retrieve 11 reports, published up to October, 2012, in which adult patients were examined with the NBS System prior to surgery. Based on data obtained from 87 patients in 2 studies, the authors found that availability of information from nTMS investigations resulted in a change to the initially proposed surgical strategy, based on anatomical imaging alone, in 25.3% of all patients. The authors concluded that “The nTMS technique spatially correlates well with the gold standard of DES. Its functional information benefits surgical decision making and changes the treatment strategy in one-fourth of cases.”

(Level of evidence IIa)

Controlled trial in 20 patients undergoing surgery for rolandic brain tumors comparing clinical accuracy of non-invasive preoperative navigated transcranial magnetic stimulation to intraoperative direct cortical stimulation. Shows that both methods localize the primary motor cortex to the same gyrus. Authors conclude that nTMS is a reliable tool for preoperative mapping of motor function.

(Level of evidence IIa)

Controlled trial in 11 patients undergoing surgery for central region tumors evaluating the reliability of non-invasive preoperative navigated transcranial magnetic stimulation (nTMS) compared with fMRI and intraoperative direct cortical stimulation. Shows that nTMS is more accurate than fMRI when direct cortical stimulation is used a golden standard. Authors conclude that nTMS anticipates information usually only enabled by DCS and therefore allows surgical planning in eloquent cortex surgery.

(Level of evidence IIa)

(Level of evidence V)

(Level of evidence III)

The study aimed to assess what influence preoperative navigated transcranial magnetic stimulation (nTMS) has on the treatment strategy and clinical outcome for suspected low-grade gliomas in presumed motor eloquent location. It was concluded that nTMS provides accurate motor mapping results also in infiltrative gliomas and enables more frequent and more extensive surgical resection of non-enhancing gliomas in or near the primary motor cortex.

(Level of evidence IIa)

NBS motor mapping was performed in eight healthy volunteers and 12 patients with brain tumors to localize and outline the cortical representation areas of facial muscles. Mapping was successful in all healthy volunteers and 10 of the 12 patients. The authors conclude that nTMS is an applicable and clinically beneficial noninvasive method to preoperatively map the cortical representation areas of the facial muscles in the lower part of the face.

Methodological validation study of facial muscle motor mapping.

Abstract
Objective: The safety of transcranial magnetic stimulation (TMS) has been previously evaluated in healthy volunteers and clinical adult populations. We sought to fill the gap in safety of TMS functional mapping in a clinical, predominately pediatric cohort.
Methods: In a retrospective chart review, we assessed TMS motor and language mapping studies in persons with epilepsy or brain tumor for adverse events and safety of TMS, and in patients with cranial metal.
Results: Out of 500 TMS sessions attempted in 429 individual patients (51% males, 82% ≤ 18 y), seizures occurred in 29 sessions (5.8%) during or after TMS with semiology consistent with their typical presentation and 53 patients (10.6%) experienced pain during stimulation. TMS was completed safely in 276 patients with cranial metal.
Conclusions: Most TMS-related adverse events were benign and transient; the most serious safety events were seizures that could not be conclusively attributed to TMS. However, useful mapping results were obtained in almost all patients. Presence of cranial metal did not adversely affect TMS mapping. We show that TMS functional mapping is safe in a largely pediatric clinical cohort.
Significance: This study demonstrates the safety of TMS functional mapping in patients with refractory epilepsy, brain tumor or cranial metal and fills a gap in knowledge for TMS safety in pediatric clinical population.

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(Level of evidence V)

Authors from 3 institutions (UCSF, San Francisco, Charité, Berlin, TU Munich, München) report their combined experience of safety and tolerability of clinical NBS motor and language mapping in 733 patients with brain tumors. During monopulse stimulation (motor mapping), 5.1% reported discomfort (VAS 1-3), and 0.4% reported pain (VAS >3). During repetitive stimulation (language mapping), 23.4% reported discomfort and 69.5% reported pain. No seizures or other adverse events were observed. The authors conclude that nTMS is safe and well-tolerated in neurosurgical patients.

Abstract: Accurate presurgical mapping of motor, speech, and language cortices, while crucial for neurosurgical planning and minimizing post-operative functional deficits, is challenging in young children with neurological disease. In such children, both invasive (cortical stimulation mapping) and non-invasive functional mapping imaging methods (MEG, fMRI) have limited success, often leading to delayed surgery or adverse post-surgical outcomes. We therefore examined the clinical utility of transcranial magnetic stimulation (TMS) in young children who require functional mapping. In a retrospective chart review of TMS studies performed on children with refractory epilepsy or a brain tumor, at our institution, we identified 47 mapping sessions in 36 children 3 years of age or younger, in whom upper and lower extremity motor mapping was attempted; and 13 children 5–6 years old in whom language mapping, using a naming paradigm, was attempted. The primary hand motor cortex was identified in at least one hemisphere in 33 of 36 patients, and in both hemispheres in 27 children. In 17 children, primary leg motor cortex was also successfully identified. The language cortices in temporal regions were successfully mapped in 11 of 13 patients, and in six of them language cortices in frontal regions were also mapped, with most children (n = 5) showing right hemisphere dominance for expressive language. Ten children had a seizure that was consistent with their clinical semiology during or immediately following TMS, none of which required intervention or impeded completion of mapping. Using TMS, both normal motor, speech, and language developmental patterns and apparent disease induced reorganization were demonstrated in this young cohort. The successful localization of motor, speech, and language cortices in young children improved the understanding of the risk-benefit ratio prior to surgery and facilitated surgical planning aimed at preserving motor, speech, and language functions. Post-operatively, motor function was preserved or improved in nine out of 11 children who underwent surgery, as was language function in all seven children who had surgery for lesions near eloquent cortices. We provide feasibility data that TMS is a safe, reliable, and effective tool to map eloquent cortices in young children.

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Abstract: 
OBJECTIVE: Navigated transcranial magnetic stimulation (nTMS) is a noninvasive technique often used for localization of the functional motor cortex via induction of motor evoked potentials (MEPs) in neurosurgical patients. There has, however, been no published record of its application in pediatric epilepsy surgery. In this study, the authors aimed to investigate the feasibility of nTMS-based motor mapping in the preoperative diagnostic workup within a population of children with medically refractory epilepsy.
METHODS: A single-institution database was screened for preoperative nTMS motor mappings obtained in pediatric patients (aged 0 to 18 years, 2012 to present) with medically refractory epilepsy. Patient clinical data, demographic information, and mapping results were extracted and used in statistical analyses.
RESULTS: Sixteen patients met the inclusion criteria, 15 of whom underwent resection. The median age was 9 years (range 0–17 years). No adverse effects were recorded during mapping. Specifically, no epileptic seizures were provoked via nTMS. Recordings of valid MEPs induced by nTMS were obtained in 10 patients. In the remaining patients, no MEPs could be elicited. Failure to generate MEPs was associated significantly with younger patient age (r = 0.8020, p = 0.0001863). The most frequent seizure control outcome was Engel Epilepsy Surgery Outcome Scale class I (9 patients).
CONCLUSIONS: Navigated TMS is a feasible, effective, and well-tolerated method for mapping the motor cortex of the upper and lower extremities in pediatric patients with epilepsy. Patient age modulates elicitability of MEPs, potentially reflecting various stages of myelination. Successful motor mapping has the potential to add to the existing presurgical diagnostic workup in this population, and further research is warranted.

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(Review)

The authors review the current safety literature on diagnostic single pulse TMS and rTMS for language mapping concluding that these are safe. The authors further provide examples of patient cases where the NBS diagnostics have been performed. The authors further state that they have mapped 70 children with epilepsy and observed only one seizure that seemed to be induced by the clicking coil sound.

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(Level of evidence V)

Case report of the youngest patient successfully mapped with NBS.

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(Level of evidence IIa)

The authors compared the nTMS motor cortical representation maps of hand and arm muscles with the results of invasive electrical cortical stimulation (ECS) in 13 patients with focal epilepsy. The 3D distance between the average nTMS site and average ECS electrode location was 11±4 mm for the hand and 16±7 mm for arm muscle representation areas. In all patients the representation areas defined with nTMS and ECS were located on the same gyrus, also in patients with abundant interictal epileptic activity on the motor gyrus.

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BACKGROUND: Navigated transcranial magnetic stimulation (nTMS) is a non-invasive method to localize the primary motor cortex (M1).

OBJECTIVE/HYPOTHESIS: To assess the safety and feasibility of nTMS as a non-invasive preoperative mode of functional localization of M1 in epilepsy surgery candidates with intractable focal epilepsy due to lesions in the vicinity of M1.

METHODS: We mapped the muscle representation areas of M1 with nTMS in 10 patients (age 2 to 55 years) with intractable epilepsy. The lesions were focal cortical dysplasia (n=6), ganglioglioma (n=2) polymicrogyria (n=1) or dysembryoblastic neuroepithelial tumour (n=1). The optimal stimulation sites and motor threshold (MT) of the distal hand or leg muscles were determined in both hemispheres. Cortical areas were mapped with stimulation intensities 100-120% of the MT to localize functional M1. Patients were on their stabile antiepileptic medication, and EEG was continuously monitored. The clinical benefit obtained with the preoperative nTMS mapping in the surgical decision making was scored as (1) essential, (2) beneficial, or (3) not beneficial, depending mainly on the difference between the functional and the presumed anatomic M1.

RESULTS: The M1 was successfully assessed in all but the 2 youngest patients (aged 2 and 5 years), in whom nTMS was unable to elicit motor responses. nTMS was regarded as essential or beneficial in the localization of M1 in relation to the lesions in 6 out of 10 cases. The optimal motor representation areas were mainly located symmetrically on the precentral gyrus, and corresponded to the presumed location of M1 in MRI. No clinical or EEG evidence of acute epileptogenic adverse effects were observed during the localization procedure. None of the operated patients developed post-operative motor deficits. CONCLUSIONS: nTMS is a safe and feasible clinical tool for the non-invasive preoperative localization of motor cortex in patients with intractable epilepsy due to focal lesions adjacent or within the presumed M1 in MRI.

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Abstract:

BACKGROUND: Cerebral cavernous malformations (CCM) may cause cavernoma-related epilepsy (CRE) and intracranial hemorrhage (ICH). Functional mapping has shown its usefulness during the resection of eloquent lesions including the treatment of brain arteriovenous malformations.
OBJECTIVE: To evaluate the impact of noninvasive functional mapping on decision-making and resection of eloquently located CCM.
METHODS: Of 126 patients with intracranial cavernomas, we prospectively included 40 consecutive patients (31.7%) with highly eloquent CCM between 2012 and 2020. We performed functional mapping via navigated transcranial magnetic stimulation (nTMS) motor mapping in 30 cases and nTMS language mapping in 20 cases. Twenty patients suffered from CRE. CCM caused ICH in 18 cases.
RESULTS: We used functional mapping data including function-based tractography in all cases. Indication toward (31 cases) or against (9 cases) CCM resection was influenced by noninvasive functional mapping in 36 cases (90%). We resected CCMs in 24 cases, and 7 patients refused the recommendation for surgery. In 19 and 4 cases, we used additional intraoperative neuromonitoring and awake craniotomy, respectively. Patients suffered from transient postoperative motor or language deficits in 2 and 2 cases, respectively. No patient suffered from permanent deficits. After 1 yr of follow-up, anti-epileptic drugs could be discontinued in all patients who underwent surgery but 1 patient.
CONCLUSION: Surgery-related deficit rates are low even for highly eloquent CCM and seizure outcome is excellent. The present results show that noninvasive functional mapping and function-based tractography is a useful tool for the decision-making process and during microsurgical resection of eloquently located CCM.

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Abstract:

OBJECTIVE

Surgical resection of brainstem cavernomas is associated with high postoperative morbidity due to the density of local vulnerable structures. Classical mapping of pathways by diffusion tensor imaging (DTI) has proven to be unspecific and confusing in many cases. In the current study, the authors aimed to establish a more reliable, specific, and objective method for somatotopic visualization of the descending motor pathways with navigated transcranial magnetic stimulation (nTMS)–based DTI fiber tracking.
METHODS

Twenty-one patients with brainstem cavernomas were examined with nTMS prior to surgery. The resting motor threshold (RMT) and cortical representation areas of hand, leg, and facial function were determined on both hemispheres. Motor evoked potential (MEP)–positive stimulation spots were then set as seed points for tractography. Somatotopic fiber tracking was performed at a fractional anisotropy (FA) value of 75% of the individual FA threshold.

RESULTS

Mapping of the motor cortex and tract reconstruction for hand, leg, and facial function was successful in all patients. The somatotopy of corticospinal and corticonuclear tracts was also clearly depicted on the brainstem level. Higher preoperative RMT values were associated with a postoperative motor deficit (p < 0.05) and correlated with a lower FA threshold (p < 0.05), revealing structural impairment of the corticospinal tract (CST) prior to surgery. In patients with a new deficit, the distance between the lesion and CST was below 1 mm.

CONCLUSIONS

nTMS-based fiber tracking enables objective somatotopic tract visualization on the brainstem level and provides a valuable instrument for preoperative planning, intraoperative orientation, and individual risk stratification. nTMS may thus increase the safety of surgical resection of brainstem cavernomas.

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(Level of evidence V)

A case series of ten patients with unruptured intracranial arteriovenous malformations (AVMs) located in or near eloquent areas in whom preoperative NBS mapping was performed. Motor mapping was conducted for six patients with AVMs near the rolandic region, and speech mapping was performed for four patients with left perisylvian AVMs. After the examination, all patients were treated with surgery, radiosurgery or observed with best medical treatment on case-by-case basis.NBS motor mapping allowed for delineation of the primary motor cortex, even if the anatomy was severely obscured by the AVM in all cases with rolandic AVMs. No plastic relocation of the primary motor cortex was observed. Repetitive stimulation of the left ventral precentral gyrus led to speech impairments in all four cases that underwent speech mapping. Right hemispheric involvement was observed in one out of four cases and potentially indicated plastic changes. No side effects were observed.

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(Level of evidence III)

The bicentric cohort study aimed to examine the influence of preoperative navigated transcranial magnetic stimulation (nTMS) motor and language mapping data on decision-making for or against surgical treatment of BAVMs.

The influence of data from nTMS on decision-making for or against treatment of BAVMs was examined by confirming/falsifying presumed motor or language eloquence.

The results of nTMS mappings changed the SM grading in nine cases. In six cases, the SM grading changed to a lower grade (= falsified eloquence); in three cases, the SM grading changed to a higher grade due to nTMS mappings (= unexpected eloquence). Out of all 34 cases, indication for surgery was supported by nTMS mappings in 15 cases (7 motors, 8 languages). In six cases, the decision against surgery was made based on nTMS mappings (three motors, three languages).

CONCLUSION: In 21 of 34 cases (62%), nTMS was a supportive argument. nTMS motor and language data can be used for a more objective decision-making regarding the treatment of BAVMs and for a more detailed SM grading regarding the rating of eloquence.

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Abstract: Many studies have established a link between extent of resection and survival in patients with gliomas. Surgeons must optimize the oncofunctional balance by maximizing the extent of resection and minimizing postoperative neurological morbidity. Preoperative functional imaging modalities are important tools for optimizing the oncofunctional balance. Transcranial magnetic stimulation (TMS) and functional magnetic resonance imaging (fMRI) are non-invasive imaging modalities that can be
used for preoperative functional language mapping. Scarce data exist evaluating the accuracy of these preoperative modalities for language mapping compared with gold standard intraoperative data in the same cohort. This study compares the accuracy of fMRI and TMS for language mapping compared with intraoperative direct cortical stimulation (DCS). We also identified significant predictors of preoperative functional imaging accuracy, as well as significant predictors of functional outcomes. Evidence from this study could inform clinical judgment as well as provide neuroscientific insight. We used geometric distances to determine copositivity between preoperative data and intraoperative data. Twenty-eight patients were included who underwent both preoperative fMRI and TMS procedures, as well as an awake craniotomy and intraoperative language mapping. We found that TMS shows significantly superior correlation to intraoperative DCS compared with fMRI. TMS also showed significantly higher sensitivity and negative predictive value than specificity and positive predictive value. Poor cognitive baseline was associated with decreased TMS accuracy as well as increased risk for worsened aphasia postoperatively. TMS has emerged as a promising preoperative language mapping tool. Future work should be done to identify the proper role of each imaging modality in a comprehensive, multimodal approach to optimize the oncofunctional balance.

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Abstract: The objective of this systematic review is to create an overview of the literature on the comparison of navigated transcranial magnetic stimulation (nTMS) as a mapping tool to the current gold standard, which is (intraoperative) direct cortical stimulation (DCS) mapping. A search in the databases of PubMed, EMBASE, and Web of Science was performed. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and recommendations were used. Thirty-five publications were included in the review, describing a total of 552 patients. All studies concerned either mapping of motor or language function. No comparative data for nTMS and DCS for other neurological functions were found. For motor mapping, the distances between the cortical representation of the different muscle groups identified by nTMS and DCS varied between 2 and 16 mm. Regarding mapping of language function, solely an object naming task was performed in the comparative studies on nTMS and DCS. Sensitivity and specificity ranged from 10 to 100% and 13.3-98%, respectively, when nTMS language mapping was compared with DCS mapping. The positive predictive value (PPV) and negative predictive value (NPV) ranged from 17 to 75% and 57-100% respectively. The available evidence for nTMS as a mapping modality for motor and language function is discussed.

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Abstract: 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.

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Abstract:
Repetitive TMS (rTMS) allows for non-invasive and transient disruption of local neuronal functioning. We used machine learning approaches to assess whether brain tumor patients can be accurately classified into aphasic and non-aphasic groups using their rTMS language mapping results as input features. Given that each tumor affects the subject-specific language networks differently, resulting in heterogenous rTMS functional mappings, we propose the use of machine learning strategies to classify potential patterns of rTMS language mapping results. We retrospectively included 90 patients with left perisylvian world health organization (WHO) grade II-IV gliomas that underwent presurgical navigated rTMS language mapping. Within our cohort, 29 of 90 (32.2%) patients suffered from at least mild aphasia as shown in the Aachen Aphasia Test based Berlin Aphasia Score (BAS). After spatial normalization to MNI 152 of all rTMS spots, we calculated the error rate (ER) in each stimulated cortical area (28 regions of interest, ROI) by automated anatomical labeling parcellation (AAL3) and IIT. We used a support vector machine (SVM) to classify significant areas in relation to aphasia. After feeding the ROIs into the SVM model, it revealed that in addition to age (w = 2.98), the ERs of the left supramarginal gyrus (w = 3.64), left inferior parietal gyrus (w = 2.28) and right pars triangularis (w = 1.34) contributed more than other features to the model. The model’s sensitivity was 86.2%, the specificity was 82.0%, the overall accuracy was 85.5% and the AUC was 89.3%. Our results demonstrate an increased vulnerability of right inferior pars triangularis to rTMS in aphasic patients due to left perisylvian gliomas. This finding points towards a functional relevant involvement of the right pars triangularis in response to aphasia. The tumor location feature, specified by calculating overlaps with white and grey matter atlases, did not affect the SVM model. The left supramarginal gyrus as a feature improved our SVM model the most. Additionally, our results could point towards a decreasing potential for neuroplasticity with age.

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Abstract
Awake surgery and intraoperative neuromonitoring represent the gold standard for surgery of lesion located in language-eloquent areas of the dominant hemisphere, enabling the maximal safe resection while preserving language function. Nevertheless, this functional mapping is invasive; it can be executed only during surgery and in selected patients. Moreover, the number of neuro-oncological bilingual patients is constantly growing, and performing awake surgery in this group of patients can be difficult. In this scenario, the application of accurate, repeatable and non-invasive preoperative mapping procedures is needed, in order to define the anatomical distribution of both languages. Repetitive navigated transcranial magnetic stimulation (rnTMS) associated with functional subcortical fiber tracking (nTMS-based DTI-FT) represents a promising and comprehensive mapping tool to display language pathway and function reorganization in neurosurgical patients. Herein we report a case of a bilingual patient affected by brain tumor in the left temporal lobe, who underwent rnTMS mapping for both languages (Romanian and Italian), disclosing the true eloquence of the anterior part of the lesion in both tests. After surgery, language abilities were intact at follow-up in both languages. This case represents a preliminary application of nTMS-based DTI-FT in neurosurgery for brain tumor in eloquent areas in a bilingual patient.

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Abstract
Preoperative language mapping with navigated transcranial magnetic stimulation (nTMS) is currently based on the disruption of performance during object naming. The resulting cortical language maps, however, lack accuracy when compared to intraoperative mapping. The question arises whether nTMS results can be improved, when another language task is considered, involving verb retrieval in sentence context. Twenty healthy German speakers were tested with object naming and a novel action naming task during nTMS language mapping. Error rates and categories in both hemispheres were compared. Action naming showed a significantly higher error rate than object naming in both hemispheres. Error category comparison revealed that this discrepancy stems from more lexico-semantic errors during action naming, indicating lexico-semantic retrieval of the verb being more affected than noun retrieval. In an area-wise comparison, higher error rates surfaced in multiple right-hemisphere areas, but only trends in the left ventral postcentral gyrus and middle superior temporal gyrus. Hesitation errors contributed significantly to the error count, but did not dull the mapping results. Inclusion of action naming coupled with a detailed error analysis may be favorable for nTMS mapping and ultimately improve accuracy in preoperative planning. Moreover, the results stress the recruitment of both left- and right-hemispheric areas during naming.

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Abstract
Navigated repetitive transcranial magnetic stimulation (nrTMS) is an innovative technique that provides insight into language function with high accuracy in time and space. So far, nrTMS has mainly been applied in presurgical language mapping of patients with intracranial neoplasms. For the present study, nrTMS was used for language mapping in primary progressive aphasia (PPA). Seven patients (median age: 70 years, 4 males) with the non-fluent variant of PPA (nfvPPA) were included in this pilot study. Trains of nrTMS (5 Hz, 100% resting motor threshold) caused virtual lesions at 46 standardized cortical stimulation targets per hemisphere. Patients’ errors in a naming task during stimulation were counted. The majority of errors induced occurred during frontal lobe stimulation (34.3%). Timing errors and non-responses were most frequent. More errors were induced in the right hemisphere (58%) than in the left hemisphere (42%). Mapping was tolerated by all patients, however, discomfort or pain was reported for stimulation of frontal areas. The elevated right-hemispheric error rate in our study could be due to a partial shift of language function to the right hemisphere in neurodegenerative aphasia during the course of disease and therefore points to the existence of neuronal plasticity in nfvPPA. While this is an interesting finding for neurodegenerative disorders per se, its promotion might also harbor future therapeutic targets.

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Abstract
Over the past years navigated repetitive transcranial magnetic stimulation (nrTMS) had become increasingly important for the preoperative examination and mapping of eloquent brain areas. Among other applications it was demonstrated that the detection of neuropsychological function, such as arithmetic processing or face recognition, is feasible with nrTMS. In order to investigate the mapping of further brain functions, this study aims to investigate the cortical mapping of categorization function via nrTMS. 20 healthy volunteers purely right-handed, with German as mother tongue underwent nrTMS mapping using 5 Hz/10 pulses. 52 cortical spots spread over each hemisphere were stimulated. The task consisted of 80 pictures of living and non-living images, which the volunteers were instructed to categorize while the simulation pulses were applied. The highest error rates for all errors of all subjects were observed in the left hemisphere’s posterior middle frontal gyrus (pMFG) with an error rate of 60%, as well as in the right pMFG and posterior supra marginal gyrus (pSMG) (45%). In total the task processing of non-living objects elicited more errors in total, than the recognition of living objects. nrTMS is able to detect cortical categorization function. Moreover, the observed bihemispheric representation, as well as the higher error incidence for the recognition of non-living objects is well in accordance with current literature. Clinical applicability for preoperative mapping in brain tumor patients but also in general neuroscience has to be evaluated as the next step.

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Abstract

Objective: A considerable number of gliomas require resection via direct electrical stimulation (DES) during awake craniotomy. Likewise, the feasibility of resecting language-eloquent gliomas purely based on navigated repetitive transcranial magnetic stimulation (nrTMS) has been shown. This study analyzes the outcomes after preoperative nrTMS-based and intraoperative DES-based glioma resection in a large cohort. Due to the necessity of making location comparable, a classification for language eloquence for gliomas is introduced.

Methods: Between March 2015 and May 2019, we prospectively enrolled 100 consecutive cases that were resected based on preoperative nrTMS language mapping (nrTMS group), and 47 cases via intraoperative DES mapping during awake craniotomy (awake group) following a standardized clinical workflow. Outcome measures were determined preoperatively, 5 days after surgery, and 3 months after surgery. To make functional eloquence comparable, we developed a classification based on prior publications and clinical experience. Groups and classification scores were correlated with clinical outcomes.

Results: The functional outcome did not differ between groups. Gross total resection was achieved in more cases in the nrTMS group (87%, vs. 72% in the awake group, p = 0.04). Nonetheless, the awake group showed significantly higher scores for eloquence than the nrTMS group (median 7 points; interquartile range 6–8 vs. 5 points; 3–6.75; p < 0.0001). Conclusion: Resecting language-eloquent gliomas purely based on nrTMS data is feasible in a high percentage of cases if the described clinical workflow is followed. Moreover, the proposed classification for language eloquence makes language-eloquent tumors comparable, as shown by its correlation with functional and radiological outcomes.

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Abstract

To date, the structural characteristics that distinguish language-involved from non-involved cortical areas are largely unclear. Particularly in patients suffering from language-eloquent brain tumors, reliable mapping of the cortico-subcortical language network is of high clinical importance to prepare and guide safe tumor resection. To investigate differences in structural characteristics between language-positive and language-negative areas, 20 patients (mean age: 63.2 ± 12.9 years, 16 males) diagnosed with language-eloquent left-hemispheric glioblastoma multiforme (GBM) underwent preoperative language mapping by navigated transcranial magnetic stimulation (nTMS) and nTMS-based diffusion tensor imaging fiber tracking (DTI FT). The number of language-positive and language-negative points as well as the gray matter intensity (GMI), normalized volumes of U-fibers, interhemispheric fibers, and fibers projecting to the cerebellum were assessed and compared between language-positive and language-negative nTMS mappings and set in correlation with aphasia grades. We found significantly lower GMI for language-positive nTMS points (5.7 ± 1.7 versus 7.1 ± 1.6, p = 0.0121). Furthermore, language-positive nTMS points were characterized by an enhanced connectivity profile, i.e., these points showed a significantly higher ratio in volumes for U-fibers (p ≤ 0.0056), interhemispheric fibers (p = 0.0494), and fibers projecting to the cerebellum (p = 0.0094). The number of language-positive nTMS points (R ≥ 0.4854, p ≤ 0.0300) as well as the ratio in volumes for U-fibers (R ≤ -0.4899, p ≤ 0.0283) were significantly associated with aphasia grades, as assessed pre- or postoperatively and during follow-up examinations. In conclusion, this study provides evidence for structural differences on cortical and subcortical levels between language-positive and language-negative areas, as detected by nTMS language mapping. The results may further increase confidence in the technique of nTMS language mapping and nTMS-based tractography in the direct clinical setting. Future studies may confirm our results in larger cohorts and may expand the findings to patients with other tumor entities than GBM.

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Background: Functional reorganization (FR) was shown in glioma patients by direct electrical stimulation (DES) during awake craniotomy. This option for repeated mapping is available in cases of tumor recurrence and after decision for a second surgery. Navigated repetitive transcranial magnetic stimulation (nrTMS) has shown a high correlation with results of DES during awake craniotomy for language-negative sites (LNS) and allows for a non-invasive evaluation of language function. This preliminary study aims to examine FR in glioma patients by nrTMS.

Methods: A cohort of eighteen patients with left-sided perisylvian gliomas underwent preoperative nrTMS language mapping twice. The mean time between mappings was 17 ± 12 months. The cortex was separated into anterior and posterior language-eloquent regions. We defined a tumor area and an area without tumor (WOT). Error rates (ER = number of errors per number of stimulations) and hemispheric dominance ratios (HDR) were calculated as the quotient of the left- and right-sided ER.

Results: In cases in which most language function was located near the tumor during the first mapping, we found significantly more LNS in the tumor area during the second mapping as compared to cases in which function was not located near the tumor (p = 0.049). Patients with seizures showed fewer LNS during the second mapping. We found more changes of cortical language function in patients with a follow-up time of more than 13 months and lower WHO-graded tumors.

Conclusion: Present results confirm that nrTMS can show FR of LNS in glioma patients. Its extent, clinical impact and correlation with DES requires further evaluation but could have a considerable impact in neuro-oncology.

Published: Front Oncol. 2019; 9: 446.

(Level of evidence III)

Case series reporting 4 adult patients with left-sided perisylvian brain lesions suspected to be at risk of language function loss if operated on. Although such patients should be operated using direct cortical stimulation during an awake surgery procedure to minimize the risk, not all patients qualify for awake surgery. In the case series 4 such patients were operated solely based on NBS-language mapping and NBS based DTI. No patient suffered from a new surgery related language deficit 3 months after surgery.

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(Level of evidence III)

A comparative study comparing patient outcomes following brain tumor surgery guided by NBS- NexSpeech language mapping to outcomes in patients without NBS-NexSpeech functional mapping. A prospectively enrolled cohort of all 25 patients evaluated for surgery for a tumor in a speech/language eloquent location between 2013-2014 (GROUP 2) were preoperatively mapped with NBS-NexSpeech. The 25 patients were compared with a control group of 25 patients who met the same in- and exclusion criteria in 2011-2013, but in whom NBS-NexSpeech results were not available for the operating surgeon (GROUP 1).

Mean anterior-posterior (ap) craniotomy extents and overall craniotomy sizes were significantly smaller for the patients in GROUP 2 (Ap: p = 0.0117; overall size: p = 0.0373), and postoperative language deficits were found significantly more frequently for the patients in GROUP 1 (p = 0.0153), although the preoperative language status did not differ between groups (p = 0.7576).

Additionally, there was a trend towards fewer unexpected tumor residuals, shorter surgery duration, less peri- or postoperative complications, shorter inpatient stay, and higher postoperative Karnofsky performance status scale (KPS) for the patients in GROUP 2.

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(Level of evidence IIa)

The paper compared non-invasive nrTMS (navigated repetitive TMS), magnetoencephalographic imaging and direct cortical stimulation (DCS) for language mapping in 12 adult patients with lesions around cortical language areas. When compared with intraoperative DCS results, the sensitivity of nTMS was found to be 90%, specificity was 98%, the positive predictive value was 69% and the negative predictive value was 99%. The authors conclude that maps of language function generated with nTMS correlate well with those generated by DCS. Negative nTMS mapping also correlates with negative DCS mapping.

Language mapping using nTMS was found to be safe and well-tolerated. In this study, the clinicians adjusted stimulation intensity to a level each patient found tolerable. Additionally, the investigators used the field navigation-features of the NBS System to avoid stimulating cranial and facial nerves.

In their discussion, the authors propose that, “the real contribution of nTMS is in the preoperative preparation that it allows. By mapping a subject before surgery, the surgeon can generate a precise map of potentially positive language sites, which then may be swiftly interrogated with DCS during surgery.”

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(Level of evidence IIa)

A good overall correlation between repetitive nTMS and DCS was observed, particularly with regard to negatively mapped regions. Non-invasive inhibition mapping with nTMS is evolving as a valuable tool for preoperative mapping of language areas.

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(Level of evidence IIa)

Three right-handed patients with left-sided gliomas (2 opercular glioblastomas, 1 astrocytoma WHO grade III of the angular gyrus) underwent preoperative language mapping by rTMS as well as intraoperative language mapping provided via direct cortical stimulation (DCS) for initial as well as for repeated Resection 7, 10, and 15 months later. Overall, preoperative rTMS was able to elicit clear language errors in all mappings. A good correlation between initial rTMS and DCS results was observed. As a consequence of brain plasticity, initial DCS and rTMS findings only corresponded with the results obtained during the second examination in one out of three patients thus suggesting changes of language organization in two of our three patients.

Published: BMC Neurosci. 2014 Jan 30; 15(1):20

(Level of evidence IIa)

The authors describe and present results of an accelerometer-based setup for detection of vocalization- related larynx vibrations combined with an automatic routine for voice onset detection for rTMS speech mapping applying naming. The results produced by the automatic routine were compared with the manually reviewed video-recordings in 12 consecutive patients during preoperative workup for epilepsy or tumor surgery.

The authors found that the automatic routine correctly detected 96% of the voice onsets, resulting in 96% sensitivity and 71% specificity. Majority (63%) of the misdetections were related to visible throat movements, extra voices before the response, or delayed naming of the previous stimuli. The no- response errors were correctly detected in 88% of events. The authors conclude that the setup for automatic detection of voice onsets provides quantitative additional data for analysis of the rTMS- induced speech response modifications. The objectively defined speech response latencies increase the repeatability, reliability and stratification of the rTMS results.

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(Level of evidence IIa)

Accuracy of NBS-rTMS and fMRI based preoperative localization of language cortex was analyzed and compared with DCS during awake surgery in 27 patients with left-sided intraparenchymal perisylvian lesions.

The receiver operating characteristics were calculated for NBS-rTMS and fMRI and compared with DCS as ground truth for regions with (w/) and without (w/o) the lesion in the mapped regions.

The authors found that the w/ subgroup revealed a sensitivity of 100% (w/o 100%), a specificity of 8% (w/o 5%), a positive predictive value of 34% (w/o: 53%), and a negative predictive value (NPV) of 100% (w/o: 100%) for the comparison of rTMS versus DCS.

Findings for the comparison of fMRI versus DCS within the w/ subgroup revealed a sensitivity of 32% (w/o:62%), a specificity of 88% (w/o: 60%), a positive predictive value of 56% (w/o: 62%), and a NPV of 73% (w/o: 60%).

The authors conclude that although strengths and weaknesses exist for both rTMS and fMRI, the results show that rTMS is less affected by a brain lesion than fMRI, especially when performing mapping of language-negative cortical regions based on sensitivity and NPV.

Published in:J Neurosurg. 2015 Aug; 123(2):314-24. doi: 10.3171/2014.10.JNS141582. Epub 2015 Apr 17

Abstract
Surgeons must optimize the onco-functional balance by maximizing the extent of resection and minimizing postoperative neurological morbidity. Optimal patient selection and surgical planning requires preoperative identification of nonresectable structures. Transcranial magnetic stimulation is a method of noninvasively mapping the cortical representations of the speech and motor systems. Despite recent promising data, its clinical relevance and appropriate role in a comprehensive mapping approach remains unknown. In this study, we aim to provide direct evidence regarding the clinical utility of transcranial magnetic stimulation by interrogating the eloquence of TMS points. Forty-two glioma patients were included in this retrospective study. We collected motor function outcomes 3 months postoperatively. We overlayed the postoperative MRI onto the preoperative MRI to visualize preoperative TMS points in the context of the surgical cavity. We then generated diffusion tensor imaging tractography to identify meaningful subsets of TMS points. We correlated the resection of preoperative imaging features with clinical outcomes. The resection of TMS-positive points was significantly predictive of permanent deficits (p = 0.05). However, four out of eight patients had TMS-positive points resected without a permanent deficit. DTI tractography at a 75% FA threshold identified which TMS points are essential and which are amenable to surgical resection. TMS combined with DTI tractography shows a significant prediction of postoperative neurological deficits with both a high positive predictive value and negative predictive value. 

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Abstract: Visualization of functionally significant subcortical white matter fibers is needed in neurosurgical procedures in order to avoid damage to the language network during resection. In an effort to achieve this, positive cortical points revealed during preoperative language mapping with navigated transcranial magnetic stimulation (nTMS) can be employed as regions of interest (ROIs) for diffusion tensor imaging (DTI) fiber tracking. However, the effect that the use of different language tasks has on nTMS mapping and subsequent DTI-fiber tracking remains unexplored. The visualization of ventral stream tracts with an assumed lexico-semantic role may especially benefit from ROIs delivered by the lexico-semantically demanding verb task, Action Naming. In a first step, bihemispheric nTMS language mapping was administered in 18 healthy participants using the standard task Object Naming and the novel task Action Naming to trigger verbs in a small sentence context. Cortical areas in which nTMS induced language errors were identified as language-positive cortical sites. In a second step, nTMS-based DTI-fiber tracking was conducted using solely these language-positive points as ROIs. The ability of the two tasks’ ROIs to visualize the dorsal tracts Arcuate Fascicle and Superior Longitudinal Fascicle, the ventral tracts Inferior Longitudinal Fascicle, Uncinate Fascicle, and Inferior Fronto-Occipital Fascicle, the speech-articulatory Cortico-Nuclear Tract, and interhemispheric commissural fibers was compared in both hemispheres. In the left hemisphere, ROIs of Action Naming led to a significantly higher fraction of overall visualized tracts, specifically in the ventral stream’s Inferior Fronto-Occipital and Inferior Longitudinal Fascicle. No difference was found between tracking with Action Naming vs. Object Naming seeds for dorsal stream tracts, neither for the speech-articulatory tract nor the inter-hemispheric connections. While the two tasks appeared equally demanding for phonological-articulatory processes, ROI seeding through the task Action Naming seemed to better visualize lexico-semantic tracts in the ventral stream. This distinction was not evident in the right hemisphere. However, the distribution of tracts exposed was, overall, mirrored relative to those in the left hemisphere network. In presurgical practice, mapping and tracking of language pathways may profit from these findings and should consider inclusion of the Action Naming task, particularly for lesions in ventral subcortical regions.

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Abstract: Tumors infiltrating the motor system lead to significant disability, often caused by corticospinal tract injury. The delineation of the healthy-pathological white matter (WM) interface area, for which diffusion magnetic resonance imaging (dMRI) has shown promising potential, may improve treatment outcome. However, up to 90% of white matter (WM) voxels include multiple fiber populations, which cannot be correctly described with traditional metrics such as fractional anisotropy (FA) or apparent diffusion coefficient (ADC). Here, we used a novel fixel-based along-tract analysis consisting of constrained spherical deconvolution (CSD)-based probabilistic tractography and fixel-based apparent fiber density (FD), capable of identifying fiber orientation specific microstructural metrics. We addressed this novel methodology’s capability to detect corticospinal tract impairment. We measured and compared tractogram-related FD and traditional microstructural metrics bihemispherically in 65 patients with WHO grade III and IV gliomas infiltrating the motor system. The cortical tractogram seeds were based on motor maps derived by transcranial magnetic stimulation. We extracted 100 equally distributed cross-sections along each streamline of corticospinal tract (CST) for along-tract statistical analysis. Cross-sections were then analyzed to detect differences between healthy and pathological hemispheres. All metrics showed significant differences between healthy and pathologic hemispheres over the entire tract and between peritumoral segments. Peritumoral values were lower for FA and FD, but higher for ADC within the entire cohort. FD was more specific to tumor-induced changes in CST than ADC or FA, whereas ADC and FA showed higher sensitivity. The bihemispheric along-tract analysis provides an approach to detect subject-specific structural changes in healthy and pathological WM. In the current clinical dataset, the more complex FD metrics did not outperform FA and ADC in terms of describing corticospinal tract impairment.

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(Level of evidence IIa)

DTI-tracking was performed both using NBS motor mapping results as seed sides and without the information in 50 patients with brain tumors to visualize white matter motor tracts. Tracts obtained with the two methods were compared to each other and the information each method provided for planning of subsequent surgery were compared. NBS-based results changed or modified surgical strategy in 23 of 50 patients (46%), whereas knowledge-based results would have changed surgical strategy in 11 of 50 patients (22%). The authors conclude that fiber tracking based on NBS by the proposed standardized algorithm represents an objective visualization method based on functional data and provides a valuable instrument for preoperative planning and intraoperative orientation and monitoring.

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(Level of evidence IIa)

DTI-tracking was performed both using NBS motor mapping results as seed sides and without the information in 20 patients with brain tumors to visualize white matter motor tracts. Tracts obtained with the two methods were compared to each other. NBS-based tractography provided a detailed somatotopic reconstruction of the CST. This NBS-based reconstruction resulted in a decreased number of fibers (305.1 ± 231.7 vs 1024 ± 193, p<0.001) and a significantly greater overlap between the motor cortex and the cortical end-region of the CST compared to the standard technique (90.5 ± 8.8% vs 58.3 ± 16.6%, p < 0.0001). Direct subcortical stimulation confirmed the CST location and the somatotopic reconstruction in all cases. These results suggest that NBS-based tractography of the CST is more accurate and less operator-dependent than the standard technique and provides a reliable anatomical and functional characterization of the motor pathway.

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(Level of evidence IIb)

This retrospective case-control study, reviewed the data of patients operated for suspected motor- eloquent lesions between 2012 and 2015. The patients underwent nTMS mapping of M1 and, from 2014, nTMS-based DTI-FT of the CST. The impact on the preoperative risk/benefit analysis, surgical strategy, craniotomy size, extent of resection (EOR), and outcome were compared with a control group.

35 patients underwent nTMS mapping of M1 (group A), 35 patients also underwent nTMS-based DTI-FT of the CST (group B), and a control group composed of 35 patients treated without nTMS (group C). The patients in groups A and B received smaller craniotomies (P = .01; P = .001), had less postoperative seizures (P = .02), and a better postoperative motor performance (P= .04) and Karnofsky Performance Status (P = .009) than the controls. Group B exhibited an improved risk/benefit analysis (P = .006), an increased EOR of nTMS-negative lesions in absence of preoperative motor deficits (P = .01), and less motor and Karnofsky Performance Status worsening in case of preoperative motor deficits (P = .02, P = .03) than group A. CONCLUSION: nTMS-based mapping enables a tailored surgical approach for motor- eloquent lesions. It may improve the risk/benefit analysis, EOR and outcome, particularly when nTMS- based DTI-FT is performed.

Published in: Neurosurgery. 2017 Nov 29. doi: 10.1093/neuros/nyx554. [Epub ahead of print]

(Level of evidence III)

The feasibility of using language-related cortical areas identified via repetitive navigated transcranial magnetic stimulation (rTMS) to seed DTI FT of subcortical language tracts was studied. in 37 patients with left-hemispheric perisylvian lesions. Language-positive rTMS stimulation spots were integrated in a deterministic tractography software as objects and used as seed regions for DTI FT.

The rTMS-based DTI FT identified all commonly known subcortical language tracts. The authors conclude that this study proves the feasibility of rTMS-based DTI FT for subcortical language tracts, provides suitable settings, and shows its easy and standardizable application for the visualization of every language tract in 86.5 % of patients.

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(Level of evidence III)

Localization of the subcortical language network was performed with 3 methods in 10 patients with brain tumors. The methods were 1) standard anatomy based DTI; 2) DTI using all obtained NBS – language mapping positive cortical locations as the cortical seed site for DTI; and 3) DTI using single NBS-language mapping positive cortical locations as the cortical seed site for DTI. The authors demonstrate the feasibility of the different methods and in this limited size study conclude that method 3 provides the best results.

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(Level of evidence IIa)

The study compares nTMS-based DTI FT of language pathways with the most reproducible protocol for language pathway tractography, using cubic regions of interest (ROIs) for the arcuate fascicle in 37 patients with left-sided perisylvian lesions. DTI FT was performed using the cubic ROIs-based protocol and the authors' nTMS-based DTI FT approach. The same minimal fiber length and fractional anisotropy were chosen (50mm and 0.2, respectively). Both protocols were performed with standard clinical tractography software.

Both methods visualized language-related fiber tracts in all 37 patients. Using the cubic ROIs-based protocol, 39.9% of these language-related fiber tracts were detected in the examined patients, as opposed to 76.0% when performing nTMS-based DTI FT. For specifically tracking the arcuate fascicle, however, the cubic ROIs-based approach showed better results (97.3% vs 75.7% with nTMS-based DTI FT).

The authors concluded that the cubic ROIs-based protocol was designed for arcuate fascicle tractography, and this study shows that it is still useful for this intention. However, superior results were obtained using the nTMS-based DTI FT for visualization of other language-related fiber tracts.

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(Level of evidence IIa)

This study was designed to evaluate whether interhemispheric connectivity (IC) detected by nTMS-based diffusion tensor imaging-fiber tracking (DTI-FT) can be used to predict surgery-related aphasia in patients with brain tumors.

38 patients with left-sided perisylvian brain lesions underwent cortical language mapping of both hemispheres by nTMS prior to awake surgery. Then, nTMS-based DTI-FT was conducted with a fractional anisotropy (FA) of 0.01 and 0.2 to visualize nTMS-based IC. Receiver operating characteristics were calculated for the prediction of a postoperative (irrespective of the preoperative state) and a new surgery-related aphasia by the presence of detectable IC.

RESULTS: Language mapping by nTMS was possible in all patients. Regarding the correlation of aphasia to nTMS-based IC, statistically significant differences were revealed for both evaluated FA values. FA of 0.2 led to a specificity of 93% (postoperative aphasia) and 90% (surgery-related aphasia).

CONCLUSIONS: According to these results, IC detected by preoperative nTMS-based DTI-FT might be regarded as a risk factor for surgery-related aphasia, with a specificity of up to 93%. However, because the majority of enrolled patients suffered from transient aphasia postoperatively, it has to be evaluated whether this approach distinctly leads to similar results among patients with permanent language deficits. Despite this restriction, this approach might contribute to individualized patient consultation prior to tumor resection in clinical practice.

Published in: J Neurosurg. 2016 Apr 1:1-12. [Epub ahead of print]

Abstract:
Background: Maximum safe resection of infiltrative brain tumors in eloquent area is the primary objective in surgical neuro-oncology. This goal can be achieved with direct electrical stimulation (DES) to perform a functional mapping of the brain in patients awake intraoperatively. When awake surgery is not possible, we propose a pipeline procedure that combines advanced techniques aiming at performing a dissection that respects the anatomo-functional connectivity of the peritumoral region. This procedure can benefit from intraoperative monitoring with computerized tomography scan (iCT-scan) and brain shift correction. Associated with this intraoperative monitoring, the additional value of preoperative investigation combining brain mapping by navigated transcranial magnetic stimulation (nTMS) with various neuroimaging modalities (tractography and resting state functional MRI) has not yet been reported.
Case Report: A 42-year-old left-handed man had increased intracranial pressure (IICP), left hand muscle deficit, and dysarthria, related to an infiltrative tumor of the right frontal lobe with large mass effect and circumscribed contrast enhancement in motor and premotor cortical areas. Spectroscopy profile and intratumoral calcifications on CT-scan suggested an WHO grade III glioma, later confirmed by histology. The aforementioned surgical procedure was considered, since standard awake surgery was not appropriate for this patient. In preoperative time, nTMS mapping of motor function (deltoid, first interosseous, and tibialis anterior muscles) was performed, combined with magnetic resonance imaging (MRI)-based tractography reconstruction of 6 neural tracts (arcuate, corticospinal, inferior fronto-occipital, uncinate and superior and inferior longitudinal fasciculi) and resting-state functional MRI connectivity (rs-fMRI) of sensorimotor and language networks. In intraoperative time, DES mapping was performed with motor evoked response recording and tumor resection was optimized using non-rigid image transformation of the preoperative data (nTMS, tractography, and rs-fMRI) to iCT data. Image guidance was updated with correction for brain shift and tissue deformation using biomechanical modeling taking into account brain elastic properties. This correction was done at crucial surgical steps, i.e., when tumor bulged through the craniotomy after dura mater opening and when approaching the presumed eloquent brain regions. This procedure allowed a total resection of the tumor region with contrast enhancement as well as a complete regression of IICP and dysarthria. Hand paresis remained stable with no additional deficit. Postoperative nTMS mapping confirmed the good functional outcome.
Conclusion: This case report and technical note highlights the value of preoperative functional evaluation by nTMS updated intraoperatively with correction of brain deformation by iCT. This multimodal approach may become the optimized technique of reference for patients with brain tumors in eloquent areas that are unsuitable for awake brain surgery.

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Review article describing NBS technology and the potential clinical applications of the technology.

Review article describing utility of NBS technology in pre-neurosurgical planning.

Method paper demonstrating the accuracy of NBS technology and importance of electric field modeling as performed by Nexstim.

Method paper on motor mapping.