Motor mapping in tumor patients

Krieg SM, et al. Resection of Motor Eloquent Metastases Aided by Preoperative nTMS-Based Motor Maps- Comparison of Two Observational Cohorts. Front Oncol. 2016 Dec 21;6:261.

(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.

Picht T et al., Presurgical navigated TMS motor cortex mapping improves outcome in glioblastoma surgery: a controlled observational study. J Neurooncol 2015 Nov 13. [Epub ahead of print]

(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”.

Krieg S et al., Changing the clinical course of glioma patients by preoperative motor mapping with navigated transcranial magnetic brain stimulation. BMC Cancer. 2015 Apr 8; 15(1):231. [Epub ahead of print]

(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).

Frey D et al., Navigated transcranial magnetic stimulation improves the treatment outcome in patients with brain tumors in motor eloquent locations. Neuro-Oncology 2014; Jun 12. pii: nou110.

(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.

Krieg SM et al., Preoperative motor mapping by navigated transcranial magnetic brain stimulation improves outcome for motor eloquent lesions. Neuro-Oncology 2014; 0, 1-9, doi: 10.1093/neuonc/nou007

(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.

Sollmann N, et al. Associations between clinical outcome and navigated transcranial magnetic stimulation characteristics in patients with motor-eloquent brain lesions...

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]

Moser T, et al. Resection of Navigated Transcranial Magnetic Stimulation-Positive Prerolandic Motor Areas Causes Permanent Impairment of Motor Function. Neurosurgery. 2017 Jul 1;81(1):99-110. doi: 10.1093/neuros/nyw169

(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.

Takahashi S et al., Navigated transcranial magnetic stimulation for mapping the motor cortex in patients with rolandic brain tumors. Neurosurg Focus, 2013 Apr; 34(4).


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.”

Picht T, et al., Preoperative Functional Mapping for Rolandic Brain Tumor Surgery: Comparison of Navigated Transcranial Magnetic Stimulation to Direct Cortical Stimulation. Neurosurgery, 2011, 69:581-589.

(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.

Forster M-T, et al., Navigated Transcranial Magnetic Stimulation and Functional Magnetic Resonance Imaging: Advanced Adjuncts in Preoperative Planning for Central Region Tumors. Neurosurgery, 2011, 68:1317-1325.

(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.

Coburger J, et al. Comparison of navigated transcranial magnetic stimulation and functional magnetic resonance imaging for preoperative mapping in rolandic tumor surgery. Neurosurg Rev. 2012. Published online Aug 11.

(Level of evidence IIa)

Takahashi S, et al. Plastic relocation of motor cortex in a patient with LGG (low grade glioma) confirmed by NBS (navigated brain stimulation). Acta Neurochir (Wien) 2012, 154(11):2003-8.

(Level of evidence V)

Picht T, et al. The preoperative use of navigated transcranial magnetic stimulation facilitates early resection of suspected low-grade gliomas in the motor cortex. Acta Neurochir (Wien). 2013 Oct; 155(10):1813-21.

(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.

Säisänen L, et al. Locating and Outlining the Cortical Motor Representation Areas of Facial Muscles with Navigated Transcranial Magnetic Stimulation. Neurosurgery. 2015 Sep; 77(3):394-405

(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.

Safety of motor and language mapping

Tarapore P, et al. Safety and Tolerability of Navigated TMS for Preoperative Mapping in Neurosurgical Patients Clin Neurophysiol (2015), doi:

(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.

Motor and language mapping in epilepsy patients

Narayana S, et al, Clinical Applications of Transcranial Magnetic Stimulation in Pediatric Neurology. J Child Neurol. Published online Oct 23.


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.

Vitikainen A-M, et al., Applicability of nTMS in locating the motor cortical representation areas in patients with epilepsy. Acta Neurochir Epub 2013 Jan 19.

(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.

Narayana S, et al. Successful motor mapping with transcranial magnetic stimulation in an infant: A case report. Neurology. 2017 Nov 14;89(20):2115-2117. doi: 10.1212/WNL.0000000000004650. Epub 2017 Oct 11.

(Level of evidence V)

Case report of the youngest patient successfully mapped with NBS.

Motor and language mapping in patients with vascular malformations

Kato N, et al. Functional brain mapping of patients with arteriovenous malformations using navigated transcranial magnetic stimulation: first experience in ten patients. Acta Neurochir (Wien). 2014 May; 156(5):885-95. doi: 10.1007/s00701-014-2043-7

(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.

Ille S, et al. The impact of nTMS mapping on treatment of brain AVMs. Acta Neurochir (Wien). 2018 Jan 24. doi: 10.1007/s00701-018-3475-2. [Epub ahead of print]

(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.

Language mapping

Ille S, et al., Resection of highly language-eloquent brain lesions based purely on rTMS language mapping without awake surgery. Acta Neurochir (Wien). 2016 Dec;158(12):2265-2275

(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.

Sollmann N et al., The impact of preoperative language mapping by repetitive navigated transcranial magnetic stimulation on the clinical course of brain tumor patients. BMC Cancer. 2015 Apr 11; 15:261. doi: 10.1186/s12885-015-1299-5.

(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.

Tarapore P, et al. Language Mapping with Navigated Repetitive TMS: Proof of Technique and Validation. NeuroImage (2013), doi: 10.1016/j.neuroimage.2013.05.018

(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.”

Picht, Krieg et al., A Comparison of Language Mapping by Preoperative Navigated Transcranial Magnetic Stimulation and Direct Cortical Stimulation during Awake Surgery. Neurosurgery 2013. Published online Feb 4.

(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.

Krieg SM, et al. Repeated mapping of cortical language sites by preoperative navigated transcranial magnetic stimulation compared to repeated intraoperative DCS mapping in awake craniotomy. BMC Neurosci. 2014 Jan 30; 15(1):20 doi: 10.1186/1471-2202-15-20.

(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.

Vitikainen A, et al. Accelerometer-based automatic voice onset detection in speech mapping with navigated repetitive transcranial magnetic stimulation. J Neurosci Methods. 2015 Sep 30; 253:70-7. doi: 10.1016/j.jneumeth.2015.05.015. Epub 2015 May 28.

(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.

Ille S, et al. Impairment of preoperative language mapping by lesion location: a functional magnetic resonance imaging, navigated transcranial magnetic stimulation, and direct cortical stimulation study.

(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

DTI in tumor patients

Frey D et al. A new approach for corticospinal tract reconstruction based on navigated transcranial stimulation and standardized fractional anisotropy values. Neuroimage 2012, 62(3):1600-9.

(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.

Conti A, et al. Navigated Transcranial Magnetic Stimulation for “Somatotopic” Tractography of the Cortico- Spinal Tract. Neurosurgery 2014, DOI: 10.1227/NEU.0000000000000502.

(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.

Raffa G, et al. The Impact of Diffusion Tensor Imaging Fiber Tracking of the Corticospinal Tract Based on Navigated Transcranial Magnetic Stimulation on Surgery of Motor-Eloquent Brain Lesions.

(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]

Negwer C, et al., Visualization of subcortical language pathways by diffusion tensor imaging fiber tracking based on rTMS language mapping. Brain Imaging Behav. 2016 Jun 20. [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.

Raffa G, et al., A Novel Technique for Region and Linguistic Specific nTMS-based DTI Fiber Tracking of Language Pathways in Brain Tumor Patients. Front Neurosci. 2016 Dec 2;10:552. eCollection 2016

(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.

Negwer C, et al., Language pathway tracking: comparing nTMS-based DTI fiber tracking with a cubic ROIs- based protocol. J Neurosurg. 2016 May 27:1-9. [Epub ahead of print]

(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.

Sollmann N, et al., Interhemispheric connectivity revealed by diffusion tensor imaging fiber tracking derived from navigated transcranial magnetic stimulation maps as a sign of language function at risk in patients with brain tumors.

(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]

Radiosurgery planning

Conti A, et al, Integration of functional neuroimaging in CyberKnife radiosurgery: feasibility and dosimetric results. Neurosurg Focus, 2013 Apr; 34(4).

(Level of evidence IIa)

For lesions lying close to critical structures, it is not always possible to stay within recommended irradiation safety limits while delivering biologically-effective radiation doses. For this reason, spatial resolution of the functional mapping method is important in order to avoid overestimation of critical volumes. In their study, the authors found “The spatial resolution of NBS is actually extremely high, since we can record the differences in cortical responses within a few millimeters”. Additionally, the authors observed that NBS was a direct measurement and not a passive recording of brain activity relying on changes in cerebral blood flow or metabolism which could be altered in the presence of brain tumors and vascular malformations, as is the case with fMRI. After treatment plan optimization, the clinicians achieved an average 17% reduction in the radiation dose to critical functional volumes in a series of 25 patients treated with CyberKnife.

NBS methodology and case reports

Ruohonen J and Karhu J. Navigated transcranial magnetic stimulation. Neurophysiol Clin 2010, 40(1):7-17.

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

Picht T. Current and potential utility of transcranial magnetic stimulation in the diagnostics before brain tumor surgery. CNS Oncol. 2014 Jul; 3(4):299-310. doi: 10.2217/cns.14.25. PubMed PMID: 25286041.

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

Schmidt S et al, Nonphysiological factors in navigated TMS studies; Confounding covariates and valid intracortical estimates. Hum Brain Mapp. 2014 Aug 29. doi: 10.1002/hbm.22611. [Epub ahead of print]

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

Julkunen P. Methods for estimating cortical motor representation size and location in navigated transcranial magnetic stimulation J Neurosci Methods. 2014 Jul 30; 232:125-33. doi: 10.1016/j.jneumeth.2014.05.020. Epub 2014 May 26.

Method paper on motor mapping.