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Abstract Glucocorticoid (GC) resistance in childhood relapsed B-cell acute lymphoblastic leukemia (B-ALL) represents an important challenge. Despite decades of clinical use, the mechanisms underlying resistance remain poorly understood. Here, we report that in B-ALL, GC paradoxically induce their own resistance by activating a phospholipase C (PLC)-mediated cell survival pathway through the chemokine receptor, CXCR4. We identify PLC as aberrantly activated in GC-resistant B-ALL and its inhibition is able to induce cell death by compromising several transcriptional programs. Mechanistically, dexamethasone (Dex) provokes CXCR4 signaling, resulting in the activation of PLC-dependent Ca2+ and protein kinase C signaling pathways, which curtail anticancer activity. Treatment with a CXCR4 antagonist or a PLC inhibitor improves survival of Dex-treated NSG mice in vivo. CXCR4/PLC axis inhibition significantly reverses Dex resistance in B-ALL cell lines (in vitro and in vivo) and cells from Dex resistant ALL patients. Our study identifies how activation of the PLC signalosome in B-ALL by Dex limits the upfront efficacy of this chemotherapeutic agent.

Abstract While de novo variants (DNV) are overall at low risk of recurrence in subsequent pregnancies, a subset is at high risk due to parental mosaicism. Accurately identifying cases of parental mosaicism is therefore important for genetic counseling in clinical care. Some studies have investigated the rate of parental mosaics, but most were either limited by the sensitivity of the techniques (i.e. exome or genome sequencing), or focused on specific types of disease such as epileptic syndromes. This study aimed to determine the proportion of parental mosaicism among the DNV causing neurodevelopmental disorders (NDDs) in a series not enriched in epilepsy syndromes. We collected 189 patients with NDD-associated DNV. We applied a smMIP enrichment method and sequenced parental blood DNA samples to an average depth of 7000x. Power simulation indicated that mosaicism with an allelic fraction of 0.5% would have been detected for 87% of positions with 90% power. We observed seven parental mosaic variants (3.7% of families), of which four (2.1% of families) had an allelic fraction of less than 1%. In total, our study identifies a relatively low proportion of parental mosaicism in NDD-associated DNVs and raises the question of a biological mechanism behind the higher rates of parental mosaicism detected in other studies, particularly those focusing on epileptic syndromes.

Fabry disease (FD) is an X-linked lysosomal disease caused by an enzyme deficiency of alpha-galactosidase A (α-gal A). This deficiency leads to the accumulation of glycosphingolipids in lysosomes, resulting in a range of clinical symptoms. The complex pathogenesis of FD involves lysosomal dysfunction, altered autophagy, and mitochondrial abnormalities. Omics sciences, particularly transcriptomic analysis, comprehensively understand molecular mechanisms underlying diseases. This study focuses on genome-wide expression analysis in an FD human podocyte model to gain insights into the underlying mechanisms of podocyte dysfunction. Human control and GLA-edited podocytes were used. Gene expression data was generated using RNA-seq analysis, and differentially expressed genes were identified using DESeq2. Principal component analysis and Spearman correlation have explored gene expression trends. Functional enrichment and Reporter metabolite analyses were conducted to identify significantly affected metabolites and metabolic pathways. Differential expression analysis revealed 247 genes with altered expression levels in GLA-edited podocytes compared to control podocytes. Among these genes, 136 were underexpressed, and 111 were overexpressed in GLA-edited cells. Functional analysis of differentially expressed genes showed their involvement in various pathways related to oxidative stress, inflammation, fatty acid metabolism, collagen and extracellular matrix homeostasis, kidney injury, apoptosis, autophagy, and cellular stress response. The study provides insights into molecular mechanisms underlying Fabry podocyte dysfunction. Integrating transcriptomics data with genome-scale metabolic modeling further unveiled metabolic alterations in GLA-edited podocytes. This comprehensive approach contributes to a better understanding of Fabry disease and may lead to identifying new biomarkers and therapeutic targets for this rare lysosomal disorder.

Cryogenic magnetoencephalography (MEG) enhances the presurgical assessment of refractory focal epilepsy (RFE). Optically pumped magnetometers (OPMs) are cryogen-free sensors that enable on-scalp MEG recordings. Here, we investigate the application of tri-axial OPMs [87Rb (Rb-OPM) and 4He gas (He-OPM)] for the detection of interictal epileptiform discharges (IEDs). IEDs were recorded simultaneously with 4 tri-axial Rb- and 4 tri-axial He-OPMs in a child with RFE. IEDs were identified visually, isolated from magnetic background noise using independent component analysis (ICA) and were studied following their optimal magnetic field orientation thanks to virtual sensors. Most IEDs (>1,000) were detectable by both He- and Rb-OPM recordings. IEDs were isolated by ICA and the resulting magnetic field oriented mostly tangential to the scalp in Rb-OPMs and radial in He-OPMs. Likely due to differences in sensor locations, the IED amplitude was higher with Rb-OPMs. This case study shows comparable ability of Rb-OPMs and He-OPMs to detect IEDs and the substantial benefits of triaxial OPMs to detect IEDs from different sensor locations. Tri-axial OPMs allow to maximize spatial brain sampling for IEDs detection with a limited number of sensors.

Although alcohol consumption during pregnancy is a major cause of behavioral and learning disabilities, most FASD infants are late- or even misdiagnosed due to clinician’s difficulties achieving early detection of alcohol-induced neurodevelopmental impairments. Neuroplacentology has emerged as a new field of research focusing on the role of the placenta in fetal brain development. Several studies have reported that prenatal alcohol exposure (PAE) dysregulates a functional placenta–cortex axis, which is involved in the control of angiogenesis and leads to neurovascular-related defects. However, these studies were focused on PlGF, a pro-angiogenic factor. The aim of the present study is to provide the first transcriptomic “placenta–cortex” signature of the effects of PAE on fetal angiogenesis. Whole mouse genome microarrays of paired placentas and cortices were performed to establish the transcriptomic inter-organ “placenta–cortex” signature in control and PAE groups at gestational day 20. Genespring comparison of the control and PAE signatures revealed that 895 and 1501 genes were only detected in one of two placenta–cortex expression profiles, respectively. Gene ontology analysis indicated that 107 of these genes were associated with vascular development, and String protein–protein interaction analysis showed that they were associated with three functional clusters. PANTHER functional classification analysis indicated that “intercellular communication” was a significantly enriched biological process, and 27 genes were encoded for neuroactive ligand/receptors interactors. Protein validation experiments involving Western blot for one ligand–receptor couple (Agt/AGTR1/2) confirmed the transcriptomic data, and Pearson statistical analysis of paired placentas and fetal cortices revealed a negative correlation between placental Atg and cortical AGTR1, which was significantly impacted by PAE. In humans, a comparison of a 38WG control placenta with a 36WG alcohol-exposed placenta revealed low Agt immunolabeling in the syncytiotrophoblast layer of the alcohol case. In conclusion, this study establishes the first transcriptomic placenta–cortex signature of a developing mouse. The data show that PAE markedly unbalances this inter-organ signature; in particular, several ligands and/or receptors involved in the control of angiogenesis. These data support that PAE modifies the existing communication between the two organs and opens new research avenues regarding the impact of placental dysfunction on the neurovascular development of fetuses. Such a signature would present a clinical value for early diagnosis of brain defects in FASD.

Abstract Background Branch points (BPs) map within short motifs upstream of acceptor splice sites (3’ss) and are essential for splicing of pre-mature mRNA. Several BP-dedicated bioinformatics tools, including HSF, SVM-BPfinder, BPP, Branchpointer, LaBranchoR and RNABPS were developed during the last decade. Here, we evaluated their capability to detect the position of BPs, and also to predict the impact on splicing of variants occurring upstream of 3’ss. Results We used a large set of constitutive and alternative human 3’ss collected from Ensembl (n = 264,787 3’ss) and from in-house RNAseq experiments (n = 51,986 3’ss). We also gathered an unprecedented collection of functional splicing data for 120 variants (62 unpublished) occurring in BP areas of disease-causing genes. Branchpointer showed the best performance to detect the relevant BPs upstream of constitutive and alternative 3’ss (99.48 and 65.84% accuracies, respectively). For variants occurring in a BP area, BPP emerged as having the best performance to predict effects on mRNA splicing, with an accuracy of 89.17%. Conclusions Our investigations revealed that Branchpointer was optimal to detect BPs upstream of 3’ss, and that BPP was most relevant to predict splicing alteration due to variants in the BP area.

Lung damage in cystic fibrosis (CF) is strongly associated with lower airway infections. Early treatment of Pseudomonas aeruginosa is recommended. Pathogen detection requires sampling of lower airway secretions, which remains a challenge in nonexpectorating patients. Our hypothesis was that chest physiotherapy would improve the quality of airway secretion samples and increase the rates of pathogens detected in nonexpectorating patients. This prospective multicentre study compared three successive methods for sampling airway secretions applied through the same session: 1) an oropharyngeal swab (OP), 2) a chest physiotherapy session followed by a provoked cough to obtain sputum (CP-SP) and 3) a second oropharyngeal swab collected after chest physiotherapy (CP-OP). Haemophilus influenzae, Staphylococcus aureus and P. aeruginosa growth cultures were assessed. Accuracy tests and an equivalence test were performed to compare the three successive methods of collection. 300 nonexpectorating children with CF were included. P. aeruginosa was detected cumulatively in 56 (18.9%) children, and according to the different collection methods in 28 (9.8%), 37 (12.4%) and 44 (14.7%) children by using OP, CP-OP and CP-SP, respectively. Compared with OP, the increased detection rate was +22% for CP-OP (p=0.029) and +57% for CP-SP (p=0.003). CP-SP had the best positive predictive value (86.3%) and negative predictive value (96.0%) for P. aeruginosa compared with the overall detection. The results of this adequately powered study show differences in the rates of pathogens detected according to the sampling method used. Chest physiotherapy enhanced detection of P. aeruginosa in nonexpectorating children with CF.

Human brain lesions in the perinatal period result in life-long neuro-disabilities impairing sensory-motor, cognitive, and behavior functions for years. Topographical aspects of brain lesions depend on gestational age at the time of insult in preterm or term infants and impaired subsequent steps of brain development and maturation. In mice, the Rice-Vannucci procedure of neonate hypoxia-ischemia (HI) was used at 5 days (P5) or P10, mimicking the development of 30 week-gestation fetus/preterm newborn, or full-term infant, respectively. Transcription response to HI was assessed at 3, 6, 12, and 24 h after insult, using micro-array technology. Statistical Pathway and Gene Ontology terms enrichments were investigated using DAVID®, Revigo® and Ingenuity Pathway Analysis (IPA®) to identify a core of transcription response to HI, age-specific regulations, and interactions with spontaneous development. Investigations were based on direction, amplitude, and duration of responses, basal expression, and annotation. Five major points deserve attention; (i) inductions exceeded repressions (60/40%) at both ages, (ii) only 20.3% (393/1938 records) were common to P5 and P10 mice, (iii) at P5, HI effects occurred early and decreased 24 h after insult whereas they were delayed at P10 and increased 24 h after insult, (iv) common responses at P5 and P10 involved inflammation, immunity, apoptosis, and angiogenesis. (v) age-specific effects occurred with higher statistical significance at P5 than at P10. Transient repression of 12 genes encoding cholesterol biosynthesis enzymes was transiently observed 12 h after HI at P5. Synaptogenesis appeared inhibited at P5 while induced at P10, showing reciprocal effects on glutamate receptors. Specific involvement of Il-1 (interleukin-1) implicated in the firing of inflammation was observed at P10. This study pointed out age-differences in HI responses kinetics, e.g., a long-lasting inflammatory response at P10 compared to P5. Whether the specific strong depression of cholesterol biosynthesis genes that could account for white matter-specific vulnerability at P5 or prevent delayed inflammation needs further investigation. Determination of putative involvement of Il-1 and the identification of upstream regulators involved in the delayed inflammation firing at P10 appears promising routes of research in the understandings of age-dependent vulnerabilities in the neonatal brain.

Optically pumped magnetometers (OPMs) are new, room-temperature alternatives to superconducting quantum interference devices (SQUIDs) for measuring the brain’s magnetic fields. The most used OPM in MagnetoEncephaloGraphy (MEG) are based on alkali atoms operating in the spin-exchange relaxation-free (SERF) regime. These sensors do not require cooling but have to be heated. Another kind of OPM, based on the parametric resonance of 4He atoms are operated at room temperature, suppressing the heat dissipation issue. They also have an advantageous bandwidth and dynamic range more suitable for MEG recordings. We quantitatively assessed the improvement (relative to a SQUID magnetometers array) in recording the magnetic field with a wearable 4He OPM-MEG system through data simulations. The OPM array and magnetoencephalography forward models were based on anatomical MRI data from an adult, a nine-year-old child, and 10 infants aged between one month and two years. Our simulations showed that a 4He OPMs array offers markedly better spatial specificity than a SQUID magnetometers array in various key performance areas (e.g., signal power, information content, and spatial resolution). Our results are also discussed regarding previous simulation results obtained for alkali OPM.

CD11c+ B cells have been reported to be increased in autoimmune diseases, but they are detected in the blood of healthy individuals as well. We aimed to characterize CD11c+ B cells from healthy donors by flow cytometry, microarray analysis, and in vitro functional assays. Here, we report that CD11c+ B cells are a distinct subpopulation of B cells, enriched in the memory subpopulation even if their phenotype is heterogeneous, with overexpression of genes involved in B-cell activation and differentiation as well as in antigen presentation. Upon activation, CD11c+ B cells can differentiate into antibody-secreting cells, and CD11c could be upregulated in CD11c− B cells by B-cell receptor activation. Finally, we show that patients with pemphigus, an autoimmune disease mediated by B cells, have a decreased frequency of CD11c+ B cell after treatment, relative to baseline. Our findings show that CD11c+ B cells are mainly memory B cells prone to differentiate into antibody secreting cells that accumulate with age, independently of gender.

ObjectivesAbatacept acts as a competitive inhibitor of the CD28/(CD80/86) costimulation signal required for T cell activation. Mechanisms of action of abatacept have not been fully investigated. The objective of this study was to provide detailed insight into the mode of action of Abatacept based on gene expression data.MethodsIn this ancillary study from the APPRAISE trial, we investigated the global molecular effects of Abatacept in whole blood samples collected prospectively in biologic naive rheumatoid arthritis patients (n = 19) at baseline and 6 months after the initiation of Abatacept therapy concomitant with methotrexate. Whole human genome microarrays (4x44K) were performed on both baseline and 6-month samples from responders and non-responders patients categorized according to EULAR criteria. T-test with Benjamini-Hochberg correction was performed to identify significant gene expression changes. Gene Ontology and Single Experiment Analysis tools allowed us to highlight specific biological mechanisms involved in methotrexate/Abatacept.ResultsIn methotrexate/Abatacept responders, 672 genes were significantly (q

Abstract Background In the current context of personalized medicine, one of the major challenges in the management of rheumatoid arthritis (RA) is to identify biomarkers that predict drug responsiveness. From the European APPRAISE trial, our main objective was to identify a gene expression profile associated with responsiveness to abatacept (ABA) + methotrexate (MTX) and to understand the involvement of this signature in the pathophysiology of RA. Methods Whole human genome microarrays (4 × 44 K) were performed from a first subset of 36 patients with RA. Data validation by quantitative reverse-transcription (qRT)-PCR was performed from a second independent subset of 32 patients with RA. Gene Ontology and WikiPathways database allowed us to highlight the specific biological mechanisms involved in predicting response to ABA/MTX. Results From the first subset of 36 patients with RA, a combination including 87 transcripts allowed almost perfect separation between responders and non-responders to ABA/MTX. Next, the second subset of patients 32 with RA allowed validation by qRT-PCR of a minimal signature with only four genes. This latter signature categorized 81% of patients with RA with 75% sensitivity, 85% specificity and 85% negative predictive value. This combination showed a significant enrichment of genes involved in electron transport chain (ETC) pathways. Seven transcripts from ETC pathways (NDUFA6, NDUFA4, UQCRQ, ATP5J, COX7A2, COX7B, COX6A1) were significantly downregulated in responders versus non-responders to ABA/MTX. Moreover, dysregulation of these genes was independent of inflammation and was specific to ABA response. Conclusion Pre-silencing of ETC genes is associated with future response to ABA/MTX and might be a crucial key to susceptibility to ABA response.

Cognitive deficits in Parkinson's disease are thought to be related to altered functional brain connectivity. To date, cognitive-related changes in Parkinson's disease have never been explored with dense-EEG with the aim of establishing a relationship between the degree of cognitive impairment, on the one hand, and alterations in the functional connectivity of brain networks, on the other hand. This study was aimed at identifying altered brain networks associated with cognitive phenotypes in Parkinson's disease using dense-EEG data recorded during rest with eyes closed. Three groups of Parkinson's disease patients (N = 124) with different cognitive phenotypes coming from a data-driven cluster analysis, were studied: G1) cognitively intact patients (63), G2) patients with mild cognitive deficits (46) and G3) patients with severe cognitive deficits (15). Functional brain networks were identified using a dense-EEG source connectivity method. Pairwise functional connectivity was computed for 68 brain regions in different EEG frequency bands. Network statistics were assessed at both global (network topology) and local (inter-regional connections) level. Results revealed progressive disruptions in functional connectivity between the three patient groups, typically in the alpha band. Differences between G1 and G2 (p

Pemphigus Vulgaris is an autoimmune disease of the skin and mucous membranes, which is due to the production of pathogenic autoantibodies targeting desmoglein (DSG) 1 and 3, which are adhesion proteins of the keratinocytes. Rituximab is an anti-CD20 mAb which induces a prolonged depletion of blood B cells. We recently showed that rituximab was more effective than a standard oral corticosteroid (CS) treatment, allowing 90% of patients to achieve complete remission (CR). Additionally, we showed that DSG-specific-B (DSG positive) cells were still detectable during the B cell recovery which follows the initial rituximab-induced B cell depletion, even in patients in CR. In order to characterize DSG positive B cells in patients in CR after rituximab or CS treatment relative to those detectable at baseline in patients with an active pemphigus, we studied the expression profile of 31 genes of interest related to inflammatory cytokines, TNF receptors and activation markers. Using quantitative Polymerase Chain Reaction performed on one cell with a microfluidic technique, we found that patients' autoreactive B cells collected at baseline had a significantly higher expression of genes encoding for IL-1β, IL-23p19, and IL-12p35 pro-inflammatory cytokines and the IRF5 transcription factor, than non-autoreactive B cells. Surprisingly, the gene expression profile of DSG positive B cells collected after rituximab treatment in patients in CR was close to that of DSG positive B cells at baseline in patients with active pemphigus, except for the IL-1β and the CD27 memory marker genes, which were under-expressed after rituximab compared to baseline. Conversely, we observed a decreased expression of genes encoding for IL-1β and IL-23p19 in patients treated with CS relative to baseline. This study showed that: (i) DSG positive autoreactive B cells have a different gene expression profile than non-autoreactive B cells; (ii) rituximab and CS have different effects on the genes' expression in autoreactive DSG positive B cells from pemphigus patients.

MgSO4 is widely used in the prevention of preterm neurological disabilities but its modes of action remain poorly established. We used a co-hybridization approach using the transcriptome in 5-day old mice treated with a single dose of MgSO4 (600 mg/kg), and/or exposed to hypoxia-ischemia (HI). The transcription of hundreds of genes was altered in all the groups. MgSO4 mainly produced repressions culminating 6 h after injection. Bio-statistical analysis revealed the repression of synaptogenesis and axonal development. The putative targets of MgSO4 were Mnk1 and Frm1. A behavioral study of adults did not detect lasting effects of neonatal MgSO4 and precluded NMDA-receptor-mediated side effects. The effects of MgSO4 plus HI exceeded the sum of the effects of separate treatments. MgSO4 prior to HI reduced inflammation and the innate immune response probably as a result of cytokine inhibition (Ccl2, Ifng, interleukins). Conversely, MgSO4 had little effect on HI-induced transcription by RNA-polymerase II. De novo MgSO4-HI affected mitochondrial function through the repression of genes of oxidative phosphorylation and many NAD-dehydrogenases. It also likely reduced protein translation by the repression of many ribosomal proteins, essentially located in synapses. All these effects appeared under the putative regulatory MgSO4 induction of the mTORC2 Rictor coding gene. Lasting effects through Sirt1 and Frm1 could account for this epigenetic footprint.

exDNA is found in various organisms, including plants. However, plant exDNA has thus far received little attention related to its origin and role in the RET (root extracellular trap). In this study, we performed the first high-throughput genomic sequencing of plant exDNA from a Fabaceae with worldwide interest: soybean (Glycine max (L.) Merr.). The origin of this exDNA was first investigated in control condition, and the results show high-coverage on organelles (mitochondria/plastid) DNA relative to nuclear DNA, as well as a mix of coding and non-coding sequences. In the second part of this study, we investigated if exDNA release was modified during an elicitation with PEP-13 (a peptide elicitor from oomycete genus Phytophthora). Our results show that treatment of roots with PEP-13 does not affect the composition of exDNA.

• Good agreement between patients and proxies on psychiatric comorbidities. • Also good agreement when evaluating sleep disorders and treatment adherence. • Agreement was especially good for respondents living with the patient. • In case of SUDEP, level of agreement allows to gather reliable information. The study aimed to determine the level of agreement between patients with epilepsy and their proxies when assessing psychiatric comorbidities, sleep disorders, and medication adherence using standardized questionnaires. This agreement study is an ancillary analysis of the PRERIES study, a matched case-control study exploring SUDEP risk factors. Controls aged 15 years and older, with active epilepsy or in remission for less than 5 years were recruited between 01/01/2011 and 03/31/2019. An interview was carried out by a trained psychologist on both the patient and a proxy-respondent. During these independent interviews, the following comorbidities were explored: psychiatric comorbidities using the MINI, the STAI- Y 2 and NDDI-E scales, sleep disorders with the SDQ-SA and Epworth scales and medication adherence. Level of agreement between patient and their proxy was estimated using Gwet's AC1&2. Among the 107 patient–proxy dyads recruited, proxy respondents were mainly family members (65.4%) or spouses (30.8%). Exploration of present major depression showed excellent agreement at 0.81 [0.65;0.97], as well as exploration of dysthymia at 0.96 [0.61;1]. Suicidal risk evaluation had a lesser agreement at 0.77 [0.60;0.94]. Agreement on anxiety was moderate 0.5 [0.38;0.62]. For sleep disorder, SDQ-SA presented a better agreement than the Epworth questionnaire with respectively 0.73 [0.51;0.95] and 0.45 [0.26;0.63]. For medication adherence, the overall agreement rate was excellent (0.90 [0.78;1]). Exploration of potential risk factors through families can give valuable and relatively robust information, especially if the respondent lives with the patient, and should be retrieved, when possible, in usual clinical setting. [ABSTRACT FROM AUTHOR]

Infants born before 29 weeks gestation incur a major risk of preterm encephalopathy and subependymal/intracerebral/intraventricular haemorrhage. In mice, an ontogenic window of haemorrhage risk was recorded up to 5 days after birth in serpine1 knock-out animals. Using proteome and transcriptome approaches in mouse forebrain microvessels, we previously described the remodelling of extracellular matrix and integrins likely strengthening the vascular wall between postnatal day 5 (P5) and P10. Haemorrhage is the ultimate outcome of vessel damage (i.e., during ischaemia), although discreet vessel insults may be involved in the aetiology of preterm encephalopathy. In this study, we examined proteins identified by mass spectrometry and segregating in gene ontology pathways in forebrain microvessels in P5, P10, and adult wild type mice. In parallel, comparative transcript levels were obtained using RNA hybridization microarrays and enriched biological pathways were extracted from genes exhibiting at least a two-fold change in expression. Five major biological functions were observed in those genes detected both as proteins and mRNA expression undergoing at least a two-fold change in expression in one or more age comparisons: energy metabolism, protein metabolism, antioxidant function, ion exchanges, and transport. Adult microvessels exhibited the highest protein and mRNA expression levels for a majority of genes. Energy metabolism-enriched gene ontology pathways pointed to the preferential occurrence of glycolysis in P5 microvessels cells versus P10 and adult preparations enriched in aerobic oxidative enzymes. Age-dependent levels of RNA coding transport proteins at the plasma membrane and mitochondria strengthened our findings based on protein data. The data suggest that immature microvessels have fewer energy supply alternatives to glycolysis than mature structures. In the context of high energy demand, this constraint might account for vascular damage and maintenance of the high bleeding occurrence in specific areas in immature brain.

In Parkinson's disease, impaired motor preparation has been related to an increased latency in the appearance of movement-related desynchronization (MRD) throughout the contralateral primary sensorimotor (PSM) cortex. Internal globus pallidus (GPi) stimulation improved movement desynchronization over the PSM cortex during movement execution but failed to improve impaired motor preparation. PET studies indicate that subthalamic nucleus (STN) stimulation partly reverses the abnormal premotor pattern of brain activation during movement. By monitoring MRD, we aimed to assess changes in premotor and PSM cortex oscillatory activity induced by bilateral STN stimulation and to compare these changes with those induced by L-dopa. Ten Parkinson's disease patients and a group of healthy, age-matched controls performed self-paced wrist flexions in each of four conditions: without either stimulation or L-dopa (the "off" condition), with stimulation and without L-dopa (On Stim), with L-dopa and without stimulation ("on drug"), and with both stimulation and L-dopa (On Both). Compared with the Off condition, in both the On Stim and the On Drug condition the Unified Parkinson's Disease Rating Scale (UPDRS) III score decreased by about 60% and in the On Both condition it decreased by 80%. The desynchronization latency over central regions contralateral to movement and the movement desynchronization over bilateral central regions were significantly increased by stimulation and by L-dopa, with a maximal effect when the two were associated. Furthermore, desynchronization latency significantly decreased over bilateral frontocentral regions in the three treatment conditions compared with the Off condition. In Parkinson's disease, STN stimulation may induce a change in abnormal cortical oscillatory activity patterns (similar to that produced by L-dopa) by decreasing the abnormal spreading of desynchronization over frontocentral regions and increasing PSM cortex activity during movement preparation and execution, with a correlated improvement in bradykinesia. Parkinsonians under treatment displayed a desynchronization pattern close to that seen in healthy, age-matched controls, although central latencies remained shorter. The study indicates that it is possible to influence cortical reactivity related to the planning and execution of voluntary movement through the basal ganglia, and furthermore that the oscillatory activity of the PSM cortex (in addition to that of premotor areas) could be of major importance in the control of movement-associated, neural activity in Parkinson's disease.

Objective: Prepulse inhibition (PPI) is an operational measure of sensory gating. PPI of cortical response to a startling pulse is known to be modulated by attention. With a time-frequency analysis, we sought to determine whether goal-directed and stimulus-driven attention differentially modulate inhibition of cortical oscillations elicited by a startling pulse. Methods: An electroencephalogram was recorded in 26 healthy controls performing an active acoustic PPI paradigm. Startling stimuli were presented alone or either 400 or 1000 ms after one of three types of visual prepulse: to-be-attended (goal-directed attention), unexpected (stimulus-driven attention) or to-be-ignored (non-focused attention). We calculated the percentage PPI for the auditory event-related spectral perturbation (ERSP) of theta (4-7 Hz), alpha (8-12 Hz), beta1 (13-20 Hz) and beta2 (20-30 Hz) oscillations and changes in inter-trial coherence (ITC), a measure of phase synchronization of electroencephalographic activity.Results: At 400 ms, (i) PPI of the ERSP of alpha, theta and beta1 oscillation was greater after an unexpected and a to-be-attended prepulse than after a to-be-ignored prepulse, and (ii) PPI of beta2 oscillations was greater after a to-be-attended than a to-be-ignored prepulse. At 1000 ms, (i) PPI of alpha oscillations was greater after an unexpected and a to-be-attended prepulse than after a to-be-ignored prepulse, and (ii) PPI of beta1 oscillations was greater after a to-be-attended than a to-be-ignored prepulse. The ITC values did not vary according to the type of prepulse.Conclusions: In an active PPI paradigm, stimulus-driven and goal-directed attention each have differential effects on the modulation of cortical oscillations.

The selection of task-relevant information requires both the focalization of attention on the task and resistance to interference from irrelevant stimuli. A previous study using the P3 component of the event-related potentials suggested that a reduced ability to resist interference could be responsible for attention disorders at early stages of Parkinson's disease (PD), with a possible role of the dorsolateral prefrontal cortex (DLPFC).Our objective was to better determine the origin of this impairment, by studying an earlier ERP component, the N2, and its subcomponents, as they reflect early inhibition processes and as they are known to have sources in the anterior cingulate cortex (ACC), which is involved together with the DLPFC in inhibition processes. Fifteen early-stage PD patients and 15 healthy controls (HCs) performed a three-stimulus visual oddball paradigm, consisting in detecting target inputs amongst standard stimuli, while resisting interference from distracter ones. A 128-channel electroencephalogram was recorded during this task and the generators of the N2 subcomponents were identified using standardized weighted low-resolution electromagnetic tomography (swLORETA).PD patients displayed fewer N2 generators than HCs in both the DLPFC and the ACC, for all types of stimuli. In contrast to controls, PD patients did not show any differences between their generators for different N2 subcomponents.Our data suggest that impaired inhibition in PD results from dysfunction of the DLPFC and the ACC during the early stages of attentional processes.

To evaluate the ability of the glycolytic enzyme alpha-enolase (ENO1) or its immunodominant peptide (pEP1) to reduce the severity of CIA in DBA/1 mice when injected in a prophylactic way.Mice were treated with mouse ENO1 or pEP1 one day prior to collagen II immunization. Clinical assessment was evaluated using 4 parameters (global and articular scores, ankle thickness and weight). Titers of serum anti-ENO1, anti-cyclic citrullinated peptides (anti-CCP) and anti-CII (total IgG and IgG1/IgG2a isotypes) antibodies were measured by ELISA at different time-points. Disease activity was assessed by histological analysis of both anterior and hind paws at the end of experimentation.Prophylactic injection of 100 μg of ENO1 reduced severity of CIA. Serum levels of anti-CII antibodies were reduced in ENO1-treated mice. Concordantly, ENO1-treated mice joints presented less severe histological signs of arthritis. ENO1 did not induce a shift toward a Th2 response since IgG1/IgG2a ratio of anti-CII antibodies remained unchanged and IL-4 serum levels were similar to those measured in the control group.Pre-immunization with ENO1 or its immunodominant peptide pEP1 reduces CIA severity at the clinical, immunological and histological levels. Effects of pEP1 were less pronounced. This immunomodulatory effect is associated with a reduction in anti-CII antibodies production but is not due to a Th1/Th2 shift.