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Abstract The effects of subthalamic nucleus deep brain stimulation (STN-DBS) on anxiety in Parkinson’s disease (PD) are understudied. We identified clinical predictors of STN-DBS effects on anxiety in this study. In this prospective, open-label, multicentre study, we assessed patients with anxiety undergoing STN-DBS for PD preoperatively and at 6-month follow-up postoperatively. We assessed the Hospital Anxiety and Depression Scale (HADS-anxiety and depression subscales), Unified PD Rating Scale-motor examination, Scales for Outcomes in PD-motor (SCOPA-M)-activities of daily living (ADL) and -motor complications, Non-Motor Symptom Scale (NMSS), PDQuestionnaire-8 (PDQ-8), and levodopa-equivalent daily dose. We tested changes at follow-up with Wilcoxon signed-rank test and corrected for multiple comparisons (Bonferroni method). We identified patients with a clinically relevant anxiety improvement of anxiety based on a designated threshold of ½ standard deviation of baseline HADS-anxiety. Moreover, we investigated predictors of HADS-anxiety changes with correlations and linear regressions. We included 50 patients with clinically relevant baseline anxiety (i.e., HADS-anxiety ≥ 8) aged 63.1 years ± 8.3 with 10.4 years ± 4.5 PD duration. HADS-anxiety improved significantly at 6-month follow-up as 80% of our cohort experienced clinically relevant anxiety improvement. In predictor analyses, worse baseline SCOPA-ADL and NMSS-urinary domain were associated with greater HADS-anxiety improvements. HADS-anxiety and PDQ-8 changes correlated moderately. Worse preoperative ADL and urinary symptoms predicted favourable postoperative anxiety outcome, which in turn was directly proportionate to greater QoL improvement. This study highlights the importance of detailed anxiety assessments alongside other non-motor and motor symptoms when advising and monitoring patients undergoing STN-DBS for PD.

Abstract Mixed reality navigation (MRN) technology is emerging as an increasingly significant and interesting topic in neurosurgery. MRN enables neurosurgeons to “see through” the head with an interactive, hybrid visualization environment that merges virtual- and physical-world elements. Offering immersive, intuitive, and reliable guidance for preoperative and intraoperative intervention of intracranial lesions, MRN showcases its potential as an economically efficient and user-friendly alternative to standard neuronavigation systems. However, the clinical research and development of MRN systems present challenges: recruiting a sufficient number of patients within a limited timeframe is difficult, and acquiring low-cost, commercially available, medically significant head phantoms is equally challenging. To accelerate the development of novel MRN systems and surmount these obstacles, the study presents a dataset designed for MRN system development and testing in neurosurgery. It includes CT and MRI data from 19 patients with intracranial lesions and derived 3D models of anatomical structures and validation references. The models are available in Wavefront object (OBJ) and Stereolithography (STL) formats, supporting the creation and assessment of neurosurgical MRN applications.

Abstract Deep brain stimulation of the subthalamic nucleus (STN-DBS) effectively treats motor and non-motor symptoms in advanced Parkinson’s disease (PD). As considerable interindividual variability of outcomes exists, neuroimaging-based biomarkers, including microstructural metrics, have been proposed to anticipate treatment response. In this prospective open-label study, we sought to detect microstructural properties of brain areas associated with short-term non-motor outcomes following STN-DBS. Thirty-seven PD patients underwent diffusion MRI and clinical assessments at preoperative baseline and 6-month follow-up. Whole brain voxel-wise analysis assessed associations between microstructural metrics and non-motor outcomes. Intact microstructure within specific areas, including the right insular cortex, right putamen, right cingulum, and bilateral corticospinal tract were associated with greater postoperative improvement of non-motor symptom burden. Furthermore, microstructural properties of distinct brain regions were associated with postoperative changes in sleep, attention/memory, urinary symptoms, and apathy. In conclusion, diffusion MRI could support preoperative patient counselling by identifying patients with above- or below-average non-motor responses.

Abstract Objective Brain tumors and metastases account for approximately 10% of all status epilepticus (SE) cases. This study described the clinical characteristics, treatment, and short- and long-term outcomes of this population. Methods This retrospective, multi-center cohort study analyzed all brain tumor patients treated for SE at the university hospitals of Frankfurt and Marburg between 2011 and 2017. Results The 208 patients (mean 61.5 ± 14.7 years of age; 51% male) presented with adult-type diffuse gliomas (55.8%), metastatic entities (25.5%), intracranial extradural tumors (14.4%), or other tumors (4.3%). The radiological criteria for tumor progression were evidenced in 128 (61.5%) patients, while 57 (27.4%) were newly diagnosed with tumor at admission and 113 (54.3%) had refractory SE. The mean hospital length of stay (LOS) was 14.8 days (median 12.0, range 1–57), 171 (82.2%) patients required intensive care (mean LOS 8.9 days, median 5, range 1–46), and 44 (21.2%) were administered mechanical ventilation. All patients exhibited significant functional status decline (modified Rankin Scale) post-SE at discharge (p

Surgical education demands extensive knowledge and skill acquisition within limited time frames, often limited by reduced training opportunities and high-pressure environments. This review evaluates the effectiveness of extended reality-based head-mounted display (ExR-HMD) technology in surgical education, examining its impact on educational outcomes and exploring its strengths and limitations. Data from PubMed, Cochrane Library, Web of Science, ScienceDirect, Scopus, ACM Digital Library, IEEE Xplore, WorldCat, and Google Scholar (Year: 2014–2024) were synthesized. After screening, 32 studies comparing ExR-HMD and traditional surgical training methods for medical students or residents were identified. Quality and bias were assessed using the Medical Education Research Study Quality Instrument, Newcastle–Ottawa Scale-Education, and Cochrane Risk of Bias Tools. Results indicate that ExR-HMD offers benefits such as increased immersion, spatial awareness, and interaction and supports motor skill acquisition theory and constructivist educational theories. However, challenges such as system fidelity, operational inconvenience, and physical discomfort were noted. Nearly half the studies reported outcomes comparable or superior to traditional methods, emphasizing the importance of social interaction. Limitations include study heterogeneity and English-only publications. ExR-HMD shows promise but needs educational theory integration and social interaction. Future research should address technical and economic barriers to global accessibility.

Background and Objectives: Microsurgical resection with intraoperative neuromonitoring is the gold standard for acoustic neurinomas (ANs) which are classified as T3 or T4 tumors according to the Hannover Classification. Microscope-based augmented reality (AR) can be beneficial in cerebellopontine angle and lateral skull base surgery, since these are small areas packed with anatomical structures and the use of this technology enables automatic 3D building of a model without the need for a surgeon to mentally perform this task of transferring 2D images seen on the microscope into imaginary 3D images, which then reduces the possibility of error and provides better orientation in the operative field. Materials and Methods: All patients who underwent surgery for resection of ANs in our department were included in this study. Clinical outcomes in terms of postoperative neurological deficits and complications were evaluated, as well as neuroradiological outcomes for tumor remnants and recurrence. Results: A total of 43 consecutive patients (25 female, median age 60.5 ± 16 years) who underwent resection of ANs via retrosigmoid osteoclastic craniotomy with the use of intraoperative neuromonitoring (22 right-sided, 14 giant tumors, 10 cystic, 7 with hydrocephalus) by a single surgeon were included in this study, with a median follow up of 41.2 ± 32.2 months. A total of 18 patients underwent subtotal resection, 1 patient partial resection and 24 patients gross total resection. A total of 27 patients underwent resection in sitting position and the rest in semi-sitting position. Out of 37 patients who had no facial nerve deficit prior to surgery, 19 patients were intact following surgery, 7 patients had House Brackmann (HB) Grade II paresis, 3 patients HB III, 7 patients HB IV and 1 patient HB V. Wound healing deficit with cerebrospinal fluid (CSF) leak occurred in 8 patients (18.6%). Operative time was 317.3 ± 99 min. One patient which had recurrence and one further patient with partial resection underwent radiotherapy following surgery. A total of 16 patients (37.2%) underwent resection using fiducial-based navigation and microscope-based AR, all in sitting position. Segmented objects of interest in AR were the sigmoid and transverse sinus, tumor outline, cranial nerves (CN) VII, VIII and V, petrous vein, cochlea and semicircular canals and brain stem. Operative time and clinical outcome did not differ between the AR and the non-AR group. However, use of AR improved orientation in the operative field for craniotomy planning and microsurgical resection by identification of important neurovascular structures. Conclusions: The single-center experience of resection of ANs showed a high rate of gross total (GTR) and subtotal resection (STR) with low recurrence. Use of AR improves intraoperative orientation and facilitates craniotomy planning and AN resection through early improved identification of important anatomical relations to structures of the inner auditory canal, venous sinuses, petrous vein, brain stem and the course of cranial nerves.

Background: A reduction in stride length is considered a key characteristic of gait kinematics in Parkinson’s disease (PD) and has been identified as a predictor of falls. Although low-frequency stimulation (LFS) has been suggested as a method to improve gait characteristics, the underlying structural network is not well understood. Objective: This study aims to investigate the structural correlates of changes in stride length during LFS (85 Hz). Methods: Objective gait performance was retrospectively evaluated in 19 PD patients who underwent deep brain stimulation (DBS) at 85 Hz and 130 Hz. Individual DBS contacts and volumes of activated tissue (VAT) were computed using preoperative magnetic resonance imaging (MRI) and postoperative computed tomography (CT) scans. Structural connectivity profiles to predetermined cortical and mesencephalic areas were estimated using a normative connectome. Results: LFS led to a significant improvement in stride length compared to 130 Hz stimulation. The intersection between VAT and the associative subregion of the subthalamic nucleus (STN) was associated with an improvement in stride length and had structural connections to the supplementary motor area, prefrontal cortex, and pedunculopontine nucleus. Conversely, we found that a lack of improvement was linked to stimulation volumes connected to cortico-diencephalic fibers bypassing the STN dorsolaterally. The robustness of the connectivity model was verified through leave-one-patient-out, 5-, and 10-fold cross cross-validation paradigms. Conclusion: These findings offer new insights into the structural connectivity that underlies gait changes following LFS. Targeting the non-motor subregion of the STN with LFS on an individual level may present a potential therapeutic approach for PD patients with gait disorders.

Abstract Background Glioblastoma multiforme (GBM) is characterized by an unfavorable prognosis for patients affected. During standard-of-care chemotherapy using temozolomide (TMZ), tumors acquire resistance thereby causing tumor recurrence. Thus, deciphering essential molecular pathways causing TMZ resistance are of high therapeutic relevance. Methods Mass spectrometry based proteomics were used to study the GBM proteome. Immunohistochemistry staining of human GBM tissue for either calpain-1 or -2 was performed to locate expression of proteases. In vitro cell based assays were used to measure cell viability and survival of primary patient-derived GBM cells and established GBM cell lines after TMZ ± calpain inhibitor administration. shRNA expression knockdowns of either calpain-1 or calpain-2 were generated to study TMZ sensitivity of the specific subunits. The Comet assay and ɣH2AX signal measurements were performed in order to assess the DNA damage amount and recognition. Finally, quantitative real-time PCR of target proteins was applied to differentiate between transcriptional and post-translational regulation. Results Calcium-dependent calpain proteases, in particular calpain-2, are more abundant in glioblastoma compared to normal brain and increased in patient-matched initial and recurrent glioblastomas. On the cellular level, pharmacological calpain inhibition increased the sensitivities of primary glioblastoma cells towards TMZ. A genetic knockdown of calpain-2 in U251 cells led to increased caspase-3 cleavage and sensitivity to neocarzinostatin, which rapidly induces DNA strand breakage. We hypothesize that calpain-2 causes desensitization of tumor cells against TMZ by preventing strong DNA damage and subsequent apoptosis via post-translational TP53 inhibition. Indeed, proteomic comparison of U251 control vs. U251 calpain-2 knockdown cells highlights perturbed levels of numerous proteins involved in DNA damage response and downstream pathways affecting TP53 and NF-κB signaling. TP53 showed increased protein abundance, but no transcriptional regulation. Conclusion TMZ-induced cell death in the presence of calpain-2 expression appears to favor DNA repair and promote cell survival. We conclude from our experiments that calpain-2 expression represents a proteomic mode that is associated with higher resistance via “priming” GBM cells to TMZ chemotherapy. Thus, calpain-2 could serve as a prognostic factor for GBM outcome.

Abstract Objective This study was performed to identify coexisting structural lesions in patients with epilepsy and known temporal encephaloceles (TEs). Methods Forty‐seven structural magnetic resonance imaging (MRI) scans of patients with epilepsy and radiologically diagnosed TEs were retrospectively reviewed visually and using an automated postprocessing software, the Morphometric Analysis Program v2018 (MAP18), to depict additional subtle, potentially epileptogenic lesions in the 3D T1‐weighted MRI data. All imaging findings were evaluated in the context of clinical and electroencephalographical findings. Results The study population consisted of 47 epilepsy patients (38.3% female, n = 18). The median age at the time of the scan was 40 years (range 12–81 years). Twenty‐one out of 47 MRI scans (44.7%) showed coexisting lesions in the initial MRI evaluation; in 38.3% (n = 18) of patients, those lesions were considered probably epileptogenic. After postprocessing, probable epileptogenic lesions were identified in 53.2% (n = 25) of patients. Malformations of cortical development had initially been reported in 17.0% (n = 8) of patients with TEs, which increased to 38.3% (n = 18) after postprocessing. TEs and other epileptogenic lesions were considered equally epileptogenic in 21.3% (n = 10) of the cases in the initial MR reports and 25.5% (n = 12) of the cases after postprocessing. Significance Temporal encephaloceles are a potential cause of MRI‐negative temporal lobe epilepsy. According to our data, TEs can occur with other lesions, suggesting that increased awareness is also required in patients with lesional epilepsy. TEs may not always be epileptogenic; hence, their occurrence with other structural pathologies may influence the presurgical evaluation and surgical approach. Finally, TEs can be associated with malformations of cortical development, which may indicate a common developmental etiology of those lesions.

Background and Objectives: The aim of this study is to present our experience in the surgical treatment of calcified thoracic herniated disc disease via a transthoracic approach in the lateral position with the use of intraoperative computed tomography (iCT) and augmented reality (AR). Materials and Methods: All patients who underwent surgery for calcified thoracic herniated disc via a transthoracic transpleural approach at our Department using iCT and microscope-based AR were included in the study. Results: Six consecutive patients (five female, median age 53.2 ± 6.4 years) with calcified herniated thoracic discs (two patients Th 10–11 level, two patients Th 7–8, one patient Th 9–10, one patient Th 11–12) were included in this case series. Indication for surgery included evidence of a calcified thoracic disc on magnet resonance imaging (MRI) and CT with spinal canal stenosis of >50% of diameter, intractable pain, and neurological deficits, as well as MRI-signs of myelopathy. Five patients had paraparesis and ataxia, and one patient had no deficit. All surgeries were performed in the lateral position via a transthoracic transpleural approach (Five from left side). CT for automatic registration was performed following the placement of the reference array, with a high registration accuracy. Microscope-based AR was used, with segmented structures of interest such as vertebral bodies, disc space, herniated disc, and dural sac. Mean operative time was 277.5 ± 156 min. The use of AR improved orientation in the operative field for identification, and tailored the resection of the herniated disc and the identification of the course of dural sac. A control-iCT scan confirmed the complete resection in five patients and incomplete resection of the herniated disc in one patient. In one patient, complications occurred, such as postoperative hematoma, and wound healing deficit occurred. Mean follow-up was 22.9 ± 16.5 months. Five patients improved following surgery, and one patient who had no deficits remained unchanged. Conclusions: Optimal surgical therapy in patients with calcified thoracic disc disease with compression of dural sac and myelopathy was resectioned via a transthoracic transpleural approach. The use of iCT-based registration and microscope-based AR significantly improved orientation in the operative field and facilitated safe resection of these lesions.

Adjuvant treatment for Glioblastoma Grade 4 with Temozolomide (TMZ) inevitably fails due to therapeutic resistance, necessitating new approaches. Apoptosis induction in GB cells is inefficient, due to an excess of anti-apoptotic XPO1/Bcl-2-family proteins. We assessed TMZ, Methotrexate (MTX), and Cytarabine (Ara-C) (apoptosis inducers) combined with XPO1/Bcl-2/Mcl-1-inhibitors (apoptosis rescue) in GB cell lines and primary GB stem-like cells (GSCs). Using CellTiter-Glo® and Caspase-3 activity assays, we generated dose–response curves and analyzed the gene and protein regulation of anti-apoptotic proteins via PCR and Western blots. Optimal drug combinations were examined for their impact on the cell cycle and apoptosis induction via FACS analysis, paralleled by the assessment of potential toxicity in healthy mouse brain slices. Ara-C and MTX proved to be 150- to 10,000-fold more potent in inducing apoptosis than TMZ. In response to inhibitors Eltanexor (XPO1; E), Venetoclax (Bcl-2; V), and A1210477 (Mcl-1; A), genes encoding for the corresponding proteins were upregulated in a compensatory manner. TMZ, MTX, and Ara-C combined with E, V, and A evidenced highly lethal effects when combined. As no significant cell death induction in mouse brain slices was observed, we conclude that this drug combination is effective in vitro and expected to have low side effects in vivo.

IntroductionDeep brain stimulation (DBS) is an established and effective therapy for movement disorders. Here, we present a case of secondary myoclonus-dystonia syndrome following acute disseminated encephalomyelitis (ADEM) in childhood, which was alleviated by DBS. Using a patient-specific connectome analysis, we sought to characterise the fibres and circuits affected by stimulation.Case reportWe report a case of a 20-year-old man with progressive dystonia, myoclonic jerks, and impaired concentration following childhood ADEM. Motor assessments utilising the Unified Myoclonus Rating Scale (UMRS) and the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) revealed a greater improvement in dystonia compared to myoclonus following adjustments of DBS parameters. These adjustments were based on visualisation of electrode position and volume of tissue activated (VTA) 3 years after surgery. A patient-specific connectome analysis using the VTA as a region of interest revealed fibre tracts connecting to the cerebello-thalamo-cortical network and the superior frontal gyrus in addition to basal ganglia circuits as particularly effective.ConclusionGlobus pallidus internus (GPi) DBS shows promise as a treatment for secondary myoclonus-dystonia syndromes. Personalised structural considerations, tailored to individual symptoms and clinical characteristics, can provide significant benefits. Patient-specific connectome analysis, specifically, offers insights into the structures involved and may enable a favourable treatment response.

Abstract Fn14 is a cell surface receptor with key functions in tissue homeostasis and injury but is also linked to chronic diseases. Despite its physiological and medical importance, the regulation of Fn14 signaling and turnover is only partly understood. Here, we demonstrate that Fn14 is cleaved within its transmembrane domain by the protease γ‐secretase, resulting in secretion of the soluble Fn14 ectodomain (sFn14). Inhibition of γ‐secretase in tumor cells reduced sFn14 secretion, increased full‐length Fn14 at the cell surface, and enhanced TWEAK ligand‐stimulated Fn14 signaling through the NFκB pathway, which led to enhanced release of the cytokine tumor necrosis factor. γ‐Secretase‐dependent sFn14 release was also detected ex vivo in primary tumor cells from glioblastoma patients, in mouse and human plasma and was strongly reduced in blood from human cancer patients dosed with a γ‐secretase inhibitor prior to chimeric antigen receptor (CAR)‐T‐cell treatment. Taken together, our study demonstrates a novel function for γ‐secretase in attenuating TWEAK/Fn14 signaling and suggests the use of sFn14 as an easily measurable pharmacodynamic biomarker to monitor γ‐secretase activity in vivo.

Abstract We report detailed functional MRI (fMRI) analyses in a patient with reflex seizures elicited by driving along a specific rural crossroad or by watching a video thereof. Semiology consisted of epigastric aura, followed by a sensory seizure of the left hand and sporadic automotor seizures. The right amygdala‐region (rh‐amygdala) was surgically and electroclinically confirmed as the epileptogenic zone. Presurgical task‐fMRI was performed, during which videos of the driving along that specific crossroad (IC), of another crossroad (NC) or noise were presented. Independent component analysis was conducted, and one component was used to aid in selection of a seed region within the rh‐amygdala for subsequent psychophysiological interaction analysis (PPI). Here, the following regions showed stronger connectivity with the rh‐amygdala seed during the IC condition compared to NC: right > left visual cortex, bilateral insulae, and right secondary somatosensory cortex (S2), potentially explaining epigastric aura and left somatosensory seizure semiology. Contralateral analyses did not reproduce these results. Overall, the ictogenic stimulus elicited enhanced connectivity of the epileptogenic rh‐amygdala with visual cortex and further regions of potential seizure spread (S2, insula) as a putative mechanism of ictogenesis. Our results highlight the potential of PPI in the analysis of stimulus‐dependent networks in patients with reflex epilepsies to gain insight into seizure generation.

Addressing conventional neurosurgical navigation systems’ high costs and complexity, this study explores the feasibility and accuracy of a simplified, cost-effective mixed reality navigation (MRN) system based on a laser crosshair simulator (LCS). A new automatic registration method was developed, featuring coplanar laser emitters and a recognizable target pattern. The workflow was integrated into Microsoft’s HoloLens-2 for practical application. The study assessed the system’s precision by utilizing life-sized 3D-printed head phantoms based on computed tomography (CT) or magnetic resonance imaging (MRI) data from 19 patients (female/male: 7/12, average age: 54.4 ± 18.5 years) with intracranial lesions. Six to seven CT/MRI-visible scalp markers were used as reference points per case. The LCS-MRN’s accuracy was evaluated through landmark-based and lesion-based analyses, using metrics such as target registration error (TRE) and Dice similarity coefficient (DSC). The system demonstrated immersive capabilities for observing intracranial structures across all cases. Analysis of 124 landmarks showed a TRE of 3.0 ± 0.5 mm, consistent across various surgical positions. The DSC of 0.83 ± 0.12 correlated significantly with lesion volume (Spearman rho = 0.813, p < 0.001). Therefore, the LCS-MRN system is a viable tool for neurosurgical planning, highlighting its low user dependency, cost-efficiency, and accuracy, with prospects for future clinical application enhancements.

Abstract Previous studies have shown less access to deep brain stimulation (DBS) for Parkinson’s disease (PD) in women compared to men raising concerns about a potential gender gap resulting from nonclinical factors or gender differences in clinical efficacy for postoperative quality of life (QoL), motor, and nonmotor symptoms (NMS) outcomes. This was a cross-sectional and a longitudinal, prospective, observational, controlled, quasi-experimental, international multicenter study. A total sample size of 505 consisted of 316 consecutively referred patients for DBS indication evaluation at the University Hospital Cologne (01/2015–09/2020) and 189 consecutively treated patients at DBS centers in the University Hospitals Cologne and Marburg, Salford’s Royal Hospital Manchester, and King’s College Hospital London. In the cross-sectional cohort, we examined gender proportions at referral, indication evaluations, and DBS surgery. In the longitudinal cohort, clinical assessments at preoperative baseline and 6-month follow-up after surgery included the PD Questionnaire-8, NMSScale, Scales for Outcomes in PD-motor scale, and levodopa-equivalent daily dose. Propensity score matching resulted in a pseudo-randomized sub-cohort balancing baseline demographic and clinical characteristics between women with PD and male controls. 316 patients were referred for DBS. 219 indication evaluations were positive (women n = 102, respectively n = 82). Women with PD were disproportionally underrepresented in referrals compared to the general PD population (relative risk [RR], 0.72; 95%CI, 0.56–0.91; P = 0.002), but more likely to be approved for DBS than men (RR, 1.17; 95%CI, 1.03–1.34; P = 0.029). Nonetheless, their total relative risk of undergoing DBS treatment was 0.74 (95%CI, 0.48–1.12) compared to men with PD. At baseline, women had longer disease duration and worse dyskinesia. Exploring QoL domains, women reported worse mobility and bodily discomfort. At follow-up, all main outcomes improved equally in both genders. Our study provides evidence of a gender gap in DBS for PD. Women and men with PD have distinct preoperative nonmotor and motor profiles. We advocate that more focus should be directed toward the implementation of gender equity as both genders benefit from DBS with equal clinical efficacy. This study provides Class II evidence of beneficial effects of DBS in women with PD compared to male controls.

Mixed Reality Navigation (MRN) is pivotal in augmented reality-assisted intelligent neurosurgical interventions. However, existing MRN registration methods face challenges in concurrently achieving low user dependency, high accuracy, and clinical applicability. This study proposes and evaluates a novel registration method based on a laser crosshair simulator, evaluating its feasibility and accuracy. A novel registration method employing a laser crosshair simulator was introduced, designed to replicate the scanner frame’s position on the patient. The system autonomously calculates the transformation, mapping coordinates from the tracking space to the reference image space. A mathematical model and workflow for registration were designed, and a Universal Windows Platform (UWP) application was developed on HoloLens-2. Finally, a head phantom was used to measure the system’s target registration error (TRE). The proposed method was successfully implemented, obviating the need for user interactions with virtual objects during the registration process. Regarding accuracy, the average deviation was 3.7 ± 1.7 mm. This method shows encouraging results in efficiency and intuitiveness and marks a valuable advancement in low-cost, easy-to-use MRN systems. The potential for enhancing accuracy and adaptability in intervention procedures positions this approach as promising for improving surgical outcomes.

Background: The need for imaging-guided optimization of Deep Brain Stimulation (DBS) parameters is increasing with recent developments of sophisticated lead designs offering highly individualized, but time-consuming and complex programming. Objective: The objective of this study was to compare changes in motor symptoms of Parkinson's Disease (PD) and the corresponding volume of the electrostatic field (VEsF) achieved by DBS programming using GUIDE XT™, a commercially available software for visualization of DBS leads within the patient-specific anatomy from fusions of preoperative magnetic resonance imaging (MRI) and postoperative computed tomography (CT) scans, versus standard-of-care clinical programming. Methods: Clinical evaluation was performed to identify the optimal set of parameters based on clinical effects in 29 patients with PD and bilateral directional leads for Subthalamic Nucleus (STN) DBS. A second DBS program was generated in GUIDE XT™ based on a VEsF optimally located within the dorsolateral STN. Reduction of motor symptoms (Movement Disorders Society Unified Parkinson's Disease Rating Scale, MDS-UPDRS) and the overlap of the corresponding VEsF of both programs were compared. Results: Clinical and imaging-guided programming resulted in a significant reduction in the MDS-UPDRS scores compared to off-state. Motor symptom control with GUIDE XT™-derived DBS program was non-inferior to standard clinical programming. The overlap of the two VEsF did not correlate with the difference in motor symptom reduction by the programs. Conclusions: Imaging-guided programming of directional DBS leads using GUIDE XT™ is possible without computational background and leads to non-inferior motor symptom control compared with clinical programming. DBS programs based on patient-specific imaging data may thus serve as starting point for clinical testing and may promote more efficient DBS programming.

Abstract In recent years, the clinical usefulness of the Wada test (WT) has been debated among researchers in the field. Therefore, we aimed to assess its contribution to the prediction of change in verbal learning and verbal memory function after epilepsy surgery. Data from 56 patients with temporal lobe epilepsy who underwent WT and subsequent surgery were analyzed retrospectively. Additionally, a standard neuropsychological assessment evaluating attentional, learning and memory, visuospatial, language, and executive function was performed both before and 12 months after surgery. Hierarchical linear regression analyses were used to determine the incremental value of WT results over socio-demographic, clinical, and neuropsychological characteristics in predicting postsurgical change in patients’ verbal learning and verbal memory function. The incorporation of WT results significantly improved the prediction models of postsurgical change in verbal learning (∆R 2 = 0.233, p = .032) and verbal memory function (∆R 2 = 0.386, p = .005). Presurgical performance and WT scores accounted for 41.8% of the variance in postsurgical change in verbal learning function, and 51.1% of the variance in postsurgical change in verbal memory function. Our findings confirm that WT results are of significant incremental value for the prediction of postsurgical change in verbal learning and verbal memory function. Thus, the WT contributes to determining the risks of epilepsy surgery and, therefore, remains an important part of the presurgical work-up of selected patients with clear clinical indications.

BackgroundNeuronavigation is routinely used in glioblastoma surgery, but its accuracy decreases during the operative procedure due to brain shift, which can be addressed utilizing intraoperative imaging. Intraoperative ultrasound (iUS) is widely available, offers excellent live imaging, and can be fully integrated into modern navigational systems. Here, we analyze the imaging features of navigated i3D US and its impact on the extent of resection (EOR) in glioblastoma surgery.MethodsDatasets of 31 glioblastoma resection procedures were evaluated. Patient registration was established using intraoperative computed tomography (iCT). Pre-operative MRI (pre-MRI) and pre-resectional ultrasound (pre-US) datasets were compared regarding segmented tumor volume, spatial overlap (Dice coefficient), the Euclidean distance of the geometric center of gravity (CoG), and the Hausdorff distance. Post-resectional ultrasound (post-US) and post-operative MRI (post-MRI) tumor volumes were analyzed and categorized into subtotal resection (STR) or gross total resection (GTR) cases.ResultsThe mean patient age was 59.3 ± 11.9 years. There was no significant difference in pre-resectional segmented tumor volumes (pre-MRI: 24.2 ± 22.3 cm3; pre-US: 24.0 ± 21.8 cm3). The Dice coefficient was 0.71 ± 0.21, the Euclidean distance of the CoG was 3.9 ± 3.0 mm, and the Hausdorff distance was 12.2 ± 6.9 mm. A total of 18 cases were categorized as GTR, 10 cases were concordantly classified as STR on MRI and ultrasound, and 3 cases had to be excluded from post-resectional analysis. In four cases, i3D US triggered further resection.ConclusionNavigated i3D US is reliably adjunct in a multimodal navigational setup for glioblastoma resection. Tumor segmentations revealed similar results in i3D US and MRI, demonstrating the capability of i3D US to delineate tumor boundaries. Additionally, i3D US has a positive influence on the EOR, allows live imaging, and depicts brain shift.

Glioblastoma (GBM) as the most common and aggressive brain tumor is characterized by genetic heterogeneity, invasiveness, radio-/chemoresistance, and occurrence of GBM stem-like cells. The metalloprotease-disintegrin ADAM8 is highly expressed in GBM tumor and immune cells and correlates with poor survival. In GBM, ADAM8 affects intracellular kinase signaling and increases expression levels of osteopontin/SPP1 and matrix metalloproteinase 9 (MMP9) by an unknown mechanism. Here we explored whether microRNA (miRNA) expression levels could be regulators of MMP9 expression in GBM cells expressing ADAM8. Initially, we identified several miRNAs as dysregulated in ADAM8-deficient U87 GBM cells. Among these, the tumor suppressor miR-181a-5p was significantly upregulated in ADAM8 knockout clones. By inhibiting kinase signaling, we found that ADAM8 downregulates expression of miR-181a-5p via activation of signal transducer and activator of transcription 3 (STAT3) and mitogen-activated protein kinase (MAPK) signaling suggesting an ADAM8-dependent silencing of miR-181a-5p. In turn, mimic miR-181a-5p transfection caused decreased cell proliferation and lower MMP9 expression in GBM cells. Furthermore, miR-181a-5p was detected in GBM cell-derived extracellular vesicles (EVs) as well as patient serum-derived EVs. We identified miR-181a-5p downregulating MMP9 expression via targeting the MAPK pathway. Analysis of patient tissue samples (n=22) revealed that in GBM, miR-181a-5p is strongly downregulated compared to ADAM8 and MMP9 mRNA expression, even in localized tumor areas. Taken together, we provide evidence for a functional axis involving ADAM8/miR-181a-5p/MAPK/MMP9 in GBM tumor cells.

Selective estrogen receptor modulators (SERMs) significantly affect survival and invasiveness of rodent pituitary adenoma (PA) cells. The impact of three clinically relevant SERMs (bazedoxifene, clomiphene, raloxifene) on invasiveness and on gene and protein expression of invasion‐related proteases [matrix metalloproteinase‐14 (MMP‐14) and A disintegrin and metalloproteinase‐12 (ADAM12)] was analyzed in murine PA cells (AtT‐20 and TtT/GF). All SERMs significantly decreased cell invasiveness. Moreover, SERMs significantly decreased expression of ADAM12 mRNA in both cell lines and of MMP‐14 mRNA in TtT/GF cells. Invasion rates of AtT‐20 and TtT/GF significantly decreased after ADAM12 gene silencing, and the invasion rate of TtT/GF cells significantly decreased after MMP‐14 gene silencing. All SERMs affected ADAM12 protein expression in AtT‐20 cells whereas bazedoxifene and raloxifene decreased MMP‐14 protein expression in TtT/GF cells. We conclude that SERMs attenuate invasiveness of murine PA cells by downregulating expression levels of invasion‐related proteases MMP‐14 and ADAM12.

Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor in adults. Despite multimodal therapy, median survival is poor at 12–15 months. At the molecular level, radio-/chemoresistance and resulting tumor progression are attributed to a small fraction of tumor cells, termed glioblastoma stem-like cells (GSCs). These CD133-expressing, self-renewing cells display the properties of multi-lineage differentiation, resulting in the heterogenous composition of GBM. MicroRNAs (miRNAs) as regulators of gene expression at the post-transcriptional level can alter many pathways pivotal to cancer stem cell fate. This study explored changes in the miRNA expression profiles in patient-derived GSCs altered on differentiation into glial fiber acid protein (GFAP)-expressing, astrocytic tumor cells using a polymerase chain reaction (PCR) array. Initially, 22 miRNAs showed higher expression in GSCs and 9 miRNAs in differentiated cells. The two most downregulated miRNAs in differentiated GSCs were miR-17-5p and miR-425-5p, whilst the most upregulated miRNAs were miR-223-3p and let-7-5p. Among those, miR-425-5p showed the highest consistency in an upregulation in all three GSCs. By transfection of a 425-5p miRNA mimic, we demonstrated downregulation of the GFAP protein in differentiated patient-derived GBM cells, providing potential evidence for direct regulation of miRNAs in the GSC/GBM cell transition.

This study aims to report on the capability of microscope-based augmented reality (AR) to evaluate registration and navigation accuracy with extracranial and intracranial landmarks and to elaborate on its opportunities and obstacles in compensation for navigation inaccuracies. In a consecutive single surgeon series of 293 patients, automatic intraoperative computed tomography-based registration was performed delivering a high initial registration accuracy with a mean target registration error of 0.84 ± 0.36 mm. Navigation accuracy is evaluated by overlaying a maximum intensity projection or pre-segmented object outlines within the recent focal plane onto the in situ patient anatomy and compensated for by translational and/or rotational in-plane transformations. Using bony landmarks (85 cases), there was two cases where a mismatch was seen. Cortical vascular structures (242 cases) showed a mismatch in 43 cases and cortex representations (40 cases) revealed two inaccurate cases. In all cases, with detected misalignment, a successful spatial compensation was performed (mean correction: bone (6.27 ± 7.31 mm), vascular (3.00 ± 1.93 mm, 0.38° ± 1.06°), and cortex (5.31 ± 1.57 mm, 1.75° ± 2.47°)) increasing navigation accuracy. AR support allows for intermediate and straightforward monitoring of accuracy, enables compensation of spatial misalignments, and thereby provides additional safety by increasing overall accuracy.

Extreme lateral interbody fusion (XLIF) has become the standard of minimally invasive lumbar segmental scoliosis treatment. Our objective is to determine the safety and efficacy of XLIF in spinal canal stenosis (SCS) and spondylodiscitis (SD). Patients treated with XLIF in our department between 2012 and 2018 were retrospectively analyzed. Patient records with clinical and radiographical parameters were evaluated. The patient cohort consists of 40 male and 32 female patients with a median age of 66.6 years. Forty-five patients had an SCS and 27 patients SD. The mean follow-up was 23 months. One level XLIF was performed in 49 patients, 2 levels in 15, 3 levels in 7 patients and 4 levels in 1 patient. All but one patient received an additional dorsal stabilization. The pain was present in all patients with a mean Visual Analogue Scale (VAS) score of 8.8 vs. postoperative VAS of 2.8 (p

BackgroundIn glioma surgery, the patient’s outcome is dramatically influenced by the extent of resection and residual tumor volume. To facilitate safe resection, neuronavigational systems are routinely used. However, due to brain shift, accuracy decreases with the course of the surgery. Intraoperative ultrasound has proved to provide excellent live imaging, which may be integrated into the navigational procedure. Here we describe the visualization of vascular landmarks and their shift during tumor resection using intraoperative navigated 3D color Doppler ultrasound (3D iUS color Doppler).MethodsSix patients suffering from glial tumors located in the temporal lobe were included in this study. Intraoperative computed tomography was used for registration. Datasets of 3D iUS color Doppler were generated before dural opening and after tumor resection, and the vascular tree was segmented manually. In each dataset, one to four landmarks were identified, compared to the preoperative MRI, and the Euclidean distance was calculated.ResultsPre-resectional mean Euclidean distance of the marked points was 4.1 ± 1.3 mm (mean ± SD), ranging from 2.6 to 6.0 mm. Post-resectional mean Euclidean distance was 4.7. ± 1.0 mm, ranging from 2.9 to 6.0 mm.Conclusion3D iUS color Doppler allows estimation of brain shift intraoperatively, thus increasing patient safety. Future implementation of the reconstructed vessel tree into the navigational setup might allow navigational updating with further consecutive increasement of accuracy.

Current standard adjuvant therapy of glioblastoma multiforme (GBM) using temozolomide (TMZ) frequently fails due to therapy resistance. Thus, novel therapeutic approaches are highly demanded. We tested the therapeutic efficacy of the second-generation XPO1 inhibitor Eltanexor using assays for cell viability and apoptosis in GBM cell lines and GBM stem-like cells. For most GBM-derived cells, IC50 concentrations for Eltanexor were below 100 nM. In correlation with reduced cell viability, apoptosis rates were significantly increased. GBM stem-like cells presented a combinatorial effect of Eltanexor with TMZ on cell viability. Furthermore, pretreatment of GBM cell lines with Eltanexor significantly enhanced radiosensitivity in vitro. To explore the mechanism of apoptosis induction by Eltanexor, TP53-dependent genes were analyzed at the mRNA and protein level. Eltanexor caused induction of TP53-related genes, TP53i3, PUMA, CDKN1A, and PML on both mRNA and protein level. Immunofluorescence of GBM cell lines treated with Eltanexor revealed a strong accumulation of CDKN1A, and, to a lesser extent, of p53 and Tp53i3 in cell nuclei as a plausible mechanism for Eltanexor-induced apoptosis. From these data, we conclude that monotherapy with Eltanexor effectively induces apoptosis in GBM cells and can be combined with current adjuvant therapies to provide a more effective therapy of GBM.

Characterization of brain tumours requires neuropathological expertise and is generally performed by histological evaluation and molecular analysis. One emerging technique to assist pathologists in future tumour diagnostics is multimodal optical spectroscopy. In the current clinical routine, tissue preprocessing with formalin is widely established and suitable for spectroscopic investigations since degradation processes impede the measurement of native tissue. However, formalin fixation results in alterations of the tissue chemistry and morphology for example by protein cross-linking. As optical spectroscopy is sensitive to these variations, we evaluate the effects of formalin fixation on multimodal brain tumour data in this proof-of-concept study. Nonfixed and formalin-fixed cross sections of different common human brain tumours were subjected to analysis of chemical variations using ultraviolet and Fourier-transform infrared microspectroscopy. Morphological changes were assessed by elastic light scattering microspectroscopy in the visible wavelength range. Data were analysed with multivariate data analysis and compared with histopathology. Tissue type classifications deduced by optical spectroscopy are highly comparable and independent from the preparation and the fixation protocol. However, formalin fixation leads to slightly better classification models due to improved stability of the tissue. As a consequence, spectroscopic methods represent an appropriate additional contrast for chemical and morphological information in neuropathological diagnosis and should be investigated to a greater extent. Furthermore, they can be included in the clinical workflow even after formalin fixation.

In contrast to commonly used approaches to improve data quality in diffusion weighted imaging, position-orientation adaptive smoothing (POAS) provides an edge-preserving post-processing approach. This study aims to investigate its potential and effects on image quality, diffusion metrics, and fiber tractography of the corticospinal tract in relation to non-post-processed and averaged data. 22 healthy volunteers were included in this study. For each volunteer five clinically applicable diffusion weighted imaging data sets were acquired and post-processed by standard averaging and POAS. POAS post-processing led to significantly higher signal-to-noise-ratios (p < 0.001), lower fractional anisotropy across the whole brain (p < 0.05) and reduced intra-subject variability of diffusion weighted imaging signal intensity and fractional anisotropy (p < 0.001, p = 0.006). Fiber tractography of the corticospinal tract resulted in significantly (p = 0.027, p = 0.014) larger tract volumes while fiber density was the lowest. Similarity across tractography results was highest for POAS post-processed data (p < 0.001). POAS post-processing enhances image quality, decreases the intra-subject variability of signal intensity and fractional anisotropy, increases fiber tract volume of the corticospinal tract, and leads to higher reproducibility of tractography results. Thus, POAS post-processing supports a reliable and more accurate fiber tractography of the corticospinal tract, being mandatory for the clinical use.

Surgical treatment of spondylodiscitis allows for rapid mobilization and shortens hospital stays, which makes surgical treatment the first-line therapy. We aim to describe our experiences with operative treatment on spondylodiscitis and to determine the parameters that are important in the prediction of outcomes. A retrospective review identified 237 patients who were operatively treated for spondylodiscitis in our institution between January 2010 and December 2018. Clinical data were collected through review of electronic records and relevant imaging. In all cases, contrast-enhancing MRI from the infected region of the spine was obtained. Leukocyte count and C-reactive protein concentrations (CRP) were determined in all the patients. We included 237 patients in the study, 87 female (36.7%) and 150 male (63.3%), with a mean age of 71.4 years. Mean follow-up was 31.6 months. Forty-five patients had spondylodiscitis of the cervical, 73 of the thoracic, and 119 of the lumbosacral spine. All the patients with spondylodiscitis of the cervical spine received instrumentation. In thoracic and lumbar spine decompression, surgery without instrumentation was performed in 26 patients as immediate surgery and in a further 28 patients in the early stages following admission, while 138 patients received instrumentation. Eighty-nine patients (37.6%) had concomitant infections. Infection healing occurred in 89% of patients. Favorable outcomes were noted in patients without concomitant infections, with a normalized CRP value and in patients who received antibiotic therapy for more than six weeks (p < 0.05). Unfavorable outcomes were noted in patients with high CRP, postoperative spondylodiscitis, and recurrent spondylodiscitis (p < 0.05). Application of antibiotic therapy for more than six weeks and normalized CRP showed a correlation with favorable outcomes, whereas concomitant infections showed a correlation with unfavorable outcomes. A detailed screening for concomitant infectious diseases is recommended.

Summary: Glioblastoma (GBM) is highly refractory to therapy and associated with poor clinical outcome. Here, we reveal a critical function of the promitotic and adhesion-mediating discoidin domain receptor 1 (DDR1) in modulating GBM therapy resistance. In GBM cultures and clinical samples, we show a DDR1 and GBM stem cell marker co-expression that correlates with patient outcome. We demonstrate that inhibition of DDR1 in combination with radiochemotherapy with temozolomide in GBM models enhances sensitivity and prolongs survival superior to conventional therapy. We identify a 14-3-3-Beclin-1-Akt1 protein complex assembling with DDR1 to be required for prosurvival Akt and mTOR signaling and regulation of autophagy-associated therapy sensitivity. Our results uncover a mechanism driven by DDR1 that controls GBM therapy resistance and provide a rationale target for the development of therapy-sensitizing agents. : Vehlow and Klapproth et al. identify the discoidin domain receptor 1 (DDR1) to assemble with a 14-3-3-Beclin-1-Akt1 protein complex, which mediates prosurvival Akt and mTOR signaling for regulating autophagy-associated glioblastoma cell sensitivity to therapy. Keywords: discoidin domain receptor 1, glioblastoma, radiochemotherapy, therapy resistance, autophagy, 14-3-3, Beclin-1, Akt1, mTOR, GBM stem-like cells, orthotopic GBM mouse model

Background. Lateral approaches to the spine have gained increased popularity due to enabling minimally invasive access to the spine, less blood loss, decreased operative time, and less postoperative pain. The objective of the study was to analyze the use of intraoperative computed tomography with navigation and the implementation of augmented reality in facilitating a lateral approach to the spine. Methods. We prospectively analyzed all patients who underwent surgery with a lateral approach to the spine from September 2016 to January 2021 using intraoperative CT applying a 32-slice movable CT scanner, which was used for automatic navigation registration. Sixteen patients, with a median age of 64.3 years, were operated on using a lateral approach to the thoracic and lumbar spine and using intraoperative CT with navigation. Indications included a herniated disc (six patients), tumors (seven), instability following the fracture of the thoracic or lumbar vertebra (two), and spondylodiscitis (one). Results. Automatic registration, applying intraoperative CT, resulted in high accuracy (target registration error: 0.84 ± 0.10 mm). The effective radiation dose of the registration CT scans was 6.16 ± 3.91 mSv. In seven patients, a control iCT scan was performed for resection and implant control, with an ED of 4.51 ± 2.48 mSv. Augmented reality (AR) was used to support surgery in 11 cases, by visualizing the tumor outline, pedicle screws, herniated discs, and surrounding structures. Of the 16 patients, corpectomy was performed in six patients with the implantation of an expandable cage, and one patient underwent discectomy using the XLIF technique. One patient experienced perioperative complications. One patient died in the early postoperative course due to severe cardiorespiratory failure. Ten patients had improved and five had unchanged neurological status at the 3-month follow up. Conclusions. Intraoperative computed tomography with navigation facilitates the application of lateral approaches to the spine for a variety of indications, including fusion procedures, tumor resection, and herniated disc surgery.

Diffusion tensor imaging (DTI)-based fiber tractography is routinely used in clinical applications to visualize major white matter tracts, such as the corticospinal tract (CST), optic radiation (OR), and arcuate fascicle (AF). Nevertheless, DTI is limited due to its capability of resolving intra-voxel multi-fiber populations. Sophisticated models often require long acquisition times not applicable in clinical practice. Diffusion kurtosis imaging (DKI), as an extension of DTI, combines sophisticated modeling of the diffusion process with short acquisition times but has rarely been investigated in fiber tractography. In this study, DTI- and DKI-based fiber tractography of the CST, OR, and AF was investigated in healthy volunteers and glioma patients. For the CST, significantly larger tract volumes were seen in DKI-based fiber tractography. Similar results were obtained for the OR, except for the right OR in patients. In the case of the AF, results of both models were comparable with DTI-based fiber tractography showing even significantly larger tract volumes in patients. In the case of the CST and OR, DKI-based fiber tractography contributes to advanced visualization under clinical time constraints, whereas for the AF, other models should be considered.

Background and objectives: Expandable cages are frequently used to reconstruct the anterior spinal column after a corpectomy. In this retrospective study, we evaluated the perioperative advantages and disadvantages of corpectomy reconstruction with an expandable cage. Materials and Methods: Eighty-six patients (45 male and 41 female patients, medium age of 61.3 years) were treated with an expandable titanium cage for a variety of indications from January 2012 to December 2019 and analyzed retrospectively. The mean follow-up was 30.7 months. Outcome was measured by clinical examination and visual analogue scale (VAS); myelopathy was classified according to the EMS (European Myelopathy Scale) and gait disturbances with the Nurick score. Radiographic analysis comprised measurement of fusion, subsidence and the C2–C7 angle. Results: Indications included spinal canal stenosis with myelopathy (46 or 53.5%), metastasis (24 or 27.9%), spondylodiscitis (12 or 14%), and fracture (4 or 4.6%). In 39 patients (45.3%), additional dorsal stabilization (360° fusion) was performed. In 13 patients, hardware failure occurred, and in 8 patients, adjacent segment disease occurred. Improvement of pain symptoms, myelopathy, and gait following surgery were statistically significant (p < 0.05), with a medium preoperative VAS of 8, a postoperative score of 3.2, and medium EMS scores of 11.3 preoperatively vs. 14.3 postoperatively. Radiographic analysis showed successful fusion in 74 patients (86%). As shown in previous studies, correction of the C2–C7 angle did not correlate with improvement of neurological symptoms. Conclusion: Our results show that expandable titanium cages are a safe and useful tool in anterior cervical corpectomies for providing adequate anterior column support and stability.

Background: Implementation of intraoperative 3D ultrasound (i3D US) into modern neuronavigational systems offers the possibility of live imaging and subsequent imaging updates. However, different modalities, image acquisition strategies, and timing of imaging influence object appearances. We analyzed the differences in object appearances in ultrasound (US) and magnetic resonance imaging (MRI) in 35 cases of brain metastasis, which were operated in a multimodal navigational setup after intraoperative computed tomography based (iCT) registration. Method: Registration accuracy was determined using the target registration error (TRE). Lesions segmented in preoperative magnetic resonance imaging (preMRI) and i3D US were compared focusing on object size, location, and similarity. Results: The mean and standard deviation (SD) of the TRE was 0.84 ± 0.36 mm. Objects were similar in size (mean ± SD in preMRI: 13.6 ± 16.0 cm3 vs. i3D US: 13.5 ± 16.0 cm3). The Dice coefficient was 0.68 ± 0.22 (mean ± SD), the Hausdorff distance 8.1 ± 2.9 mm (mean ± SD), and the Euclidean distance of the centers of gravity 3.7 ± 2.5 mm (mean ± SD). Conclusion: i3D US clearly delineates tumor boundaries and allows live updating of imaging for compensation of brain shift, which can already be identified to a significant amount before dural opening.