EEG-fMRI in awake rat and whole-brain simulations show decreased brain responsiveness to sensory stimulations during absence seizures.

In patients suffering absence epilepsy, recurring seizures can significantly decrease their quality of life and lead to yet untreatable comorbidities. Absence seizures are characterized by spike-and-wave discharges on the electroencephalogram associated with a transient alteration of consciousness. However, it is still unknown how the brain responds to external stimuli during and outside of seizures. This study aimed to investigate responsiveness to visual and somatosensory stimulation in Genetic Absence Epilepsy Rats from Strasbourg (GAERS), a well-established rat model for absence epilepsy. Animals were imaged under non-curarized awake state using a quiet, zero echo time, functional magnetic resonance imaging (fMRI) sequence. Sensory stimulations were applied during interictal and ictal periods. Whole-brain hemodynamic responses were compared between these two states. Additionally, a mean-field simulation model was used to explain the changes of neural responsiveness to visual stimulation between states. During a seizure, whole-brain responses to both sensory stimulations were suppressed and spatially hindered. In the cortex, hemodynamic responses were negatively polarized during seizures, despite the application of a stimulus. The mean-field simulation revealed restricted propagation of activity due to stimulation and agreed well with fMRI findings. Results suggest that sensory processing is hindered or even suppressed by the occurrence of an absence seizure, potentially contributing to decreased responsiveness during this absence epileptic process.

MP3: Medical Software for Processing Multi-Parametric Images Pipelines.

This article presents an open source software able to convert, display, and process medical images. It differentiates itself from the existing software by its ability to design complex processing pipelines and to wisely execute them on a large databases. An MP3 pipeline can contain unlimited homemade or ready-made processes and can be carried out with a parallel execution system. As a viewer, MP3 allows display of up to four images together and to draw Regions Of Interest (ROI). Two applications showing the strengths of the software are presented as examples: a preclinical study involving Magnetic Resonance Imaging (MRI) data and a clinical one involving Computed Tomography (CT) images. MP3 is downloadable at https://github.com/nifm-gin/MP3.

MRI Assessment of Oxygen Metabolism and Hemodynamic Status in Symptomatic Intracranial Atherosclerotic Stenosis: A Pilot Study.

BACKGROUND AND PURPOSE: Hemodynamic and metabolic impairment in intracranial atherosclerotic stenosis (ICAS) may promote stroke vulnerability particularly in borderzone areas. Perfusion and oxygen mapping magnetic resonance imaging (MRI) may provide useful information in this setting. METHODS: In this pilot study, patients with symptomatic atherosclerotic anterior circulation stenosis ≥60%, without other sources of ischemic stroke, were included. High-resolution vessel wall MRI quantified the stenosis degree, and hemodynamic and metabolic impairment was assessed at baseline using dynamic susceptibility contrast perfusion and multiparametric quantitative blood-oxygen-level-dependent (mqBOLD) oxygenation MRI. All parameters were assessed within both hemispheres and in borderzone areas. RESULTS: Forty-three subjects with intracranial artery narrowing were screened from November 2014 to January 2016. Eleven patients met the study criteria (mean ± standard deviation age = 64.4 ± 10.6 years, the mean degree of stenosis was 76.9 ± 23.4%). No interhemispheric differences were observed across oxygen (cerebral metabolic rate of oxygen and tissular saturation of oxygen) or perfusion (mean transit time, time to maximum, Tmax , normalized cerebral blood volume [nCBV], and normalized cerebral blood flow) parameters. A positive correlation was observed between the stenosis degree and ipsilateral nCBV (R = .77, P = .008). In addition, a significant increase in CBV was observed in anterior cortical borderzones ipsilateral to stenosis (nCBV = 7.20 ± 1.81 vs. 5.45 ± 1.40 mL/100 g, P = .02). CONCLUSION: Symptomatic ICAS had no global impact on perfusion and oxygen mapping MRI at resting state. A significant increase in nCBV was found within anterior borderzone areas.

Hyperosmolar treatment of soman-induced brain lesions in mice: evaluation of the effects through diffusion-weighted magnetic resonance imaging and through histology.

PURPOSE: A convulsive dose of soman induces seizure-related brain damage (SRBD), including cerebral edema (CE) and neuronal loss. In the present study on soman-intoxicated mice, we applied diffusion-weighted magnetic resonance imaging (DW-MRI) and quantitative histology, and we measured brain water content to investigate the antiedematous and neuroprotective efficacies of two hyperosmolar treatments: mannitol (Mann) and hypertonic saline (HTS). METHODS: Mice intoxicated with soman (172 microg/kg after a protective pretreatment) were administered 1 min and 5-h post-challenge an i.v. bolus of saline, of Mann or of HTS. 1 day later, mice were examined with DW-MRI and then sacrificed for brain histology. Additional animals were intoxicated and treated similarly for the measurement of the brain water content (dry/wet weight method). RESULTS: In intoxicated controls, a significant decrease of the apparent diffusion coefficient (ADC), numerous damaged (eosinophilic) cells, high edema scores, and a significant increase in brain water content were detected 24-h post-challenge in sensitive brain structures. These soman-induced changes were not significantly modified by treatment with Mann or HTS. CONCLUSIONS: Treatment with hyperosmolar solutions did not reduce the effects of soman on ADC, on cell damage and on CE. Therefore, despite similar treatment protocols, the prominent protection by Mann that was previously demonstrated by others in poisoned rats, was not reproduced in our murine model.

MRI-guided clinical 6-MV radiosensitization of glioma using a unique gadolinium-based nanoparticles injection.

AIM: This study reports the use of gadolinium-based AGuIX nanoparticles (NPs) as a theranostic tool for both image-guided radiation therapy and radiosensitization of brain tumors. MATERIALS & METHODS: Pharmacokinetics and regulatory toxicology investigations were performed on rodents. The AGuIX NPs' tumor accumulation was studied by MRI before 6-MV irradiation. RESULTS: AGuIX NPs exhibited a great safety profile. A single intravenous administration enabled the tumor delineation by MRI with a T1 tumor contrast enhancement up to 24 h, and the tumor volume reduction when combined with a clinical 6-MV radiotherapy. CONCLUSION: This study demonstrates the efficacy and the potential of AGuIX NPs for image-guided radiation therapy, promising properties that will be assessed in the upcoming Phase I clinical trial.

An MRI-based classification scheme to predict passive access of 5 to 50-nm large nanoparticles to tumors.

Nanoparticles are useful tools in oncology because of their capacity to passively accumulate in tumors in particular via the enhanced permeability and retention (EPR) effect. However, the importance and reliability of this effect remains controversial and quite often unpredictable. In this preclinical study, we used optical imaging to detect the accumulation of three types of fluorescent nanoparticles in eight different subcutaneous and orthotopic tumor models, and dynamic contrast-enhanced and vessel size index Magnetic Resonance Imaging (MRI) to measure the functional parameters of these tumors. The results demonstrate that the permeability and blood volume fraction determined by MRI are useful parameters for predicting the capacity of a tumor to accumulate nanoparticles. Translated to a clinical situation, this strategy could help anticipate the EPR effect of a particular tumor and thus its accessibility to nanomedicines.

Microtubule-associated protein 6 mediates neuronal connectivity through Semaphorin 3E-dependent signalling for axonal growth.

Structural microtubule associated proteins (MAPs) stabilize microtubules, a property that was thought to be essential for development, maintenance and function of neuronal circuits. However, deletion of the structural MAPs in mice does not lead to major neurodevelopment defects. Here we demonstrate a role for MAP6 in brain wiring that is independent of microtubule binding. We find that MAP6 deletion disrupts brain connectivity and is associated with a lack of post-commissural fornix fibres. MAP6 contributes to fornix development by regulating axonal elongation induced by Semaphorin 3E. We show that MAP6 acts downstream of receptor activation through a mechanism that requires a proline-rich domain distinct from its microtubule-stabilizing domains. We also show that MAP6 directly binds to SH3 domain proteins known to be involved in neurite extension and semaphorin function. We conclude that MAP6 is critical to interface guidance molecules with intracellular signalling effectors during the development of cerebral axon tracts.

Blood-brain barrier permeability to manganese and to Gd-DOTA in a rat model of transient cerebral ischaemia.

Loss of integrity of the blood-brain barrier (BBB) and brain swelling is a potentially lethal complication of reperfusion in human stroke. To assess the time course of BBB modifications, we performed angiography, diffusion-weighted imaging, T1-weighted (T1 W) imaging and T1 mapping, and monitored acute changes after middle cerebral artery occlusion and recanalization in rats (n = 27). The animals were grouped according to the duration of occlusion: 30 min (group A, n = 8), 1 h 30 min (group B, n = 9), and 2 h 30 min (group C, n = 10). For 17 animals (four in group A, six in group B, and seven in group C), MnCl2 and dimeglumine gadoterate (Gd-DOTA) were injected at 13 min and 34 min after recanalization, respectively. The 10 remaining animals (control groups) underwent the same acquisition protocols, but no contrast agents were injected. Cell damage was determined 1 h after recanalization on haematoxylin and eosin-stained sections. Our results indicate that in the middle cerebral artery occlusion model in the rat, changes in BBB permeability assessed by contrast agent extravasation occur within the first hour of reperfusion, even after an occlusion period not exceeding 30 min. No differences between BBB permeability to Gd-DOTA and Mn2+ were detected in our experimental conditions. The reduction in apparent diffusion coefficient during occlusion appears to be a good predictor of BBB modifications after reperfusion in this model.

Cerebral edema induced in mice by a convulsive dose of soman. Evaluation through diffusion-weighted magnetic resonance imaging and histology.

PURPOSE: In the present study, diffusion-weighted magnetic resonance imaging (DW-MRI) and histology were used to assess cerebral edema and lesions in mice intoxicated by a convulsive dose of soman, an organophosphate compound acting as an irreversible cholinesterase inhibitor. METHODS: Three hours and 24 h after the intoxication with soman (172 microg/kg), the mice were anesthetized with an isoflurane/N(2)O mixture and their brain examined with DW-MRI. After the imaging sessions, the mice were sacrificed for histological analysis of their brain. RESULTS: A decrease in the apparent diffusion coefficient (ADC) was detected as soon as 3 h after the intoxication and was found strongly enhanced at 24 h. A correlation was obtained between the ADC change and the severity of the overall brain damage (edema and cellular degeneration): the more severe the damage, the stronger the ADC drop. Anesthesia was shown to interrupt soman-induced seizures and to attenuate edema and cell change in certain sensitive brain areas. Finally, brain water content was assessed using the traditional dry/wet weight method. A significant increase of brain water was observed following the intoxication. CONCLUSIONS: The ADC decrease observed in the present study suggests that brain edema in soman poisoning is mainly intracellular and cytotoxic. Since entry of water into the brain was also evidenced, this type of edema is certainly mixed with others (vasogenic, hydrostatic, osmotic). The present study confirms the potential of DW-MRI as a non-invasive tool for monitoring the acute neuropathological consequences (edema and neurodegeneration) of soman-induced seizures.

The effects of sustained hyperventilation on regional cerebral blood volume in thiopental-anesthetized rats.

UNLABELLED: Sustained hyperventilation has a time-limited effect on cerebrovascular dynamics. We investigated whether this effect was similar among brain regions by measuring regional cerebral blood volume (CBV) with steady-state susceptibility contrast magnetic resonance imaging during 3 h of hyperventilation. Regional CBV was determined in nine thiopental-anesthetized, mechanically-ventilated rats every 30 min in the dorsoparietal neocortex, the corpus striatum, and the cerebellum. The corpus striatum was the only brain region showing a stable reduction in CBV during the hypocapnic episode (PaCO(2), 24 +/- 3 mm Hg). In contrast, neocortex and, to a lesser extent, cerebellum exhibited a progressive return toward normal values despite continued hypocapnia. No evidence of a rebound in CBV was found on return to normal ventilation in the three brain regions. We conclude that sustained hyperventilation can lead to an uneven change in the reduction of CBV, possibly because of differences of brain vessels in their sensitivity to extracellular pH. Our results in neocortex confirm the transient effect of sustained hyperventilation on cerebral hemodynamics. IMPLICATIONS: Sustained hyperventilation has a transient effect in decreasing cerebral blood volume (CBV). Using susceptibility contrast magnetic resonance imaging in thiopental-anesthetized rats, we found differences between brain regions in their transient CBV response to sustained hyperventilation.