Changes in brain connectivity and neurovascular dynamics during dexmedetomidine-induced loss of consciousness.

Understanding the neurophysiological changes underlying conscious-unconscious transitions is a key goal in neuroscience. Using magnetic resonance neuroimaging, we investigate the network connectivity and neurovascular changes occurring as the human brain transitions from wakefulness to dexmedetomidine-induced hypnosis, and recovery. Hypnosis led to widespread decreases in functional connectivity strength and increased structure-function coupling, indicating functional patterns more constrained by the underlying anatomical connectivity.

Effects of the Quinone Analog Ubiquinone-5 on Murine Mitochondria and Hypnosis.

Background: A functional anesthetic target has long been suspected to reside within mitochondria, and disruption of bioenergetic capacity is believed to play a role in the anesthetic response. Unfortunately, the exact mechanism by which changes in mitochondrial target activity result in clinically relevant anesthetic endpoints remains unknown. Here, the authors leveraged knowledge of propofol toxicity to guide drug discovery and uncover a previously unknown pharmacologic target within mitochondria.

A probabilistic model of behavioural emergence from general anaesthesia in mice.

Background: Time to emergence from general anaesthesia is highly variable between individuals. This variability has been attributed to individual differences in anaesthetic sensitivity. However, this hypothesis has not been verified experimentally.

Parafacial GABAergic neurone ablation induces behavioural resistance to volatile anaesthetic-induced hypnosis without reducing sleep.

Background: It is hypothesised that general anaesthetics co-opt the neural circuits regulating endogenous sleep and wakefulness to produce hypnosis. To further probe this association, we focused on the GABAergic neurones of the parafacial zone (PZ), a brainstem site capable of promoting non-rapid eye movement sleep.

Methods: To determine whether PZ neurones are activated by a hypnotic dose of anaesthetics, c-Fos immunohistochemistry was performed.

The Administration of Ketamine Is Associated with Dose-Dependent Stabilization of Cortical Dynamics in Humans.

During wakefulness, external stimuli elicit conscious experiences. In contrast, dreams and drug-induced dissociated states are characterized by vivid internally generated conscious experiences and reduced ability to perceive external stimuli. Understanding the physiological distinctions between normal wakefulness and dissociated states may therefore disambiguate signatures of responsiveness to external stimuli from those that underlie conscious experience.

Nitrous oxide activates layer 5 prefrontal neurons via SK2 channel inhibition for antidepressant effect.

Nitrous oxide (NO) induces rapid and durable antidepressant effects. The cellular and circuit mechanisms mediating this process are not known. Here we find that a single dose of inhaled NO induces rapid and specific activation of layer V (L5) pyramidal neurons in the cingulate cortex of rodents exposed to chronic stress conditions.

Nitrous Oxide activates layer 5 prefrontal neurons via SK2 channel inhibition for antidepressant effect.

Nitrous oxide (NO) induces rapid and durable antidepressant effects. The cellular and circuit mechanisms mediating this process are not known. Here we find that a single dose of inhaled NO induces rapid and specific activation of layer V (L5) pyramidal neurons in the cingulate cortex of rodents exposed to chronic stress conditions.

Changes in brain connectivity and neurovascular dynamics during dexmedetomidine-induced loss of consciousness.

Understanding the neurophysiological changes that occur during loss and recovery of consciousness is a fundamental aim in neuroscience and has marked clinical relevance. Here, we utilize multimodal magnetic resonance neuroimaging to investigate changes in regional network connectivity and neurovascular dynamics as the brain transitions from wakefulness to dexmedetomidine-induced unconsciousness, and finally into early-stage recovery of consciousness. We observed widespread decreases in functional connectivity strength across the whole brain, and targeted increases in structure-function coupling (SFC) across select networks-especially the cerebellum-as individuals transitioned from wakefulness to hypnosis.

Neural assemblies coordinated by cortical waves are associated with waking and hallucinatory brain states.

The relationship between sensory stimuli and perceptions is brain-state dependent: in wakefulness, suprathreshold stimuli evoke perceptions; under anesthesia, perceptions are abolished; and during dreaming and in dissociated states, percepts are internally generated. Here, we exploit this state dependence to identify brain activity associated with internally generated or stimulus-evoked perceptions. In awake mice, visual stimuli phase reset spontaneous cortical waves to elicit 3-6 Hz feedback traveling waves.

Hormonal basis of sex differences in anesthetic sensitivity.

General anesthesia-a pharmacologically induced reversible state of unconsciousness-enables millions of life-saving procedures. Anesthetics induce unconsciousness in part by impinging upon sexually dimorphic and hormonally sensitive hypothalamic circuits regulating sleep and wakefulness. Thus, we hypothesized that anesthetic sensitivity should be sex-dependent and modulated by sex hormones.

One node among many: sevoflurane-induced hypnosis and the challenge of an integrative network-level view of anaesthetic action.

Building on their known ability to influence sleep and arousal, Li and colleagues show that modulating the activity of glutamatergic pedunculopontine tegmental neurones also alters sevoflurane-induced hypnosis. This finding adds support for the shared sleep-anaesthesia circuit hypothesis. However, the expanding recognition of many neuronal clusters capable of modulating anaesthetic hypnosis raises the question of how disparate and anatomically distant sites ultimately interact to coordinate global changes in the state of the brain.

Neural assemblies coordinated by cortical waves are associated with waking and hallucinatory brain states.

The relationship between sensory stimuli and perceptions is brain-state dependent: in wakefulness stimuli evoke perceptions; under anesthesia perceptions are abolished; during dreaming and in dissociated states, percepts are internally generated. Here, we exploit this state dependence to identify brain activity associated with internally generated or stimulus-evoked perception. In awake mice, visual stimuli phase reset spontaneous cortical waves to elicit 3-6 Hz feedback traveling waves.

Photoadduction of Anesthetic Ligands in Mouse Brain Markedly Extends Sedation and Hypnosis.

Photoaffinity ligands are best known as tools used to identify the specific binding sites of drugs to their molecular targets. However, photoaffinity ligands have the potential to further define critical neuroanatomic targets of drug action. In the brains of WT male mice, we demonstrate the feasibility of using photoaffinity ligands to prolong anesthesia via targeted yet spatially restricted photoadduction of azi--propofol (aziPm), a photoreactive analog of the general anesthetic propofol.

Ketamine triggers a switch in excitatory neuronal activity across neocortex.

The brain can become transiently disconnected from the environment while maintaining vivid, internally generated experiences. This so-called 'dissociated state' can occur in pathological conditions and under the influence of psychedelics or the anesthetic ketamine (KET). The cellular and circuit mechanisms producing the dissociative state remain poorly understood.

Quiescence during burst suppression and postictal generalized EEG suppression are distinct patterns of activity.

Objective: Periods of low-amplitude electroencephalographic (EEG) signal (quiescence) are present during both anesthetic-induced burst suppression (BS) and postictal generalized electroencephalographic suppression (PGES). PGES following generalized seizures induced by electroconvulsive therapy (ECT) has been previously linked to antidepressant response. The commonality of quiescence during both BS and PGES motivated trials to recapitulate the antidepressant effects of ECT using high doses of anesthetics.

Visual evoked feedforward-feedback traveling waves organize neural activity across the cortical hierarchy in mice.

Sensory processing is distributed among many brain regions that interact via feedforward and feedback signaling. Neuronal oscillations have been shown to mediate intercortical feedforward and feedback interactions. Yet, the macroscopic structure of the multitude of such oscillations remains unclear.

Anesthesia: Synaptic power failure.

One of the greatest unresolved mysteries in medicine relates to the molecular and neuronal mechanisms through which general anesthetics abolish perception. A new study in mice with mutations affecting mitochondrial complex 1 suggests that anesthetic-disruption of cellular energetics impairs endocytosis to alter synaptic function.

The posterior dominant rhythm: an electroencephalographic biomarker for cognitive recovery after general anaesthesia.

Background: The posterior dominant rhythm (PDR) was the first oscillatory pattern noted in the EEG. Evoked by wakeful eyelid closure, these oscillations dissipate over seconds during loss of arousal. The peak frequency of the PDR maintains stability over years, suggesting utility as a state biomarker in the surveillance of acute cognitive impairments.

Distinct and Dissociable EEG Networks Are Associated With Recovery of Cognitive Function Following Anesthesia-Induced Unconsciousness.

The temporal trajectories and neural mechanisms of recovery of cognitive function after a major perturbation of consciousness is of both clinical and neuroscientific interest. The purpose of the present study was to investigate network-level changes in functional brain connectivity associated with the recovery and return of six cognitive functions after general anesthesia. High-density electroencephalograms (EEG) were recorded from healthy volunteers undergoing a clinically relevant anesthesia protocol (propofol induction and isoflurane maintenance), and age-matched healthy controls.

QSIPrep: an integrative platform for preprocessing and reconstructing diffusion MRI data.

Diffusion-weighted magnetic resonance imaging (dMRI) is the primary method for noninvasively studying the organization of white matter in the human brain. Here we introduce QSIPrep, an integrative software platform for the processing of diffusion images that is compatible with nearly all dMRI sampling schemes. Drawing on a diverse set of software suites to capitalize on their complementary strengths, QSIPrep facilitates the implementation of best practices for processing of diffusion images.

Differential classification of states of consciousness using envelope- and phase-based functional connectivity.

The development of sophisticated computational tools to quantify changes in the brain's oscillatory dynamics across states of consciousness have included both envelope- and phase-based measures of functional connectivity (FC), but there are very few direct comparisons of these techniques using the same dataset. The goal of this study was to compare an envelope-based (i.e.

Recovery of consciousness and cognition after general anesthesia in humans.

Understanding how the brain recovers from unconsciousness can inform neurobiological theories of consciousness and guide clinical investigation. To address this question, we conducted a multicenter study of 60 healthy humans, half of whom received general anesthesia for 3 hr and half of whom served as awake controls. We administered a battery of neurocognitive tests and recorded electroencephalography to assess cortical dynamics.

Preoptic Area Modulation of Arousal in Natural and Drug Induced Unconscious States.

The role of the hypothalamic preoptic area (POA) in arousal state regulation has been studied since Constantin von Economo first recognized its importance in the early twentieth century. Over the intervening decades, the POA has been shown to modulate arousal in both natural (sleep and wake) as well as drug-induced (anesthetic-induced unconsciousness) states. While the POA is well known for its role in sleep promotion, populations of wake-promoting neurons within the region have also been identified.