Lizette Heine

Diagnostic precision of PET imaging and functional MRI in disorders of consciousness: a clinical validation study

BACKGROUND Bedside clinical examinations can have high rates of misdiagnosis of unresponsive wakefulness syndrome (vegetative state) or minimally conscious state. The diagnostic and prognostic usefulness of neuroimaging-based approaches has not been established in a clinical setting. We did a validation study of two neuroimaging-based diagnostic methods: PET imaging and functional MRI (fMRI). METHODS For this clinical validation study, we included patients referred to the University Hospital of Liège, Belgium, between January, 2008, and June, 2012, who were diagnosed by our unit with unresponsive wakefulness syndrome, locked-in syndrome, or minimally conscious state with traumatic or non-traumatic causes. We did repeated standardised clinical assessments with the Coma Recovery Scale-Revised (CRS-R), cerebral (18)F-fluorodeoxyglucose (FDG) PET, and fMRI during mental activation tasks. We calculated the diagnostic accuracy of both imaging methods with CRS-R diagnosis as reference. We assessed outcome after 12 months with the Glasgow Outcome Scale-Extended. FINDINGS We included 41 patients with unresponsive wakefulness syndrome, four with locked-in syndrome, and 81 in a minimally conscious state (48=traumatic, 78=non-traumatic; 110=chronic, 16=subacute). (18)F-FDG PET had high sensitivity for identification of patients in a minimally conscious state (93%, 95% CI 85-98) and high congruence (85%, 77-90) with behavioural CRS-R scores. The active fMRI method was less sensitive at diagnosis of a minimally conscious state (45%, 30-61) and had lower overall congruence with behavioural scores (63%, 51-73) than PET imaging. (18)F-FDG PET correctly predicted outcome in 75 of 102 patients (74%, 64-81), and fMRI in 36 of 65 patients (56%, 43-67). 13 of 41 (32%) of the behaviourally unresponsive patients (ie, diagnosed as unresponsive with CRS-R) showed brain activity compatible with (minimal) consciousness (ie, activity associated with consciousness, but diminished compared with fully conscious individuals) on at least one neuroimaging test; 69% of these (9 of 13) patients subsequently recovered consciousness. INTERPRETATION Cerebral (18)F-FDG PET could be used to complement bedside examinations and predict long-term recovery of patients with unresponsive wakefulness syndrome. Active fMRI might also be useful for differential diagnosis, but seems to be less accurate. FUNDING The Belgian National Funds for Scientific Research (FNRS), Fonds Léon Fredericq, the European Commission, the James McDonnell Foundation, the Mind Science Foundation, the French Speaking Community Concerted Research Action, the University of Copenhagen, and the University of Liège.

Resting state networks and consciousness Alterations of multiple resting state network connectivity in physiological, pharmacological and pathological consciousness states

In order to better understand the functional contribution of resting state activity to conscious cognition, we aimed to review increases and decreases in functional magnetic resonance imaging (fMRI) functional connectivity under physiological (sleep), pharmacological (anesthesia), and pathological altered states of consciousness, such as brain death, coma, vegetative state/unresponsive wakefulness syndrome, and minimally conscious state. The reviewed resting state networks were the DMN, left and right executive control, salience, sensorimotor, auditory, and visual networks. We highlight some methodological issues concerning resting state analyses in severely injured brains mainly in terms of hypothesis-driven seed-based correlation analysis and data-driven independent components analysis approaches. Finally, we attempt to contextualize our discussion within theoretical frameworks of conscious processes. We think that this “lesion” approach allows us to better determine the necessary conditions under which normal conscious cognition takes place. At the clinical level, we acknowledge the technical merits of the resting state paradigm. Indeed, fast and easy acquisitions are preferable to activation paradigms in clinical populations. Finally, we emphasize the need to validate the diagnostic and prognostic value of fMRI resting state measurements in non-communicating brain damaged patients.

Intrinsic functional connectivity differentiates minimally conscious from unresponsive patients

Despite advances in resting state functional magnetic resonance imaging investigations, clinicians remain with the challenge of how to implement this paradigm on an individualized basis. Here, we assessed the clinical relevance of resting state functional magnetic resonance imaging acquisitions in patients with disorders of consciousness by means of a systems-level approach. Three clinical centres collected data from 73 patients in minimally conscious state, vegetative state/unresponsive wakefulness syndrome and coma. The main analysis was performed on the data set coming from one centre (Liège) including 51 patients (26 minimally conscious state, 19 vegetative state/unresponsive wakefulness syndrome, six coma; 15 females; mean age 49 ± 18 years, range 11-87; 16 traumatic, 32 non-traumatic of which 13 anoxic, three mixed; 35 patients assessed >1 month post-insult) for whom the clinical diagnosis with the Coma Recovery Scale-Revised was congruent with positron emission tomography scanning. Group-level functional connectivity was investigated for the default mode, frontoparietal, salience, auditory, sensorimotor and visual networks using a multiple-seed correlation approach. Between-group inferential statistics and machine learning were used to identify each networks capacity to discriminate between patients in minimally conscious state and vegetative state/unresponsive wakefulness syndrome. Data collected from 22 patients scanned in two other centres (Salzburg: 10 minimally conscious state, five vegetative state/unresponsive wakefulness syndrome; New York: five minimally conscious state, one vegetative state/unresponsive wakefulness syndrome, one emerged from minimally conscious state) were used to validate the classification with the selected features. Coma Recovery Scale-Revised total scores correlated with key regions of each network reflecting their involvement in consciousness-related processes. All networks had a high discriminative capacity (>80%) for separating patients in a minimally conscious state and vegetative state/unresponsive wakefulness syndrome. Among them, the auditory network was ranked the most highly. The regions of the auditory network which were more functionally connected in patients in minimally conscious state compared to vegetative state/unresponsive wakefulness syndrome encompassed bilateral auditory and visual cortices. Connectivity values in these three regions discriminated congruently 20 of 22 independently assessed patients. Our findings point to the significance of preserved abilities for multisensory integration and top-down processing in minimal consciousness seemingly supported by auditory-visual crossmodal connectivity, and promote the clinical utility of the resting paradigm for single-patient diagnostics.

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

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 (18)F-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 (Spearmans r=0·50 [95% CI 0·26 to 0·61]; p<0·0001) and negative default mode network connectivity (Spearmans 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).

The repetition of behavioral assessments in diagnosis of disorders of consciousness

To determine whether repeated examinations using the Coma Recovery Scale‐Revised (CRS‐R) have an impact on diagnostic accuracy of patients with disorders of consciousness and to provide guidelines regarding the number of assessments required for obtaining a reliable diagnosis.

Looking for the self in pathological unconsciousness.

There is an intimate relationship between consciousness and the notion of self. By studying patients with disorders of consciousness, we are offered with a unique lesion approach to tackle the neural correlates of self in the absence of subjective reports. Studies employing neuroimaging techniques point to the critical involvement of midline anterior and posterior cortices in response to the passive presentation of self-referential stimuli, such as the patient’s own name and own face. Also, resting state studies show that these midline regions are severely impaired as a function of the level of consciousness. Theoretical frameworks combining all this progress surpass the functional localization of self-related cognition and suggest a dynamic system-level approach to the phenomenological complexity of subjectivity. Importantly for non-communicating patients suffering from disorders of consciousness, the clinical translation of these technologies will allow medical professionals and families to better comprehend these disorders and plan efficient medical management for these patients.

Mindsight: Diagnostics in Disorders of Consciousness

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.

Measuring consciousness in coma and related states.

Consciousness is a prismatic and ambiguous concept that still eludes any universal definition. Severe acquired brain injuries resulting in a disorder of consciousness (DOC) provide a model from which insights into consciousness can be drawn. A number of recent studies highlight the difficulty in making a diagnosis in patients with DOC based only on behavioral assessments. Here we aim to provide an overview of how neuroimaging techniques can help assess patients with DOC. Such techniques are expected to facilitate a more accurate understanding of brain function in states of unconsciousness and to improve the evaluation of the patients cognitive abilities by providing both diagnostic and prognostic indicators.

Assessment of visual fixation in vegetative and minimally conscious states.

BackgroundVisual fixation plays a key role in the differentiation between vegetative state/unresponsive wakefulness (VS/UWS) syndrome and minimally conscious state (MCS). However, the use of different stimuli changes the frequency of visual fixation occured in patients, thereby possibly affecting the accuracy of the diagnosis. In order to establish a standardized assessment of visual fixation in patients in disorders of consciousness (DOC), we compared the frequency of visual fixation elicited by mirror,a ball and a light.MethodVisual fixation was assessed in eighty-one post-comatose patients diagnosed with a MCS or VS/UWS. Occurrence of fixation to different stimuli was analysis used Chi-square testing.Result40 (49%) out of the 81 patients showed fixation to visual stimuli. Among those, significantly more patients (39, 48%) had visual fixation elicited by mirror compared to a ball (23, 28%) and mirror compared to a light (20, 25%).ConclusionThe use of a mirror during the assessment of visual fixation showed higher positive response rate, compared to other stimuli in eliciting a visual fixating response. Therefore, fixation elicited by a mirror can be a very sensitive and accurate test to differentiate the two disorders of consciousness.

Detection of visual pursuit in patients in minimally conscious state: a matter of stimuli and visual plane?

Abstract Objectives: The aim of this study was to determine whether the assessment of pursuit eye movements in patients in minimally conscious state (MCS) is influenced by the choice of the visual stimulus (study 1) and by the moving plane (study 2). Methods: Patients with MCS (MCS− and MCS+) in the acute (<1 month post-injury) or chronic (>1 month) setting were assessed. The Coma Recovery Scale-Revised (CRS-R) procedure was used to test visual pursuit of a moving mirror, object and person (study 1, n = 88) and to test vertical and horizontal visual tracking (study 2, n = 94). Results: Study 1: Patients with visual pursuit tracked preferentially the moving mirror over the moving person or object. Study 2: Patients displaying visual pursuit, especially in MCS− and in chronic setting, preferentially tracked on the horizontal rather than the vertical plane. Conclusion: The findings confirm the importance of using a mirror to assess visual pursuit in patients in MCS and of initiating testing using the horizontal plane, specifically in patients in MCS− and those in chronic setting. Assessment should then be done on the vertical plane if visual pursuit is not detected on the horizontal plane.