Noninvasive- and invasive mapping reveals similar language network centralities - A function-based connectome analysis.

BACKGROUND: Former comparisons between direct cortical stimulation (DCS) and navigated transcranial magnetic stimulation (nTMS) only focused on cortical mapping. While both can be combined with diffusion tensor imaging, their differences in the visualization of subcortical and even network levels remain unclear. Network centrality is an essential parameter in network analysis to measure the importance of nodes identified by mapping. Those include Degree centrality, Eigenvector centrality, Closeness centrality, Betweenness centrality, and PageRank centrality. While DCS and nTMS have repeatedly been compared on the cortical level, the underlying network identified by both has not been investigated yet. METHOD: 27 patients with brain lesions necessitating preoperative nTMS and intraoperative DCS language mapping during awake craniotomy were enrolled. Function-based connectome analysis was performed based on the cortical nodes obtained through the two mapping methods, and language-related network centralities were compared. RESULTS: Compared with DCS language mapping, the positive predictive value of cortical nTMS language mapping is 74.1%, with good consistency of tractography for the arcuate fascicle and superior longitudinal fascicle. Moreover, network centralities did not differ between the two mapping methods. However, ventral stream tracts can be better traced based on nTMS mappings, demonstrating its strengths in acquiring language-related networks. In addition, it showed lower centralities than other brain areas, with decentralization as an indicator of language function loss. CONCLUSION: This study deepens the understanding of language-related functional anatomy and proves that non-invasive mapping-based network analysis is comparable to the language network identified via invasive cortical mapping.

Motor mapping of the hand muscles using peripheral innervation-based navigated transcranial magnetic stimulation to identify functional reorganization of primary motor regions in malignant tumors.

Tumor-related motor reorganization remains unclear. Navigated transcranial magnetic stimulation (nTMS) can investigate plasticity non-invasively. nTMS-induced motor-evoked potentials (MEPs) of different muscles are commonly used to measure the center of gravity (CoG), the location with the highest density of corticospinal neurons in the precentral gyrus. We hypothesized that a peripheral innervation-based MEP analysis could outline the tumor-induced motor reorganization with a higher clinical and oncological relevance. Then, 21 patients harboring tumors inside the left corticospinal tract (CST) or precentral gyrus were enrolled in group one (G1), and 24 patients with tumors outside the left CST or precentral gyrus were enrolled in Group 2 (G2). Median- and ulnar-nerve-based MEP analysis combined with diffusion tensor imaging fiber tracking was used to explore motor function distribution. There was no significant difference in CoGs or size of motor regions and underlying tracts between G1 and G2. However, G1 involved a sparser distribution of motor regions and more motor-positive sites in the supramarginal gyrus-tumors inside motor areas induced motor reorganization. We propose an "anchor-and-ship theory" hypothesis for this process of motor reorganization: motor CoGs are stably located in the cortical projection area of the CST, like a seated anchor, as the core area for motor output. Primary motor regions can relocate to nearby gyri via synaptic plasticity and association fibers, like a ship moving around its anchor. This principle can anticipate functional reorganization and be used as a neuro-oncological tool for local therapy, such as radiotherapy or surgery.

Permanent deterioration of fine motor skills after the resection of tumors in the supplementary motor area.

Supplementary motor area syndrome (SMAS) represents a common neurosurgical sequela. The incidence and time frame of its occurrence have yet to be characterized after surgery for brain tumors. We examined patients suffering from a brain tumor preoperatively, postoperatively, and during follow-up examinations after three months, including fine motor skills testing and transcranial magnetic stimulation (TMS). 13 patients suffering from a tumor in the dorsal part of the superior frontal gyrus underwent preoperative, early postoperative, and 3-month follow-up testing of fine motor skills using the Jebsen-Taylor Hand Function Test (JHFT) and the Nine-Hole Peg Test (NHPT) consisting of 8 subtests for both upper extremities. They completed TMS for cortical motor function mapping. Test completion times (TCTs) were recorded and compared. No patient suffered from neurological deficits before surgery. On postoperative day one, we detected motor deficits in two patients, which remained clinically stable at a 3-month follow-up. Except for page-turning, every subtest indicated a significant worsening of function, reflected by longer TCTs (p < 0.05) in the postoperative examinations for the contralateral upper extremity (contralateral to the tumor manifestation). At 3-month follow-up examinations for the contralateral upper extremity, each subtest indicated significant worsening compared to the preoperative status despite improvement to the immediate postoperative level. We also detected significantly longer TCTs (p < 0.05) postoperatively in the ipsilateral upper extremity. This study suggests a long-term worsening of fine motor skills even three months after SMA tumor resection, indicating the necessity of targeted physical therapy for these patients.

Improving specificity of stimulation-based language mapping in stuttering glioma patients: A mixed methods serial case study.

Objective: Stimulation-based language mapping relies on identifying stimulation-induced language disruptions, which preexisting speech disorders affecting the laryngeal and orofacial speech system can confound. This study ascertained the effects of preexisting stuttering on pre- and intraoperative language mapping to improve the reliability and specificity of established language mapping protocols in the context of speech fluency disorders. Method: Differentiation-ability of a speech therapist and two experienced nrTMS examiners between stuttering symptoms and stimulation-induced language errors during preoperative mappings were retrospectively compared (05/2018-01/2021). Subsequently, the impact of stuttering on intraoperative mappings was evaluated in all prospective patients (01/2021-12/2022). Results: In the first part, 4.85 % of 103 glioma patients stuttered. While both examiners had a significant agreement for misclassifying pauses in speech flow and prolongations (Κ ≥ 0.50, p ≤ 0.02, respectively), less experience resulted in more misclassified stuttering symptoms. In one awake surgery case within the second part, stuttering decreased the reliability of intraoperative language mapping.Comparison with Existing Method(s): By thoroughly differentiating speech fluency symptoms from stimulation-induced disruptions, the reliability and proportion of stuttering symptoms falsely attributed to stimulation-induced language network disruptions can be improved. This may increase the consistency and specificity of language mapping results in stuttering glioma patients. Conclusions: Preexisting stuttering negatively impacted language mapping specificity. Thus, surgical planning and the functional outcome may benefit substantially from thoroughly differentiating speech fluency symptoms from stimulation-induced disruptions by trained specialists.

Neuronavigated repetitive transcranial magnetic stimulation as novel mapping technique provides insights into language function in primary progressive aphasia.

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.

Elucidating the structural-functional connectome of language in glioma-induced aphasia using nTMS and DTI.

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

Paired-pulse navigated TMS is more effective than single-pulse navigated TMS for mapping upper extremity muscles in brain tumor patients.

OBJECTIVE: Single-pulse navigated transcranial magnetic stimulation (sp-nTMS) is used for presurgical motor mapping in patients with motor-eloquent lesions. However, recently introduced paired-pulse nTMS (pp-nTMS) with biphasic pulses could improve motor mapping. METHODS: Thirty-four patients (mean age: 56.0 ± 12.7 years, 53.0% high-grade glioma) with motor-eloquent lesions underwent motor mapping of upper extremity representations and nTMS-based tractography of the corticospinal tract (CST) by both sp-nTMS and pp-nTMS with biphasic pulses for the tumor-affected hemisphere before resection. RESULTS: In three patients (8.8%), conventional sp-nTMS did not provide motor-positive points, in contrast to pp-nTMS that was capable of generating motor maps in all patients. Good concordance between pp-nTMS and sp-nTMS in the spatial location of motor hotspots and center of gravity (CoG) as well as for CST tracking was observed, with pp-nTMS leading to similar motor map volumes (585.0 ± 667.8 vs. 586.8 ± 204.2 mm3, p = 0.9889) with considerably lower resting motor thresholds (35.0 ± 8.8 vs. 32.8 ± 7.6% of stimulator output, p = 0.0004). CONCLUSIONS: Pp-nTMS with biphasic pulses may provide motor maps even in highly demanding cases with tumor-affected motor structures or edema, using lower stimulation intensity compared to sp-nTMS. SIGNIFICANCE: Pp-nTMS with biphasic pulses could replace standardly used sp-nTMS for motor mapping and may be safer due to lower stimulation intensity.

Short-Interval Intracortical Facilitation Improves Efficacy in nTMS Motor Mapping of Lower Extremity Muscle Representations in Patients with Supra-Tentorial Brain Tumors.

Navigated transcranial magnetic stimulation (nTMS) is increasingly used for mapping of motor function prior to surgery in patients harboring motor-eloquent brain lesions. To date, single-pulse nTMS (sp-nTMS) has been predominantly used for this purpose, but novel paired-pulse nTMS (pp-nTMS) with biphasic pulse application has been made available recently. The purpose of this study was to systematically evaluate pp-nTMS with biphasic pulses in comparison to conventionally used sp-nTMS for preoperative motor mapping of lower extremity (lE) muscle representations. Thirty-nine patients (mean age: 56.3 ± 13.5 years, 69.2% males) harboring motor-eloquent brain lesions of different entity underwent motor mapping of lE muscle representations in lesion-affected hemispheres and nTMS-based tractography of the corticospinal tract (CST) using data from sp-nTMS and pp-nTMS with biphasic pulses, respectively. Compared to sp-nTMS, pp-nTMS enabled motor mapping with lower stimulation intensities (61.8 ± 13.8% versus 50.7 ± 11.6% of maximum stimulator output, p < 0.0001), and it provided reliable motor maps even in the most demanding cases where sp-nTMS failed (pp-nTMS was able to provide a motor map in five patients in whom sp-nTMS did not provide any motor-positive points, and pp-nTMS was the only modality to provide a motor map in one patient who also did not show motor-positive points during intraoperative stimulation). Fiber volumes of the tracked CST were slightly higher when motor maps of pp-nTMS were used, and CST tracking using pp-nTMS data was also possible in the five patients in whom sp-nTMS failed. In conclusion, application of pp-nTMS with biphasic pulses enables preoperative motor mapping of lE muscle representations even in the most challenging patients in whom the motor system is at high risk due to lesion location or resection.

Function-Based Tractography of the Language Network Correlates with Aphasia in Patients with Language-Eloquent Glioblastoma.

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.

Risk Assessment by Presurgical Tractography Using Navigated TMS Maps in Patients with Highly Motor- or Language-Eloquent Brain Tumors.

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.

Navigated transcranial magnetic stimulation of the supplementary motor cortex disrupts fine motor skills in healthy adults.

Navigated transcranial magnetic stimulation (nTMS) over the supplementary motor area (SMA) may impact fine motor skills. This study evaluates different nTMS parameters in their capacity to affect fine motor performance on the way to develop an SMA mapping protocol. Twenty healthy volunteers performed a variety of fine motor tests during baseline and nTMS to the SMA using 5 Hz, 10 Hz, and theta-burst stimulation (TBS). Effects on performance were measured by test completion times (TCTs), standard deviation of inter-tap interval (SDIT), and visible coordination problems (VCPs). The predominant stimulation effect was slowing of TCTs, i.e. a slowdown of test performances during stimulation. Furthermore, participants exhibited VCPs like accidental use of contralateral limbs or inability to coordinate movements. More instances of significant differences between baseline and stimulation occurred during stimulation of the right hemisphere compared to left-hemispheric stimulation. In conclusion, nTMS to the SMA could enable new approaches in neuroscience and enable structured mapping approaches. Specifically, this study supports interhemispheric differences in motor control as right-hemispheric stimulation resulted in clearer impairments. The application of our nTMS-based setup to assess the function of the SMA should be applied in patients with changed anatomo-functional representations as the next step, e.g. among patients with eloquent brain tumors.

Methylseleninic Acid Sensitizes Ovarian Cancer Cells to T-Cell Mediated Killing by Decreasing PDL1 and VEGF Levels.

Redox active selenium (Se) compounds at sub toxic doses act as pro-oxidants with cytotoxic effects on tumor cells and are promising future chemotherapeutic agents. However, little is known about how Se compounds affect immune cells in the tumor microenvironment. We demonstrate that the inorganic Se compound selenite and the organic methylseleninic acid (MSA) do not, despite their pro-oxidant function, influence the viability of immune cells, at doses that gives cytotoxic effects in ovarian cancer cell lines. Treatment of the ovarian cancer cell line A2780 with selenite and MSA increases NK cell mediated lysis, and enhances the cytolytic activity of T cells. Increased T cell function was observed after incubation of T cells in preconditioned media from tumor cells treated with MSA, an effect that was coupled to decreased levels of PDL1, HIF-1α, and VEGF. In conclusion, redox active selenium compounds do not kill or inactivate immune cells at doses required for anti-cancer treatment, and we demonstrate that MSA enhances T cell-mediated tumor cell killing via PDL1 and VEGF inhibition.

Setup presentation and clinical outcome analysis of treating highly language-eloquent gliomas via preoperative navigated transcranial magnetic stimulation and tractography.

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