Person:

Rhee, James

Understanding the neural basis of consciousness is fundamental to neuroscience research. Disruptions in cortico-cortical connectivity have been suggested as a primary mechanism of unconsciousness. By using a novel combination of positron emission tomography and functional magnetic resonance imaging, we studied anesthesia-induced unconsciousness and recovery using the α2-agonist dexmedetomidine. During unconsciousness, cerebral metabolic rate of glucose and cerebral blood flow were preferentially decreased in the thalamus, the Default Mode Network (DMN), and the bilateral Frontoparietal Networks (FPNs). Cortico-cortical functional connectivity within the DMN and FPNs was preserved. However, DMN thalamo-cortical functional connectivity was disrupted. Recovery from this state was associated with sustained reduction in cerebral blood flow and restored DMN thalamo-cortical functional connectivity. We report that loss of thalamo-cortical functional connectivity is sufficient to produce unconsciousness. DOI: http://dx.doi.org/10.7554/eLife.04499.001

Anesthetic drugs are typically administered to induce altered states of arousal that range from sedation to general anesthesia (GA). Systems neuroscience studies are currently being used to investigate the neural circuit mechanisms of anesthesia-induced altered arousal states. These studies suggest that by disrupting the oscillatory dynamics that are associated with arousal states, anesthesia-induced oscillations are a putative mechanism through which anesthetic drugs produce altered states of arousal. However, an empirical clinical observation is that even at relatively stable anesthetic doses, patients are sometimes intermittently responsive to verbal commands during states of light sedation. During these periods, prominent anesthesia-induced neural oscillations such as slow-delta (0.1–4 Hz) oscillations are notably absent. Neural correlates of intermittent responsiveness during light sedation have been insufficiently investigated. A principled understanding of the neural correlates of intermittent responsiveness may fundamentally advance our understanding of neural dynamics that are essential for maintaining arousal states, and how they are disrupted by anesthetics. Therefore, we performed a high-density (128 channels) electroencephalogram (EEG) study (n = 8) of sevoflurane-induced altered arousal in healthy volunteers. We administered temporally precise behavioral stimuli every 5 s to assess responsiveness. Here, we show that decreased eyes-closed, awake-alpha (8–12 Hz) oscillation power is associated with lack of responsiveness during sevoflurane effect-onset and -offset. We also show that anteriorization—the transition from occipitally dominant awake-alpha oscillations to frontally dominant anesthesia induced-alpha oscillations—is not a binary phenomenon. Rather, we suggest that periods, which were defined by lack of responsiveness, represent an intermediate brain state. We conclude that awake-alpha oscillation, previously thought to be an idling rhythm, is associated with responsiveness to behavioral stimuli.

An improved understanding of the neural correlates of altered arousal states is fundamental for precise brain state targeting in clinical settings. More specifically, electroencephalogram recordings are now increasingly being used to relate drug-specific oscillatory dynamics to clinically desired altered arousal states. Dexmedetomidine is an anesthetic adjunct typically administered in operating rooms and intensive care units to produce and maintain a sedative brain state. However, a high-density electroencephalogram characterization of the neural correlates of the dexmedetomidine-induced altered arousal state has not been previously accomplished. Therefore, we administered dexmedetomidine (1mcg/kg bolus over 10 minutes, followed by 0.7mcg/kg/hr over 50 minutes) and recorded high-density electroencephalogram signals in healthy volunteers, 18–36 years old (n = 8). We analyzed the data with multitaper spectral and global coherence methods. We found that dexmedetomidine was associated with increased slow-delta oscillations across the entire scalp, increased theta oscillations in occipital regions, increased spindle oscillations in frontal regions, and decreased beta oscillations across the entire scalp. The theta and spindle oscillations were globally coherent. During recovery from this state, these electroencephalogram signatures reverted towards baseline signatures. We report that dexmedetomidine-induced electroencephalogram signatures more closely approximate the human sleep onset process than previously appreciated. We suggest that these signatures may be targeted by real time visualization of the electroencephalogram or spectrogram in clinical settings. Additionally, these signatures may aid the development of control systems for principled neurophysiological based brain-state targeting.

Epidemiological and experimental data implicate branched chain amino acids (BCAAs) in the development of insulin resistance, but the mechanisms underlying this link remain unclear.1–3 Insulin resistance in skeletal muscle stems from excess accumulation of lipid species4, a process that requires blood-borne lipids to first traverse the blood vessel wall. Little is known, however, of how this trans-endothelial transport occurs or is regulated. Here, we leverage PGC-1α, a transcriptional coactivator that regulates broad programs of FA consumption, to identify 3-hydroxy-isobutyrate (3-HIB), a catabolic intermediate of the BCAA valine, as a novel paracrine regulator of trans-endothelial fatty acids (FA) transport. 3-HIB is secreted from muscle cells, activates endothelial FA transport, stimulates muscle FA uptake in vivo, and promotes muscle lipid accumulation and insulin resistance in animals. Conversely, inhibiting the synthesis of 3-HIB in muscle cells blocks the promotion of endothelial FA uptake. 3-HIB levels are elevated in muscle from db/db mice and from subjects with diabetes. These data thus unveil a novel mechanism that regulates trans-endothelial flux of FAs, revealing 3-HIB as a new bioactive signaling metabolite that links the regulation of FA flux to BCAA catabolism and provides a mechanistic explanation for how increased BCAA catabolic flux can cause diabetes.