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Functional near-infrared spectroscopy (fNIRS) long channels signals are contaminated by motion artifacts and extra-cerebral tissues activity during motor production. In this study, we aimed at quantifying these limitations using an fNIRS continuous-wave system during whole-body movement (i.e., cycling task). Using motion-capture recordings, physiological monitoring and short channels, our results showed a high stability of the headset during whole-body movements production and demonstrated the ability of short channels to capture physiological extra-cerebral activity., {"references":["https://doi.org/10.1016/j.neuroimage.2020.117597","https://doi.org/10.1016/j.neuroimage.2013.05.004"]}

Even with the recent works on fNIRS robustness and reproducibility, this technique still lacks of standardised methodological precautions and evidence-based recommendations to guide whole-body movement protocol building. We present a procedure that aimed at verifying the stability of the fNIRS headset during whole-body movements, to properly track the anatomical locations of the recorded signals. In addition, we showed that averaging at least 10 trials for a block-design procedure is necessary to improve fNIRS reproducibility and to obtain a robust haemodynamic response. Finally, we demonstrated that the test–retest reliability of fNIRS signals is high, even in whole-body movement motor paradigms., {"references":["] Guérin, S. M. R., Vincent, M. A., Karageorghis, C. I., & Delevoye-Turrell, Y. N. (2021). Effects of motor tempo on frontal brain activity: An fNIRS study. NeuroImage, 230, Article 117597. https://doi.org/10.1016/j.neuroimage.2020.117597"]}

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Adipose tissue is a key regulator of whole-body metabolic fitness because of its role in controlling insulin sensitivity. Obesity is associated with hypertrophic adipocytes with impaired glucose absorption; a phenomenon existing in the ultra-rare monogenic disorder Alström syndrome consisting of severe insulin resistance. Inactivation of ALMS1 directly inhibits insulin-mediated glucose absorption in the white adipose tissue and induces severe insulin resistance, which leads to type 2 diabetes, accelerated non-alcoholic liver disease and fibrosis. These phenotypes were reversed by specific adipocyte-ALMS1 reactivation in vivo. Subsequently, ALMS1 was found to bind to PKC alpha in the adipocyte and upon insulin signaling PKC alpha is released from ALMS1. Alpha helices in the kinase domain of PKC alpha were therefore screened to identify a peptide sequence that interfered with the ALMS1-PKC alpha protein interaction. When incubated with cultured human adipocytes, the stapled peptide termed PATAS, for Peptide derived of PKC Alpha Targeting AlmS, triggered insulin-independent glucose absorption, de novo lipogenesis and cellular glucose utilization. In vivo, PATAS reduced whole-body insulin resistance, improved glucose intolerance, fasting glucose, liver steatosis and fibrosis in rodents. Thus, PATAS represents a novel first-in-class peptide that targets the adipocyte to ameliorate insulin resistance and its associated comorbidities.

Barded-Biedl syndrome (BBS) is a rare genetic disorder with an unmet medical need for retinal degeneration. Small-molecule drugs were previously identified to slow down the apoptosis of photoreceptors in BBS mouse models. Clinical translation was not practical due to the necessity of repetitive invasive intravitreal injections for pediatric populations. Non-invasive methods of retinal drug targeting are a prerequisite for acceptable adaptation to the targeted pediatric patient population. Here, we present the development and functional testing of a non-invasive, topical, magnetically assisted delivery system, harnessing the ability of magnetic nanoparticles (MNPs) to cargo two drugs (guanabenz and valproic acid) with anti-unfolded protein response (UPR) properties towards the retina. Using magnetic resonance imaging (MRI), we showed the MNPs’ presence in the retina of Bbs wild-type mice, and their photoreceptor localization was validated using transmission electron microscopy (TEM). Subsequent electroretinogram recordings (ERGs) demonstrated that we achieved beneficial biological effects with the magnetically assisted treatment translating the maintained light detection in Bbs−/− mice (KO). To our knowledge, this is the first demonstration of efficient magnetic drug targeting in the photoreceptors in vivo after topical administration. This non-invasive, needle-free technology expands the application of SMDs for the treatment of a vast spectrum of retinal degenerations and other ocular diseases.

International audience

International audience; People are able to modify the spontaneous pace of their actions to interact with their environment and others. This ability is underpinned by high-level cognitive functions but little is known in regard to the brain areas that underlie such temporal control. A salient practical issue is that current neuroimaging techniques (e.g., EEG, fMRI) are extremely sensitive to movement, which renders challenging any investigation of brain activity in the realm of whole-body motor paradigms. Within the last decade, the noninvasive imaging method of functional near-infrared spectroscopy (fNIRS) has become the reference tool for experimental motor paradigms due to its tolerance to motion artefacts. In the present study, we used a continuous-wave fNIRS system to record the prefrontal and motor hemodynamic responses of 16 participants, while they performed a spatial-tapping task varying in motor complexity and externally-paced tempi (i.e., 300 ms, 500 ms, 1200 ms). To discriminate between physiological noise and cerebral meaningful signals, the physiological data (i.e., heart and respiratory rates) were recorded so that frequency bands of such signals could be regressed from the fNIRS data. Particular attention was taken to control the precise position of the optodes in reference to the cranio-cerebral correlates of the NIR channels throughout the experimental session. Results indicated that fast pacing relied on greater activity of the motor areas whereas moving at close-to-spontaneous pace placed a heavier load on posterior prefrontal processes. These results provide new insight concerning the role of frontal cognitive control in modulating the pacing of voluntary motor behaviors.

Obesity is a major risk factor for insulin resistance (IR) and its attendant complications. The pathogenic mechanisms linking them remain poorly understood, partly due to a lack of intermediary monogenic human phenotypes. Here, we report on a monogenic form of IR-prone obesity, Alström syndrome (ALMS). Twenty-three subjects with monogenic or polygenic obesity underwent hyperinsulinaemic-euglycemic clamping with concomitant adipose tissue (AT) microdialysis and an in-depth analysis of subcutaneous AT histology. We have shown a relative adipose tissue failure in monogenic obese cohort; a finding supported by observations in a novel conditional mouse model (Almsflin/flin) and ALMS1-silenced human primary adipocytes. Whereas, selective reactivation of ALMS1 gene in adipose tissue of an ALMS conditional knockdown mice model (Almsflin/flin;Adipo-Cre+/-) restores systemic insulin sensitivity and glucose tolerance. Hence, we show for the first time the relative adipose tissue failure in human obese cohorts to be a major determinant of accelerated IR without evidence of lipodystrophy. These new insights into adipocyte driven insulin resistance may assist development of adipose tissue targeted therapeutic strategies for diabetes.

Alström Syndrome (ALMS) is an ultra-rare multisystem genetic disorder caused by autosomal recessive variants in the ALMS1 gene, which is located on chromosome 2p13. ALMS is a multisystem, progressive disease characterised by visual disturbance, hearing impairment, cardiomyopathy, childhood obesity, extreme insulin resistance, accelerated non-alcoholic fatty liver disease (NAFLD), renal dysfunction, respiratory disease, endocrine and urologic disorders. Clinical symptoms first appear in infancy with great variability in age of onset and severity. ALMS has an estimated incidence of 1 case per 1,000,000 live births and ethnically or geographically isolated populations have a higher-than-average frequency. The rarity and complexity of the syndrome and the lack of expertise can lead to delayed diagnosis, misdiagnosis and inadequate care. Multidisciplinary and multiprofessional teams of experts are essential for the management of patients with ALMS, as early diagnosis and intervention can slow the progression of multi-organ dysfunctions and improve patient quality of life.These guidelines are intended to define standard of care for patients suspected or diagnosed with ALMS of any age. All information contained in this document has originated from a systematic review of the literature and the experiences of the authors in their care of patients with ALMS. The Appraisal of Guidelines for Research & Evaluation (AGREE II) system was adopted for the development of the guidelines and for defining the related levels of evidence and strengths of recommendations.These guidelines are addressed to: a) specialist centres, other hospital-based medical teams and staffs involved with the care of ALMS patients, b) family physicians and other primary caregivers and c) patients and their families.

Bardet Biedl syndrome (BBS) is a rare inherited syndromic condition characterized by renal and extra-renal disorders. Renal defect, at either structural or functional level, is one of the cardinal clinical features, and is a major cause of morbidity. However, the pathogenic mechanism underlying its dysfunction remains largely unknown, and to date only symptomatic treatment with no specific therapy is available for these patients. Elucidating aberrant cellular and/or systemic processes that impact kidney function is therefore a prerequisite to develop targeted innovative therapeutic strategies for the BBS patients. Given the proven role of BBS proteins in the function of the primary cilium (PC) and considering the clinical overlapping of BBS with other ciliopathies, BBS is considered the result of disruption of ciliary activities. The present review aims at giving an updated overview of the spectrum of renal abnormalities in BBS patients according to the existing scientific literature, and discusses the possible role of intrinsic PC dysfunction into the pathogenesis of renal defects based on the most recent findings demonstrating a possible role of systemic factors in favoring the progression of renal disease. (c) 2017 The Author(s) Published by S. Karger AG, Basel

The development of an innovative drug delivery system to target, after topical administration, the retina with bioactive agents against retinal pathologies is a major challenge. Currently, the sole approach to target these tissues is through intravitreous injection, but this is not free from problematics such as severe side effects and rapid clearance of small molecules from the vitreous.We aim to synthesize, develop and formulate a new magnetic nanoparticle‐mediated delivery technology that shall allow achieving needle‐free, anesthesia‐free delivery of active drugs to the retina after topical administration assisted by magnetic targeting.

International audience; Cilia are highly conserved and ubiquitously expressed organelles. Ciliary defects of genetic origins lead to ci-liopathies, in which retinal degeneration (RD) is one cardinal clinical feature. In order to efficiently find and design new therapeutic strategies the underlying mechanism of retinal degeneration of three murine model was compared. The rodent models correspond to three emblematic ciliopathies, namely: Bardet-Biedl Syndrome (BBS), Alström Syndrome (ALMS) and CEP290-mediated Leber Congenital Amaurosis (LCA). Scotopic rodent electroretinography (ERG) was used to test the retinal function of mice, Transmitted Electron microscopy (T.E.M) was performed to assess retinal structural defects and real-time PCR for targeted genes was used to monitor the expression levels of the major apoptotic Caspase-related pathways in retinal extracts to identify pathological pathways driving the RD in order to identify potential therapeutic targets. We found that BBS and CEP290-mediated LCA mouse models exhibit perinatal retinal degeneration associated with rhodopsin mis-localization in the photoreceptor and the induction of an Endoplasmic Reticulum (ER) stress. On the other hand, the tested ALMS mouse model, displayed a slower degeneration phenotype, with no Rhodopsin mislocalization nor ER-stress activity. Our data points out that behind the general phenotype of vision loss associated with these ciliopathies, the mechanisms and kinetics of disease progression are different.

Studying rare genetic disorders, associating type 2 diabetes, is a valuable approach to decipher disease origins as a specific causal gene can be linked to the diabetic phenotype. Understanding the related protein functions favors the discovery of new pathways, hence the design of new therapies. We focused on an ultra-rare genetic disorder, the Alström syndrome, associated with severe early-onset type 2 diabetes, obesity, steatosis and generalized fibrosis and for which a unique gene is consistently found mutated in ALMS patients, ALMS1 gene. Combining clinical, multiomics and in vivo mouse data, we discovered that ALMS1 regulates the ultimate steps of insulin signaling in the adipocyte, controlling fusion of GLUT4 sorting vesicles with the plasma membrane. ALMS1 binds to αPKC in the GLUT4 sorting vesicles vicinity and, under insulin stimulus, releases αPKC to trigger GLUT4 plasma membrane entry and glucose absorption. ALMS1 inactivation specifically inhibits adipocyte’s glucose absorption. In mice, the diabetic, steatotic and fibrotic phenotypes were linked to switching adipocyte energy tropism from glucose to lipids corelated with fatty acid transporters’ upregulation like FATP2 in the adipocyte; also observed in ALMS patients’ adipocytes. This change in fuel source in the adipocyte is the underlying cause for the observed metabolic disorders in vivo; primarily mediated through lipid signaling. Insulin-independent glucose absorption was achieved in normal adipocytes using a cell-penetrant, stapled peptide termed PATAS that targets ALMS1/αPKC protein interaction and in vivo can restore physiological adipocyte’s glucose energy tropism. Several in-house and outsourced experiments have demonstrated that PATAS administration significantly improves glucose intolerance, fasting blood glucose levels, liver steatosis and fibrosis in different mouse and rat models thereby making PATAS a potential novel drug to treat type 2 diabetes and its associated complications. Disclosure V. Marion: Research Support; Self; Rhythm Pharmaceuticals, Inc. Stock/Shareholder; Self; ALMS THERAPEUTICS.

Olfactory bulb (OB) volume evaluation by magnetic resonance imaging (MRI) has been demonstrated to be related to olfactory dysfunction in many different diseases. Olfactory dysfunction is often overlooked in Bardet-Biedl syndrome (BBS) patients and is rarely objectively evaluated by MRI. We present a series of 20 BBS patients with olfactory dysfunction. The OB was evaluated separately and blindly by two radiologists (SR and SM) with 3 Tesla MRI imaging comparatively to 12 normal control subjects by global visual evaluation and by quantitative measurement of OB volume. In the 12 control cases OB visual evaluation was considered as normal in all cases for radiologist (SR) and in 10 cases for radiologist (SM). In the 20 BBS patients, OB visual evaluation was considered as abnormal in 18 cases for SR and in all cases for SM. OB volumetric evaluation for SR and SM in BBS patients was able to provide significant correlation between BBS and olfactory dysfunction. This study indicates that OB volume evaluation by MRI imaging like structural MRI scan for gray matter modifications demonstrates that olfactory dysfunction in BBS patients is a constant and cardinal symptom integrated in a genetical syndrome with peripheral and central olfactory structure alterations.

The "Awake brain surgery" consists in removing some infiltrative and slow-growing brain tumor tissues in an awake patient. The neurosurgeon performs an anatomo-functional mapping of the brain by electrically stimulating brain areas near the tumor to discriminate functional versus nonfunctional areas. This stimulation is both made cortically and subcortically to preserve the anatomical connectivity on-line. During the surgery itself, the patient is involved by performing some behavioral tasks of interest (intra-operative assessments). Despite marked functional deficits after the surgery the recovery of these patients remains impressive with respect to the lesion volume. These observations question our understanding of brain dynamics and plasticity phenomena. The electrical stimulation procedure associated to the intra-operative assessments are thus critical aspects that need to be optimized in order to improve the precision of the anatomo-functional mapping of the brain and to better understand its dynamics and plasticity for these patients. More specifically, this multidisciplinary project aims at better understanding the electrophysiological effects of the direct electrical stimulation during the surgery using intra-operative electroencephalographic and electrocorticographic recordings. A method to detect off-line remote electrophysiological effects and neuromodulations due to the application of electrical stimulation will be developped for further on-line applications during the surgery, in order to optimize electrical stimulations and improve the anatomo-functional brain mapping. By more systematically performing these precise measurements during the surgery we hope to better understand brain dynamics and plasticity in order to improve the surgical planning, rehabilitation, and quality of life of the patients.; La « chirurgie éveillée » consiste à retirer des tumeurs lentes et infiltrantes chez un patient éveillé. Le neurochirurgien pratique une cartographie anatomo-fonctionnelle du cerveau en stimulant électriquement les zones près de la tumeur, pour discriminer celles qui sont fonctionnelles de celles qui ne le sont plus. Cette stimulation est effectuée au niveau cortical et sous-cortical pour préserver la connectivité anatomique en temps réel. Pendant la chirurgie même, le patient est impliqué et réalise des tâches comportementales d'intérêts (évaluations intra-opératoires). Malgré des déficits fonctionnels marqués après la chirurgie, la récupération de ces patients reste impressionnante en regard du volume de la lésion. Ces observations questionnent notre compréhension des phénomènes de dynamique et de plasticité cérébrale. La procédure de stimulation électrique et les évaluations intra-opératoires constituent des aspects critiques qui nécessitent d'être optimisés dans le but d'améliorer la précision de la cartographie anatomo-fonctionnelle du cerveau et de mieux comprendre sa dynamique et sa plasticité chez ces patients. Plus spécifiquement, ce projet pluridisciplinaire a pour but de mieux comprendre les effets électrophysiologiques de la stimulation électrique directe pendant la chirurgie (en utilisant des enregistrements électroencéphalographiques et électrocorticographiques). Une méthode pour mesurer puis détecter a posteriori les effets électrophysiologiques et les neuromodulations induites par l'application de la stimulation électrique sera développée pour une détection en temps-réel ultérieure au cours de la chirurgie, dans le but d'optimiser les stimulations électriques et améliorer la cartographie anatomo-fonctionnelle. En réalisant de manière plus systématique ces mesures précises, pendant la chirurgie, nous espérons mieux comprendre la dynamique et la plasticité cérébrale dans le but d'améliorer la planification chirurgicale, la rééducation et la qualité de vie des patients.

The "Awake brain surgery" consists in removing some infiltrative and slow-growing brain tumor tissues in an awake patient. The neurosurgeon performs an anatomo-functional mapping of the brain by electrically stimulating brain areas near the tumor to discriminate functional versus nonfunctional areas. This stimulation is both made cortically and subcortically to preserve the anatomical connectivity on-line. During the surgery itself, the patient is involved by performing some behavioral tasks of interest (intra-operative assessments). Despite marked functional deficits after the surgery the recovery of these patients remains impressive with respect to the lesion volume. These observations question our understanding of brain dynamics and plasticity phenomena. The electrical stimulation procedure associated to the intra-operative assessments are thus critical aspects that need to be optimized in order to improve the precision of the anatomo-functional mapping of the brain and to better understand its dynamics and plasticity for these patients. More specifically, this multidisciplinary project aims at better understanding the electrophysiological effects of the direct electrical stimulation during the surgery using intra-operative electroencephalographic and electrocorticographic recordings. A method to detect off-line remote electrophysiological effects and neuromodulations due to the application of electrical stimulation will be developped for further on-line applications during the surgery, in order to optimize electrical stimulations and improve the anatomo-functional brain mapping. By more systematically performing these precise measurements during the surgery we hope to better understand brain dynamics and plasticity in order to improve the surgical planning, rehabilitation, and quality of life of the patients.; La « chirurgie éveillée » consiste à retirer des tumeurs lentes et infiltrantes chez un patient éveillé. Le neurochirurgien pratique une cartographie anatomo-fonctionnelle du cerveau en stimulant électriquement les zones près de la tumeur, pour discriminer celles qui sont fonctionnelles de celles qui ne le sont plus. Cette stimulation est effectuée au niveau cortical et sous-cortical pour préserver la connectivité anatomique en temps réel. Pendant la chirurgie même, le patient est impliqué et réalise des tâches comportementales d'intérêts (évaluations intra-opératoires). Malgré des déficits fonctionnels marqués après la chirurgie, la récupération de ces patients reste impressionnante en regard du volume de la lésion. Ces observations questionnent notre compréhension des phénomènes de dynamique et de plasticité cérébrale. La procédure de stimulation électrique et les évaluations intra-opératoires constituent des aspects critiques qui nécessitent d'être optimisés dans le but d'améliorer la précision de la cartographie anatomo-fonctionnelle du cerveau et de mieux comprendre sa dynamique et sa plasticité chez ces patients. Plus spécifiquement, ce projet pluridisciplinaire a pour but de mieux comprendre les effets électrophysiologiques de la stimulation électrique directe pendant la chirurgie (en utilisant des enregistrements électroencéphalographiques et électrocorticographiques). Une méthode pour mesurer puis détecter a posteriori les effets électrophysiologiques et les neuromodulations induites par l'application de la stimulation électrique sera développée pour une détection en temps-réel ultérieure au cours de la chirurgie, dans le but d'optimiser les stimulations électriques et améliorer la cartographie anatomo-fonctionnelle. En réalisant de manière plus systématique ces mesures précises, pendant la chirurgie, nous espérons mieux comprendre la dynamique et la plasticité cérébrale dans le but d'améliorer la planification chirurgicale, la rééducation et la qualité de vie des patients.

The primary cilium is a specialized organelle, present at the surface of most eukaryotic cells, whose main function is to detect, integrate and transmit intra- and extra-cellular signals. Its dysfunction usually results in a group of severe clinical manifestations nowadays termed ciliopathies. The latter can be of syndromic nature with multi-organ dysfunctions and can also be associated with a morbid obese phenotype, like it is the case in the iconic ciliopathy, the Bardet Biedl syndrome (BBS). This review will discuss the contribution of the unique context offered by the emblematic BBS for understanding the mechanisms leading to obesity via the involvement of the primary cilium together with identification of novel molecular players and signaling pathways it has helped to highlight. In the current context of translational medicine and system biology, this article will also discuss the potential benefits and challenges posed by these techniques via multi-level approaches to better dissect the underlying mechanisms leading to the complex condition of obesity.

Bardet-Biedl syndrome (BBS) is a well-recognized ciliopathy characterized by cardinal features namely: early onset retinitis pigmentosa, polydactyly, obesity, hypogonadism, renal and cognitive impairment. Recently, disorders of olfaction (anosmia, hyposmia) have been also described in BBS patients. Moreover, morphological brain anomalies have been reported and prompt for further investigations to determine whether they are primary or secondary to peripheral organ involvement (i.e. visual or olfactory neuronal tissue). The objective of this article is to evaluate olfactory disorders in BBS patients and to investigate putative correlation with morphological cerebral anomalies. To this end, 20 BBS patients were recruited and evaluated for olfaction using the University of Pennsylvania Smell Identification Test (UPSIT). All of them underwent a structural magnetic resonance imaging (MRI) scan. We first investigated brain morphological differences between BBS subjects and 14 healthy volunteers. Then, we showed objective olfaction disorders in BBS patients and highlight correlation between gray matter volume reduction and olfaction dysfunction in several brain areas.

International audience; IRECT electrical stimulation (DES) has long been used to perform real-time functional mapping of the brain. More recently, this technique was introduced in the neurosurgery of slow-growing and infiltrative brain tumors to guide the resection with great success. By generating transient perturbations, this method allows the real-time identification of both cortical areas and subcortical networks that are essential for the function. Thus, as much as possible, non-functional tissue can be removed while minimizing the sequelae. However, the understanding of the electrophysiological effects of DES and, in particular its remote propagation, remains an open and key question. DES can be used to probe on-line and in-vivo the spatio-temporal connectivity and the dynamics of functional networks by associating electrophysiological recordings. Such methodology has been performed using electrocorticography (ECoG) and implanted grids on the surface of grey matter for pre-surgical planning of drug resistant epileptic patients. Some of these results suggest a local cortico-cortical propagation of evoked potentials (EPs) with DES. However, the propagation through subcortical pathways and at distant sites needs more direct evidences. To investigate more remote effects of DES (i.e. cortico-subcortico-cortical EPs), electroencephalographic (EEG) recordings would be of some interest. Intra-operative EEG recordings were studied to analyze if and how stimulation currents spread at distant sites and more especially if they can be perceptible in the " controlesional " hemisphere. In other words, does DES induce EPs? Does DES modify the frequency contents included in the natural activity of the brain? We also aimed to measure the effects of DES on functional connectivity, i.e. to determine if DES modifies the correlation between the different EEG signals between the pre, intra and post-DES phases. To our knowledge, this approach has never been performed. Data were collected during an awake brain surgery (without interfering with the surgical routine) for one patient harboring a right frontal hemisphere tumor and under local anesthesia. Neural activity was recorded from the surface of the skull (EEG, sampling frequency of 2048 Hz) on 4 sites (3 controlesional sites: F3, C3 and O1 and 1 ipsilesional site: O2; the lesion was centered on F4, Fp2 and F8). DES was delivered with a bipolar electrode using standard parameters (biphasic square pulse, 60 Hz, ~ 2 mA). First we tried to measure EPs when DES is applied cortically and subcortically. To maximize the EPs while minimizing the noise and the artifacts, EEG signals were synchronized and averaged upon a given time window (500 ms). The phases when DES is applied can be recognized by the appearance of artefacts on the natural EEG activity. However, whereas EPs have been observed in ECoG [2, 3], no EP was detected in our EEG data. With a 60 Hz frequency, stimulation artefacts can hide EPs. Indeed, the nervous time of conduction is close to the stimulation period, in particular for the interhemispheric transfer (around 20 ms). Choosing a stimulation frequency lower than 60 Hz could limit artefacts and make the detection of EPs easier. In consequence it is planned to study the time-frequency content of the neural data. To reduce bias and variance problems, multitaper spectral estimation could be used. We will look for modifications of the spectrum for each period of stimulation, before, during and after DES. In addition, functional connectivity also remains to be studied by looking at the correlation between signals from various electrodes, especially between electrodes located in the ipsi vs. controlesional hemisphere. We will present the setup, the data analysis protocol and the preliminary results.