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Keywords = corticospinal tract mapping

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17 pages, 6488 KiB  
Systematic Review
Magnetic Resonance Neuroimaging in Amyotrophic Lateral Sclerosis: A Comprehensive Umbrella Review of 18 Studies
by Sadegh Ghaderi, Sana Mohammadi and Farzad Fatehi
Brain Sci. 2025, 15(7), 715; https://doi.org/10.3390/brainsci15070715 - 3 Jul 2025
Viewed by 503
Abstract
Background/Objectives: Despite extensive research, the underlying causes of amyotrophic lateral sclerosis (ALS) remain unclear. This umbrella review aims to synthesize a vast body of evidence from advanced magnetic resonance imaging (MRI) studies of ALS, encompassing a wide range of neuroimaging techniques and patient [...] Read more.
Background/Objectives: Despite extensive research, the underlying causes of amyotrophic lateral sclerosis (ALS) remain unclear. This umbrella review aims to synthesize a vast body of evidence from advanced magnetic resonance imaging (MRI) studies of ALS, encompassing a wide range of neuroimaging techniques and patient cohorts. Methods: Following the PRISMA guidelines, we conducted an extensive search of four databases (PubMed, Scopus, Web of Science, and Embase) for articles published until 3 December 2024. Data extraction and quality assessment were independently performed using the AMSTAR2 tool. Results: This review included 18 studies that incorporated data from over 29,000 ALS patients. Structural MRI consistently showed gray matter atrophy in the motor and extra-motor regions, with significant white matter (WM) atrophy in the corticospinal tract and corpus callosum. Magnetic resonance spectroscopy revealed metabolic disruptions, including reduced N-acetylaspartate and elevated choline levels. Functional MRI studies have demonstrated altered brain activation patterns and functional connectivity, reflecting compensatory mechanisms and neurodegeneration. fMRI also demonstrated disrupted motor network connectivity and alterations in the default mode network. Diffusion MRI highlighted microstructural changes, particularly reduced fractional anisotropy in the WM tracts. Susceptibility-weighted imaging and quantitative susceptibility mapping revealed iron accumulation in the motor cortex and non-motor regions. Perfusion MRI indicated hypoperfusion in regions associated with cognitive impairment. Conclusions: Multiparametric MRI consistently highlights widespread structural, functional, and metabolic changes in ALS, reflecting neurodegeneration and compensatory mechanisms. Full article
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15 pages, 1728 KiB  
Article
Risk Factors for Neurological Deficits Following Brain Tumor Resection in the Supplementary Motor Area (SMA): A 66-Case Double-Center Study
by Lucio De Maria, Karl Schaller, Daniel Kiss-Bodolay, Giuseppe Barbagallo and Jibril Osman Farah
Cancers 2025, 17(8), 1369; https://doi.org/10.3390/cancers17081369 - 19 Apr 2025
Viewed by 612
Abstract
Background: Resection or damage of the supplementary motor area (SMA) is associated with the development of a transient negative motor response defined as SMA syndrome. The risk of neurological deficits after resection in the SMA has been reported to vary widely from 23% [...] Read more.
Background: Resection or damage of the supplementary motor area (SMA) is associated with the development of a transient negative motor response defined as SMA syndrome. The risk of neurological deficits after resection in the SMA has been reported to vary widely from 23% to 100%. Various influencing factors can be involved. However, since tumors in the SMA are relatively infrequent, most of the evidence for surgical treatment of these lesions is based on small, retrospective, single-center case series. Furthermore, previous studies focused only on a few variables, and our knowledge regarding the outcome of these patients is still limited. Objective: To better define the risk of neurological deficits after brain tumor resection in the SMA. Methods: We retrospectively reviewed 66 surgeries that involved the SMA for gliomas and metastasis in 53 patients from two separate centers. Out of those, 13 cases were recurrence of the disease. We carefully evaluated various clinical factors, preoperative neuroimaging, intraoperative neurophysiology monitoring, and anatomical factors. By using Fisher’s exact probability test, we examined the relationship between these factors and the occurrence of postoperative neurological deficits. Statistical significance was considered at a p-value of less than 0.05. Results: In 28 cases, patients experienced neurological deficits after surgery. Among those cases, 26 experienced partial SMA syndrome, one experienced complete SMA syndrome, and one experienced a permanent neurological deficit. The research found that the patient’s past medical history (p = 0.005), lack of intraoperative language mapping (p = 0.044), and extent of resection (p = 0.040) significantly influenced the occurrence of language deficits. Additionally, the proximity between the corticospinal tract and the tumor (p = 0.005) and fMRI activation of the SMA in response to motor tasks (p = 0.044) were found to correlate with the development of motor deficits. However, there was no correlation found between the lack of intraoperative monitoring of motor-evoked potentials (MEPs) and the development of motor deficits (p > 0.05). Conclusions: Certain pre-existing medical conditions may increase the risk of postoperative language deficits. Intraoperative language mapping can help prevent these deficits. The extent of resection, along with the anatomical characteristics of the resection cavity, correlates with postoperative outcomes. Tractography and fMRI can assist in predicting the risk of motor deficits. Although intraoperative MEP monitoring can help prevent permanent motor deficits, it does not appear to prevent the transient deficits characteristic of SMA syndrome. Further intraoperative studies are needed to refine mapping and monitoring strategies for tumors involving the SMA and pre-SMA. Full article
(This article belongs to the Section Methods and Technologies Development)
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20 pages, 6351 KiB  
Article
Intraoperative Neurophysiological Monitoring in Syringomyelia Surgery: A Multimodal Approach
by M. Ángeles Sánchez Roldán, Dulce Moncho, Kimia Rahnama, Daniela Santa-Cruz, Elena Lainez, Daniel Baiget, Ivette Chocrón, Darío Gándara, Agustín Bescós, Juan Sahuquillo and María A. Poca
J. Clin. Med. 2023, 12(16), 5200; https://doi.org/10.3390/jcm12165200 - 10 Aug 2023
Cited by 2 | Viewed by 1898
Abstract
Syringomyelia can be associated with multiple etiologies. The treatment of the underlying causes is first-line therapy; however, a direct approach to the syrinx is accepted as rescue treatment. Any direct intervention on the syrinx requires a myelotomy, posing a significant risk of iatrogenic [...] Read more.
Syringomyelia can be associated with multiple etiologies. The treatment of the underlying causes is first-line therapy; however, a direct approach to the syrinx is accepted as rescue treatment. Any direct intervention on the syrinx requires a myelotomy, posing a significant risk of iatrogenic spinal cord (SC) injury. Intraoperative neurophysiological monitoring (IONM) is crucial to detect and prevent surgically induced damage in neural SC pathways. We retrospectively reviewed the perioperative and intraoperative neurophysiological data and perioperative neurological examinations in ten cases of syringomyelia surgery. All the monitored modalities remained stable throughout the surgery in six cases, correlating with no new postoperative neurological deficits. In two patients, significant transitory attenuation, or loss of motor evoked potentials (MEPs), were observed and recovered after a corrective surgical maneuver, with no new postoperative deficits. In two cases, a significant MEP decrement was noted, which lasted until the end of the surgery and was associated with postoperative weakness. A transitory train of neurotonic electromyography (EMG) discharges was reported in one case. The surgical plan was adjusted, and the patient showed no postoperative deficits. The dorsal nerve roots were stimulated and identified in the seven cases where the myelotomy was performed via the dorsal root entry zone. Dorsal column mapping guided the myelotomy entry zone in four of the cases. In conclusion, multimodal IONM is feasible and reliable and may help prevent iatrogenic SC injury during syringomyelia surgery. Full article
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21 pages, 2934 KiB  
Review
Assessment of Motor Evoked Potentials in Multiple Sclerosis
by Joško Šoda, Sanda Pavelin, Igor Vujović and Maja Rogić Vidaković
Sensors 2023, 23(1), 497; https://doi.org/10.3390/s23010497 - 2 Jan 2023
Cited by 11 | Viewed by 7000
Abstract
Transcranial magnetic stimulation (TMS) is a noninvasive technique mainly used for the assessment of corticospinal tract integrity and excitability of the primary motor cortices. Motor evoked potentials (MEPs) play a pivotal role in TMS studies. TMS clinical guidelines, concerning the use and interpretation [...] Read more.
Transcranial magnetic stimulation (TMS) is a noninvasive technique mainly used for the assessment of corticospinal tract integrity and excitability of the primary motor cortices. Motor evoked potentials (MEPs) play a pivotal role in TMS studies. TMS clinical guidelines, concerning the use and interpretation of MEPs in diagnosing and monitoring corticospinal tract integrity in people with multiple sclerosis (pwMS), were established almost ten years ago and refer mainly to the use of TMS implementation; this comprises the magnetic stimulator connected to a standard EMG unit, with the positioning of the coil performed by using the external landmarks on the head. The aim of the present work was to conduct a narrative literature review on the MEP assessment and outcome measures in clinical and research settings, assessed by TMS Methodological characteristics of different TMS system implementations (TMS without navigation, line-navigated TMS and e-field-navigated TMS); these were discussed in the context of mapping the corticospinal tract integrity in MS. An MEP assessment of two case reports, by using an e-field-navigated TMS, was presented; the results of the correspondence between the e-field-navigated TMS with MRI, and the EDSS classifications were presented. Practical and technical guiding principles for the improvement of TMS studies in MEP assessment for MS are discussed, suggesting the use of e-field TMS assessment in the sense that it can improve the accuracy of corticospinal tract integrity testing by providing a more objective correspondence of the neurophysiological (e-field-navigated TMS) and clinical (Expanded Disability Status Scale—EDSS) classifications. Full article
(This article belongs to the Special Issue Sensor Technologies for Human Health Monitoring)
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17 pages, 1554 KiB  
Article
Dose Reduction to Motor Structures in Adjuvant Fractionated Stereotactic Radiotherapy of Brain Metastases: nTMS-Derived DTI-Based Motor Fiber Tracking in Treatment Planning
by Christian D. Diehl, Enrike Rosenkranz, Maximilian Schwendner, Martin Mißlbeck, Nico Sollmann, Sebastian Ille, Bernhard Meyer, Stephanie E. Combs and Sandro M. Krieg
Cancers 2023, 15(1), 282; https://doi.org/10.3390/cancers15010282 - 31 Dec 2022
Cited by 2 | Viewed by 3181
Abstract
Background: Resection of brain metastases (BM) close to motor structures is challenging for treatment. Navigated transcranial magnetic stimulation (nTMS) motor mapping, combined with diffusion tensor imaging (DTI)-based fiber tracking (DTI-FTmot.TMS), is a valuable tool in neurosurgery to preserve motor function. This [...] Read more.
Background: Resection of brain metastases (BM) close to motor structures is challenging for treatment. Navigated transcranial magnetic stimulation (nTMS) motor mapping, combined with diffusion tensor imaging (DTI)-based fiber tracking (DTI-FTmot.TMS), is a valuable tool in neurosurgery to preserve motor function. This study aimed to assess the practicability of DTI-FTmot.TMS for local adjuvant radiotherapy (RT) planning of BM. Methods: Presurgically generated DTI-FTmot.TMS-based corticospinal tract (CST) reconstructions (FTmot.TMS) of 24 patients with 25 BM resected during later surgery were incorporated into the RT planning system. Completed fractionated stereotactic intensity-modulated RT (IMRT) plans were retrospectively analyzed and adapted to preserve FTmot.TMS. Results: In regular plans, mean dose (Dmean) of complete FTmot.TMS was 5.2 ± 2.4 Gy. Regarding planning risk volume (PRV-FTTMS) portions outside of the planning target volume (PTV) within the 17.5 Gy (50%) isodose line, the DTI-FTmot.TMS Dmean was significantly reduced by 33.0% (range, 5.9–57.6%) from 23.4 ± 3.3 Gy to 15.9 ± 4.7 Gy (p < 0.001). There was no significant decline in the effective treatment dose, with PTV Dmean 35.6 ± 0.9 Gy vs. 36.0 ± 1.2 Gy (p = 0.063) after adaption. Conclusions: The DTI-FTmot.TMS-based CST reconstructions could be implemented in adjuvant IMRT planning of BM. A significant dose reduction regarding motor structures within critical dose levels seems possible. Full article
(This article belongs to the Special Issue Advances in Modern Radiation Oncology)
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13 pages, 3973 KiB  
Article
Simultaneous Motor and Visual Intraoperative Neuromonitoring in Asleep Parietal Lobe Surgery: Dual Strip Technique
by Devika Rajashekar, Jose Pedro Lavrador, Prajwal Ghimire, Hannah Keeble, Lauren Harris, Noemia Pereira, Sabina Patel, Ahmad Beyh, Richard Gullan, Keyoumars Ashkan, Ranjeev Bhangoo and Francesco Vergani
J. Pers. Med. 2022, 12(9), 1478; https://doi.org/10.3390/jpm12091478 - 9 Sep 2022
Cited by 5 | Viewed by 2310
Abstract
Background: The role played by the non-dominant parietal lobe in motor cognition, attention and spatial awareness networks has potentiated the use of awake surgery. When this is not feasible, asleep monitoring and mapping techniques should be used to achieve an onco-functional balance. [...] Read more.
Background: The role played by the non-dominant parietal lobe in motor cognition, attention and spatial awareness networks has potentiated the use of awake surgery. When this is not feasible, asleep monitoring and mapping techniques should be used to achieve an onco-functional balance. Objective: This study aims to assess the feasibility of a dual-strip method to obtain direct cortical stimulation for continuous real-time cortical monitoring and subcortical mapping of motor and visual pathways simultaneously in parietal lobe tumour surgery. Methods: Single-centre prospective study between 19 May–20 November of patients with intrinsic non-dominant parietal-lobe tumours. Two subdural strips were used to simultaneously map and monitor motor and visual pathways. Results: Fifteen patients were included. With regards to motor function, a large proportion of patients had abnormal interhemispheric resting motor threshold ratio (iRMTr) (71.4%), abnormal Cortical Excitability Score (CES) (85.7%), close distance to the corticospinal tract—Lesion-To-Tract Distance (LTD)—4.2 mm, Cavity-To-Tract Distance (CTD)—7 mm and intraoperative subcortical distance—6.4 mm. Concerning visual function, the LTD and CTD for optic radiations (OR) were 0.5 mm and 3.4 mm, respectively; the mean intensity for positive subcortical stimulation of OR was 12 mA ± 2.3 mA and 5/6 patients with deterioration of VEPs > 50% had persistent hemianopia and transgression of ORs. Twelve patients remained stable, one patient had a de-novo transitory hemiparesis, and two showed improvements in motor symptoms. A higher iRMTr for lower limbs was related with a worse motor outcome (p = 0.013) and a longer CTD to OR was directly related with a better visual outcome (p = 0.041). At 2 weeks after hospital discharge, all patients were ambulatory at home, and all proceeded to have oncological treatment. Conclusion: We propose motor and visual function boundaries for asleep surgery of intrinsic non-dominant parietal tumours. Pre-operative abnormal cortical excitability of the motor cortex, deterioration of the VEP recordings and CTD < 2 mm from the OR were related to poorer outcomes. Full article
(This article belongs to the Section Clinical Medicine, Cell, and Organism Physiology)
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8 pages, 961 KiB  
Article
Brain Connectivity Affecting Gait Function after Unilateral Supratentorial Stroke
by Hyun-Ah Lee and Dae-Hyun Kim
Brain Sci. 2021, 11(7), 870; https://doi.org/10.3390/brainsci11070870 - 29 Jun 2021
Cited by 4 | Viewed by 2478
Abstract
Gait dysfunction is a leading cause of long-term disability after stroke. The mechanisms underlying recovery of gait function are unknown. We retrospectively evaluated the association between structural connectivity and gait function in 127 patients with unilateral supratentorial stroke (>1 month after stroke). All [...] Read more.
Gait dysfunction is a leading cause of long-term disability after stroke. The mechanisms underlying recovery of gait function are unknown. We retrospectively evaluated the association between structural connectivity and gait function in 127 patients with unilateral supratentorial stroke (>1 month after stroke). All patients underwent T1-weighted, diffusion tensor imaging and functional ambulation categorization. Voxel-wise linear regression analyses of the images were conducted using fractional anisotropy, mean diffusivity, and mode of anisotropy mapping as dependent variables, while the functional ambulation category was used as an independent variable with age and days after stroke as covariates. The functional ambulation category was positively associated with increased fractional anisotropy in the lesioned cortico-ponto-cerebellar system, corona radiata of the non-lesioned corticospinal tract pathway, bilateral medial lemniscus in the brainstem, and the corpus callosum. The functional ambulation category was also positively associated with increased mode of anisotropy in the lesioned posterior corpus callosum. In conclusion, structural connectivity associated with motor coordination and feedback affects gait function after stroke. Diffusion tensor imaging for evaluating structural connectivity can help to predict gait recovery and target rehabilitation goals after stroke. Full article
(This article belongs to the Special Issue At the Frontiers of Neurorehabilitation)
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10 pages, 1918 KiB  
Article
White Matter Survival within and around the Hematoma: Quantification by MRI in Patients with Intracerebral Hemorrhage
by Nemanja Novakovic, Joseph R. Linzey, Thomas L. Chenevert, Joseph J. Gemmete, Jonathan P. Troost, Guohua Xi, Richard F. Keep, Aditya S. Pandey and Neeraj Chaudhary
Biomolecules 2021, 11(6), 910; https://doi.org/10.3390/biom11060910 - 18 Jun 2021
Cited by 9 | Viewed by 3244
Abstract
White matter (WM) injury and survival after intracerebral hemorrhage (ICH) has received insufficient attention. WM disruption surrounding the hematoma has been documented in animal models with histology, but rarely in human ICH with noninvasive means, like magnetic resonance imaging (MRI). A few human [...] Read more.
White matter (WM) injury and survival after intracerebral hemorrhage (ICH) has received insufficient attention. WM disruption surrounding the hematoma has been documented in animal models with histology, but rarely in human ICH with noninvasive means, like magnetic resonance imaging (MRI). A few human MRI studies have investigated changes in long WM tracts after ICH remote from the hematoma, like the corticospinal tract, but have not attempted to obtain an unbiased quantification of WM changes within and around the hematoma over time. This study attempts such quantification from 3 to 30 days post ictus. Thirteen patients with mild to moderate ICH underwent diffusion tensor imaging (DTI) MRI at 3, 14, and 30 days. Fractional anisotropy (FA) maps were used to calculate the volume of tissue with FA > 0.5, both within the hematoma (lesion) and in the perilesional tissue. At day 3, the percentages of both lesional and perilesional tissue with an FA > 0.5 were significantly less than contralateral, unaffected, anatomically identical tissue. This perilesional contralateral difference persisted at day 14, but there was no significant difference at day 30. The loss of perilesional tissue with FA > 0.5 increased with increasing hematoma size at day 3 and day 14. All patients had some tissue within the lesion with FA > 0.5 at all time points. This did not decrease with duration after ictus, suggesting the persistence of white matter within the hematoma/lesion. These results outline an approach to quantify WM injury, both within and surrounding the hematoma, after mild to moderate ICH using DTI MRI. This may be important for monitoring treatment strategies, such as hematoma evacuation, and assessing efficacy noninvasively. Full article
(This article belongs to the Special Issue Intracerebral Hemorrhage: Advances in Preclinical Studies)
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18 pages, 3223 KiB  
Article
Short-Interval Intracortical Facilitation Improves Efficacy in nTMS Motor Mapping of Lower Extremity Muscle Representations in Patients with Supra-Tentorial Brain Tumors
by Haosu Zhang, Petro Julkunen, Axel Schröder, Anna Kelm, Sebastian Ille, Claus Zimmer, Minna Pitkänen, Bernhard Meyer, Sandro M. Krieg and Nico Sollmann
Cancers 2020, 12(11), 3233; https://doi.org/10.3390/cancers12113233 - 2 Nov 2020
Cited by 8 | Viewed by 3004
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Perioperative Imaging and Mapping Methods in Glioma Patients)
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19 pages, 5914 KiB  
Article
Risk Assessment by Presurgical Tractography Using Navigated TMS Maps in Patients with Highly Motor- or Language-Eloquent Brain Tumors
by Nico Sollmann, Haosu Zhang, Alessia Fratini, Noémie Wildschuetz, Sebastian Ille, Axel Schröder, Claus Zimmer, Bernhard Meyer and Sandro M. Krieg
Cancers 2020, 12(5), 1264; https://doi.org/10.3390/cancers12051264 - 17 May 2020
Cited by 66 | Viewed by 5408
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Brain Tumors)
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