In this functional magnetic resonance imaging study, we examined the effect of mild propofol sedation and propofol-induced unconsciousness on resting state brain connectivity, using graph analysis based on independent component analysis and a classical seed-based analysis. Contrary to previous propofol research, which mainly emphasized the importance of connectivity in the default mode network (DMN) and external control network (ECN), we focused on the salience network, thalamus, and brainstem. The importance of these brain regions in brain arousal and organization merits a more detailed examination of their connectivity response to propofol. We found that the salience network disintegrated during propofol-induced unconsciousness. The thalamus decreased connectivity with the DMN, ECN, and salience network, while increasing connectivity with sensorimotor and auditory/insular cortices. Brainstem regions disconnected from the DMN with unconsciousness, while the pontine tegmental area increased connectivity with the insulae during mild sedation. These findings illustrate that loss of consciousness is associated with a wide variety of decreases and increases of both cortical and subcortical connectivity. It furthermore stresses the necessity of also examining resting state connectivity in networks representing arousal, not only those associated with awareness.

Committee number: 'Comité d'Ethique Hospitalo-Facultaire Universitaire de Liège' (707); EudraCT number: 2012-003562-40; internal reference: 20121/135; accepted on August 31, 2012; Chair: Prof G. Rorive. As it was considered a phase I clinical trial, this protocol does not appear on the EudraCT public website.

Our findings indicate that connectivity decreases associated with propofol sedation, involving the thalamus and insula, are relatively small compared with those already caused by DOC-associated structural brain injury. Nonetheless, given the known importance of the thalamus in brain arousal, its disruption could well reflect the diminished movement obtained in these patients. However, more research is needed on this topic to fully address the research question.

Main objective: Disorders of consciousness (DOC; encompassing coma, vegetative state/unresponsive wakefulness syndrome (VS/UWS) and minimally conscious state minus/plus (MCS-/+)) are associated with structural brain injury. The extent of this damage remains poorly understood and merits a detailed examination using novel analysis techniques. Research design/methods and procedures: This study used voxel-based morphometry (VBM) on structural magnetic resonance imaging scans of 61 patients with DOC to examine grey and white matter injury associated with DOC, time spent in DOC, aetiology and diagnosis. Main outcomes and results: DOC and time spent in DOC were found to be associated with widespread structural brain injury, although the latter did not correlate strongly with injury in the right cerebral hemisphere. Traumatic, as compared to non-traumatic aetiology, was related to more injury in the brainstem, midbrain, thalamus, hypothalamus, basal forebrain, cerebellum, and posterior corpus callosum. Potential structural differences were found between VS/ UWS and MCS and between MCS-and MCS+, but need further examination. Conclusions: The findings indicate that both traumatic and non-traumatic DOC are associated with widespread structural brain injury, although differences exist that could lead to aetiologyspecific treatment strategies. Furthermore, the high degree of atrophy occurring after initial brain injury prompts the development and use of neuroprotective techniques to potentially increase patients' chances of recovery. KeywordsVegetative state/unresponsive wakefulness syndrome, minimally conscious state, structural brain injury, voxel-based morphometry History

Propofol is one of the most commonly used anesthetics in the world, but much remains unknown about the mechanisms by which it induces loss of consciousness. In this resting-state functional magnetic resonance imaging study, we examined qualitative and quantitative changes of resting-state networks (RSNs), total brain connectivity, and mean oscillation frequencies of the regional blood oxygenation level-dependent (BOLD) signal, associated with propofol-induced mild sedation and loss of responsiveness in healthy subjects. We found that detectability of RSNs diminished significantly with loss of responsiveness, and total brain connectivity decreased strongly in the frontal cortex, which was associated with increased mean oscillation frequencies of the BOLD signal. Our results suggest a pivotal role of the frontal cortex in propofol-induced loss of responsiveness.

Diagnosis of patients with disorders of consciousness (comprising coma, vegetative state/unresponsive wakefulness syndrome, and minimally conscious state) has long been dependent on unstandardized behavioral tests. The arrival of standardized behavioral tools, and especially the Coma Recovery Scale revised, uncovered a high rate of misdiagnosis. Ancillary techniques, such as brain imaging and electrophysiological examinations, are ever more often being deployed to aid in the search for remaining consciousness. They are used to look for brain activity patterns similar to those found in healthy controls. The development of portable and cheaper devices will make these techniques more widely available.

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