White matter tracts and executive functions: a review of causal and correlation evidence.

Executive functions are high-level cognitive processes involving abilities such as working memory/updating, set-shifting and inhibition. These complex cognitive functions are enabled by interactions among widely distributed cognitive networks, supported by white matter tracts. Executive impairment is frequent in neurological conditions affecting white matter; however, whether specific tracts are crucial for normal executive functions is unclear. We review causal and correlation evidence from studies that used direct electrical stimulation during awake surgery for gliomas, voxel-based and tract-based lesion-symptom mapping, and diffusion tensor imaging to explore associations between the integrity of white matter tracts and executive functions in healthy and impaired adults. The corpus callosum was consistently associated with all executive processes, notably its anterior segments. Both causal and correlation evidence showed prominent support of the superior longitudinal fasciculus to executive functions, notably to working memory. More specifically, strong evidence suggested that the second branch of the superior longitudinal fasciculus is crucial for all executive functions, especially for flexibility. Global results showed left lateralization for verbal tasks and right lateralization for executive tasks with visual demands. The frontal aslant tract potentially supports executive functions, however, additional evidence is needed to clarify whether its involvement in executive tasks goes beyond the control of language. Converging evidence indicates that a right-lateralized network of tracts connecting cortical and subcortical grey matter regions supports the performance of tasks assessing response inhibition, some suggesting a role for the right anterior thalamic radiation. Finally, correlation evidence suggests a role for the cingulum bundle in executive functions, especially in tasks assessing inhibition. We discuss these findings in light of current knowledge about the functional role of these tracts, descriptions of the brain networks supporting executive functions and clinical implications for individuals with brain tumours.

Combining resting state functional MRI with intraoperative cortical stimulation to map the mentalizing network.

OBJECTIVE: To infer the face-based mentalizing network from resting-state functional MRI (rsfMRI) using a seed-based correlation analysis with regions of interest identified during intraoperative cortical electrostimulation. METHODS: We retrospectively included 23 patients in whom cortical electrostimulation induced transient face-based mentalizing impairment during 'awake' craniotomy for resection of a right-sided diffuse low-grade glioma. Positive stimulation sites were recorded and transferred to the patients' preoperative normalized MRI, and then used as seeds for subsequent seed-to-voxel functional connectivity analyses. The analyses, conducted with an uncorrected voxel-level p-value of 0.001 and a false-discovery-rate cluster-level p-value of 0.05, allowed identification of the cortical structures, functionally coupled with the mentalizing-related sites. RESULTS: Two clusters of responsive stimulations were identified intraoperatively - one in the right dorsolateral prefrontal cortex (dlPFC, n = 13) and the other in the right inferior frontal gyrus (IFG, n = 10). A whole group level analysis revealed that stimulation sites correlated mainly with voxels located in the pars triangularis of the IFG, the dorsolateral and dorsomedial prefrontal cortices, the temporo-parietal junction, the posterior superior temporal sulcus, and the posterior inferior temporal/fusiform gyrus. Other analyses, taking into consideration the location of the responsive sites (IFG versus dlPFC cluster), highlighted only minor differences between both groups. CONCLUSIONS: The present study successfully demonstrated the involvement of a large-scale neural network in the face-based mentalizing that strongly matches networks, classically identified using task-based fMRI paradigms. We thus validated the combination of rsfMRI and stimulation mapping as a powerful approach to identify functional networks in brain-damaged patients.

Zn2+-triggered self-assembly of Gonadorelin [6-D-Phe] to produce nanostructures and fibrils.

A synthetic derivative, GnRH [6-D-Phe], stable against enzymatic degradation, self-assembles and forms nanostructures and fibrils upon a pH shift in the presence of different concentrations of Zn2+ in vitro. Attenuated Total Reflection Fourier Transform Infrared spectroscopy (ATR-FTIR) revealed the existence of higher order assembly of Zn2+: GnRH [6-D-Phe]. Nuclear Magnetic Resonance spectroscopy (NMR) indicated a weak interaction between Zn2+ and GnRH [6-D-Phe]. Atomic Force Microscopy (AFM) showed the existence of GnRH [6-D-Phe] oligomers and fibrils. Molecular Dynamic (MD) simulation of the 10:1 Zn2+: GnRH [6-D-Phe] explored the interaction and dimerization processes. In contrast to already existing short peptide fibrils, GnRH [6-D-Phe] nanostructures and fibrils form in a Tris-buffered pH environment in a controlled manner through a temperature reduction and a pH shift. The lyophilized Zn2+: GnRH [6-D-Phe] assembly was tested as a platform for the sustained delivery of GnRH [6-D-Phe] and incorporated into two different oil vehicle matrices. The in vitro release was slow and continuous over 14 days and not influenced by the oil matrix.

Neuropsychological evidence for the crucial role of the right arcuate fasciculus in the face-based mentalizing network: A disconnection analysis.

Recent evidence from axonal stimulation mapping studies suggests that at least two white matter connectivities in the right hemisphere may be involved in face-based mentalizing, i.e. the ability to infer complex cognitive and affective states from human faces: the inferior fronto-occipital (IFOF) and the superior longitudinal/arcuate (SLF/AF) fasciculi. However, to date, only a handful of neuropsychological studies have focused on the white matter tracts subserving mentalizing in general, and face-based mentalizing in particular. Therefore, the main goal of this study was to confirm the abovementioned results by applying voxelwise and tractwise lesion-symptom analyses to a set of behavioral data obtained from a large and homogeneous group of neurological participants. More precisely, 122 patients operated on for diffuse low-grade glioma were assessed postoperatively with the well-validated "Reading the Mind in the Eyes" (RME) test. For each patient, the resection cavity and the residual tumor infiltration were mapped separately on the respective postoperative structural MRI. Behavioral data, previously controlled for sociodemographic factors, were then submitted to a standard voxel-based and to a less conservative, region-of-interest (ROI)-based, lesion-deficit analyses. Results were invariably the same: no anatomo-functional relationships were pinpointed by these investigations, making thus impossible the cortical topological localization of mentalizing deficits. In a second time, two kinds of tractwise lesion-symptom analyses based on the damaged volume and the disconnection probabilities of the white matter tracts, were performed. All results were corrected with the Bonferroni correction. Converging and strong evidence was found that resection-related disconnection of the right AF is especially deleterious for face-based mentalizing. More anecdotally, we identified the involvement of certain ventral tracts, especially the IFOF and the uncinate fasciculus (UF). Taken as a whole, the reported findings confirm the critical role of the right AF in mentalizing abilities. From a more clinical standpoint, they highlight the necessity to perform an intraoperative map of this connectivity during awake surgery in order to avoid long-lasting social cognition disorders.

Left Spatial Neglect Evoked by Electrostimulation of the Right Inferior Fronto-occipital Fasciculus.

Left spatial neglect is a debilitating condition that may occur after lesion of many cortical territories in the right hemisphere. At the subcortical level, the second and third branches of the right superior longitudinal fasciculus has emerged as strong candidates in conveying information exchanges within the attention networks as their damage has been repeatedly associated to spatial neglect in neuromodulation and neuropsychological studies. Yet, a few cases of spatial neglect have also been observed after damage to the right inferior fronto-occipital fasciculus (IFOF), suggesting an involvement of this associative connectivity in spatial attention. Here we report three rare cases of patients having undergone a wide-awake craniotomy with direct electrostimulation for right temporal glioma. An intraoperative monitoring of spatial cognition was performed using a standard line bisection task. Responsive cortical sites were observed in the supramarginal gyrus and the posterior part of both the middle and superior temporal gyri. Critically, in all patients, significant rightward deviations were observed by the stimulation of the white matter deep in the temporal lobe, along the roof of the inferior horn of the lateral ventricle-a well-known anatomical landmark to identify the IFOF. Disconnection analyses confirmed the high probability of IFOF disconnection during neglect-related stimulations. Taken together, our findings provide support for a role of the right IFOF in spatial cognition. We discuss these results in the light of the newly discovered fronto-parietal connections of the IFOF and suggest that some subcomponents of this tract might be involved in between-system integration within the attention network.

IDH mutation and 1p19q codeletion distinguish two radiological patterns of diffuse low-grade gliomas.

Diffuse low-grade gliomas (DLGG) prognosis is variable, depending on several factors, including the isocitrate dehydrogenase (IDH) mutation and the 1p19q codeletion. A few studies suggested associations between these parameters and tumor radiological characteristics including topography. Our aim was analyzing the correlations between the IDH and 1p19q statuses and the tumor intracerebral distribution (at the lobar and voxel levels), volume, and borders. We conducted a retrospective, monocentric study on a consecutive series of 198 DLGG patients. The IDH and 1p19q statuses were recorded. The pre-treatment magnetic resonance FLAIR imagings were reviewed for determination of lobar topography, tumor volume, and characterisation of tumor borders (sharp or indistinct). We conducted a voxel-based lesion-symptom mapping analysis to investigate the correlations between the IDH and 1p19q statuses and topography at the voxel level. The IDH mutation and 1p19q statuses were correlated with the tumor topography defined using lobar anatomy (p < 0.001 and p = 0.004, respectively). Frontal tumors were more frequently IDH-mutant (87.1 vs. 57.4%) and 1p19q codeleted (45.2 vs. 17.0%) than temporo-insular lesions. At the voxel level, these associations were not found. Tumors with sharp borders were more frequently IDH-mutant (p = 0.001) while tumors with indistinct borders were more frequently IDH wild-type and 1p19q non-codeleted (p < 0.001). Larger tumors at diagnosis (possibly linked to a slower growth rate) were more frequently IDH-mutant (p < 0.001). IDH wild-type, 1p19q non-codeleted temporo-insular tumors are distinct from IDH-mutant, 1p19q codeleted frontal tumors. Further studies are needed to determine whether the therapeutic strategy should be adapted to each pattern.

Neural pathways subserving face-based mentalizing.

Over the past few years, considerable progress has been done in clarifying the neural networks underlying mentalizing. However, although the cortical architecture of this function is relatively well understood, the white matter pathways that may be involved in conveying neural signals within the mentalizing network remain to be elucidated. To gain insight into this matter, a detailed stimulation mapping of face-based mentalizing was performed in 27 patients undergoing awake surgery for a right-sided diffuse low-grade glioma (DLGG). Direct electrical stimulation (DES) was applied to both the cortical and subcortical levels. In perfect agreement with previous literature using face-based mentalizing tasks, cortical sites were identified in the posterior inferior frontal gyrus (IFG), the dorsolateral prefrontal cortex (dlPFC), and the posterior superior temporal gyrus (pSTG). Most importantly, critical sites were found along the inferior fronto-occipital fasciculus (IFOF), and within the white matter fibres supplying the dlPFC. Disconnectome analyses confirmed the very high probability of IFOF disconnection during temporal subcortical stimulation, and revealed an additional implication of the superior longitudinal fasciculus/arcuate fasciculus (SLF/AF) during prefrontal subcortical stimulations. Altogether, these findings suggest that functional integrity of both the IFOF and the SLF is required for accurately inferring complex mental states from human faces.

[Single center experience with bevacizumab in a cohort of patients treated for a relapsing glioblastoma]. / Expérience monocentrique d'un traitement par bévacizumab dans la prise en charge des glioblastomes récidivant.

PURPOSE: Although there is no standard treatment for recurrent glioblastoma, prospective data in selected patients have suggested the usefulness of bevacizumab. We report our single center experience with bevacizumab in a cohort of patients treated for a relapsing glioblastoma. METHODS: We performed a retrospective analysis of consecutive patients treated with bevacizumab for a relapsed glioblastoma, between 2008 and 2013. Tumor responses, toxicities, time to progression and overall survival rates were analyzed. RESULTS: Thirty-five consecutive patients were identified. They were treated with bevacizumab 10mg/kg biweekly, associated with irinotecan (n=29; 84%), temozolomide (n=3; 9%) or as single agent (n=3; 9%) for a glioblastoma relapsing after chemoradiation (n=29) or after first line temozolomide only because of a poor general health status or because of multifocal tumor. Two (6%), 28 (80%) and five (14%) patients presented with Recursive Partitioning Analysis (RPA) III, IV and V-VI, respectively. After 2-3 months of treatment, median dose of prednisolone per patient was decreased three times. Clinical improvements or stability were reported in eight (23%) and 17 patients (49%). The best tumor response was partial response in 14 patients (40%), stable disease in nine patients (26%) and tumor progression in 11 patients (31%). Toxicities requiring treatment disruption were reported in five patients (14%). Median survival was 18.4 months (5-41 months). Median time interval between bevacizumab initiation and its disruption because of clinical/radiological progression and/or toxicity was 5.0 months (0.6-21.4 months). Median survival from bevacizumab initiation was 8.1 months (1.4-34 months). CONCLUSION: This single center retrospective experience suggests that bevacizumab is active for recurrent glioblastoma, in a series of poorly selected patients. Median survival times were in the range of those reported in therapeutic trials. This study questions the validity of usual predictive factors in the era of bevacizumab.

A Probabilistic Atlas of Diffuse WHO Grade II Glioma Locations in the Brain.

Diffuse WHO grade II gliomas are diffusively infiltrative brain tumors characterized by an unavoidable anaplastic transformation. Their management is strongly dependent on their location in the brain due to interactions with functional regions and potential differences in molecular biology. In this paper, we present the construction of a probabilistic atlas mapping the preferential locations of diffuse WHO grade II gliomas in the brain. This is carried out through a sparse graph whose nodes correspond to clusters of tumors clustered together based on their spatial proximity. The interest of such an atlas is illustrated via two applications. The first one correlates tumor location with the patient's age via a statistical analysis, highlighting the interest of the atlas for studying the origins and behavior of the tumors. The second exploits the fact that the tumors have preferential locations for automatic segmentation. Through a coupled decomposed Markov Random Field model, the atlas guides the segmentation process, and characterizes which preferential location the tumor belongs to and consequently which behavior it could be associated to. Leave-one-out cross validation experiments on a large database highlight the robustness of the graph, and yield promising segmentation results.

Surgical management of multicentric diffuse low-grade gliomas: functional and oncological outcomes: clinical article.

OBJECT: Multicentric diffuse low-grade gliomas (DLGGs) are defined as widely separated lesions in different lobes or hemispheres where there is no anatomical continuity between lesions. This condition is rare and its clinicopathological characteristics have been scarcely described in the literature. Here, the authors report the first consecutive surgical series of multicentric DLGGs with functional and oncological outcomes. METHODS: A retrospective review of patients surgically treated for histopathologically confirmed multicentric DLGGs between 2000 and 2012 was performed. Information regarding clinical features, surgical procedures, histopathological results, and clinical outcomes was collected and analyzed. RESULTS: Five consecutive patients were included in this study. There were 3 men and 2 women, whose mean age was 27.4 years (range 23-35 years). The mean follow-up period after surgery was 46 months (range 11-138 months). Gross-total or subtotal resection was achieved in all cases, using a single surgery in 3 patients and a 2-stage surgery in 2 patients. There was no mortality or permanent morbidity associated with surgery. The Karnofsky Performance Scale score ranged between 90 and 100 in all cases. Adjuvant chemotherapy was administered in 2 patients because of tumor regrowth with no malignant transformation. CONCLUSIONS: Multicentric DLGGs can be removed safely without inducing severe permanent neurological deficits. Interestingly, a single-stage resection of multiple lesions within different lobes may be performed if tumors are located in the same hemisphere. Therefore, the authors suggest considering surgery as the first therapeutic option for multicentric DLGGs, as in solitary DLGGs.

Awake surgery for WHO Grade II gliomas within "noneloquent" areas in the left dominant hemisphere: toward a "supratotal" resection. Clinical article.

OBJECT: It has been demonstrated that an extensive resection (total or subtotal) may significantly increase the overall survival in patients with WHO Grade II gliomas (low-grade gliomas [LGGs]). Yet, recent data have shown that conventional MR imaging underestimates the spatial extent of LGG, since tumor cells were found up to 20 mm around MR imaging abnormalities. Thus, it was hypothesized that an extended resection with a margin beyond MR imaging-defined abnormalities-a "supratotal" resection-might improve the outcome of LGG. However, because of the frequent location of LGG within "eloquent" brain areas, it is often difficult to achieve such a supratotal resection. This could nevertheless be possible when LGGs involve "noneloquent" areas, even in the left dominant hemisphere. The authors report on their use of awake electrical mapping to tailor the resection according to functional boundaries, that is, to pursue the resection beyond MR imaging-defined abnormalities, until corticosubcortical eloquent structures are encountered. Their aim was to apply this reliable surgical technique to LGGs located not within eloquent areas but distant from eloquent areas, to take a margin around the LGG visible on MR imaging while preserving brain function. METHODS: Fifteen right-handed patients with a total of 17 tumors underwent resection of WHO Grade II gliomas involving nonfunctional areas within the left dominant hemisphere. In all patients, seizures were the initial manifestation of the tumors. Awake surgery with intraoperative electrostimulation was performed in all cases. The resection was continued until the surgeon reached cortical and subcortical areas crucial for brain function, especially language, as defined by the intrasurgical electrical mapping. The extent of resection was evaluated on postoperative FLAIR-weighted MR images. RESULTS: Despite transient neurological worsening in 60% of cases, all patients recovered and returned to a normal life. Seizure control was obtained in all patients with a decrease of antiepileptic drug therapy. Postoperative MR imaging showed that total resection was achieved in all 17 tumors and supratotal resection in 15. The average volume of the postoperative cavity (36.8 cm(3)) was significantly larger than the mean preoperative tumor volume (26.6 cm(3)) (p = 0.009). Neuropathological examination confirmed the diagnosis of WHO Grade II glioma in all cases. The mean duration of postoperative follow-up was 35.7 months (range 6-135 months). Only 4 of 15 patients experienced recurrence (without anaplastic transformation); the average time to recurrence in these cases was 38 months; radiotherapy was performed 6 years after the relapse in 1 case; no other patients received any adjuvant treatment. This series was compared with a control group of 29 patients who had "only" complete resection: anaplastic transformation was observed in 7 cases in the control group but not in any case in the series of patients who underwent supracomplete resection (p = 0.037). Furthermore, adjuvant treatment was administered in 10 patients in the control group compared with 1 patient who underwent supracomplete resection (p = 0.043). CONCLUSIONS: These findings support the usefulness of awake surgery with intraoperative functional (language) mapping with the attempt to perform supratotal resection of LGGs involving noneloquent areas in the left hemisphere. Indeed, the extent of resection was significantly increased in all cases but 2, with no additional permanent deficit and with control of seizures in all patients. The goal of supracomplete resection is currently to delay the anaplastic transformation, even if it does not (yet) enable a cure.