Elsevier

The Lancet Neurology

Volume 15, Issue 8, July 2016, Pages 830-842
The Lancet Neurology

Articles
Neural correlates of consciousness in patients who have emerged from a minimally conscious state: a cross-sectional multimodal imaging study

https://doi.org/10.1016/S1474-4422(16)00111-3Get rights and content

Summary

Background

Between pathologically impaired consciousness and normal consciousness exists a scarcely researched transition zone, referred to as emergence from minimally conscious state, in which patients regain the capacity for functional communication, object use, or both. We investigated neural correlates of consciousness in these patients compared with patients with disorders of consciousness and healthy controls, by multimodal imaging.

Methods

In this cross-sectional, multimodal imaging study, patients with unresponsive wakefulness syndrome, patients in a minimally conscious state, and patients who had emerged from a minimally conscious state, diagnosed with the Coma Recovery Scale–Revised, were recruited from the neurology department of the Centre Hospitalier Universitaire de Liège, Belgium. Key exclusion criteria were neuroimaging examination in an acute state, sedation or anaesthesia during scanning, large focal brain damage, motion parameters of more than 3 mm in translation and 3° in rotation, and suboptimal segmentation and normalisation. We acquired resting state functional and structural MRI data and 18F-fluorodeoxyglucose (FDG) PET data; we used seed-based functional MRI (fMRI) analysis to investigate positive default mode network connectivity (within-network correlations) and negative default mode network connectivity (between-network anticorrelations). We correlated FDG-PET brain metabolism with fMRI connectivity. We used voxel-based morphometry to test the effect of anatomical deformations on functional connectivity.

Findings

We recruited a convenience sample of 58 patients (21 [36%] with unresponsive wakefulness syndrome, 24 [41%] in a minimally conscious state, and 13 [22%] who had emerged from a minimally conscious state) and 35 healthy controls between Oct 1, 2009, and Oct 31, 2014. We detected consciousness-level-dependent increases (from unresponsive wakefulness syndrome, minimally conscious state, emergence from minimally conscious state, to healthy controls) for positive and negative default mode network connectivity, brain metabolism, and grey matter volume (p<0·05 false discovery rate corrected for multiple comparisons). Positive default mode network connectivity differed between patients and controls but not among patient groups (F test p<0·0001). Negative default mode network connectivity was only detected in healthy controls and in those who had emerged from a minimally conscious state; patients with unresponsive wakefulness syndrome or in a minimally conscious state showed pathological between-network positive connectivity (hyperconnectivity; F test p<0·0001). Brain metabolism correlated with positive default mode network connectivity (Spearman's r=0·50 [95% CI 0·26 to 0·61]; p<0·0001) and negative default mode network connectivity (Spearman's r=–0·52 [–0·35 to −0·67); p<0·0001). Grey matter volume did not differ between the studied groups (F test p=0·06).

Interpretation

Partial preservation of between-network anticorrelations, which are seemingly of neuronal origin and cannot be solely explained by morphological deformations, characterise patients who have emerged from a minimally conscious state. Conversely, patients with disorders of consciousness show pathological between-network correlations. Apart from a deeper understanding of the neural correlates of consciousness, these findings have clinical implications and might be particularly relevant for outcome prediction and could inspire new therapeutic options.

Funding

Belgian National Funds for Scientific Research (FNRS), European Commission, Natural Sciences and Engineering Research Council of Canada, James McDonnell Foundation, European Space Agency, Mind Science Foundation, French Speaking Community Concerted Research Action, Fondazione Europea di Ricerca Biomedica, University and University Hospital of Liège (Liège, Belgium), and University of Western Ontario (London, ON, Canada).

Introduction

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.

Section snippets

Study design and participants

We did a cross-sectional multimodal imaging study. Patients were included in the study after they had a behavioural assessment with the Coma Recovery Scale–Revised (CRS-R; appendix p 2) in French21, 22 and had been diagnosed as having unresponsive wakefulness syndrome, being in a minimally conscious state, or having emerged from a minimally conscious state. Patients were recruited from Centre Hospitalier Universitaire de Liège, Belgium. The inclusion criteria were any disorders of

Results

Between Oct 1, 2009, and Oct 31, 2014, 281 patients with disorders of consciousness caused by brain damage were admitted into the Centre Hospitalier Universitaire de Liège. After application of the exclusion criteria (appendix p 2–3), we included in our study a convenience sample of 58 patients (21 [36%] with unresponsive wakefulness syndrome, 24 [41%] in a minimally conscious state, and 13 [22%] who had emerged from a minimally conscious state). 20 (34%) patients were men, 36 (62%) patients

Discussion

In this cross-sectional study, patients with unresponsive wakefulness syndrome and those in a minimally conscious state had restricted, albeit preserved, positive default mode network connectivity (ie, within-network correlations or correlations within the default mode network), in line with previous findings.15, 16, 38, 47 Patients who had emerged from a minimally conscious state also showed positive default mode network connectivity, thus placing them along the spectrum of consciousness.

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