Cortical and subcortical connectivity changes during decreasing levels of consciousness in humans: a functional magnetic resonance imaging study using propofol.

While ubiquitous, pharmacological manipulation of consciousness remains poorly defined and incompletely understood (Prys-Roberts, 1987). This retards anesthetic drug development, confounds interpretation of animal studies conducted under anesthesia, and limits the sensitivity of clinical monitors of cerebral function to intact perception. Animal and human studies propose a functional "switch" at the level of the thalamus, with inhibition of thalamo-cortical transmission characterizing loss of consciousness (Alkire et al., 2000; Mashour, 2006). We investigated the effects of propofol, widely used for anesthesia and sedation, on spontaneous and evoked cerebral activity using functional magnetic resonance imaging (fMRI). A series of auditory and noxious stimuli was presented to eight healthy volunteers at three behavioral states: awake, "sedated" and "unresponsive." Performance in a verbal task and the absence of a response to verbal stimulation, rather than propofol concentrations, were used to define these states clinically. Analysis of stimulus-related blood oxygenation level-dependent signal changes identified reductions in cortical and subcortical responses to auditory and noxious stimuli in sedated and unresponsive states. A specific reduction in activity within the putamen was noted and further investigated with functional connectivity analysis. Progressive failure to perceive or respond to auditory or noxious stimuli was associated with a reduction in the functional connectivity between the putamen and other brain regions, while thalamo-cortical connectivity was relatively preserved. This result has not been previously described and suggests that disruption of subcortical thalamo-regulatory systems may occur before, or even precipitate, failure of thalamo-cortical transmission with the induction of unconsciousness.