ObjectiveFollowing surgery, focal seizures relapse in 20% to 50% of cases due to the difficulty of delimiting the epileptogenic zone (EZ) by current imaging or electrophysiological techniques. Here, we evaluate an unbiased metabolomics approach based on ex vivo and in vivo nuclear magnetic resonance spectroscopy (MRS) methods to discriminate the EZ in a mouse model of mesiotemporal lobe epilepsy (MTLE).MethodsFour weeks after unilateral injection of kainic acid (KA) into the dorsal hippocampus of mice (KA‐MTLE model), we analyzed hippocampal and cortical samples with high‐resolution magic angle spinning (HRMAS) magnetic resonance spectroscopy (MRS). Using advanced multivariate statistics, we identified the metabolites that best discriminate the injected dorsal hippocampus (EZ) and developed an in vivo MEGAPRESS MRS method to focus on the detection of these metabolites in the same mouse model.ResultsMultivariate analysis of HRMAS data provided evidence that γ‐aminobutyric acid (GABA) is largely increased in the EZ of KA‐MTLE mice and is the metabolite that best discriminates the EZ when compared to sham and, more importantly, when compared to adjacent brain regions. These results were confirmed by capillary electrophoresis analysis and were not reversed by a chronic exposition to an antiepileptic drug (carbamazepine). Then, using in vivo noninvasive GABA‐edited MRS, we confirmed that a high GABA increase is specific to the injected hippocampus of KA‐MTLE mice.SignificanceOur strategy using ex vivo MRS‐based untargeted metabolomics to select the most discriminant metabolite(s), followed by in vivo MRS‐based targeted metabolomics, is an unbiased approach to accurately define the EZ in a mouse model of focal epilepsy. Results suggest that GABA is a specific biomarker of the EZ in MTLE.
Purpose This work aims to explore the effect of Blood Brain Barrier (BBB) opening using ultrasound combined with microbubbles injection on cerebral blood flow in rats. Methods Two groups of n = 5 rats were included in this study. The first group was used to investigate the impact of BBB opening on the Arterial Spin Labeling (ASL) signal, in particular on the arterial transit time (ATT). The second group was used to analyze the spatiotemporal evolution of the change in cerebral blood flow (CBF) over time following BBB opening and validate these results using DSC‐MRI. Results Using pCASL, a decrease in CBF of up to 29.6prefix±15.1%$$ 29.6\pm 15.1\% $$ was observed in the target hemisphere, associated with an increase in arterial transit time. The latter was estimated to be normal533prefix±normal121ms$$ 533\pm 12\mathrm{1ms} $$ in the BBB opening impacted regions against normal409prefix±normal93ms$$ 409\pm 93\mathrm{ms} $$ in the contralateral hemisphere. The spatio‐temporal analysis of CBF maps indicated a nonlocal hypoperfusion. DSC‐MRI measurements were consistent with the obtained results. Conclusion This study provided strong evidence that BBB opening using microbubble intravenous injection induces a transient hypoperfusion. A spatiotemporal analysis of the hypoperfusion changes allows to establish some points of similarity with the cortical spreading depression phenomenon.
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