Claire Leroy - Academia.edu (original) (raw)
Papers by Claire Leroy
Addiction Biology
A large body of preclinical research has shown that neuroimmunity plays a key role in the deleter... more A large body of preclinical research has shown that neuroimmunity plays a key role in the deleterious effects of alcohol (ethanol) to the brain. Translational imaging techniques are needed to monitor the efficacy of strategies to prevent or mitigate neuroinflammation and alleviate ethanol‐induced neurotoxicity. Opioid receptor antagonists such as nalmefene are antagonists of the toll‐like receptor 4, which may block the proinflammatory signaling cascade induced by ethanol at this specific target. Male adolescent rats received a validated protocol of ethanol injection (i.p, 3 g/kg daily for two consecutive days followed by two resting days) during 14 days. Positron emission tomography (PET) imaging with the translocator protein 18 kDa (TSPO) radioligand [18F]DPA‐714 was performed at day‐15. Toxicity induced by repeated binge‐like ethanol exposure (71% mortality) was drastically reduced by nalmefene pretreatment (0.4 mg/kg, 14% mortality). No mortality was observed in animals that rec...
European Journal of Nuclear Medicine and Molecular Imaging, 2021
Recent research in last years in substance use disorders (SUD) synthesized a proinflammatory hypo... more Recent research in last years in substance use disorders (SUD) synthesized a proinflammatory hypothesis of SUD based on reported pieces of evidence of non-neuronal central immune signalling pathways modulated by drug of abuse and that contribute to their pharmacodynamic actions. Positron emission tomography has been shown to be a precious imaging technique to study in vivo neurochemical processes involved in SUD and to highlight the central immune signalling actions of drugs of abuse. In this review, we investigate the contribution of the central immune system, with a particular focus on translocator protein 18 kDa (TSPO) imaging, associated with a series of drugs involved in substance use disorders (SUD) specifically alcohol, opioids, tobacco, methamphetamine, cocaine, and cannabis. The large majority of preclinical and clinical studies presented in this review converges towards SUD modulation of the neuroimmune responses and TSPO expression and speculated a pivotal positioning in the pathogenesis of SUD. However, some contradictions concerning the same drug or between preclinical and clinical studies make it difficult to draw a clear picture about the significance of glial state in SUD. Significant disparities in clinical and biological characteristics are present between investigated populations among studies. Heterogeneity in genetic factors and other clinical co-morbidities, difficult to be reproduced in animal models, may affect findings. On the other hand, technical aspects including study designs, radioligand limitations, or PET imaging quantification methods could impact the study results and should be considered to explain discrepancies in outcomes. The supposed neuroimmune component of SUD provides new therapeutic approaches in the prediction and treatment of SUD pointing to the central immune signalling.
Journal of Affective Disorders, 2019
HAL is a multidisciplinary open access archive for the deposit and dissemination of scientific re... more HAL is a multidisciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L'archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés. Distributed under a Creative Commons Attribution-NonCommercial| 4.0 International License
Society of Nuclear Medicine Annual Meeting Abstracts, May 1, 2009
![Research paper thumbnail of The neuronal component of gray matter damage in multiple sclerosis: A [11C]flumazenil positron emission tomography study](https://attachments.academia-assets.com/120093541/thumbnails/1.jpg)
](Annals of Neurology, 2015
Objective: Using positron emission tomography (PET) with [ 11 C]flumazenil ([ 11 C]FMZ), an antag... more Objective: Using positron emission tomography (PET) with [ 11 C]flumazenil ([ 11 C]FMZ), an antagonist of the central benzodiazepine site located within the GABA A receptor, we quantified and mapped neuronal damage in the gray matter (GM) of patients with multiple sclerosis (MS) at distinct disease stages. We investigated the relationship between neuronal damage and white matter (WM) lesions and evaluated the clinical relevance of this neuronal PET metric. Methods: A cohort of 18 MS patients (9 progressive and 9 relapsing-remitting) was compared to healthy controls and underwent neurological and cognitive evaluations, high-resolution dynamic [ 11 C]FMZ PET imaging and brain magnetic resonance imaging. [ 11 C]FMZ binding was estimated using the partial saturation protocol providing voxelwise absolute quantification of GABA A receptor concentration. PET data were evaluated using a region of interest (ROI) approach as well as on a vertex-by-vertex basis. Results: [ 11 C]FMZ binding was significantly decreased in the cortical GM of MS patients, compared to controls (-10%). Cortical mapping of benzodiazepine receptor concentration ([ 11 C]FMZ Bmax) revealed significant intergroup differences in the bilateral parietal cortices and right frontal areas. ROI analyses taking into account GM volume changes showed extensive decrease in [ 11 C]FMZ binding in bilateral parietal, cingulate, and insular cortices as well as in the thalami, amygdalae, and hippocampi. These changes were significant in both progressive and relapsingremitting forms of the disease and correlated with WM T2-weighted lesion load. [ 11 C]FMZ cortical binding correlated with cognitive performance. Interpretation: This pilot study showed that PET with [ 11 C]FMZ could be a promising and sensitive quantitative marker to assess and map the neuronal substrate of GM pathology in MS.
![Research paper thumbnail of Identification et quantification d’une neurodégénérescence précoce au cours de la sclérose en plaques avec la tomographie à émission de positons au [11C]-Flumazenil](https://attachments.academia-assets.com/120093540/thumbnails/1.jpg)
](
Epilepsia, 2003
Summary: Purpose: Acute caffeine exposure has proconvulsant effects and worsens epileptic and is... more Summary: Purpose: Acute caffeine exposure has proconvulsant effects and worsens epileptic and ischemic neuronal damage. Surprisingly, prolonged caffeine exposure decreases the susceptibility to seizures and the extent of ischemic damage. We explored whether the exposure to a low long‐term dose of caffeine could protect the brain from neuronal damage and epileptogenesis in the lithium‐pilocarpine model of temporal lobe epilepsy.Methods: Rats received either plain tap water or water containing caffeine (0.3 g/L) for 15 days before the induction of status epilepticus (SE) by lithium‐pilocarpine and for 7 days after SE. The extent of neuronal damage was assessed in the hippocampus and piriform and entorhinal cortices in brain sections stained with thionine and obtained from animals killed 7 days after SE. The latency to spontaneous recurrent seizures was controlled by video monitoring.Results: Caffeine treatment induced a marked, almost total neuroprotection in CA1 and a very limited p...
Frontiers in Neuroscience
AimBuprenorphine mainly acts as an agonist of mu-opioid receptors (mu-OR). High dose buprenorphin... more AimBuprenorphine mainly acts as an agonist of mu-opioid receptors (mu-OR). High dose buprenorphine does not cause respiratory depression and can be safely administered to elicit typical opioid effects and explore pharmacodynamics. Acute buprenorphine, associated with functional and quantitative neuroimaging, may therefore provide a fully translational pharmacological challenge to explore the variability of response to opioids in vivo. We hypothesized that the CNS effects of acute buprenorphine could be monitored through changes in regional brain glucose metabolism, assessed using 18F-FDG microPET in rats.Materials and methodsFirst, level of receptor occupancy associated with a single dose of buprenorphine (0.1 mg/kg, s.c) was investigated through blocking experiments using 11C-buprenorphine PET imaging. Behavioral study using the elevated plus-maze test (EPM) was performed to assess the impact of the selected dose on anxiety and also locomotor activity. Then, brain PET imaging using...
European Psychiatry, Mar 1, 2011
1/In juvenile patients, a cross-sectional ALE meta-analysis of both brain structure and function ... more 1/In juvenile patients, a cross-sectional ALE meta-analysis of both brain structure and function regional deviations in 270 articles allowed to cluster the diagnosed disorders into three sets with respectively marked affective, cognitive, and psychomotor phenomenology. The group with affective phenomenology was characterized by abnormalities of the frontal-limbic regions; the group with “cognition deficits” (incl. schizophrenia) mainly related to cortex abnormalities; and the psychomotor condition was associated with abnormalities in the basal ganglia. Therefore, early regional brain abnormalities might interact with the analysis of subsequent treatments effects in MR studies of brain structure and function of chronic mental disorders. 2/In chronic patients, brain imaging studies of antipsychotic drugs using dopamine receptor radioligands &PET scanner have consistently demonstrated the prevalence of their dose-dependent action in basal ganglia. This information has led to theoretical windows for optimal drug dosage. Recent measures of the dopamine transporter in chronic antipsychotic treatment, or in chronic use of drugs of addiction (e.g. tobacco, cannabis) suggest opposite changes of the adioligand uptake in both conditions. Therefore, control for the associated confounding addictions is required for in vivo analysis of antipsychotic action on the dopamine regulation in cortex and subcortical regions. 3/In treatment-resistant patients, MR & PET imaging studies have detected deviations of both brain structure and function, therefore suggesting biomarker of treatment response. 4/Conclusion: stage of illness, addictions, multimodal imaging, should be considered as covariates for brain imaging determinations of treatment effects in patients with chronic mental disorders.
![Research paper thumbnail of Dopamine Transporter Correlates and Occupancy by Modafinil in Cocaine-Dependent Patients: A Controlled Study With High-Resolution PET and [11C]-PE2I](https://attachments.academia-assets.com/110013020/thumbnails/1.jpg)
](Neuropsychopharmacology, Feb 9, 2016
Modafinil is a candidate compound for the treatment of cocaine addiction that binds to the dopami... more Modafinil is a candidate compound for the treatment of cocaine addiction that binds to the dopamine transporter (DAT) in healthy humans, as observed by positron emission tomography (PET). This mechanism, analogous to that of cocaine, might mediate a putative therapeutic effect of modafinil on cocaine dependence, though the binding of modafinil to DAT has never been assessed in cocainedependent patients. We aimed at quantifying the DAT availability during a controlled treatment by modafinil, and its clinical and psychometric correlates in cocaine-dependent patients at the onset of abstinence initiation. Twenty-nine cocaine-dependent male patients were enrolled in a 3-month trial for cocaine abstinence. Modafinil was used in a randomized double-blind placebo-controlled design and was administered as follows: 400 mg/day for 26 days, then 300 mg/day for 30 days, and 200 mg/day for 31 days. Participants were examined twice during a 17-day hospitalization for their DAT availability using PET and [ 11 C]-PE2I and for assessments of craving, depressive symptoms, working memory, and decision-making. Cocaine abstinence was further assessed during a 10-week outpatient follow-up period. Baseline [ 11 C]-PE2I-binding potential covaried with risk taking and craving index in striatal and extrastriatal regions. A 65.6% decrease of binding potential was detected in patients receiving modafinil for 2 weeks, whereas placebo induced no significant change. During hospitalization, an equivalent improvement in clinical outcomes was observed in both treatment groups, and during the outpatient follow-up there were more therapeutic failures in the modafinil-treated group. Therefore, these results do not support the usefulness of modafinil to treat cocaine addiction.
Patients with temporal lobe epilepsy (TLE) usually had an initial precipitating injury in early c... more Patients with temporal lobe epilepsy (TLE) usually had an initial precipitating injury in early childhood. However, epilepsy does not develop in all children who have undergone an early insult. As in patients, the consequences of the lithium-pilocarpine-induced status epilepticus (SE) are age dependent, and only a subset of 21-day-old rats will develop epilepsy. Thus with magnetic resonance imaging (MRI), we explored the differences in the evolution of lesions in these two populations of rats. Methods: SE was induced in 21-day-old rats by the injection of lithium and pilocarpine. T 2-weighted images and T 2 relaxation-time measurements were used for detection of lesions from 6 h to 4 months after SE. Results: Three populations of rats could be distinguished. The first one had neither MRI anomalies nor modification of the T 2 relaxation time, and these rats did not develop epilepsy.
Neuropsychopharmacology, 2021
A wide range of buprenorphine doses are used for either pain management or maintenance therapy in... more A wide range of buprenorphine doses are used for either pain management or maintenance therapy in opioid addiction. The complex in vitro profile of buprenorphine, with affinity for µ-, δ-, and κ-opioid receptors (OR), makes it difficult to predict its doserelated neuropharmacology in vivo. In rats, microPET imaging and pretreatment by OR antagonists were performed to assess the binding of radiolabeled buprenorphine (microdose 11 C-buprenorphine) to OR subtypes in vivo (n = 4 per condition). The µ-selective antagonist naloxonazine (10 mg/kg) and the non-selective OR antagonist naloxone (1 mg/kg) blocked the binding of 11 Cbuprenorphine, while pretreatment by the δ-selective (naltrindole, 3 mg/kg) or the κ-selective antagonist (norbinaltorphimine, 10 mg/kg) did not. In four macaques, PET imaging and kinetic modeling enabled description of the regional brain kinetics of 11 Cbuprenorphine, co-injected with increasing doses of unlabeled buprenorphine. No saturation of the brain penetration of buprenorphine was observed for doses up to 0.11 mg/kg. Regional differences in buprenorphine-associated receptor occupancy were observed. Analgesic doses of buprenorphine (0.003 and 0.006 mg/kg), respectively, occupied 20% and 49% of receptors in the thalamus while saturating the low but significant binding observed in cerebellum and occipital cortex. Occupancy >90% was achieved in most brain regions with plasma concentrations >7 µg/L. PET data obtained after co-injection of an analgesic dose of buprenorphine (0.003 mg/kg) predicted the binding potential of microdose 11 C-buprenorphine. This strategy could be further combined with pharmacodynamic exploration or pharmacological MRI to investigate the neuropharmacokinetics and neuroreceptor correlate, at least at µ-OR, of the acute effects of buprenorphine in humans.
NeuroImage, 2021
Whole brain estimation of the haemodynamic response function (HRF) in functional magnetic resonan... more Whole brain estimation of the haemodynamic response function (HRF) in functional magnetic resonance imaging (fMRI) is critical to get insight on the global status of the neurovascular coupling of an individual in healthy or pathological condition. Most of existing approaches in the literature works on task-fMRI data and relies on the experimental paradigm as a surrogate of neural activity, hence remaining inoperative on resting-stage fMRI (rs-fMRI) data. To cope with this issue, recent works have performed either a two-step analysis to detect large neural events and then characterize the HRF shape or a joint estimation of both the neural and haemodynamic components in an univariate fashion. In this work, we express the neural activity signals as a combination of piece-wise constant temporal atoms associated with sparse spatial maps and introduce an haemodynamic parcellation of the brain featuring a temporally dilated version of a given HRF model in each parcel with unknown dilation parameters. We formulate the joint estimation of the HRF shapes and spatio-temporal neural representations as a multivariate semi-blind deconvolution problem in a paradigm-free setting and introduce constraints inspired from the dictionary learning literature to ease its identifiability. A fast alternating minimization algorithm, along with its efficient implementation, is proposed and validated on both synthetic and real rs-fMRI data at the subject level. To demonstrate its significance at the population level, we apply this new framework to the UK Biobank data set, first for the discrimination of haemodynamic territories between balanced groups (= 24 individuals in each) patients with an history of stroke and healthy controls and second, for the analysis of normal aging on the neurovascular coupling. Overall, we statistically demonstrate that a pathology like stroke or a condition like normal brain aging induce longer haemodynamic delays in certain brain areas (e.g. Willis polygon, occipital, temporal and frontal cortices) and that this haemodynamic feature may be predictive with an accuracy of 74 % of the individual's age in a supervised classification task performed on = 459 subjects.
Alzheimer's Research & Therapy, 2020
Background Current demographic trends point towards an aging society entailing increasing occurre... more Background Current demographic trends point towards an aging society entailing increasing occurrence and burden of neurodegenerative diseases. In this context, understanding physiological aging and its turning point into neurodegeneration is essential for the development of possible biomarkers and future therapeutics of brain disease. Methods The SENIOR study represents a longitudinal, observational study including cognitively healthy elderlies aged between 50 and 70 years old at the time of inclusion, being followed annually over 10 years. Our multimodal protocol includes structural, diffusion, functional, and sodium magnetic resonance imaging (MRI) at 3 T and 7 T, positron emission tomography (PET), blood samples, genetics, audiometry, and neuropsychological and neurological examinations as well as assessment of neuronal risk factors. Results One hundred forty-two participants (50% females) were enrolled in the SENIOR cohort with a mean age of 60 (SD 6.3) years at baseline. Baseli...
The international journal of neuropsychopharmacology, Jan 15, 2018
Modafinil, a nonamphetaminic wake-promoting compound, is prescribed as first line therapy in narc... more Modafinil, a nonamphetaminic wake-promoting compound, is prescribed as first line therapy in narcolepsy, an invalidating disorder characterized by excessive daytime sleepiness and cataplexy. Although its mode of action remains incompletely known, recent studies indicated that modafinil modulates astroglial connexin-based gap junctional communication as administration of a low dose of flecainide, an astroglial connexin inhibitor, enhanced the wake-promoting and procognitive activity of modafinil in rodents and healthy volunteers. The aim of this study is to investigate changes in glucose cerebral metabolism in rodents, induced by the combination of modafinil+flecainide low dose (called THN102). The impact of THN102 on brain glucose metabolism was noninvasively investigated using 18F-2-fluoro-2-deoxy-D-glucose Positron Emission Tomography imaging in Sprague-Dawley male rats. Animals were injected with vehicle, flecainide, modafinil, or THN102 and further injected with 18F-2-fluoro-2-d...
Biological Psychiatry, 2017
International audienc
Addiction Biology
A large body of preclinical research has shown that neuroimmunity plays a key role in the deleter... more A large body of preclinical research has shown that neuroimmunity plays a key role in the deleterious effects of alcohol (ethanol) to the brain. Translational imaging techniques are needed to monitor the efficacy of strategies to prevent or mitigate neuroinflammation and alleviate ethanol‐induced neurotoxicity. Opioid receptor antagonists such as nalmefene are antagonists of the toll‐like receptor 4, which may block the proinflammatory signaling cascade induced by ethanol at this specific target. Male adolescent rats received a validated protocol of ethanol injection (i.p, 3 g/kg daily for two consecutive days followed by two resting days) during 14 days. Positron emission tomography (PET) imaging with the translocator protein 18 kDa (TSPO) radioligand [18F]DPA‐714 was performed at day‐15. Toxicity induced by repeated binge‐like ethanol exposure (71% mortality) was drastically reduced by nalmefene pretreatment (0.4 mg/kg, 14% mortality). No mortality was observed in animals that rec...
European Journal of Nuclear Medicine and Molecular Imaging, 2021
Recent research in last years in substance use disorders (SUD) synthesized a proinflammatory hypo... more Recent research in last years in substance use disorders (SUD) synthesized a proinflammatory hypothesis of SUD based on reported pieces of evidence of non-neuronal central immune signalling pathways modulated by drug of abuse and that contribute to their pharmacodynamic actions. Positron emission tomography has been shown to be a precious imaging technique to study in vivo neurochemical processes involved in SUD and to highlight the central immune signalling actions of drugs of abuse. In this review, we investigate the contribution of the central immune system, with a particular focus on translocator protein 18 kDa (TSPO) imaging, associated with a series of drugs involved in substance use disorders (SUD) specifically alcohol, opioids, tobacco, methamphetamine, cocaine, and cannabis. The large majority of preclinical and clinical studies presented in this review converges towards SUD modulation of the neuroimmune responses and TSPO expression and speculated a pivotal positioning in the pathogenesis of SUD. However, some contradictions concerning the same drug or between preclinical and clinical studies make it difficult to draw a clear picture about the significance of glial state in SUD. Significant disparities in clinical and biological characteristics are present between investigated populations among studies. Heterogeneity in genetic factors and other clinical co-morbidities, difficult to be reproduced in animal models, may affect findings. On the other hand, technical aspects including study designs, radioligand limitations, or PET imaging quantification methods could impact the study results and should be considered to explain discrepancies in outcomes. The supposed neuroimmune component of SUD provides new therapeutic approaches in the prediction and treatment of SUD pointing to the central immune signalling.
Journal of Affective Disorders, 2019
HAL is a multidisciplinary open access archive for the deposit and dissemination of scientific re... more HAL is a multidisciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L'archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés. Distributed under a Creative Commons Attribution-NonCommercial| 4.0 International License
Society of Nuclear Medicine Annual Meeting Abstracts, May 1, 2009
Annals of Neurology, 2015
Objective: Using positron emission tomography (PET) with [ 11 C]flumazenil ([ 11 C]FMZ), an antag... more Objective: Using positron emission tomography (PET) with [ 11 C]flumazenil ([ 11 C]FMZ), an antagonist of the central benzodiazepine site located within the GABA A receptor, we quantified and mapped neuronal damage in the gray matter (GM) of patients with multiple sclerosis (MS) at distinct disease stages. We investigated the relationship between neuronal damage and white matter (WM) lesions and evaluated the clinical relevance of this neuronal PET metric. Methods: A cohort of 18 MS patients (9 progressive and 9 relapsing-remitting) was compared to healthy controls and underwent neurological and cognitive evaluations, high-resolution dynamic [ 11 C]FMZ PET imaging and brain magnetic resonance imaging. [ 11 C]FMZ binding was estimated using the partial saturation protocol providing voxelwise absolute quantification of GABA A receptor concentration. PET data were evaluated using a region of interest (ROI) approach as well as on a vertex-by-vertex basis. Results: [ 11 C]FMZ binding was significantly decreased in the cortical GM of MS patients, compared to controls (-10%). Cortical mapping of benzodiazepine receptor concentration ([ 11 C]FMZ Bmax) revealed significant intergroup differences in the bilateral parietal cortices and right frontal areas. ROI analyses taking into account GM volume changes showed extensive decrease in [ 11 C]FMZ binding in bilateral parietal, cingulate, and insular cortices as well as in the thalami, amygdalae, and hippocampi. These changes were significant in both progressive and relapsingremitting forms of the disease and correlated with WM T2-weighted lesion load. [ 11 C]FMZ cortical binding correlated with cognitive performance. Interpretation: This pilot study showed that PET with [ 11 C]FMZ could be a promising and sensitive quantitative marker to assess and map the neuronal substrate of GM pathology in MS.
Epilepsia, 2003
Summary: Purpose: Acute caffeine exposure has proconvulsant effects and worsens epileptic and is... more Summary: Purpose: Acute caffeine exposure has proconvulsant effects and worsens epileptic and ischemic neuronal damage. Surprisingly, prolonged caffeine exposure decreases the susceptibility to seizures and the extent of ischemic damage. We explored whether the exposure to a low long‐term dose of caffeine could protect the brain from neuronal damage and epileptogenesis in the lithium‐pilocarpine model of temporal lobe epilepsy.Methods: Rats received either plain tap water or water containing caffeine (0.3 g/L) for 15 days before the induction of status epilepticus (SE) by lithium‐pilocarpine and for 7 days after SE. The extent of neuronal damage was assessed in the hippocampus and piriform and entorhinal cortices in brain sections stained with thionine and obtained from animals killed 7 days after SE. The latency to spontaneous recurrent seizures was controlled by video monitoring.Results: Caffeine treatment induced a marked, almost total neuroprotection in CA1 and a very limited p...
Frontiers in Neuroscience
AimBuprenorphine mainly acts as an agonist of mu-opioid receptors (mu-OR). High dose buprenorphin... more AimBuprenorphine mainly acts as an agonist of mu-opioid receptors (mu-OR). High dose buprenorphine does not cause respiratory depression and can be safely administered to elicit typical opioid effects and explore pharmacodynamics. Acute buprenorphine, associated with functional and quantitative neuroimaging, may therefore provide a fully translational pharmacological challenge to explore the variability of response to opioids in vivo. We hypothesized that the CNS effects of acute buprenorphine could be monitored through changes in regional brain glucose metabolism, assessed using 18F-FDG microPET in rats.Materials and methodsFirst, level of receptor occupancy associated with a single dose of buprenorphine (0.1 mg/kg, s.c) was investigated through blocking experiments using 11C-buprenorphine PET imaging. Behavioral study using the elevated plus-maze test (EPM) was performed to assess the impact of the selected dose on anxiety and also locomotor activity. Then, brain PET imaging using...
European Psychiatry, Mar 1, 2011
1/In juvenile patients, a cross-sectional ALE meta-analysis of both brain structure and function ... more 1/In juvenile patients, a cross-sectional ALE meta-analysis of both brain structure and function regional deviations in 270 articles allowed to cluster the diagnosed disorders into three sets with respectively marked affective, cognitive, and psychomotor phenomenology. The group with affective phenomenology was characterized by abnormalities of the frontal-limbic regions; the group with “cognition deficits” (incl. schizophrenia) mainly related to cortex abnormalities; and the psychomotor condition was associated with abnormalities in the basal ganglia. Therefore, early regional brain abnormalities might interact with the analysis of subsequent treatments effects in MR studies of brain structure and function of chronic mental disorders. 2/In chronic patients, brain imaging studies of antipsychotic drugs using dopamine receptor radioligands &PET scanner have consistently demonstrated the prevalence of their dose-dependent action in basal ganglia. This information has led to theoretical windows for optimal drug dosage. Recent measures of the dopamine transporter in chronic antipsychotic treatment, or in chronic use of drugs of addiction (e.g. tobacco, cannabis) suggest opposite changes of the adioligand uptake in both conditions. Therefore, control for the associated confounding addictions is required for in vivo analysis of antipsychotic action on the dopamine regulation in cortex and subcortical regions. 3/In treatment-resistant patients, MR & PET imaging studies have detected deviations of both brain structure and function, therefore suggesting biomarker of treatment response. 4/Conclusion: stage of illness, addictions, multimodal imaging, should be considered as covariates for brain imaging determinations of treatment effects in patients with chronic mental disorders.
Neuropsychopharmacology, Feb 9, 2016
Modafinil is a candidate compound for the treatment of cocaine addiction that binds to the dopami... more Modafinil is a candidate compound for the treatment of cocaine addiction that binds to the dopamine transporter (DAT) in healthy humans, as observed by positron emission tomography (PET). This mechanism, analogous to that of cocaine, might mediate a putative therapeutic effect of modafinil on cocaine dependence, though the binding of modafinil to DAT has never been assessed in cocainedependent patients. We aimed at quantifying the DAT availability during a controlled treatment by modafinil, and its clinical and psychometric correlates in cocaine-dependent patients at the onset of abstinence initiation. Twenty-nine cocaine-dependent male patients were enrolled in a 3-month trial for cocaine abstinence. Modafinil was used in a randomized double-blind placebo-controlled design and was administered as follows: 400 mg/day for 26 days, then 300 mg/day for 30 days, and 200 mg/day for 31 days. Participants were examined twice during a 17-day hospitalization for their DAT availability using PET and [ 11 C]-PE2I and for assessments of craving, depressive symptoms, working memory, and decision-making. Cocaine abstinence was further assessed during a 10-week outpatient follow-up period. Baseline [ 11 C]-PE2I-binding potential covaried with risk taking and craving index in striatal and extrastriatal regions. A 65.6% decrease of binding potential was detected in patients receiving modafinil for 2 weeks, whereas placebo induced no significant change. During hospitalization, an equivalent improvement in clinical outcomes was observed in both treatment groups, and during the outpatient follow-up there were more therapeutic failures in the modafinil-treated group. Therefore, these results do not support the usefulness of modafinil to treat cocaine addiction.
Patients with temporal lobe epilepsy (TLE) usually had an initial precipitating injury in early c... more Patients with temporal lobe epilepsy (TLE) usually had an initial precipitating injury in early childhood. However, epilepsy does not develop in all children who have undergone an early insult. As in patients, the consequences of the lithium-pilocarpine-induced status epilepticus (SE) are age dependent, and only a subset of 21-day-old rats will develop epilepsy. Thus with magnetic resonance imaging (MRI), we explored the differences in the evolution of lesions in these two populations of rats. Methods: SE was induced in 21-day-old rats by the injection of lithium and pilocarpine. T 2-weighted images and T 2 relaxation-time measurements were used for detection of lesions from 6 h to 4 months after SE. Results: Three populations of rats could be distinguished. The first one had neither MRI anomalies nor modification of the T 2 relaxation time, and these rats did not develop epilepsy.
Neuropsychopharmacology, 2021
A wide range of buprenorphine doses are used for either pain management or maintenance therapy in... more A wide range of buprenorphine doses are used for either pain management or maintenance therapy in opioid addiction. The complex in vitro profile of buprenorphine, with affinity for µ-, δ-, and κ-opioid receptors (OR), makes it difficult to predict its doserelated neuropharmacology in vivo. In rats, microPET imaging and pretreatment by OR antagonists were performed to assess the binding of radiolabeled buprenorphine (microdose 11 C-buprenorphine) to OR subtypes in vivo (n = 4 per condition). The µ-selective antagonist naloxonazine (10 mg/kg) and the non-selective OR antagonist naloxone (1 mg/kg) blocked the binding of 11 Cbuprenorphine, while pretreatment by the δ-selective (naltrindole, 3 mg/kg) or the κ-selective antagonist (norbinaltorphimine, 10 mg/kg) did not. In four macaques, PET imaging and kinetic modeling enabled description of the regional brain kinetics of 11 Cbuprenorphine, co-injected with increasing doses of unlabeled buprenorphine. No saturation of the brain penetration of buprenorphine was observed for doses up to 0.11 mg/kg. Regional differences in buprenorphine-associated receptor occupancy were observed. Analgesic doses of buprenorphine (0.003 and 0.006 mg/kg), respectively, occupied 20% and 49% of receptors in the thalamus while saturating the low but significant binding observed in cerebellum and occipital cortex. Occupancy >90% was achieved in most brain regions with plasma concentrations >7 µg/L. PET data obtained after co-injection of an analgesic dose of buprenorphine (0.003 mg/kg) predicted the binding potential of microdose 11 C-buprenorphine. This strategy could be further combined with pharmacodynamic exploration or pharmacological MRI to investigate the neuropharmacokinetics and neuroreceptor correlate, at least at µ-OR, of the acute effects of buprenorphine in humans.
NeuroImage, 2021
Whole brain estimation of the haemodynamic response function (HRF) in functional magnetic resonan... more Whole brain estimation of the haemodynamic response function (HRF) in functional magnetic resonance imaging (fMRI) is critical to get insight on the global status of the neurovascular coupling of an individual in healthy or pathological condition. Most of existing approaches in the literature works on task-fMRI data and relies on the experimental paradigm as a surrogate of neural activity, hence remaining inoperative on resting-stage fMRI (rs-fMRI) data. To cope with this issue, recent works have performed either a two-step analysis to detect large neural events and then characterize the HRF shape or a joint estimation of both the neural and haemodynamic components in an univariate fashion. In this work, we express the neural activity signals as a combination of piece-wise constant temporal atoms associated with sparse spatial maps and introduce an haemodynamic parcellation of the brain featuring a temporally dilated version of a given HRF model in each parcel with unknown dilation parameters. We formulate the joint estimation of the HRF shapes and spatio-temporal neural representations as a multivariate semi-blind deconvolution problem in a paradigm-free setting and introduce constraints inspired from the dictionary learning literature to ease its identifiability. A fast alternating minimization algorithm, along with its efficient implementation, is proposed and validated on both synthetic and real rs-fMRI data at the subject level. To demonstrate its significance at the population level, we apply this new framework to the UK Biobank data set, first for the discrimination of haemodynamic territories between balanced groups (= 24 individuals in each) patients with an history of stroke and healthy controls and second, for the analysis of normal aging on the neurovascular coupling. Overall, we statistically demonstrate that a pathology like stroke or a condition like normal brain aging induce longer haemodynamic delays in certain brain areas (e.g. Willis polygon, occipital, temporal and frontal cortices) and that this haemodynamic feature may be predictive with an accuracy of 74 % of the individual's age in a supervised classification task performed on = 459 subjects.
Alzheimer's Research & Therapy, 2020
Background Current demographic trends point towards an aging society entailing increasing occurre... more Background Current demographic trends point towards an aging society entailing increasing occurrence and burden of neurodegenerative diseases. In this context, understanding physiological aging and its turning point into neurodegeneration is essential for the development of possible biomarkers and future therapeutics of brain disease. Methods The SENIOR study represents a longitudinal, observational study including cognitively healthy elderlies aged between 50 and 70 years old at the time of inclusion, being followed annually over 10 years. Our multimodal protocol includes structural, diffusion, functional, and sodium magnetic resonance imaging (MRI) at 3 T and 7 T, positron emission tomography (PET), blood samples, genetics, audiometry, and neuropsychological and neurological examinations as well as assessment of neuronal risk factors. Results One hundred forty-two participants (50% females) were enrolled in the SENIOR cohort with a mean age of 60 (SD 6.3) years at baseline. Baseli...
The international journal of neuropsychopharmacology, Jan 15, 2018
Modafinil, a nonamphetaminic wake-promoting compound, is prescribed as first line therapy in narc... more Modafinil, a nonamphetaminic wake-promoting compound, is prescribed as first line therapy in narcolepsy, an invalidating disorder characterized by excessive daytime sleepiness and cataplexy. Although its mode of action remains incompletely known, recent studies indicated that modafinil modulates astroglial connexin-based gap junctional communication as administration of a low dose of flecainide, an astroglial connexin inhibitor, enhanced the wake-promoting and procognitive activity of modafinil in rodents and healthy volunteers. The aim of this study is to investigate changes in glucose cerebral metabolism in rodents, induced by the combination of modafinil+flecainide low dose (called THN102). The impact of THN102 on brain glucose metabolism was noninvasively investigated using 18F-2-fluoro-2-deoxy-D-glucose Positron Emission Tomography imaging in Sprague-Dawley male rats. Animals were injected with vehicle, flecainide, modafinil, or THN102 and further injected with 18F-2-fluoro-2-d...
Biological Psychiatry, 2017
International audienc