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Background and Hypothesis Converging lines of evidence suggest that dysfunction of cortical GABAergic inhibitory interneurons is a core feature of psychosis. This dysfunction is thought to underlie neuroimaging abnormalities commonly found in patients with psychosis, particularly in the hippocampus. These include increases in resting cerebral blood flow (CBF) and glutamatergic metabolite levels, and decreases in ligand binding to GABAA α5 receptors and to the synaptic density marker synaptic vesicle glycoprotein 2A (SV2A). However, direct links between inhibitory interneuron dysfunction and these neuroimaging readouts are yet to be established. Conditional deletion of a schizophrenia susceptibility gene, the tyrosine kinase receptor Erbb4, from cortical and hippocampal inhibitory interneurons leads to synaptic defects, and behavioral and cognitive phenotypes relevant to psychosis in mice. Study Design Here, we investigated how this inhibitory interneuron disruption affects hippocampal in vivo neuroimaging readouts. Adult Erbb4 conditional mutant mice (Lhx6-Cre;Erbb4F/F, n = 12) and their wild-type littermates (Erbb4F/F, n = 12) were scanned in a 9.4T magnetic resonance scanner to quantify CBF and glutamatergic metabolite levels (glutamine, glutamate, GABA). Subsequently, we assessed GABAA receptors and SV2A density using quantitative autoradiography. Results Erbb4 mutant mice showed significantly elevated ventral hippccampus CBF and glutamine levels, and decreased SV2A density across hippocampus sub-regions compared to wild-type littermates. No significant GABAA receptor density differences were identified. Conclusions These findings demonstrate that specific disruption of cortical inhibitory interneurons in mice recapitulate some of the key neuroimaging findings in patients with psychosis, and link inhibitory interneuron deficits to non-invasive measures of brain function and neurochemistry that can be used across species.

Acute ischemic stroke results in an ischemic core surrounded by a tissue at risk, named the penumbra, which is potentially salvageable. One way to differentiate the tissues is to measure the hypoxia status. The purpose of the current study is to correlate the abnormal brain tissue volume derived from magnetic resonance-based imaging of brain oxygen saturation (S

International audience; Recent evidence has shown that even mild mutations in the Huntingtin gene that are associated with late-onset Huntington’s disease (HD) disrupt various aspects of human neurodevelopment. To determine whether these seemingly subtle early defects affect adult neural function, we investigated neural circuit physiology in newborn HD mice. During the first postnatal week, HD mice have less cortical layer 2/3 excitatory synaptic activity than wild-type mice, express fewer glutamatergic receptors, and show sensorimotor deficits. The circuit self-normalizes in the second postnatal week but the mice nonetheless develop HD. Pharmacologically enhancing glutamatergic transmission during the neonatal period, however, rescues these deficits and preserves sensorimotor function, cognition, and spine and synapse density as well as brain region volume in HD adult mice.

ImUnity is an original deep-learning model designed for efficient and flexible MR image harmonization. A VAE-GAN network, coupled with a confusion module and an optional biological preservation module, uses multiple 2D-slices taken from different anatomical locations in each subject of the training database, as well as image contrast transformations for its self-supervised training. It eventually generates 'corrected' MR images that can be used for various multi-center population studies. Using 3 open source databases (ABIDE, OASIS and SRPBS), which contain MR images from multiple acquisition scanner types or vendors and a large range of subjects ages, we show that ImUnity: (1) outperforms state-of-the-art methods in terms of quality of images generated using traveling subjects; (2) removes sites or scanner biases while improving patients classification; (3) harmonizes data coming from new sites or scanners without the need for an additional fine-tuning and (4) allows the selection of multiple MR reconstructed images according to the desired applications. Tested here on T1-weighted images, ImUnity could be used to harmonize other types of medical images., 15 pages, 7 Figures

Vascular dysfunction is increasingly recognized to play a role in the development of Alzheimer’s disease (AD). The relation between vascular dysfunction and the neuropathological amyloid β accumulation characteristic for AD is however unclear. The limited resolution of in vivo imaging techniques, the intricate 3D structure of the microvasculature and the different co-occurring types of amyloid β accumulation in patients hamper studying this relation in patients. Here, we therefore employed the APP/PS1 mouse model, which develops parenchymal amyloid β plaques, to study the effect of parenchymal amyloid β plaques on the structure and function of the vasculature. Blood vessels and amyloid β plaques were fluorescently labeled in vivo with lectin-DyLight594 and methoxy XO4, respectively, in APP/PS1 mice at old age. The brain tissue was cleared post-mortem with the CUBIC clearing protocol, which allowed structural imaging at microscopic resolution of the vessels and plaques in a large 3D volume. Segmentation of the vasculature enabled mapping of the microvascular Cerebral Blood Volume (mCBV), which ranged from 2 % to 5 % in the white matter and the thalamus, respectively. No mCBV differences were observed between APP/PS1 mice and wild type (WT) control mice. The effect of the amyloid β plaques on vascular function was studied in vivo by measuring Cerebral Blood Flow (CBF) and Arterial Transit Time (ATT) with Arterial Spin Labeling (ASL) MRI. Similar to the mCBV findings, no differences were observed in CBF or ATT between APP/PS1 and control mice, indicating that brain vascular morphology and function in this mouse model are preserved in the presence of amyloid β plaques.

International audience; Objective: Improving the identification of the epileptogenic zone and associated seizure-spreading regions represents a significant challenge. Innovative brain-imaging modalities tracking neurovascular dynamics during seizures may provide new disease biomarkers.Methods: With use of a multi-parametric magnetic resonance imaging (MRI) analysis at 9.4 Tesla, we examined, elaborated, and combined multiple cellular and cerebrovascular MRI read-outs as imaging biomarkers of the epileptogenic and seizure-propagating regions. Analyses were performed in an experimental model of mesial temporal lobe epilepsy (MTLE) generated by unilateral intra-hippocampal injection of kainic acid (KA).Results: In the ipsilateral epileptogenic hippocampi, tissue T1 and blood-brain barrier (BBB) permeability to gadolinium were increased 48-72 hours post-KA, as compared to sham and contralateral hippocampi. BBB permeability endured during spontaneous focal seizures (4-6 weeks), along with a significant increase of apparent diffusion coefficient (ADC) and blood volume fraction (BVf). Simultaneously, ADC and BVf were augmented in the contralateral hippocampus, a region characterized by electroencephalographic seizure spreading, discrete histological neurovascular cell modifications, and no tissue sclerosis. We next asked whether combining all the acquired MRI parameters could deliver criteria to classify the epileptogenic from the seizure-spreading and sham hippocampi in these experimental conditions and over time. To differentiate sham from epileptogenic areas, the automatic multi-parametric classification provided a maximum accuracy of 97.5% (32 regions) 48-72 hours post-KA and of 100% (60 regions) at spontaneous seizures stage. To differentiate sham, epileptogenic, and seizure-spreading areas, the accuracies of the automatic classification were 93.1% (42 regions) 48-72 hours post-KA and 95% (80 regions) at spontaneous seizure stage.Significance: Combining multi-parametric MRI acquisition and machine-learning analyses delivers specific imaging identifiers to segregate the epileptogenic from the contralateral seizure-spreading hippocampi in experimental MTLE. The potential clinical value of our findings is critically discussed.

Task-free functional connectivity in animal models provides an experimental framework to examine connectivity phenomena under controlled conditions and allows comparison with invasive or terminal procedures. To date, animal acquisitions are performed with varying protocols and analyses that hamper result comparison and integration. We introduce StandardRat, a consensus rat functional MRI acquisition protocol tested across 20 centers. To develop this protocol with optimized acquisition and processing parameters, we initially aggregated 65 functional imaging datasets acquired in rats from 46 centers. We developed a reproducible pipeline for the analysis of rat data acquired with diverse protocols and determined experimental and processing parameters associated with a more robust functional connectivity detection. We show that the standardized protocol enhances biologically plausible functional connectivity patterns, relative to pre-existing acquisitions. The protocol and processing pipeline described here are openly shared with the neuroimaging community to promote interoperability and cooperation towards tackling the most important challenges in neuroscience.

International audience; VPS35 is a core component of the retromer complex involved in familial forms of neurodegenerative diseases such as Parkinson's and Alzheimer's disease. In mice, VPS35 is expressed during early brain development. However, previous studies have reported that VPS35 activity is largely dispensable for normal neuronal development and initial elaboration of axonal projections. Here, we evaluated the role of VPS35 in the mouse embryonic brain using two Cre-driver lines that remove Vps35 from the cortex at different prenatal stages. We found that Vps35 mutant mice displayed microcephaly and decreased cortical thickness from the embryonic stages to adulthood. VPS35 also regulates cortical development by affecting a subpopulation of neural progenitor cells and the survival of postmitotic neurons. In addition, we showed that a lack of VPS35 leads to hypoplasia and misrouting of several axonal projections, including the anterior commissure and fornix. Furthermore, VPS35 deficiency impairs the non-autonomous development of thalamocortical axons (TCAs), which show severe disruption of innervation and terminal arborization in the cortex. Together, these data demonstrate that VPS35 plays a greater role in embryonic development of the mammalian brain than it was previously thought.

BackgroundA growing body of evidence supports the idea that mitochondrial dysfunction might represent a key feature of Parkinson’s disease (PD). Central regulators of energy production, mitochondria are also involved in several other essential functions such as cell death pathways and neuroinflammation which make them a potential therapeutic target for PD management. Interestingly, recent studies related to PD have reported a neuroprotective effect of targeting mitochondrial pyruvate carrier (MPC) by the insulin sensitizer MSDC-0160. As the sole point of entry of pyruvate into the mitochondrial matrix, MPC plays a crucial role in energetic metabolism which is impacted in PD. This study therefore aimed at providing insights into the mechanisms underlying the neuroprotective effect of MSDC-0160.MethodsWe investigated behavioral, cellular and metabolic impact of chronic MSDC-0160 treatment in unilateral 6-OHDA PD rats. We evaluated mitochondrial related processes through the expression of pivotal mitochondrial enzymes in dorsal striatal biopsies and the level of metabolites in serum samples using nuclear magnetic resonance spectroscopy (NMR)-based metabolomics.ResultsMSDC-0160 treatment in unilateral 6-OHDA rats improved motor behavior, decreased dopaminergic denervation and reduced mTOR activity and neuroinflammation. Concomitantly, MSDC-0160 administration strongly modified energy metabolism as revealed by increased ketogenesis, beta oxidation and glutamate oxidation to satisfy energy needs and maintain energy homeostasis.ConclusionMSDC-0160 exerts its neuroprotective effect through reorganization of multiple pathways connected to energy metabolism.

Functional magnetic resonance imaging (fMRI) techniques using the blood-oxygen level-dependent (BOLD) signal have shown great potential as clinical biomarkers of disease. Thus, using these techniques in preclinical rodent models is an urgent need. Calibrated fMRI is a promising technique that can provide high-resolution mapping of cerebral oxygen metabolism (CMRO2). However, calibrated fMRI is difficult to use in rodent models for several reasons: rodents are anesthetized, stimulation-induced changes are small, and gas challenges induce noisy CMRO2 predictions. We used, in mice, a relaxometry-based calibrated fMRI method which uses cerebral blood flow (CBF) and the BOLD-sensitive magnetic relaxation component, R2′, the same parameter derived in the deoxyhemoglobin-dilution model of calibrated fMRI. This method does not use any gas challenges, which we tested on mice in both awake and anesthetized states. As anesthesia induces a whole-brain change, our protocol allowed us to overcome the former limitations of rodent studies using calibrated fMRI. We revealed 1.5-2 times higher CMRO2, dependent upon brain region, in the awake state versus the anesthetized state. Our results agree with alternative measurements of whole-brain CMRO2 in the same mice and previous human anesthesia studies. The use of calibrated fMRI in rodents has much potential for preclinical fMRI.

BackgroundCare management of Parkinson’s disease (PD) patients currently remains symptomatic, especially because diagnosis relying on the expression of the cardinal motor symptoms is made too late. Detecting PD earlier therefore represents a key step for developing therapies able to delay or slow down its progression.MethodsWe investigated metabolic markers in three different animal models of PD, mimicking different phases of the disease assessed by behavioral and histological evaluation, and in 2 cohorts of de novo PD patients (n = 95). Serum and brain tissue samples were analyzed by nuclear magnetic resonance spectroscopy and data submitted to advanced multivariate statistics.ResultsOur translational strategy reveals common metabolic dysregulations in serum of the different animal models and PD patients. Some of them were mirrored in the tissue samples, possibly reflecting pathophysiological mechanisms associated with PD development. Interestingly, some metabolic dysregulations appeared before motor symptom emergence, and could represent early biomarkers of PD.Finally, we built a composite biomarker with a combination of 6 metabolites. This biomarker discriminated animals mimicking PD from controls, even from the first, non-motor signs and very interestingly, also discriminated PD patients from healthy subjects.ConclusionFrom our translational study which included three animal models and two PD patient cohorts, we propose a promising composite biomarker exhibiting a high level of predictivity for PD diagnosis in its early phase, before motor symptoms appearance.FundingsANR, DOPALCOMP, Institut National de la Santé et de la Recherche Médicale, Grenoble Alpes University.

The gold standard to diagnose intracerebral lesions after traumatic brain injury (TBI) is computed tomography (CT) scan, and due to its accessibility and improved quality of images, the global burden of CT scan for TBI patients is increasing. The recent developments of automated determination of traumatic brain lesions and medical-decision process using artificial intelligence (AI) represent opportunities to help clinicians in screening more patients, identifying the nature and volume of lesions and estimating the patient outcome. This short review will summarize what is ongoing with the use of AI and CT scan for patients with TBI.

Objective Inflammatory cerebrovascular damage occurs in epilepsy. Here, we tested the hypothesis that a pericyte-glia scar forms around the outer wall of hippocampal capillaries in a model of temporal lobe epilepsy associated with hippocampal sclerosis. We studied the participation of stromal cells expressing platelet-derived growth factor receptor beta (PDGFRβ) and extracellular matrix modifications to the perivascular scar during epileptogenesis. Methods We used NG2DsRed/C57BL6 mice and induced status epilepticus (SE) followed by epileptogenesis and spontaneous recurrent seizures (SRS) by means of unilateral intrahippocampal injection of kainic acid (KA). For pharmacological assessment, we used organotypic hippocampal cultures (OHCs) where ictal electrographic activity was elicited by KA or bicuculline. Results NG2DsRed pericytes, GFAP astroglia, and IBA1 microglia are reactive and converge to form a pericapillary multicellular scar in the CA hippocampal regions during epileptogenesis and at SRS. The capillaries are leaky as indicated by fluorescein entering the parenchyma from the peripheral blood. Concomitantly, PDGFRβ transcript and protein levels were significantly increased. Within the regional scar, a fibrotic-like PDGFRβ mesh developed around the capillaries, peaking at 1 week post-SE and regressing, but not resolving, at SRS. Abnormal distribution or accumulation of extracellular matrix collagens III/IV occurred in the CA regions during seizure progression. PDGFRβ/DAPI cells were in direct contact with or adjacent to the damaged NG2DsRed pericytes at the capillary interface, consistent with the notion of stromal cell reactivity or fibroblast formation. Inducing electrographic activity in OHCs was sufficient to augment PDGFRβ reactivity around the capillaries. The latter effect was pharmacologically mimicked by treating OHCs with the PDGFRβ agonist PDGF-BB and it was diminished by the PDGFRβ inhibitor imatinib. Significance The reported multicellular activation and scar are traits of perivascular inflammation and hippocampal sclerosis in experimental epilepsy, with an implication for neurovascular dysfunction. Modulation of PDGFRβ could be exploited to target inflammation in this chronic disease setting.

Alzheimer’s disease (AD) is the leading cause of cognitive impairment and dementia in elder individuals. According to the current biomarker framework for “unbiased descriptive classification”, biomarkers of neurodegeneration, “N”, constitute a critical component in the tri-category “A/T/N” system. Current biomarkers of neurodegeneration suffer from potential drawbacks such as requiring invasive lumbar puncture, involving ionizing radiation, or representing a late, irreversible marker. Recent human studies have suggested that reduced brain oxygen metabolism may be a new functional marker of neurodegeneration in AD, but the heterogeneity and the presence of mixed pathology in human patients did not allow a full understanding of the role of oxygen extraction and metabolism in AD. In this report, global brain oxygen metabolism and related physiological parameters were studied in two AD mouse models with relatively pure pathology, using advanced MRI techniques including T(2)-relaxation-under-spin-tagging (TRUST) and phase contrast (PC) MRI. Additionally, regional cerebral blood flow (CBF) was determined with pseudo-continuous arterial spin labeling (pCASL). Reduced global oxygen extraction fraction (OEF) (by −18.7%, P=0.008), unit-mass cerebral metabolic rate of oxygen (CMRO(2)) (by −17.4%, P=0.04), and total CMRO(2) (TCMRO(2)) (by −30.8%, P0.05), suggesting a normal vascular function. In contrast, in an amyloid AD model (B6;SJL-Tg(APPSWE)2576Kha), referred to as APP mice, that did not reveal brain volume reduction, relatively intact brain oxygen extraction and metabolism were found (P>0.05). Consistent with the imaging data, behavioral measures of walking distance were impaired in Tau4RΔK mice (P=0.004), but not in the APP mice (P=0.88). Collectively, these findings support the hypothesis that non-invasive MRI measurement of brain oxygen metabolism may be a promising biomarker of neurodegeneration in AD.

Despite the potential to guide clinical management of spinal cord injury and disease, noninvasive methods of monitoring perfusion status of the spinal cord clinically remain an unmet need. In this study, we optimized pseudo-continuous arterial spin labeling (pCASL) for the rodent cervical spinal cord and demonstrate its utility in identifying perfusion deficits in an acute contusion injury model. High-resolution perfusion sagittal images with reduced imaging artifacts were obtained with optimized background suppression and imaging readout. Following moderate contusion injury, perfusion was clearly and reliably decreased at the site of injury. Implementation of time-encoded pCASL confirmed injury site perfusion deficits with blood flow measurements corrected for variability in arterial transit times. The noninvasive protocol of pCASL in the spinal cord can be utilized in future applications to examine perfusion changes after therapeutic interventions in the rat and translation to patients may offer critical implications for patient management.

ObjectivesThe determination of the volume of brain lesions after trauma is challenging. Manual delineation is observer-dependent and time-consuming which inhibits the practice in clinical routine. We propose and evaluate an automated atlas-based quantification procedure (AQP) based on the detection of abnormal mean diffusivity (MD) values computed from diffusion-weighted MR images.MethodsWe measured the performance of AQP versus manual delineation consensus by independent raters in two series of experiments: i) realistic trauma phantoms (n=5) where abnormal MD values were assigned to healthy brain images according to the intensity, form and location of lesion observed in real TBI cases; ii) severe TBI patients (n=12 patients) who underwent MR imaging within 10 days after injury.ResultsIn realistic trauma phantoms, no statistical difference in Dice similarity coefficient, precision and brain lesion volumes was found between AQP, the rater consensus and the ground truth lesion delineations. Similar findings were obtained when comparing AQP and manual annotations for TBI patients. The intra-class correlation coefficient between AQP and manual delineation was 0.70 in realistic phantoms and 0.92 in TBI patients. The volume of brain lesions detected in TBI patients was 59 ml (19-84 ml) (median; 25-75th centiles).Conclusionsour results indicate that an automatic quantification procedure could accurately determine with accuracy the volume of brain lesions after trauma. This presents an opportunity to support the individualized management of severe TBI patients.Key pointsThe management of patients with severe traumatic brain injury is complex, and access to objective quantitative information lesion volumes can support clinical decision-making.An automated delineation procedure was developed to determine the nature and volume of brain lesions post-trauma.This procedure was based on diffusion weighted MR-imaging to quantify the volume of vasogenic and cellular edema from realistic phantoms and patients with severe traumatic brain injury.Nature and quantification of the brain lesions volume compared favorably with manual delineation of brain lesions by a panel of experts.

This editorial review of the Research Topic Appning describes several solutions to support the sharing of animal imaging data and processing tools. Appning promotes the federation of multiple sources of information, processing tools and shows how this contributes to the diffusion of knowledge distributed in various preclinical imaging centers.

International audience; BackgroundCare management of Parkinson's disease (PD) patients currently remains symptomatic, mainly because diagnosis relying on the expression of the cardinal motor symptoms is made too late. Earlier detection of PD therefore represents a key step for developing therapies able to delay or slow down its progression.MethodsWe investigated metabolic markers in 3 different animal models of PD, mimicking different phases of the disease assessed by behavioral and histological evaluation, and in 3 cohorts of de novo PD patients and matched controls (n = 129). Serum and brain tissue samples were analyzed by nuclear magnetic resonance spectroscopy and data submitted to advanced multivariate statistics.ResultsOur translational strategy reveals common metabolic dysregulations in serum of the different animal models and PD patients. Some of them were mirrored in the tissue samples, possibly reflecting pathophysiological mechanisms associated with PD development. Interestingly, some metabolic dysregulations appeared before motor symptom emergence and could represent early biomarkers of PD. Finally, we built a composite biomarker with a combination of 6 metabolites. This biomarker discriminated animals mimicking PD from controls, even from the first, nonmotor signs and, very interestingly, also discriminated PD patients from healthy subjects.ConclusionFrom our translational study, which included 3 animal models and 3 de novo PD patient cohorts, we propose a promising biomarker exhibiting a high accuracy for de novo PD diagnosis that may possibly predict early PD development, before motor symptoms appear.FundingFrench National Research Agency (ANR), DOPALCOMP, Institut National de la Santé et de la Recherche Médicale, Université Grenoble Alpes, Association France Parkinson.

International audience; Objective Connectivity networks are crucial to understand the brain resting-state activity using functional magnetic resonance imaging (rs-fMRI). Alterations of these brain networks may highlight important findings concerning the resilience of the brain to different disorders. The focus of this paper is to evaluate the robustness of brain network estimations, discriminate them under anesthesia and compare them to generative models. Approach The extraction of brain functional connectivity (FC) networks is difficult and biased due to the properties of the data: low signal to noise ratio, high dimension low sample size. We propose to use wavelet correlations to assess FC between brain areas under anesthesia using four anesthetics (isoflurane, etomidate, medetomidine, urethane). The networks are then deduced from the functional connectivity matrices by applying statistical thresholds computed using the number of samples at a given scale of wavelet decomposition. Graph measures are extracted and extensive comparisons with generative models of structured networks are conducted. Main results The sample size and filtering are critical to obtain significant correlations values and thereby detect connections between regions. This is necessary to construct networks different from random ones as shown using rs-fMRI brain networks of dead rats. Brain networks under anesthesia on rats have topological features that are mixing small-world, scale-free and random networks. Betweenness centrality indicates that hubs are present in brain networks obtained from anesthetized rats but locations of these hubs are altered by anesthesia. Significance Understanding the effects of anesthesia on brain areas is of particular importance in the context of animal research since animal models are commonly used to explore functions, evaluate lesions or illnesses, and test new drugs. More generally, results indicate that the use of correlations in the context of fMRI signals is robust but must be treated with caution. Solutions are proposed in order to control spurious correlations by setting them to zero. Anesthetized rat brain networks versus models 2

In Vivo Gamma-Aminobutyric Acid Increase as a Biomarker of the Epileptogenic Zone: An Unbiased Metabolomics Approach Hamelin S, Stupar V, Maziere L, et al. Epilepsia. 2021;62(1):163-175.Objective:Following 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).Methods:Four 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) 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.Results:Multivariate 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 with sham and, more importantly, when compared with 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.Significance:Our 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.

Intravenously injected theranostic Gd-based nanoparticles enable targeting and MRI detection of brain metastases in patients., The use of radiosensitizing nanoparticles with both imaging and therapeutic properties on the same nano-object is regarded as a major and promising approach to improve the effectiveness of radiotherapy. Here, we report the MRI findings of a phase 1 clinical trial with a single intravenous administration of Gd-based AGuIX nanoparticles, conducted in 15 patients with four types of brain metastases (melanoma, lung, colon, and breast). The nanoparticles were found to accumulate and to increase image contrast in all types of brain metastases with MRI enhancements equivalent to that of a clinically used contrast agent. The presence of nanoparticles in metastases was monitored and quantified with MRI and was noticed up to 1 week after their administration. To take advantage of the radiosensitizing property of the nanoparticles, patients underwent radiotherapy sessions following their administration. This protocol has been extended to a multicentric phase 2 clinical trial including 100 patients.

There has been growing interest in the use of hypertonic sodium lactate (HSL) solution following traumatic brain injury (TBI) in humans. However, little is known about the effects of HSL on functional deficits with respect to the hyperosmotic nature of HSL. We have compared the effects of HSL solution and isotonic saline solution using sensorimotor and cognitive tests for 14 days post-trauma in animals. Thirty minutes after trauma (impact-acceleration model), anesthetized rats were randomly allocated to receive a 2-h infusion of isotonic saline solution (TBI-saline group) or HSL (TBI-HSL group) (n = 10 rats per group). In another series of experiments using a similar protocol, the effects of equiosmolar doses of HSL and hypertonic saline solution (HSS) were compared in TBI rats (n = 10 rats per group). Blood lactate and ion concentrations were measured during the 2-h infusions. Compared to the TBI-saline group, the TBI-HSL group had a reduced latency to complete the adhesive removal test: 6 s (5–9) (median [25–75th centiles]) versus 13 s (8–17) on day 7, and 5 s (5–9) versus 11 s (8–26) on day 14 (P

Similarly to human population imaging, there are several well-founded motivations for animal population imaging, the most notable being the improvement of the validity of statistical results by pooling a sufficient number of animal data provided by different imaging centers. In this paper, we demonstrate the feasibility of such a multicenter animal study, sharing raw data from forty rats and processing pipelines between four imaging centers. As specific use case, we considered the estimation of T1 and T2 maps for the healthy rat brain at 7T. We quantitatively report about the variability observed across two data provider centers and evaluate the influence of image processing steps on the final maps, by using three fitting algorithms from three centers. Finally, to derive relaxation time values per brain area, two multi-atlas segmentation pipelines from different centers were executed on two different platforms. In this study, the impact of the acquisition was 2.21% (not significant) and 9.52% on T1 and T2 estimates while the impact of the data processing pipeline was not significant (1.04% and 3.33%, respectively). In addition, the computed normality values can serve as relaxometry reference maps to explore differences to animal models of pathologies.

International audience; Standard parameter estimation from vascular magnetic resonance fingerprinting (MRF) data is based on matching the MRF signals to their best counterparts in a grid of coupled simulated signals and parameters, referred to as a dictionary. To reach a good accuracy, the matching requires an informative dictionary whose cost, in terms of design, storage and exploration, is rapidly prohibitive for even moderate numbers of parameters. In this work, we propose an alternative dictionary-based \textcolor{black}{statistical} learning (DB-SL) approach made of three steps: 1) a quasi-random sampling strategy to produce efficiently an informative dictionary, 2) an inverse statistical regression model to learn from the dictionary a correspondence between fingerprints and parameters, and 3) the use of this mapping to provide both parameter estimates and their confidence indices. The proposed DB-SL approach is compared to both the standard dictionary-based matching (DBM) method and to a dictionary-based deep learning (DB-DL) method. Performance is illustrated first on synthetic signals including scalable and standard MRF signals with spatial undersampling noise. Then, vascular MRF signals are considered both through simulations and real data acquired in tumor bearing rats. Overall, the two learning methods yield more accurate parameter estimates than matching and to a range not limited to the dictionary boundaries. DB-SL in particular resists to higher noise levels and provides in addition confidence indices on the estimates at no additional cost. DB-SL appears as a promising method to reduce simulation needs and computational requirements, while modeling sources of uncertainty and providing both accurate and interpretable results.

Purpose To investigate the heating induced by (pseudo)-continuous arterial spin labeling ((p)CASL) sequences in vivo at 9.4T and to evaluate the benefit of a dedicated labeling coil. Methods Temperature was measured continuously in the brain, neck, and rectum of 9 rats with fiber-optic temperature probes while running pCASL-EPI and CASL-EPI sequences, with labeling B1 amplitudes (B1ave ) of 3, 5, and 7 μT and using a dedicated labeling RF coil or a volume coil. From the temperature time courses, the corresponding specific absorption rate (SAR) was computed. A trade-off between SAR and labeling quality was determined based on measured inversion efficiencies. Results ASL experiments with standard parameters (B1ave = 5 µT, Tacq = 4 min, labeling with volume coil) lead to a brain temperature increase due to RF of 0.72 ± 0.46 K for pCASL and 0.25 ± 0.17 K for CASL. Using a dedicated labeling coil reduced the RF-induced SAR by a factor of 10 in the brain and a factor of 2 in the neck. Besides SAR due to RF, heat from the coil decoupling circuits produced significant temperature increases. When labeling with a dedicated coil, this mechanism was the dominant source of brain heating. At equivalent RF-SAR, CASL provided slightly superior label efficiency to pCASL and is therefore the preferred sequence when an ASL coil is available. Conclusion B1ave = 4-5 µT provided a good compromise between label efficiency and SAR, both for pCASL and CASL. The sensitivity of animals to heating should be taken into account when optimizing preclinical ASL protocols and may require reducing scan duration or lowering B1ave .

Purpose Radiotherapy is known to enhance permeability of brain tumor vessels. Our study compared the blood barrier permeability changes induced by synchrotron microbeam radiation therapy (MRT, which relies on spatial fractionation of the incident X-ray beam into parallel micron-wide beams) with changes induces by a spatially uniform synchrotron X-ray radiotherapy. Methods and Materials Male rats bearing malignant intracranial F98 gliomas were randomized into 3 groups: untreated, exposed to MRT (peak and valley dose: 241 and 10.5 Gy respectively) or exposed to broad beam irradiation (BB) delivered at comparable doses (i.e., equivalent to MRT valley dose); both applied by two arrays, intersecting orthogonally the tumor region. Vessel permeability was monitored in vivo by magnetic resonance imaging (MRI) 1 day before (T-1) and 1, 2, 7 and 14 days after treatment start. To find out whether physiological parameters influence vascular permeability, we have evaluated vessel integrity in tumor area with different values for cerebral blood flow, blood volume, oedema and tissue oxygenation. Results MRT does not modify the vascular permeability of normal brain tissue. MRT-induced increase of tumor vascular permeability was detectable from T 2 with a maximum at T 7 after exposure while BB enhanced vessel permeability only at T 7 . At this stage, MRT was more efficient at increasing tumor vessel permeability (BB vs untreated: +19.1%; p=0.0467; MRT vs untreated: +44.8%; p 14 (MRT vs BB, +22.6%; p=0.0199). We also showed that MRT was more efficient at targeting highly oxygenated (high blood volume and flow) and more proliferative parts of the tumor than BB. Conclusions MRT-induced increased tumor vascular permeability is (i) significantly greater, (ii) earlier and more prolonged than that induced by BB irradiation, especially in highly proliferative tumor areas and (iii) targets all tumor areas discriminated by physiological characteristics, including those not damaged by homogeneous irradiation.

Purpose To evaluate a prescan-based radiofrequency phase-correction strategy for unbalanced pseudo-continuous arterial spin labeling (pCASL) at 9.4 T in vivo and to test its robustness toward suboptimal shim conditions. Methods Label and control interpulse phases were optimized separately by means of two prescans in rats. The mean perfusion as well as the interhemispherical symmetry were measured for several phase combinations (optimized versus theoretical phases) to evaluate the correction quality. Interpulse phases were also optimized under degraded shim conditions (i.e., up to four times the study shim values) to test the strategy's robustness. Results For all tested shim conditions, the full arterial spin labeling (ASL) signal could be restored. Without any correction, the relative ASL signal was 1.4 ± 1.7%. It increased to 3.6 ± 1.4% with an optimized label phase and to 5.3 ± 1.2% with optimized label and control phases. Moreover, asymmetry between brain hemispheres, which could be as high as 100% without phase optimization, was dramatically reduced to 1 ± 3% when applying optimized label and control phases. Conclusions Pseudo-continuous ASL at high magnetic field is very sensitive to shim conditions. Label and control radiofrequency phase optimization based on prescans robustly maximizes the ASL signal obtained with unbalanced pCASL and minimizes the asymmetry between hemispheres. Magn Reson Med, 2017. © 2017 International Society for Magnetic Resonance in Medicine.

International audience; Under anesthesia, systemic variables and CBF are modified. How does this alter the connectivity measures obtained with rs-fMRI? To tackle this question, we explored the effect of four different anesthetics on Long Evans and Wistar rats with multimodal recordings of rs-fMRI, systemic variables and CBF. After multimodal signal processing, we show that the blood-oxygen-level-dependent (BOLD) variations and functional connectivity (FC) evaluated at low frequencies (0.031-0.25 Hz) do not depend on systemic variables and are preserved across a large interval of baseline CBF values. Based on these findings, we found that most brain areas remain functionally active under any anesthetics, i.e. connected to at least one other brain area, as shown by the connectivity graphs. In addition, we quantified the influence of nodes by a measure of functional connectivity strength to show the specific areas targeted by anesthetics and compare correlation values of edges at different levels. These measures enable us to highlight the specific network alterations induced by anesthetics. Altogether, this suggests that changes in connectivity could be evaluated under anesthesia, routinely used in the control of neurological injury.

International audience; We formulated an ultra-small, gadolinium-based nanoparticle (AGuIX) with theranostic properties to simultaneously enhance MRI tumor delineation and radiosensitization in a glioma model. The 9L glioma cells were orthotopically implanted in 10-week-old Fischer rats. The intra-tumoral accumulation of AGuIX was quantified using MRI T1-maps. Rats randomized to intervention cohorts were subsequently treated with daily temozolomide for five consecutive days before radiotherapy treatment. Collectively, a series of 32 rats were divided into untreated (n = 7), temozolomide-only (n = 7), temozolomide and MRT (n = 9), AGuIX and MRT (n = 7), and triple therapy (temozolomide, AGuIX NPs, and MRT; n = 9) cohorts. AGuIX nanoparticles achieved a maximum intra-tumoral concentration (expressed as concentration of Gd3+) at 1 h after intravenous injection, reaching a mean of 227.9 ± 60 lM. This was compared to concentrations of 10.5 ± 9.2 lM and 62.9 ± 24.7 lM in the contralateral hemisphere and cheek, respectively. There was a slower washout in the intra-tumor region, with sustained tumor-to-contralateral ratio of AGuIX, up to 14-fold, for each time point. The combination of AGuIX or temozolomide with MRT improved the median survival time (40 days) compared to the MeST of control rats (25 days) (p < 0.002). There was a trend towards further increased survival when the three treatments were combined (MeST of 46 days). This study demonstrated the selective accumulation of AGuIX in high grade glioma, as well as the potential survival benefits when combined with chemoradiation.

International audience; Water diffusion is an optimal tool for investigating the architecture of brain tissue on which modern medical diagnostic imaging techniques rely. However, intrinsic tissue heterogeneity causes systematic deviations from pure free-water diffusion behaviour. To date, numerous theoretical and empirical approaches have been proposed to explain the non-Gaussian profile of this process. The aim of this work is to shed light on the physics piloting water diffusion in brain tissue at the micrometre-to-atomic scale. Combined diffusion magnetic resonance imaging and first pioneering neutron scattering experiments on bovine brain tissue have been performed in order to probe diffusion distances up to macromolecular separation. The coexistence of free-like and confined water populations in brain tissue extracted from a bovine right hemisphere has been revealed at the micrometre and atomic scale. The results are relevant for improving the modelling of the physics driving intra- and extracellular water diffusion in brain, with evident benefit for the diffusion magnetic resonance imaging technique, nowadays widely used to diagnose, at the micrometre scale, brain diseases such as ischemia and tumours.

International audience; We address the issue of selecting automatically the number of components in mixture models with non-Gaussian components. As a more efficient alternative to the traditional comparison of several model scores in a range, we consider procedures based on a single run of the inference scheme. Starting from an overfitting mixture in a Bayesian setting, we investigate two strategies to eliminate superfluous components. We implement these strategies for mixtures of multiple scale distributions which exhibit a variety of shapes not necessarily elliptical while remaining analytical and tractable in multiple dimensions. A Bayesian formulation and a tractable inference procedure based on variational approximation are proposed. Preliminary results on simulated and real data show promising performance in terms of model selection and computational time.

Understanding the dynamics of brain tumor progression is essential for optimal treatment planning. Cast in a mathematical formulation, it is typically viewed as evaluation of a system of partial differential equations, wherein the physiological processes that govern the growth of the tumor are considered. To personalize the model, i.e. find a relevant set of parameters, with respect to the tumor dynamics of a particular patient, the model is informed from empirical data, e.g., medical images obtained from diagnostic modalities, such as magnetic-resonance imaging. Existing model-observation coupling schemes require a large number of forward integrations of the biophysical model and rely on simplifying assumption on the functional form, linking the output of the model with the image information. In this work, we propose a learning-based technique for the estimation of tumor growth model parameters from medical scans. The technique allows for explicit evaluation of the posterior distribution of the parameters by sequentially training a mixture-density network, relaxing the constraint on the functional form and reducing the number of samples necessary to propagate through the forward model for the estimation. We test the method on synthetic and real scans of rats injected with brain tumors to calibrate the model and to predict tumor progression.

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.

The functional roles of the Caudate nucleus (Cd) are well known. Selective Cd lesions can be found in neurological disorders. However, little is known about the dynamics of the behavioral changes during progressive Cd ablation. Current stereotactic radiosurgery technologies allow the progressive ablation of a brain region with limited adverse effects in surrounding normal tissues. This could be of high interest for the study of the modified behavioral functions in relation with the degree of impairment of the brain structures. Using hypofractionated stereotactic radiotherapy combined with synchrotron microbeam radiation, we investigated, during one year after irradiation, the effects of unilateral radio-ablation of the right Cd on the behavior of Yucatan minipigs. The right Cd was irradiated to a minimal dose of 35.5 Gy delivered in three fractions. MRI-based morphological brain integrity and behavioral functions, i.e. locomotion, motivation/hedonism were assessed. We detected a progressive radio-necrosis leading to a quasi-total ablation one year after irradiation, with an additional alteration of surrounding areas. Transitory changes in the motivation/hedonism were firstly detected, then on locomotion, suggesting the influence of different compensatory mechanisms depending on the functions related to Cd and possibly some surrounding areas. We concluded that early behavioral changes related to eating functions are relevant markers for the early detection of ongoing lesions occurring in Cd-related neurological disorders.

International audience; AGuIX® are sub-5 nm nanoparticles made of a polysiloxane matrix and gadolinium chelates. This nanoparticle has been recently accepted in clinical trials in association with radiotherapy. This review will summarize the principal preclinical results that have led to first in man administration. No evidence of toxicity has been observed during regulatory toxicity tests on two animal species (rodents and monkeys). Biodistributions on different animal models have shown passive uptake in tumours due to enhanced permeability and retention effect combined with renal elimination of the nanoparticles after intravenous administration. High radiosensitizing effect has been observed with different types of irradiations in vitro and in vivo on a large number of cancer types (brain, lung, melanoma, head and neck…). The review concludes with the second generation of AGuIX nanoparticles and the first preliminary results on human.