Recombinant myelin oligodendrocyte glycoprotein quality modifies evolution of experimental autoimmune encephalitis in macaques

The authors describe quantitatively and qualitatively different forms of experimental autoimmune encephalitis (EAE) in cynomolgus macaques. They found that bacterial contaminants within recombinant human myelin oligodendrocyte glycoprotein seemed to aggravate disease evolution. They provide anatomopathological features of fulminant and progressive forms of EAE, allowing them to distinguish specific factors influencing the evolution of this model of autoimmune demyelinating disease. Experimental autoimmune encephalitis (EAE) is a well-recognized model for the study of human acquired demyelinating diseases (ADD), a group of inflammatory disorders of the central nervous system (CNS) characterized by inflammation, myelin loss, and neurological impairment of variable severity. In rodents, EAE is typically induced by active immunization with a combination of myelin-derived antigen and a strong adjuvant as complete Freund's adjuvant (CFA), containing components of the mycobacterial wall, while myelin antigen alone or associated with other bacterial components, as lipopolysaccharides (LPS), often fails to induce EAE. In contrast to this, EAE can be efficiently induced in non-human primates by immunization with the recombinant human myelin oligodendrocyte glycoprotein (rhMOG), produced in Escherichia coli (E. coli), purified and formulated with incomplete Freund's adjuvant (IFA), which lacks bacterial elements. Here, we provide evidence indicating how trace amounts of bacterial contaminants within rhMOG may influence the course and severity of EAE in the cynomolgus macaque immunized with rhMOG/IFA. The residual amount of E. coli contaminants, as detected with mass spectrometry within rhMOG protein stocks, were found to significantly modulate the severity of clinical, radiological, and histologic hallmarks of EAE in macaques. Indeed, animals receiving the purest rhMOG showed milder disease severity, increased numbers of remissions, and reduced brain damage. Histologically, these animals presented a wider diversity of lesion types, including changes in normal-appearing white matter and prephagocytic lesions. Non-human primates EAE model with milder histologic lesions reflect more accurately ADD and permits to study of the pathogenesis of disease initiation and progression

Gearing up for action: attentive tracking dynamically tunes sensory and motor oscillations in the alpha and beta band

Allocation of attention during goal-directed behavior entails simultaneous processing of relevant and attenuation of irrelevant information. How the brain delegates such processes when confronted with dynamic (biological motion) stimuli and harnesses relevant sensory information for sculpting prospective responses remains unclear. We analyzed neuromagnetic signals that were recorded while participants attentively tracked an actor’s pointing movement that ended at the location where subsequently the response-cue indicated the required response. We found the observers’ spatial allocation of attention to be dynamically reflected in lateralized parieto-occipital alpha (8-12Hz) activity and to have a lasting influence on motor preparation. Specifically, beta (16-25Hz) power modulation reflected observers’ tendency to selectively prepare for a spatially compatible response even before knowing the required one. We discuss the observed frequency-specific and temporally evolving neural activity within a framework of integrated visuomotor processing and point towards possible implications about the mechanisms involved in action observation

Preclinical evaluation of PHH-1V vaccine candidate against SARS-CoV-2 in non-human primates

SARS-CoV-2 emerged in December 2019 and quickly spread worldwide, continuously striking with an unpredictable evolution. Despite the success in vaccine production and mass vaccination programs, the situation is not still completely controlled, and therefore accessible second-generation vaccines are required to mitigate the pandemic. We previously developed an adjuvanted vaccine candidate coded PHH-1V, based on a heterodimer fusion protein comprising the RBD domain of two SARS-CoV-2 variants. Here, we report data on the efficacy, safety, and immunogenicity of PHH-1V in cynomolgus macaques. PHH-1V prime-boost vaccination induces high levels of RBD-specific IgG binding and neutralizing antibodies against several SARS-CoV-2 variants, as well as a balanced Th1/Th2 cellular immune response. Remarkably, PHH-1V vaccination prevents SARS-CoV-2 replication in the lower respiratory tract and significantly reduces viral load in the upper respiratory tract after an experimental infection. These results highlight the potential use of the PHH-1V vaccine in humans, currently undergoing Phase III clinical trials.Anna Moya and Mireia Muntada for the ELISA analysis; Clara Panosa and Ester Puigvert for her assistance in the production of the vaccine antigen; Glòria Pujol and Eduard Fossas for their assistance in review of the manuscript; and Adrián Lázaro-Frías from Evidenze Health España S.L. for providing medical writing support during the preparation of this paper funded by Hipra Scientific, S.L.U. This project was partially funded by the Centre for the Development of Industrial Technology (CDTI, IDI20210115), a public organization answering to the Spanish Ministry of Science and Innovation.info:eu-repo/semantics/publishedVersio

Timing in motor cortex : from cue anticipation to movement preparation

Le contexte temporel influence profondément la façon dont nous nous comportons. De manière similaire, il donne forme à l'activité du cortex moteur (LFP et potentiels d'action), pendant la préparation motrice, mais aussi en absence de préparation d'un mouvement.The temporal context deeply shapes the motor cortical activity (spikes and LFPs), during movement preparation but also outside movement preparation

Behavioral/Systems/Cognitive On the Anticipatory Precue Activity in Motor Cortex

International audienceMotor cortical neurons are activated during movement preparation and execution, and in response to task-relevant visual cues. A few studies also report activation before the expected presentation of cues. Here, we study specifically this anticipatory activity preceding visual cues in motor cortical areas. We recorded the activity of 1215 neurons in the motor cortex of two macaque monkeys while they performed a center-out reaching task, including two consecutive delays of equal duration, known in advance. During the first delay (D1), they had to await the spatial cue and only reach to the cued target after the second delay (D2). Forty-two percent of the neurons displayed anticipatory activity during D1. Among these anticipatory neurons, 59% increased (D1up) their activity and the remaining decreased (D1down) their activity. By classifying the neurons according to these firing rate profiles during D1, we found that the activity during D2 differed in a systematic way. The D1up neurons were more likely to discharge phasically soon after the spatial cue and were less active during movement execution, whereas the D1down neurons showed the opposite pattern. But, regardless of their temporal activity profiles, the two categories seemed equally involved in early and late motor preparation, as reflected in their directional selectivity. This precue activity in motor cortex may reflect two complementary, coexisting processes: the facilitation of incoming spatial information in parallel with the downregulation of corticospinal excitability to prevent a premature response

Is there an Intrinsic Relationship between LFP Beta Oscillation Amplitude and Firing Rate of Individual Neurons in Macaque Motor Cortex?

International audienceThe properties of motor cortical local field potential (LFP) beta oscillations have been extensively studied. Their relationship to the local neuronal spiking activity was also addressed. Yet, whether there is an intrinsic relationship between the amplitude of beta oscillations and the firing rate of individual neurons remains controversial. Some studies suggest a mapping of spike rate onto beta amplitude, while others find no systematic relationship. To help resolve this controversy, we quantified in macaque motor cortex the correlation between beta amplitude and neuronal spike count during visuomotor behavior. First, in an analysis termed "task-related correlation", single-trial data obtained across all trial epochs were included. These correlations were significant in up to 32% of cases and often strong. However, a trial-shuff ling control analysis recombining beta amplitudes and spike counts from different trials revealed these task-related correlations to ref lect systematic, yet independent, modulations of the 2 signals with the task. Second, in an analysis termed "trial-by-trial correlation", only data from fixed trial epochs were included, and correlations were calculated across trials. Trial-by-trial correlations were weak and rarely significant. We conclude that there is no intrinsic relationship between the firing rate of individual neurons and LFP beta oscillation amplitude in macaque motor cortex

Population statistics uncovers baseline correlation in the cerebral cortex

Unitary Event (UE) analysis [1,2] is a statistical method that enables to analyze in a time resolved manner excess spike correlation between simultaneously recorded neurons by comparing the empirical spike coincidences (precision of a few ms) to the expected number based on the firing rates of the neurons. UEs are identified as spike synchrony events that significantly exceed the expected level measured by the surprise. Using this method we were able to identify interactive processes in the cortical network by the occurrence of significant excess spike synchrony. The surprise typically modulates in time in relation to behavior [3], which is interpreted as a modulation of functional correlation. In order to test if the occurences of UEs are systematic across data sets and across neuronal sampling, we derived a meta statistics for the significance estimation by comparing the cumulative empirical coincidence counts and the cumulative expected coincidence counts across trials and neuron pairs. As a result we found systematic occurrence of UEs as a function of behavioral practice [4].However, we also observed two additional aspects: 1) the resulting surprise measure exhibits a slight constant positive offset, and 2) the modulation depth of the surprise is the larger the more data (neuron pairs) are included in the analysis. These effects led us to the question if they are features of network processes, or if they are the result of false positives due to a not yet identified flaw in the UE analysis. The latter explanation was excluded by testing the UE analysis with synthetic data: the analysis of an increasing number of independent data sets does not lead to false discoveries. The increase of the surprise with increasing pairs of correlated data, however, is a clear indication of more evidence: the more pairs are considered, the larger the surprise, which is a correct and desired property of the UE analysis. Interestingly, the fraction of empirical coincidences to the expected coincidences is not dependent on the number of pairs, but still modulates in time coherently with the surprise in relation to behavior. A possible explanation for the positive offset came from network theory [5], where small spike correlations between pairs of neurons were shown to be present in random balanced networks of biologically realistic connectivity. They are interpreted as baseline correlations (BC) since they occur independent of functional correlations in the network. Our current work focuses on estimating the degree of BC from experimental data in order to include it in the null-hypothesis of the UE analysis to reliably estimate the degree of functional correlation independent from baseline correlation. References[1] Grün, Diesmann, Grammont, Riehle, Aertsen (1999) J Neurosci Methods, 94(1): 67-79.[2] Grün, Diesmann, Aertsen (2002a,b) Neural Comput, 14(1): 43-80; 81-19 .[3] Riehle, Grün, Diesmann, Aertsen (1997) Science 278: 1950-1953.[4] Kilavik, Roux, Ponce-Alvarez, Confais, Grün, Riehle (2009) J Neurosci, 29(40): 12653-12663

Context-Related Frequency Modulations of Macaque Motor Cortical LFP Beta Oscillations

International audienceThe local field potential (LFP) is a population measure, mainly reflecting local synaptic activity. Beta oscillations (12-40 Hz) occur in motor cortical LFPs, but their functional relevance remains controversial. Power modulation studies have related beta oscillations to a ''resting'' motor cortex, postural maintenance, attention, sensorimotor binding and planning. Frequency modulations were largely overlooked. We here describe context-related beta frequency modulations in motor cortical LFPs. Two monkeys performed a reaching task with 2 delays. The first delay demanded attention in time in expectation of the visual spatial cue, whereas the second delay involved visuomotor integration and movement preparation. The frequency in 2 beta bands (around 20 and 30 Hz) was systematically 2-5 Hz lower during cue expectancy than during visuomotor integration and preparation. Furthermore, the frequency was directionally selective during preparation, with about 3 Hz difference between preferred and nonpreferred directions. Direction decoding with frequency gave similar accuracy as with beta power, and decoding accuracy improved significantly when combining power and frequency, suggesting that frequency might provide an additional signal for brain-machine interfaces. In conclusion, multiple beta bands coexist in motor cortex, and frequency modulations within each band are as behaviorally meaningful as power modulations, reflecting the changing behavioral context and the movement direction during preparation