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The branched-chain amino acids: leucine, isoleucine and valine occupy a special place among the essential amino acids because of their importance not only in the structure of proteins but also in general and cerebral metabolism. Among the first amino acids absorbed after food intake, they play a major role in the regulation of protein synthesis and insulin secretion. They are involved in the modulation of brain uptake of monoamine precursors with which they may compete for occupancy of a common transporter. In the brain, branched-chain amino acids are involved not only in protein synthesis but also in the metabolic cycles of GABA and Glutamate, and in energy metabolism. In particular, they can affect GABAergic neurons and the excitation/inhibition balance. Branched-chain amino acids are known for the 24-hour rhythmicity of their plasma concentrations, which is remarkably conserved in rodent models. This rhythmicity is partly circadian, independent of sleep and food. Moreover, their concentration increases when sleep is disturbed and in obesity and diabetes. The mechanisms regulating these rhythms and their physiological impact remain poorly understood. In this context, the Drosophila model has not yet been widely used, but it is highly relevant and the first results indicate that it can generate new concepts. The elucidation of the metabolism and fluxes of branched-chain amino acids is beginning to shed light on the mysterious connections between clock, sleep, and metabolism, opening the possibility of new therapies., Les acides aminés branchés : leucine, isoleucine et valine occupent une place particulière parmi les acides aminés essentiels de par leur importance non seulement dans la structure des protéines mais aussi dans le métabolisme général et cérébral. Ils sont parmi les premiers acides aminés absorbés après la prise alimentaire et jouent un rôle majeur dans la régulation de la synthèse protéique et de la sécrétion d’insuline. Ils participent à la modulation de l’import cérébral des précurseurs de monoamines avec lesquels ils peuvent entrer en compétition pour l’occupation d’un transporteur commun. Dans le cerveau, les acides aminés branchés interviennent également dans les cycles métaboliques du GABA et du Glutamate, et dans le métabolisme énergétique. Ils peuvent notamment affecter les neurones GABAergiques et la balance excitation/inhibition. Les acides aminés branchés sont connus pour la rythmicité sur 24h de leurs concentrations plasmatiques qui est remarquablement conservée chez les modèles rongeurs. Cette rythmicité est en partie circadienne, indépendante du sommeil et de l’alimentation. Par ailleurs leur concentration augmente lorsque le sommeil est perturbé ainsi que dans l’obésité et le diabète. Les mécanismes régulant ces rythmes et leur impact physiologique restent mal compris. Dans ce contexte, le modèle drosophile a encore été peu utilisé, mais il a toute sa pertinence et les premiers résultats indiquent qu’il peut générer de nouveaux concepts. L’élucidation du métabolisme et des flux des acides aminés branchés commence à éclairer les connections mystérieuses qui existent entre horloge, sommeil, et métabolisme, ouvrant la possibilité de nouvelles thérapies.

The protein phosphatase 2A complex (PP2A), the major Ser/Thr phosphatase in the brain, is involved in a number of signalling pathways and functions, including the regulation of crucial proteins for neurodegeneration, such as alpha-synuclein, tau and LRRK2. Here, we report the identification of variants in the PTPA/PPP2R4 gene, encoding a major PP2A activator, in two families with early-onset parkinsonism and intellectual disability. We carried out clinical studies and genetic analyses, including genome-wide linkage analysis, whole-exome sequencing, and Sanger sequencing of candidate variants. We next performed functional studies on the disease-associated variants in cultured cells and knock-down of ptpa in Drosophila melanogaster. We first identified a homozygous PTPA variant, c.893T>G (p.Met298Arg), in patients from a South African family with early-onset parkinsonism and intellectual disability. Screening of a large series of additional families yielded a second homozygous variant, c.512C>A (p.Ala171Asp), in a Libyan family with a similar phenotype. Both variants co-segregate with disease in the respective families. The affected subjects display juvenile-onset parkinsonism and intellectual disability. The motor symptoms were responsive to treatment with levodopa and deep brain stimulation of the subthalamic nucleus. In overexpression studies, both the PTPA p.Ala171Asp and p.Met298Arg variants were associated with decreased PTPA RNA stability and decreased PTPA protein levels; the p.Ala171Asp variant additionally displayed decreased PTPA protein stability. Crucially, expression of both variants was associated with decreased PP2A complex levels and impaired PP2A phosphatase activation. PTPA orthologue knock-down in Drosophila neurons induced a significant impairment of locomotion in the climbing test. This defect was age-dependent and fully reversed by L-DOPA treatment. We conclude that bi-allelic missense PTPA variants associated with impaired activation of the PP2A phosphatase cause autosomal recessive early-onset parkinsonism with intellectual disability. Our findings might also provide new insights for understanding the role of the PP2A complex in the pathogenesis of more common forms of neurodegeneration.

International audience; On June 2022, the 2nd Webinar "Neurodevelopmental Disorders (NDD) without boundaries took place at the Imagine Institute in Paris and was broadcasted live and in replay. The aim of this webinar is to address NDD in a dimensional rather than in a categorical approach. Several speakers were invited to present their researches on the subject. Classifications in NDD were discussed: irritability in NDD, involvement of the immune system in neurodevelopment, nutrition and gut microbiota modulate brain inflammation and neurodevelopment, co-occurring conditions in autistic adolescents and adults without intellectual disability. Classifications in psychiatric disorders were asked: mapping the effect of genes on cognition and autism risk, epigenetics and symptomatic trajectory in neurodevelopmental disorders, the autism-schizophrenia continuum in two examples: minor neurological signs and EEG microstates, the cerebellum in schizophrenia and autism: from imaging to intervention perspectives. Both genetic and environmental factors, along with clinical and imaging features, argue toward a continnum between NDD but also with adult psychiatric presentations. This new paradigm could modify the therapeutic strategy, with the development of large-spectrum treatments or new psychotherapies addressing co-occuring symptoms. The complexity and the heterogeneity of NDD apply well to the next scientific and political challenges: developing international convergence to push back the frontiers of our knowledge. This article is a summary of the 2nd webinar "Neurodevelopmental Disorders (NDD) without boundaries: research and interventions beyond classifications" sponsored by the French National Academy of Medicine, the autism and neurodevelopmental disorders scientific interest group (GIS), the International Research Network Dev-O-Psy and the French Institute of Psychiatry (GDR3557). Oral presentations are available as a replay on the following website (in French): https://autisme-neurodev.org/evenements/2022/04/12/tnd-sans-frontieres-la-recherche-et-les-interventions-au-dela-des-classifications/ .

In prodromal and early schizophrenia, disorders of attention and perception are associated with structural and chemical brain abnormalities, and with dysfunctional corticothalamic networks exhibiting disturbed brain rhythms. The underlying mechanisms are elusive. The non-competitive NMDA receptor antagonist ketamine simulates the symptoms of prodromal and early schizophrenia, including disturbances in ongoing and task & sensory-related broadband beta-/gamma-frequency (17-29 Hz/30-80 Hz) oscillations in corticothalamic networks. In normal healthy subjects and rodents, complex integration processes, like sensory perception, induce transient, large-scale synchronized beta/gamma oscillations in a time window of a few hundreds of ms (200-700 ms) after the presentation of the object of attention (e.g., sensory stimulation). Our goal was to use an electrophysiological multisite network approach to investigate, in lightly anesthetized rats, the effects of a single psychotomimetic dose (2.5 mg/kg, subcutaneous) of ketamine on sensory stimulus-induced oscillations. Ketamine transiently increased the power of baseline beta/gamma oscillations and decreased sensory-induced beta/gamma oscillations. In addition, it disrupted information transferability in both the somatosensory thalamus and the related cortex and decreased the sensory-induced thalamocortical connectivity in the broadband gamma range. In conclusion, the present findings support the hypothesis that NMDA receptor antagonism disrupts the transfer of perceptual information in the somatosensory cortico-thalamo-cortical system.LAY ABSTRACTCognitive deficit is usual in schizophrenia. Perception- or task-related beta/gamma-frequency oscillations are decreased. In healthy humans and rodents, ketamine-induced NMDA receptor antagonism simulates the symptoms of early schizophrenia and excessively amplifies baseline beta/gamma oscillations. In the present study, using an electrophysiological multisite network approach in a rodent model, it is demonstrated that ketamine, systemically administered at a single psychotomimetic dose, increases baseline beta/gamma oscillations, decreases beta/gamma responses induced by sensory stimulation in a short time window (200-700 ms), and disrupts information transfer in the cortico-thalamo-cortical network. The present findings have mechanistic relevance for cognitive deficits in schizophrenia.

International audience; Cargo transport by molecular motors along microtubules is essential for the function of eucaryotic cells, in particular neurons in which axonal transport defects constitute the early pathological features of neurodegenerative diseases. Mainly studied in motor and sensory neurons, axonal transport is still difficult to characterize in neurons of the brain in absence of appropriate in vivo tools. Here, we measured fast axonal transport by tracing the second harmonic generation (SHG) signal of potassium titanyl phosphate (KTP) nanocrystals endocytosed by brain neurons of zebrafish (Zf) larvae. Thanks to the optical translucency of Zf larvae and of the perfect photostability of nanoKTP SHG, we achieved a high scanning speed of 20 frames (of ≈ 90 μ m×60 μ m size) per second in Zf brain. We focused our study on endolysosomal vesicle transport in axons of known polarization, separately analyzing kinesin and dynein motor-driven displacements. To validate our assay, we used either loss-of-function mutations of dynein or kinesin 1 or the dynein inhibitor dynapyrazole, and quantified several transport parameters. We successfully demonstrated that dynapyrazole reduces nanoKTP mobile fraction and retrograde run length consistently, while the retrograde run length increased in kinesin 1 mutants. Taking advantage of nanoKTP SHG directional emission, we also quantified fluctuations of vesicle orientation. Thus, by combining endocytosis of nanocrystals having non-linear response, fast two-photon microscopy, and high-throughput analysis, we are able to finely monitor fast axonal transport in vivo in the brain of a vertebrate, and reveal subtle axonal transport alterations. The high spatiotemporal resolution achieved in our model may be relevant to precisely investigate axonal transport impairment associated to disease models.

International audience; Background: In acute intracerebral hemorrhage (ICH), the prognostic value of the MRI spot sign on hematoma expansion (HE) and poor functional outcome is poorly known.Methods: We retrospectively included patients admitted over a 4-year period for an acute ICH in a single institution using MRI as the first-line imaging tool. The presence and number of MRI spot signs on contrast-enhanced T1-weighted imaging was evaluated by one neuroradiologist, blinded from outcomes. The primary outcome was HE, defined as > 6 mL or > 33% ICH volume growth from initial MRI to 24-48 h follow-up imaging; the secondary outcome was poor 3-month modified Rankin score (4-6).Results: Overall, 147 patients were included, and 62% had a spot sign. Among the 130 patients with follow-up imaging, 24% experienced HE. HE occurred in 6%, 21% and 43% patients with 0, 1 and ≥ 2 spots, respectively (P < 0.001). The MRI spot sign was independently associated with HE (adjusted OR 6.15 [95% CI 1.60-23.65]; P = 0.008), with a dose-dependent effect. The negative and positive predictive values of the spot sign for HE were 0.94 and 0.35, respectively. Poor functional outcome occurred in 27%, 32% and 71% patients with 0, 1 and ≥ 2 spots, respectively (P < 0.001). In multivariable analysis, the presence of ≥ 2 spots was independently associated with poor functional outcome (adjusted OR 3.67 [95% CI 1.21-11.10]; P = 0.024).Conclusion: The MRI spot sign is an independent biomarker of HE, and the presence of ≥ 2 spots is independently associated with poor 3-month outcome. The lack of spot sign is highly predictive of a favorable evolution.

Early-life determinants are thought to be a major factor in the rapid increase of obesity. However, while maternal nutrition has been extensively studied, the effects of breastfeeding by the infant on the reprogramming of energy balance in childhood and throughout adulthood remain largely unknown. Here we show that delayed weaning in rat pups protects them against diet-induced obesity in adulthood, through enhanced brown adipose tissue thermogenesis and energy expenditure. In-depth metabolic phenotyping in this rat model as well as in transgenic mice reveals that the effects of prolonged suckling are mediated by increased hepatic fibroblast growth factor 21 (FGF21) production and tanycyte-controlled access to the hypothalamus in adulthood. Specifically, FGF21 activates GABA-containing neurons expressing dopamine receptor 2 in the lateral hypothalamic area and zona incerta. Prolonged breastfeeding thus constitutes a protective mechanism against obesity by affecting long-lasting physiological changes in liver-to-hypothalamus communication and hypothalamic metabolic regulation. This work was supported by grants from: L.M.S.: Instituto de Salud Carlos III and co-funded by FEDER (PI18/00998), FEDER/Ministerio de Ciencia, Innovación y Universidades-Agencia Estatal de Investigación (C.D.: BFU2017-87721; M.L.: RTI2018–101840-B-I00; R.N.: RTI2018-099413-B-I00 and RED2018-102379-T), Xunta de Galicia (M.L.: 2016-PG068; R.N.: 2016-PG057 and 2020-PG015), Fundación BBVA (R.N.: Fundación Atresmedia (to M.L. and R.N.), Fundación La Caixa (to M.L. and R.N.), Fundación Jesus Serra and European Foundation for the Study of Diabetes (to R.N.). The research leading to these results also received funding from the European Community’s H2020 Framework Programme under the following grant: ERC Synergy Grant-2019-WATCH- 810331 to M.S., V.P. and R.N. Centro de Investigación Biomédica en Red (CIBER) de Fisiopatología de la Obesidad y Nutrición (CIBERobn). CIBERobn is an initiative of the Instituto de Salud Carlos III (ISCIII) of Spain, which is supported by FEDER funds. This work was supported by Inserm, Fondation pour la Recherche Médicale, ANR-EPITRACES (to E.V.). Research from the M.F. laboratory was supported by the Spanish Agencia Estatal de Investigación, co-funded by the FEDER Programme of the EU (BFU2016-80899-P and PID2019-105739GB-I00 grants; AEI/FEDER, UE). M.F. is recipient of a Ramón y Cajal award (RYC-2014-16779). C.F. is a recipient of a Sara Borrel award (ISCIII CD19/0078). O.A. is a recipient of the Miguel Servet grant (ISCIIII). Sí

Chloé Chamard,1,2 Jerome J Maller,3,4 Nicolas Menjot,5 Eloi Debourdeau,1 Virginie Nael,6 Karen Ritchie,2,7 Isabelle Carriere,2,&ast; Vincent Daien1,2,8,&ast; 1Department of Ophthalmology, Gui de Chauliac Hospital, Montpellier, F-34000, France; 2Institute for Neurosciences of Montpellier INM, University Montpellier, INSERM, Montpellier, F-34091, France; 3General Electric Healthcare, Melbourne, VIC, Australia; 4Monash Alfred Psychiatry Research Centre, Melbourne, VIC, Australia; 5Department of Neuroradiology, Gui de Chauliac Hospital, Montpellier, F-34000, France; 6Bordeaux Population Health Research Center, UMR 1219, University Bordeaux, INSERM, Bordeaux, F-33000, France; 7Department of Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK; 8The Save Sight Institute, Sydney Medical School, the University of Sydney, Sydney, NSW, Australia&ast;These authors contributed equally to this workCorrespondence: Chloé Chamard, Department of Ophthalmology, Gui de Chauliac Hospital, 80 avenue Augustin Fliche, Montpellier, F-34000, France, Tel +33 6 33 55 65 06, Email chloe.chamard@gmail.comPurpose: Visual impairment is a major cause of disability and impairment of cognitive function in older people. Brain structural changes associated with visual function impairment are not well understood. The objective of this study was to assess the association between visual function and cortical thickness in older adults.Methods: Participants were selected from the French population-based ESPRIT cohort of 2259 community-dwelling adults ≥ 65 years old enrolled between 1999 and 2001. We considered visual function and brain MRI images at the 12-year follow-up in participants who were right-handed and free of dementia and/or stroke, randomly selected from the whole cohort. High-resolution structural T1-weighted brain scans acquired with a 3-Tesla scanner. Regional reconstruction and segmentation involved using the FreeSurfer image-analysis suite.Results: A total of 215 participants were included (mean [SD] age 81.8 [3.7] years; 53.0% women): 30 (14.0%) had central vision loss and 185 (86.0%) normal central vision. Vision loss was associated with thinner cortical thickness in the right insula (within the lateral sulcus of the brain) as compared with the control group (mean thickness 2.38 [0.04] vs 2.50 [0.03] mm, 4.8% thinning, pcorrected= 0.04) after adjustment for age, sex, lifetime depression and cardiovascular disease.Conclusion: The present study describes a significant thinning of the right insular cortex in older adults with vision loss. The insula subserves a wide variety of functions in humans ranging from sensory and affective processing to high-level cognitive processing. Reduced insula thickness associated with vision loss may increase cognitive burden in the ageing brain.Keywords: visual function, vision, cortical thickness, brain, morphometry, MRI

International audience; The term neurovascular unit (NVU) describes the structural and functional liaison between specialized brain endothelium, glial and mural cells, and neurons. Within the NVU, the blood-brain barrier (BBB) is the microvascular structure regulating neuronal physiology, immune cross-talk, and its properties adapt to brain aging. Here, we analyze a research framework where NVU dysfunction, caused by acute insults or disease progression in the aging brain, represents a converging mechanism underlying late-onset seizures or epilepsy and neurological or neurodegenerative sequelae. Alongside, seizure activity may accelerate brain aging by sustaining regional NVU dysfunction, and a cerebrovascular pathology may link seizures to comorbidities. Next, we focus on NVU diagnostic approaches that could be tailored to seizure conditions in the elderly. We also examine the impending disease-modifying strategies based on the restoration of NVU cells and, more in general, the homeostatic control of anti- and pro-inflammatory players. We conclude with an outlook on current pre-clinical knowledge gaps and clinical challenges pertinent to seizure onset and conditions in an aging population.

International audience; Patients with chronic pain, especially orofacial pain, often suffer from affective disorders, including anxiety. Previous studies largely focused on the role of the caudal anterior cingulate cortex (cACC) in affective responses to pain, long-term potentiation (LTP) in cACC being thought to mediate the interaction between anxiety and chronic pain. But recent evidence indicates that the rostral ACC (rACC), too, is implicated in processing affective pain. However, whether such processing is associated with neuronal and/or synaptic plasticity is still unknown. We addressed this issue in a chronic facial inflammatory pain model (complete Freund's adjuvant model) in rats, by combining behavior, Fos protein immunochemistry and ex vivo intracellular recordings in rACC slices prepared from these animals. Facial mechanical allodynia occurs immediately after CFA injection, peaks at post-injection day 3 and progressively recovers until post-injection days 10-11, whereas anxiety is delayed, being present at post-injection day 10, when sensory hypersensitivity is relieved, but, notably, not at post-injection day 3. Fos expression reveals that neuronal activity follows a bi-phasic time course in bilateral rACC: first enhanced at post-injection day 3, it gets strongly depressed at post-injection day 10. Ex vivo recordings from lamina V pyramidal neurons, the rACC projecting neurons, show that both their intrinsic excitability and excitatory synaptic inputs have undergone long-term depression (LTD) at post-injection day 10. Thus chronic pain processing is associated with dynamic changes in rACC activity: first enhanced and subsequently decreased, at the time of anxiety-like behavior. Chronic pain-induced anxiety might thus result from a rACC deactivation-cACC hyperactivation interplay.

International audience; Background: : The aim of this retrospective study is to explore the prognostic value of different contrast enhancement imaging patterns in childhood Guillain–Barré syndrome by comparing the clinical, laboratory, and therapeutic outcomes.Methods: : We included a total of 37 patients who were diagnosed and followed up by a pediatric neurology team at Montpellier University Hospital between 2000 and 2016. All images were reinterpreted by the first author and a senior pediatric neuroradiology staff member in two different sessions; in the case of disagreement, the expert's reading was considered.Results: : The study group comprised 22 (59.5%) boys and 15 (40.5%) girls. The age ranged from 1.5 year to 14.8 years. Muscle weakness was present in 33 (89.2%) patients. Cranial nerves involvement was observed in 22 (59.5%) patients, while 29 (78.4%) patients had albuminocytological dissociation. In 27 (73%) patients, contrast enhancement or thickening of the lumbosacral nerve roots was found. Simultaneous spinal nerve root and cranial nerve enhancement was noted in five (17.2%) patients, while isolated cranial nerve enhancement was identified in three (10.3%) patients. Clinical and radiological cranial nerve involvement was found in seven (18.9%) patients, while isolated clinical cranial nerves involvement occurred in 13 (35.1%) patients. No significant correlation between different magnetic resonance imaging (MRI) enhancement patterns and short-term or long-term outcomes was found in our cohort.Conclusion: : Contrast-enhanced brain and spinal MRI is a sensitive and recommended supportive test for diagnosing acute inflammatory polyradiculopathy in children. Its predictive value for clinical, and therapeutic outcomes in the short or long term has not yet been proved

International audience; Background In acute ischemic stroke (AIS), fluid-attenuated inversion recovery (FLAIR) is used for treatment decisions when onset time is unknown. Synthetic FLAIR could be generated with deep learning from information embedded in diffusion-weighted imaging (DWI) and could replace acquired FLAIR sequence (real FLAIR) and shorten MRI duration. Purpose To compare performance of synthetic and real FLAIR for DWI-FLAIR mismatch estimation and identification of patients presenting within 4.5 hours from symptom onset. Materials and Methods In this retrospective study, all pretreatment and early follow-up ( .99). Conclusion Synthetic fluid-attenuated inversion recovery (FLAIR) had diagnostic performances similar to real FLAIR in depicting diffusion-weighted imaging-FLAIR mismatch and in helping to identify early acute ischemic stroke, and it may accelerate MRI protocols. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Carroll and Hurley in this issue.

In most cases, vestibular schwannomas with papilledema are associated with intracranial hypertension secondary to hydrocephalus (obstructive or communicating). We describe the atypical case of a 39-years-old man who presented with bilateral papilledema revealing a vestibular schwannoma, but without hydrocephalus and with normal intracranial pressure. Ophtalmologic signs were completely resolved after tumor removal. The pathophysiological mechanism generally described to explain bilateral papilledema in such cases is tumor-induced hyperproteinorachia. However, in the absence of hydrocephalus or intracranial hypertension, this case raises the question of the mechanisms involved in the visual impairment related to vestibular schwannoma., Les schwannomes vestibulaires avec œdème papillaire sont en général associés à une hypertension intracrânienne secondaire à une hydrocéphalie (communicante ou obstructive). Nous décrivons ici le cas atypique d’un homme de 39 ans ayant présenté un œdème papillaire révélateur d’un schwannome vestibulaire, mais sans hydrocéphalie et avec une pression intracrânienne normale. L’exérèse tumorale a permis une régression complète des signes ophtalmologiques. En l’absence d’obstruction ventriculaire, le mécanisme physiopathologique généralement décrit pour expliquer l’atteinte visuelle est l’hydrocéphalie secondaire à une hyperprotéinorachie. Cependant, en l’absence d’hydrocéphalie ou d’hypertension intracrânienne, ce cas soulève la question des mécanismes impliqués dans l’atteinte visuelle secondaire à la présence d’un schwannome vestibulaire

Reproduction, growth, stress, and metabolism are determined by endocrine/neuroendocrine systems that regulate circulating hormone concentrations. All these systems generate rhythms and changes in hormone pulsatility observed in a variety of pathophysiological states. Thus, the output of endocrine/neuroendocrine systems must be regulated within a narrow window of effective hormone concentrations but must also maintain a capacity for plasticity to respond to changing physiological demands. Remarkably most endocrinologists still have a "textbook" view of endocrine gland organization which has emanated from 20th century histological studies on thin 2D tissue sections. However, 21st -century technological advances, including in-depth 3D imaging of specific cell types have vastly changed our knowledge. We now know that various levels of multicellular organization can be found across different glands, that organizational motifs can vary between species and can be modified to enhance or decrease hormonal release. This article focuses on how the organization of cells regulates hormone output using three endocrine/neuroendocrine glands that present different levels of organization and complexity: the adrenal medulla, with a single neuroendocrine cell type; the anterior pituitary, with multiple intermingled cell types; and the pancreas with multiple intermingled cell types organized into distinct functional units. We give an overview of recent methodologies that allow the study of the different components within endocrine systems, particularly their temporal and spatial relationships. We believe the emerging findings about network organization, and its impact on hormone secretion, are crucial to understanding how homeostatic regulation of endocrine axes is carried out within endocrine organs themselves.

International audience; The activation of phagocytic cells is a hallmark of many neurological diseases. Imaging them in their 3-dimensional cerebral environment over time is crucial to better understand their role in disease pathogenesis and to monitor their potential therapeutic effects. Phagocytic cells have the ability to internalize metal-based contrast agents both in vitro and in vivo and can thus be tracked by magnetic resonance imaging (MRI) or computed tomography (CT). In this review article, we summarize the different labelling strategies, contrast agents, and in vivo imaging modalities that can be used to monitor cells with phagocytic activity in the central nervous system using MRI and CT, with a focus on clinical applications. Metal-based nanoparticle contrast agents such as gadolinium, gold and iron are ideal candidates for these applications as they have favourable magnetic and/or radiopaque properties and can be fine-tuned for optimal uptake by phagocytic cells. However, they also come with downsides due to their potential toxicity, especially in the brain where they might accumulate. We therefore conclude our review by discussing the pitfalls, safety and potential for clinical translation of these metal-based neuroimaging techniques. Early results in patients with neuropathologies such as multiple sclerosis, stroke, trauma, cerebral aneurysm and glioblastoma are promising. If the challenges represented by safety issues are overcome, phagocytic cells imaging will be a very valuable tool for studying and understanding the inflammatory response and evaluating treatments that aim at mitigating this response in patients with neurological diseases.

In Drosophila melanogaster, pheromonal communication is mainly mediated through sex-specific cuticular hydrocarbons (and derived compounds) and the male lipidic pheromone 11 - cis - Vaccényl Acétate (cVA). When deposited together on the feeding substrate they attract conspecifics males and females, promoting mating and collective behaviors. Initially described as stereotyped, recent findings showed that adult response to pheromones could be plastic and depend on the juvenile experience of an individual (i.e. imprinting). In this context, we studied cVA imprinting through its aggregative effect in individuals whose imprinting has been manipulated.The first goal, behavioral, was to study long-range attraction of cVA (or not)-imprinted males and females presented with a dual food choice in a flight tunnel. Foods were either naturally labelled by conspecifics (depositing their pheromonal and microbial compounds) or manually enriched with cVA. This first experiment was completed by the analysis of labeled food headspaces to decipher sources and natures of volatiles odorant compounds attracting Drosophila. This experiment highlighted the necessity of an early larval contact with cVA to modulate adult attraction to the pheromone. However, manual larval exposure to cVA alone was not sufficient to fully restore adult attraction,which may indicate that other compounds are needed in the pheromone imprinting. Food choice finally appeared to be a sex-specific behavior dependent on the nature of the food labelling and the dual food choice presented.The second goal was to study the electrophysiological antennal response of cVA (or not)-imprinted males and females when presented with a short-range puff of the pheromone. Recording showed modulation of the peripheric response according to pre-imaginal exposure to cVA but not the sex. It seems that sex-specific long-range attraction in the flight tunnel is rather explained by the central dimorphism of cVA–neural olfactory system than by a different peripheral detection of the pheromone. Finally, the similarity of peripheric response in unimprinted and manually imprinted individuals to cVA alone support the hypothesis that larval imprinting to cVA needs additional parental compounds to be fully effective in adult., Chez Drosophila melanogaster, la communication phéromonale se fait majoritairement au moyen des hydrocarbures cuticulaires sexuellement spécifiques (et de produits dérivés) et du 11 - cis - vaccényl acétate (cVA), phéromone lipidique mâle. Leur dépôt conjoint sur la nourriture, véritable signature chimique de l’espèce, attire mâles et femelles conspécifiques et favorise accouplements et comportements collectifs. Initialement décrite comme stéréotypée, il a récemment été montré que la réponse adulte aux phéromones pouvait cependant être plastique et dépendre notamment de l’expérience juvénile d’un individu (i.e. imprégnation). Dans ce contexte, le phénomène d’empreinte au cVA a fait l’objet d’une analyse à travers l’étude du rôle agrégatif de la phéromone chez des individus dont l’imprégnation a été manipulée.La première échelle, comportementale, avait pour but d’étudier l’attraction à distance de mâles et femelles imprégnées ou non au cVA vers un choix de nourritures marquées au moyen d’un tunnel de vol. Le marquage était soit réalisé naturellement par les dépôts phéromonaux et microbiotiques de conspécifiques, soit manuellement par dépôt de cVA synthétique. Cette première expérience a fait l’objet d’une analyse complémentaire des espaces de tête des nourritures utilisées visant à étudier la nature et l’origine des odorants émis. Les résultats ont mis en évidence la nécessité d’un contact larvaire avec le cVA dans la modulation de l’attraction adulte à la phéromone, cependant l’exposition synthétique au cVA seul ne suffit pas à rétablir pleinement l’attraction naturelle, supposant que d’autres composés sont impliqués dans l’imprégnation. L’attractivité des nourritures apparait de plus dépendante du sexe de la Drosophile testée, de la nature du marquage présent sur la nourriture et du choix de nourritures proposées.La deuxième échelle, électrophysiologique, avait pour but d’étudier la réponse antennaire de mâles et femelles imprégnés ou non au cVA lors de la diffusion à courte distance de la phéromone. Les enregistrements ont mis en évidence l’existence de différences de réponses périphériques selon l’exposition pré-imaginale à la phéromone, mais pas selon le sexe. Il semble donc que les différences de comportements observables entre mâles et femelles en tunnel de vol s’expliquent par le dimorphisme central de circuiterie du cVA plutôt que par une détection périphérique différente de la phéromone. Finalement, l’absence de différence de réponses entre les individus non – imprégnés et synthétiquement imprégnés soutient davantage la nécessité de contact avec d’autres composés en plus du cVA pendant la période larvaire afin de permettre l’imprégnation totale à la phéromone.

National audience; There is increased interest in the neuroimaging community to record data provenance, i.e. all steps leading to the creation of a dataset, in order to improve transparency and reproducibility of studies. The NIDM-Results specification provides a software-independent standardised format for representing neuroimaging results. But currently, there is no mechanism to read this format from the standard neuroimaging tools. Here, we introduce an NIDM-Results viewer for SPM, publically available at: https://github.com/incf-nidash/nidmresults-spmhtml

While breastfeeding is the recommended feeding mode in infancy, rates are low in some Western societies, and infants are widely fed formula. France, in particular, shows high rates of infant formula use, including formulas with protein hydrolysates. The degree of protein hydrolysis has previously been associated with neurodevelopmental outcomes. The present study examines the associations between the protein’s hydrolysis degree in infant formula and child neurodevelopment up to 3.5 years of age in the French nationwide ELFE study. Parents reported on brand and name of the formula used at 2 months and protein hydrolysis degree was derived from the ingredient list. Analyses were based on 6979 infants (92.2%, 6.8% and 1% consuming non-hydrolysed, partially and extensively hydrolysed formulas, respectively). Neurodevelopment was assessed at age 1 and 3.5 years with the Child Development Inventory (CDI), at age 2 years with the MacArthur-Bates Communicative Development Inventories and at age 3.5 years with the Picture Similarities sub-scale (British Ability Scales). Associations between protein hydrolysis degree and child neurodevelopment were assessed using linear and logistic regression for overall scores and poor CDI sub-domain scores (th centile), respectively. Among formula-fed infants, protein hydrolysis degree in infant formula was not associated with overall neurodevelopmental scores up to 3.5 years. Some associations were found with the motor skills CDI sub-domain but they were not consistent at 1 and 3.5 years as well as across sensitivity analyses. The use of hydrolysed formula appears safe in terms of overall neurodevelopment, and research should further investigate specific neurodevelopmental domains.

International audience; ObjectiveThe acoustic characteristics of stimuli influence the characteristics of the corresponding evoked potentials in healthy subjects. Own-name stimuli are used in clinical practice to assess the level of consciousness in intensive care units. The influence of the acoustic variability of these stimuli has never been evaluated. Here, we explored the influence of this variability on the characteristics of the subject’s own name (SON) P300.MethodsWe retrospectively analyzed 251 disorders of consciousness patients from Lyon and Paris Hospitals who underwent an “own-name protocol”. A reverse correlation analysis was performed to test for an association between acoustic properties of own-names stimuli used and the characteristics of the P300 wave observed.ResultsOwn-names pronounced with increasing pitch prosody showed P300 responses 66 ms earlier than own-names that had a decreasing prosody [IC95% = 6.36; 125.9 ms].ConclusionsSpeech prosody of the stimuli in the “own name protocol” is associated with latencies differences of the P300 response among patients for whom these responses were observed. Further investigations are needed to confirm these results.SignificanceSpeech prosody of the stimuli in the “own name protocol” is a non-negligible parameter, associated with P300 latency differences. Speech prosody should be standardized in SON P300 studies.

International audience; Objective: The aim was to study the evolution of disability in spinocerebellar ataxias (SCAs) type 1, 2, 3, and 6 (SCA1, 2, 3, 6). Methods: We analyzed data of two longitudinal cohorts (RISCA, EUROSCA) which recruited ataxic and non-ataxic SCA1, SCA2, SCA3, and SCA6 mutation carriers. To study disability, we used a five-stage system for ataxia defined by walking ability (stages 0-3) and death (stage 4). Transitions were analyzed using a multi-state model with proportional transition hazards. Based on the hazard estimates, transition probabilities and the expected lengths of stay in each stage were calculated. We further studied the effect of sex and CAG repeat length on progression. Results: Data of 3138 visits in 677 participants were analyzed. Median SARA scores for SCA1, SCA2, SCA3, and SCA6 ranged from 1.5 (interquartile range [IQR] = 0.0-3.5) to 3.5 (IQR = 1.4-6.1) in stage 0, 11.5 (IQR = 9.6-14.0) to 13.8 (IQR = 11.0-16.0) in stage 1, 19.0 (IQR = 17.0-21.0) to 23.8 (IQR = 19.5-27.0) in stage 2, and 28.5 (IQR = 26.0-32.5) to 34.0 (IQR = 32.6-37.1) in stage 3. Modeling allowed to calculate the subtype-specific probability to be in a certain stage at a given age and duration of each stage. CAG repeat length was associated with faster progression in SCA1 (HR, 95% CI: 1.1, 1.1-1.2), SCA2 (1.2, 1.1-1.3), and SCA3 (1.1, 1.0-1.2). In SCA6, female sex was associated with faster progression (1.7, 1.1-2.6). Interpretation: Our data are important for counselling of patients, assessment of the relevance of outcome markers, and design of clinical trials.

Tourette disorder (TD) is characterized by tics, which are sudden repetitive involuntary movements or vocalizations. Deficits in inhibitory control in TD patients remain inconclusive from the traditional method of estimating the ability to stop an impending action, which requires careful interpretation of a metric derived from race model. One possible explanation for these inconsistencies is that race model’s assumptions of independent and stochastic rise of GO and STOP process to a fixed threshold are often violated, making the classical metric to assess inhibitory control less robust. Here, we used a pair of metrics derived from a recent alternative model to address why stopping performance in TD is unaffected despite atypical neural circuitry. These new metrics distinguish between proactive and reactive inhibitory control and estimate them separately. When these metrics in adult TD group were contrasted with healthy controls (HC), we identified robust deficits in reactive control, but not in proactive control in TD. The TD group exhibited difficulty in slowing down the speed of movement preparation, which they rectified by their intact ability to postpone the movement.

Intestinal gluconeogenesis (IGN), gastric bypass (GBP) and gut microbiota positively regulate glucose homeostasis and diet-induced dysmetabolism. GBP modulates gut microbiota, whether IGN could shape it has not been investigated. We studied gut microbiota and microbiome in wild type and IGN-deficient mice, undergoing GBP or not, and fed on either a normal chow (NC) or a high-fat/high-sucrose (HFHS) diet. We also studied fecal and urine metabolome in NC-fed mice. IGN and GBP had a different effect on the gut microbiota of mice fed with NC and HFHS diet. IGN inactivation increased abundance of Deltaproteobacteria on NC and of Proteobacteria such as Helicobacter on HFHS diet. GBP increased abundance of Firmicutes and Proteobacteria on NC-fed WT mice and of Firmicutes, Bacteroidetes and Proteobacteria on HFHS-fed WT mice. The combined effect of IGN inactivation and GBP increased abundance of Actinobacteria on NC and the abundance of Enterococcaceae and Enterobacteriaceae on HFHS diet. A reduction was observed in the amounf of short-chain fatty acids in fecal (by GBP) and in both fecal and urine (by IGN inactivation) metabolome. IGN and GBP, separately or combined, shape gut microbiota and microbiome on NC- and HFHS-fed mice, and modify fecal and urine metabolome.

International audience; Abstract Transcranial direct current stimulation (tDCS) is an emerging noninvasive brain neuromodulation technique aimed at relieving symptoms associated with psychiatric disorders, including addiction. The goal of the present study was to better identify which phase of alcohol-related behavior (hedonic effect, behavioral sensitization, self-administration, or motivation to obtain the drug) might be modulated by repeated anodal tDCS over the frontal cortex (0.2 mA, 20 min, twice a day for 5 consecutive days), using female mice as a model. Our data showed that tDCS did not modulate the hedonic effects of ethanol as assessed by a conditioned place preference test (CPP) or the expression of ethanol-induced behavioral sensitization. Interestingly, tDCS robustly reduced reacquisition of ethanol consumption (50% decrease) following extinction of self-administration in an operant paradigm. Furthermore, tDCS significantly decreased motivation to drink ethanol on a progressive ratio schedule (30% decrease). Taken together, our results show a dissociation between the effects of tDCS on “liking” (hedonic aspect; no effect in the CPP) and “wanting” (motivation; decreased consumption on a progressive ratio schedule). Our tDCS procedure in rodents will allow us to better understand its mechanisms of action in order to accelerate its use as a complementary and innovative tool to help alcohol-dependent patients maintain abstinence or reduce ethanol intake.

Making accurate decisions based on unreliable sensory evidence requires cognitive inference. Dysfunction of n-methyl-d-aspartate (NMDA) receptors impairs the integration of noisy input in theoretical models of neural circuits, but whether and how this synaptic alteration impairs human inference and confidence during uncertain decisions remains unknown. Here we use placebo-controlled infusions of ketamine to characterize the causal effect of human NMDA receptor hypofunction on cognitive inference and its neural correlates. At the behavioral level, ketamine triggers inference errors and elevated decision uncertainty. At the neural level, ketamine is associated with imbalanced coding of evidence and premature response preparation in electroencephalographic (EEG) activity. Through computational modeling of inference and confidence, we propose that this specific pattern of behavioral and neural impairments reflects an early commitment to inaccurate decisions, which aims at resolving the abnormal uncertainty generated by NMDA receptor hypofunction., In uncertain conditions, people make accurate decisions by considering multiple pieces of information. Here, the authors show that pharmacological n-methyl-d-aspartate (NMDA) receptor hypofunction is associated with elevated uncertainty and premature decisions based on unreliable evidence.

International audience; Autonomic status epilepticus (Aut SE) is a condition characterized by ongoing focal autonomic seizure lasting for >30 min. Aut SE can show a variety of clinical manifestations including vomiting, nausea, changes in heart rate, piloerection, pupillary abnormalities, and visual abnormalities. Although Aut SE is a common finding in childhood in the context of Panayiotopoulos syndrome, few reports have described this condition during adulthood. In the present report, we describe a case of Aut SE in an adult patient with parasellar meningioma and bilateral frontotemporal epileptiform activity on EEG record.

RationaleCongenital Central Hypoventilation Syndrome (CCHS) is characterized by life-threatening sleep hypoventilation, and is caused by PHOX2B gene mutations, most frequently the PHOX2B27Ala/+ mutation, with patients requiring lifelong ventilatory support. It is unclear whether obstructive apneas are part of the syndrome.ObjectivesTo determine whether Phox2b27Ala/+ mice, which present the main symptoms of CCHS and die within hours after birth, also express obstructive apneas, and to investigate potential underlying mechanisms.MethodsApneas were classified as central, obstructive or mixed by using a novel system combining pneumotachography and laser detection of abdominal movement immediately after birth. Several respiratory nuclei involved in airway patency were examined by immunohistochemistry and electrophysiology in brainstem-spinal cord preparation.Measurements and Main ResultsThe median (interquartile range) of obstructive apnea frequency was 2.3/min (1.5-3.3) in Phox2b27Ala/+ pups versus 0.6/min (0.4-1.0) in wildtypes (P < 0.0001). Obstructive apnea duration was 2.7s (2.3-3.9) in Phox2b27Ala/+ pups versus 1.7s (1.1-1.9) in wildtypes (P < 0.0001). Central and mixed apneas presented similar, significant differences. In Phox2b27Ala/+ preparations, the hypoglossal nucleus had fewer (P < 0.05) and smaller (P < 0.01) neurons, compared to wildtypes. Importantly, coordination of phrenic and hypoglossal motor activities was disrupted, as evidenced by the longer and variable delay of hypoglossal with respect to phrenic activity onset (P < 0.001).ConclusionsThe Phox2b27Ala/+ mutation predisposed pups not only to hypoventilation and central apneas, but also to obstructive and mixed apneas, likely due to hypoglossal dysgenesis. These results thus demand attention towards obstructive events in infants with CCHS.

Every brain is unique, having its structural and functional organisation shaped by both genetic and environmental factors over the course of its development. Brain image studies tend to produce results by averaging across a group of subjects, under a common assumption that it is possible to subdivide the cortex into homogeneous areas while maintaining a correspondence across subjects. This paper questions such assumption: can the structural and functional properties of a specific region of an atlas be assumed to be the same across subjects? This question is addressed by looking at the network representation of the brain, with nodes corresponding to brain regions and edges to their structural relationships. We perform graph matching on a set of control patients and on parcellations of different granularity to understand which is the connectivity misalignment between regions. The graph matching is unsupervised andreveals interesting insight on local misalignment of brain regions across subjects.

Autism spectrum disorders (ASD) are characterised by atypical social communication and stereotyped behaviours. Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are detected in 1-2% of patients with ASD and intellectual disability (ID), but the mechanisms underpinning the symptoms remain largely unknown. Here, we characterized the behaviour of Shank3 mutant mice deleted for exon 11 ( Shank3 $^{Δ11/Δ11}$ ) from three to twelve months of age. We observed decreased locomotor activity, increased stereotyped self-grooming and atypical socio-sexual interaction compared to wild-type littermates. We then used RNAseq on four brain regions of the same animals to identify differentially expressed genes (DEG). DEGs were identified mainly in the striatum and were associated with synaptic transmission (e.g. Grm2 , Dlgap1 ), G-protein-signalling pathways (e.g. Gnal , Prkcg1 , and Camk2g ), as well as excitation/inhibition balance (e.g. Gad2 ). Downregulated and upregulated genes were respectively enriched in the gene clusters of medium-sized spiny neurons expressing the dopamine 1 (D1-MSN) and the dopamine 2 receptor (D2-MSN). Moreover, expression of DEGs reported as striosome markers within the striatum ( Cnr1 , Gnal1 , Gad2 , and Drd4 ) were positively correlated with excessive self-grooming. Finally, we showed that the striosome compartment of Shank3 Shank3 $^{Δ11/Δ11}$ mice was enlarged and displayed higher expression of GAD65 compared to wild-type mice. Altogether, these results shed light on a possible role of the striosomes/matrix imbalance in excessive self-grooming in Shank3Shank3 $^{Δ11/Δ11}$ mice. Such striatal alterations could be present in a subgroup of patients with ASD and ID and could open the way to new therapeutic approaches.

A bustling literature spanning philosophy, psychology and social sciences aims for a better understanding of the collective patterns of emotions stirring human society. To date, however, this endeavour is still in need of a unifying conceptual framework and empirical evidence regarding the characteristics, antecedents and consequences of collective emotion remains sparse. To foster progress in the field, we examine existing accounts and identify three characteristics of collective emotion: emotion alignment, feeling of social connectedness and mutual awareness. We then propose a typology of collective emotion that accounts for the dynamic interplay of social and cognitive processes. Crucially, this typology allows for integrating different accounts and research traditions into an experimental framework that generates testable predictions regarding the mechanisms and consequences of collective emotion. Finally, we review available empirical evidence in social and cognitive sciences and we discuss future directions for an evidence-based approach to collective emotion.

International audience; Patients with schizophrenia are often unaware of their condition and the consequences of their illness. This lack of insight results in impaired functioning, treatment non-adherence and poor prognosis. Here, we aimed to investigate the effects of non-invasive brain stimulation (NIBS) on two forms of insight, clinical and cognitive, in patients with schizophrenia. We conducted a systematic review of the literature registered in the PROSPERO database (CRD42020220323) according to PRISMA guidelines. The literature search was conducted in Medline and Web of Science databases based on studies published up until October 2020 that included pre-NIBS and post-NIBS measurements of clinical and/or cognitive insight in adults with schizophrenia. A total of 14 studies were finally included, and their methodological quality was assessed by using the QualSyst tool. Despite the lack of well-conducted large randomized-controlled studies using insight as the primary outcome, the available findings provide preliminary evidence that NIBS can improve clinical insight in patients with schizophrenia, with a majority of studies using transcranial direct current stimulation with a left frontotemporal montage. Further studies should investigate the effect of NIBS on insight as a primary outcome and how these effects on insight could translate into clinical and functional benefits in patients with schizophrenia.

International audience; Cancer-related cognitive impairment (CRCI) has increasingly been identified over the last two decades in non-CNS system cancer patients. Across Europe, researchers have contributed to this effort by developing preclinical models, exploring underlying mechanisms and assessing cognitive and quality of life changes. The ultimate goal is to develop interventions to treat patients experiencing CRCI. To do so, new challenges need to be addressed requiring the implementation of multidisciplinary research groups. In this consensus paper, we summarize the state of the art in the field of CRCI combined with the future challenges and action plans in Europe. These challenges include data sharing/pooling, standardization of assessments as well as assessing additional biomarkers and neuroimaging investigations, notably through translational studies. We conclude this position paper with specific actions for Europe based on shared scientific expert opinion and stakeholders involved in the Innovative Partnership for Action Against Cancer, with a particular focus on cognitive intervention programs.

International audience; The serotonin 5-HT6 receptor (5-HT6R) is a promising target to improve cognitive symptoms of psychiatric diseases of neurodevelopmental origin, such as autism spectrum disorders and schizophrenia. However, its expression and localization at different stages of brain development remain largely unknown, due to the lack of specific antibodies to detect endogenous 5-HT6R. Here, we used transgenic mice expressing a GFP-tagged 5-HT6R under the control of its endogenous promoter (Knock-in) as well as embryonic stem cells expressing the GFP-tagged receptor to extensively characterize its expression at cellular and subcellular levels during development. We show that the receptor is already expressed at E13.5 in the cortex, the striatum, the ventricular zone, and to a lesser extent the subventricular zone. In adulthood, it is preferentially found in projection neurons of the hippocampus and cerebral cortex, in striatal medium-sized spiny neurons, as well as in a large proportion of astrocytes, while it is expressed in a minor population of interneurons. Whereas the receptor is almost exclusively detected in the primary cilia of neurons at embryonic and adult stages and in differentiated stem cells, it is located in the somatodendritic compartment of neurons from some brain regions at the neonatal stage and in the soma of undifferentiated stem cells. Finally, knocking-out the receptor induces a shortening of the primary cilium, suggesting that it plays a role in its function. This study provides the first global picture of 5-HT6R expression pattern in the mouse brain at different developmental stages. It reveals dynamic changes in receptor localization in neurons at the neonatal stage, which might underlie its key role in neuronal differentiation and psychiatric disorders of neurodevelopmental origin.

International audience; AbstractAberrant cortisol and activation of the glucocorticoid receptor (GR) play an essential role in age-related progression of Alzheimer's disease (AD). However, the GR pathways required for influencing the pathobiology of AD dementia remain unknown. To address this, we studied an early phase of AD-like progression in the well-established APP/PS1 mouse model combined with targeted mutations in the BDNF-dependent GR phosphorylation sites (serines 134/267) using molecular, behavioral and neuroimaging approaches. We found that disrupting GR phosphorylation (S134A/S267A) in mice exacerbated the deleterious effects of the APP/PS1 genotype on mortality, neuroplasticity and cognition, without affecting either amyloid-β deposition or vascular pathology. The dynamics, maturation and retention of task-induced new dendritic spines of cortical excitatory neurons required GR phosphorylation at the BDNF-dependent sites that amyloid-β compromised. Parallel studies in postmortem human prefrontal cortex revealed AD subjects had downregulated BDNF signaling and concomitant upregulated cortisol pathway activation, which correlated with cognitive decline. These results provide key evidence that the loss of neurotrophin-mediated GR phosphorylation pathway promotes the detrimental effects of the brain cortisol response that contributes to the onset and/or progression of AD dementia. These findings have important translational implications as they provide a novel approach to treating AD dementia by identifying drugs that increase GR phosphorylation selectively at the neurotrophic sites to improve memory and cognition.

International audience; Background: In recent years, several blinded randomized controlled trials (RCT) have been conducted on cognitive rehabilitation (CR) in adults with multiple sclerosis (MS). Objective: To review all blinded RCTs on CR in MS published since 2013. Methods: The National Library of Medicine database (Medline) and PSYCINFO were searched using the keywords MS and CR or cognitive training or NP rehabilitation or memory rehabilitation or attention rehabilitation. Results: After the exclusion of some papers not specifically focused on CR, a final list of 26 studies was established. The papers belong to three main categories: individual specific rehabilitation (8studies), group rehabilitation (4 studies), and computerized training (CT) (14 studies), while one study combined group rehabilitation and CT. Among the individual rehabilitation studies, 5 were devoted to memory, and most of the 19 other selected studies were about several cognitive domains. Most of the studies mainly concerned RRMS patients, except for 2 studies that were carried out exclusively in progressive forms. Despite the methodological limitations of some studies and the great heterogeneity of the protocols, the results are generally in favor of the efficacy of CR in neuropsychological tests. Conclusion: Recent blinded RCTs about CR in MS show promising results. © 2021 by the author. Licensee MDPI, Basel, Switzerland.

Background We developed five tablet-based tasks (applications) to measure multiple components of manual dexterity. Aim: to test reliability and validity of tablet-based dexterity measures in healthy participants. Methods Tasks included: (1) Finger recognition to assess mental rotation capacity. The subject taps with the finger indicated on a virtual hand in three orientations (reaction time, correct trials). (2) Rhythm tapping to evaluate timing of finger movements performed with, and subsequently without, an auditory cue (inter-stimulus interval). (3) Multi-finger tapping to assess independent finger movements (reaction time, correct trials, unwanted finger movements). (4) Sequence tapping to assess production and memorization of visually cued finger sequences (successful taps). (5) Line-tracking to assess movement speed and accuracy while tracking an unpredictably moving line on the screen with the fingertip (duration, error). To study inter-rater reliability, 34 healthy subjects (mean age 35 years) performed the tablet tasks twice with two raters. Relative reliability (Intra-class correlation, ICC) and absolute reliability (Standard error of measurement, SEM) were established. Task validity was evaluated in 54 healthy subjects (mean age 49 years, range: 20–78 years) by correlating tablet measures with age, clinical dexterity assessments (time taken to pick-up objects in Box and Block Test, BBT and Moberg Pick Up Test, MPUT) and with measures obtained using a finger force-sensor device. Results Most timing measures showed excellent reliability. Poor to excellent reliability was found for correct trials across tasks, and reliability was poor for unwanted movements. Inter-session learning occurred in some measures. Age correlated with slower and more variable reaction times in finger recognition, less correct trials in multi-finger tapping, and slower line-tracking. Reaction times correlated with those obtained using a finger force-sensor device. No significant correlations between tablet measures and BBT or MPUT were found. Inter-task correlation among tablet-derived measures was weak. Conclusions Most tablet-based dexterity measures showed good-to-excellent reliability (ICC ≥ 0.60) except for unwanted movements during multi-finger tapping. Age-related decline in performance and association with finger force-sensor measures support validity of tablet measures. Tablet-based components of dexterity complement conventional clinical dexterity assessments. Future work is required to establish measurement properties in patients with neurological and psychiatric disorders.

Intracellular Ca2+signals of oligodendroglia, the myelin-forming cells of the central nervous system, regulate vital cellular processes including myelination. However, studies on oligodendroglia Ca2+signal dynamics are still scarce, especially during myelin repair, and there are no software solutions to properly analyze the unique Ca2+signal characteristics in these cells. Here, we provide a comprehensive experimental and analytical workflow to acquire and analyze Ca2+imaging data of oligodendroglia at the population and single-cell levels in preclinical mouse models of myelin repair. We report diverseex vivoandin vivoexperimental protocols to obtain reproducible Ca2+imaging data from oligodendroglia in demyelinated lesions. Importantly, we provide an analytical pipeline containing two free, open source and cross-platform software programs, Occam and post-prOccam, that enable the fully automated analysis of one- and two-photon Ca2+imaging datasets from oligodendroglia obtained by eitherex vivoorin vivoCa2+imaging techniques. This versatile and accessible experimental and analytical framework, which revealed significant but uncorrelated spontaneous Ca2+activity in oligodendroglia inside demyelinated lesions, should facilitate the elucidation of Ca2+-mediated mechanisms underlying remyelination and therefore help to accelerate the development of therapeutic strategies for the many myelin-related disorders, such as multiple sclerosis.

From the development of a neuron through morphogenesis and migration to mature stages with plasticity events, all stages of a neuron’s life requires the neuronal cytoskeleton. Actin filaments and microtubules (MT) are the main elements of the cytoskeleton. They are dynamic polymers regulated by associated proteins that helps them assemble, disassemble or stabilize and organize them in specific structures. The Microtubule Associated Protein 6 (MAP6) is known for its unique ability to stabilize neuronal MTs. MAP6 also regulate the actin cytoskeleton in dendritic spines during neuronal plasticity events. MAP6 regulation of the MT and actin cytoskeletons is required for normal neuronal development and function and affects mice behavior and cognitive abilities. As such, MAP6 knock-out mouse is a model of schizophrenia. A precise understanding of how MAP6 interacts and modulates the cytoskeleton was lacking at the molecular level. By using in vitro reconstitution systems, we showed that MAP6 is a MT stabilizer that induces MT coiling. By demonstrating that MT coiling is due to MAP6 localization in the MT lumen, we identified the first neuronal Microtubule Inner Protein (MIP). This discovery paves the way to decipher the physiological role of neuronal MIPs. It is now clear that several proteins involved in either MT or actin regulation are in fact able to regulate both cytoskeletons. By analyzing MT and actin assembly in the presence of MAP6 both in separated and simultaneous systems, we identify MAP6 as the first protein able to promote both MT and actin filament nucleation. Moreover, MT nucleation and MAP6 MIP activities are linked. MAP6 is also structuring the cytoskeleton by forming actin bundles and crosslinking actin filaments with microtubules. Finally, we show that MAP6 isoforms differentially regulate the cytoskeleton through phase separation mechanisms. Overall, the use of minimal reconstitution systems allowed us to demonstrate that MAP6 is a multifunctional regulator of the cytoskeleton., Du développement d'un neurone, en passant par la morphogenèse et la migration, jusqu'aux stades de maturité avec des événements de plasticité, toutes les étapes de la vie d'un neurone nécessitent le cytosquelette neuronal. Les filaments d'actine et les microtubules (MT) sont les principaux éléments du cytosquelette. Ce sont des polymères dynamiques régulés par des protéines associées qui les aident à s'assembler, à se désassembler ou à se stabiliser et à s'organiser en structures spécifiques. La protéine associée aux microtubules 6 (MAP6) est connue pour sa capacité unique à stabiliser les MTs neuronaux. MAP6 régule également le cytosquelette d'actine dans les épines dendritiques pendant les événements de plasticité neuronale. La régulation par MAP6 des cytosquelettes de MTs et d'actine est nécessaire au développement et au fonctionnement normal des neurones et affecte le comportement et les capacités cognitives des souris. À ce titre, la souris knock-out MAP6 est un modèle de schizophrénie. Une compréhension précise de la manière dont MAP6 interagit et module le cytosquelette faisait défaut au niveau moléculaire. En utilisant des systèmes de reconstitution in vitro, nous avons montré que MAP6 est un stabilisateur des MTs qui induit la formation de MTs hélicoïdaux. En démontrant que la formation de MTs en hélices est due à la localisation de MAP6 dans la lumière des MTs, nous avons identifié la première protéine interne des microtubules (MIP) neuronale. Cette découverte ouvre la voie au décryptage du rôle physiologique des MIPs neuronales. Il est maintenant clair que certaines protéines impliquées dans la régulation des MTs ou de l'actine sont en fait capables de réguler les deux cytosquelettes. En analysant l'assemblage des MTs et de l'actine en présence de MAP6 dans des systèmes séparés et simultanés, nous identifions MAP6 comme la première protéine capable de promouvoir la nucléation des MTs et des filaments d'actine. De plus, la nucléation des MT et les activités MIP de MAP6 sont liées. MAP6 structure également le cytosquelette en formant des faisceaux d'actine et en réticulant les filaments d'actine avec les microtubules. Enfin, nous montrons que les isoformes de MAP6 régulent de manière différentielle le cytosquelette par des mécanismes de séparation de phase. Globalement, l'utilisation de systèmes de reconstitution in vitro nous a permis de démontrer que MAP6 est un régulateur multifonctionnel du cytosquelette.

Background Health-related quality of life (HRQoL) is an important clinical outcome in Alcohol Use Disorder (AUD) and is considered as a relevant indicator of treatment success. While a better understanding of the factors affecting HRQoL would enable to adjust patients’ care to favour treatment outcome, the determinants of HRQoL in AUD remain unclear. This study aims at describing HRQoL in AUD patients and at identifying its best predictors. Methods 53 recently detoxified patients with severe AUD (sAUD) underwent a cognitive assessment and filled in a HRQoL questionnaire dedicated to AUD patients (Alcohol Quality of Life Scale; AQoLS), as well as questionnaires concerning socio-demographics, alcohol history, sleep quality, depression, anxiety and impulsivity. 38 healthy controls (HC) underwent the same assessment (except AQoLS) in order to identify the altered cognitive and clinical variables that could potentially be determinants of HRQoL in sAUD. Results sAUD patients reported that alcohol affects their HRQoL mainly in the “negative emotions”, “control”, “relationships”, and “sleep” domains. Compared to HC, they were impaired on episodic memory, working memory, executive functions, and processing speed tasks. They also reported lower sleep quality, higher depression, anxiety and impulsivity. No association was found between AQoLS total score and socio-demographics, cognitive performance, or sleep quality in patients. We found a significant correlation between HRQoL and depression/anxiety as well as impulsivity. Anxiety and impulsivity were indeed the only significant predictors of HRQoL, explaining 47.7% of the variance. Conclusion Anxiety and impulsivity are crucial determinants of HRQoL in recently detoxified sAUD patients. Since anxiety and impulsivity are frequent issues in addiction and especially in AUD, they should be particularly considered by clinicians to favour treatment outcomes.

International audience; No abstract available

International audience; Because catecholamines secretion mainly relies on the excitable nature of adrenal chromaffin cells, monitoring their electrical activity is an essential step in assessing the adrenal medullary tissue function. The difficult access to the gland in vivo allows only population activity to be recorded in this condition. In vitro preparations allow recordings of spontaneous or evoked activity from single or multiple cells, depending on the biological samples used (dissociated chromaffin cells versus adrenal tissue preparations). In this chapter, I provide a detailed description of the techniques used for electrophysiological recordings in rodent chromaffin cells in acute adrenal slices, using the patch-clamp technique. This methodology allows preservation of the tissue integrity and detection of action potentials, synaptic activity, and secretory events; it is thus suitable for the study of adrenomedullary activity-secretion coupling.

The nitric oxide (NO) signaling pathway in hypothalamic neurons plays a key role in the regulation of the secretion of gonadotropin-releasing hormone (GnRH), which is crucial for reproduction. We hypothesized that a disruption of neuronal NO synthase (NOS1) activity underlies some forms of hypogonadotropic hypogonadism. Whole-exome sequencing was performed on a cohort of 341 probands with congenital hypogonadotropic hypogonadism to identify ultrarare variants in NOS1 . The activity of the identified NOS1 mutant proteins was assessed by their ability to promote nitrite and cGMP production in vitro. In addition, physiological and pharmacological characterization was carried out in a Nos1 -deficient mouse model. We identified five heterozygous NOS1 loss-of-function mutations in six probands with congenital hypogonadotropic hypogonadism (2%), who displayed additional phenotypes including anosmia, hearing loss, and intellectual disability. NOS1 was found to be transiently expressed by GnRH neurons in the nose of both humans and mice, and Nos1 deficiency in mice resulted in dose-dependent defects in sexual maturation as well as in olfaction, hearing, and cognition. The pharmacological inhibition of NO production in postnatal mice revealed a critical time window during which Nos1 activity shaped minipuberty and sexual maturation. Inhaled NO treatment at minipuberty rescued both reproductive and behavioral phenotypes in Nos1 -deficient mice. In summary, lack of NOS1 activity led to GnRH deficiency associated with sensory and intellectual comorbidities in humans and mice. NO treatment during minipuberty reversed deficits in sexual maturation, olfaction, and cognition in Nos1 mutant mice, suggesting a potential therapy for humans with NO deficiency.

International audience

This study of a cohort of 1-year treatment-compliant survivors of a suicide attempt examined for the first time whether a high CYP2D6-CYP2C19 metabolic capacity (pharmacogenes related to psychopathology, suicide, and attempt severity) and/or polypharmacy treatments predicted repeat suicide attempts, adjusting for sociodemographic and clinical factors as confounders. Of the 461 (63% women) consecutively hospitalized patients who attempted suicide and were evaluated and treated after an index attempt, 191 (67.5% women) attended their 6- and 12-month follow-up sessions. Clinicians were blinded to the activity scores (AS) of their genotypes, which were calculated as the sum of the values assigned to each allele (CYP2C19 *2, *17; CYP2D6 *3, *4, *4xN, *5, *6, *10, wtxN). No differences were found in polypharmacy prescription patterns and the variability of CYP2D6 and CYP2C19 genotypes between adherents and dropouts, but the formers were older, with a higher frequency of anxiety and bipolar disorders and fewer alcohol and substance use disorders. The risk of reattempts was higher for CYP2D6 ultrarapid (AS > 2) metabolizers (β = 0.561, p = 0.005) and violent suicide survivors (β = −0.219, p = 0.042) if the attempt occurred during the first 6-month period, individuals with an increased number of MINI DSM-IV Axis I mental disorders (β = 0.092, p = 0.032) during the second 6-month period and individuals with a combined high CYP2D6-CYP2C19 metabolic capacity (AS > 4) (β = 0.345, p = 0.024) and an increased use of drugs other than antidepressants, anxiolytics-depressants and antipsychotics-lithium (β = 0.088, p = 0.005) in multiple repeaters during both periods. CYP2D6 and CYP2C19 rapid metabolism and polypharmacy treatment for somatic comorbidities must be considered to prevent the severe side effects of short-term multiple suicide reattempts after a previous attempt.

Recovery of dexterous hand use is critical for functional outcome after stroke. Grip force recordings can inform on maximal motor output and modulatory and inhibitory cerebral functions, but how these actually contribute to recovery of dexterous hand use is unclear. This cohort study used serially assessed measures of hand kinetics to test the hypothesis that behavioural measures of motor modulation and inhibition explain dexterity recovery beyond that explained by measures of motor output alone. We also investigated the structural and functional connectivity correlates of grip force control recovery. Eighty-nine adults (median age = 54 years, 26% females) with first-ever ischaemic or haemorrhagic stroke and persistent arm and hand paresis were assessed longitudinally, at 3 weeks, and at 3 and 6 months after stroke. Kinetic measures included: maximal grip force, accuracy of precision and power grip force control, and ability to release force abruptly. Dexterous hand use was assessed clinically with the Box and Block Test and motor impairment with the upper extremity Fugl-Meyer Assessment. Structural and functional MRI was used to assess weighted corticospinal tract lesion load, voxel-based lesion symptom mapping and interhemispheric resting-state functional connectivity. Fifty-three per cent of patients had severe initial motor impairment and a majority still had residual force control impairments at 6 months. Force release at 3 weeks explained 11% additional variance of Box and Block Test outcome at 6 months, above that explained by initial scores (67%). Other kinetic measures did not explain additional variance of recovery. The predictive value of force release remained significant when controlling for corticospinal tract lesion load and clinical measures. Corticospinal tract lesion load correlated with recovery in grip force control measures. Lesions involving the parietal operculum, insular cortex, putamen and fronto-striatal tracts were also related to poorer force modulation and release. Lesions to fronto-striatal tracts explained an additional 5% of variance in force release beyond the 43% explained by corticospinal injury alone. Interhemispheric functional connectivity did not relate to force control recovery. We conclude that not only voluntary force generation but also force release (reflecting motor inhibition) are important for recovery of dexterous hand use after stroke. Although corticospinal injury is a main determinant of recovery, lesions to integrative somatosensory areas and fronto-parietal white matter (involved in motor inhibition) explain additional variance in post-stroke force release recovery. Our findings indicate that post-stroke upper limb motor impairment profiling, which is essential for targeted treatment, should consider both voluntary grasp generation and inhibition.

Purpose of review Recent evidence suggests high tumor mutational burden (TMB-H) as a predictor of response to immune checkpoint blockade (ICB) in cancer. However, results in TMB-H gliomas have been inconsistent. In this article, we discuss the main pathways leading to TMB-H in glioma and how these might affect immunotherapy response. Recent findings Recent characterization of TMB-H gliomas showed that 'post-treatment' related to mismatch repair (MMR) deficiency is the most common mechanism leading to TMB-H in gliomas. Unexpectedly, preliminary evidence suggested that benefit with ICB is rare in this population. Contrary to expectations, ICB response was reported in a subset of TMB-H gliomas associated with constitutional MMR or polymerase epsilon (POLE) defects (e.g., constitutional biallelic MMRd deficiency). In other cancers, several trials suggest increased ICB efficacy is critically associated with increased lymphocyte infiltration at baseline which is missing in most gliomas. Further characterization of the immune microenvironment of gliomas is needed to identify biomarkers to select the patients who will benefit from ICB. Summary Intrinsic molecular and immunological differences between gliomas and other cancers might explain the lack of efficacy of ICB in a subset of TMB-H gliomas. Novel combinations and biomarkers are awaited to improve immunotherapy response in these cancers.

International audience; Rats are born deaf and start hearing at the end of the second postnatal week, when the ear canals open and low-intensity sounds start to evoke responses in the auditory cortex. Here, using μECoG electrode arrays and intracortical silicon probe recordings, we found that bone-conducted (BC) sounds evoked biphasic responses in the auditory cortex starting from postnatal day (P) 8. The initial phase of these responses, generated by thalamocortical input, was followed by intracortical propagation within supragranular layers. BC-evoked responses co-localized with the responses evoked by electrical stimulation of the cochlea and the deepest layers of the inferior colliculus prior to onset of low-threshold hearing (P13), as well as with the responses evoked by high-frequency (30 kHz) lowintensity (70 dB) air-conducted sounds after that. Thus, BC signals reach high-frequency processing regions of the auditory cortex well before the onset of low-threshold hearing, reflecting early integrity of the auditory system.

Elevated states of brain plasticity typical for critical periods of early postnatal life can be reinstated in the adult brain through interventions, such as antidepressant treatment and environmental enrichment, and induced plasticity may be critical for the antidepressant action. Parvalbumin-positive (PV) interneurons regulate the closure of developmental critical periods and can alternate between high and low plasticity states in response to experience in adulthood. We now show that PV plasticity states and cortical networks are regulated through the activation of TrkB neurotrophin receptors. Visual cortical plasticity induced by fluoxetine, a widely prescribed selective serotonin reuptake inhibitor (SSRI) antidepressant, was lost in mice with reduced expression of TrkB in PV interneurons. Conversely, optogenetic gain-of-function studies revealed that activation of an optically activatable TrkB (optoTrkB) specifically in PV interneurons switches adult cortical networks into a state of elevated plasticity within minutes by decreasing the intrinsic excitability of PV interneurons, recapitulating the effects of fluoxetine. TrkB activation shifted cortical networks towards a low PV configuration, promoting oscillatory synchrony, increased excitatory-inhibitory balance, and ocular dominance plasticity. OptoTrkB activation promotes the phosphorylation of Kv3.1 channels and reduces the expression of Kv3.2 mRNA providing a mechanism for the lower excitability. In addition, decreased expression and puncta of Synaptotagmin2 (Syt2), a presynaptic marker of PV interneurons involved in Ca2+-dependent neurotransmitter release, suggests lower inputs onto pyramidal neurons suppressing feed-forward inhibition. Together, the results provide mechanistic insights into how TrkB activation in PV interneurons orchestrates the activity of cortical networks and mediating antidepressant responses in the adult brain.

The study of states of arousal is key to understand the principles of consciousness. Yet, how different brain states emerge from the collective activity of brain regions remains unknown. Here, we studied the fMRI brain activity of monkeys during wakefulness and anesthesia-induced loss of consciousness. We showed that the coupling between each brain region and the rest of the cortex provides an efficient statistic to classify the two brain states. Based on this and other statistics, we estimated maximum entropy models to derive collective, macroscopic properties that quantify the system’s capabilities to produce work, to contain information, and to transmit it, which were all maximized in the awake state. The differences in these properties were consistent with a phase transition from critical dynamics in the awake state to supercritical dynamics in the anesthetized state. Moreover, information-theoretic measures identified those parameters that impacted the most the network dynamics. We found that changes in the state of consciousness primarily depended on changes in network couplings of insular, cingulate, and parietal cortices. Our findings suggest that the brain state transition underlying the loss of consciousness is predominantly driven by the uncoupling of specific brain regions from the rest of the network. A.P.A., B.J., and G.D. received funding from the FLAG-ERA JTC (PCI2018-092891). G.D. acknowledges funding from the European Union’s Horizon 2020 FET Flagship Human Brain Project under Grant Agreement 785907 HBP SGA1, SGA2, and SGA3, the Spanish Ministry Research Project PSI2016-75688-P (AEI/FEDER), the Catalan Research Group Support 2017 SGR 1545, and AWAKENING (PID2019-105772GB-I00, AEI FEDER EU) funded by the Spanish Ministry of Science, Innovation and Universities (MCIU), State Research Agency (AEI) and European Regional Development Funds (FEDER). M.L.K. is supported by the ERC Consolidator Grant: CAREGIVING (n. 615539), Center for Music in the Brain, funded by the Danish National Research Foundation (DNRF117), and Centre for Eudaimonia and Human Flourishing funded by the Pettit and Carlsberg Foundations. BJ received funding from Fondation Bettencourt-Schueller, Université Paris-Saclay (UVSQ), Fondation de France, Collège de France and from INSERM. CMS was supported by Comisión Nacional de Investigación Ciencia y Tecnología (CONICYT, currently ANID) through Programa Formacion de Capital Avanzado (PFCHA), Doctoral scholarship Becas Chile: CONICYT PFCHA/DOCTORADO BECAS CHILE/2016—72170507.

No curative treatment is available for any deficits induced by spinal cord injury (SCI). Following injury, microglia undergo highly diverse activation processes, including proliferation, and play a critical role on functional recovery.In a translational objective, we investigated whether a transient pharmacological reduction of microglia proliferation after injury is beneficial for functional recovery after SCI in mice and nonhuman primates. The colony stimulating factor-1 receptor (CSF1R) regulates proliferation, differentiation, and survival of microglia, we thus used an oral administration of GW2580, a CSF1R inhibitor.First, transient post-injury GW2580 administration in mice improves motor function recovery, promotes tissues preservation and/or reorganization (identified by coherent anti-stokes Raman scattering microscopy), and modulates glial reactivity.Second, post-injury GW2580-treatment in nonhuman primates reduces microglia proliferation, improves functional motor function recovery, and promotes tissue protection. Notably, three months after lesion microglia reactivity returned to baseline value.Finally, to initiate the investigation on molecular mechanisms induced by a transient post-SCI GW2580-treatment, we used microglia-specific transcriptomic analysis in mice. Notably, we detected a downregulation in the expression of inflammatory-associated genes and we identified genes that were up-regulated by SCI and further downregulated by the treatment.Thus, a transient oral GW2580 treatment post-injury may provide a promising therapeutic strategy for SCI patients and may also be extended to other central nervous system disorders displaying microglia activation.