Publications by authors named "Olivier Renaud"

40 Publications

Cnr2 Is Important for Ribbon Synapse Maturation and Function in Hair Cells and Photoreceptors.

Front Mol Neurosci 2021 20;14:624265. Epub 2021 Apr 20.

Department of Anatomy and Neurobiology, School of Medicine, University of Puerto Rico, San Juan, Puerto Rico.

The role of the cannabinoid receptor 2 (CNR2) is still poorly described in sensory epithelia. We found strong expression in hair cells (HCs) of the inner ear and the lateral line (LL), a superficial sensory structure in fish. Next, we demonstrated that sensory synapses in HCs were severely perturbed in larvae lacking cnr2. Appearance and distribution of presynaptic ribbons and calcium channels (Ca1.3) were profoundly altered in mutant animals. Clustering of membrane-associated guanylate kinase (MAGUK) in post-synaptic densities (PSDs) was also heavily affected, suggesting a role for cnr2 for maintaining the sensory synapse. Furthermore, vesicular trafficking in HCs was strongly perturbed suggesting a retrograde action of the endocannabinoid system (ECs) via cnr2 that was modulating HC mechanotransduction. We found similar perturbations in retinal ribbon synapses. Finally, we showed that larval swimming behaviors after sound and light stimulations were significantly different in mutant animals. Thus, we propose that cnr2 is critical for the processing of sensory information in the developing larva.
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http://dx.doi.org/10.3389/fnmol.2021.624265DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8093779PMC
April 2021

Imaging the response to DNA damage in heterochromatin domains reveals core principles of heterochromatin maintenance.

Nat Commun 2021 04 23;12(1):2428. Epub 2021 Apr 23.

Epigenetics and Cell Fate Centre, UMR7216 CNRS, Université de Paris, Paris, France.

Heterochromatin is a critical chromatin compartment, whose integrity governs genome stability and cell fate transitions. How heterochromatin features, including higher-order chromatin folding and histone modifications associated with transcriptional silencing, are maintained following a genotoxic stress challenge is unknown. Here, we establish a system for targeting UV damage to pericentric heterochromatin in mammalian cells and for tracking the heterochromatin response to UV in real time. We uncover profound heterochromatin compaction changes during repair, orchestrated by the UV damage sensor DDB2, which stimulates linker histone displacement from chromatin. Despite massive heterochromatin unfolding, heterochromatin-specific histone modifications and transcriptional silencing are maintained. We unveil a central role for the methyltransferase SETDB1 in the maintenance of heterochromatic histone marks after UV. SETDB1 coordinates histone methylation with new histone deposition in damaged heterochromatin, thus protecting cells from genome instability. Our data shed light on fundamental molecular mechanisms safeguarding higher-order chromatin integrity following DNA damage.
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http://dx.doi.org/10.1038/s41467-021-22575-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8065061PMC
April 2021

Shared and Anxiety-Specific Pediatric Psychopathology Dimensions Manifest Distributed Neural Correlates.

Biol Psychiatry 2021 03 9;89(6):579-587. Epub 2020 Nov 9.

Emotion and Development Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland.

Background: Imaging research has not yet delivered reliable psychiatric biomarkers. One challenge, particularly among youth, is high comorbidity. This challenge might be met through canonical correlation analysis designed to model mutual dependencies between symptom dimensions and neural measures. We mapped the multivariate associations that intrinsic functional connectivity manifests with pediatric symptoms of anxiety, irritability, and attention-deficit/hyperactivity disorder (ADHD) as common, impactful, co-occurring problems. We evaluate the replicability of such latent dimensions in an independent sample.

Methods: We obtained ratings of anxiety, irritability, and ADHD, and 10 minutes of resting-state functional magnetic resonance imaging data, from two independent cohorts. Both cohorts (discovery: n = 182; replication: n = 326) included treatment-seeking youth with anxiety disorders, with disruptive mood dysregulation disorder, with ADHD, or without psychopathology. Functional connectivity was modeled as partial correlations among 216 brain areas. Using canonical correlation analysis and independent component analysis jointly we sought maximally correlated, maximally interpretable latent dimensions of brain connectivity and clinical symptoms.

Results: We identified seven canonical variates in the discovery and five in the replication cohort. Of these canonical variates, three exhibited similarities across datasets: two variates consistently captured shared aspects of irritability, ADHD, and anxiety, while the third was specific to anxiety. Across cohorts, canonical variates did not relate to specific resting-state networks but comprised edges interconnecting established networks within and across both hemispheres.

Conclusions: Findings revealed two replicable types of clinical variates, one related to multiple symptom dimensions and a second relatively specific to anxiety. Both types involved a multitude of broadly distributed, weak brain connections as opposed to strong connections encompassing known resting-state networks.
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http://dx.doi.org/10.1016/j.biopsych.2020.10.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7889729PMC
March 2021

Fetal hemoglobin rescues ineffective erythropoiesis in sickle cell disease.

Haematologica 2020 08 27. Epub 2020 Aug 27.

Inserm - INTS - University of Paris, Paris, France;

While ineffective erythropoiesis has long been recognized as a key contributor to anemia in thalassemia, its role in anemia of sickle cell disease (SCD) has not been critically explored. Using in vitro and in vivo derived human erythroblasts we assessed the extent of ineffective erythropoiesis in SCD. Modeling the bone marrow hypoxic environment, we found that hypoxia induces death of sickle erythroblasts starting at the polychromatic stage, positively selecting cells with high levels of fetal hemoglobin (HbF). Cell death was associated with cytoplasmic sequestration of heat shock protein 70 and was rescued by induction of HbF synthesis. Importantly, we document that in bone marrow of SCD patients similar cell loss occurs during the final stages of terminal differentiation. Our study provides evidence for ineffective erythropoiesis in SCD and highlights an anti-apoptotic role for HbF during the terminal stages of erythroid differentiation. These findings imply that the beneficial effect on anemia of increased HbF levels is not only due to the increased life span of red cells but also a consequence of decreased ineffective erythropoiesis.
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http://dx.doi.org/10.3324/haematol.2020.265462DOI Listing
August 2020

Permutation inference for canonical correlation analysis.

Neuroimage 2020 10 27;220:117065. Epub 2020 Jun 27.

Big Data Institute, University of Oxford, Oxford, UK.

Canonical correlation analysis (CCA) has become a key tool for population neuroimaging, allowing investigation of associations between many imaging and non-imaging measurements. As age, sex and other variables are often a source of variability not of direct interest, previous work has used CCA on residuals from a model that removes these effects, then proceeded directly to permutation inference. We show that a simple permutation test, as typically used to identify significant modes of shared variation on such data adjusted for nuisance variables, produces inflated error rates. The reason is that residualisation introduces dependencies among the observations that violate the exchangeability assumption. Even in the absence of nuisance variables, however, a simple permutation test for CCA also leads to excess error rates for all canonical correlations other than the first. The reason is that a simple permutation scheme does not ignore the variability already explained by previous canonical variables. Here we propose solutions for both problems: in the case of nuisance variables, we show that transforming the residuals to a lower dimensional basis where exchangeability holds results in a valid permutation test; for more general cases, with or without nuisance variables, we propose estimating the canonical correlations in a stepwise manner, removing at each iteration the variance already explained, while dealing with different number of variables in both sides. We also discuss how to address the multiplicity of tests, proposing an admissible test that is not conservative, and provide a complete algorithm for permutation inference for CCA.
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http://dx.doi.org/10.1016/j.neuroimage.2020.117065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7573815PMC
October 2020

Self-defining memories after severe traumatic brain injury: A preliminary study.

J Neuropsychol 2021 03 9;15(1):112-128. Epub 2020 Jun 9.

Faculty of Psychology and Educational Sciences, University of Geneva, Switzerland.

Autobiographical memory plays a major role in the (re)construction of sense of identity, a recurrent issue after a traumatic brain injury (TBI). Although the recall of specific autobiographical events is frequently impaired in patients with TBI, little is known about how these changes affect their sense of self and identity. Thus, we examined self-defining memories (SDMs), that is, the most significant personal memories supporting one's sense of identity, in 16 patients with severe TBI and in matched controls. To this end, participants recalled three SDMs and rated their emotions in response to memory retrieval. In addition, characteristics of SDMs such as specificity, meaning-making, self-connections that reflect identity stability or identity change, content (theme, presence of tension, and redemption sequences) were analysed by independent raters. The main results showed that patients' SDMs were less specific and contained fewer redemption sequences than did those of controls but did not significantly differ in thematic content, presence of tension, meaning-making, self-connections that reflect identity stability or identity change and affective responses to memory retrieval. Furthermore, among the patients' memories that refer to the TBI-related event itself, only one contained an explicit meaning. Despite the lack of specificity in memories, patients with severe TBI were able to extract meaning from personal memories although they could struggle with integrating the TBI-related event into their sense of identity. These characteristics of SDMs may contribute to disturbances in sense of self and continuity in patients with severe TBI, as well as difficulties in personal or social adjustment. These results also open up relevant prospects for psychological interventions in identity-related issues in patients with TBI.
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http://dx.doi.org/10.1111/jnp.12212DOI Listing
March 2021

Attention shifting and subliminal cueing under high attentional load: an EEG study using emotional faces.

Neuroreport 2019 12;30(18):1251-1255

Faculty of Psychology and Educational Sciences.

Emotional expressions and attentional processes interact such that emotion increases perceptual sensitivity in modality-specific brain areas leading to more efficient processing of the stimulus. In the current study, we asked the question of whether the emotional expressions can be processed subliminally when faces are attended but the emotional expression is irrelevant. We presented angry and neutral male and female faces supraliminally and subliminally to participants in an attention-shifting paradigm. Emotional expression was irrelevant to the task, but the gender of the face was predictive of the location of a subsequent target. Analysis of reaction times revealed that, in the supraliminal condition, targets appearing at validly cued locations produced quicker responses than targets at invalidly cued locations. Target-locked event-related potentials (ERPs) confirmed this result and showed that attention selection elicited higher responses at attended locations, as reflected by the N1 component. However, voluntary attention shifting was not triggered when the cue was not consciously perceived. No effects of emotion were observed following target presentation, suggesting that the high attentional load required by the experiment may have prevented the processing of emotion for undetectable faces, as demonstrated by the fact that, following cue onset, the N170 was modulated by emotion in supraliminal trials only. We therefore show that emotional expressions cannot be processed without awareness when faces are attended, but the emotional expression is irrelevant.
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http://dx.doi.org/10.1097/WNR.0000000000001349DOI Listing
December 2019

Dimerization and phosphorylation of Lutheran/basal cell adhesion molecule are critical for its function in cell migration on laminin.

J Biol Chem 2019 10 14;294(41):14911-14921. Epub 2019 Aug 14.

Université de Paris, UMR_S1134, BIGR, Inserm, F-75015 Paris, France

Tumor cell migration depends on the interactions of adhesion proteins with the extracellular matrix. Lutheran/basal cell adhesion molecule (Lu/BCAM) promotes tumor cell migration by binding to laminin α5 chain, a subunit of laminins 511 and 521. Lu/BCAM is a type I transmembrane protein with a cytoplasmic domain of 59 (Lu) or 19 (Lu(v13)) amino acids. Here, using an array of techniques, including site-directed mutagenesis, immunoblotting, FRET, and proximity-ligation assays, we show that both Lu and Lu(v13) form homodimers at the cell surface of epithelial cancer cells. We mapped two small--small motifs in the transmembrane domain as potential sites for monomers docking and identified three cysteines in the cytoplasmic domain as being critical for covalently stabilizing dimers. We further found that Lu dimerization and phosphorylation of its cytoplasmic domain were concomitantly needed to promote cell migration. We conclude that Lu is the critical isoform supporting tumor cell migration on laminin 521 and that the Lu:Lu(v13) ratio at the cell surface may control the balance between cellular firm adhesion and migration.
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http://dx.doi.org/10.1074/jbc.RA119.007521DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6791331PMC
October 2019

Accounting for stimulus and participant effects in event-related potential analyses to increase the replicability of studies.

J Neurosci Methods 2018 11 16;309:218-227. Epub 2018 Sep 16.

Methodology and Data Analysis, Section of Psychology, FPSE, University of Geneva, Bd du Pont d'Arve 42, 1205 Genève, Switzerland.

Background: Event-related potentials (ERPs) are increasingly used in cognitive science. With their high temporal resolution, they offer a unique window into cognitive processes and their time course. In this paper, we focus on ERP experiments whose designs involve selecting participants and stimuli amongst many. Recently, Westfall et al. (2017) highlighted the drastic consequences of not considering stimuli as a random variable in fMRI studies with such designs. Most ERP studies in cognitive psychology suffer from the same drawback.

New Method: We advocate the use of the Quasi-F or Mixed-effects models instead of the classical ANOVA/by-participant F1 statistic to analyze ERP datasets in which the dependent variable is reduced to one measure per trial (e.g., mean amplitude). We combine Quasi-F statistic and cluster mass tests to analyze datasets with multiple measures per trial. Doing so allows us to treat stimulus as a random variable while correcting for multiple comparisons.

Results: Simulations show that the use of Quasi-F statistics with cluster mass tests allows maintaining the family wise error rates close to the nominal alpha level of 0.05.

Comparison With Existing Methods: Simulations reveal that the classical ANOVA/F1 approach has an alarming FWER, demonstrating the superiority of models that treat both participant and stimulus as random variables, like the Quasi-F approach.

Conclusions: Our simulations question the validity of studies in which stimulus is not treated as a random variable. Failure to change the current standards feeds the replicability crisis.
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http://dx.doi.org/10.1016/j.jneumeth.2018.09.016DOI Listing
November 2018

A novel non-invasive method to measure splenic filtration function in humans.

Haematologica 2018 10 7;103(10):e436-e439. Epub 2018 Jun 7.

Biologie Intégrée du Globule Rouge UMR_S1134, Inserm, Univ. Paris Diderot, Sorbonne Paris Cité, Univ. de la Réunion, Univ. des Antilles, France

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http://dx.doi.org/10.3324/haematol.2018.188920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6165803PMC
October 2018

Interaction and threshold effects of appraisal on componential patterns of emotion: A study using cross-cultural semantic data.

Emotion 2019 Apr 7;19(3):425-442. Epub 2018 Jun 7.

Swiss Center for Affective Sciences, University of Geneva.

Studies that investigated the relation between appraisal and emotion have largely focused on the linear effect of appraisal criteria on subjective feelings (e.g., the effect of appraised goal obstruction on anger). Emotional responding can be extended to include more than just feelings, however. Componential definitions of emotion also add motivation, physiology, and expression. Moreover, a linear model is not compatible with the idea held by many appraisal theorists that appraisal criteria interact to produce emotional responding. In the present study, we modeled adaptive nonlinear interaction effects of appraisal criteria on motivation, expression, and physiology simultaneously. We applied a combination of principal component analysis for data reduction and multivariate adaptive regression splines (MARS) for automatic interaction identification. Data were obtained from a large-scale cross-cultural study on emotion concepts conducted in 27 countries, which represented semantic profiles of component information in 24 common emotion words. Results of modeling indicated that (a) appraisal of relevance, familiarity, goal compatibility, coping potential, and suddenness showed main effects on component responses; (b) appraisals of agency and norm compatibility uniquely showed interaction effects on component responses; (c) interaction effects explained significant variance only in some component responses but not all; and (d) the emotion patterns simulated by the fitted MARS model could be clustered according to qualitative emotion categories. (PsycINFO Database Record (c) 2019 APA, all rights reserved).
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http://dx.doi.org/10.1037/emo0000449DOI Listing
April 2019

Clonal analysis of Notch1-expressing cells reveals the existence of unipotent stem cells that retain long-term plasticity in the embryonic mammary gland.

Nat Cell Biol 2018 06 21;20(6):677-687. Epub 2018 May 21.

Institut Curie, PSL Research University, INSERM, CNRS, Paris, France.

Recent lineage tracing studies have revealed that mammary gland homeostasis relies on unipotent stem cells. However, whether and when lineage restriction occurs during embryonic mammary development, and which signals orchestrate cell fate specification, remain unknown. Using a combination of in vivo clonal analysis with whole mount immunofluorescence and mathematical modelling of clonal dynamics, we found that embryonic multipotent mammary cells become lineage-restricted surprisingly early in development, with evidence for unipotency as early as E12.5 and no statistically discernable bipotency after E15.5. To gain insights into the mechanisms governing the switch from multipotency to unipotency, we used gain-of-function Notch1 mice and demonstrated that Notch activation cell autonomously dictates luminal cell fate specification to both embryonic and basally committed mammary cells. These functional studies have important implications for understanding the signals underlying cell plasticity and serve to clarify how reactivation of embryonic programs in adult cells can lead to cancer.
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http://dx.doi.org/10.1038/s41556-018-0108-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6984964PMC
June 2018

Time, frequency, and time-varying Granger-causality measures in neuroscience.

Stat Med 2018 05 15;37(11):1910-1931. Epub 2018 Mar 15.

Methodology and Data Analysis, Department of Psychology, University of Geneva, Geneva, Switzerland.

This article proposes a systematic methodological review and an objective criticism of existing methods enabling the derivation of time, frequency, and time-varying Granger-causality statistics in neuroscience. The capacity to describe the causal links between signals recorded at different brain locations during a neuroscience experiment is indeed of primary interest for neuroscientists, who often have very precise prior hypotheses about the relationships between recorded brain signals. The increasing interest and the huge number of publications related to this topic calls for this systematic review, which describes the very complex methodological aspects underlying the derivation of these statistics. In this article, we first present a general framework that allows us to review and compare Granger-causality statistics in the time domain, and the link with transfer entropy. Then, the spectral and the time-varying extensions are exposed and discussed together with their estimation and distributional properties. Although not the focus of this article, partial and conditional Granger causality, dynamical causal modelling, directed transfer function, directed coherence, partial directed coherence, and their variant are also mentioned.
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http://dx.doi.org/10.1002/sim.7621DOI Listing
May 2018

Individual Differences in Developmental Change: Quantifying the Amplitude and Heterogeneity in Cognitive Change across Old Age.

J Intell 2018 Feb 28;6(1). Epub 2018 Feb 28.

Center for the Interdisciplinary Study of Gerontology and Vulnerability (CIGEV), University of Geneva, 1211 Geneva, Switzerland.

It is well known that cognitive decline in older adults is of smaller amplitude in longitudinal than in cross-sectional studies. Yet, the measure of interest rests generally with aggregated group data. A focus on individual developmental trajectories is rare, mainly because it is difficult to assess intraindividual change reliably. Individual differences in developmental trajectories may differ quantitatively (e.g., larger or smaller decline) or qualitatively (e.g., decline vs improvement), as well as in the degree of heterogeneity of change across different cognitive domains or different tasks. The present paper aims at exploring, within the Geneva Variability Study, individual change across several cognitive domains in 92 older adults (aged 59-89 years at baseline) over a maximum of seven years and a half. Two novel, complementary methods were used to explore change in cognitive performance while remaining entirely at the intra-individual level. A bootstrap based confidence interval was estimated, for each participant and for each experimental condition, making it possible to define three patterns: stability, increase or decrease in performance. Within-person ANOVAs were also conducted for each individual on all the tasks. Those two methods allowed quantifying the direction, the amplitude and the heterogeneity of change for each individual. Results show that trajectories differed widely among individuals and that decline is far from being the rule.
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http://dx.doi.org/10.3390/jintelligence6010010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6480728PMC
February 2018

Cerebellar gray matter explains bimanual coordination performance in children and older adults.

Neurobiol Aging 2018 05 2;65:109-120. Epub 2018 Feb 2.

KU Leuven, Department of Movement Sciences, Movement Control and Neuroplasticity Research Group, Leuven, Belgium; KU Leuven, Leuven Research Institute for Neuroscience & Disease (LIND), Leuven, Belgium.

The cerebellum appears to undergo late maturation in children and early decline at older age. Whether these age-related changes affect bimanual coordination performance remains unclear at best. Here, we identified the ages at which bimanual coordination performance stops improving and starts declining. In an independent cohort, we defined brain regions of interest involved in bimanual coordination using functional magnetic resonance imaging. We used these regions of interest to investigate the extent to which the gray matter of cerebellar and other brain regions explains bimanual coordination performance from 10- to 80-year-olds. Results showed that bimanual coordination performance starts declining from the age of 40 years. In participants aged 10-20 years, cerebellar lobule VI was the only significant brain predictor of bimanual coordination performance. In participants aged 60-80 years, this cerebellar region, together with the primary sensorimotor cortex, formed a group of strongest predictors. These results from 2 independent samples (10-20 and 60-80 years) suggest that cerebellar lobule VI is critical for the development and preservation of bimanual coordination skills in children and older adults, respectively. In addition, post hoc analyses suggested that the primary motor cortex mediated the adverse effect of age on bimanual coordination performance in older adults.
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http://dx.doi.org/10.1016/j.neurobiolaging.2018.01.016DOI Listing
May 2018

Visual stimuli modulate frontal oscillatory rhythms in a cortically blind patient: Evidence for top-down visual processing.

Clin Neurophysiol 2017 May 23;128(5):770-779. Epub 2017 Feb 23.

Methodology and Data Analysis, Department of Psychology, University of Geneva, Switzerland.

Objective: We investigated neuronal correlates of faces versus non-faces processing in a cortically blind patient (TN) and a group of healthy age-matched controls in order to test electrophysiological correlates of the processing of pertinent stimuli in this patient.

Methods: An EEG paradigm was used, in which intact and scrambled faces were displayed on a screen. First, time-frequency transforms were conducted on the patients' data alone. These oscillations were then compared to the frontal activity of six control participants.

Results: Post stimulus oscillatory modulations (synchronisation in theta and alpha frequency bands) of both intact and scrambled faces at frontal scalp sites were observed in TN. These modulations were different for correct and incorrect responses. A more important increase in the theta band for incorrect responses was observed. The oscillatory rhythms highlighted in blindsight and in frontal regions differ from the ones observed in control participants.

Conclusion: Despite the destruction of the visual cortex, oscillatory rhythms are not cancelled out but are shifted to anterior regions, revealing the activity of an alternate pathway for residual visual function.

Significance: The results provide evidence for a top-down cognitive control process in blindsight.
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http://dx.doi.org/10.1016/j.clinph.2017.02.009DOI Listing
May 2017

Vocal emotion decoding in the subthalamic nucleus: An intracranial ERP study in Parkinson's disease.

Brain Lang 2017 May 12;168:1-11. Epub 2017 Jan 12.

'Neuroscience of Emotion and Affective Dynamics' Laboratory, Department of Psychology & Swiss Center for Affective Sciences, University of Geneva, 40 bd du Pont d'Arve, 1205 Geneva, Switzerland; Neuropsychology Unit, Department of Neurology, University Hospitals of Geneva, Rue Gabrielle-Perret-Gentil 4, 1205 Geneva, Switzerland.

Using intracranial local field potential (LFP) recordings in patients with Parkinson's disease (PD) undergoing deep brain stimulation (DBS), we explored the electrophysiological activity of the subthalamic nucleus (STN) in response to emotional stimuli in the auditory modality. Previous studies focused on the influence of visual stimuli. To this end, we recorded LFPs within the STN in response to angry, happy, and neutral prosodies in 13 patients with PD who had just undergone implantation of DBS electrodes. We observed specific modulation of the right STN in response to anger and happiness, as opposed to neutral prosody, occurring at around 200-300ms post-onset, and later at around 850-950ms post-onset for anger and at around 3250-3350ms post-onset for happiness. Taken together with previous reports of modulated STN activity in response to emotional visual stimuli, the present results appear to confirm that the STN is involved in emotion processing irrespective of stimulus valence and sensory modality.
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http://dx.doi.org/10.1016/j.bandl.2016.12.003DOI Listing
May 2017

Real-Time Tracking of Parental Histones Reveals Their Contribution to Chromatin Integrity Following DNA Damage.

Mol Cell 2016 10 15;64(1):65-78. Epub 2016 Sep 15.

Epigenetics & Cell Fate Centre, UMR7216 CNRS, Paris Diderot University, Sorbonne Paris Cité, F-75013 Paris, France. Electronic address:

Chromatin integrity is critical for cell function and identity but is challenged by DNA damage. To understand how chromatin architecture and the information that it conveys are preserved or altered following genotoxic stress, we established a system for real-time tracking of parental histones, which characterize the pre-damage chromatin state. Focusing on histone H3 dynamics after local UVC irradiation in human cells, we demonstrate that parental histones rapidly redistribute around damaged regions by a dual mechanism combining chromatin opening and histone mobilization on chromatin. Importantly, parental histones almost entirely recover and mix with new histones in repairing chromatin. Our data further define a close coordination of parental histone dynamics with DNA repair progression through the damage sensor DDB2 (DNA damage-binding protein 2). We speculate that this mechanism may contribute to maintaining a memory of the original chromatin landscape and may help preserve epigenome stability in response to DNA damage.
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http://dx.doi.org/10.1016/j.molcel.2016.08.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5065526PMC
October 2016

Whole-brain grey matter density predicts balance stability irrespective of age and protects older adults from falling.

Gait Posture 2016 Mar 29;45:143-50. Epub 2016 Jan 29.

Movement Control and Neuroplasticity Research Group, Department of Kinesiology, Biomedical Sciences Group, KU Leuven, Leuven, Belgium; Leuven Research Institute for Neuroscience & Disease (LIND), KU Leuven, Leuven, Belgium.

Functional and structural imaging studies have demonstrated the involvement of the brain in balance control. Nevertheless, how decisive grey matter density and white matter microstructural organisation are in predicting balance stability, and especially when linked to the effects of ageing, remains unclear. Standing balance was tested on a platform moving at different frequencies and amplitudes in 30 young and 30 older adults, with eyes open and with eyes closed. Centre of pressure variance was used as an indicator of balance instability. The mean density of grey matter and mean white matter microstructural organisation were measured using voxel-based morphometry and diffusion tensor imaging, respectively. Mixed-effects models were built to analyse the extent to which age, grey matter density, and white matter microstructural organisation predicted balance instability. Results showed that both grey matter density and age independently predicted balance instability. These predictions were reinforced when the level of difficulty of the conditions increased. Furthermore, grey matter predicted balance instability beyond age and at least as consistently as age across conditions. In other words, for balance stability, the level of whole-brain grey matter density is at least as decisive as being young or old. Finally, brain grey matter appeared to be protective against falls in older adults as age increased the probability of losing balance in older adults with low, but not moderate or high grey matter density. No such results were observed for white matter microstructural organisation, thereby reinforcing the specificity of our grey matter findings.
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http://dx.doi.org/10.1016/j.gaitpost.2016.01.019DOI Listing
March 2016

Numerical abilities in children with congenital hemiplegia: an investigation of the role of finger use in number processing.

Dev Neuropsychol 2014 ;39(2):88-100

a FAPSE, University of Geneva , Geneva , Switzerland.

In this study, we assessed basic and more complex non-symbolic and symbolic numerical task abilities in children with hemiplegia and obtained a detailed picture of their strengths and weaknesses in the numerical domain. Those children, who experience difficulties in finger gnosia and spontaneous use of fingers in counting, exhibit difficulties in finger pattern recognition and symbolic numerical tasks. However, their non-symbolic numerical abilities and arithmetic skills are preserved. These original results are discussed in light of the "manumerical cognition" hypothesis, which postulates that the use of fingers in numerical activities during childhood shapes our comprehension of numbers.
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http://dx.doi.org/10.1080/87565641.2013.860979DOI Listing
April 2014

Poor reward sensitivity and apathy after stroke: implication of basal ganglia.

Neurology 2013 Nov 9;81(19):1674-80. Epub 2013 Oct 9.

From the Cognitive Psychopathology and Neuropsychology Unit (L.R., M.V.d.L.), Swiss Centre for Affective Sciences (L.R., M.V.d.L.), Methodology & Data Analysis (O.R.), and Department of Neuroscience, University Medical Center (R.S.), University of Geneva, Switzerland; Cognitive Psychopathology Unit (M.V.d.L.), University of Liège, Belgium; Neurology Unit (L.R., J.-B.E., L.S., J.-M.A.), Department of Medicine, Faculty of Sciences, University of Fribourg; and Department of Neurology (P.M.), Centre Hospitalier Universitaire Vaudois and University of Lausanne, Switzerland.

Objective: To examine the relationship between reward sensitivity and self-reported apathy in stroke patients and to investigate the neuroanatomical correlates of both reward sensitivity and apathy.

Methods: In this prospective study, 55 chronic stroke patients were administered a questionnaire to assess apathy and a laboratory task to examine reward sensitivity by measuring motivationally driven behavior ("reinforcement-related speeding"). Fifteen participants without brain damage served as controls for the laboratory task. Negative mood, working memory, and global cognitive functioning were also measured to determine whether reward insensitivity and apathy were secondary to cognitive impairments or negative mood. Voxel-based lesion-symptom mapping was used to explore the neuroanatomical substrates of reward sensitivity and apathy.

Results: Participants showed reinforcement-related speeding in the highly reinforced condition of the laboratory task. However, this effect was significant for the controls only. For patients, poorer reward sensitivity was associated with greater self-reported apathy (p < 0.05) beyond negative mood and after lesion size was controlled for. Neither apathy nor reward sensitivity was related to working memory or global cognitive functioning. Voxel-based lesion-symptom mapping showed that damage to the ventral putamen and globus pallidus, dorsal thalamus, and left insula and prefrontal cortex was associated with poorer reward sensitivity. The putamen and thalamus were also involved in self-reported apathy.

Conclusions: Poor reward sensitivity in stroke patients with damage to the ventral basal ganglia, dorsal thalamus, insula, or prefrontal cortex constitutes a core feature of apathy. These results provide valuable insight into the neural mechanisms and brain substrate underlying apathy.
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http://dx.doi.org/10.1212/01.wnl.0000435290.49598.1dDOI Listing
November 2013

Sex hormones and mental rotation: an intensive longitudinal investigation.

Horm Behav 2013 Feb 21;63(2):345-51. Epub 2012 Dec 21.

Department of Psychology, University of Geneva, 40 bd Pont-d'Arve, Switzerland.

The present study used an intensive longitudinal design to examine whether mental rotation performance varies according to a monthly cycle in both males and females and whether these variations are related to variations in progesterone, estradiol, and testosterone levels. We collected reaction time and accuracy data for 10 males and seven females each workday over eight weeks using 136 pairs of mental rotation stimuli/day, and measured sexual hormones concentrations in the saliva twice a week. A mixed linear model statistical analysis revealed that all females and seven males showed significant cycle effects in mental rotation performance. The female cycle showed an amplitude that was twice as large compared with the amplitude found in males. For males and females, estradiol and testosterone were significantly linearly and quadratically related to interindividual variation in performance at the beginning of the study (progesterone was linearly related to performance for females). The association between testosterone and performance differed across sexes: for males, it had an inverse U-shape, for females it was U-shaped. Towards the end of the study, none of the hormones were significantly related to performance anymore. Thus, the relationship between hormones and mental rotation performance disappeared with repeated testing. Only estradiol levels were significantly elevated at the lowest point of the cycle in mental rotation performance in females. In conclusion, in this intensive longitudinal study spanning two months, a monthly cycle in mental rotation performance was found among both males and females, with a larger cycle's amplitude for females.
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http://dx.doi.org/10.1016/j.yhbeh.2012.12.007DOI Listing
February 2013

Studying cell behavior in whole zebrafish embryos by confocal live imaging: application to hematopoietic stem cells.

Nat Protoc 2011 Nov 10;6(12):1897-904. Epub 2011 Nov 10.

Institut Curie, Centre de Recherche, PICT-IBiSA, Paris, France.

Confocal live imaging is a key tool for studying cell behavior in the whole zebrafish embryo. Here we provide a detailed protocol that is adaptable for imaging any progenitor cell behavior in live zebrafish embryos. As an example, we imaged the emergence of the first hematopoietic stem cells from the aorta. We discuss the importance of selecting the appropriate zebrafish transgenic line as well as methods for immobilization of embryos to be imaged. In addition, we highlight the confocal microscopy acquisition parameters required for stem cell imaging and the software tools we used to analyze 4D movies. The whole protocol takes 2 h 15 min and allows confocal live imaging from a few hours to several days.
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http://dx.doi.org/10.1038/nprot.2011.408DOI Listing
November 2011

Nocturnal regrets and insomnia in elderly people.

Int J Aging Hum Dev 2011 ;73(4):371-93

Swiss Center for Affective Sciences, University of Geneva, Geneva, Switzerland.

Despite their importance for general health, emotion-related factors have rarely been considered in the etiology of late-life insomnia. This study explored the relations between impulsivity, regret experiences, use of different thought-control strategies, and insomnia severity in a sample of older adults whose age ranged from 51 to 98 years. Results revealed that: (a) regret frequency varies across the hours of the day, with a peak in the evening when people are trying to fall asleep; (b) individuals scoring high on impulsive urgency are particularly prone to experience nocturnal regrets; (c) nocturnal regrets are associated with insomnia severity, independently of other well-known risk factors such as depression, sleep-interfering medical conditions, and medications; and (d) the thought-control strategies of self-attacking, thought suppression, and worry are positively associated with the frequency of nocturnal regrets and insomnia severity. These findings indicate that dysfunctional regret regulation plays an important role for sleep disturbances in elderly people.
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http://dx.doi.org/10.2190/AG.73.4.fDOI Listing
June 2012

Aggregation of mononuclear and red blood cells through an {alpha}4{beta}1-Lu/basal cell adhesion molecule interaction in sickle cell disease.

Haematologica 2010 Nov 18;95(11):1841-8. Epub 2010 Jun 18.

INSERM, UMRS 665, INTS, 6 rue Alexandre Cabanel, 75015 Paris, France.

Background: Abnormal interactions between red blood cells, leukocytes and endothelial cells play a critical role in the occurrence of the painful vaso-occlusive crises associated with sickle cell disease. We investigated the interaction between circulating leukocytes and red blood cells which could lead to aggregate formation, enhancing the incidence of vaso-occlusive crises.

Design And Methods: Blood samples from patients with sickle cell disease (n=25) and healthy subjects (n=5) were analyzed by imaging and classical flow cytometry after density gradient separation. The identity of the cells in the peripheral blood mononuclear cell layer was determined using antibodies directed specifically against white (anti-CD45) or red (anti-glycophorin A) blood cells.

Results: Aggregates between red blood cells and peripheral blood mononuclear cells were visualized in whole blood from patients with sickle cell disease. The aggregation rate was 10-fold higher in these patients than in control subjects. Both mature red blood cells and reticulocytes were involved in these aggregates through their interaction with mononuclear cells, mainly with monocytes. The size of the aggregates was variable, with one mononuclear cell binding to one, two or several red blood cells. Erythroid Lu/basal cell adhesion molecule and α(4)β(1) integrin were involved in aggregate formation. The aggregation rate was lower in patients treated with hydroxycarbamide than in untreated patients.

Conclusions: Our study gives visual evidence of the existence of circulating red blood cell-peripheral blood mononuclear cell aggregates in patients with sickle cell disease and shows that these aggregates are decreased during hydroxycarbamide treatment. Our results strongly suggest that erythroid Lu/basal cell adhesion molecule proteins are implicated in these aggregates through their interaction with α(4)β(1) integrin on peripheral blood mononuclear cells.
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http://dx.doi.org/10.3324/haematol.2010.026294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2966905PMC
November 2010

Role of the interaction between Lu/BCAM and the spectrin-based membrane skeleton in the increased adhesion of hereditary spherocytosis red cells to laminin.

Br J Haematol 2010 Feb;148(3):456-65

Inserm, UMR-S 665, Paris.

Lu/BCAM, the unique erythroid receptor for laminin 511/521, interacts with the erythrocyte membrane skeleton through spectrin binding. It has been reported that Hereditary Spherocytosis red blood cells (HS RBC) exhibit increased adhesion to laminin. We investigated the role of Lu/BCAM-spectrin interaction in the RBC adhesion properties of 2 splenectomised HS patients characterized by 40% spectrin deficiency. Under physiological flow conditions, HS RBC exhibited an exaggerated adhesion to laminin that was completely abolished by soluble Lu/BCAM. Triton extraction experiments revealed that a greater fraction of Lu/BCAM was unlinked to the membrane skeleton of HS RBC, as compared to normal RBC. Disruption of the spectrin interaction site in Lu/BCAM expressed in the transfected K562 cell line resulted in a weakened interaction to the skeleton and an enhanced interaction to laminin. These results demonstrated that the adhesion of HS RBC to laminin was mediated by Lu/BCAM and that its interaction with the spectrin-based skeleton negatively regulated cell adhesion to laminin. Finally, the results of this study strongly suggest that the reinforced adhesiveness of spectrin-deficient HS RBC to laminin is partly brought about by an impaired interaction between Lu/BCAM and the membrane skeleton.
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http://dx.doi.org/10.1111/j.1365-2141.2009.07973.xDOI Listing
February 2010

HIV-1 Nef inhibits ruffles, induces filopodia, and modulates migration of infected lymphocytes.

J Virol 2010 Mar 16;84(5):2282-93. Epub 2009 Dec 16.

Virus and Immunity Unit, Department of Virology, Institut Pasteur, URA CNRS 3015, 28 rue du Dr. Roux, Paris Cedex 15, France.

The HIV-1 Nef protein is a pathogenic factor modulating the behavior of infected cells. Nef induces actin cytoskeleton changes and impairs cell migration toward chemokines. We further characterized the morphology, cytoskeleton dynamics, and motility of HIV-1-infected lymphocytes. By using scanning electron microscopy, confocal immunofluorescence microscopy, and ImageStream technology, which combines flow cytometry and automated imaging, we report that HIV-1 induces a characteristic remodeling of the actin cytoskeleton. In infected lymphocytes, ruffle formation is inhibited, whereas long, thin filopodium-like protrusions are induced. Cells infected with HIV with nef deleted display a normal phenotype, and Nef expression alone, in the absence of other viral proteins, induces morphological changes. We also used an innovative imaging system to immobilize and visualize living individual cells in suspension. When combined with confocal "axial tomography," this technique greatly enhances three-dimensional optical resolution. With this technique, we confirmed the induction of long filopodium-like structures in unfixed Nef-expressing lymphocytes. The cytoskeleton reorganization induced by Nef is associated with an important impairment of cell movements. The adhesion and spreading of infected cells to fibronectin, their spontaneous motility, and their migration toward chemokines (CXCL12, CCL3, and CCL19) were all significantly decreased. Therefore, Nef induces complex effects on the lymphocyte actin cytoskeleton and cellular morphology, which likely impacts the capacity of infected cells to circulate and to encounter and communicate with bystander cells.
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http://dx.doi.org/10.1128/JVI.02230-09DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2820911PMC
March 2010

Electron-multiplying charge-coupled detector-based bioluminescence recording of single-cell Ca2+.

J Biomed Opt 2008 May-Jun;13(3):031211

Plate-forme d'Imagerie Dynamique, Imagopole,Institut Pasteur, Paris, France.

The construction and application of genetically encoded intracellular calcium concentration ([Ca2+]i) indicators has a checkered history. Excitement raised over the creation of new probes is often followed by disappointment when it is found that the initial demonstrations of [Ca2+]i sensing capability cannot be leveraged into real scientific advances. Recombinant apo-aequorin cloned from Aequorea victoria was the first Ca2+ sensitive protein genetically targeted to subcellular compartments. In the jellyfish, bioluminescence resonance energy transfer (BRET) between Ca2+ bound aequorin and green fluorescent protein (GFP) emits green light. Similarly, Ca2+ sensitive bioluminescent reporters undergoing BRET have been constructed between aequorin and GFP, and more recently with other fluorescent protein variants. These hybrid proteins display red-shifted spectrums and have higher light intensities and stability compared to aequorin alone. We report BRET measurement of single-cell [Ca2+]i based on the use of electron-multiplying charge-coupled-detector (EMCCD) imaging camera technology, mounted on either a bioluminescence or conventional microscope. Our results show for the first time how these new technologies make facile long-term monitoring of [Ca2+]i at the single-cell level, obviating the need for expensive, fragile, and sophisticated equipment based on image-photon-detectors (IPD) that were until now the only technical recourse to dynamic BRET experiments of this type.
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http://dx.doi.org/10.1117/1.2937236DOI Listing
September 2008

A Bayesian reconstruction method for micro-rotation imaging in light microscopy.

Microsc Res Tech 2008 Feb;71(2):158-67

Laboratory of Computational Engineering, Helsinki University of Technology, FI-02015 TKK, Finland.

The authors present a three-dimensional (3D) reconstruction algorithm and reconstruction-based deblurring method for light microscopy using a micro-rotation device. In contrast to conventional 3D optical imaging where the focal plane is shifted along the optical axis, micro-rotation imaging employs dielectric fields to rotate the object inside a fixed optical set-up. To address this entirely new 3D-imaging modality, the authors present a reconstruction algorithm based on Bayesian inversion theory and use the total variation function as a structure prior. The spectral properties of the reconstruction by simulations that illustrate the strengths and the weaknesses of the micro-rotation approach, compared with conventional 3D optical imaging, were studied. The reconstruction from real data sets shows that this method is promising for 3D reconstruction and offers itself as a deblurring method using a reconstruction-based procedure for removing out-of-focus light from the micro-rotation image series.
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http://dx.doi.org/10.1002/jemt.20550DOI Listing
February 2008