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

Abstract

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.

Figures

Figure 1.

Physiology and psychophysical data. a, Propofol effect site concentrations were significantly different across states (repeated-measures ANOVA, p < 0.001). b, There were not significant changes in physiological parameters across states. c, Time to completion of the verbal task was significantly longer when sedated compared with awake (p = 0.002). d, Discrimination index was significantly lower when sedated compared with awake (p < 0.001). A, Awake; S, sedated; U, unresponsive; SBP, systolic blood pressure; DBP, diastolic blood pressure; EtCO2, end-tidal carbon dioxide; HR, heart rate; SpO2, oxyhemoglobin saturation.

Figure 2.

Group ANOVA demonstrating a main effect of “state” on activity in response to auditory (upper row) and noxious (lower row) stimulation. A significant reduction in responses to auditory stimulation was observed bilaterally in the putamen, pallidum, amygdala, superior temporal gyrus, anterior insula and anterior cingulate cortex. A significant reduction in responses to noxious stimulation was observed in the insula bilaterally and in the right putamen and pallidum, contralateral to the noxious stimuli. Data were thresholded at Z > 2.3, cluster-corrected p < 0.05.

Figure 3.

Schematic illustrating functional connectivity changes of the putamen and thalamus. a, Paired mean BOLD signals (averaged across subjects and region) from three regions of interest are shown in overlay. Plots show volumes 350–450 (during which stimuli were presented at the same times to each subject) of 660 total volumes. Bar charts of the respective correlations were calculated across the entire 660 volume time series for individuals and then averaged. b illustrates the observed change in correlation, plotted on a unit circle, between the BOLD signal from the thalamus (left) and putamen (right) and each of 12 specific brain regions. S1, Primary somatosensory cortex; STG, superior temporal gyrus; ACC, anterior cingulate cortex; SN, substantia nigra; PAC, primary auditory cortex; PCC, precuneus cortex.

Figure 4.

Regions where ANOVA revealed significantly reduced functional connectivity with the putamen (above in blue) or thalamus (below in orange) with deepening sedation. Data were thresholded at Z > 2.3, cluster corrected p < 0.05.