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The functional roles of the precuneus are unclear. Focal precuneus lesions are rare, making it difficult to identify robust brain–behavior relationships. Distinct functional subdivisions of the precuneus have been proposed based on unique connectivity profiles. This includes an association of the anterior division with bodily awareness, the central region with complex cognition, and the posterior division with visual processing. Our goal was to test the hypothesis that the central precuneus is preferentially involved (compared to the other sectors of the precuneus) in executive function, as estimated from performance on the trail-making test (TMT). 35 patients with focal brain lesions involving the precuneus were included from the University of Iowa and Montpellier University. Multivariate lesion symptom mapping of TMT performance was performed to evaluate whether lesion location was associated with impaired task performance. Lesion symptom mapping revealed a statistically significant association of central precuneus lesions with impaired TMT performance (r = 0.43, p < 0.01). Further, a functional network derived from this precuneus region showed connectivity to other cortical areas implicated in executive function, including the dorsolateral prefrontal cortex and inferior parietal lobe. This analysis provides support for the role of the central precuneus in executive function, consistent with the unique connectivity pattern of the central precuneus with a broader network implicated in cognitive control and executive function.

International audience; Executive functions (EF) may be significantly impaired following low-grade glioma (LGG) surgery, especially in the event of white matter (WM) disruption. The aim of this study was to identify the connective tracts associated with EF impairments after LGG surgery, and to provide new insights into the WM network architecture of EF. EF measurements were collected in 270 patients at the chronic postoperative phase. This comprised cognitive flexibility, verbal inhibition and fluency abilities (phonological and categorical). The scores were z-corrected for age and educational level, and further submitted to a principal component analysis (PCA). Tracwise and disconnectome-behavior analyses were then performed using EF measures independently but also the extracted components from PCA. For the first analyses, 15 tracts of interest were selected. Two principal components were extracted from the behavioral data, interpreted as 'EF' and 'language' components. Robust, bonferroni-corrected correlations were established between the EF component and Layers II and III of the left superior longitudinal fasciculus, and between phonological fluency/inhibition and the same tracts. Less powerful but still significant correlations were also observed with the left frontal aslant and fronto-striatal tracts. These results were confirmed by disconnectome-behavior analyses. Our results indicate that surgically-related disruption of the fronto-parietal and the frontal cortico-subcortical connectivity, and of the frontal aslant tract, is related to long-lasting EF impairments. In addition to providing new insights into the WM pathways supporting EF, these findings are especially useful for both surgical planning and the predictive approach of neuropsychological disorders in the context of LGG surgery.

International audience; Τhe middle longitudinal fasciculus (MdLF) was initially identified in humans as a discrete subcortical pathway connecting the superior temporal gyrus (STG) to the angular gyrus (AG). Further anatomo-imaging studies, however, proposed more sophisticated but conflicting connectivity patterns and have created a vague perception on its functional anatomy. Our aim was, therefore, to investigate the ambiguous structural architecture of this tract through focused cadaveric dissections augmented by a tailored DTI protocol in healthy participants from the Human Connectome dataset. Three segments and connectivity patterns were consistently recorded: the MdLF-I, connecting the dorsolateral Temporal Pole (TP) and STG to the Superior Parietal Lobule/Precuneus, through the Heschl's gyrus; the MdLF-II, connecting the dorsolateral TP and the STG with the Parieto-occipital area through the posterior transverse gyri and the MdLF-III connecting the most anterior part of the TP to the posterior border of the occipital lobe through the AG. The lack of an established termination pattern to the AG and the fact that no significant leftward asymmetry is disclosed tend to shift the paradigm away from language function. Conversely, the theory of "where" and "what" auditory pathways, the essential relationship of the MdLF with the auditory cortex and the functional role of the cortical areas implicated in its connectivity tend to shift the paradigm towards auditory function. Allegedly, the MdLF-I and MdLF-II segments could underpin the perception of auditory representations; whereas, the MdLF-III could potentially subserve the integration of auditory and visual information.

International audience; Few studies addressed the evolution of brain activity before and after brain tumor resection. Using a fMRI naming task, we evaluated possible underlying plasticity phenomena. Thirty-two patients with left low-grade gliomas (16 women; age = 38.6 ± 8.31 years) and 19 healthy controls (7 women; age = 42.4 ± 12.1) were included in the study. An overt picture-naming task (DO80) was performed pre and post (3 months) surgery, as well as within the MRI in a covert manner. Exams included an injected 3DT1, a T2FLAIR, a DTI and a GE-EPI (task) sequence. Activations maps were compared with picture naming score, FA and MD maps were estimated, a VLSM analysis was performed on tumor masks, and disconnectome maps were reconstructed. Pre-surgery, the left parahippocampal gyrus (LPH) was inversely associated with task performance. Increased pre-post surgery left lingual gyrus (LLG) activity was found related to decreased picture naming performance. The evolution of left lingual gyrus (LLG) activity was negatively associated with the evolution of picture naming performance. In controls, the LPH was functionally connected to the right precentral gyrus (RPCG) and slightly to the LLG. This was not clearly retrieved in the patient group. Preoperatively, the LLG was connected to the left planum temporale and to the right lingual gyrus. The same result was found for controls. Postoperatively, the LLG was only connected to the RPCG. No association was found between evolution of FA/MD and evolution of picture naming performance. There is not one unique pattern of pre- and postoperative plasticity concerning picture-naming performance in DLGG patients.

International audience; The surgical resection of insular gliomas remains a challenge. Middle cerebral artery perforating arteries and deep functional pathways affect the extent of resection and the rate of post-operative morbidity. The authors performed a systematic review and meta-analysis of the literature examining early and permanent post-operative deficits in patients who underwent resection of insular gliomas using awake craniotomy with direct electrical stimulation (DES) versus surgery under general anesthesia. A systematic search of three databases was performed for studies published between 1990 and 2018. Random-effect meta-analysis was used to pool the rate of early and permanent post-operative deficits. Random-effect meta-regression was used to examine the association between the rate of post-operative deficit and the anesthesia protocol. We included eight studies evaluating 227 patients with insular glioma. The rate of permanent sequelae was lower after awake craniotomy with DES (3.5% vs 15.7%; P = .001), and early deficits were lower after surgery under general anesthesia (27.3% vs 47.7%; P = .04). Awake surgery was significantly more common among patients with tumor located within the dominant hemisphere (P < .001). No significant association arose between the rates of post-operative deficits and the use of intraoperative neuronavigation and the neurophysiological monitoring. Furthermore, neither extent of resection nor tumor histology influenced the onset of permanent sequelae. Awake craniotomy with DES is associated with a significantly lower rate of permanent neurological morbidity after an early increase of transient post-operative deficits. These data support the use of awake mapping in insular glioma resection.

Background Glioblastoma is the most frequent primary malignant brain tumor. In daily practice and at whole country level, oncological care management for glioblastoma patients is not completely known. Objectives To describe oncological patterns of care, prognostic factors, and survival for all patients in France with newly-diagnosed and histologically confirmed glioblastoma, and evaluate the impact of extended temozolomide use at the population level. Methods Nationwide population-based cohort study including all patients with newly-diagnosed and histologically confirmed glioblastoma in France in 2008 and followed until 2015. Results Data from 2053 glioblastoma patients were analyzed (male/female ratio 1.5, median age 64 years). Median overall survival (OS) was 11.2 [95% confidence interval (CI) 10.7–11.9] months. The first-line therapy and corresponding median survival (MS, in months) were: 13% did not receive any oncological treatment (biopsy only) (MS = 1.8, 95% CI 1.6–2.1), 27% received treatment without the combination of radiotherapy (RT)–temozolomide (MS = 5.9, 95% CI 5.5–6.6), 60% received treatment including the initiation of the concomitant phase of RT–temozolomide (MS = 16.4, 95% CI 15.2–17.4) whom 44% of patients initiated the temozolomide adjuvant phase (MS = 18.9, 95% CI 18.0–19.8). Only 22% patients received 6 cycles or more of adjuvant temozolomide (MS = 25.5, 95% CI 24.0–28.3). The multivariate analysis showed that the risk of mortality was significantly higher for the non-progressive patients who stopped at 6 cycles (standard protocol) than those who continued the treatment, hazard ratio = 1.5 (95% CI 1.2–1.9). Conclusion In non-progressive patients, prolonging the adjuvant temozolomide beyond 6 cycles may improve OS. Electronic supplementary material The online version of this article (10.1007/s11060-018-03065-z) contains supplementary material, which is available to authorized users.

International audience; INTRODUCTION:Brain mapping through a direct cortical and subcortical electrical stimulation during an awake craniotomy has gained an increasing popularity as a powerful tool to prevent neurological deficit while increasing extent of resection of hemispheric diffuse low-grade gliomas in adults. However, few case reports or very limited series of awake surgery in children are currently available in the literature.METHODS:In this paper, we review the oncological and functional differences between pediatric and adult populations, and the methodological specificities that may limit the use of awake mapping in pediatric low-grade glioma surgery.RESULTS:This could be explained by the fact that pediatric low-grade gliomas have a different epidemiology and biologic behavior in comparison to adults, with pilocytic astrocytomas (WHO grade I glioma) as the most frequent histotype, and with WHO grade II gliomas less prone to anaplastic transformation than their adult counterparts. In addition, aside from the issue of poor collaboration of younger children under 10 years of age, some anatomical and functional peculiarities of children developing brain (cortical and subcortical myelination, maturation of neural networks and of specialized cortical areas) can influence direct electrical stimulation methodology and sensitivity, limiting its use in children.CONCLUSIONS:Therefore, even though awake procedure with cortical and axonal stimulation mapping can be adapted in a specific subgroup of children with a diffuse glioma from the age of 10 years, only few pediatric patients are nonetheless candidates for awake brain surgery.

International audience; Although a large amount of data supports early surgical resection for symptomatic diffuse low-grade glioma, the therapeutic strategy is still a matter of debate regarding incidentally discovered diffuse low-grade glioma. Indeed, early and "preventive" surgery has recently been proposed in asymptomatic patients with silent diffuse low-grade glioma with better outcomes. The present review discusses the importance of an early diagnosis and of a preventive surgical treatment to improve the outcomes of incidental diffuse low-grade glioma and suggests the possible relevance of a tailored screening policy.

At present, direct electrical stimulation (DES) is the only technique that allows directin vivomapping of white matter tracts in humans. In this Review, Hugues Duffau discusses the insights into functional connectivity that have been gained from DES during awake surgery for brain lesions. In addition, the author considers the clinical implications of a paradigmatic shift from a localizationist model to a hodotopical model of cerebral processing. Despite advances in the new science of connectomics, which aims to comprehensively map neural connections at both structural and functional levels, techniques to directly study the function of white matter tracts in vivo in humans have proved elusive. Direct electrical stimulation (DES) mapping of the subcortical fibres offers a unique opportunity to investigate the functional connectivity of the brain. This original method permits real-time anatomo-functional correlations, especially with regard to neural pathways, in awake patients undergoing brain surgery. In this article, the goal is to review new insights, gained from axonal DES, into the functional connectivity underlying the sensorimotor, visuospatial, language and sociocognitive systems. Interactions between these neural networks and multimodal systems, such as working memory, attention, executive functions and consciousness, can also be investigated by axonal stimulation. In this networking model of conation and cognition, brain processing is not conceived as the sum of several subfunctions, but results from the integration and potentiation of parallel—though partially overlapping—subnetworks. This hodotopical account, supported by axonal DES, improves our understanding of neuroplasticity and its limitations. The clinical implications of this paradigmatic shift from localizationism to hodotopy, in the context of brain surgery, neurology, neurorehabilitation and psychiatry, are discussed.

International audience; Low-grade gliomas (GII) inescapably progress to high-grade gliomas (GIII). The duration of this transition is highly variable between patients and reliable predictive markers do not exist. We noticed in a subset of cases of GII, obtained by awake neurosurgery, the presence of microfoci with high cellular density, high vascular density, or minimal endothelial proliferation, which we called GII+. Our aim was to investigate whether these foci display immunohistochemical and molecular characteristics similar to GIII and whether their presence is correlated to poor prognosis. We analyzed cell proliferation, hypoxia, vascularization, and alterations of tumorigenic pathways by immunohistochemistry (Ki-67, CD31, HIF-1-alpha, EGFR, P-AKT, P53, MDM2) and fluorescence in situ hybridization (EGFR, MDM2, PDGFRA) in the hypercellular foci of 16 GII+ cases. We compared overall survival between GII, GII+, and GIII. Ki-67, and CD31 expression was higher in the foci than in the tumor background in all cases. Aberrant expression of protein markers and genomic aberrations were also observed in some foci, distinct from the tumor background. Survival was shorter in GII+ than in GII cases. Our results suggest that these foci are the early histological hallmark of anaplastic transformation, which is supported by molecular aberrations. Our study is the first to demonstrate intratumoral morphological, immunohistochemical, and molecular heterogeneity in resection specimens of GII, the presence of which is correlated to shorter survival. Our findings question the discriminative capacity of the current glioma classification and provide arguments in favor of the creation of a grade intermediate between GII and GIII, to optimize the treatment strategy of GII.

Diffuse WHO grade II and III gliomas (DGII/IIIG) are rare tumors, with few specific epidemiological studies. We aimed at describing the geographical distribution of a homogeneous series of histologically confirmed DGII/IIIG, over a four-year period (2006-2009), at a national level. The methodology is based on a multidisciplinary national network already established by the French Brain Tumor DataBase and data collected directly from every neuropathology department. Personal home addresses were collected for confirmed cases. For each region, the incidence of DGII/IIIG was analyzed and standardized on the age and sex distribution of the French population. The number of patients with newly diagnosed, histologically confirmed DGII/IIIG was 4,790. The overall crude rate was 19.4/10(6). To enable international comparisons, standardized rates were calculated as follows: 19.8/10(6), 18.8/10(6) and 16.0/10(6) (reference population, Europe, US and world, respectively). The geographical distribution by region showed significant differences, with higher incidence rates in Northeast and central parts of France. This work is the first studying the geographical distribution of a pure series of DGII/IIIG at a national level. It demonstrates significant heterogeneity in the distribution, and raises the question of the role of environmental and/or genetic risk(s) factor(s) for DGII/IIIG.

International audience; Despite a better understanding of their anatomy, the functional role of frontal pathways, i.e., the fronto-striatal tract (FST) and frontal aslant tract (FAT), remains obscure. We studied 19 patients who underwent awake surgery for a frontal glioma (14 left, 5 right) by performing intraoperative electrical mapping of both fascicles during motor and language tasks. Furthermore, we evaluated the relationship between these tracts and the eventual onset of transient postoperative disorders. We also performed post-surgical tract-specific measurements on probabilistic tractography. All patients but one experienced intraoperative inhibition of movement and/or speech during subcortical electrostimulation. On postoperative tractography, the subcortical distribution of stimulated sites corresponded to the spatial course of the FST and/or FAT. Furthermore, we found a significant correlation between postoperative worsening and distances between these tracts and resection cavity. A resection close to the (right or left) FST was correlated with transitory motor initiation disorders (p = 0.026), while a resection close to the left FAT was associated with transient speech initiation disorders (p = 0.003). Moreover, the measurements of average distances between resection cavity and left FAT showed a positive correlation with verbal fluency in both semantic (p = 0.019) and phonemic scores (p = 0.017), while average distances between surgical cavity and left FST showed a positive correlation with verbal fluency scores in both semantic (p = 0.0003) and phonemic modalities (p = 0.037). We suggest that FST and FAT would cooperatively play a role in self-initiated movement and speech, as a part of "negative motor network" involving the pre-supplementary motor area, left inferior frontal gyrus and caudate nucleus.

Our understanding of brain movement control has changed over the last two decades. Recent findings in the monkey and in humans have led to a parallel and interconnected network. Nevertheless, little is known about these networks. Here, we present two cases of patients with a parietal low-grade glioma. They underwent surgery under local anesthesia with cortical and subcortical mapping. For patient 1, subcortical electrostimulation immediately posterior to thalamocortical fibers induced movement disorders, with an inhibition of leg and arm movements medially and, more laterally, an acceleration of arm movement. For patient 2, electrostimulation of white matter immediately posterior to thalamocortical fibers induced an inhibition of both arm movement. It means that the detected fibers in the parietal lobe may be involved in the motor control modulation. They are distributed veil-like immediately posterior to thalamocortical pathways and could correspond to a fronto-parietal movement control subnetwork. These two cases highlight the major role of the subcortical connectivity in movement regulation, involving parietal lobe, thus the necessity to be identified and preserved during brain surgery.

The incidence of glioblastoma (GBM) has increased in patients aged 70 years or older, and will continue to grow. Elderly GBM patients have been excluded from most clinical trials; furthermore, optimal care management as well as benefit/risk ratio of GBM treatments are still being debated. This study describes oncological patterns of care, prognostic factors, and survival for patients ≥70 years in France. We identified patients over 70 with newly diagnosed and histologically confirmed GBM on data previously published by the French Brain Tumor DataBase. We included 265 patients. Neurological deficits and mental status disorders were the most frequent symptoms. The surgery consisted of resection (RS n = 95) or biopsy (B n = 170); 98 patients did not have subsequent oncological treatment. After surgery, first-line treatment consisted of radiotherapy (RT n = 76), chemotherapy (CT n = 52), and concomitant radiochemotherapy (CRC n = 39). The median age at diagnosis was 76, 74, and 73 years, respectively, for the untreated, B + RT and/or CT, RS ± RT and/or CT groups. Median survival (in days, 95 % CI) with these main strategies, when analyzed according to surgical groups, was: B-CT n = 41, 199[155–280]; B-CRC n = 21, 318[166–480]; B-RT n = 37, 149[130–214]; RS-CT n = 11, 245[211–na]; RS-CRC n = 18, 372[349–593]; RS-RT n = 39, 269[218–343]. This population study for elderly GBM patients is one of the most important in Europe, and could be considered as a historical cohort to compare future treatments. Moreover, we can hypothesize that elderly patients (versus patients

Left-handers have a more bilateral language representation than right-handers. Therefore, in left-handers with a low-grade glioma (LGG) in the left hemisphere (LH), one could hypothesize that the right hemisphere (RH) might allow language compensation, at least partly, with no or only a minor persistent role of the LH in speech. However, although LGG induces language reorganization in right-handed patients, little is known in left-handers. Here, we report the first series of left-handers who underwent awake surgery for a left LGG using intraoperative mapping, in order to investigate whether there was still an involvement of LH in language. Ten consecutive left-handed patients were operated for a left LGG (three frontal, four paralimbic, one parietal, one temporal, one parieto-temporal tumor) using an awake procedure with intraoperative electrical language mapping. Intraoperative language disorders were elicited in all cases but one by electrostimulation in the LH. Cortical language sites were detected in nine cases. Subcortical stimulation also demonstrated the crucial role of left white matter pathways in language, including the inferior occipital-frontal fascicle, arcuate fascicle, lateral segment of the superior longitudinal fascicle and fibers from the ventral premotor cortex. Moreover, stimulation of deep gray nuclei generated language disturbances in four patients. These nine patients experienced transient postoperative language worsening, supporting the persistent critical role of LH in speech. In only one patient, no language deficit was evoked intraoperatively and postoperatively. The ten patients returned to a normal life. Total or subtotal resection was achieved in all cases but one. Our results suggest that, even though the RH may participate in language compensation, the LH in left-handers still plays a crucial role, despite a left slow-growing LGG. Thus, we propose to routinely consider awake surgery for left LGG removal in left-handers patients, to optimize the extent of resection while preserving language.

The association of diffuse, low-grade glioma (DLGG) with other intracranial pathologies is a rare condition, raising the question of what constitutes its most effective therapeutic management. It is not known whether this is a simple coincidence or whether there is a higher significant risk involved with the co-existence of DLGG and another disease. We report the first consecutive series of nine patients who underwent surgical resection for such a glioma. We reviewed DLGGs removed between 1998 and 2013 that were associated with another intracranial pathology. For all cases, we collected and analyzed information regarding clinico-radiological features, surgical procedures, and clinical outcomes. Nine consecutive patients (four men, five women, mean age: 38.8 years) presented with a conjunction of DLGG and another disease: two cases of vestibular schwannoma, two pituitary adenomas, two meningiomas, one lymphoma, one arteriovenous malformation, and one case of multiple sclerosis. The DLGG was diagnosed because of seizures in four patients and incidentally in the other five patients. The average delay between the diagnosis of the glioma and its resection was 40.8 months (range 1–84 months). The mean follow-up after surgery was 43 months (6–120 months). Gross-total or subtotal resection was achieved in all cases. There were no cases of mortality or permanent morbidity associated with surgery. The Karnofsky Performance Scale score was 90 or 100 in all cases. The associated pathology was treated surgically in three cases, medically in four cases, and tracked under observation in two cases. These intracranial diseases, especially meningiomas and pituitary adenomas, might have a significant higher risk to be associated with DLGGs in comparison with their incidence and prevalence in the general population. Active management of this rare, dual pathology allows patients to enjoy a normal and prolonged quality of life. We therefore suggest considering early and maximal surgical resection as the first therapeutic option for DLGGs combined with another intracranial disease, as is done in the case of isolated DLGGs.

Gross total removal of glioma is limited by proximity to eloquent brain. Awake surgery allows for intraoperative monitoring to safely identify eloquent regions. However, data on adverse psychological effects induced in these patients is limited.This study explored patients' perception of awake surgery for glioma, with special focus on intraoperative pain and anxiety.This study was conducted at five neurosurgical centers within the European Low Grade Glioma Network. Patients underwent awake surgery for glioma according to the protocol of the individual center. Pain and discomfort were measured during the awake phase. Postoperatively, patients answered a questionnaire on aspects of their operation.One hundred five patients were enrolled. Pain levels on a 10-cm visual analogue scale were 1.3 cm at the beginning, 1.9 cm the middle, and 2.1 cm at the end of awake phase. Levels of anxiety were 2.2 cm, 2.5 cm and 2.6 cm, respectively. Women and patients younger than 60 years exhibited highest mean anxiety levels. The patient questionnaire revealed that the majority of patients feel comfortable with the procedure. Discomfort resulted from head fixation or positioning on the operating table.We demonstrate that awake surgery is well tolerated, as neither intraoperative nor postoperative assessment revealed major disadvantages. Concerning practical lessons learned from this study, we emphasize the importance of minimizing pain and preparing patients thoroughly to reduce anxiety and maximize cooperation. Awake surgery is an excellent treatment modality for brain tumors with very positive perception by patients.

The involvement of eloquent brain areas may preclude the total/subtotal surgical resection of diffuse low-grade gliomas (DLGGs). The feasibility and functional tolerance of neoadjuvant chemotherapy have been demonstrated in such cases. The present study assesses the clinical and radiological impact of neoadjuvant chemotherapy on the natural course of DLGG. Seventeen patients without feasible surgical resection (infiltration of functional areas and/or large contralateral extension) were retrospectively selected. Temozolomide based neoadjuvant chemotherapy was initiated, inducing a tumor volume decrease and allowing a functional based maximal surgical resection. The median follow-up since initial radiological diagnosis was 5.9 years (range, 1.4–11). The median time to malignant transformation was 5.9 years. Six patients (35 %) had 1p19q codeletion, 12 patients (70 %) with IDH mutation and MGMT promoter methylation, and eight patients (47 %) had p53 overexpression. Chemotherapy reduced tumor volume (median −35.6 %, range −61.6 to −5.1 %) in contralateral hemisphere through the corpus callosum in seven cases (41 %) and in ipsi-lesional functional areas in ten cases (59 %). Chemotherapy significantly decreased the imaging tumor growth (measured by the velocity of diametric expansion VDE) with a median of −3.2 mm/year (range, −29.8 to −0.9 mm/year) (p < 0.001). A tumor volume decrease of more than 20 % was correlated with a lower postoperative residual tumor (median 2 cc, p = 0.04), a greater extent of resection (93.1 vs. 89.5 %), a higher probability of total/subtotal removal. Neoadjuvant chemotherapy with Temozolomide could optimize the surgical resection of DLGGs and could impact their natural history. Further large prospective studies with long-term follow-up are needed.

WHO grade II glioma, i.e. diffuse low-grade glioma, is a pre-malignant tumour, usually revealed by seizures in young patients with a normal life. This tumour has a constant growth, and will inescapably become anaplastic. Surgical resection significantly increases the overall survival by delaying the malignant transformation. Thus, the dilemma is to perform early surgery in order to optimise the extent of resection (and thus the median survival) by removing smaller tumours while preserving the quality of life. To this end, the new concept proposed in this review is to achieve surgical resection according to functional and not to oncological boundaries. In other words, the principle is to first understand the cerebral anatomo-functional organisation at the individual level (because of a major inter-individual variability), with the aim of resecting a part of the brain invaded by a diffuse chronic disease, on the condition nonetheless that this part of the brain can be functionally compensated-i.e. with no consequences on the quality of life. To this end, in addition to the preoperative functional neuroimaging and the intraoperative electrical cortical mapping in awake patients, it is also crucial to map both horizontal cortico-cortical connectivity (long-distance association fibres) as well as vertical cortico-subcortical connectivity (projection fibres), with the aim to preserve the networks underlying the minimal common core of the brain. Interestingly, this "hodotopical" workframe, based on the study of both cortical epicentres and subcortical pathways, opens the door to mechanisms of functional reshaping. These recent technical and conceptual advances in the hodotopical and plastic view of brain processing have allowed a dramatic improvement of the benefit-to-risk ratio of surgery, concerning both oncological and functional outcomes. In summary, it is time to move towards "functional neurooncology" and "preventive neurosurgery" in low-grade gliomas. Stronger interactions with fundamental neurosciences should be developed, in order (1) to build updated models of cognition and brain plasticity; (2) to elaborate biomathematical models of low-grade glioma growth and migration; (3) to study in silico the dynamic interactions between the natural course of this disease and the adaptative behaviour of its host (the brain), with the goal to adapt the best individualised therapeutic strategy.

Awake surgery with intraoperative brain mapping is highly recommended for patients with diffuse low-grade gliomas in language areas, to maximise the extent of resection while preserving the integrity of functional networks and thus quality of life. The picture-naming test "DO.80" is the gold standard for language assessment before, during, and after surgery. Cognitive functioning is correlated with quality of life, itself linked with return to work. Our objective was to evaluate the significance of measuring naming speed, and its correlation with the return to professional activities. Two complementary studies are reported. In the first retrospective study, eleven patients were examined post-operatively. Five patients were selected because they were not able to resume their professional activities ("no return group 1"). They were compared with a control group of six patients who are working normally after surgery ("return group 1"). The eleven patients performed a global language and neuropsychological assessment, with a post-operative median follow-up of 35 months. In a subsequent prospective study, twelve patients were examined pre-operatively and post-operatively. Six patients who were not able to return to work ("no return group 2") were compared with a control group of six patients who were working normally after the surgery ("return group 2"). The twelve patients performed a pre and post-operative language assessment, with a median follow-up of 9 months. Our results show, for the first time, that naming speed is significantly correlated with a major criterion of quality of life: the return to professional activities. There were no differences between the two groups regarding other measures of cognition. Assessing naming times, and not only naming accuracy, is essential in the management of low-grade glioma patients, before, during, and after surgery, to preserve their quality of life by resuming their previous professional activity. Our results have fundamental implications concerning the comprehension of language processing and its relationship with cognitive functioning.

WHO grade II glioma (G2G) is a pre-malignant tumor, usually revealed by seizures in young patients living normal lives. G2G grows constantly and will inevitably become anaplastic. Surgical resection significantly increases the overall survival by delaying malignant transformation. Recently, a similar natural history was demonstrated in a patient with incidental G2G, with continuous growth and risk of anaplasia. Here, the aim was to study for the first time the functional results and extent of resection in a prospective series of patients who underwent resection for incidental G2G within eloquent areas.G2G involving functional regions in the left dominant hemisphere was incidentally diagnosed in 11 asymptomatic patients. Resection was achieved in all cases after demonstration of a volumetric increase on serial MRIs. Intraoperative awake mapping was performed in the 11 patients.There were no cases of mortality or permanent postoperative deficit. A subtotal, total or even "supratotal" resection was achieved in the 11 cases, with no partial resections. All patients resumed normal social and professional lives, with no seizures (KPS 100). Due to slow tumor re-growth in three patients with subtotal resection, adjuvant chemotherapy was administrated in two cases and radiotherapy in one. With a mean follow-up of 40 months since surgery, there was no anaplastic transformation.These results show that surgery can be considered in incidental G2G, even in critical areas, with a minimal risk and optimal resection, thanks to intraoperative mapping. Such findings raise the question of an early detection.

As the natural course of WHO grade II glioma (G2G) during their initial silent period is unknown, the G2G genesis and their "date of birth" are a matter of debate. Here, a left temporo-insular G2G was discovered incidentally in a 31-year-old man in 2009 (MRI performed for a Chiari malformation). The mean tumor diameter increased from 29 (April 2009) to 31 mm (October 2009) before surgery. Since we recently demonstrated that the growth rate is constant during the initial silent period in G2G, the extrapolation backward in time leads to date the glioma birth in 2002. This observation is in agreement with an MRI performed in 1997, where no signal abnormality was detected. To our knowledge, this is the first report demonstrating that the tumorigenesis of a G2G occurs during the young adult period. In addition, estimation of the date of birth may serve as a reproducible "starting point" when analyzing survivals in series of G2G.

While the fundamental and clinical contribution of direct electrical stimulation (DES) of the brain is now well acknowledged, its advantages and limitations have not been re-evaluated for a long time.Here, we critically review exactly what DES can tell us about cerebral function.First, we show that DES is highly sensitive for detecting the cortical and axonal eloquent structures. Moreover, DES also provides a unique opportunity to study brain connectivity, since each area responsive to stimulation is in fact an input gate into a large-scale network rather than an isolated discrete functional site. DES, however, also has a limitation: its specificity is suboptimal. Indeed, DES may lead to interpretations that a structure is crucial because of the induction of a transient functional response when stimulated, whereas (1) this effect is caused by the backward spreading of the electro-stimulation along the network to an essential area and/or (2) the stimulated region can be functionally compensated owing to long-term brain plasticity mechanisms.In brief, although DES is still the gold standard for brain mapping, its combination with new methods such as perioperative neurofunctional imaging and biomathematical modeling is now mandatory, in order to clearly differentiate those networks that are actually indispensable to function from those that can be compensated.

Multicentric WHO grade II gliomas constitute a rare entity. Their pathogenesis and treatment are still a matter of debate. We present a 23 year-old female with two synchronous but separate WHO grade II oligodendrogliomas in the temporal and frontal lobes. The two lesions showed independent evolution, requiring surgical treatment at different stages. For a recurrence of the disease at the frontal site, a temozolomide chemotherapy regimen was commenced with a favourable response. After 7 years follow-up, the patient is free of neurological symptoms and enjoys a normal life. The problems concerning the pathophysiology, diagnosis and treatment of this condition are discussed. On the basis of our results, we suggest that an active therapeutic strategy, by combining multiple surgical procedures and complementary treatment, should be systematically considered in multicentric WHO grade II gliomas, as in similar unifocal neoplasms.

Despite a better understanding of the anatomy of the uncinate fasciculus (UF), its function remains poorly known. Our aim was to study the exact role of UF in language, and the possible existence of parallel distributed language networks within the “ventral stream”, underlaid by distinct subcortical tracts – namely the inferior occipito-temporal fasciculus (IOF) and UF. We report a series of 13 patients operated on awake for a glioma involving the left anterior temporal lobe or the orbitofrontal area. We used intraoperative electrostimulation, to perform accurate and reliable anatomofunctional correlations both at cortical and subcortical levels. Using postoperative MRI, we correlated these functional findings with the anatomical locations of the sites where language disturbances were elicited by stimulation. Intraoperative cortical stimulation found perilesional language sites in all cases. Subcortically, semantic paraphasia were induced in the 13 patients by stimulating the IOF, and phonological paraphasia were generated in 6 patients by stimulating the arcuate fasciculus. Interestingly, subcortical stimulation never elicited any language disturbances when performed at the level of the UF. Moreover, after a transient postoperative language deficit, all patients recovered, despite the removal of at least one part of the UF, as confirmed by control MRI. We suggest that UF is not systematically essential for language. It can be explained by the fact that the “semantic ventral stream” might be constituted by at least two parallel pathways, i. e. a direct pathway underlaid by the IOF, crucial for language semantics, and an indirect pathway subserved by UF, which can be functionally compensated. However, we have to underline the fact not all language functions can be probed during surgery, and that more sensitive tasks have now to be added.

We report on a young woman operated for a ganglioglioma involving the right auditory cortex (AC), presenting with auditory seizures. Despite a normal pre-operative examination, a specific post-operative disorder affecting the perception of a human voice occurred. The patient was unable to recognise the tone of familiar voices while she recognised the expressed content. A temporal lobectomy for recurrence was performed two years later. The patient recovered from the voice perception deficit. This report shows that (1) a discrete site within the AC is specifically involved in the perception of tone of the human voice (2) functional compensation is possible.

The advent of magnetic resonance imaging (MRI) has allowed the follow-up of tumor growth by precise volumetric measurements. Such information about tumor dynamics is, however, usually not fully integrated in the therapeutic management, and the assessment of tumor evolution is still limited to qualitative description. In parallel, computational models have been developed to simulate in silico tumor growth and treatment efficacy. Nevertheless, direct clinical interest of these models remains questionable, and there is a gap between scientific advances and clinical practice. In this paper, WHO grade II glioma will serve as a paradigmatic example to illustrate that computational models allow characterizing tumor dynamics from serial MRIs. The role of these dynamics for both therapeutic management and biological research will be discussed.

The aim of the study was to investigate the ability of (1)HMRS to reflect proliferative activity of diffuse low-grade gliomas (WHO grade II). Between November 2002 and March 2007, a prospective study was performed on consecutive patients with suspected supratentorial hemispheric diffuse low-grade tumors. All the patients underwent MR examination using uniform procedures, and then surgical resection or biopsy within 2 weeks of the MR examination. Proliferative activity of the tumors was assessed by Ki-67 immunochemistry (Mb-1) on paraffin embedded tumor sections. Spectroscopic data was compared with Ki-67 labeling index and other histologic data such as histological subtype, cellular atypia, cellular density using univariate and multivariate analysis. 82 of 97 consecutive patients had histologically confirmed WHO grade 2 gliomas. Ki-67 proliferation index (PI) was correlated with specific spectral patterns: (1) low PI (4%) was associated with increased Cho/Cr and absence of both free lipids or lactates; (2) intermediate PI (4-8%) was associated with resonance of lactates; and (3) high PI (8%) was characterized by a resonance of free lipids. On multivariate analysis, resonance of lactates and resonance of free lipids appeared as independent predictors of intermediate PI (P0.001) and high PI (P0.001), respectively; moreover, free lipids resonance was correlated with cellular atypia (P0.05). This study suggests that (1)HMRS is a reliable tool to evaluate the proliferation activity of WHO grade 2 glioma and to identify potentially more aggressive clinical behavior.

The diagnosis of primary central nervous system lymphoma (PCNSL) should always be considered as an emergency because of the therapeutic consequences it implies. In immunocompetent patients, it relies on stereotactic biopsy. Unfortunately, clinical and radiological features may be misleading and delay the diagnostic procedure. The case we report here illustrates the contribution of magnetic resonance spectroscopy in the diagnostic approach of a very atypical PCNSL.

OBJECT: Low grade gliomas are both proliferative and diffusive tumors, as recently modelized. When proliferation is predominant, the tumor is rather bulky and its main locations are the supplementary motor area and the paralimbic system. Diffusion occurs preferentially along white matter tracts. Recent anatomo-functional studies, performed both in vitro and in vivo, have described the fiber tracts centered around the insula. We thus propose to analyze the extension of paralimbic low grade gliomas in terms of invaded subcortical pathways. METHODS: We retrospectively reviewed the MRIs of patients followed for a WHO grade II glioma at the Salp?i? Hospital between 1991 and 2003. We selected patients with tumors centered on the insula and extending in temporal and frontal lobes (Type 2b-2c-3 of Yasargil's classification). We then analyzed on FLAIR sequences the extension (tracked on successive examinations before any treatment) along two main fasciculi in that area: the uncinate and arcuate fasciculi. RESULTS: A total of 40 patients fulfilled the inclusion criteria. The uncinate fasiculus was invaded in 28 cases, the arcuate fasciculus in 9 cases, and both fasciculi in 3 cases. Longitudinal follow-up was available in 16 cases, and confirmed the preferential extension along these fasciculi. CONCLUSION: This kinetic analysis of extension of paralimbic low grade gliomas confirms that these tumors spread along distinct subcortical fasciculi. Due to the functional role of these pathways, this classification could be useful to elaborate therapeutic strategy (prognosis index, pre- and intra-operative neuropsychological testing, functional outcome).

Our purpose was to evaluate the postoperative aneurysm occlusion volume and clinical results of treating unruptured intracranial aneurysm using three-dimensional (3D) coils. Over a 2-year period 62 aneurysms (39 with a neckor =4 mm, 23 with a neck4 mm) in 62 patients in five participating centres were treated. The procedure consisted, firstly, of framing the aneurysm with one or more spherical 3D coils, and secondly, of filling it with two-dimensional (2D) helical coils. Anatomical and clinical results were evaluated by univariate analysis. Multivariate analysis was used to identify independent predictors of these results. For neck sizesor =4 and4 mm, angiographic occlusion was complete in 31 (79%) and 16 (70%) aneurysms, respectively; the mean percentage of occlusion volume was 31.4% and 29.5%, respectively, and postoperative morbidity was 3% and 4%, respectively, with no significant differences between the two groups. There were no deaths. However, occlusion volume correlated with sac size (P = 0.037) and sac-to-neck ratio1.5 (P = 0.073), except when three or more 3D coils per aneurysm were used (P = 0.516 and P = 0.308, respectively). Occlusion volume correlated with the number of 3D coils per aneurysm (P0.001) and was an independent predictor of angiographic complete occlusion (P = 0.002). The use of the largest number of 3D coils per aneurysm was safe and may improve the postoperative volume and angiographic occlusion of aneurysms with a neck4 mm, provided the sac-to-neck ratio isor =1.5.

Despite recent literature advocating the surgical removal of symptomatic Cavernous Angiomas (CA), even in critical brain areas, very few observations of insular CA surgery have been described, particularly in the left hemisphere. We report the case of a successful resection of a CA located in the dominant insula, using both neuronavigation and intra-operative functional mapping. This 33-year-old right-handed man harbored a left insular CA, revealed by generalized seizures following a bleed confirmed on MRI. The preoperative examination was normal. A stereotactic-guided surgery was performed under local anesthesia, with intra-operative functional mapping using direct cortico-subcortical electrical stimulation in the awake patient--allowing the surgeon to achieve total resection of both CA and pericavernomatous gliosis, as shown on repeated postoperative MRIs. There was no postsurgical deficit, nor any seizure without treatment (follow-up: 4.5 years). The diagnosis of CA was confirmed by histological examination. Taking account of the risk of morbidity due to the natural history of CA, particularly in eloquent brain regions, we suggest to routinely consider the possibility of a surgical treatment in cases of symptomatic (left dominant) insular CA, using combined intra-operative anatomical and physiological localization methods.

With the aim to better evaluate the role of the insula in seizures and the therapeutic implications, we analyzed the rate of insular low-grade gliomas (LGG) presenting with medically refractory epilepsy, detailed their ictal symptoms, and described the epileptological results following their surgical resection.Eleven patients (8 men, 3 women, mean age: 35 years) harboring an insular LGG generating intractable seizures, underwent tumor removal and perilesional opercular cortex resection (lesionectomy "plus") using intraoperative functional electrical mapping, combined with ultrasonography and/or neuronavigation.Despite the occurrence of five postoperative deficits, the patients recovered in all cases. The epileptological results showed improvement in all cases: 9 Engel's Class I (82%), 1 Class II and 1 Class III. Ten lesionectomies were total [3] or subtotal [7], while one resection was partial (the patient in Engel's III).The high rate of pharmacologically intractable seizures associated with insular LGG, and the favorable epilepsy outcome following surgical resection of these tumors seemingly indicate that the insular cortex itself may induce chronic seizures when injured. These results suggest, taking account of the technical surgical progress allowing now to minimize the morbidity after surgery in this region, that there is another indication than the sole oncological reason for surgery in patients with diffuse insular glioma -- even if total tumor removal is not systematically possible.

Gliomas can display marked changes in the concentrations of energy metabolism molecules such as creatine (Cr), phosphocreatine (PCr) and lactate, as measured using magnetic resonance spectroscopy (MRS). Moreover, the BOLD (blood oxygen level dependent) contrast enhancement in functional magnetic resonance imaging (fMRI) can be reduced or missing within or near gliomas, while neural activity is not significantly reduced (so-called neurovascular decoupling), so that the location of functionally eloquent areas using fMRI can be erroneous. In this paper, we adapt a previously developed model of the coupling between neural activation, energy metabolism and hemodynamics, by including the venous dilatation “Balloon model” of Buxton and Frank. We show that decreasing the cerebral blood flow (CBF) baseline value, or the CBF increase fraction, results in a decrease of the BOLD signal and an increase of the lactate peak during a sustained activation. Baseline lactate and PCr levels are not significantly affected by CBF baseline reduction, but are altered even by a moderate decrease of mitochondrial respiration. Decreasing the total Cr and PCr concentration reduces the BOLD signal after the initial overshoot. In conclusion, we suggest that the coupled use of BOLD fMRI and MRS could contribute to a better understanding of the neurovascular and metabolic decoupling in gliomas.

¶ Indications of surgical treatment for lesions in the central nervous system depend on the risk of a definitive neurological deficit, related to the benefit of resection. Detection of eloquent areas is then necessary because of major individual variability. Neuro-imaging functional techniques are in development and are beginning to be efficient for cortical sensorymotor mapping, but still lack sensitivity and specificity for language mapping, and remain unable to give real-time data during surgery and to perform sub-cortical mapping. The more precise and reliable method of functional mapping is represented by the intra-operative direct electrical stimulations (DES), which allow identification and preservation of essential pathways for motricity, sensibility and language, at each level of the central nervous system (cortico-subcortical). We report our experience of DES in the surgery of tumours and vascular malformations located in supra-tentorial brain eloquent areas, with a consecutive series of 60 patients operated on under general or local anaesthesia, from November 1996 until May 1999 in our department at La Salpetriere Hospital. Presenting symptoms in the 60 subjects (39 males, 21 females, mean age: 45 years) were seizures in 37 cases with normal clinical examination, and mild neurological deficit in 29 cases. MRI showed 60 supra-tentorial brain lesions: 30 precentral, 12 postcentral, 14 perisylvian in the dominant hemisphere, 4 deep-seated. All subjects underwent surgical resection using DES, with supratentorial cortico-subcortical mapping under general anaesthesia for motor areas detection in 43 cases and under local anaesthesia for sensori-motor and/or language tasks in 17 cases. The final histological diagnosis was 44 gliomas (31 low-grade and 13 high-grade), 9 metastasis, 3 cavernomas, 4 arteriovenous malformations (AVM). Resection was total or subtotal in 52 cases (87%) and partial in 8 cases (13%). 29 patients had no post-operative deficit, while the other 31 patients were impaired post-operatively, with in all cases, except 3, a complete recovery delayed for 15 days to 3 months (overall morbidity: 5%). The median follow up was 14 months. Intra-operative direct electrical stimulations of the central nervous system constitute a reliable, precise and safe method, allowing the realization of a functional mapping useful for all operations of lesions located in eloquent areas. This technique allows a minimization of definitive post-operative neurological deficit, and concurrently an improvement in the quality of resection.