Effects of Anesthetic Agents on Brain Blood Oxygenation Level Revealed with Ultra-High Field MRI

During general anesthesia it is crucial to control systemic hemodynamics and oxygenation levels. However, anesthetic agents can affect cerebral hemodynamics and metabolism in a drug-dependent manner, while systemic hemodynamics is stable. Brain-wide monitoring of this effect remains highly challenging. Because T2*-weighted imaging at ultra-high magnetic field strengths benefits from a dramatic increase in contrast to noise ratio, we hypothesized that it could monitor anesthesia effects on brain blood oxygenation. We scanned rat brains at 7T and 17.2T under general anesthesia using different anesthetics (isoflurane, ketamine-xylazine, medetomidine). We showed that the brain/vessels contrast in T2*-weighted images at 17.2T varied directly according to the applied pharmacological anesthetic agent, a phenomenon that was visible, but to a much smaller extent at 7T. This variation is in agreement with the mechanism of action of these agents. These data demonstrate that preclinical ultra-high field MRI can monitor the effects of a given drug on brain blood oxygenation level in the absence of systemic blood oxygenation changes and of any neural stimulation

Production de dopamine dans le striatum par transfert lentiviral des gènes de la TH, AADC et CH1 (étude dans des modèles primates de la maladie de Parkinson)

La déplétion dopaminergique du striatum entraîne une akinésie et une difficulté à initier les programmes moteurs qui caractérisent la maladie de Parkinson. Cependant, le traitement dopaminergique oral discontinu et chronique induit des fluctuations motrices et des mouvements anormaux involontaires appelés dyskinésies. Ici nous rapportons que le transfert lentiviral des gènes codant pour la biosynthèse de la dopamine (TH, AADC, CH1) aux cellules du striatum a induit une modification du fonctionnement cellulaire avec une sécrétion locale de dopamine, une restauration importante du comportement moteur, une prévention complète des complications motrices induites par le traitement dopaminergique systémique, une résistance à l induction des complications motrices après administration de médicaments dopaminergiques dans des modèles primates de la maladie de Parkinson avancée. La production locale et continue de dopamine par transfert lentiviral de gènes a permis également de restaurer la circuiterie des ganglions de la base en normalisant l activité neuronale électrique dans le globus pallidus interne ainsi que le métabolisme du noyau subthalamique. Nos résultats démontrent que la thérapie génique de la dopamine a un potentiel pour restaurer la fonction dopaminergique perdue au cours de la maladie de Parkinson.Reduced dopamine innervation of the striatum in Parkinson s disease results in akinesia and difficulty in initiating different motor programs. Conversely, enhanced striatal dopamine activity after months of pulsatile dopaminergic treatment will instead give rise to motor fluctuations and abnormal involuntary movements called dyskinesias. A concept postulates that a continuous delivery of a dopaminergic molecule will prevent motor complications by restoring dopaminergic tonus in the striatum. Whereas current systemic pharmacological strategies fail to restore local dopamine levels, grafting with fetal dopaminergic neurons in the striatum have been associated with off-phase dyskinesias. Here we report that striatal delivery of genes necessary for dopamine synthesis, i.e. TH, AADC, and CH1, in a single lentiviral vector restored the dopaminergic tonus, corrected motor deficits, prevented and reversed drug induced motor complications in primate models of advanced Parkinson s disease. Lentiviral dopamine production in the striatum normalized internal globus pallidus neuronal activity and restored subthalamic nucleus metabolism. Our results demonstrate that dopamine gene therapy has a potential to solve the clinically relevant issue of parkinsonism correction in patients.PARIS-BIUSJ-Thèses (751052125) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Stimulation thalamique et tremblement essentiel

PARIS6-Bibl.Pitié-Salpêtrie (751132101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Revisiting the standard for modeling functional brain network activity: application to consciousness

Consciousness can be characterized by studying spontaneous fluctuations in brain activity, commonly measured with resting-state functional Magnetic Resonance Imaging (rs-fMRI). Previous rs-fMRI studies in monkeys and humans have shown that different levels of consciousness are defined by the relative prevalence of different dynamical functional connectivity patterns, also called brain patterns. These patterns closely match the underlying structural connectivity when consciousness is lost. The results suggest that changes in the state of consciousness lead to changes in connectivity patterns, not only at the level of co-activation strength between regions, but also at the level of entire networks.Here, we use a linear latent variable model that provides interpretable brain networks to reveal a new signature of consciousness and its chemically induced loss during anesthesia. To identify interpretable spatial signatures of consciousness, we apply a four-step framework by i) generating a list of atlases, ii) filtering and extracting the time series associated with the brain Regions of Interest (ROIs) of each atlas, iii) decomposing the signals into tailored brain networks with associated Brain Network Activities (BNAs), and iv) performing statistical inference and multivariate analysis of the BNAs. The novelty of the framework lies in the adoption of a constrained linear latent variable model that provides BNAs based on identifiable and disjoint ROIs, called brain networks, and the ability to offer a sound basis for atlas selection given the underlying clinical question.The model yields a set of tailored brain networks and associated BNAs that characterize states of consciousness. Our results suggest that a network composed of fronto-parietal and cingular cortices strongly influences the shift of consciousness state, especially between anesthesia and wakefulness. Interestingly, this observation is consistent with the global neural workspace theory of consciousness. We also decipher the level of anesthesia from rs-fMRI-derived BNAs. We identify neurobiologically relevant brain networks that provide novel interpretable signatures of consciousness and its loss during anesthesia. These findings pave the way for translational applications such as the diagnosis of consciousness disorders

Pypreclin: An automatic pipeline for macaque functional MRI preprocessing

International audienceNon-human primate functional MRI (fMRI) is a growing field in neuroscience. However, there is no standardized method for monkey fMRI data analysis, specifically for data preprocessing. The preprocessing of monkey fMRI data is challenged by several technical and experimental specificities of the monkey research such as artifacts related to body movements or to intracranial leads. Here we propose to address these challenges by developing a new versatile pipeline for macaque fMRI preprocessing. We developed a Python module, Pypreclin, to process raw images using state of the art algorithms embedded in a fully automatic pipeline. To evaluate its robustness, we applied Pypreclin to fMRI data acquired at 3T in both awake and anesthetized macaques, with or without iron oxide contrast agent, using single loop or multichannel phased-array coils, combined or not with intracranial implanted electrodes. We performed both resting-state and auditory evoked fMRI and compared the results of Pypreclin to a previously employed preprocessing pipeline. Pypreclin successfully achieved the registration of the fMRI data to the macaque brain template in all the experimental conditions. Moreover, Pypreclin enables more accurate locations of auditory evoked activations in relation to the gray matter at corrected level in the awake fMRI condition. Finally, using the Primate neuroimaging Data-Exchange open access platform, we could further validate Pypreclin for monkey fMRI images that were acquired at ultra-high fields, from other institutions and using different protocols. Pypreclin is a validated preprocessing tool that adapts to diverse experimental and technical situations of monkey fMRI. Pypreclin code is available on open source data sharing platform

Deep learning models reveal the link between dynamic brain connectivity patterns and states of consciousness

Decoding states of consciousness from brain activity is a central challenge in neuroscience. Dynamic functional connectivity (dFC) allows the study of short-term temporal changes in functional connectivity (FC) between distributed brain areas. By clustering dFC matrices from resting-state fMRI, we previously described "brain patterns" that underlie different functional configurations of the brain at rest. The networks associated with these patterns have been extensively analyzed. However, the overall dynamic organization and how it relates to consciousness remains unclear. We hypothesized that deep learning networks would help to model this relationship. Using low-dimensional variational autoencoders (VAE), recent studies have attempted to learn meaningful representations that can help explain consciousness. Here, we investigated the complexity ofselecting such a generative model to study brain dynamics, and extended the available methods for latent space characterization and modeling. Therefore, our contributions are threefold. First, in comparison with probabilistic principal component analysis and sparse VAE, we showed that the selected low-dimensional VAE exhibits balanced performance in reconstructing dFCs and classifying brain patterns. The organization of the obtained low-dimensional dFC latent representations was then explored. We showed how these representations stratify the dynamic organization of the brain patterns as well as the experimental conditions. Finally, we proposed to delve into the proposed brain computational model. A receptive field analysis was first applied to identify preferred directions in the latent space to move from one brain pattern to another. Then, an ablation studywas achieved where specific brain areas were virtually inactivated. We demonstrated the efficiency of the model in summarizing consciousness-specific information that is encoded in key inter-areal connections, as described in the global neural workspace theory of consciousness. The proposed framework advocates the possibility to develop an interpretable computational brain model of interest for disorders of consciousness, paving the way for a dynamic diagnostic support tool

Signature of consciousness in the dynamics of resting-state brain activity

At rest, the brain is traversed by spontaneous functional connectivity patterns. Two hypotheses have been proposed for their origins: they may reflect a continuous stream of ongoing cognitive processes as well as random fluctuations shaped by a fixed anatomical connectivity matrix. Here we show that both sources contribute to the shaping of resting-state networks, yet with distinct contributions during consciousness and anesthesia. We measured dynamical functional connectivity with functional MRI during the resting state in awake and anesthetized monkeys. Under anesthesia, the more frequent functional connectivity patterns inherit the structure of anatomical connectivity, exhibit fewer small-world properties, and lack negative correlations. Conversely, wakefulness is characterized by the sequential exploration of a richer repertoire of functional configurations, often dissimilar to anatomical structure, and comprising positive and negative correlations among brain regions. These results reconcile theories of consciousness with observations of long-range correlation in the anesthetized brain and show that a rich functional dynamics might constitute a signature of consciousness, with potential clinical implications for the detection of awareness in anesthesia and brain-lesioned patients.Fil: Barttfeld, Pablo. Commissariat A Energie Atomique; Francia. Institut National de la Santé et de la Recherche Médicale; Francia. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Uhrig, Lynn. Commissariat A Energie Atomique; Francia. Institut National de la Santé et de la Recherche Médicale; FranciaFil: Sitt, Jacobo Diego. Commissariat A Energie Atomique; Francia. Institut National de la Santé et de la Recherche Médicale; Francia. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Sigman, Mariano. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Física de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Física de Buenos Aires; Argentina. Universidad Torcuato Di Tella; ArgentinaFil: Jarraya, Béchir. Commissariat A Energie Atomique; Francia. Institut National de la Santé et de la Recherche Médicale; FranciaFil: Dehaene, Stanislas. Commissariat A Energie Atomique; Francia. Institut National de la Santé et de la Recherche Médicale; Franci

Deep brain stimulation of the thalamus restores signatures of consciousness in a nonhuman primate model

International audienceLoss of consciousness is associated with the disruption of long-range thalamocortical and corticocortical brain communication. We tested the hypothesis that deep brain stimulation (DBS) of central thalamus might restore both arousal and awareness following consciousness loss. We applied anesthesia to suppress consciousness in nonhuman primates. During anesthesia, central thalamic stimulation induced arousal in an on-off manner and increased functional magnetic resonance imaging activity in prefrontal, parietal, and cingulate cortices. Moreover, DBS restored a broad dynamic repertoire of spontaneous resting-state activity, previously described as a signature of consciousness. None of these effects were obtained during the stimulation of a control site in the ventrolateral thalamus. Last, DBS restored a broad hierarchical response to auditory violations that was disrupted under anesthesia. Thus, DBS restored the two dimensions of consciousness, arousal and conscious access, following consciousness loss, paving the way to its therapeutical translation in patients with disorders of consciousness

Sedation Agents Differentially Modulate Cortical and Subcortical Blood Oxygenation: Evidence from Ultra-High Field MRI at 17.2 T

<div><p>Background</p><p>Sedation agents affect brain hemodynamic and metabolism leading to specific modifications of the cerebral blood oxygenation level. We previously demonstrated that ultra-high field (UHF) MRI detects changes in cortical blood oxygenation following the administration of sedation drugs commonly used in animal research. Here we applied the UHF-MRI method to study clinically relevant sedation drugs for their effects on cortical and subcortical (thalamus, striatum) oxygenation levels.</p><p>Methods</p><p>We acquired T2*-weighted images of Sprague-Dawley rat brains at 17.2T <i>in vivo</i>. During each MRI session, rats were first anesthetized with isoflurane, then with a second sedative agent (sevoflurane, propofol, midazolam, medetomidine or ketamine-xylazine) after stopping isoflurane. We computed a T2*-oxygenation-ratio that aimed at estimating cerebral blood oxygenation level for each sedative agent in each region of interest: cortex, hippocampus, thalamus and striatum.</p><p>Results</p><p>The T2*-oxygenation-ratio was consistent across scan sessions. This ratio was higher with inhalational agents than with intravenous agents. Under sevoflurane and medetomidine, T2*-oxygenation-ratio was homogenous across the brain regions. Intravenous agents (except medetomidine) induced a T2*-oxygenation-ratio imbalance between cortex and subcortical regions: T2*-oxygenation-ratio was higher in the cortex than the subcortical areas under ketamine-xylazine; T2*-oxygenation-ratio was higher in subcortical regions than in the cortex under propofol or midazolam.</p><p>Conclusion</p><p>Preclinical UHF MRI is a powerful method to monitor the changes in cerebral blood oxygenation level induced by sedative agents across brain structures. This approach also allows for a classification of sedative agents based on their differential effects on cerebral blood oxygenation level.</p></div

Classification of sedative agents based on their effects on the blood oxygenation level assessed by MRI at 17.2 T.

<p>A: The relative oxygenation ratio of isoflurane, sevoflurane, propofol, midazolam, medetomidine and ketamine-xylazine is displayed using a colored disk with variable intensity. Lower color saturation intensity corresponds to lower CBO level, and vice a versa. B: Proposed algorithm to identify anesthetic agents based on relative CBO in the cortex and thalamus as assessed by T2*-oxygenation-ratio. Low signal, T2*-oxygenation-ratio<50000; High signal, T2*-oxygenation-ratio>50000.</p