Impaired creative cognition after surgery for an IDH-mutated glioma: A proof-of-concept study.

Assessment of high cognitive functions, such as creativity, is often overlooked in medical practice. However, it is crucial to understand the impact of brain tumors, specifically low-grade gliomas, on creative cognition, as these tumors predominantly affect brain regions associated with cognitive creativity. In this study, we investigated creative cognition using the Alternative Uses Task (AUT) and the Combination of Associates Task (CAT) in a cohort of 29 patients who underwent brain surgery for a low-grade glioma, along with 27 control participants. While the group of patients did not exhibit deficits in clinical neuropsychological assessments, our results revealed significant impairment in generating original and creative ideas compared to the control group. Furthermore, when analyzing the specific brain regions affected by the tumors, patients with lesions overlapping the left rostro-lateral prefrontal cortex, a critical region for creativity, displayed more pronounced impairments in the CAT compared to patients with lesions outside this region. These findings provide proof of concept that patients can experience impaired creative cognition following surgery for low-grade glioma, highlighting the importance of assessing higher-order cognitive functions, including creativity, in neurosurgical patients. Moreover, beyond its clinical relevance, our study contributes to advancing our understanding of the neuroscience of creativity.

Predictors of cognition after glioma surgery: connectotomy, structure-function phenotype, plasticity.

Determining preoperatively the maximal extent of resection that would preserve cognitive functions is the core challenge of brain tumor surgery. Over the last decade, the methodological framework to achieve this goal has been thoroughly renewed: the population-level topographically-focused voxel-based lesion-symptom mapping has been progressively overshadowed by machine learning (ML) algorithmics, in which the problem is framed as predicting cognitive outcomes in a patient-specific manner from a typically large set of variables. However, the choice of these predictors is of utmost importance, as they should be both informative and parsimonious. In this perspective, we first introduce the concept of connectotomy: instead of parametrizing resection topography through the status (intact/resected) of a huge number of voxels (or parcels) paving the whole brain in the cartesian 3D-space, the connectotomy models the resection in the connectivity space, by computing a handful number of networks disconnection indices, measuring how the structural connectivity sustaining each network of interest was hit by the resection. This connectivity-informed reduction of dimensionality is a necessary step for efficiently implementing ML tools, given the relatively small number of patient-examples in available training datasets. We further argue that two other major sources of interindividual variability must be considered to improve the accuracy with which outcomes are predicted: the underlying structure-function phenotype and neuroplasticity, for which we provide an in-depth review and propose new ways of determining relevant predictors. We finally discuss the benefits of our approach for precision surgery of glioma.

Verbal fluency predicts work resumption after awake surgery in low-grade glioma patients.

BACKGROUND: Resuming professional activity after awake surgery for diffuse low-grade glioma (DLGG) is an important goal, which is not reached in every patient. Cognitive deficits can occur and persist after surgery. In this study, we analyzed the impact of mild cognitive impairments on the work resumption. METHODS: Fifty-four surgeries (including five redo surgeries) performed between 2012 and 2020 for grade 2 (45) and 3 (nine) DLGG in 49 professionally active patients (mean age 40 [range 23-58.) were included. We retrospectively extracted the results of semantic and phonemic verbal fluency tests from preoperative and 4-month postoperative cognitive assessments. Patients were interviewed about their working life after surgery, between April and June 2021. RESULTS: Patients (85%) returned to work, most within 3 to 6 months. Patients (76%) reported subjective complaints (primarily fatigue). Self-reported symptoms and individual and clinical variables had no impact on the work resumption. Late-postoperative average Z-scores in verbal fluency tasks were significantly lower than preoperative for the entire cohort (Wilcoxon test, p < 0.001 for semantic and p = 0.008 for phonemic fluency). The decrease in Z-scores was significantly greater (Mann Whitney U-test, semantic, p = 0.018; phonemic, p = 0.004) in the group of patients who did not return to work than in the group of patients who did. CONCLUSION: The proportion of patients returning to work was comparable to similar studies. A decrease in verbal fluency tasks could predict the inability to return to work.

Multimodal study of multilevel pulvino-temporal connections: a new piece in the puzzle of lexical retrieval networks.

Advanced methods of imaging and mapping the healthy and lesioned brain allowed to identify the cortical nodes and white matter tracts supporting the dual neurofunctional organization of language networks in a dorsal phonological and a ventral semantic stream. Much less understood are the anatomical correlates of the interaction between the two streams, one hypothesis being that of a sub-cortically mediated interaction, through crossed cortico-striato-thalamo-cortical and cortico-thalamo-cortical loops. In this regard, the pulvinar is the thalamic subdivision that has most regularly appeared as implicated in the processing of lexical retrieval. However, descriptions of its connections with temporal (language) areas remain scarce. Here we assess this pulvino-temporal connectivity using a combination of state-of-the-art techniques: white matter stimulation in awake surgery and post-operative diffusion MRI (n = 4), virtual dissection from the Human Connectome Project 3 T and 7 T datasets (n = 172), and operative microscope-assisted post-mortem fiber dissection (n = 12). We demonstrate the presence of four fundamental fiber contingents: i) the anterior component (Arnold's bundle proper) initially described by Arnold in the 19th century, and destined to the anterior temporal lobe; ii) the Optic Radiations (OR)-like component, that leaves the pulvinar accompanying the optical radiations and reaches the posterior basal temporal cortices; iii) the lateral component, that crosses orthogonally the temporal stem and reaches the middle temporal gyrus; and iv) the Auditory Radiations (AR)-like component, that leaves the pulvinar accompanying the auditory radiations to the superomedial aspect of the temporal operculum, just posteriorly to Heschl's gyrus. Each of those components might correspond to a different level of information processing involved in the lexical retrieval process of picture naming.

Electrostimulation of the white matter of the posterior insula and medial operculum: perception of vibrations, heat, and pain.

ABSTRACT: This study aimed to characterize the sensory responses observed when electrically stimulating the white matter surrounding the posterior insula and medial operculum (PIMO). We reviewed patients operated on under awake conditions for a glioma located in the temporoparietal junction. Patients' perceptions were retrieved from operative reports. Stimulation points were registered in the Montreal Neurological Institute template. A total of 12 stimulation points in 8 patients were analyzed. Painful sensations in the contralateral leg were reported (5 sites in 5 patients) when stimulating the white matter close to the parcel OP2/3 of the Glasser atlas. Pain had diverse qualities: burning, tingling, crushing, or electric shock. More laterally, in the white matter of OP1, pain and heat sensations in the upper part of the body were described (5 sites in 2 patients). Intermingled with these sites, vibration sensations were also reported (3 sites in 2 patients). Based on the tractograms of 44 subjects from the Human Connectome Project data set, we built a template of the pathways linking the thalamus to OP2/3 and OP1. Pain sites were located in the thalamo-OP2/3 and thalamo-OP1 tracts. Heat sites were located in the thalamo-OP1 tract. In the 227 awake surgeries performed for a tumor located outside of the PIMO region, no patients ever reported pain or heat sensations when stimulating the white matter. Thus, we propose that the thalamo-PIMO connections constitute the main cortical inputs for nociception and thermoception and emphasize that preserving these fibers is of utmost importance to prevent the postoperative onset of a debilitating insulo-opercular pain syndrome.

Segmentation of glioblastomas in early post-operative multi-modal MRI with deep neural networks.

Extent of resection after surgery is one of the main prognostic factors for patients diagnosed with glioblastoma. To achieve this, accurate segmentation and classification of residual tumor from post-operative MR images is essential. The current standard method for estimating it is subject to high inter- and intra-rater variability, and an automated method for segmentation of residual tumor in early post-operative MRI could lead to a more accurate estimation of extent of resection. In this study, two state-of-the-art neural network architectures for pre-operative segmentation were trained for the task. The models were extensively validated on a multicenter dataset with nearly 1000 patients, from 12 hospitals in Europe and the United States. The best performance achieved was a 61% Dice score, and the best classification performance was about 80% balanced accuracy, with a demonstrated ability to generalize across hospitals. In addition, the segmentation performance of the best models was on par with human expert raters. The predicted segmentations can be used to accurately classify the patients into those with residual tumor, and those with gross total resection.

Multi-class glioma segmentation on real-world data with missing MRI sequences: comparison of three deep learning algorithms.

This study tests the generalisability of three Brain Tumor Segmentation (BraTS) challenge models using a multi-center dataset of varying image quality and incomplete MRI datasets. In this retrospective study, DeepMedic, no-new-Unet (nn-Unet), and NVIDIA-net (nv-Net) were trained and tested using manual segmentations from preoperative MRI of glioblastoma (GBM) and low-grade gliomas (LGG) from the BraTS 2021 dataset (1251 in total), in addition to 275 GBM and 205 LGG acquired clinically across 12 hospitals worldwide. Data was split into 80% training, 5% validation, and 15% internal test data. An additional external test-set of 158 GBM and 69 LGG was used to assess generalisability to other hospitals' data. All models' median Dice similarity coefficient (DSC) for both test sets were within, or higher than, previously reported human inter-rater agreement (range of 0.74-0.85). For both test sets, nn-Unet achieved the highest DSC (internal = 0.86, external = 0.93) and the lowest Hausdorff distances (10.07, 13.87 mm, respectively) for all tumor classes (p < 0.001). By applying Sparsified training, missing MRI sequences did not statistically affect the performance. nn-Unet achieves accurate segmentations in clinical settings even in the presence of incomplete MRI datasets. This facilitates future clinical adoption of automated glioma segmentation, which could help inform treatment planning and glioma monitoring.

Oncological and functional outcomes support early resection of incidental IDH-mutated glioma.

PURPOSE: The main objective was to assess the neuropsychological, epileptical, and oncological outcomes in a series of patients operated on for a IDH-mutated diffuse low-grade glioma (DLGG) of incidental discovery (iDLGG). METHODS: We retrospectively reviewed a consecutive series of surgically treated adults with DLGG and selected cases incidentally discovered. Tumor volumes, growth rates, and extents of resection (EOR) were assessed by volumetric measures of fluid-attenuated inversion recovery magnetic resonance imaging. The data on oncological, functional, and epileptical results were retrieved from the patients' digital files. RESULTS: Among all patients with DLGG resected at our center between June 2011 and April 2022, we found eleven cases with an incidental discovery. Resection was supratotal, gross total, and subtotal in 45.5%, 26.4%, and 18.1% of cases, respectively. The rate of epileptic seizures after the surgery was 9.1%. There were 45.4% of patients that had tumor progressions and the overall mean time to tumor progression was 42 months. After the surgery, 3 (27.3%) patients had mild neurocognitive deteriorations, which impeded the return to work in one patient (9.1%). There were no differences with previous series regarding clinical, radiological, and molecular characteristics. Similar results were also found for functional, surgical, epileptical, and oncological outcomes. CONCLUSION: Although the right approach for iDLGG is still a matter of debate, our data support the safety and effectiveness of early surgical resection. More studies are needed to firmly ground this early "preventive" surgery approach.

How far does electrical stimulation activate white matter tracts? A computational modeling study.

OBJECTIVE: The aim of this study was to model how the different parameters of electrical stimulation (intensity, pulse shape, probe geometry) influence the extent of white matter activation. METHODS: The electrical potentials generated by the stimulating electrodes were determined by solving Laplace equation. The temporal evolution of membrane potentials at each nodes of Ranvier of an axon was then computed by solving the coupled system of differential equations describing membrane dynamics and cable propagation. RESULTS: Regions of unilateral propagation were observed for monophasic pulses delivered with a bipolar probe aligned along the tract. For biphasic pulses, the largest activation areas and depths were found with a high inter-electrode-distance (IED) bipolar probe, oriented orthogonally to the tract. The smallest activation areas and depths were found for bipolar stimulations with the probe aligned parallel to the tract and low IED. For isotropic white matter regions, the activation area and depth were three times larger than for anisotropic white matter tracts. CONCLUSIONS: Bipolar probes with biphasic pulses offer the greatest versatility: an orthogonal orientation acts as two monopolars (increased sensitivity when searching for a tract), whereas a parallel orientation corresponds to a single monopolar (increased specificity). Activation is more superficial when stimulating highly anisotropic tracts. SIGNIFICANCE: This knowledge is essential for interpreting the behavorial effects of stimulation and the recordings of axono-cortical evoked potentials.

Oncological, cognitive, and employment outcomes in a series of patients with IDH-mutated glioma resected following neoadjuvant chemotherapy.

PURPOSE: Maximal safe tumor resection is the first line of treatment for IDH-mutated gliomas. However, when upfront surgical resection is deemed unsatisfactory due to tumor size and location, chemotherapy could represent an interesting alternative for reducing glioma extension and allowing for a safer and more efficient removal. METHODS: We performed a retrospective study (June 2011 to December 2021) on patients with IDH-mutated gliomas undergoing chemotherapy with a neoadjuvant intent, followed by surgical excision in awake conditions. MRI-imaging follow-up was conducted every 3-6 months. Neuropsychological assessments (NPSA) were performed for all patients before surgery, during post-operative period, and at later follow-up, and patients were periodically interviewed about their clinical and job status. RESULTS: We included 6 patients who underwent awake surgery after neoadjuvant chemotherapy (temozolomide in 5 cases, PCV in 1 case) for an IDH-mutated glioma (3 oligodendrogliomas and 3 astrocytomas). Median tumor volume reduction was 47%, allowing for complete resection in one patient, subtotal resection in 4 patients, and partial resection in 1 patient. No major adverse effects were observed under chemotherapy. At the 4 months NPSA, a worsening of flexibility was observed in 2 patients (verbal fluencies in one case and trail making test in the other). Three out of the four patients working full time before procedure resumed their job full time, after a 7 to 10 months delay. CONCLUSION: Neoadjuvant chemotherapy followed by maximal safe resection can be offered to patients affected by IDH-mutated gliomas for whom upfront surgery would be inadequate. More studies are necessary given the limited size of our sample.

High perilesional T2-FLAIR signal around anterior temporal perivascular spaces: How can fluid suppressed Amide Proton Transfer weighted imaging further comfort the diagnosis.

Areas of marked T2-FLAIR hyperintensity around perivascular spaces can be misdiagnosed as tumor, especially in case of lesion evolution. In this report, we show and describe increased T2-FLAIR signal intensity around anterior temporal perivascular spaces in three patients and shortly review this poorly known entity. In addition, we discuss for the first time the added value of fluid suppressed APTw imaging, an emerging noninvasive molecular technique, in the characterization of this "do not touch" abnormality.

Short-range axono-cortical evoked-potentials in brain tumor surgery: Waveform characteristics as markers of direct connectivity.

OBJECTIVE: Intraoperative measurement of axono-cortical evoked potentials (ACEP) has emerged as a promising tool for studying neural connectivity. However, it is often difficult to determine if the activity recorded by cortical grids is generated by stimulated tracts or by spurious phenomena. This study aimed to identify criteria that would indicate a direct neurophysiological connection between a recording contact and a stimulated pathway. METHODS: Electrical stimulation was applied to white matter fascicles within the resection cavity, while the evoked response was recorded at the cortical level in seven patients. RESULTS: By analyzing the ACEP recordings, we identified a main epicenter characterized by a very early positive (or negative) evoked response occurring just after the stimulation artifact (<5 ms, |Amplitude| > 100 µV) followed by an early and large negative (or positive) monophasic evoked response (<40 ms; |Amplitude| > 300 µV). The neighboring activity had a different waveform and was attenuated compared to the hot-spot activity. CONCLUSIONS: It is possible to distinguish the hotspot with direct connectivity to the stimulated site from neighboring activity using the identified criteria. SIGNIFICANCE: The electrogenesis of the ACEP at the hotspot and neighboring activity is discussed.

Natural history of spinal cord metastasis from brain glioblastomas.

BACKGROUND AND OBJECTIVES: Spinal cord metastasis arising from an intracranial glioblastoma is a rare and late event during the natural course of the disease. These pathological entities remain poorly characterized. This study aimed to identify and investigate the timeline, clinical and imaging findings, and prognostic factors of spinal cord metastasis from a glioblastoma. METHODS: Consecutive histopathological cases of spinal cord metastasis from glioblastomas in adults entered in the French nationwide database between January 2004 and 2016 were screened. RESULTS: Overall, 14 adult patients with a brain glioblastoma (median age 55.2 years) and harboring a spinal cord metastasis were included. The median overall survival as 16.0 months (range, 9.8-22.2). The median spinal cord Metastasis Free Survival (time interval between the glioblastoma diagnosis and the spinal cord metastasis diagnosis) was 13.6 months (range, 0.0-27.9). The occurrence of a spinal cord metastasis diagnosis greatly impacted neurological status: 57.2% of patients were not ambulatory, which contributed to dramatically decreased Karnofsky Performance Status (KPS) scores (12/14, 85.7% with a KPS score ≤ 70). The median overall survival following spinal cord metastasis was 3.3 months (range, 1.3-5.3). Patients with a cerebral ventricle effraction during the initial brain surgery had a shorter spinal cord Metastasis Free Survival (6.6 vs 18.3 months, p = 0.023). Out of the 14 patients, eleven (78.6%) had a brain IDH-wildtype glioblastoma. CONCLUSIONS: Spinal cord metastasis from a brain IDH-wildtype glioblastoma has a poor prognosis. Spinal MRI can be proposed during the follow-up of glioblastoma patients especially those who have benefited from cerebral surgical resection with opening of the cerebral ventricles.

Opposed evolution of the osseous and soft parts of progestin-associated osteomeningioma after progestin intake discontinuation.

OBJECTIVE: Numerous studies have confirmed a strong association between progestins and meningiomas and the regression and/or stabilization of meningiomas after discontinuation of treatment. Osteomeningiomas represent a small subgroup of meningiomas that appear to be more common among progestin-related meningiomas. However, the specificity of the behavior of this subset of meningiomas after discontinuation of progestin has not yet been assessed. METHODS: Thirty-six patients (mean age 49.5 years) who presented with at least one progestin-related osteomeningioma (48 tumors total) were identified from a prospectively collected database of patients and had been referred to our department for meningioma and had documented use of cyproterone acetate, nomegestrol acetate, and/or chlormadinone acetate. Hormonal treatment was stopped at the time of diagnosis for all the patients, and the clinical and radiological evolution of this subgroup of tumors was evaluated. RESULTS: For half of the 36 patients, treatment was prescribed for signs of hyperandrogenism, such as hirsutism, alopecia, or acne. Most lesions were spheno-orbital (35.4%) or frontal (31.2%). Although the tissular part of the meningioma shrank in 77.1% of cases, the osseous part exhibited discordant behavior with 81.3% showing volume progression. The combination of estrogens, as well as the prolonged duration of progestin treatment, seems to increase the risk of progression of the osseous part after treatment discontinuation (p = 0.02 and p = 0.028, respectively). No patient required surgical treatment at diagnosis or during the study. CONCLUSIONS: These results show that while the soft intracranial part of progestin-related osteomeningioma tumor is the most likely to regress after treatment discontinuation, the bony part is more likely to increase in volume. These findings suggest the need for careful follow-up of these patients, especially those with tumors near the optical apparatus.