Study protocol of IMAGINE-HD: imaging iron accumulation and neuroinflammation with 7T-MRI + CSF in Huntington's disease

IntroductionStrong evidence suggests a significant role for iron accumulation in the brain in addition to the well-documented neurodegenerative aspects of Huntington’s disease (HD). The putative mechanisms by which iron is linked to the HD pathogenesis are multiple, including oxidative stress, ferroptosis and neuroinflammation. However, no previous study in a neurodegenerative disease has linked the observed increase of brain iron accumulation as measured by MRI with well-established cerebrospinal fluid (CSF) and blood biomarkers for iron accumulation, or with associated processes such as neuroinflammation. This study is designed to link quantitative data from iron levels and neuroinflammation metabolites obtained from 7T MRI of HD patients, with specific and well-known clinical biofluid markers for iron accumulation, neurodegeneration and neuroinflammation. Biofluid markers will provide quantitative measures of overall iron accumulation, neurodegeneration and neuroinflammation, while MRI measurements on the other hand will provide quantitative spatial information on brain pathology, neuroinflammation and brain iron accumulation, which will be linked to clinical outcome measures.MethodsThis is an observational cross-sectional study, IMAGINE-HD, in HD gene expansion carriers and healthy controls. We include premanifest HD gene expansion carriers and patients with manifest HD in an early or moderate stage. The study includes a 7T MRI scan of the brain, clinical evaluation, motor, functional, and neuropsychological assessments, and sampling of CSF and blood for the detection of iron, neurodegenerative and inflammatory markers. Quantitative Susceptibility Maps will be reconstructed using T2* weighted images to quantify brain iron levels and Magnetic Resonance Spectroscopy will be used to obtain information about neuroinflammation by measuring cell-specific intracellular metabolites’ level and diffusion. Age and sex matched healthy subjects are included as a control group.DiscussionResults from this study will provide an important basis for the evaluation of brain iron levels and neuroinflammation metabolites as an imaging biomarker for disease stage in HD and their relationship with the salient pathomechanisms of the disease on the one hand, and with clinical outcome on the other.Radiolog

Cortical glutamate and gamma-aminobutyric acid over the course of a provoked migraine attack, a 7 Tesla magnetic resonance spectroscopy study

Enhanced activity of the glutamatergic system has been linked to migraine pathophysiology. The present study aimed to assess the involvement of the glutamatergic system in the onset of attacks. We provoked attacks by infusion of glyceryl trinitrate (GTN; 0.5 µg/kg/min over 20 min) in 24 female episodic migraineurs without aura and 13 female age-matched healthy controls. Over the course of a single day participants were scanned three times at fixed time slots (baseline before GTN infusion, 90 min and 270 min after start of GTN infusion). Single-volume proton magnetic resonance spectra (1H–MRS) were acquired at 7 Tesla from a volume of interest (VOI, 2x2x3 cm) in the visual cortex. We assessed the concentrations of glutamate, its major precursor glutamine, and its product gamma-aminobutyric acid (GABA) over the course of a provoked attack. The preictal state was defined as the period after GTN infusion until the migraine-like headache started, independent of possible experienced premonitory symptoms, and the ictal state was defined as the period with provoked migraine-like headache. Data were analyzed using a linear mixed-effect model for repeated measures. Glutamate and glutamine levels did not change from interictal to the preictal and ictal state. GABA levels increased from interictal towards the preictal state for migraine patients compared with healthy controls. We conclude that high resolution 7T MRS is able to show changes in the glutamatergic system towards a triggered migraine attack, by revealing an increased GABA concentration associated with the onset of a migraine attack

Population diversity and function of hyperpolarization-activated current in olfactory bulb mitral cells

Although neurons are known to exhibit a broad array of intrinsic properties that impact critically on the computations they perform, very few studies have quantified such biophysical diversity and its functional consequences. Using in vivo and in vitro whole-cell recordings here we show that mitral cells are extremely heterogeneous in their expression of a rebound depolarization (sag) at hyperpolarized potentials that is mediated by a ZD7288-sensitive current with properties typical of hyperpolarization-activated cyclic nucleotide gated (HCN) channels. The variability in sag expression reflects a functionally diverse population of mitral cells. For example, those cells with large amplitude sag exhibit more membrane noise, a lower rheobase and fire action potentials more regularly than cells where sag is absent. Thus, cell-to-cell variability in sag potential amplitude reflects diversity in the integrative properties of mitral cells that ensures a broad dynamic range for odor representation across these principal neurons

Regulation of Spike Timing-Dependent Plasticity of Olfactory Inputs in Mitral Cells in the Rat Olfactory Bulb

The recent history of activity input onto granule cells (GCs) in the main olfactory bulb can affect the strength of lateral inhibition, which functions to generate contrast enhancement. However, at the plasticity level, it is unknown whether and how the prior modification of lateral inhibition modulates the subsequent induction of long-lasting changes of the excitatory olfactory nerve (ON) inputs to mitral cells (MCs). Here we found that the repetitive stimulation of two distinct excitatory inputs to the GCs induced a persistent modification of lateral inhibition in MCs in opposing directions. This bidirectional modification of inhibitory inputs differentially regulated the subsequent synaptic plasticity of the excitatory ON inputs to the MCs, which was induced by the repetitive pairing of excitatory postsynaptic potentials (EPSPs) with postsynaptic bursts. The regulation of spike timing-dependent plasticity (STDP) was achieved by the regulation of the inter-spike-interval (ISI) of the postsynaptic bursts. This novel form of inhibition-dependent regulation of plasticity may contribute to the encoding or processing of olfactory information in the olfactory bulb

Brain intracellular metabolites are freely diffusing along cell fibers in grey and white matter, as measured by diffusion-weighted MR spectroscopy in the human brain at 7 T

Neuro Imaging Researc

Effets de scénarios d'adaptation au changement climatique sur les caractéristiques spatio-temporelles perçues des sécheresses

International audienceDrought events develop in both space and time and they are therefore best described through summary joint spatiotemporal characteristics, like mean duration, mean affected area and total magnitude. This study addresses the issue of future projections of such characteristics of drought events over France through three main research questions: (1) Are downscaled climate projections able to reproduce spatio-temporal characteristics of meteorological and agricultural droughts in France over a present-day period? (2) How such characteristics will evolve over the 21st century under different emissions scenarios? (3) How would perceived drought characteristics evolve under theoretical adaptation scenarios? These questions are addressed using the Isba land surface model, downscaled climate projections from the ARPEGE General Circulation Model under three emissions scenarios, as well as results from a previously performed 50-year multilevel and multiscale drought reanalysis over France (Vidal et al., 2010). Spatio-temporal characteristics of meteorological and agricultural drought events are computed using the Standardized Precipitation Index (SPI) and the Standardized Soil Wetness Index (SSWI), respectively, and for time scales of 3 and 12 months. Results first show that the distributions of joint spatio-temporal characteristics of observed events are well reproduced by the downscaled hydroclimate projections over a present-day period. All spatio-temporal characteristics of drought events are then found to dramatically increase over the 21st century under all considered emissions scenarios, with stronger changes for agricultural droughts. Two theoretical adaptation scenarios are eventually built based on hypotheses of adaptation to evolving climate and hydrological normals. The two scenarios differ by the way the transient adaptation is performed for a given date in the future, with reference to the normals over either the previous 30-year window (“retrospective” adaptation) or over a 30-year period centred around the date considered (“prospective” adaptation). These adaptation scenarios are translated into local-scale transient drought thresholds, as opposed to a non-adaptation scenario where the drought threshold remains constant. The perceived spatio-temporal characteristics derived from the theoretical adaptation scenarios show much reduced changes, but they call for more realistic scenarios at both the catchment and national scale in order to accurately assess the combined effect of local-scale adaptation and global-scale mitigation. This study thus proposes a proof of concept for using standardized drought indices for (1) assessing projections of spatio-temporal drought characteristics and (2) building theoretical adaptation scenarios and associated perceived changes in hydrological impact studies (Vidal et al., submitted)

Earth System Sciences Evolution of spatio-temporal drought characteristics: validation, projections and effect of adaptation scenarios

www.hydrol-earth-syst-sci.net/16/2935/2012/ doi:10.5194/hess-16-2935-201

Changes in drought characteristics in France during the 21st century

International audienceStandardized drought indices such as the Standardized Precipitation Index (SPI) have been shown to be highly relevant for drought reconstruction and drought monitoring. Such indices can be built to deal with different types of drought (meteorological, agricultural and hydrological) and to study droughts at different time and spatial scales. In this study, a 50-year multilevel and multiscale drought reanalysis over France recently built with Safran-Isba-Modcou hydrometeorological suite will serve as a basis for assessing the impact of climate change on droughts. An ensemble of climate projections have been statistically downscaled in order to force the Isba and Modcou hydrological models over France and generate 8-km gridded soil moisture time series as well as streamflow time series at more than 900 locations. Two different statistical downscaling methods have been applied using the Safran high resolution atmospheric reanalysis dataset over France: a method based on weather types and regressions, and a quantile-quantile method. As a first step, transient runs from only one general circulation model have been used under different climate scenarios. Three different standardized indices previously applied for the drought reanalysis are here used to estimate the evolution of droughts in the future: the commonly used SPI, the Standardized SoilWetness Index (SSWI) based on soil moisture simulated by Isba and the Standardized Flow Index (SFI) based on streamflow computed by Modcou. Changes in the characteristics (occurrence, intensity, duration, spatial scale) of meteorological, agricultural and hydrological droughts in France during the 21st century are here presented using the different drought indices. This panel of indices may provide useful information at the level of interest of different human activities (water supply, irrigation, hydropower, etc.)

Caractérisation des sécheresses en France au cours du XXIe siècle

International audienceCet article présente une étude de l'impact du changement climatique sur les événements de sécheresse sur le territoire français, en considérant l'ensemble des composantes du cycle hydrologique et les incertitudes liées aux projections climatiques pour le XXIe siècle. / This article presents a study of the impact of climate change on drought events in France, by integrating all components of the hydrological cycle and by taking account of uncertainties in 21st century climate

Effet de scénarios d'adaptation et d'atténuation du changement climatique sur les caractéristiques spatio-temporelles des sécheresses

International audienceDrought events develop in both space and time and they are therefore best described through summary joint spatio-temporal characteristics, like mean duration, mean affected area and total magnitude. This study addresses the issue of future projections of such characteristics of drought events over France through three main research questions: (1) Are downscaled climate projections able to reproduce spatio-temporal characteristics of meteorological and agricultural droughts in France over a present-day period? (2) How such characteristics will evolve over the 21st century under different emissions/mitigation scenarios? (3) How would perceived drought characteristics evolve under theoretical adaptation scenarios? These questions are addressed using the Isba land surface model, downscaled climate projections from the ARPEGE General Circulation Model under three emissions scenarios, as well as results from a previously performed 50-year multilevel and multiscale drought reanalysis over France (Vidal et al., 2010). Spatio-temporal characteristics of meteorological and agricultural drought events are computed using the Standardized Precipitation Index (SPI) and the Standardized Soil Wetness Index (SSWI), respectively, and for time scales of 3 and 12 months. Results first show that the distributions of joint spatio-temporal characteristics of observed events are well reproduced by the downscaled hydroclimate projections over a present-day period. All spatio-temporal characteristics of drought events are then found to dramatically increase over the 21st century under all considered emissions scenarios, with stronger changes for agricultural droughts. Two theoretical adaptation scenarios are eventually built based on hypotheses of adaptation to evolving climate and hydrological normals. The two scenarios differ by the way the transient adaptation is performed for a given date in the future, with reference to the normals over either the previous 30-year window (“retrospective” adaptation) or over a 30-year period centred around the date considered (“prospective” adaptation). These adaptation scenarios are translated into local-scale transient drought thresholds, as opposed to a non-adaptation scenario where the drought threshold remains constant. The perceived spatio-temporal characteristics derived from the theoretical adaptation scenarios show much reduced changes, but they call for more realistic scenarios at both the catchment and national scale in order to accurately assess the combined effect of local-scale adaptation and global-scale mitigation.This study thus proposes a proof of concept for using standardized drought indices for (1) assessing projections of spatio-temporal drought characteristics and (2) building theoretical adaptation scenarios and associated perceived changes in hydrological impact studies