Resting State Functional Connectivity of the Rat Claustrum

The claustrum is structurally connected with many cortical areas.A major hurdle standing in the way of understanding claustrum function is the difficulty in assessing the global functional connectivity (FC) of this structure. The primary issues lie in the inability to isolate claustrum signal from the adjacent insular cortex (Ins), caudate/putamen (CPu), and endopiriform nucleus (Endo). To address this issue, we used (7T) fMRI in the rat and describe a novel analytic method to study claustrum without signal contamination from the surrounding structures. Using this approach, we acquired claustrum signal distinct from Ins, CPu, and Endo, and used this claustrum signal to determine whole brain resting state functional connectivity (RSFC). Claustrum RSFC was distinct from the adjacent structures and displayed extensive connections with sensory cortices and the cingulate cortex, consistent with known structural connectivity of the claustrum. These results suggest fMRI and improved analysis can be combined to accurately assay claustrum function

Fasting prevents medetomidine-induced hyperglycaemia and alterations of neurovascular coupling in the somatosensory cortex of the rat during noxious stimulation

Abstract Medetomidine and isoflurane are commonly used for general anaesthesia in fMRI studies, but they alter cerebral blood flow (CBF) regulation and neurovascular coupling (NVC). In addition, medetomidine induces hypoinsulinemia and hyperglycaemia, which also alter CBF regulation and NVC. Furthermore, sudden changes in arterial pressure induced by noxious stimulation may affect NVC differently under medetomidine and isoflurane anaesthesia, considering their different effects on vascular functions. The first objective of this study was to compare NVC under medetomidine and isoflurane anaesthesia during noxious stimulation. The second objective was to examine whether fasting may improve NVC by reducing medetomidine-induced hyperglycaemia. In male Wister rats, noxious electrical stimulation was applied to the sciatic nerve in fasted or non-fasted animals. CBF and local field potentials (LFP) were recorded in the somatosensory cortex to assess NVC (CBF/LFP ratio). The CBF/LFP ratio was increased by medetomidine compared with isoflurane (p = 0.004), but this effect was abolished by fasting (p = 0.8). Accordingly, medetomidine produced a threefold increase in blood glucose (p < 0.001), but this effect was also abolished by fasting (p = 0.3). This indicates that isoflurane and medetomidine anaesthesia alter NVC differently, but the undesirable glucose dependent effects of medetomidine on NVC can be prevented by fasting

Isoflurane-Induced Burst Suppression Increases Intrinsic Functional Connectivity of the Monkey Brain

Animal functional magnetic resonance imaging (fMRI) has provided key insights into the physiological mechanisms underlying healthy and diseased brain states. In non-human primates, resting-state fMRI studies are commonly conducted under isoflurane anesthesia, where anesthetic concentration is used to roughly infer anesthesia depth. However, within the recommended isoflurane concentration range (1.00–1.50%), the brain state can switch from moderate anesthesia characterized by stable slow wave (SW) electroencephalogram (EEG) signals to deep anesthesia characterized by burst suppression (BS), which is electrophysiologically distinct from the resting state. To confirm the occurrence rate of BS activity in common setting of animal fMRI study, we conducted simultaneous resting-state EEG and fMRI experiments on 16 monkeys anesthetized using 0.80–1.30% isoflurane, and detected BS activity in two of them. Datasets either featured with BS or SW activity from these two monkeys were analyzed to investigate the intrinsic functional connectivity (FC) patterns during BS. In datasets with BS activity, we observed robust coupling between the BS pattern (the binary alternation between burst and suppression activity in EEG signal) and filtered BOLD signals in most brain areas, which was associated with a non-specific enhancement in whole brain connectivity. After eliminating the BS coupling effect by regressing out the BS pattern, we detected an overall increase in FC with a few decreased connectivity compared to datasets with SW activity. These affected connections were preferentially distributed within orbitofrontal cortex, between orbitofrontal and prefrontal/cingulate/occipital cortex, and between temporal and parietal cortex. Persistence of the default mode network and recovery of thalamocortical connections were also detected under deep anesthesia with BS activity. Taken together, the observed spatially specific alterations in BS activity induced by isoflurane not only highlight the necessity of EEG monitoring and careful data preprocessing in fMRI studies on anesthetized animals, but also advance our understanding of the underlying multi-phased mechanisms of anesthesia

Cellular Mechanisms Underlying State-Dependent Neural Inhibition with Magnetic Stimulation

Novel stimulation protocols for neuromodulation with magnetic fields are explored in clinical and laboratory settings. Recent evidence suggests that the activation state of the nervous system plays a significant role in the outcome of magnetic stimulation, but the underlying cellular and molecular mechanisms of state-dependency have not been completely investigated. We recently reported that high frequency magnetic stimulation could inhibit neural activity when the neuron was in a low active state. In this paper, we investigate state-dependent neural modulation by applying a magnetic field to single neurons, using the novel micro-coil technology. High frequency magnetic stimulation suppressed single neuron activity in a state-dependent manner. It inhibited neurons in slow-firing states, but spared neurons from fast-firing states, when the same magnetic stimuli were applied. Using a multi-compartment NEURON model, we found that dynamics of voltage-dependent sodium and potassium channels were significantly altered by the magnetic stimulation in the slow-firing neurons, but not in the fast-firing neurons. Variability in neural activity should be monitored and explored to optimize the outcome of magnetic stimulation in basic laboratory research and clinical practice. If selective stimulation can be programmed to match the appropriate neural state, prosthetic implants and brain-machine interfaces can be designed based on these concepts to achieve optimal results

Neurophysiological mechanisms of transcranial alternating current stimulation

Neuronal oscillations are the primary basis for precise temporal coordination of neuronal processing and are linked to different brain functions. Transcranial alternating current stimulation (tACS) has demonstrated promising potential in improving cognition by entraining neural oscillations. Despite positive findings in recent decades, the results obtained are sometimes rife with variance and replicability problems, and the findings translation to humans is quite challenging. A thorough understanding of the mechanisms underlying tACS is necessitated for accurate interpretation of experimental results. Animal models are useful for understanding tACS mechanisms, optimizing parameter administration, and improving rational design for broad horizons of tACS. Here, we review recent electrophysiological advances in tACS from animal models, as well as discuss some critical issues for results coordination and translation. We hope to provide an overview of neurophysiological mechanisms and recommendations for future consideration to improve its validity, specificity, and reproducibility

From a systems view to spotting a hidden island : A narrative review implicating insula function in alcoholism

Excessive use of alcohol promotes the development of alcohol addiction, but the understanding of how alcohol induced brain alterations lead to addiction remains limited. To further this understanding, we adopted an unbiased discovery strategy based on the principles of systems medicine. We used functional magnetic resonance imaging data from patients and animal models of alcohol addiction-like behaviors, and developed mathematical models of the 'relapse-prone' network states to identify brain sites and functional networks that can be selectively targeted by therapeutic interventions. Our systems level, non-local, and largely unbiased analyses converged on a few well-defined brain regions, with the insula emerging as one of the most consistent findings across studies. In proof-of-concept experiments we were able to demonstrate that it is possible to guide network dynamics towards increased resilience in animals but an initial translation into a clinical trial targeting the insula failed. Here, in a narrative review, we summarize the key experiments, methodological developments and knowledge gained from this complete round of a discovery cycle moving from identification of 'relapse-prone' network states in humans and animals to target validation and intervention trial. Future concerted efforts are necessary to gain a deeper understanding of insula function a in a state-dependent, circuit-specific and cell population perspective, and to develop the means for insula-directed interventions, before therapeutic targeting of this structure may become possible.Peer reviewe

Identifying Respiration-Related Aliasing Artifacts in the Rodent Resting-State fMRI

Resting-state functional magnetic resonance imaging (rs-fMRI) combined with optogenetics and electrophysiological/calcium recordings in animal models is becoming a popular platform to investigate brain dynamics under specific neurological states. Physiological noise originating from the cardiac and respiration signal is the dominant interference in human rs-fMRI and extensive efforts have been made to reduce these artifacts from the human data. In animal fMRI studies, physiological noise sources including the respiratory and cardiorespiratory artifacts to the rs-fMRI signal fluctuation have typically been less investigated. In this article, we demonstrate evidence of aliasing effects into the low-frequency rs-fMRI signal fluctuation mainly due to respiration-induced B0 offsets in anesthetized rats. This aliased signal was examined by systematically altering the fMRI sampling rate, i.e., the time of repetition (TR), in free-breathing conditions and by adjusting the rate of ventilation. Anesthetized rats under ventilation showed a significantly narrower frequency bandwidth of the aliasing effect than free-breathing animals. It was found that the aliasing effect could be further reduced in ventilated animals with a muscle relaxant. This work elucidates the respiration-related aliasing effects on the rs-fMRI signal fluctuation from anesthetized rats, indicating non-negligible physiological noise needed to be taken care of in both awake and anesthetized animal rs-fMRI studies

Identifying reproducible resting state networks and functional connectivity alterations following chronic restraint stress in anaesthetized rats

BackgroundResting-state functional MRI (rs-fMRI) in rodent models have the potential to bridge invasive experiments and observational human studies, increasing our understanding of functional alterations in the brains of patients with depression. A major limitation in current rodent rs-fMRI studies is that there has been no consensus on healthy baseline resting-state networks (RSNs) that are reproducible in rodents. Therefore, the present study aimed to construct reproducible RSNs in a large dataset of healthy rats and then evaluate functional connectivity changes within and between these RSNs following a chronic restraint stress (CRS) model within the same animals.MethodsA combined MRI dataset of 109 Sprague Dawley rats at baseline and after two weeks of CRS, collected during four separate experiments conducted by our lab in 2019 and 2020, was re-analysed. The mICA and gRAICAR toolbox were first applied to detect optimal and reproducible ICA components and then a hierarchical clustering algorithm (FSLNets) was applied to construct reproducible RSNs. Ridge-regularized partial correlation (FSLNets) was used to evaluate the changes in the direct connection between and within identified networks in the same animals following CRS.ResultsFour large-scale networks in anesthetised rats were identified: the DMN-like, spatial attention-limbic, corpus striatum, and autonomic network, which are homologous across species. CRS decreased the anticorrelation between DMN-like and autonomic network. CRS decreased the correlation between amygdala and a functional complex (nucleus accumbens and ventral pallidum) in the right hemisphere within the corpus striatum network. However, a high individual variability in the functional connectivity before and after CRS within RSNs was observed.ConclusionThe functional connectivity changes detected in rodents following CRS differ from reported functional connectivity alterations in patients with depression. A simple interpretation of this difference is that the rodent response to CRS does not reflect the complexity of depression as it is experienced by humans. Nonetheless, the high inter-subject variability of functional connectivity within networks suggests that rats demonstrate different neural phenotypes, like humans. Therefore, future efforts in classifying neural phenotypes in rodents might improve the sensitivity and translational impact of models used to address aetiology and treatment of psychiatric conditions including depression

Identification and neuromodulation of brain states to promote recovery of consciousness

Experimental and clinical studies of consciousness identify brain states (i.e., transient, relevant features of the brain associated with the state of consciousness) in a non-systematic manner and largely independent from the research into the induction of state changes. In this narrative review with a focus on patients with a disorder of consciousness (DoC), we synthesize advances on the identification of brain states associated with consciousness in animal models and physiological (sleep), pharmacological (anesthesia) and pathological (DoC) states of altered consciousness in human. We show that in reduced consciousness the frequencies in which the brain operates are slowed down and that the pattern of functional communication in the brain is sparser, less efficient, and less complex. The results also highlight damaged resting state networks, in particular the default mode network, decreased connectivity in long-range connections and in the thalamocortical loops. Next, we show that therapeutic approaches to treat DoC, through pharmacology (e.g., amantadine, zolpidem), and (non-)invasive brain stimulation (e.g., transcranial current stimulation, deep brain stimulation) have shown some effectiveness to promote consciousness recovery. It seems that these deteriorated features of conscious brain states may improve in response to these neuromodulation approaches, yet, targeting often remains non-specific and does not always lead to (behavioral) improvements. Furthermore, in silico model-based approaches allow the development of personalized assessment of the effect of treatment on brain-wide dynamics. Although still in infancy, the fields of brain state identification and neuromodulation of brain states in relation to consciousness are showing fascinating developments that, when united, might propel the development of new and better targeted techniques for DoC. For example, brain states could be identified in a predictive setting, and the theoretical and empirical testing (i.e., in animals, under anesthesia and patients with a DoC) of neuromodulation techniques to promote consciousness could be investigated. This review further helps to identify where challenges and opportunities lay for the maturation of brain state research in the context of states of consciousness. Finally, it aids in recognizing possibilities and obstacles for the clinical translation of these diagnostic techniques and neuromodulation treatment options across both the multi-modal and multi-species approaches outlined throughout the review. This paper presents interactive figures, supported by the Live Paper initiative of the Human Brain Project, enabling the interaction with data and figures illustrating the concepts in the paper through EBRAINS (go to https://wiki.ebrains.eu/bin/view/Collabs/live-paper-states-altered-consciousness and get started with an EBRAINS account).NA is research fellow, OG is Research Associate, and SL is research director at FRS-FNRS. JA is postdoctoral fellow at the FWO. The study was further supported by the University and University Hospital of Liège, the BIAL Foundation, the Belgian National Funds for Scientific Research (FRS-FNRS), the European Union's Horizon 2020 Framework Programme for Research and Innovation under the Specific Grant Agreement No. 945539 (Human Brain Project SGA3), the FNRS PDR project (T.0134.21), the ERA-Net FLAG-ERA JTC2021 project ModelDXConsciousness (Human Brain Project Partnering Project), the fund Generet, the King Baudouin Foundation, the Télévie Foundation, the European Space Agency (ESA) and the Belgian Federal Science Policy Office (BELSPO) in the framework of the PRODEX Programme, the Public Utility Foundation 'Université Européenne du Travail', "Fondazione Europea di Ricerca Biomedica", the BIAL Foundation, the Mind Science Foundation, the European Commission, the Fondation Leon Fredericq, the Mind-Care foundation, the DOCMA project (EU-H2020-MSCA–RISE–778234), the National Natural Science Foundation of China (Joint Research Project 81471100) and the European Foundation of Biomedical Research FERB Onlus

Early brain activity : Translations between bedside and laboratory

Neural activity is both a driver of brain development and a readout of developmental processes. Changes in neuronal activity are therefore both the cause and consequence of neurodevelopmental compromises. Here, we review the assessment of neuronal activities in both preclinical models and clinical situations. We focus on issues that require urgent translational research, the challenges and bottlenecks preventing translation of biomedical research into new clinical diagnostics or treatments, and possibilities to overcome these barriers. The key questions are (i) what can be measured in clinical settings versus animal experiments, (ii) how do measurements relate to particular stages of development, and (iii) how can we balance practical and ethical realities with methodological compromises in measurements and treatments.Peer reviewe