Mild Propofol Sedation Reduces Frontal Lobe and Thalamic Cerebral Blood Flow: An Arterial Spin Labeling Study

The Observer's Assessment of Alertness/Sedation (OAA/S) Scale was developed to measure the level of alertness in subjects who are sedated. This scale was tested in 18 subjects in a three-period crossover study to assess its reliability and its criterion, behavioral, and construct validity. After receiving either placebo or a titrated dose of midazolam to produce light or heavy sedation, each subject was administered two sedation scales (OAA/S Scale and a Visual Analogue Scale) and two performances tests (Digit Symbol Substitution Test and Serial Sevens Subtraction). Two raters individually evaluated the subject's level of alertness on each of the two sedation scales. The results obtained on the OAA/S Scale were reliable and valid as measured by high correlations between the two raters and high correlations between the OAA/S Scale and two of the three standard tests used in this study. The OAA/S Scale was sensitive to the level of midazolam administered; all pairwise comparisons were significant (p less than 0.05) for all three treatment levels at both test periods.

Mechanisms of anesthesia-induced loss of consciousness remain poorly understood. Resting-state functional magnetic resonance imaging allows investigating whole-brain connectivity changes during pharmacological modulation of the level of consciousness. Low-frequency spontaneous blood oxygen level-dependent fluctuations were measured in 19 healthy volunteers during wakefulness, mild sedation, deep sedation with clinical unconsciousness, and subsequent recovery of consciousness. Propofol-induced decrease in consciousness linearly correlates with decreased corticocortical and thalamocortical connectivity in frontoparietal networks (i.e., default- and executive-control networks). Furthermore, during propofol-induced unconsciousness, a negative correlation was identified between thalamic and cortical activity in these networks. Finally, negative correlations between default network and lateral frontoparietal cortices activity, present during wakefulness, decreased proportionally to propofol-induced loss of consciousness. In contrast, connectivity was globally preserved in low-level sensory cortices, (i.e., in auditory and visual networks across sedation stages). This was paired with preserved thalamocortical connectivity in these networks. Rather, waning of consciousness was associated with a loss of cross-modal interactions between visual and auditory networks. Our results shed light on the functional significance of spontaneous brain activity fluctuations observed in functional magnetic resonance imaging. They suggest that propofol-induced unconsciousness could be linked to a breakdown of cerebral temporal architecture that modifies both within- and between-network connectivity and thus prevents communication between low-level sensory and higher-order frontoparietal cortices, thought to be necessary for perception of external stimuli. They emphasize the importance of thalamocortical connectivity in higher-order cognitive brain networks in the genesis of conscious perception.

Frontoparietal connectivity has been suggested to be important in conscious processing and its interruption is thought to be one mechanism of general anesthesia. Data in animals demonstrate that feedforward processing of information may persist during the anesthetized state, while feedback processing is inhibited. We investigated the directionality and functional organization of frontoparietal connectivity in 10 human subjects anesthetized with propofol on two separate occasions. Multichannel electroencephalography and a computational method of assessing directed functional connectivity were employed. We demonstrate that directed feedback connectivity is diminished with loss of consciousness and returns with responsiveness to verbal command. We also applied the Dendrogram classification method to assess the global organization of directed functional connectivity during consciousness and anesthesia. We demonstrate a state-specific hierarchy and subject-specific subhierarchy in functional organization. These data support the hypothesis that specific states of human consciousness are defined by specific states of frontoparietal connectivity.