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International audience; OBJECTIVE: To analyze the conceptual and practical implications of a hodotopic approach in neurosurgery, and to compare the similarities and the differences in neuroplasticity mechanisms between low-grade gliomas and nonlesional epilepsy. METHODS: We review the recent data about the hodotopic organization of the brain connectome, alongside the organization of epileptic networks, and analyze how these two structures interact, suggesting therapeutic prospects. Then we focus on the mechanisms of neuroplasticity involved in glioma natural course and after glioma surgery. Comparing these mechanisms with those in action in an epileptic brain highlights their differences, but more importantly, gives an original perspective to the consequences of surgery on an epileptic brain and what could be expected after pathologic white matter removal. RESULTS: The organization of the brain connectome and the neuroplasticity is the same in all humans, but different pathologic mechanisms are involved, and specific therapeutic approaches have been developed in epilepsy and glioma surgery. We demonstrate that the "connectome" point of view can enrich epilepsy care. We also underscore how theoretical and practical tools commonly used in epilepsy investigations, such as invasive electroencephalography, can be of great help in awake surgery in general. SIGNIFICANCE: Putting together advances in understanding of connectomics and neuroplasticity, leads to significant conceptual improvements in epilepsy surgery.

The most accepted framework of language processing includes a dorsal phonological and a ventral semantic pathway, connecting a wide network of distributed cortical hubs. However, the cortico-subcortical connectivity and the reciprocal anatomical relationships of this dual-stream system are not completely clarified. We performed an original blunt microdissection of 10 hemispheres with the exposition of locoregional short fibers and six long-range fascicles involved in language elaboration. Special attention was addressed to the analysis of termination sites and anatomical relationships between long- and short-range fascicles. We correlated these anatomical findings with a topographical analysis of 93 functional responses located at the terminal sites of the language bundles, collected by direct electrical stimulation in 108 right-handers. The locations of phonological and semantic paraphasias, verbal apraxia, speech arrest, pure anomia, and alexia were statistically analyzed, and the respective barycenters were computed in the MNI space. We found that terminations of main language bundles and functional responses have a wider distribution in respect to the classical definition of language territories. Our analysis showed that dorsal and ventral streams have a similar anatomical layer organization. These pathways are parallel and relatively segregated over their subcortical course while their terminal fibers are strictly overlapped at the cortical level. Finally, the anatomical features of the U-fibers suggested a role of locoregional integration between the phonological, semantic, and executive subnetworks of language, in particular within the inferoventral frontal lobe and the temporoparietal junction, which revealed to be the main criss-cross regions between the dorsal and ventral pathways. Hum Brain Mapp 37:3858-3872, 2016. © 2016 Wiley Periodicals, Inc.

Objectives To ascertain the neural network mediating reading using intraoperative electrostimulation. Experimental design A cortical and axonal intraoperative electrical mapping of reading processes was achieved in seven patients who underwent awake surgery for a left occipitotemporal glioma. We performed resection cavity overlapping and superimposition with a diffusion tensor imaging-based white matter atlas. We assessed the relationship between the location of resection cavities and the occurrence of reading impairments of regular, irregular, and pseudowords. Principal observations Intraoperative stimulation of the left posterior inferior temporal cortex (ITCp) elicited reading disturbances. Subcortical stimulation at the anterior portion of the visual word form area (VWFA) induced addressed phonology (irregular words reading) disturbances. Subcortical stimulation of the connection between VWFA and the posterior segment of the arcuate fascicle (AFp) induced both addressed and assembled phonology (irregular and pseudowords reading) disturbances. Postoperative assessment showed that resection of the posterior portion of the inferior longitudinal fascicle (ILFp), connecting the visual cortex to VWFA, induced long-term and global reading impairment. Resection of the terminations of left AFp in the ITCp-induced irregular and pseudowords reading disturbances with no impairment of regular words reading. Resection of the anterior portion of ILF did not induce reading impairment. Conclusions Our data support an inner posterior-to-anterior hierarchical coding of letter strings in the VWFA and a crucial role of the left ILFp to provide visual inputs to the VWFA. Furthermore, we suggest that the AFp is involved in an interactive feedback system between visual and nonvisual information, recruited when reading irregular and pseudowords. Hum Brain Mapp 36:2215–2230, 2015. © 2015 Wiley Periodicals, Inc.

The temporo-parieto-occipital (TPO) junction is a complex brain territory heavily involved in several high-level neurological functions, such as language, visuo-spatial recognition, writing, reading, symbol processing, calculation, self-processing, working memory, musical memory, and face and object recognition. Recent studies indicate that this area is covered by a thick network of white matter (WM) connections, which provide efficient and multimodal integration of information between both local and distant cortical nodes. It is important for neurosurgeons to have good knowledge of the three-dimensional subcortical organisation of this highly connected region to minimise post-operative permanent deficits. The aim of this dissection study was to highlight the subcortical functional anatomy from a topographical surgical perspective. Eight human hemispheres (four left, four right) obtained from four human cadavers were dissected according to Klingler's technique. Proceeding latero-medially, the authors describe the anatomical courses of and the relationships between the main pathways crossing the TPO. The results obtained from dissection were first integrated with diffusion tensor imaging reconstructions and subsequently with functional data obtained from three surgical cases, all resection of infiltrating glial tumours using direct electrical mapping in awake patients. The subcortical limits for performing safe lesionectomies within the TPO region are as follows: within the parietal region, the anterior horizontal part of the superior longitudinal fasciculus and, more deeply, the arcuate fasciculus; dorsally, the vertical projective thalamo-cortical fibres. For lesions located within the temporal and occipital lobes, the resection should be tailored according to the orientation of the horizontal associative pathways (the inferior fronto-occipital fascicle, inferior longitudinal fascicle and optic radiation). The relationships between the WM tracts and the ventricle system were also examined. These results indicate that a detailed anatomo-functional awareness of the WM architecture within the TPO area is mandatory when approaching intrinsic brain lesions to optimise surgical results and to minimise post-operative morbidity.

INTRODUCTION Diffuse low-grade glioma (DLGG) is a progressive primary brain tumor for which several stages can be discerned (see Fig. 1). First, glioma-initiating cells neoplastically transform, which we define as the biologic birth. This nascent glioma does not give rise to any symptoms and even remains below the detection limit of routine magnetic resonance imaging (MRI), during what we term the occult stage. Second, at some point, the glioma becomes visible on MRI, yet the patient is still asymptomatic; we refer to this as the clinically silent stage. During this stage, gliomas can be incidentally discovered on brain MRI, for instance, in healthy volunteers from a study, in trauma patients requiring brain imaging, or in clients of commercial screening programs. Third, the glioma elicits clinical symptoms, usually an epileptic seizure, entering what we define as its symptomatic stage. Fourth, at some point in time, the glioma switches its rather indolent behavior toward an aggressive one, in keeping with the onset of neoangiogenesis and malignancy, until the patient dies from tumor spread and growth. To date, oncologic therapy has failed to cure patients with DLGG, but a significant delay of malignant transformation and death from disease can be achieved by appropriate and timely treatment. The treatment modalities include surgical resection, chemotherapy, and radiotherapy. Considerable debate has focused on the optimal timing of each treatment modality. Despite the lack of evidence from randomized surgical trials, expert opinion based on accumulating evidence from observational studies favors early resective surgery for symptomatic DLGG because of both a substantial survival benefit and lowmorbidity. Currently, patients with DLGG are almost always diagnosed in their symptomatic period. However, given the increasing availability of MRI and more liberal brain imaging indications, incidental discoveries of a silent DLGG are becoming more frequent. The management of these patients has been discussed in several recent publications. In particular, early surgery has been advocated, arguing that the sooner the surgery, the higher the chances to perform a (supra)complete, functionally safe resection guided by the use of intraoperative brain-stimulation mapping. The idea that the early detection of silent DLGG could contribute to a cure for these tumors even led some authors to propose a screening policy. However, before setting up a population screening, with the objective of offering immediate treatment to any patient diagnosed with a silent DLGG, at least 2 fundamental questions, among many others, remain to be answered. First, what is the risk over a lifetime of dyingwith a silent glioma from another cause compared with the risk of dying from the evolution of the silent glioma? In other words, is there a risk of overtreatment? Second, how long is the silent stage of a DLGG; or, stated differently, what is the average lead time? In this commentary, we address these 2 questions based on epidemiologic computations and biomathematical models of glioma growth, and we address the issue of a screening policy.

Summary In nontumoral epilepsy surgery, the main goal for all preoperative investigation is to first determine the epileptogenic zone, and then to analyze its relation to eloquent cortex, in order to control seizures while avoiding adverse postoperative neurologic outcome. To this end, in addition to neuropsychological assessment, functional neuroimaging and scalp electroencephalography, extraoperative recording, and electrical mapping, especially using subdural strip- or grid-electrodes, has been reported extensively. Nonetheless, in tumoral epilepsy surgery, the rationale is different. Indeed, the first aim is rather to maximize the extent of tumor resection while minimizing postsurgical morbidity, in order to increase the median survival as well as to preserve quality of life. As a consequence, as frequently seen in infiltrating tumors such as gliomas, where these lesions not only grow but also migrate along white matter tracts, the resection should be performed according to functional boundaries both at cortical and subcortical levels. With this in mind, extraoperative mapping by strips/grids is often not sufficient in tumoral surgery, since in essence, it allows study of the cortex but cannot map subcortical pathways. Therefore, intraoperative electrostimulation mapping, especially in awake patients, is more appropriate in tumor surgery, because this technique allows real-time detection of areas crucial for cerebral functions—eloquent cortex and fibers—throughout the resection. In summary, rather than choosing one or the other of different mapping techniques, methodology should be adapted to each pathology, that is, extraoperative mapping in nontumoral epilepsy surgery and intraoperative mapping in tumoral surgery.

Objectives: Cortical areas involved in bimanual coordination have been regularly studied by functional neuroimaging and electroencephalography. However, the subcortical connectivity underly- ing this complex function has received less attention. Here, we used the technique of direct electrosti- mulation in awake patients who underwent surgery for brain glioma, with the goal to investigate the white matter pathways subserving bimanual coordination. Experimental design: Eight patients were operated under local anesthesia for a frontal low-grade glioma. Intraoperative subcortical electrostimu- lation mapping was used to search interference with bimanual coordination. The corresponding stimu- lation sites were reported on brain MRI. Principal observations: All patients presented a complete arrest of the movement of both hands during unilateral subcortical stimulation of the white matter under- neath the dorsal premotor cortex and the posterior part of the supplementary motor area, rostrally to the corticospinal tract, until the caudate nucleus and the anterior arm of the internal capsule. No movement deficits, especially no disturbances of bimanual coordination, were observed 3 months after surgery. Conclusions: This is the first evidence of bilateral negative motor responses elicited by unilat- eral subcortical stimulation. Such findings support the existence of a bilateral cortico-subcortical net- work connecting the premotor cortices, basal ganglia, and spinal cord, involved in the control of bimanual coordination. A better understanding of this modulatory motor circuit may have important implications in fundamental neurosciences as well as in brain surgery. Hum Brain Mapp 00:000-000, 2013. V C 2013 Wiley Periodicals, Inc.

r r Abstract: Objectives: Despite previous lesional and functional neuroimaging studies, the actual role of the left ventral premotor cortex (vPMC), i.e., the lateral part of the precentral gyrus, is still poorly known. Experimental design:We report a series of eight patients with a glioma involving the left vPMC, who underwent awake surgery with intraoperative cortical and subcortical language mapping. The function of the vPMC, its subcortical connections, and its reorganization potential are investigated in the light of surgical findings and language outcome after resection. Principal observations: Electrostimulation of both the vPMC and subcortical white matter tract underneath the vPMC, that is, the anterior segment of the lateral part of the superior longitudinal fascicle (SLF), induced speech production disturbances with anarthria in all cases. Moreover, although some degrees of redistribution of the vPMC have been found in four patients, allowing its partial resection with no permanent speech disorders, this area was none- theless still detected more medially in the precentral gyrus in the eight patients, despite its invasion by the glioma. Moreover, a direct connection of the vPMC with the SLF was preserved in all cases. Conclu- sions: Our original data suggest that the vPMC plays a crucial role in the speech production network and that its plastic potential is limited. We propose that this limitation is due to an anatomical con- straint, namely the necessity for the left vPMC to remain connected to the lateral SLF. Beyond funda- mental implications, such knowledge may have clinical applications, especially in surgery for tumors involving this cortico-subcortical circuit. Hum Brain Mapp 00:000-000, 2013. V C 2013 Wiley Periodicals, Inc.

Objectives: Recent anatomical-functional studies have transformed our understanding of cerebral motor control away from a hierarchical structure and toward parallel and interconnected specialized circuits. Subcortical electrical stimulation during awake surgery provides a unique opportunity to identify white matter tracts involved in motor control. For the first time, this study reports the findings on motor modulatory responses evoked by subcortical stimulation and investigates the cortico-subcortical connectivity of cerebral motor control. Experimental design: Twenty-one selected patients were operated while awake for frontal, insular, and parietal diffuse low-grade gliomas. Subcortical electrostimulation mapping was used to search for interference with voluntary movements. The corresponding stimulation sites were localized on brain schemas using the anterior and posterior commissures method. Principal observations: Subcortical negative motor responses were evoked in 20/21 patients, whereas acceleration of voluntary movements and positive motor responses were observed in three and five patients, respectively. The majority of the stimulation sites were detected rostral of the corticospinal tract near the vertical anterior-commissural line, and additional sites were seen in the frontal and parietal white matter. Conclusions: The diverse interferences with motor function resulting in inhibition and acceleration imply a modulatory influence of the detected fiber network. The subcortical stimulation sites were distributed veil-like, anterior to the primary motor fibers, suggesting descending pathways originating from premotor areas known for negative motor response characteristics. Further stimulation sites in the parietal white matter as well as in the anterior arm of the internal capsule indicate a large-scale fronto-parietal motor control network. Hum Brain Mapp, 2012. © 2012 Wiley Periodicals, Inc.

Objectives: Here we present a model aiming to provide an estimate of time from tumour genesis, for grade II gliomas. The model is based on a differential equation describing the diffusion–proliferation process. We have applied our model to situations where tumour diameter was shown to increase linearly with time, with characteristic diametric velocity. Materials and methods: We have performed numerical simulations to analyse data, on patients with grade II gliomas and to extract information concerning time of tumour biological onset, as well as radiology and distribution of model parameters. Results and conclusions: We show that the estimate of tumour onset obtained from extrapolation using a constant velocity assumption, always underestimates biological tumour age, and that the correction one should add to this estimate is given roughly by 20 ⁄v (year), where v is the diametric velocity of expansion of the tumour (expressed in mm ⁄year). Within the assumptions of the model, we have identified two types of tumour: the first corresponds to very slowly growing tumours that appear during adolescence, and the second type corresponds to slowly growing tumours that appear later, during early adulthood. That all these tumours become detectable around a mean patient age of 30 years could be interesting for formulation of strategies for early detection of tumours.

Classical fiber dissection of post mortem human brains enables us to isolate a fiber tract by removing the cortex and overlying white matter. In the current work, a modification of the dissection methodology is presented that preserves the cortex and the relationships within the brain during all stages of dissection, i.e. ‘cortex-sparing fiber dissection’. Thirty post mortem human hemispheres (15 right side and 15 left side) were dissected using cortex-sparing fiber dissection. Magnetic resonance imaging study of a healthy brain was analyzed using diffusion tensor imaging (DTI)-based tractography software. DTI fiber tract reconstructions were compared with cortex-sparing fiber dissection results. The fibers of the superior longitudinal fasciculus (SLF), inferior fronto-occipital fasciculus (IFOF), inferior longitudinal fasciculus (ILF) and uncinate fasciculus (UF) were isolated so as to enable identification of their cortical terminations. Two segments of the SLF were identified: first, an indirect and superficial component composed of a horizontal and vertical segment; and second, a direct and deep component or arcuate fasciculus. The IFOF runs within the insula, temporal stem and sagittal stratum, and connects the frontal operculum with the occipital, parietal and temporo-basal cortex. The UF crosses the limen insulae and connects the orbito-frontal gyri with the anterior temporal lobe. Finally, a portion of the ILF was isolated connecting the fusiform gyrus with the occipital gyri. These results indicate that cortex-sparing fiber dissection facilitates study of the 3D anatomy of human brain tracts, enabling the tracing of fibers to their terminations in the cortex. Consequently, it is an important tool for neurosurgical training and neuroanatomical research.

Neural foundations of syntactic gender processing remain poorly understood. We used electrostimulation mapping in nine right‐handed awake patients during surgery for a glioma within the left hemisphere, to study whether the cortico‐subcortical structures involved in naming versus syntactic gender processing are common or distinct. In French, the article determines the grammatical gender. Thus, the patient was asked to perform a picture naming task and to give the appropriate article for each picture, with and without stimulation. Cortical stimulation elicited reproducible syntactic gender disturbances in six patients, in the inferior frontal gyrus (three cases), and in the posterior middle temporal gyrus (three cases). Interestingly, no naming disorders were generated during stimulation of the syntactic sites, while cortical areas inducing naming disturbances never elicited grammatical gender errors when stimulated. Moreover, at the subcortical level, stimulation of the white matter lateral to the caudate nucleus induced gender errors in three patients, with no naming disorders. Using cortico‐subcortical electrical mapping in awake patients, we demonstrate for the first time (1) a double dissociation between syntactic gender and naming processing, supporting independent network model rather than serial theory, (2) the involvement of the left inferior frontal gyrus, especially the pars triangularis, and the posterior left middle temporal gyrus in grammatical gender processing, (3) the existence of white matter pathways, likely a sub‐part of the left superior longitudinal fasciculus, underlying a large‐scale distributed cortico‐subcortical circuit which might selectively sub‐serve syntactic gender processing, even if interconnected with parallel sub‐networks involved in naming (semantic and phonological) processing. Hum Brain Mapp, 2011. © 2010 Wiley‐Liss, Inc.

Objective To evaluate the natural progression and the impact of temozolomide in low-grade gliomas and to correlate these changes with the profile of genetic alterations. Methods The mean tumor diameter (MTD) of low-grade gliomas was evaluated on serial magnetic resonance images before (n = 39), during, and after (n = 107) treatment with neoadjuvant temozolomide. MTD growth curves were correlated with chromosomes 1p-19q loss and p53 overexpression in the tumors. Results Before temozolomide onset, MTD increased linearly over time, indicating a continuous growth that was significantly slower in 1p-19q deleted tumors (3.4 vs 5.9mm/year; p = 0.0016) and in tumors that did not overexpress p53 (4.2 vs 6.3mm/year; p = 0.05). During temozolomide treatment, almost all patients (92%) experienced initial decrease of MTD. Subsequently, some tumors started to resume growth despite continuous administration of temozolomide, with a lower rate of relapse in 1p-19q deleted tumors (16.6 vs 58%; p = 0.0004) and in tumors that did not overexpress p53 (26 vs 68%; p = 0.003). When temozolomide was discontinued in the absence of tumor progression, a majority of tumors resumed their progressive growth within a year. Interpretation Untreated low-grade gliomas grow continuously at a rate that is influenced by the genetic alterations of the tumors. Temozolomide reverses this pattern at the onset, but this effect is often brief in patients whose tumors overexpress p53 and do not harbor the 1p-19q codeletion, suggesting acquired chemoresistance. A majority of tumors will resume their growth when treatment is discontinued, raising the issue of the optimal duration of treatment in continuously responding patients. Ann Neurol 2007;61:484–490

A consecutive series of 143 unselected adult patients with histologically proved World Health Organization grade II gliomas was reviewed to assess the prognostic value of growth rates of mean tumor diameters on successive magnetic resonance images before treatment. There is an inverse correlation between growth rates and survival (p < 0.001; median survival at 5.16 years for a growth rate of 8mm/year or more; median survival >15.0 years for a growth rate

A recent computational model of brain tumor growth, developed to better describe how gliomas invade through the adjacent brain parenchyma, is based on two major elements: cell proliferation and isotropic cell diffusion. On the basis of this model, glioma growth has been simulated in a virtual brain, provided by a 3D segmented MRI atlas. However, it is commonly accepted that glial cells preferentially migrate along the direction of fiber tracts. Therefore, in this paper, the model has been improved by including anisotropic extension of gliomas. The method is based on a cell diffusion tensor derived from water diffusion tensor (as given by MRI diffusion tensor imaging). Results of simulations have been compared with two clinical examples demonstrating typical growth patterns of low-grade gliomas centered around the insula. The shape and the kinetic evolution are better simulated with anisotropic rather than isotropic diffusion. The best fit is obtained when the anisotropy of the cell diffusion tensor is increased to greater anisotropy than the observed water diffusion tensor. The shape of the tumor is also influenced by the initial location of the tumor. Anisotropic brain tumor growth simulations provide a means to determine the initial location of a low-grade glioma as well as its cell diffusion tensor, both of which might reflect the biological characteristics of invasion.

BACKGROUND The objectives of this study were to register the brain locations in a consecutive series of low-grade gliomas (LGGs) and compare these localizations with the locations of de novo glioblastomas (GBMs) that were collected during the same period in an effort to analyze whether LGGs are situated in preferential areas and to review the pathophysiologic hypothesis of such a phenomenon. METHODS One hundred thirty-two patients with LGG and 102 patients with GBM who were followed consecutively between 1996 and 2003 by the authors were reviewed, whatever their treatment. Using anatomic, three-dimensional magnetic resonance imaging, the location of each tumor was analyzed accurately according to a classification system based on the proximity of eloquent areas previously reported by the authors. RESULTS One hundred nine LGGs (82.6%), compared with 55 GBMs (53.9%), were situated within functional regions (P < 0.001). More specifically, 36 LGGs (27.3%), compared with 11 GBMs (10.8%), were localized in the region of the supplementary motor area (SMA) (P < 0.001); and 33 LGGs (25%), compared with 11 GBMs (10.8%), were located within the insula (P < 0.001). CONCLUSIONS The current findings suggest that LGGs are located preferentially in “secondary” functional areas (immediately near the so-called primary eloquent regions), especially within the SMA and the insular lobe. This preferential localization may be explained by developmental, cytomyeloarchitectonic, neurochemical, metabolic, and functional reasons. A better knowledge of the pathophysiologic mechanisms underlying preferential LGGs locations may improve understanding of the genesis and natural history of these tumors and, subsequently, their management. Cancer 2004. © 2004 American Cancer Society.

Twelve pregnancies in 11 adult women harboring World Health Organization (WHO) grade II gliomas (GIIGs) prior to pregnancy were reviewed to address whether pregnancy affects tumor growth using a quantitative approach of the radiological velocity of diametric expansion (VDE) on successive magnetic resonance images. VDE was significantly increased during pregnancy as compared to prepregnancy (p < 0.001) and to postdelivery (p = 0.012) periods. Pregnancy increases the radiological growth rates of GIIGs. An increase in seizure frequency was observed concomitantly in 40% of cases and further oncological treatment was started after delivery in 25% of cases.

The goal of this study was to detail the composition of dorsal fronto-parietal connections in the human brain, focusing on the dorsal component of superior longitudinal fasciculus (SLF), short association fibers, their three-dimensional organization, and relationships with adjacent projection and commissural fibers. Ten human cerebral hemispheres (five left and five right) were obtained from necropsy specimens. The technique for specimen preparation was adapted from that previously described by Ludwig and Klingler for spreading groups of white matter fibers, rendering tracts visible and dissectible. Near the superior border of the hemisphere, we observed an overall organization consisting of a succession of "U" fibers in both sides of a narrow and irregular intermediary layer of white matter. Dissection of the core fibers leads to the corona radiata (intermingled with the callosal radiations) on the lateral aspect and to the callosal radiations at the medial aspect of the hemisphere. Based on our findings, the fiber dissection technique does not provide evidence of the presence of long horizontal association fibers in such location, as suggested by brain imaging techniques. The results of this study lead us to hypothesize that dorsal regions of the frontal and parietal lobes superior to the level of the cingulate sulcus are connected by a succession of short association pathways. Dissectible long association fibers are only encountered in a zone restricted to a lower and deeper portion of the superior parietal lobule. These fibers are clearly integrated in the lower portions of the SLF/arcuate fasciculus complex.