Exploring molecular glioblastoma: Insights from advanced imaging for a nuanced understanding of the molecularly defined malignant biology.

Background: Molecular glioblastoma (molGB) does not exhibit the histologic hallmarks of a grade 4 glioma but is nevertheless diagnosed as glioblastoma when harboring specific molecular markers. MolGB can easily be mistaken for similar-appearing lower-grade astrocytomas. Here, we investigated how advanced imaging could reflect the underlying tumor biology. Methods: Clinical and imaging data were collected for 7 molGB grade 4, 9 astrocytomas grade 2, and 12 astrocytomas grade 3. Four neuroradiologists performed VASARI-scoring of conventional imaging, and their inter-reader agreement was assessed using Fleiss κ coefficient. To evaluate the potential of advanced imaging, 2-sample t test, 1-way ANOVA, Mann-Whitney U, and Kruskal-Wallis test were performed to test for significant differences between apparent diffusion coefficient (ADC) and relative cerebral blood volume (rCBV) that were extracted fully automatically from the whole tumor volume. Results: While conventional VASARI imaging features did not allow for reliable differentiation between glioma entities, rCBV was significantly higher in molGB compared to astrocytomas for the 5th and 95th percentile, mean, and median values (P < .05). ADC values were significantly lower in molGB than in astrocytomas for mean, median, and the 95th percentile (P < .05). Although no molGB showed contrast enhancement initially, we observed enhancement in the short-term follow-up of 1 patient. Discussion: Quantitative analysis of diffusion and perfusion parameters shows potential in reflecting the malignant tumor biology of molGB. It may increase awareness of molGB in a nonenhancing, "benign" appearing tumor. Our results support the emerging hypothesis that molGB might present glioblastoma captured at an early stage of gliomagenesis.

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.

Arterial Spin Labeling (ASL) in Neuroradiological Diagnostics - Methodological Overview and Use Cases.

BACKGROUND: Arterial spin labeling (ASL) is a magnetic resonance imaging (MRI)-based technique using labeled blood-water of the brain-feeding arteries as an endogenous tracer to derive information about brain perfusion. It enables the assessment of cerebral blood flow (CBF). METHOD: This review aims to provide a methodological and technical overview of ASL techniques, and to give examples of clinical use cases for various diseases affecting the central nervous system (CNS). There is a special focus on recent developments including super-selective ASL (ssASL) and time-resolved ASL-based magnetic resonance angiography (MRA) and on diseases commonly not leading to characteristic alterations on conventional structural MRI (e. g., concussion or migraine). RESULTS: ASL-derived CBF may represent a clinically relevant parameter in various pathologies such as cerebrovascular diseases, neoplasms, or neurodegenerative diseases. Furthermore, ASL has also been used to investigate CBF in mild traumatic brain injury or migraine, potentially leading to the establishment of imaging-based biomarkers. Recent advances made possible the acquisition of ssASL by selective labeling of single brain-feeding arteries, enabling spatial perfusion territory mapping dependent on blood flow of a specific preselected artery. Furthermore, ASL-based MRA has been introduced, providing time-resolved delineation of single intracranial vessels. CONCLUSION: Perfusion imaging by ASL has shown promise in various diseases of the CNS. Given that ASL does not require intravenous administration of a gadolinium-based contrast agent, it may be of particular interest for investigations in pediatric cohorts, patients with impaired kidney function, patients with relevant allergies, or patients that undergo serial MRI for clinical indications such as disease monitoring. KEY POINTS: · ASL is an MRI technique that uses labeled blood-water as an endogenous tracer for brain perfusion imaging.. · It allows the assessment of CBF without the need for administration of a gadolinium-based contrast agent.. · CBF quantification by ASL has been used in several pathologies including brain tumors or neurodegenerative diseases.. · Vessel-selective ASL methods can provide brain perfusion territory mapping in cerebrovascular diseases.. · ASL may be of particular interest in patient cohorts with caveats concerning gadolinium administration..

Navigated transcranial magnetic stimulation mapping of the motor cortex for preoperative diagnostics in pediatric epilepsy.

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

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.

Application of Navigated Transcranial Magnetic Stimulation to Map the Supplementary Motor Area in Healthy Subjects.

PURPOSE: The supplementary motor area is involved in the planning and coordination of movement sequences. This study investigates the potential of repetitive navigated transcranial magnetic stimulation for systematic mapping of the supplementary motor area by interfering with normal movement coordination processing. METHODS: Ten healthy females (median age: 23.5 years) performed the Jebsen-Taylor Hand Function Test, first without stimulation (baseline) and afterward during application of repetitive navigated transcranial magnetic stimulation with 10 Hz to 6 cortical sites located within the supplementary motor area of both hemispheres. The test completion times (TCTs) were then compared between baseline performances and performances during stimulation. RESULTS: We found significant slowing of TCTs in simulated page turning (baseline TCT 3.68 ± 0.67 seconds vs. stimulation TCT 4.04 ± 0.63 seconds, P = 0.0136), lifting small objects (baseline TCT 5.11 ± 0.72 seconds vs. stimulation TCT 5.47 ± 0.66 seconds, P = 0.0010), and simulated feeding (baseline TCT 6.10 ± 0.73 seconds vs. stimulation TCT 6.59 ± 0.81 seconds, P = 0.0027). Three other subtests were not affected, whereas one subtest was performed significantly faster (baseline TCT 17.09 ± 7.31 seconds vs. stimulation TCT 15.44 ± 5.72 seconds, P = 0.0073) under stimulation. CONCLUSIONS: Repetitive navigated transcranial magnetic stimulation is capable of influencing the performance of healthy participants in a task relying on hand coordination. Our approach can serve as a mapping tool for the supplementary motor area, potentially relevant for preoperative diagnostics in patients with brain tumors, epilepsy, or other brain lesions to improve outcome and potentially predict clinical course and postoperative recovery.

Function-specific Tractography of Language Pathways Based on nTMS Mapping in Patients with Supratentorial Lesions.

PURPOSE: In patients with supratentorial lesions diffusion tensor imaging fiber tracking (DTI-FT) is increasingly used to visualize subcortical fiber courses. Navigated transcranial magnetic stimulation (nTMS) was applied in this study to reveal specific cortical functions by investigating the particular language errors elicited by stimulation. To make DTI-FT more function-specific, the identified language-positive nTMS spots were used as regions of interest (ROIs). METHODS: In this study 40 patients (mean age 53.8 ± 16.0 years) harboring language-eloquent left hemispheric lesions underwent preoperative nTMS language mapping. All induced error categories were separately defined as a ROI and used for function-specific nTMS-based DTI-FT. The fractions of patients showing various subcortical language-related pathways and the fibers-per-tract ratio (number of visualized fibers divided by the number of visualized tracts) were evaluated and compared for tractography with the single error types against less specific tractography including all identified cortical language sites (all errors except hesitations). RESULTS: The nTMS-based DTI-FT using all errors except hesitations led to high fractions of visualized tracts (81.1% of patients), with a fibers-per-tract ratio of 538.4 ± 340.5. When only using performance errors, a predominant visualization of the superior longitudinal fascicle (SLF) occurred, which is known to be involved in articulatory processes. Fibers-per-tract ratios were comparatively stable for all single error categories when compared to all errors except hesitations (p > 0.05). CONCLUSION: This is one of the first studies aiming on function-specific tractography. The results demonstrated that when using different error categories as ROIs, more detailed nTMS-based DTI-FT and, therefore, potentially superior intraoperative guidance becomes possible.

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.