Overt speech critically changes lateralization index and did not allow determination of hemispheric dominance for language: an fMRI study.

BACKGROUND: Pre-surgical mapping of language using functional MRI aimed principally to determine the dominant hemisphere. This mapping is currently performed using covert linguistic task in way to avoid motion artefacts potentially biasing the results. However, overt task is closer to natural speaking, allows a control on the performance of the task, and may be easier to perform for stressed patients and children. However, overt task, by activating phonological areas on both hemispheres and areas involved in pitch prosody control in the non-dominant hemisphere, is expected to modify the determination of the dominant hemisphere by the calculation of the lateralization index (LI). OBJECTIVE: Here, we analyzed the modifications in the LI and the interactions between cognitive networks during covert and overt speech task. METHODS: Thirty-three volunteers participated in this study, all but four were right-handed. They performed three functional sessions consisting of (1) covert and (2) overt generation of a short sentence semantically linked with an audibly presented word, from which we estimated the "Covert" and "Overt" contrasts, and a (3) resting-state session. The resting-state session was submitted to spatial independent component analysis to identify language network at rest (LANG), cingulo-opercular network (CO), and ventral attention network (VAN). The LI was calculated using the bootstrapping method. RESULTS: The LI of the LANG was the most left-lateralized (0.66 ± 0.38). The LI shifted from a moderate leftward lateralization for the Covert contrast (0.32 ± 0.38) to a right lateralization for the Overt contrast (- 0.13 ± 0.30). The LI significantly differed from each other. This rightward shift was due to the recruitment of right hemispheric temporal areas together with the nodes of the CO. CONCLUSION: Analyzing the overt speech by fMRI allowed improvement in the physiological knowledge regarding the coordinated activity of the intrinsic connectivity networks. However, the rightward shift of the LI in this condition did not provide the basic information on the hemispheric language dominance. Overt linguistic task cannot be recommended for clinical purpose when determining hemispheric dominance for language.

Overt speech feasibility using continuous functional magnetic resonance imaging: Isolation of areas involved in phonology and prosody.

To avoid motion artifacts, almost all speech-related functional magnetic resonance imagings (fMRIs) are performed covertly to detect language activations. This method may be difficult to execute, especially by patients with brain tumors, and does not allow the identification of phonological areas. Here, we aimed to evaluate overt task feasibility. Thirty-three volunteers participated in this study. They performed two functional sessions of covert and overt generation of a short sentence semantically linked with a word. Three main contrasts were performed: Covert and Overt for the isolation of language-activated areas, and Overt > Covert for the isolation of the motor cortical activation of speech. fMRI data preprocessing was performed with and without unwarping, and with and without regression of movement parameters as confounding variables. All types of results were compared to each other. For the Overt contrast, Dice coefficients showed strong overlap between each pair of types of results: 0.98 for the pair with and without unwarping, and 0.9 for the pair with and without movement parameter regression. The Overt > Covert contrast allowed isolation of motor laryngeal activations with high statistical reliability and revealed the right-lateralized temporal activity related to acoustic feedback. Overt speaking during magnetic resonance imaging induced few artifacts and did not significantly affect the results, allowing the identification of areas involved in primary motor control and prosodic regulation of speech. Unwarping and motion artifact regression in the postprocessing step, seem to not be necessary. Changes in lateralization of cortical activity by overt speech shall be explored before using these tasks for presurgical mapping.

Phase I/IIa study of concomitant radiotherapy with olaparib and temozolomide in unresectable or partially resectable glioblastoma: OLA-TMZ-RTE-01 trial protocol.

BACKGROUND: Despite multimodality treatments including neurosurgery, radiotherapy and chemotherapy, glioblastoma (GBM) prognosis remains poor. GBM is classically considered as a radioresistant tumor, because of its high local recurrence rate, inside the irradiation field. The development of new radiosensitizer is crucial to improve the patient outcomes. Pre-clinical data showed that Poly (ADP-ribose) polymerase inhibitors (PARPi) could be considered as a promising class of radiosensitizer. The aim of this study is to evaluate Olaparib, a PARPi, as radiosensitizing agent, combined with the Stupp protocol, namely temozolomide (TMZ) and intensity modulated radiotherapy (IMRT) in first line treatment of partially or non-resected GBM. METHODS: The OLA-TMZ-RTE-01 study is a multicenter non-randomized phase I/IIa trial including unresectable or partially resectable GBM patients, from 18 to 70 years old. A two-step dose-escalation phase I design will first determine the recommended phase 2 dose (RP2D) of olaparib, delivered concomitantly with TMZ plus conventional irradiation for 6 weeks and as single agent for 4 weeks (radiotherapy period), and second, the RP2D of olaparib combined with adjuvant TMZ (maintenance period). Phase IIa will assess the 18-month overall survival (OS) of this combination. In both phase I and IIa separately considered, the progression-free survival, the objective response rate, the neurocognitive functions of patients, emotional disorders among caregivers, the survival without toxicity, degradation nor progression, the complications onset and the morphologic and functional MRI (magnetic resonance imaging) parameters will be also assessed as secondary objectives. Ancillary objectives will explore alteration of the DNA repair pathways on biopsy tumor, proton magnetic resonance spectroscopy parameters to differentiate tumor relapse and radionecrosis, and an expanded cognition evaluation. Up to 79 patients will be enrolled: 30 patients in the phase I and 49 patients in the phase IIa. DISCUSSION: Combining PARP inhibitors, such as olaparib, with radiotherapy and chemotherapy in GBM may improve survival outcomes, while sparing healthy tissue and preserving neurocognitive function, given the replication-dependent efficacy of olaparib, and the increased PARP expression in GBM as compared to non-neoplastic brain tissue. Ancillary studies will help to identify genetic biomarkers predictive of PARPi efficacy as radiosensitizer. TRIAL REGISTRATION: NCT03212742 , registered June, 7, 2017. Protocol version: Version 2.2 dated from 2017/08/18.

Comparison between MRI-derived ADC maps and 18FLT-PET in pre-operative glioblastoma.

BACKGROUND AND PURPOSE: Among principal MRI sequences used for a better pre-therapeutic characterization of glioblastoma (GBM), DWI-derived ADC is expected to be a good parameter for the evaluation of cellularity, due to restricted water diffusivity. We aimed here to compare ADC maps to 18FLT-PET, a proliferation tracer, in GBM cases. MATERIALS AND METHODS: Patients underwent 18FLT-PET, followed by multiparametric magnetic resonance imaging (MRI) just prior to surgery. We analysed in this study twenty GBM confirmed patients. The 5th percentile (5p) of the ADC values were thresholded to define the ADCmin ROI, while the 95th percentile (95p) of the SUV FLT values were used to define the FLTmax ROI. The statistical and spatial correlations between these two groups of ROIs were analyzed. RESULTS: We did not observe any significant correlations between ADCmin and FLTmax cut-off values (R2=0.0285), neither between ADCmin and FLTmax ROIs (mean Dice=0.09±0.12). Mean ADC values in the FLTmax defined ROI were significantly higher than the values in the ADCmin ROI (P<0.001). Mean FLT values in the FLTmax ROI were significantly higher than the values in the ADCmin ROI (P<0.001). CONCLUSIONS: When comparing ADC maps to 18FLT uptake, we did not observe significant anatomical overlap nor correlation, between the regions of low ADC and high FLT disabling to clearly link ADC values to cellular proliferation. The exact significance of ADC maps in GBM has yet to be elaborated.

New insights into the anatomo-functional architecture of the right sagittal stratum and its surrounding pathways: an axonal electrostimulation mapping study.

The sagittal stratum (SS) is a large sheet-like structure where major axonal fiber tracts cross, though its anatomical delineations are still debated. Here we investigated the poorly studied anatomo-functional organization of the right SS using direct electrical stimulation (DES) in patients undergoing wide-awake surgery for a cerebral glioma. Seventeen patients were included. There were six males, the mean age was 38 years old. One patient underwent surgery twice. Fourteen patients were right-handed and one was ambidextrous. Behavior tasks were used to monitor online the patients' functions during DES, including visual and somesthetic processes, semantics, language, spatial and social cognition. Beyond the cortical DES, the mapping of axonal pathways evoked various functional responses. At the level of the core of the right SS, there were visual disturbances, visual hemi-agnosia, semantic paraphasia, left spatial neglect, confusion and comprehension difficulties, anomia, and mentalizing disturbances. At the level of the surrounding axonal pathways, there were left spatial neglect, anomia, vertigo, dysesthesia, and hearing disturbances. Our functionally defined three-dimensional map indicates that this complex region has a multilayered functional architecture, and supports an organization founded on two anatomical systems: a core system formed by the optic radiations, inferior longitudinal fasciculus, and inferior fronto-occipital fasciculus, and a peripheral one composed of surrounding or intersecting white matter tracts, including the superior longitudinal fasciculus/arcuate fasciculus, thalamocortical radiations, auditory radiations, and parieto-insular vestibular system. These results should prompt neurosurgeons to achieve awake DES mapping within the right SS because of the likelihood of causing multiple and irreversible structural disconnections.

Simultaneous Mapping of Vasculature, Hypoxia, and Proliferation Using Dynamic Susceptibility Contrast MRI, 18F-FMISO PET, and 18F-FLT PET in Relation to Contrast Enhancement in Newly Diagnosed Glioblastoma.

Conventional MRI plays a key role in the management of patients with high-grade glioma, but multiparametric MRI and PET tracers could provide further information to better characterize tumor metabolism and heterogeneity by identifying regions having a high risk of recurrence. In this study, we focused on proliferation, hypervascularization, and hypoxia, all factors considered indicative of poor prognosis. They were assessed by measuring uptake of 18F-3'-deoxy-3'-18F-fluorothymidine (18F-FLT), relative cerebral blood volume (rCBV) maps, and uptake of 18F-fluoromisonidazole (18F-FMISO), respectively. For each modality, the volumes and high-uptake subvolumes (hot spots) were semiautomatically segmented and compared with the contrast enhancement (CE) volume on T1-weighted gadolinium-enhanced (T1w-Gd) images, commonly used in the management of patients with glioblastoma. Methods: Dynamic susceptibility contrast-enhanced MRI (31 patients), 18F-FLT PET (20 patients), or 18F-FMISO PET (20 patients), for a total of 31 patients, was performed on preoperative glioblastoma patients. Volumes and hot spots were segmented on SUV maps for 18F-FLT PET (using the fuzzy locally adaptive bayesian algorithm) and 18F-FMISO PET (using a mean contralateral image + 3.3 SDs) and on rCBV maps (using a mean contralateral image + 1.96 SDs) for dynamic susceptibility contrast-enhanced MRI and overlaid on T1w-Gd images. For each modality, the percentages of the peripheral volumes and the peripheral hot spots outside the CE volume were calculated. Results: All tumors showed highly proliferated, hypervascularized, and hypoxic regions. The images also showed pronounced heterogeneity of both tracers regarding their uptake and rCBV maps, within each individual patient. Overlaid volumes on T1w-Gd images showed that some proliferative, hypervascularized, and hypoxic regions extended beyond the CE volume but with marked differences between patients. The ranges of peripheral volume outside the CE volume were 1.6%-155.5%, 1.5%-89.5%, and 3.1%-78.0% for 18F-FLT, rCBV, and 18F-FMISO, respectively. All patients had hyperproliferative hot spots outside the CE volume, whereas hypervascularized and hypoxic hot spots were detected mainly within the enhancing region. Conclusion: Spatial analysis of multiparametric maps with segmented volumes and hot spots provides valuable information to optimize the management and treatment of patients with glioblastoma.

Clip-first policy versus coil-first policy for the exclusion of middle cerebral artery aneurysms.

OBJECTIVE: Middle cerebral artery (MCA) aneurysms are a particular subset of intracranial aneurysms that can be excluded by clipping or coiling. A comparison of the results between these two methods is often limited by a selection bias in which wide-neck and large aneurysms are frequently treated with surgery. Here, the authors report the results of two centers using opposing policies in the management of MCA aneurysms: one center used a clip-first policy while the other used a coil-first policy, which limited the selection bias and ensured a good comparison of these two treatment modalities. METHODS: All patients treated for either ruptured or unruptured MCA aneurysms at one of two institutions between January 2012 and December 2015 were eligible for inclusion in this study. At one center a clip-first policy was applied, whereas the other applied a coil-first policy. The authors retrospectively reviewed the medical records of these patients and compared their clinical and radiological outcomes. RESULTS: A total of 187 aneurysms were treated during the inclusion period; 88 aneurysms were treated by coiling and 99 aneurysms by clipping. The baseline patient and radiological characteristics were similar between the two groups, but the clinical presentation of the ruptured aneurysm cohort differed slightly. In the ruptured cohort (n = 90), although patients in the coiling group had a higher rate of additional surgery, the complication rate, functional outcome, and risk of death were similar between the two treatment groups. In the unruptured cohort (n = 97), the complication rate, functional outcome, and risk of death were also similar between the two treatment groups, although the risk of discomfort related to the temporal muscle atrophy was higher in the surgical group. Overall, the rate of complete occlusion was higher in the clipping group (84.2%) than in the coiling group (31%), which led to a higher risk in the coiling group of aneurysm retreatment within the first 2 years (p = 0.04). CONCLUSIONS: Clipping and coiling for MCA aneurysm treatment provide the same clinical outcome for ruptured and unruptured aneurysms. However, clipping provides higher short- and long-term rates of complete exclusion, which in turn decreases the risk of aneurysm retreatment. Whether this lower occlusion rate can have a clinical impact in the long-term must be further evaluated.

Resting-state functional magnetic resonance imaging versus task-based activity for language mapping and correlation with perioperative cortical mapping.

INTRODUCTION: Preoperative language mapping using functional magnetic resonance imaging (fMRI) aims to identify eloquent areas in the vicinity of surgically resectable brain lesions. fMRI methodology relies on the blood-oxygen-level-dependent (BOLD) analysis to identify brain language areas. Task-based fMRI studies the BOLD signal increase in brain areas during a language task to identify brain language areas, which requires patients' cooperation, whereas resting-state fMRI (rsfMRI) allows identification of functional networks without performing any explicit task through the analysis of the synchronicity of spontaneous BOLD signal oscillation between brain areas. The aim of this study was to compare preoperative language mapping using rsfMRI and task fMRI to cortical mapping (CM) during awake craniotomies. METHODS: Fifty adult patients surgically treated for a brain lesion were enrolled. All patients had a presurgical language mapping with both task fMRI and rsfMRI. Identified language networks were compared to perioperative language mapping using electric cortical stimulation. RESULTS: Resting-state fMRI was able to detect brain language areas during CM with a sensitivity of 100% compared to 65.6% with task fMRI. However, we were not able to perform a specificity analysis and compare task-based and rest fMRI with our perioperative setting in the current study. In second-order analysis, task fMRI imaging included main nodes of the SN and main areas involved in semantics were identified in rsfMRI. CONCLUSION: Resting-state fMRI for presurgical language mapping is easy to implement, allowing the identification of functional brain language network with a greater sensitivity than task-based fMRI, at the cost of some precautions and a lower specificity. Further study is required to compare both the sensitivity and the specificity of the two methods and to evaluate the clinical value of rsfMRI as an alternative tool for the presurgical identification of brain language areas.

In Vivo Relationship Between Hypoxia and Angiogenesis in Human Glioblastoma: A Multimodal Imaging Study.

Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor. This aggressiveness is in part attributed to the closely interrelated phenomena tumor hypoxia and angiogenesis, although few in vivo data exist in human brain tumors. This work aimed to study hypoxia and angiogenesis, in vivo and in situ, in patients admitted with GBM using multimodal imaging. Methods: Twenty-three GBM patients were assessed by 18F-fluoromisonidazole (18F-FMISO) PET and conventional and perfusion MRI before surgery. The level and location of hypoxia (18F-FMISO uptake, evaluated by tumor-to-blood [T/B] ratio), vascularization (cerebral blood volume [CBV]), and vascular permeability (contrast enhancement after gadolinium injection) were analyzed. The spatial relationship between tumor hypoxia and angiogenesis was assessed by an overlap analysis of the volume of 18F-FMISO uptake and the volumes of the high CBV regions and the contrast-enhancement regions. Results: A significant correlation was found between hypoxia and hypervascularization, especially for their maximum values (volume of maximal tumor hypoxia vs. relative CBV: r = 0.61, P = 0.002) and their volumes (hypoxia vs. hypervascularization: r = 0.91, P < 0.001). A large proportion of the high CBVs collocated with hypoxia (81.3%) and with contrast enhancement (46.5%). Conclusion: These results support the hypothesis of a tight association between hypoxia and angiogenesis. Our results suggest that there is insufficient tumor oxygenation in human GBM, despite increased tumor vascularization.