Local orchestration of distributed functional patterns supporting loss and restoration of consciousness in the primate brain.

A central challenge of neuroscience is to elucidate how brain function supports consciousness. Here, we combine the specificity of focal deep brain stimulation with fMRI coverage of the entire cortex, in awake and anaesthetised non-human primates. During propofol, sevoflurane, or ketamine anaesthesia, and subsequent restoration of responsiveness by electrical stimulation of the central thalamus, we investigate how loss of consciousness impacts distributed patterns of structure-function organisation across scales. We report that distributed brain activity under anaesthesia is increasingly constrained by brain structure across scales, coinciding with anaesthetic-induced collapse of multiple dimensions of hierarchical cortical organisation. These distributed signatures are observed across different anaesthetics, and they are reversed by electrical stimulation of the central thalamus, coinciding with recovery of behavioural markers of arousal. No such effects were observed upon stimulating the ventral lateral thalamus, demonstrating specificity. Overall, we identify consistent distributed signatures of consciousness that are orchestrated by specific thalamic nuclei.

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

Loss 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.

Epidemiology and complications of anaesthesia in the French centres that participated to NECTARINE: A secondary analysis.

INTRODUCTION: Neonatal and infant anaesthesia are associated with a high risk of perioperative complications. The aim of the current study was to describe those risks in France using the French data from the NECTARINE study. MATERIAL AND METHODS: Data from the French centres that participated to the NECTARINE study were analysed. The primary goal of the study was the description of patients' characteristics, procedures and perioperative management and their comparison with the results of the European NECTARINE study. Secondary outcomes were the description of major perioperative complications and death. RESULTS: Overall, 926 procedures collected in 15 centres (all teaching hospitals) were analysed. Comparison between the French and European NECTARINE cohorts found few differences related to patients' characteristics and procedures. The rate of interventions for critical events (respiratory, haemodynamic, and metabolic) was similar between the two cohorts. Near-infrared spectroscopy monitoring was used in 12% of procedures. Nearly none of the thresholds for these interventions met the published standards. By day 30, complications (respiratory, haemodynamic, metabolic, renal, and liver failure) and death were observed in 14.4% [95% CI 11.6-16.4]% and 1.8% [95% CI 1.1-2.9] of cases, respectively. DISCUSSION: Although the health status of the patients in the French cohort was less severe, procedures, management and postoperative complications and mortality rates were similar to the European cohort. However, thresholds for interventions were often inadequate in both cohorts. Efforts should be undertaken to improve the knowledge and use of new monitoring devices in this population.

Macroscopic Quantities of Collective Brain Activity during Wakefulness and Anesthesia.

The study of states of arousal is key to understand the principles of consciousness. Yet, how different brain states emerge from the collective activity of brain regions remains unknown. Here, we studied the fMRI brain activity of monkeys during wakefulness and anesthesia-induced loss of consciousness. We showed that the coupling between each brain region and the rest of the cortex provides an efficient statistic to classify the two brain states. Based on this and other statistics, we estimated maximum entropy models to derive collective, macroscopic properties that quantify the system's capabilities to produce work, to contain information, and to transmit it, which were all maximized in the awake state. The differences in these properties were consistent with a phase transition from critical dynamics in the awake state to supercritical dynamics in the anesthetized state. Moreover, information-theoretic measures identified those parameters that impacted the most the network dynamics. We found that changes in the state of consciousness primarily depended on changes in network couplings of insular, cingulate, and parietal cortices. Our findings suggest that the brain state transition underlying the loss of consciousness is predominantly driven by the uncoupling of specific brain regions from the rest of the network.

Combining brain perturbation and neuroimaging in non-human primates.

Brain perturbation studies allow detailed causal inferences of behavioral and neural processes. Because the combination of brain perturbation methods and neural measurement techniques is inherently challenging, research in humans has predominantly focused on non-invasive, indirect brain perturbations, or neurological lesion studies. Non-human primates have been indispensable as a neurobiological system that is highly similar to humans while simultaneously being more experimentally tractable, allowing visualization of the functional and structural impact of systematic brain perturbation. This review considers the state of the art in non-human primate brain perturbation with a focus on approaches that can be combined with neuroimaging. We consider both non-reversible (lesions) and reversible or temporary perturbations such as electrical, pharmacological, optical, optogenetic, chemogenetic, pathway-selective, and ultrasound based interference methods. Method-specific considerations from the research and development community are offered to facilitate research in this field and support further innovations. We conclude by identifying novel avenues for further research and innovation and by highlighting the clinical translational potential of the methods.

A collaborative resource platform for non-human primate neuroimaging.

Neuroimaging non-human primates (NHPs) is a growing, yet highly specialized field of neuroscience. Resources that were primarily developed for human neuroimaging often need to be significantly adapted for use with NHPs or other animals, which has led to an abundance of custom, in-house solutions. In recent years, the global NHP neuroimaging community has made significant efforts to transform the field towards more open and collaborative practices. Here we present the PRIMatE Resource Exchange (PRIME-RE), a new collaborative online platform for NHP neuroimaging. PRIME-RE is a dynamic community-driven hub for the exchange of practical knowledge, specialized analytical tools, and open data repositories, specifically related to NHP neuroimaging. PRIME-RE caters to both researchers and developers who are either new to the field, looking to stay abreast of the latest developments, or seeking to collaboratively advance the field .

Hierarchical disruption in the cortex of anesthetized monkeys as a new signature of consciousness loss.

Anesthesia induces a reconfiguration of the repertoire of functional brain states leading to a high function-structure similarity. However, it is unclear how these functional changes lead to loss of consciousness. Here we suggest that the mechanism of conscious access is related to a general dynamical rearrangement of the intrinsic hierarchical organization of the cortex. To measure cortical hierarchy, we applied the Intrinsic Ignition analysis to resting-state fMRI data acquired in awake and anesthetized macaques. Our results reveal the existence of spatial and temporal hierarchical differences of neural activity within the macaque cortex, with a strong modulation by the depth of anesthesia and the employed anesthetic agent. Higher values of Intrinsic Ignition correspond to rich and flexible brain dynamics whereas lower values correspond to poor and rigid, structurally driven brain dynamics. Moreover, spatial and temporal hierarchical dimensions are disrupted in a different manner, involving different hierarchical brain networks. All together suggest that disruption of brain hierarchy is a new signature of consciousness loss.

Signature of consciousness in brain-wide synchronization patterns of monkey and human fMRI signals.

During the sleep-wake cycle, the brain undergoes profound dynamical changes, which manifest subjectively as transitions between conscious experience and unconsciousness. Yet, neurophysiological signatures that can objectively distinguish different consciousness states based are scarce. Here, we show that differences in the level of brain-wide signals can reliably distinguish different stages of sleep and anesthesia from the awake state in human and monkey fMRI resting state data. Moreover, a whole-brain computational model can faithfully reproduce changes in global synchronization and other metrics such as functional connectivity, structure-function relationship, integration and segregation across vigilance states. We demonstrate that the awake brain is close to a Hopf bifurcation, which naturally coincides with the emergence of globally correlated fMRI signals. Furthermore, simulating lesions of individual brain areas highlights the importance of connectivity hubs in the posterior brain and subcortical nuclei for maintaining the model in the awake state, as predicted by graph-theoretical analyses of structural data.

Pypreclin: An automatic pipeline for macaque functional MRI preprocessing.

Non-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.

Resting-state Dynamics as a Cortical Signature of Anesthesia in Monkeys.

WHAT WE ALREADY KNOW ABOUT THIS TOPIC: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: The mechanism by which anesthetics induce a loss of consciousness remains a puzzling problem. We hypothesized that a cortical signature of anesthesia could be found in an increase in similarity between the matrix of resting-state functional correlations and the anatomical connectivity matrix of the brain, resulting in an increased function-structure similarity. METHODS: We acquired resting-state functional magnetic resonance images in macaque monkeys during wakefulness (n = 3) or anesthesia with propofol (n = 3), ketamine (n = 3), or sevoflurane (n = 3). We used the k-means algorithm to cluster dynamic resting-state data into independent functional brain states. For each condition, we performed a regression analysis to quantify function-structure similarity and the repertoire of functional brain states. RESULTS: Seven functional brain states were clustered and ranked according to their similarity to structural connectivity, with higher ranks corresponding to higher function-structure similarity and lower ranks corresponding to lower correlation between brain function and brain anatomy. Anesthesia shifted the brain state composition from a low rank (rounded rank [mean ± SD]) in the awake condition (awake rank = 4 [3.58 ± 1.03]) to high ranks in the different anesthetic conditions (ketamine rank = 6 [6.10 ± 0.32]; moderate propofol rank = 6 [6.15 ± 0.76]; deep propofol rank = 6 [6.16 ± 0.46]; moderate sevoflurane rank = 5 [5.10 ± 0.81]; deep sevoflurane rank = 6 [5.81 ± 1.11]; P < 0.0001). CONCLUSIONS: Whatever the molecular mechanism, anesthesia led to a massive reconfiguration of the repertoire of functional brain states that became predominantly shaped by brain anatomy (high function-structure similarity), giving rise to a well-defined cortical signature of anesthesia-induced loss of consciousness.

Cerebral responses to local and global auditory novelty under general anesthesia.

Primate brains can detect a variety of unexpected deviations in auditory sequences. The local-global paradigm dissociates two hierarchical levels of auditory predictive coding by examining the brain responses to first-order (local) and second-order (global) sequence violations. Using the macaque model, we previously demonstrated that, in the awake state, local violations cause focal auditory responses while global violations activate a brain circuit comprising prefrontal, parietal and cingulate cortices. Here we used the same local-global auditory paradigm to clarify the encoding of the hierarchical auditory regularities in anesthetized monkeys and compared their brain responses to those obtained in the awake state as measured with fMRI. Both, propofol, a GABAA-agonist, and ketamine, an NMDA-antagonist, left intact or even enhanced the cortical response to auditory inputs. The local effect vanished during propofol anesthesia and shifted spatially during ketamine anesthesia compared with wakefulness. Under increasing levels of propofol, we observed a progressive disorganization of the global effect in prefrontal, parietal and cingulate cortices and its complete suppression under ketamine anesthesia. Anesthesia also suppressed thalamic activations to the global effect. These results suggest that anesthesia preserves initial auditory processing, but disturbs both short-term and long-term auditory predictive coding mechanisms. The disorganization of auditory novelty processing under anesthesia relates to a loss of thalamic responses to novelty and to a disruption of higher-order functional cortical networks in parietal, prefrontal and cingular cortices.

Representation of numerical and sequential patterns in macaque and human brains.

The ability to extract deep structures from auditory sequences is a fundamental prerequisite of language acquisition. Using fMRI in untrained macaques and humans, we investigated the brain areas involved in representing two abstract properties of a series of tones: total number of items and tone-repetition pattern. Both species represented the number of tones in intraparietal and dorsal premotor areas and the tone-repetition pattern in ventral prefrontal cortex and basal ganglia. However, we observed a joint sensitivity to both parameters only in humans, within bilateral inferior frontal and superior temporal regions. In the left hemisphere, those sites coincided with areas involved in language processing. Thus, while some abstract properties of auditory sequences are available to non-human primates, a recently evolved circuit may endow humans with a unique ability for representing linguistic and non-linguistic sequences in a unified manner.

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.

FID navigator-based MR thermometry method to monitor small temperature changes in the brain of ventilated animals.

An MR thermometry method is proposed for measuring in vivo small temperature changes engendered by external RF heat sources. The method relies on reproducible and stable respiration and therefore currently applies to ventilated animals whose breathing is carefully controlled. It first consists in characterizing the stability of the main magnetic field as well as the variations induced by breathing during a first monitoring stage. Second, RF heating is applied while the phase and thus temperature evolutions are continuously measured, the corrections due to breathing and field drift being made thanks to the data accumulated during the first period. The RF heat source is finally stopped and the temperature rise likewise is continuously monitored during a third and last stage to observe the animal cooling down and to validate the assumptions made for correcting for the main field variation and the physiological noise. Experiments were performed with a clinical 7 T scanner on an anesthetized baboon and with a dedicated RF heating setup. Analysis of the data reveals a precision around 0.1°C, which allows us to reliably measure sub-degree temperature rises in the muscle and in the brain of the animal.

Quantification of iron in the non-human primate brain with diffusion-weighted magnetic resonance imaging.

Pathological iron deposits in the brain, especially within basal ganglia, are linked to severe neurodegenerative disorders like Parkinson's disease. As iron induces local changes in magnetic susceptibility, its presence can be visualized with magnetic resonance imaging (MRI). The usual approach, based on iron induced changes in magnetic relaxation (T2/T2'), is often prone, however, to confounding artifacts and lacks specificity. Here, we propose a new method to quantify and map iron deposits using water diffusion MRI. This method is based on the differential sensitivity of two image acquisition schemes to the local magnetic field gradients induced by iron deposits and their cross-term with gradient pulses used for diffusion encoding. Iron concentration could be imaged and estimated with high accuracy in the brain cortex, the thalamus, the substantia nigra and the globus pallidus of macaques, showing iron distributions in agreement with literature. Additionally, iron maps could clearly show a dramatic increase in iron content upon injection of an UltraSmall Particle Iron Oxide (USPIO) contrast agent, notably in the cortex and the thalamus, reflecting regional differences in blood volume. The method will benefit clinical investigations on the effect of iron deposits in the brain or other organs, as iron deposits are increasingly seen as a biomarker for a wide range of diseases, notably, neurodegenerative diseases in the pre-symptomatic stage. It also has the potential for quantifying variations in blood volume induced by brain activation in fMRI studies using USPIOs.

Sedation agents differentially modulate cortical and subcortical blood oxygenation: evidence from ultra-high field MRI at 17.2 T.

BACKGROUND: 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. METHODS: We acquired T2*-weighted images of Sprague-Dawley rat brains at 17.2T in vivo. 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. RESULTS: 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. CONCLUSION: 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.

A hierarchy of responses to auditory regularities in the macaque brain.

Can monkeys learn simple auditory sequences and detect when a new sequence deviates from the stored pattern? Here we tested the predictive-coding hypothesis, which postulates that cortical areas encode internal models of sensory sequences at multiple hierarchical levels, and use these predictive models to detect deviant stimuli. In humans, hierarchical predictive coding has been supported by studies of auditory sequence processing, but it is unclear whether internal hierarchical models of auditory sequences are also available to nonhuman animals. Using fMRI, we evaluated the encoding of auditory regularities in awake monkeys listening to first- and second-order sequence violations. We observed distinct fMRI responses to first-order violations in auditory cortex and to second-order violations in a frontoparietal network, a distinction only demonstrated in conscious humans so far. The results indicate that the capacity to represent and predict the structure of auditory sequences is shared by humans and nonhuman primates.

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 T(2)*-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 T(2)*-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.

Direct visualization of non-human primate subcortical nuclei with contrast-enhanced high field MRI.

Subcortical nuclei are increasingly targeted for deep brain stimulation (DBS) and for gene transfer to treat neurological and psychiatric disorders. For a successful outcome in patients, it is critical to place DBS electrodes or infuse viral vectors accurately within targeted nuclei. However current MRI approaches are still limited to localize brainstem and basal ganglia nuclei accurately. By combining ultra-high resolution structural MRI and contrast-enhanced MRI using iron oxide nanoparticles at high field (3T and 7T), we could precisely locate the subcortical nuclei, in particular the subthalamic nucleus in macaques, and validate this location by intracranial electrophysiological mapping. The present data pave the way to a clinical application.

Use of recombinant activated factor VII in intractable bleeding during pediatric neurosurgical procedures.

OBJECTIVE: To report the use of recombinant activated factor VII (NovoSeven; Novo Nordisk A/S, Bagsvaerd, Denmark) in children undergoing major neurosurgical procedures and experiencing massive uncontrolled hemorrhagic shock. DESIGN: Retrospective review of patients and analysis of clinical and biological effects of an intravenous administration of recombinant activated factor VII. SETTING: Neurosurgical anesthesia and critical care unit of a pediatric university hospital. PATIENTS/SUBJECTS: Four children, <12-kg body weight, experiencing life-threatening perioperative hemorrhage required conventional treatment (massive red blood cells, fresh frozen plasma, platelet transfusion, and surgical hemostatic maneuvers) that failed to obtain definite hemostasis. INTERVENTIONS: Intravenous administration of recombinant activated factor VII (100 microg/kg). RESULTS: Intravenous administration resulted in a significant decrease in blood loss within minutes (preventing further need of transfusion), normalization of biological hemostasis markers, and improved surgical hemostasis. No side effects of recombinant activated factor VII were noted, and all patients, except one, had a good recovery. CONCLUSIONS: These four patients support the use of recombinant activated factor VII as a useful adjunct to control massive life-threatening bleeding during pediatric neurosurgical procedures when other means failed. However, the data are still limited in children, and more extensive research is needed to define the indications of recombinant activated factor VII in massive surgical hemorrhage in low-weight children.