Disruption of thalamic functional connectivity is a neural correlate of dexmedetomidine-induced unconsciousness

Akeju, Oluwaseun; Loggia, Marco L.; Catana, Ciprian; Pavone, Kara J.; Vázquez, Rafael; Rhee, James; Ramirez, Violeta Contreras; Chonde, Daniel B.; Izquierdo‐Garcia, David; Arabasz, Grae; Hsu, Shirley; Habeeb, Kathleen; Hooker, Jacob M.; Napadow, Vitaly; Brown, Emery N.; Purdon, Patrick L.

doi:10.7554/elife.04499

Cited by 146 publications

(142 citation statements)

References 84 publications

(130 reference statements)

Supporting

Mentioning

114

Contrasting

Unclassified

Order By: Relevance

“…LC neurons project to the basal forebrain, preoptic area (POA), hypothalamus, thalamus and cortex 18,37 . The effect of norepinephrine blockade on the POA, in particular, has wide ranging ‘upstream’ effects involving several neurotransmitters and neural networks, leading to decreased arousal, sleep-like states or deep sedation 18 .…”

Section: Discussionmentioning

confidence: 99%

Anesthesia with Dexmedetomidine and Low-dose Isoflurane Increases Solute Transport via the Glymphatic Pathway in Rat Brain When Compared with High-dose Isoflurane

et al. 2017

View full text Add to dashboard Cite

Background The glymphatic pathway transports cerebrospinal fluid through the brain, thereby facilitating waste removal. A unique aspect of this pathway is that its function depends on the state of consciousness of the brain and is associated with norepinephrine activity. A current view is that all anesthetics will increase glymphatic transport by inducing unconsciousness. This view implies that the effect of anesthetics on glymphatic transport should be independent of their mechanism of action, as long as they induce unconsciousness. We tested this hypothesis by comparing the supplementary effect of dexmedetomidine, which lowers norepinephrine, with isoflurane only, which does not. Methods Female rats were anesthetized with either isoflurane (N = 8) or dexmedetomidine plus low-dose isoflurane (N = 8). Physiologic parameters were recorded continuously. Glymphatic transport was quantified by contrast-enhanced magnetic resonance imaging. Cerebrospinal fluid and gray and white matter volumes were quantified from T1 maps, and blood vessel diameters were extracted from time-of-flight magnetic resonance angiograms. Electroencephalograms were recorded in separate groups of rats. Results Glymphatic transport was enhanced by 32% in rats anesthetized with dexmedetomidine plus low-dose isoflurane when compared with isoflurane. In the hippocampus, glymphatic clearance was sixfold more efficient during dexmedetomidine plus low-dose isoflurane anesthesia when compared with isoflurane. The respiratory and blood gas status was comparable in rats anesthetized with the two different anesthesia regimens. In the dexmedetomidine plus low-dose isoflurane rats, spindle oscillations (9 to 15 Hz) could be observed but not in isoflurane anesthetized rats. Conclusions We propose that anesthetics affect the glymphatic pathway transport not simply by inducing unconsciousness but also by additional mechanisms, one of which is the repression of norepinephrine release.

show abstract

Section: Discussionmentioning

confidence: 99%

Anesthesia with Dexmedetomidine and Low-dose Isoflurane Increases Solute Transport via the Glymphatic Pathway in Rat Brain When Compared with High-dose Isoflurane

et al. 2017

View full text Add to dashboard Cite

show abstract

“…The hypnotic effects of α 2 -AR agonists were initially proposed to be mediated by presynaptic α 2A -ARs on noradrenergic projections from the locus coeruleus to mimic endogenous sleep mechanisms. 45,48 While indirect neurophysiological studies in vivo continue to invoke this mechanism, 49 genetic studies provide strong evidence that non-adrenergic, not noradrenergic, α 2A -ARs mediate the sedative, hypnotic and anesthetic-sparing actions of α 2 -AR agonists. 9,10,46,47 Plausible targets for the hypnotic and anesthetic-sparing effects of α 2 -AR agonists include direct suppression of synaptic transmission in cortico-cortical 3 and thalamo-cortical networks.…”

Section: Discussionmentioning

confidence: 99%

“…9,10,46,47 Plausible targets for the hypnotic and anesthetic-sparing effects of α 2 -AR agonists include direct suppression of synaptic transmission in cortico-cortical 3 and thalamo-cortical networks. 48,49 A recent study in vivo using the TetTag-hM 3 D q system to record and reactivate neuronal groups activated by DEX implicates the preoptic hypothalamus and neighboring dorsal structures in DEX-induced sedation. 46 …”

Section: Discussionmentioning

confidence: 99%

α2-Adrenergic Receptor and Isoflurane Modulation of Presynaptic Ca2+ Influx and Exocytosis in Hippocampal Neurons

2016

View full text Add to dashboard Cite

Background Evidence indicates that the anesthetic-sparing effects of α2-adrenergic receptor (AR) agonists involve α2A-AR heteroreceptors on nonadrenergic neurons. Since volatile anesthetics inhibit neurotransmitter release by reducing synaptic vesicle (SV) exocytosis, the authors hypothesized that α2-AR agonists inhibit nonadrenergic SV exocytosis and thereby potentiate presynaptic inhibition of exocytosis by isoflurane. Methods Quantitative imaging of fluorescent biosensors of action potential–evoked SV exocytosis (synaptophysin-pHluorin) and Ca2+ influx (GCaMP6) were used to characterize presynaptic actions of the clinically used α2-AR agonists dexmedetomidine and clonidine, and their interaction with isoflurane, in cultured rat hippocampal neurons. Results Dexmedetomidine (0.1 μM, n = 10) or clonidine (0.5 μM, n = 8) inhibited action potential–evoked exocytosis (54 ± 5% and 59 ± 8% of control, respectively; P < 0.001). Effects on exocytosis were blocked by the subtype-nonselective α2-AR antagonist atipamezole or the α2A-AR–selective antagonist BRL 44408 but not by the α2C-AR–selective antagonist JP 1302. Dexmedetomidine inhibited exocytosis and presynaptic Ca2+ influx without affecting Ca2+ coupling to exocytosis, consistent with an effect upstream of Ca2+–exocytosis coupling. Exocytosis coupled to both N-type and P/Q-type Ca2+ channels was inhibited by dexmedetomidine or clonidine. Dexmedetomidine potentiated inhibition of exocytosis by 0.7 mM isoflurane (to 42 ± 5%, compared to 63 ± 8% for isoflurane alone; P < 0.05). Conclusions Hippocampal SV exocytosis is inhibited by α2A-AR activation in proportion to reduced Ca2+ entry. These effects are additive with those of isoflurane, consistent with a role for α2A-AR presynaptic heteroreceptor inhibition of nonadrenergic synaptic transmission in the anesthetic-sparing effects of α2A-AR agonists.

show abstract

“…In both rodents and humans, the medial prefrontal cortex is part of a larger resting-state "default mode" network that is active in the absence of external stimuli and that is functionally connected with thalamus (47). The medial prefrontal cortex in particular is active in self-referential tasks (48) and during states of "internal consciousness" (49).…”

Section: Discussionmentioning

confidence: 99%

Thalamocortical synchronization during induction and emergence from propofol-induced unconsciousness

Flores

Hartnack

Fath

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

151

130

View full text Add to dashboard Cite

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...

show abstract

Disruption of thalamic functional connectivity is a neural correlate of dexmedetomidine-induced unconsciousness

Cited by 146 publications

References 84 publications

Anesthesia with Dexmedetomidine and Low-dose Isoflurane Increases Solute Transport via the Glymphatic Pathway in Rat Brain When Compared with High-dose Isoflurane

Anesthesia with Dexmedetomidine and Low-dose Isoflurane Increases Solute Transport via the Glymphatic Pathway in Rat Brain When Compared with High-dose Isoflurane

α2-Adrenergic Receptor and Isoflurane Modulation of Presynaptic Ca2+ Influx and Exocytosis in Hippocampal Neurons

Thalamocortical synchronization during induction and emergence from propofol-induced unconsciousness

Contact Info

Product

Resources

About