Background The neural mechanisms of anesthetic vapors have not been studied in depth. However, modeling and experimental studies on the intravenous anesthetic propofol indicate that potentiation of γ-Aminobutyric acid receptors leads to a state of thalamocortical synchrony, observed as coherent frontal alpha oscillations, associated with unconsciousness. Sevoflurane, an ether derivative, also potentiates γ-Aminobutyric acid receptors. However, in humans, sevoflurane-induced coherent frontal alpha oscillations have not been well detailed. Methods To study the electroencephalogram dynamics induced by sevoflurane, we identified age and gender matched patients in which sevoflurane (n = 30) or propofol (n = 30) were used as the sole agent for maintenance of general anesthesia during routine surgery. We compared the electroencephalogram signatures of sevoflurane to propofol using time-varying spectral and coherence methods. Results Sevoflurane general anesthesia is characterized by alpha oscillations with maximum power and coherence at ~10 Hz, (mean±std; peak power, 4.3dB ± 3.5; peak coherence, 0.73 ± 0.1). These alpha oscillations are similar to those observed during propofol general anesthesia, which also has maximum power and coherence at ~10 Hz (peak power, 2.1dB ± 4.3; peak coherence, 0.71 ± 0.1). However, sevoflurane also exhibited a distinct theta coherence signature (peak frequency, 4.9Hz ± 0.6; peak coherence, 0.58 ± 0.1). Slow oscillations were observed in both cases, with no significant difference in power or coherence. Conclusion Our results indicate that sevoflurane, like propofol, induces coherent frontal alpha oscillations and slow oscillations in humans to sustain the anesthesia-induced unconscious state. These results suggest a shared molecular and systems-level mechanism for the unconscious state induced by these drugs.
Background Electroencephalogram patterns observed during sedation with dexmedetomidine appear similar to those observed during general anesthesia with propofol. This is evident with the occurrence of slow (0.1–1 Hz), delta (1–4 Hz), propofol-induced alpha (8–12 Hz), and dexmedetomidine-induced spindle (12–16 Hz) oscillations. However, these drugs have different molecular mechanisms and behavioral properties, and are likely accompanied by distinguishing neural circuit dynamics. Methods We measured 64-channel electroencephalogram under dexmedetomidine (n = 9) and propofol (n = 8) in healthy volunteers, 18–36 years of age. We administered dexmedetomidine with a 1mcg/kg loading bolus over 10 minutes, followed by a 0.7mcg/kg/hr infusion. For propofol, we used a computer controlled infusion to target the effect-site concentration gradually from and 0 µg/mL to 5 µg/mL. Volunteers listened to auditory stimuli and responded by button-press to determine unconsciousness. We analyzed the electroencephalogram using multitaper spectral and coherence analysis. Results Dexmedetomidine was characterized by spindles with maximum power and coherence at ~13 Hz, (mean±std; power, −10.8dB±3.6; coherence, 0.8±0.08), while propofol was characterized with frontal alpha oscillations with peak frequency at ~11 Hz (power, 1.1dB±4.5; coherence, 0.9±0.05). Notably, slow oscillation power during a general anesthetic state under propofol (power, 13.2dB±2.4) was much larger than during sedative states under both propofol (power, −2.5dB±3.5) and dexmedetomidine (power, −0.4dB±3.1). Conclusion Our results indicate that dexmedetomidine and propofol place patients into different brain states, and suggests that propofol enables a deeper state of unconsciousness by inducing large amplitude slow oscillations that produce prolonged states of neuronal silence.
General anesthesia (GA) is a reversible drug-induced state of altered arousal required for more than 60,000 surgical procedures each day in the United States alone. Sedation and unconsciousness under GA are associated with stereotyped electrophysiological oscillations that are thought to reflect profound disruptions of activity in neuronal circuits that mediate awareness and cognition. Computational models make specific predictions about the role of the cortex and thalamus in these oscillations. In this paper, we provide in vivo evidence in rats that alpha oscillations (10-15 Hz) induced by the commonly used anesthetic drug propofol are synchronized between the thalamus and the medial prefrontal cortex. We also show that at deep levels of unconsciousness where movement ceases, coherent thalamocortical delta oscillations (1-5 Hz) develop, distinct from concurrent slow oscillations (0.1-1 Hz). The structure of these oscillations in both cortex and thalamus closely parallel those observed in the human electroencephalogram during propofol-induced unconsciousness. During emergence from GA, this synchronized activity dissipates in a sequence different from that observed during loss of consciousness. A possible explanation is that recovery from anesthesiainduced unconsciousness follows a "boot-up" sequence actively driven by ascending arousal centers. The involvement of medial prefrontal cortex suggests that when these oscillations (alpha, delta, slow) are observed in humans, self-awareness and internal consciousness would be impaired if not abolished. These studies advance our understanding of anesthesia-induced unconsciousness and altered arousal and further establish principled neurophysiological markers of these states.anesthesia | prefrontal cortex | thalamus | coherence | propofol G eneral anesthesia (GA) is a reversible drug-induced state consisting of unconsciousness, analgesia, amnesia, akinesia, and physiological stability (1). In the United States nearly 60,000 surgical procedures are conducted under GA every day, making GA one of the most common manipulations of the brain and central nervous system in medicine (1). The molecular mechanisms by which anesthetic drugs alter brain function have been well characterized (2, 3). Detailed analyses of neural circuitand systems-level mechanisms of GA are more recent (1, 4, 5). Understanding the system-wide effects of anesthetic drugs is necessary in order to understand how these drugs produce states of altered arousal and unconsciousness.One of the most commonly used anesthetic drugs is 2,6-diisopropylphenol (propofol), a GABA-A receptor agonist (6). Electroencephalogram (EEG) recordings in humans during gradual induction of unconsciousness with propofol show the appearance of frontal β oscillations (15-30 Hz) at the onset of sedation, followed by the appearance of coherent frontal α (8-12 Hz) oscillations (7-10) and widespread slow (0.1-1 Hz) and δ (1-4 Hz) oscillations (7, 11, 12) when subjects no longer respond to sensory stimuli. Biophysical models of neuronal dy...
Objective Ketamine is a widely used drug with clinical and research applications, and also known to be used as a recreational drug. Ketamine produces conspicuous changes in the electrocorticographic (ECoG) signals observed both in humans and rodents. In rodents, the intracranial ECoG displays a High-Frequency Oscillation (HFO) which power is modulated non-linearly by ketamine dose. Despite the widespread use of ketamine there is no model description of the relationship between the pharmacokinetic-pharmacodynamics (PK-PD) of ketamine and the observed HFO power. Approach In the present study, we developed a PK-PD model based on estimated ketamine concentration, its known pharmacological actions, and observed ECoG effects. The main pharmacological action of ketamine is antagonism of the NMDA receptor (NMDAR), which in rodents is accompanied by a high-frequency oscillation (HFO) observed in the ECoG. At high doses, however, ketamine also acts at non-NMDAR sites, produces loss of consciousness, and the transient disappearance of the HFO. We propose a two-compartment PK model that represents the concentration of ketamine, and a PD model based in opposing effects of the NMDAR and non-NMDAR actions on the HFO power. Main results We recorded ECoG from the cortex of rats after two doses of ketamine, and extracted the HFO power from the ECoG spectrograms. We fit the PK-PD model to the time course of the HFO power, and showed that the model reproduces the dose-dependent profile of the HFO power. The model provides good fits even in the presence of high variability in HFO power across animals. As expected, the model does not provide good fits to the HFO power after dosing the pure NMDAR antagonist MK-801. Significance Our study provides a simple model to relate the observed electrophysiological effects of ketamine to its actions at the molecular level at different concentrations. This will improve the study of ketamine and rodent models of schizophrenia to better understand the wide and divergent range of effects that ketamine has.
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