Resting-state Network-specific Breakdown of Functional Connectivity during Ketamine Alteration of Consciousness in Volunteers.

BACKGROUND: Consciousness-altering anesthetic agents disturb connectivity between brain regions composing the resting-state consciousness networks (RSNs). The default mode network (DMn), executive control network, salience network (SALn), auditory network, sensorimotor network (SMn), and visual network sustain mentation. Ketamine modifies consciousness differently from other agents, producing psychedelic dreaming and no apparent interaction with the environment. The authors used functional magnetic resonance imaging to explore ketamine-induced changes in RSNs connectivity. METHODS: Fourteen healthy volunteers received stepwise intravenous infusions of ketamine up to loss of responsiveness. Because of agitation, data from six subjects were excluded from analysis. RSNs connectivity was compared between absence of ketamine (wake state [W1]), light ketamine sedation, and ketamine-induced unresponsiveness (deep sedation [S2]). RESULTS: Increasing the depth of ketamine sedation from W1 to S2 altered DMn and SALn connectivity and suppressed the anticorrelated activity between DMn and other brain regions. During S2, DMn connectivity, particularly between the medial prefrontal cortex and the remaining network (effect size β [95% CI]: W1 = 0.20 [0.18 to 0.22]; S2 = 0.07 [0.04 to 0.09]), and DMn anticorrelated activity (e.g., right sensory cortex: W1 = -0.07 [-0.09 to -0.04]; S2 = 0.04 [0.01 to 0.06]) were broken down. SALn connectivity was nonuniformly suppressed (e.g., left parietal operculum: W1 = 0.08 [0.06 to 0.09]; S2 = 0.05 [0.02 to 0.07]). Executive control networks, auditory network, SMn, and visual network were minimally affected. CONCLUSIONS: Ketamine induces specific changes in connectivity within and between RSNs. Breakdown of frontoparietal DMn connectivity and DMn anticorrelation and sensory and SMn connectivity preservation are common to ketamine and propofol-induced alterations of consciousness

Muting, not fragmentation, of functional brain networks under general anesthesia

© 2021 Changes in resting-state functional connectivity (rs-FC) under general anesthesia have been widely studied with the goal of identifying neural signatures of consciousness. This work has commonly revealed an apparent fragmentation of whole-brain network structure during unconsciousness, which has been interpreted as reflecting a break-down in connectivity and a disruption of the brain\u27s ability to integrate information. Here we show, by studying rs-FC under varying depths of isoflurane-induced anesthesia in nonhuman primates, that this apparent fragmentation, rather than reflecting an actual change in network structure, can be simply explained as the result of a global reduction in FC. Specifically, by comparing the actual FC data to surrogate data sets that we derived to test competing hypotheses of how FC changes as a function of dose, we found that increases in whole-brain modularity and the number of network communities – considered hallmarks of fragmentation – are artifacts of constructing FC networks by thresholding based on correlation magnitude. Taken together, our findings suggest that deepening levels of unconsciousness are instead associated with the increasingly muted expression of functional networks, an observation that constrains current interpretations as to how anesthesia-induced FC changes map onto existing neurobiological theories of consciousness

The (un)conscious mouse as a model for human brain functions: key principles of anesthesia and their impact on translational neuroimaging

In recent years, technical and procedural advances have brought functional magnetic resonance imaging (fMRI) to the field of murine neuroscience. Due to its unique capacity to measure functional activity non-invasively, across the entire brain, fMRI allows for the direct comparison of large-scale murine and human brain functions. This opens an avenue for bidirectional translational strategies to address fundamental questions ranging from neurological disorders to the nature of consciousness. The key challenges of murine fMRI are: (1) to generate and maintain functional brain states that approximate those of calm and relaxed human volunteers, while (2) preserving neurovascular coupling and physiological baseline conditions. Low-dose anesthetic protocols are commonly applied in murine functional brain studies to prevent stress and facilitate a calm and relaxed condition among animals. Yet, current mono-anesthesia has been shown to impair neural transmission and hemodynamic integrity. By linking the current state of murine electrophysiology, Ca(2+) imaging and fMRI of anesthetic effects to findings from human studies, this systematic review proposes general principles to design, apply and monitor anesthetic protocols in a more sophisticated way. The further development of balanced multimodal anesthesia, combining two or more drugs with complementary modes of action helps to shape and maintain specific brain states and relevant aspects of murine physiology. Functional connectivity and its dynamic repertoire as assessed by fMRI can be used to make inferences about cortical states and provide additional information about whole-brain functional dynamics. Based on this, a simple and comprehensive functional neurosignature pattern can be determined for use in defining brain states and anesthetic depth in rest and in response to stimuli. Such a signature can be evaluated and shared between labs to indicate the brain state of a mouse during experiments, an important step toward translating findings across species

The thalamocortical symphony:How thalamus and cortex play together in schizophrenia and plasticity

The work presented in this thesis aimed at investigating the function and mechanism of corticothalamic-thalamocortical network in schizophrenia and experience-dependent plasticity, further discussed their possible connection.In Chapter 2, we examined the effects of low-dose ketamine on the corticothalamic circuit (CTC) system. Our findings reveal that ketamine induces abnormal spindle activity and gamma oscillations in the CTC system. Notably, ketamine also leads to a transition in thalamic neurons from burst-firing to tonic action potential mode, which may underlie deficits in spindle oscillations. Chapter 3 addresses sensory perception deficits in schizophrenia, emphasizing disruptions in beta and gamma frequency oscillations due to signal-to-noise ratio imbalances. Chapter 4 explores experience-dependent plasticity, highlighting the role of thalamic synaptic inhibition in ocular dominance plasticity and the influence of cortical feedback. Chapter 5 investigates the involvement of endocannabinoids, particularly CB1 receptors, in inhibitory synaptic maturation and ocular dominance plasticity within the primary visual cortex.The general discussion raises the possibility of a link between neural plasticity and schizophrenia, particularly during the transformative phase of adolescence when the brain undergoes significant changes. An abnormal balance between inhibition and excitation, influenced by GABAergic maturation deficits, connectivity disruptions, and altered perceptual information transfer, may contribute to the development of schizophrenia.This thesis offers valuable insights into the intricate mechanisms underlying schizophrenia, with a particular focus on the CTC circuit, NMDA receptors, and endocannabinoids in the context of neuronal plasticity and cognitive function

The thalamocortical symphony:How thalamus and cortex play together in schizophrenia and plasticity

The work presented in this thesis aimed at investigating the function and mechanism of corticothalamic-thalamocortical network in schizophrenia and experience-dependent plasticity, further discussed their possible connection.In Chapter 2, we examined the effects of low-dose ketamine on the corticothalamic circuit (CTC) system. Our findings reveal that ketamine induces abnormal spindle activity and gamma oscillations in the CTC system. Notably, ketamine also leads to a transition in thalamic neurons from burst-firing to tonic action potential mode, which may underlie deficits in spindle oscillations. Chapter 3 addresses sensory perception deficits in schizophrenia, emphasizing disruptions in beta and gamma frequency oscillations due to signal-to-noise ratio imbalances. Chapter 4 explores experience-dependent plasticity, highlighting the role of thalamic synaptic inhibition in ocular dominance plasticity and the influence of cortical feedback. Chapter 5 investigates the involvement of endocannabinoids, particularly CB1 receptors, in inhibitory synaptic maturation and ocular dominance plasticity within the primary visual cortex.The general discussion raises the possibility of a link between neural plasticity and schizophrenia, particularly during the transformative phase of adolescence when the brain undergoes significant changes. An abnormal balance between inhibition and excitation, influenced by GABAergic maturation deficits, connectivity disruptions, and altered perceptual information transfer, may contribute to the development of schizophrenia.This thesis offers valuable insights into the intricate mechanisms underlying schizophrenia, with a particular focus on the CTC circuit, NMDA receptors, and endocannabinoids in the context of neuronal plasticity and cognitive function

Monkey in the middle: why non-human primates are needed to bridge the gap in resting-state investigations

Resting-state investigations based on the evaluation of intrinsic low-frequency fluctuations of the BOLD fMRI signal have been extensively utilized to map the structure and dynamics of large-scale functional network organization in humans. In addition to increasing our knowledge of normal brain connectivity, disruptions of the spontaneous hemodynamic fluctuations have been suggested as possible diagnostic indicators of neurological and psychiatric disease states. Though the non-invasive technique has been received with much acclamation, open questions remain regarding the origin, organization, phylogenesis, as well as the basis of disease-related alterations underlying the signal patterns. Experimental work utilizing animal models, including the use of neurophysiological recordings and pharmacological manipulations, therefore, represents a critical component in the understanding and successful application of resting-state analysis, as it affords a range of experimental manipulations not possible in human subjects. In this article, we review recent rodent and non-human primate studies and based on the examination of the homologous brain architecture propose the latter to be the best-suited model for exploring these unresolved resting-state concerns. Ongoing work examining the correspondence of functional and structural connectivity, state-dependency and the neuronal correlates of the hemodynamic oscillations are discussed. We then consider the potential experiments that will allow insight into different brain states and disease-related network disruptions that can extend the clinical applications of resting-state fMRI (RS-fMRI)

Circuits for active vision : parallel tectothalamocortical visual pathways in the mouse.

Vision is a critical sensation for the interaction between humans and their surrounding environment. The eyes connect with the brain via retinal ganglion cell axons, which transmit visual sensory information from the periphery into the central nervous system for further processing, eventually leading to visual perception and the visual guidance of movement. Two main targets of retinal axons are the superior colliculus (SC) and the dorsal thalamus. From the SC, visual information is conveyed to the dorsal thalamus, and from the dorsal thalamus visual information is conveyed to the cortex, striatum and amygdala. This dissertation is focused on the functional properties of two parallel pathways from the SC to the dorsal thalamus: a pathway from the SC to the retinorecipient dorsolateral geniculate nucleus (dLGN) to the cortex, and a pathway from the SC to the pulvinar nucleus to the cortex. The experiments described in this dissertation used viral vector injections, tract tracing, in vitro whole cell patch clamp, optogenetics, electron and confocal microscopy, transgenic mouse lines and immunohistochemical staining techniques to elucidate the roles of the SC-dLGN-cortex pathway and SC-pulvinar-cortex pathway in visual coding. The first series of experiments revealed that SC and retinal inputs converge to innervate the proximal dendrites of cells in the dorsolateral shell of the dLGN that project to layer I of the striate cortex. The second series of experiments revealed the organization of subdivisions of the pulvinar nucleus in relation to inputs from the SC. The final series of experiments revealed the distribution and ultrastructure of pulvinocortical terminals, and identified the cell types activated by pulvinocortical synapses. Major targets of pulvinocortical terminals were identified as corticostriatal cells, suggesting that pulvinar acts as a hub connecting the SC, cortex and striatum

The INSIDEOUT framework provides precise signatures of the balance of intrinsic and extrinsic dynamics in brain states

Finding precise signatures of different brain states is a central, unsolved question in neuroscience. We reformulated the problem to quantify the 'inside out' balance of intrinsic and extrinsic brain dynamics in brain states. The difference in brain state can be described as differences in the detailed causal interactions found in the underlying intrinsic brain dynamics. We used a thermodynamics framework to quantify the breaking of the detailed balance captured by the level of asymmetry in temporal processing, i.e. the arrow of time. Specifically, the temporal asymmetry was computed by the time-shifted correlation matrices for the forward and reversed time series, reflecting the level of non-reversibility/non-equilibrium. We found precise, distinguishing signatures in terms of the reversibility and hierarchy of large-scale dynamics in three radically different brain states (awake, deep sleep and anaesthesia) in electrocorticography data from non-human primates. Significantly lower levels of reversibility were found in deep sleep and anaesthesia compared to wakefulness. Non-wakeful states also showed a flatter hierarchy, reflecting the diversity of the reversibility across the brain. Overall, this provides signatures of the breaking of detailed balance in different brain states, perhaps reflecting levels of conscious awareness

Longitudinal two-photon imaging in somatosensory cortex of behaving mice reveals dendritic spine formation enhancement by subchronic administration of low-dose ketamine

Ketamine, a well-known anesthetic, has recently attracted renewed attention as a fast-acting antidepressant. A single dose of ketamine induces rapid synaptogenesis, which may underlie its antidepressant effect. To test whether repeated exposure to ketamine triggers sustained synaptogenesis, we administered a sub-anesthetic dose of ketamine (10 mg/kg i.p.) once-daily for 5 days, and repeatedly imaged dendritic spines of the YFP-expressing pyramidal neurons in somatosensory cortex of awake female mice using in vivo two-photon microscopy. We found that the spine formation rate became significantly higher at 72-132 h after the first ketamine injection (but not at 6-24 h), while the rate of elimination of pre-existing spines remained unchanged. In contrast to the net gain of spines observed in ketamine-treated mice, the vehicle-injected control mice exhibited a net loss typical for young-adult animals undergoing synapse pruning. Ketamine-induced spinogenesis was correlated with increased PSD-95 and phosphorylated actin, consistent with formation of new synapses. Moreover, structural synaptic plasticity caused by ketamine was paralleled by a significant improvement in the nest building behavioral assay. Taken together, our data show that subchronic low-dose ketamine induces a sustained shift towards spine formation.Peer reviewe

Changes in Cortical Connectivity and Gene Expression of the Rostral Forelimb Area After Ischemic Infarct in Motor Cortex in the Rat

Stroke is a large and growing problem in the United States. There are 795,000 incidences each year, and most are new incidences. Survivors are left with lasting functional deficits, and therefore stroke is one of the leading causes of adult disability in humans. Some function is regained that was lost to stroke, and this recovery is correlated to physiological reorganization. That is to say, after stroke the brain functions differently. The physiological reorganization may be based on anatomical reorganization. If this is true, the brain acts differently, because it is wired differently after stroke. The anatomical reorganization may be based on expression differences; thus, leading to the conclusion that the brain is wired differently because genes were expressed in different ways after the stroke. The series of studies within this dissertation lead the reader down this train of thought and show evidence for it by using adult rats in a model of ischemic injury to the cortex, and compare the connectivity and gene expression patterns of lesioned brains to non-lesioned brains