Anthony G. Hudetz - US grants

SUMMARY The overall goal of this project is to understand the mechanisms by which general anesthetics suppress consciousness and allow its return during emergence. Our general hypothesis is that anesthetics remove consciousness by disrupting functional integration across cortical neuronal networks. The proposed project builds upon our one-and-a-half decade-long investigation into the systems neuroscience mechanisms of anesthesia. In our prior work, we investigated the effect of volatile anesthetics on the power and coherence of gamma oscillations, and on their preferential role in corticocortical feedback vs. feedforward signaling as a neuronal correlate of unconsciousness. Subsequently, we focused on how the dynamics of spiking activity of cortical neurons and the complexity of their interactions were modulated by anesthetics. Here, using optogenetic and electrical microstimulation techniques, we extend this work to examine how cortical top- down, subcortical bottom-up and local state modulations alter cortical neuronal interactions associated with loss and return of consciousness. We will examine spontaneous ongoing activity and sensory stimulus-related neuronal interactions across visual and association cortex and will directly interrogate functional circuits using selective microstimulation for the first time. We will test the hypothesis that the complexity of spontaneous and stimulus-driven neuronal interactions will undergo a distinct transition associated with loss and recovery of consciousness as a function brain state modified by anesthetic dose, top-down and bottom-up modulation, and general cortical excitability. We will study the concentration-dependent effect of four representative anesthetic agents with different pharmacological profiles: desflurane, propofol, dexmedetomidine, and ketamine to find a common, agent-invariant neuronal correlate of unconsciousness. State changes at select anesthetic concentrations will be elicited by cortical or subcortical stimulation, neuronal silencing, and subnoxious somatosensory arousal. Parallel spike trains and local field potentials will be recorded from visual and adjacent association cortices using chronically implanted multielectrode arrays in unrestrained rats. Spontaneous and visual stimulus-related excitatory and inhibitory monosynaptic connectivity, neuronal interaction complexity, and microstimulation-induced effective connectivity within and between each cortical region will be derived. These experiments will provide essential new information about the role of cortical neuronal interactions in information integration as a function of conscious state and help uncover the degree to which both globally and locally driven neuronal activity is altered by brain states. The proposed work will advance our understanding of the neural mechanism of anesthesia and the neurobiological basis of consciousness at an integrative level. Our findings will augment the basic scientific knowledge necessary for the future development of novel electrophysiological monitoring of the state of consciousness and for the development of new approaches to manipulate the state consciousness for general anesthesia.

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.