PROJECT SUMMARY / ABSTRACT The overall goal of our work is to better understand the systems-level neuronal mechanisms by which general anesthetics produce loss of consciousness. Our general hypothesis has been that anesthetics suppress consciousness by disrupting the functioning of large-scale brain networks that support information integration in the brain. The specific aims of the present proposal significantly advance and expand, both conceptually and experimentally, our work conducted during the period of the first award. Specifically, we intend to test if sedated participants who no longer respond behaviorally to spoken command are still able to perceive and understand environmental signals and volitionally control their mentation in a task-related manner. We will test this hypothesis by functional magnetic resonance imaging (fMRI) applied to assess the healthy participants' (healthy volunteers) ability to generate willful, neuroanatomically specific, blood-oxygen-level dependent (BOLD) responses during two established mental-imagery tasks (playing tennis and spatial navigation). We hypothesize that under specific conditions of sedation, subjects will retain their capacity for mental imagery despite their failure to initiate an overt response. If so, then the new findings may induce a paradigm shift in the clinical assessment of consciousness in anesthesia. They would also establish validation for monitoring disorders of consciousness and establish generality of the finding between disorders of consciousness and general anesthesia. As a second aim, we intend to determine for the first time, the neural conditions for the participants' ability for volitional mental imagery. We hypothesize that spontaneous fluctuations of brain states during sedation directly influence and predict the participants' ability for mental imagery. If confirmed, this would imply a novel causal link between the state of intrinsic network activity and volitional mental activity in reduced states of consciousness. This would have extremely important translational significance for optimizing brain-computer interfaces for the aid of patients with behavioral compromise or reduced consciousness. Finally, in a third aim, we will determine the neural correlates of distorted perception under sedation using complex, temporally structured stimuli such as music. The latter studies should yield insight into how sedation may alter the temporal integration of complex stimuli supporting conscious experience. Taken together, the project should significantly advance our understanding of the fundamental neuronal mechanisms of anesthetic modulation of conscious cognition with a significant translational and paradigmatic impact for the clinical assessment of the state of consciousness and for the potential communication of patients via volitional mental activity.