RESUMO
During recovery from anesthesia, brain activity switches abruptly between a small set of discrete states. Surprisingly, this switching also occurs under constant doses of anesthesia, even in the absence of stimuli. These metastable states and the transitions between them are thought to form a "scaffold" that ultimately guides the brain back to wakefulness. The processes that constrain cortical activity patterns to these states and govern how states are coordinated between different cortical regions are unknown. If state transitions were driven by subcortical modulation, different cortical sites should exhibit near-synchronous state transitions. Conversely, spatiotemporal heterogeneity would suggest that state transitions are coordinated through corticocortical interactions. To differentiate between these hypotheses, we quantified synchrony of brain states in male rats exposed to a fixed isoflurane concentration. States were defined from spectra of local field potentials recorded across layers of visual and motor cortices. A transition synchrony measure shows that most state transitions are highly localized. Furthermore, while most pairs of cortical sites exhibit statistically significant coupling of both states and state transition times, coupling strength is typically weak. States and state transitions in the thalamic input layer (L4) are particularly decoupled from those in supragranular and infragranular layers. This suggests that state transitions are not imposed on the cortex by broadly projecting modulatory systems. Although each pairwise interaction is typically weak, we show that the multitude of such weak interactions is sufficient to confine global activity to a small number of discrete states.SIGNIFICANCE STATEMENT The brain consistently recovers to wakefulness after anesthesia, but this process is poorly understood. Previous work revealed that, during recovery from anesthesia, corticothalamic activity falls into one of several discrete patterns. The neuronal mechanisms constraining the cortex to just a few discrete states remain unknown. Global states could be coordinated by fluctuations in subcortical nuclei that project broadly to the cortex. Alternatively, these states may emerge from interactions within the cortex itself. Here, we provide evidence for the latter possibility by demonstrating that most pairs of cortical sites exhibit weak coupling. We thereby lay groundwork for future investigations of the specific cellular and network mechanisms of corticocortical activity state coupling.
Assuntos
Anestesia , Isoflurano , Ratos , Masculino , Animais , Isoflurano/farmacologia , Vigília/fisiologia , Neurônios/fisiologia , TálamoRESUMO
BACKGROUND: Recent studies of anesthetic-induced unconsciousness in humans have focused predominantly on the intravenous drug propofol and have identified anterior dominance of alpha rhythms and frontal phase-amplitude coupling patterns as neurophysiological markers. However, it is unclear whether the correlates of propofol-induced unconsciousness are generalizable to inhaled anesthetics, which have distinct molecular targets and which are used more commonly in clinical practice. METHODS: The authors recorded 64-channel electroencephalograms in healthy human participants during consciousness, sevoflurane-induced unconsciousness, and recovery (n = 10; n = 7 suitable for analysis). Spectrograms and scalp distributions of low-frequency (1 Hz) and alpha (10 Hz) power were analyzed, and phase-amplitude modulation between these two frequencies was calculated in frontal and parietal regions. Phase lag index was used to assess phase relationships across the cortex. RESULTS: At concentrations sufficient for unconsciousness, sevoflurane did not result in a consistent anteriorization of alpha power; the relationship between low-frequency phase and alpha amplitude in the frontal cortex did not undergo characteristic transitions. By contrast, there was significant cross-frequency coupling in the parietal region during consciousness that was not observed after loss of consciousness. Furthermore, a reversible disruption of anterior-posterior phase relationships in the alpha bandwidth was identified as a correlate of sevoflurane-induced unconsciousness. CONCLUSION: In humans, sevoflurane-induced unconsciousness is not correlated with anteriorization of alpha and related cross-frequency patterns, but rather by a disruption of phase-amplitude coupling in the parietal region and phase-phase relationships across the cortex.
Assuntos
Anestésicos Inalatórios/farmacologia , Éteres Metílicos/farmacologia , Inconsciência/induzido quimicamente , Ritmo alfa/efeitos dos fármacos , Anestésicos Intravenosos/farmacologia , Comportamento/efeitos dos fármacos , Eletroencefalografia/efeitos dos fármacos , Feminino , Humanos , Masculino , Propofol/farmacologia , Sevoflurano , Inconsciência/psicologia , Adulto JovemRESUMO
Previous research demonstrates that the underlying state of the brain influences how sensory stimuli are processed. Canonically, the state of the brain has been defined by quantifying the spectral characteristics of spontaneous fluctuations in local field potentials (LFP). Here, we utilized isoflurane and propofol anesthesia to parametrically alter the spectral state of the murine brain. With either drug, we produce slow wave activity, with low anesthetic doses, or burst suppression, with higher doses. We find that while spontaneous LFP oscillations were similar, the average visual-evoked potential (VEP) was always smaller in amplitude and shorter in duration under propofol than under comparable doses of isoflurane. This diminished average VEP results from increased trial-to-trial variability in VEPs under propofol. One feature of single trial VEPs that was consistent in all animals was visual-evoked gamma band oscillation (20-60 Hz). This gamma band oscillation was coherent between trials in the early phase (<250 ms) of the visual evoked potential under isoflurane. Inter trial phase coherence (ITPC) of gamma oscillations was dramatically attenuated in the same propofol anesthetized mice despite similar spontaneous oscillations in the LFP. This suggests that while both anesthetics lead to loss of consciousness (LOC), elicit slow oscillations and burst suppression, only the isoflurane permits phase resetting of gamma oscillations by visual stimuli. These results demonstrate that accurate characterization of a brain state must include both spontaneous as well as stimulus-induced perturbations of brain activity.
RESUMO
BACKGROUND: Carbon monoxide (CO) poisoning is the leading cause of poisoning mortality and morbidity in the USA. Carboxyhemoglobin (COHb) levels are not predictive of severity or prognosis. At this time, the measurement of mitochondrial respiration may serve as a biomarker in CO poisoning. The primary objective of this study was to assess changes in mitochondrial function consisting of respiration and generation of reactive oxygen species (ROS) in peripheral blood mononuclear cells (PBMCs) obtained from patients with CO poisoning. METHODS: PBMCs from patients having confirmed CO exposure treated with hyperbaric oxygen or HBO (CO group) and healthy controls (control group) were analyzed with high-resolution respirometry. PBMCs were placed in a 2-ml chamber at a final concentration of 3-4 × 106 cells/ml to simultaneously obtain both respiration and hydrogen peroxide (H2O2) production. In the CO group, we performed measurements before and after patients underwent their first HBO treatment. RESULTS: We enrolled a total of 17 subjects, including 7 subjects with confirmed CO poisoning and 10 subjects in the control group. The CO group included five (71.4%) men and two (28.6%) women having a median COHb of 28%. There was a significant decrease in respiration as measured in pmol O2 × s- 1 × 10- 6 PBMCs in the CO group (pre-HBO) when compared to the control group: maximal respiration (18.4 ± 2.4 versus 35.4 ± 2.8, P < 0.001); uncoupled Complex I respiration (19.8 ± 1.8 versus 41.1 ± 3.8, P < 0.001); uncoupled Complex I + II respiration (32.3 ± 3.2 versus 58.3 ± 3.1, P < 0.001); Complex IV respiration (43.5 ± 2.9 versus 63.6 ± 6.31, P < 0.05). There were also similar differences measured in the CO group before and after HBO treatment with an overall increase in respiration present after treatment. We also determined the rate of H2O2 production simultaneously with the measurement of respiration. There was an overall significant increase in the H2O2 production in the CO group after HBO treatment when compared to prior HBO treatment and the control group. CONCLUSIONS: In this study, PBMCs obtained from subjects with CO poisoning have an overall decrease in respiration (similar H2O2 production) when compared to controls. The inhibition of Complex IV respiration is from CO binding leading to a downstream decrease in respiration at other complexes. PBMCs obtained from CO-poisoned individuals immediately following initial HBO therapy displayed an overall increase in both respiration and H2O2 production. The study findings demonstrate that treatment with HBO resulted in improved cellular respiration but a higher H2O2 production. It is unclear if the increased production of H2O2 in HBO treatment is detrimental.
RESUMO
Mechanisms through which anesthetics disrupt neuronal activity are incompletely understood. In order to study anesthetic mechanisms in the intact brain, tight control over anesthetic pharmacology in a genetically and neurophysiologically accessible animal model is essential. Here, we developed a pharmacokinetic model that quantitatively describes propofol distribution into and elimination out of the brain. To develop the model, we used jugular venous catheters to infuse propofol in mice and measured propofol concentration in serial timed brain and blood samples using high performance liquid chromatography (HPLC). We then used adaptive fitting procedures to find parameters of a three compartment pharmacokinetic model such that all measurements collected in the blood and in the brain across different infusion schemes are fit by a single model. The purpose of the model was to develop target controlled infusion (TCI) capable of maintaining constant brain propofol concentration at the desired level. We validated the model for two different targeted concentrations in independent cohorts of experiments not used for model fitting. The predictions made by the model were unbiased, and the measured brain concentration was indistinguishable from the targeted concentration. We also verified that at the targeted concentration, state of anesthesia evidenced by slowing of the electroencephalogram and behavioral unresponsiveness was attained. Thus, we developed a useful tool for performing experiments necessitating use of anesthetics and for the investigation of mechanisms of action of propofol in mice.