Synchrotron-generated microbeams induce hippocampal transections in rats

Synchrotron-generated microplanar beams (microbeams) provide the most stereo-selective irradiation modality known today. This novel irradiation modality has been shown to control seizures originating from eloquent cortex causing no neurological deficit in experimental animals. To test the hypothesis that application of microbeams in the hippocampus, the most common source of refractory seizures, is safe and does not induce severe side effects, we used microbeams to induce transections to the hippocampus of healthy rats. An array of parallel microbeams carrying an incident dose of 600 Gy was delivered to the rat hippocampus. Immunohistochemistry of phosphorylated gamma-H2AX showed cell death along the microbeam irradiation paths in rats 48 hours after irradiation. No evident behavioral or neurological deficits were observed during the 3-month period of observation. MR imaging showed no signs of radio-induced edema or radionecrosis 3 months after irradiation. Histological analysis showed a very well preserved hippocampal cytoarchitecture and confirmed the presence of clear-cut microscopic transections across the hippocampus. These data support the use of synchrotron-generated microbeams as a novel tool to slice the hippocampus of living rats in a minimally invasive way, providing (i) a novel experimental model to study hippocampal function and (ii) a new treatment tool for patients affected by refractory epilepsy induced by mesial temporal sclerosis

High-Precision Radiosurgical Dose Delivery by Interlaced Microbeam Arrays of High-Flux Low-Energy Synchrotron X-Rays

Microbeam Radiation Therapy (MRT) is a preclinical form of radiosurgery dedicated to brain tumor treatment. It uses micrometer-wide synchrotron-generated X-ray beams on the basis of spatial beam fractionation. Due to the radioresistance of normal brain vasculature to MRT, a continuous blood supply can be maintained which would in part explain the surprising tolerance of normal tissues to very high radiation doses (hundreds of Gy). Based on this well described normal tissue sparing effect of microplanar beams, we developed a new irradiation geometry which allows the delivery of a high uniform dose deposition at a given brain target whereas surrounding normal tissues are irradiated by well tolerated parallel microbeams only. Normal rat brains were exposed to 4 focally interlaced arrays of 10 microplanar beams (52 µm wide, spaced 200 µm on-center, 50 to 350 keV in energy range), targeted from 4 different ports, with a peak entrance dose of 200Gy each, to deliver an homogenous dose to a target volume of 7 mm3 in the caudate nucleus. Magnetic resonance imaging follow-up of rats showed a highly localized increase in blood vessel permeability, starting 1 week after irradiation. Contrast agent diffusion was confined to the target volume and was still observed 1 month after irradiation, along with histopathological changes, including damaged blood vessels. No changes in vessel permeability were detected in the normal brain tissue surrounding the target. The interlacing radiation-induced reduction of spontaneous seizures of epileptic rats illustrated the potential pre-clinical applications of this new irradiation geometry. Finally, Monte Carlo simulations performed on a human-sized head phantom suggested that synchrotron photons can be used for human radiosurgical applications. Our data show that interlaced microbeam irradiation allows a high homogeneous dose deposition in a brain target and leads to a confined tissue necrosis while sparing surrounding tissues. The use of synchrotron-generated X-rays enables delivery of high doses for destruction of small focal regions in human brains, with sharper dose fall-offs than those described in any other conventional radiation therapy

Paramètres influençant la fatigue auditive chez les professionnels du secteur de la musique amplifiée

Les professionnels du secteur de la musique amplifiée sont fréquemment exposés à des niveaux sonores proche de 100 dB(A). Cette population souffre souvent de déficits auditif qui peuvent être particulièrement handicapant pour leur activité. Ce constat « a posteriori » n’est pas satisfaisant dans le cadre d’une politique de prévention. L’évaluation de la fatigue auditive, phénomène physiologique réversible, permettrait d'identifier précocement les situations délétères pour la santé auditive et la mise en place d'actions de prévention avant l’installation d’un déficit auditif permanent. Si on peut aujourd’hui mesurer la fatigue auditive, on connaît encore mal les facteurs induisant une fatigue lors d’une exposition en milieu professionnel, notamment lors d'expositions complexes présentant de fortes variations comme celles observées dans le secteur de la musique. L'objectif de ce travail était par conséquent de déterminer les paramètres de l'exposition sonore et les caractéristiques individuelles influençant fortement la fatigue auditive lors d’une exposition sonore complexe. Les mesures ont été réalisées sur 67 volontaires âgés de 19 à 57 ans, dont 43 étaient exposés à de la musique amplifiée, tandis que 24 étaient non exposés au bruit. Comme attendu, les résultats montrent que la fatigue auditive, est corrélée à l’énergie sonore reçue pendant la journée de travail, mais, fait nouveau, l’étude met en évidence que la distribution temporelle de l’énergie sonore influence également le degré de fatigue. A énergie constante, la stabilité des niveaux sonores tend à augmenter la fatigue. L'instabilité du bruit pourrait en effet permettre des périodes de récupération partielle de la fatigue auditive, même si les périodes « calmes » sont de courtes durées. Les implications en termes de prévention des risques auditifs dans les secteurs du spectacle et de l’industrie seront discutées

Auditory Toxicology

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Dynamical Analysis of Brain Seizure Activity from EEG Signals

International audienceA sudden emergence of seizure activity on a normal background EEG can be seen from visual inspection of the intracranial EEG (iEEG) recordings of Genetic Absence Epilepsy Rat from Strasbourg (GAERS). We observe that most of the recording channels from different brain regions display seizure activity. We wonder if the brain behavior changes within a given seizure. Using source separation methods on temporal sliding windows, we develop a map of dynamic behavior to study this dynamicity. The map is built by computing the correlation functions between the main sources extracted in different time windows. The proposed method is applied on iEEG of four GAERS. We see that the behavior of brain changes about 0.5s-1.5s after onset when the relevant temporal sources become very similar. The corresponding spatial maps for each time window shows that the seizure activity starts from a focus and propagates quickly

Histological analysis of vestibular explants to assess toxicity of chemicals

peer reviewedMany epidemiologic and experimental studies have shown that occupational exposures to aromatic solvents can induce hearing deficits in both humans and laboratory rodents. Although the end-organ of balance, the vestibular labyrinth, is in the inner ear, and has morphological and functional similarities with the cochlea, no information is available on the adverse effects of solvents on this receptor. However, epidemiological data suggest that solvent exposure can generate balance disorders, which might increase the risk of falls. In this paper, we describe the methods for assessing peripheral vestibulotoxicity using cultured vestibular samples (utricles and ampullae) collected from newborn rats. After a few days in culture, these sensory tissues become spheres filled with endolymph, which we call “cysts”. Endolymphatic potassium concentration measurements and histopathological observations were performed to understand the toxic mechanisms and identify the cellular targets of a chemical exposure, an aromatic solvent in this case. The model was tested using molecules with known effects: ouabain, a blocker of Na+/K+ ATPase pumps, gentamicin, a cytotoxic antibiotic for vestibular hair cells, and finally styrene, an aromatic solvent used in industry with well-known cochleotoxic properties

Prediction of soman-induced cerebral damage by distortion product otoacoustic emissions.

International audienceThe organophosphorus nerve agent soman is an irreversible cholinesterase (ChE) inhibitor that can produce long-lasting seizures and seizure-related brain damage (SRBD) in which acetylcholine and glutamate are involved. Since these neurotransmitters play a key-role in the auditory function, it was hypothesized that a hearing test may be an efficient way for detecting the central effects of soman intoxication. In the present study, distortion product otoacoustic emissions (DPOAEs), a non-invasive audiometric method, were used in rats administered with soman (70 μg/kg). Four hours post-soman, DPOAE intensities were significantly decreased. They returned to baseline one day later. The amplitude of the temporary drop of the DPOAEs was well related to the severity of the intoxication. The greatest change was recorded in the rats that survived long-lasting convulsions, i.e. those that showed the highest ChE inhibition in brain and severe encephalopathy. Furthermore, the administration, immediately after soman, of a three-drug therapy composed of atropine sulfate, HI-6 and avizafone abolished the convulsions, the transient drop of DPOAEs at 4h and the occurrence of SRBD at 28 h without modifying brain ChE inhibition. This showed that DPOAE change was not directly related to soman-induced inhibition of cerebral ChE but rather to its neuropathological consequences. The present findings strongly suggest that DPOAEs represent a promising non-invasive tool to predict SRBD occurrence in nerve agent poisoning and to control the efficacy of a neuroprotective treatment

Aberrant neuronal connectivity in the cortex drives generation of seizures in rat Absence Epilepsy

International audienceAbsence epilepsy belongs to genetic epilepsies and is characterized by recurrent generalized seizures that are concomitant with alterations of consciousness and associated with cognitive comorbidities. Little is known about the mechanisms leading to occurrence of epileptic seizures (i.e. epileptogenesis) and, in particular, it remains an open question as to whether neuronal hypersynchronization, a key feature in seizure initiation, could result from aberrant structural connectivity within neuronal networks endowing them with epileptic properties. In the present study, we addressed this question using a genetic model of absence epilepsy in the rat where seizures initiate in the whisker primary somatosensory cortex (wS1). We hypothesized that alterations in structural connectivity of neuronal networks within wS1 contribute to pathological neuronal synchronization responsible for seizures. First, we used rabies virus-mediated retrograde synaptic tracing and showed that cortical neurons located in both upper- and deep-layers of wS1 displayed aberrant and significantly increased connectivity in the genetic model of absence epilepsy, as highlighted by a higher number of presynaptic partners. Next, we showed at the functional level that disrupting these aberrant wS1 neuronal networks with synchrotron X-ray-mediated cortical microtransections drastically decreased both the synchronization and seizure power of wS1 neurons, as revealed by in vivo local field potential recordings with multichannel probes. Taken together, our data provide for the first time strong evidence that increased structural connectivity patterns of cortical neurons represent critical pathological substrates for increased neuronal synchronization and generation of absence seizures