Disorders of consciousness involve profound disruption in awareness as result of massive brain damage.1, 2, 3, 4, 5 For example, patients in a vegetative state (known as unresponsive wakefulness syndrome)6 can retain wakefulness, as shown by eye opening, but their behaviour is restricted to reflexive motor activity; therefore, they do not show signs of awareness of themselves or their environment. When patients show signs of fluctuating but reproducible non-reflex behaviour (eg, visual pursuit or command following) but remain unable to functionally communicate (ie, communicate in a meaningful way), they are considered to be in a minimally conscious state.7 Emergence from this state is denoted when patients regain sufficient consciousness to functionally communicate or use objects through movements that are compatible with the object's specific function.7
Research in context
Evidence before this study
We searched MEDLINE for reports published between Jan 1, 2000, and April 30, 2015, with variations of the terms “disorders of consciousness”, “vegetative state”, “minimally conscious state”, “unresponsive wakefulness syndrome”, “EMCS”, “neuroimaging”, “MRI”, “PET”, “resting-state fMRI”, and “resting-state fMRI anticorrelation”. Searches were not restricted by language of publication. We reviewed relevant original research and review articles and their reference lists. Among neuroimaging studies of disorders of consciousness, we found several studies comparing patients in a vegetative state or with unresponsive wakefulness syndrome and minimally conscious state to healthy controls, and studies comparing unresponsive wakefulness syndrome to minimally conscious state by 18F-fluorodeoxyglucose (FDG)-PET and functional positive connectivity. For negative functional connectivity in disorders of consciousness, we found one case report on a patient with unresponsive wakefulness syndrome. We found a study on brain metabolism comparing patients who had emerged from a minimally conscious state to healthy controls. We found no studies on functional connectivity (both positive and negative) in patients who had emerged from a minimally conscious state. We found no studies comparing neuronal blood-oxygen-level-dependent functional MRI (fMRI) negative connectivity (ie, neuronal anticorrelation) with FDG-PET brain metabolism or studies comparing neuronal blood-oxygen-level-dependent fMRI positive connectivity with FDG-PET.
Added value of this study
Our findings provide evidence of the neuronal origin of the negative blood-oxygen-level-dependent connectivity pattern (ie, default mode network negative connectivity or between-network anticorrelations) and its crucial role in the emergence of high cognitive function.
Implications of all the available evidence
Our results are relevant in the clinical setting because they might provide outcome predictors in patients with disorders of consciousness, could possibly improve diagnosis, and could eventually help with the development of new therapeutic options.
Behavioural (clinical) assessment relies upon motor responsiveness; however, absence of responsiveness does not necessarily correspond to absence of awareness, because patients might have acquired motor and language deficits as a result of their brain damage, complicating the clinical assessment.3 Therefore, motor-independent imaging technologies have been developed to avoid diagnostic error intrinsic to behavioural assessment.8 Differential brain patterns in patients in a minimally conscious state and those with unresponsive wakefulness syndrome have been investigated in the passive (ie, after sensory stimulation), active (ie, probing motor-independent signs of command following), and task-free resting states.3 Assessment during resting state is particularly opportune for patients with disorders of consciousness because patient interaction and application of possibly difficult experimental set-ups are not required.
Neuroimaging assessments during resting state suggest a specific brain organisation encompassing mainly the posterior cingulate cortex and adjacent precuneus, and the anterior cingulate cortex and mesiofrontal regions, known as the default mode network.9 In healthy people, this network showed a competing anticorrelated activity with a set of areas encompassing mainly lateral fronto-parietal and motor regions (task-positive network).10, 11, 12 The default mode network and the task-positive network have been related to the perception of internal thoughts and the external world, respectively.13
The anticorrelation between the default mode network and the task-positive network (ie, negative default mode network connectivity, or between-network anticorrelations) is associated with cognitive function, suggesting that an increase in anticorrelation indicates an increase in capacity to switch between internal and external modes of attention.14 Positive default mode network connectivity (ie, within-network correlations) has been investigated in disorders of consciousness, showing that disruption increases with consciousness impairment, ranging from a minimally conscious state, unresponsive wakefulness syndrome, to coma.15, 16 So far, decreased negative default mode network connectivity has been reported in a small sample of patients under propofol anaesthesia, in brain death, and in a patient with unresponsive wakefulness syndrome.17, 18 Additionally, although positive default mode network connectivity has been reported to correlate with brain metabolism in healthy controls,19 the possible correlation of negative default mode network connectivity with brain metabolism has not been investigated in health or disease.
So far, emergence from a minimally conscious state has been investigated by PET, and findings suggest that positive and negative default mode network connectivity networks are both metabolically preserved when a patient emerges from a minimally conscious state, but not in patients with unresponsive wakefulness syndrome or in those in a minimally conscious state.20 This evidence suggests that negative default mode network connectivity, which seemingly requires metabolic activity in both networks, might be a distinctive feature of emergence from a minimally conscious state.
In this cross-sectional study, we aim to describe positive and negative default mode network connectivities in patients with unresponsive wakefulness syndrome, patients in a minimally conscious state, those who have emerged from a minimally conscious state, and healthy controls. To test whether positive and negative default mode network connectivity could be of neuronal origin, we compared the functional connectivity pattern with brain metabolic information using PET. To exclude the effect of anatomical deformations on functional connectivity changes, we also investigated group differences in grey matter volume using MRI voxel-based morphometry.