Structural changes in eloquent cortex secondary to glioma in sensorimotor area.

This study aims to investigate the structural reorganization in the sensorimotor area of the brain in patients with gliomas, distinguishing between those with impaired and unimpaired strength. Using voxel-based morphometry (VBM) and region of interest (ROI) analysis, gray matter volumes (GMV) were compared in the contralesional primary motor gyrus, primary sensory gyrus, premotor area, bilateral supplementary motor area, and medial Brodmann area 8 (BA8). The results revealed that in patients with right hemisphere gliomas, the right medial BA8 volume was significantly larger in the impaired group than in the unimpaired group, with both groups exceeding the volume in 16 healthy controls (HCs). In patients with left hemisphere gliomas, the right supplementary motor area (SMA) was more pronounced in the impaired group compared to the unimpaired group, and both groups were greater than HCs. Additionally, the volumes of the right medial BA8 in both the impaired group were greater than HCs. Contralateral expansions in the gray matter of hand- and trunk-related cortices of the premotor area, precentral gyrus, and postcentral gyrus were observed compared to HCs. Furthermore, a negative correlation was found between hand Medical Research Council (MRC) score and volumes of the contralateral SMA and bilateral medial BA8. Notably, our findings reveal consistent results across both analytical approaches in identifying significant structural reorganizations within the sensorimotor cortex. These consistent findings underscore the adaptive neuroplastic responses to glioma presence, highlighting potential areas of interest for further neurosurgical planning and rehabilitation strategies.

Glioblastoma and brain connectivity: the need for a paradigm shift.

Despite substantial advances in cancer treatment, for patients with glioblastoma prognosis remains bleak. The emerging field of cancer neuroscience reveals intricate functional interplays between glioblastoma and the cellular architecture of the brain, encompassing neurons, glia, and vessels. New findings underscore the role of structural and functional connections within hierarchical networks, known as the connectome. These connections contribute to the location, spread, and recurrence of a glioblastoma, and a patient's overall survival, revealing a complex interplay between the tumour and the CNS. This mounting evidence prompts a paradigm shift, challenging the perception of glioblastomas as mere foreign bodies within the brain. Instead, these tumours are intricately woven into the structural and functional fabric of the brain. This radical change in thinking holds profound implications for the understanding and treatment of glioblastomas, which could unveil new prognostic factors and surgical strategies and optimise radiotherapy. Additionally, a connectivity approach suggests that non-invasive brain stimulation could disrupt pathological neuron-glioma interactions within specific networks.

Glioma.

Gliomas are primary brain tumours that are thought to develop from neural stem or progenitor cells that carry tumour-initiating genetic alterations. Based on microscopic appearance and molecular characteristics, they are classified according to the WHO classification of central nervous system (CNS) tumours and graded into CNS WHO grades 1-4 from a low to high grade of malignancy. Diffusely infiltrating gliomas in adults comprise three tumour types with distinct natural course of disease, response to treatment and outcome: isocitrate dehydrogenase (IDH)-mutant and 1p/19q-codeleted oligodendrogliomas with the best prognosis; IDH-mutant astrocytomas with intermediate outcome; and IDH-wild-type glioblastomas with poor prognosis. Pilocytic astrocytoma is the most common glioma in children and is characterized by circumscribed growth, frequent BRAF alterations and favourable prognosis. Diffuse gliomas in children are divided into clinically indolent low-grade tumours and high-grade tumours with aggressive behaviour, with histone 3 K27-altered diffuse midline glioma being the leading cause of glioma-related death in children. Ependymal tumours are subdivided into biologically and prognostically distinct types on the basis of histology, molecular biomarkers and location. Although surgery, radiotherapy and alkylating agent chemotherapy are the mainstay of glioma treatment, individually tailored strategies based on tumour-intrinsic dominant signalling pathways have improved outcome in subsets of patients.

Indirect functional connectivity does not predict overall survival in glioblastoma.

BACKGROUND: Lesion network mapping (LNM) is a popular framework to assess clinical syndromes following brain injury. The classical approach involves embedding lesions from patients into a normative functional connectome and using the corresponding functional maps as proxies for disconnections. However, previous studies indicated limited predictive power of this approach in behavioral deficits. We hypothesized similarly low predictiveness for overall survival (OS) in glioblastoma (GBM). METHODS: A retrospective dataset of patients with GBM was included (n = 99). Lesion masks were registered in the normative space to compute disconnectivity maps. The brain functional normative connectome consisted in data from 173 healthy subjects obtained from the Human Connectome Project. A modified version of the LNM was then applied to core regions of GBM masks. Linear regression, classification, and principal component (PCA) analyses were conducted to explore the relationship between disconnectivity and OS. OS was considered both as continuous and categorical (low, intermediate, and high survival) variable. RESULTS: The results revealed no significant associations between OS and network disconnection strength when analyzed at both voxel-wise and classification levels. Moreover, patients stratified into different OS groups did not exhibit significant differences in network connectivity patterns. The spatial similarity among the first PCA of network maps for each OS group suggested a lack of distinctive network patterns associated with survival duration. CONCLUSIONS: Compared with indirect structural measures, functional indirect mapping does not provide significant predictive power for OS in patients with GBM. These findings are consistent with previous research that demonstrated the limitations of indirect functional measures in predicting clinical outcomes, underscoring the need for more comprehensive methodologies and a deeper understanding of the factors influencing clinical outcomes in this challenging disease.

Peaglet: A user-friendly probabilistic Kernel density estimation of intracranial cortical and subcortical stimulation sites.

BACKGROUND: Data on human brain function obtained with direct electrical stimulation (DES) in neurosurgical patients have been recently integrated and combined with modern neuroimaging techniques, allowing a connectome-based approach fed by intraoperative DES data. Within this framework is crucial to develop reliable methods for spatial localization of DES-derived information to be integrated within the neuroimaging workflow. NEW METHOD: To this aim, we applied the Kernel Density Estimation for modelling the distribution of DES sites from different patients into the MNI space. The algorithm has been embedded in a MATLAB-based User Interface, Peaglet. It allows an accurate probabilistic weighted and unweighted estimation of DES sites location both at cortical level, by using shortest path calculation along the brain 3D geometric topology, and subcortical level, by using a volume-based approach. RESULTS: We applied Peaglet to investigate spatial estimation of cortical and subcortical stimulation sites provided by recent brain tumour studies. The resulting NIfTI maps have been anatomically investigated with neuroimaging open-source tools. COMPARISON WITH EXISTING METHODS: Peaglet processes differently cortical and subcortical data following their distinguishing geometrical features, increasing anatomical specificity of DES-related results and their reliability within neuroimaging environments. CONCLUSIONS: Peaglet provides a robust probabilistic estimation of the cortical and subcortical distribution of DES sites going beyond a region of interest approach, respecting cortical and subcortical intrinsic geometrical features. Results can be easily integrated within the neuroimaging workflow to drive connectomic analysis.

Targeting inflammation in glioblastoma: An updated review from pathophysiology to novel therapeutic approaches.

Glioblastoma (GBM) is a highly aggressive primary malignant brain tumor with a dismal prognosis despite current treatment strategies. Inflammation plays an essential role in GBM pathophysiology, contributing to tumor growth, invasion, immunosuppression, and angiogenesis. As a result, pharmacological intervention with anti-inflammatory drugs has been used as a potential approach for the management of GBM. To provide an overview of the current understanding of GBM pathophysiology, potential therapeutic applications of anti-inflammatory drugs in GBM, conventional treatments of glioblastoma and emerging therapeutic approaches currently under investigation. A narrative review was carried out, scanning publications from 2000 to 2023 on PubMed and Google Scholar. The search was not guided by a set research question or a specific search method but rather focused on the area of interest. Conventional treatments such as surgery, radiotherapy, and chemotherapy have shown some benefits, but their effectiveness is limited by various factors such as tumor heterogeneity and resistance.

An Optimization Numerical Spiking Neural Membrane System with Adaptive Multi-Mutation Operators for Brain Tumor Segmentation.

Magnetic Resonance Imaging (MRI) is an important diagnostic technique for brain tumors due to its ability to generate images without tissue damage or skull artifacts. Therefore, MRI images are widely used to achieve the segmentation of brain tumors. This paper is the first attempt to discuss the use of optimization spiking neural P systems to improve the threshold segmentation of brain tumor images. To be specific, a threshold segmentation approach based on optimization numerical spiking neural P systems with adaptive multi-mutation operators (ONSNPSamos) is proposed to segment brain tumor images. More specifically, an ONSNPSamo with a multi-mutation strategy is introduced to balance exploration and exploitation abilities. At the same time, an approach combining the ONSNPSamo and connectivity algorithms is proposed to address the brain tumor segmentation problem. Our experimental results from CEC 2017 benchmarks (basic, shifted and rotated, hybrid, and composition function optimization problems) demonstrate that the ONSNPSamo is better than or close to 12 optimization algorithms. Furthermore, case studies from BraTS 2019 show that the approach combining the ONSNPSamo and connectivity algorithms can more effectively segment brain tumor images than most algorithms involved.

Cortico-cortical evoked potentials of language tracts in minimally invasive glioma surgery guided by Penfield stimulation.

OBJECTIVE: We investigated the feasibility of recording cortico-cortical evoked potentials (CCEPs) in patients with low- and high-grade glioma. We compared CCEPs during awake and asleep surgery, as well as those stimulated from the functional Broca area and recorded from the functional Wernicke area (BtW), and vice versa (WtB). We also analyzed CCEP properties according to tumor location, histopathology, and aphasia. METHODS: We included 20 patients who underwent minimally invasive surgery in an asleep-awake-asleep setting. Strip electrode placement was guided by classical Penfield stimulation of positive language sites and fiber tracking of the arcuate fascicle. CCEPs were elicited with alternating monophasic single pulses of 1.1 Hz frequency and recorded as averaged signals. Intraoperatively, there was no post-processing of the signal. RESULTS: Ninety-seven CCEPs from 19 patients were analyzed. There was no significant difference in CCEP properties when comparing awake versus asleep, nor BtW versus WtB. CCEP amplitude and latency were affected by tumor location and histopathology. CCEP features after tumor resection correlated with short- and long-term postoperative aphasia. CONCLUSION: CCEP recordings are feasible during minimally invasive surgery. CCEPs might be surrogate markers for altered connectivity of the language tracts. SIGNIFICANCE: This study may guide the incorporation of CCEPs into intraoperative neurophysiological monitoring.

Motor or non-motor speech interference? A multimodal fMRI and direct cortical stimulation mapping study.

We retrospectively analyzed data from 15 patients, with a normal pre-operative cognitive performance, undergoing awake surgery for left fronto-temporal low-grade glioma. We combined a pre-surgical measure (fMRI maps of motor- and language-related centers) with intra-surgical measures (MNI-registered cortical sites data obtained during intra-operative direct electrical stimulation, DES, while they performed the two most common language tasks: number counting and picture naming). Selective DES effects along the precentral gyrus/inferior frontal gyrus (and/or the connected speech articulation network) were obtained. DES of the precentral gyrus evoked the motor speech arrest, i.e., anarthria (with apparent mentalis muscle movements). We calculated the number of shared voxels between the lip-tongue and overt counting related- and silent naming-related fMRI maps and the Volumes of Interest (VOIs) obtained by merging together the MNI sites at which a given speech disturbance was observed, normalized on their mean the values (i.e., Z score). Both tongue- and lips-related movements fMRI maps maximally overlapped (Z = 1.05 and Z = 0.94 for lips and tongue vs. 0.16 and -1.003 for counting and naming) with the motor speech arrest seed. DES of the inferior frontal gyrus, pars opercularis and the rolandic operculum induced speech arrest proper (without apparent mentalis muscle movements). This area maximally overlapped with overt counting-related fMRI map (Z = -0.11 and Z = 0.09 for lips and tongue vs. 0.9 and 0.0006 for counting and naming). Interestingly, our fMRI maps indicated reduced Broca's area activity during silent speech compared to overt speech. Lastly, DES of the inferior frontal gyrus, pars opercularis and triangularis evoked variations of the output, i.e., dysarthria, a motor speech disorder occurring when patients cannot control the muscles used to produce articulated sounds (phonemes). Silent object naming-related fMRI map maximally overlapped (Z = -0.93 and Z = -1.04 for lips and tongue vs. -1.07 and 0.99 for counting and naming) with this seed. Speech disturbances evoked by DES may be thought of as selective interferences with specific recruitment of left inferior frontal gyrus and precentral cortex which are differentiable in terms of the specific interference induced.

Patterning Networks of Grade IV Glioblastoma on Silicon Chip.

Glioblastoma (GBM) is the most aggressive high-grade brain cancer with a median survival time of <15 months. Due to GBMs fast and infiltrative growth patient prognosis is poor with recurrence after treatment common. Investigating GBMs ability to communicate, specifically via Ca2+ signaling, within its functional tumour networks may unlock new therapeutics to reduce the rapid infiltration and growth which currently makes treatment ineffective. This work aims to produce patterned networks of GBM cells such that the Ca2+ communication at a network level can be repeatedly and reliably investigated.

Remote neuronal activity drives glioma progression through SEMA4F.

The tumour microenvironment plays an essential role in malignancy, and neurons have emerged as a key component of the tumour microenvironment that promotes tumourigenesis across a host of cancers1,2. Recent studies on glioblastoma (GBM) highlight bidirectional signalling between tumours and neurons that propagates a vicious cycle of proliferation, synaptic integration and brain hyperactivity3-8; however, the identity of neuronal subtypes and tumour subpopulations driving this phenomenon is incompletely understood. Here we show that callosal projection neurons located in the hemisphere contralateral to primary GBM tumours promote progression and widespread infiltration. Using this platform to examine GBM infiltration, we identified an activity-dependent infiltrating population present at the leading edge of mouse and human tumours that is enriched for axon guidance genes. High-throughput, in vivo screening of these genes identified SEMA4F as a key regulator of tumourigenesis and activity-dependent progression. Furthermore, SEMA4F promotes the activity-dependent infiltrating population and propagates bidirectional signalling with neurons by remodelling tumour-adjacent synapses towards brain network hyperactivity. Collectively our studies demonstrate that subsets of neurons in locations remote to primary GBM promote malignant progression, and also show new mechanisms of glioma progression that are regulated by neuronal activity.

Early growth response 1 promoted the invasion of glioblastoma multiforme by elevating HMGB1.

BACKGROUND: Glioblastoma multiforme (GBM) is the most common and deadly glioma subtype. Early growth response 1 (EGR1) participates in the progression of several cancer types, but the expression and function of EGR1 in GBM was rarely investigated. METHODS: The expressions of EGR1 in GBM were detected with qRT-PCR and immunohistochemistry in 12 pairs of fresh GBM tissues and 116 paraffin-embedded specimens. The patients were divided into high and low EGR1 groups according to the IHC score of EGR1, and the prognostic significances of different groups were evaluated with univariate and multivariate analyses. With in-vitro experiments, we assessed the role of EGR1 in the proliferation and invasion of GBM cells. RESULTS: In our study, EGR1 was up-regulated in GBM tissues compared with tumor-adjacent normal tissues. High expression of EGR1 or HMGB1 were unfavorable prognostic biomarkers of GBM. Coexpression of EGR1 and HMGB1 could predict the prognosis of GBM more sensitively. EGR1 facilitated the proliferation and invasion of GBM cells. Moreover, EGR1 promoted the invasion, instead of proliferation, of GBM cells by elevating the expression of HMGB1. CONCLUSIONS: ERG1 was a prognostic biomarker of GBM, and ERG1 and HMGB1 synergistically could predict the GBM prognosis more precisely. ERG1 could promote GBM cell invasion by inducing HMGB1 expression.

Selective effects of a brain tumor on the metric representation of the hand: a pre- versus post-surgery comparison.

Body representation disorders are complex, varied, striking, and very disabling in most cases. Deficits of body representation have been described after lesions to multimodal and sensorimotor cortical areas. A few studies have reported the effects of tumors on the representation of the body, but little is known about the changes after tumor resection. Moreover, the impact of brain lesions on the hand size representation has been investigated in few clinical cases. Hands are of special importance, as no other body part has the ability for movement and interaction with the environment that the hands have, and we use them for a multitude of daily activities. Studies with clinical population can add further knowledge into the way hands are represented. Here, we report a single case study of a patient (AM) who was an expert bodybuilder and underwent a surgery to remove a glioblastoma in the left posterior prefrontal and precentral cortex at the level of the hand's motor region. Pre- (20 days) and post- (4 months) surgery assessment did not show any motor or cognitive impairments. A hand localization task was used, before and after surgery (12 months), to measure possible changes of the metric representation of his right hand. Results showed a post-surgery modulation of the typically distorted hand representation, with an overall accuracy improvement, especially on width dimension. These findings support the direct involvement of sensorimotor areas in the implicit representation of the body size and its relevance on defining specific size representation dimensions.

The University of Pennsylvania glioblastoma (UPenn-GBM) cohort: advanced MRI, clinical, genomics, & radiomics.

Glioblastoma is the most common aggressive adult brain tumor. Numerous studies have reported results from either private institutional data or publicly available datasets. However, current public datasets are limited in terms of: a) number of subjects, b) lack of consistent acquisition protocol, c) data quality, or d) accompanying clinical, demographic, and molecular information. Toward alleviating these limitations, we contribute the "University of Pennsylvania Glioblastoma Imaging, Genomics, and Radiomics" (UPenn-GBM) dataset, which describes the currently largest publicly available comprehensive collection of 630 patients diagnosed with de novo glioblastoma. The UPenn-GBM dataset includes (a) advanced multi-parametric magnetic resonance imaging scans acquired during routine clinical practice, at the University of Pennsylvania Health System, (b) accompanying clinical, demographic, and molecular information, (d) perfusion and diffusion derivative volumes, (e) computationally-derived and manually-revised expert annotations of tumor sub-regions, as well as (f) quantitative imaging (also known as radiomic) features corresponding to each of these regions. This collection describes our contribution towards repeatable, reproducible, and comparative quantitative studies leading to new predictive, prognostic, and diagnostic assessments.

Better detection of reduced motor functioning in brain tumor survivors based on objective motor assessments: an incentive for improved standardized follow-up.

Long-term sequelae are well-known in childhood brain tumor survivors, but motor functioning remains poorly described. This cross-sectional study aimed to assess objective motor functioning, patient-specific risk factors, and parental perceptions. Fifty-two childhood brain tumor patients (pilocytic astrocytoma, medulloblastoma, and other types) who were at least 6 months out of treatment were evaluated. Mean age at testing was 11.7 years. Objective motor functioning was assessed with the Movement Assessment Battery for Children (MABC-2-NL) and/or Bruininks-Oseretsky test of motor proficiency (BOT-2). Functional walking capacity was assessed with the 6-min walk test (6MWT). Parent-reported motor functioning was addressed using the ABILHAND-Kids, ABILOCO-Kids questionnaires, and a standardized anamnesis. Patients showed impaired motor functioning in all domains (p < 0.001). Regarding risk factors, younger age at diagnosis (< 5 year) was significantly associated with lower scores on body coordination (p = 0.006). Adjuvant treatment resulted in lower scores for fine manual control of the BOT-2 (p = 0.024) and balance of MABC-2-NL (p = 0.036). Finally, questionnaires revealed an underestimation of motor problems as perceived by the parents. In conclusion, many children who are in follow-up for a brain tumor show impaired motor functioning on multiple aspects, with younger age at diagnosis and adjuvant treatment as specific risk factors. Based on the questionnaires and anamnesis, motor problems appear to be underestimated by the parents.  Conclusion: These findings point to the need for timely prospective screening of motor functioning. Based on a screening assessment, adequate rehabilitation programs can be applied in childhood brain tumor survivors, aiming to reduce the adverse impact on their daily lives, both for functional activities and cardiovascular fitness. What is Known: • A pediatric brain tumor and its treatment are associated with potential long-term motor sequelae. • Test assessments could enable us to objectify motor functioning of these patients. What is New: • Pediatric brain tumors survivors show lower motor performance compared to the norm, which is often underestimated by parents. • Younger age at diagnosis and adjuvant treatment could be specific risk factors.

Standardized reporting of adverse events and functional status from the first 5 years of awake surgery for gliomas: a population-based single-institution consecutive series.

OBJECTIVE: To report our experience and investigate frequencies of adverse events and functional status from the first 5 years of performing awake surgery for gliomas in a single-center population-based setting. METHODS: We conducted a review of all patients with a glioma treated with awake surgery during the first 5 years following introduction of awake surgery at our center (February 2015 to February 2020). We assessed functional and radiological outcome, with adverse events classified according to the Landriel-Ibanez classification for neurosurgical complications, while neurological deficits were further subdivided into transient vs permanent. We sought to analyze our initial results and learning curve, as well as compare our results with literature. RESULTS: Forty-two patients were included. The median age was 38 years (range 18-66) and 13 (31%) were female. The indication for awake surgery was a presumed glioma in or near an eloquent area. The overall 30-day complication rate was 25 (59%), with 19 (45%) grade I complications, 3 (7%) grade II complications, and 3 (7%) grade III complications. Fifteen patients (36%) experienced transient neurological deficits, and 11 (26%) permanent neurological deficits. At 3-month follow-up, the Karnofsky Performance Score was 80 or higher for the entire cohort. The median extent of resection was 87%, with GTR achieved in 11 (26%). In search of potential learning curve difficulties, patients were divided into the 21 patients treated first (Early Group) versus the remaining 21 patients treated later (Late Group); no statistically significant difference in operating time, amount of tumor removed, or incidence of long-term postoperative neurological deficit was identified between groups. No awake surgery was aborted due to seizures. Comparison to the literature was limited by the diverse and unsystematic way in which previous studies have reported adverse events after awake craniotomy for gliomas. CONCLUSION: We provide a standardized report of adverse events and functional status following awake surgery for glioma during a single-center 5-year learning period, with similar rates of severe adverse events and functional outcome compared to literature without concerns of substantial learning curve difficulties. However, this comparison was flawed by non-standardized reporting of complications, highlighting a demand for more standardized reporting of adverse events after awake craniotomies.

Mind the gap: IgG4-related disease mimicking infectious cerebral mass lesions.

BACKGROUND: Cerebral intraparenchymal masses represent usually a neoplastic, or infectious differential diagnostic workup in neurology or infectious disease units. CASE PRESENTATION: Our patient was an 82-year-old male presenting with seizures, cerebral masses and a history of past treated pulmonary tuberculosis. Initial workup included a differential diagnosis of an infectious mass/multiple abscess. After exclusion of infectious or primary neoplastic origins by negative HIV serology, the absence of immune suppression, endocarditic lesions, negative results of blood cultures and bronchoalveolar lavage, negative cerebrospinal fluid workout on spinal tap led to exclusion of infectious causes. A surgical procedure was performed to access one of the lesions. This yielded a firm, cyst-like mass of histiocytic granulomatous tissue with a conspicuous plasmacellular component and a relevant IgG4 plasmacellular component consistent with IgG4-related disease. Steroid treatment determined conspicuous improvement and led to discharge of the patient. CONCLUSION: Parenchymal IgG4-related disease may be included as a new entity in the differential diagnosis of single or multiple cerebral masses in addition to infectious or neoplastic etiology.