Towards a tractography-based risk stratification model for language area associated gliomas.

OBJECTIVES: Injury to major white matter pathways during language-area associated glioma surgery often leads to permanent loss of neurological function. The aim was to establish standardized tractography of language pathways as a predictor of language outcome in clinical neurosurgery. METHODS: We prospectively analyzed 50 surgical cases of patients with left perisylvian, diffuse gliomas. Standardized preoperative Diffusion-Tensor-Imaging (DTI)-based tractography of the 5 main language tracts (Arcuate Fasciculus [AF], Frontal Aslant Tract [FAT], Inferior Fronto-Occipital Fasciculus [IFOF], Inferior Longitudinal Fasciculus [ILF], Uncinate Fasciculus [UF]) and spatial analysis of tumor and tracts was performed. Postoperative imaging and the resulting resection map were analyzed for potential surgical injury of tracts. The language status was assessed preoperatively, postoperatively and after 3 months using the Aachen Aphasia Test and Berlin Aphasia Score. Correlation analyses, two-step cluster analysis and binary logistic regression were used to analyze associations of tractography results with language outcome after surgery. RESULTS: In 14 out of 50 patients (28%), new aphasic symptoms were detected 3 months after surgery. The preoperative infiltration of the AF was associated with functional worsening (cc = 0.314; p = 0.019). Cluster analysis of tract injury profiles revealed two areas particularly related to aphasia: the temporo-parieto-occipital junction (TPO; temporo-parietal AF, middle IFOF, middle ILF) and the temporal stem/peri-insular white matter (middle IFOF, anterior ILF, temporal UF, temporal AF). Injury to these areas (TPO: OR: 23.04; CI: 4.11 - 129.06; temporal stem: OR: 21.96; CI: 2.93 - 164.41) was associated with a higher-risk of persisting aphasia. CONCLUSIONS: Tractography of language pathways can help to determine the individual aphasia risk profile pre-surgically. The TPO and temporal stem/peri-insular white matter were confirmed as functional nodes particularly sensitive to surgical injuries.

Incidence and linguistic quality of speech errors: a comparison of preoperative transcranial magnetic stimulation and intraoperative direct cortex stimulation.

OBJECTIVE: Given the interindividual variance of functional language anatomy, risk prediction based merely on anatomical data is insufficient in language area-related brain tumor surgery, suggesting the need for direct cortical and subcortical mapping during awake surgery. Reliable, noninvasive preoperative methods of language localization hold the potential for reducing the necessity for awake procedures and may improve patient counseling and surgical planning. Repetitive navigated transcranial magnetic stimulation (rnTMS) is an evolving tool for localizing language-eloquent areas. The aim of this study was to investigate the reliability of rnTMS in locating cortical language sites. METHODS: Twenty-five patients with brain tumors in speech-related areas were prospectively evaluated with preoperative rnTMS (5 Hz, train of five, average 105% resting motor threshold) and navigated direct cortical stimulation (DCS; bipolar, 50 Hz, 6-8 mA, 200-µsec pulse width) during awake surgeries employing a picture-naming task. Positive and negative stimulation spots within the craniotomy were documented in the same MRI data set. TMS and DCS language-positive areas were compared with regard to their spatial overlap, their allocation in a cortical parcellation system, and their linguistic qualities. RESULTS: There were over twofold more positive language spots within the exposed area on rnTMS than on DCS. The comparison of positive rnTMS and DCS (ground truth) overlaps revealed low sensitivity (35%) and low positive predictive value (16%) but high specificity (90%) and high negative predictive value (96%). Within the overlaps, there was no correlation in error quality. On DCS, 73% of language-positive spots were located in the pars opercularis and pars triangularis of the frontal operculum and 24% within the supramarginal gyrus and dorsal portion of the superior temporal gyrus, while on rnTMS language positivity was distributed more evenly over a large number of gyri. CONCLUSIONS: The current protocol for rnTMS for language mapping identified language-negative sites with good dependability but was unable to reliably detect language-positive spots. Further refinements of the technique will be needed to establish rnTMS language mapping as a useful clinical tool.

Preoperative transcranial magnetic stimulation for picture naming is reliable in mapping segments of the arcuate fasciculus.

In preoperative planning for neurosurgery, both anatomical (diffusion imaging tractography) and functional tools (MR-navigated transcranial magnetic stimulation) are increasingly used to identify and preserve eloquent language structures specific to individuals. Using these tools in healthy adults shows that speech production errors occur mainly in perisylvian cortical sites that correspond to subject-specific terminations of the major language pathway, the arcuate fasciculus. It is not clear whether this correspondence remains in oncological patients with altered tissue. We studied a heterogeneous cohort of 30 patients (fourteen male, mean age 44), undergoing a first or second surgery for a left hemisphere brain tumour in a language-eloquent region, to test whether speech production errors induced by preoperative transcranial magnetic stimulation had consistent anatomical correspondence to the arcuate fasciculus. We used navigated repetitive transcranial magnetic stimulation during picture naming and recorded different perisylvian sites where transient interference to speech production occurred. Spherical deconvolution diffusion imaging tractography was performed to map the direct fronto-temporal and indirect (fronto-parietal and parieto-temporal) segments of the arcuate fasciculus in each patient. Speech production errors were reported in all patients when stimulating the frontal lobe, and in over 90% of patients in the parietal lobe. Errors were less frequent in the temporal lobe (54%). In all patients, at least one error site corresponded to a termination of the arcuate fasciculus, particularly in the frontal and parietal lobes, despite distorted anatomy due to a lesion and/or previous resection. Our results indicate that there is strong correspondence between terminations of the arcuate fasciculus and speech errors. This indicates that white matter anatomy may be a robust marker for identifying functionally eloquent cortex, particularly in the frontal and parietal lobe. This knowledge may improve targets for preoperative mapping of language in the neurosurgical setting.

Manual for clinical language tractography.

BACKGROUND: We introduce a user-friendly, standardized protocol for tractography of the major language fiber bundles. METHOD: The introduced method uses dMRI images for tractography whereas the ROI definition is based on structural T1 MPRAGE MRI templates, without normalization to MNI space. ROIs for five language-relevant fiber bundles were visualized on an axial, coronal, or sagittal view of T1 MPRAGE images. The ROIs were defined based upon the tracts' obligatory pathways, derived from literature and own experiences in peritumoral tractography. RESULTS: The resulting guideline was evaluated for each fiber bundle in ten healthy subjects and ten patients by one expert and three raters. Overall, 300 ROIs were evaluated and compared. The targeted language fiber bundles could be tracked in 88% of the ROI pairs, based on the raters' result blinded ROI placements. The evaluation indicated that the precision of the ROIs did not relate to the varying experience of the raters. CONCLUSIONS: Our guideline introduces a standardized language tractography method for routine preoperative workup and for research contexts. The ROI placement guideline based on easy-to-identify anatomical landmarks proved to be user-friendly and accurate, also in inexperienced test persons.

Aphasia and cognitive impairment decrease the reliability of rnTMS language mapping.

BACKGROUND: Navigated transcranial magnetic stimulation (nTMS) is a non-invasive mapping tool to locate functional areas of the brain. While gaining importance in the preoperative planning process in motor eloquent regions, its usefulness for reliably identifying language areas is still being discussed. The aim of this study was to identify biometric factors which might influence and therefore bias the results of repetitive nTMS (rnTMS) over cortex areas relevant for language. METHOD: We included data of 101 patients with language eloquent brain lesions who underwent preoperative rnTMS examination bihemispherically. Prior to rnTMS mapping, all patients performed two to three baseline runs of a picture-naming paradigm without stimulation, and only promptly and correctly named objects were retained for TMS mapping. Nine biometric factors (age, gender, baseline dataset, cognitive performance score, aphasia score, histology of lesion, affected hemisphere, location of lesion on the hemisphere, pain caused by examination) were included in the statistical analysis measuring their correlation with the incidence of errors during baseline naming as well as during rnTMS mapping. RESULTS: The incidence of baseline errors correlated with aphasia (p < 0.0001) and cognitive impairment (p < 0.0001). No significant correlation was observed between most biometric factors and errors during rnTMS mapping. Factors significantly affecting the incidence of errors during rnTMS mapping were again aphasia (p < 0.023) and cognitive impairment (p < 0.038). Patients affected by those factors showed a significantly higher baseline error rate, starting at 28% error rate. CONCLUSIONS: Patients with pre-existing aphasia or severe cognitive impairment did still make significantly more mistakes during rnTMS mapping than non-aphasic patients despite baseline stratification, rendering the question of whether the procedure is reliable in those patient groups. Baseline testing revealed a cut-off point at 28% error rate. Interestingly, age or pain (caused by the examination) did not bias the results.

Specific DTI seeding and diffusivity-analysis improve the quality and prognostic value of TMS-based deterministic DTI of the pyramidal tract.

OBJECT: Navigated transcranial magnetic stimulation (nTMS) combined with diffusion tensor imaging (DTI) is used preoperatively in patients with eloquent-located brain lesions and allows analyzing non-invasively the spatial relationship between the tumor and functional areas (e.g. the motor cortex and the corticospinal tract [CST]). In this study, we examined the diffusion parameters FA (fractional anisotropy) and ADC (apparent diffusion coefficient) within the CST in different locations and analyzed their interrater reliability and usefulness for predicting the patients' motor outcome with a precise approach of specific region of interest (ROI) seeding based on the color-coded FA-map. METHODS: Prospectively collected data of 30 patients undergoing bihemispheric nTMS mapping followed by nTMS-based DTI fiber tracking prior to surgery of motor eloquent high-grade gliomas were analyzed by 2 experienced and 1 unexperienced examiner. The following data were scrutinized for both hemispheres after tractography based on nTMS-motor positive cortical seeds and a 2nd region of interest in one layer of the caudal pons defined by the color-coded FA-map: the pre- and postoperative motor status (day of discharge und 3 months), the closest distance between the tracts and the tumor (TTD), the fractional anisotropy (FA) and the apparent diffusion coefficient (ADC). The latter as an average within the CST as well as specific values in different locations (peritumoral, mesencephal, pontine). RESULTS: Lower average FA-values within the affected CST as well as higher average ADC-values are significantly associated with deteriorated postoperative motor function (p = 0.006 and p = 0.026 respectively). Segmental analysis within the CST revealed that the diffusion parameters are especially disturbed on a peritumoral level and that the degree of their impairment correlates with motor deficits (FA p = 0.065, ADC p = 0.007). No significant segmental variation was seen in the healthy hemisphere. The interrater reliability showed perfect agreement for almost all analyzed parameters. CONCLUSIONS: Adding diffusion weighted imaging derived information on the structural integrity of the nTMS-based tractography results improves the predictive power for postoperative motor outcome. Utilizing a second subcortical ROI which is specifically seeded based on the color-coded FA map increases the tracking quality of the CST independently of the examiner's experience. Further prospective studies are needed to validate the nTMS-based prediction of the patient's outcome.

A Novel Technique for Region and Linguistic Specific nTMS-based DTI Fiber Tracking of Language Pathways in Brain Tumor Patients.

Navigated transcranial magnetic stimulation (nTMS) has recently been introduced as a non-invasive tool for functional mapping of cortical language areas prior to surgery. It correlates well with intraoperative neurophysiological monitoring (IONM) findings, allowing defining the best surgical strategy to preserve cortical language areas during surgery for language-eloquent tumors. Nevertheless, nTMS allows only for cortical mapping and postoperative language deficits are often caused by injury to subcortical language pathways. Nowadays, the only way to preoperatively visualize language subcortical white matter tracts consists in DTI fiber tracking (DTI-FT). However, standard DTI-FT is based on anatomical landmarks that vary interindividually and can be obscured by the presence of the tumor itself. It has been demonstrated that combining nTMS with DTI-FT allows for a more reliable visualization of the motor pathway in brain tumor patients. Nevertheless, no description about such a combination has been reported for the language network. The aim of the present study is to describe and assess the feasibility and reliability of using cortical seeding areas defined by error type-specific nTMS language mapping (nTMS-positive spots) to perform DTI-FT in patients affected by language-eloquent brain tumors. We describe a novel technique for a nTMS-based DTI-FT to visualize the complex cortico-subcortical connections of the language network. We analyzed quantitative findings, such as fractional anisotropy values and ratios, and the number of visualized connections of nTMS-positive spots with subcortical pathways, and we compared them with results obtained by using the standard DTI-FT technique. We also analyzed the functional concordance between connected cortical nTMS-positive spots and subcortical pathways, and the likelihood of connection for nTMS-positive vs. nTMS-negative cortical spots. We demonstrated, that the nTMS-based approach, especially what we call the "single-spot" strategy, is able to provide a reliable and more detailed reconstruction of the complex cortico-subcortical language network as compared to the standard DTI-FT. We believe this technique represents a beneficial new strategy for customized preoperative planning in patients affected by tumors in presumed language eloquent location, providing anatomo-functional information to plan language-preserving surgery.

Resection of Motor Eloquent Metastases Aided by Preoperative nTMS-Based Motor Maps-Comparison of Two Observational Cohorts.

INTRODUCTION: Preoperative mapping of motor areas with navigated transcranial magnetic stimulation (nTMS) has been shown to improve surgical outcomes for peri-Rolandic lesions and, in particular, for gliomas. However, the impact of this technique on surgical outcomes for peri-Rolandic metastatic lesions is yet unknown. OBJECTIVE: To investigate the impact of nTMS on surgical outcomes for peri-Rolandic metastatic lesions, various clinical parameters were analyzed in our international study group. METHODS: Two prospectively enrolled cohorts were compared by investigating patients receiving preoperative nTMS (2010-2015; 120 patients) and patients who did not receive preoperative nTMS (2006-2015; 130 patients). Tumor location, pathology, size, and preoperative deficits were comparable. RESULTS: The nTMS group showed a lower rate of residual tumor on postoperative magnetic resonance imaging (odds ratio 0.3025; 95% confidence interval 0.1356-0.6749). On long-term follow-up, surgery-related paresis was decreased in the nTMS group (nTMS vs. non-nTMS; improved: 30.8 vs. 13.1%, unchanged: 65.8 vs. 73.8%, worse: 3.4 vs. 13.1% of patients; p = 0.0002). Moreover, the nTMS group received smaller craniotomies (nTMS: 16.7 ± 8.6 cm2 vs. non-nTMS: 25.0 ± 17.1 cm2; p < 0.0001). Surgical time differed significantly between the two groups (nTMS: 128.8 ± 49.4 min vs. non-nTMS: 158.0 ± 65.8 min; p = 0.0002). CONCLUSION: This non-randomized study suggests that preoperative motor mapping by nTMS may improve the treatment of patients undergoing surgical resection of metastases in peri-Rolandic regions. These findings suggest that further evaluation with a prospective, randomized trial may be warranted.