La neuro-imagerie: un outil diagnostique des etats de conscience alteree.
Thonnard, Marie ; Boly, Mélanie ; et al
in Medecine Sciences : M/S (2011), 27(1), 77-81
Vegetative and minimally conscious states diagnosis remained a major clinical challenge. New paradigms such as measurement of the global cerebral metabolism, the structural and functional integrity of ... [more ▼]
Vegetative and minimally conscious states diagnosis remained a major clinical challenge. New paradigms such as measurement of the global cerebral metabolism, the structural and functional integrity of fronto-parietal network, or the spontaneous activity in resting state have been shown to be helpful to disentangle vegetative from minimally conscious patients. Active neuroimagery paradigms also allow detecting voluntary and conscious activity in non-communicative patients. The implementation of these methods in clinical routine could permit to reduce the current high rate of misdiagnosis (40%). [less ▲]Detailed reference viewed: 45 (6 ULg)
From unresponsive wakefulness to minimally conscious PLUS and functional locked-in syndromes: recent advances in our understanding of disorders of consciousness.
Bruno, Marie-Aurélie ; Vanhaudenhuyse, Audrey ; Thibaut, Aurore et al
in Journal of Neurology (2011), 258(7), 1373-84
Functional neuroimaging and electrophysiology studies are changing our understanding of patients with coma and related states. Some severely brain damaged patients may show residual cortical processing in ... [more ▼]
Functional neuroimaging and electrophysiology studies are changing our understanding of patients with coma and related states. Some severely brain damaged patients may show residual cortical processing in the absence of behavioural signs of consciousness. Given these new findings, the diagnostic errors and their potential effects on treatment as well as concerns regarding the negative associations intrinsic to the term vegetative state, the European Task Force on Disorders of Consciousness has recently proposed the more neutral and descriptive term unresponsive wakefulness syndrome. When vegetative/unresponsive patients show minimal signs of consciousness but are unable to reliably communicate the term minimally responsive or minimally conscious state (MCS) is used. MCS was recently subcategorized based on the complexity of patients' behaviours: MCS+ describes high-level behavioural responses (i.e., command following, intelligible verbalizations or non-functional communication) and MCS- describes low-level behavioural responses (i.e., visual pursuit, localization of noxious stimulation or contingent behaviour such as appropriate smiling or crying to emotional stimuli). Finally, patients who show non-behavioural evidence of consciousness or communication only measurable via para-clinical testing (i.e., functional MRI, positron emission tomography, EEG or evoked potentials) can be considered to be in a functional locked-in syndrome. An improved assessment of brain function in coma and related states is not only changing nosology and medical care but also offers a better-documented diagnosis and prognosis and helps to further identify the neural correlates of human consciousness. [less ▲]Detailed reference viewed: 49 (3 ULg)
"Relevance vector machine" consciousness classifier applied to cerebral metabolism of vegetative and locked-in patients.
Phillips, Christophe ; Bruno, Marie-Aurélie ; Maquet, Pierre et al
in NeuroImage (2011), 56(2), 797808
The vegetative state is a devastating condition where patients awaken from their coma (i.e., open their eyes) but fail to show any behavioural sign of conscious awareness. Locked-in syndrome patients also ... [more ▼]
The vegetative state is a devastating condition where patients awaken from their coma (i.e., open their eyes) but fail to show any behavioural sign of conscious awareness. Locked-in syndrome patients also awaken from their coma and are unable to show any motor response to command (except for small eye movements or blinks) but recover full conscious awareness of self and environment. Bedside evaluation of residual cognitive function in coma survivors often is difficult because motor responses may be very limited or inconsistent. We here aimed to disentangle vegetative from "locked-in" patients by an automatic procedure based on machine learning using fluorodeoxyglucose PET data obtained in 37 healthy controls and in 13 patients in a vegetative state. Next, the trained machine was tested on brain scans obtained in 8 patients with locked-in syndrome. We used a sparse probabilistic Bayesian learning framework called "relevance vector machine" (RVM) to classify the scans. The trained RVM classifier, applied on an input scan, returns a probability value (p-value) of being in one class or the other, here being "conscious" or not. Training on the control and vegetative state groups was assessed with a leave-one-out cross-validation procedure, leading to 100% classification accuracy. When applied on the locked-in patients, all scans were classified as "conscious" with a mean p-value of .95 (min .85). In conclusion, even with this relatively limited data set, we could train a classifier distinguishing between normal consciousness (i.e., wakeful conscious awareness) and the vegetative state (i.e., wakeful unawareness). Cross-validation also indicated that the clinical classification and the one predicted by the automatic RVM classifier were in accordance. Moreover, when applied on a third group of "locked-in" consciously aware patients, they all had a strong probability of being similar to the normal controls, as expected. Therefore, RVM classification of cerebral metabolic images obtained in coma survivors could become a useful tool for the automated PET-based diagnosis of altered states of consciousness. [less ▲]Detailed reference viewed: 77 (15 ULg)
Attitudes towards end-of-life issues in disorders of consciousness : a European survey
Demertzi, Athina ; LEDOUX, Didier ; Bruno, Marie-Aurélie et al
in Journal of Neurology (2011)
Previous European surveys showed the support of healthcare professionals for treatment withdrawal [i.e., artificial nutrition and hydration (ANH) in chronic vegetative state (VS) patients]. The recent ... [more ▼]
Previous European surveys showed the support of healthcare professionals for treatment withdrawal [i.e., artificial nutrition and hydration (ANH) in chronic vegetative state (VS) patients]. The recent definition of minimally conscious state (MCS), and possibly research advances (e.g., functional neuroimaging), may have lead to uncertainty regarding potential residual perception and may have influenced opinions of healthcare professionals. The aim of the study was to update the end-of-life attitudes towards VS and to determine the end-of-life attitudes towards MCS. A 16-item questionnaire related to consciousness, pain and end-of-life issues in chronic (i.e., >1 year) VS and MCS and locked-in syndrome was distributed among attendants of medical and scientific conferences around Europe (n = 59). During a lecture, the items were explained orally to the attendants who needed to provide written yes/no responses. Chi-square tests and logistic regression analyses identified differences and associations for age, European region, religiosity, profession, and gender. We here report data on items concerning end-of-life issues on chronic VS and MCS. Responses were collected from 2,475 participants. For chronic VS (>1 year), 66% of healthcare professionals agreed to withdraw treatment and 82% wished not to be kept alive (P < 0.001). For chronic MCS (>1 year), less attendants agreed to withdraw treatment (28%, P < 0.001) and wished not to be kept alive (67%, P < 0.001). MCS was considered worse than VS for the patients in 54% and for their families in 42% of the sample. Respondents’ opinions were associated with geographic region and religiosity. Our data show that end-of-life opinions differ for VS as compared to MCS. The introduction of the diagnostic criteria for MCS has not substantially changed the opinions on end-of-life issues on permanent VS. Additionally, the existing legal ambiguity around MCS may have influenced the audience to draw a line between expressing preferences for self versus others, by implicitly recognizing that the latter could be a step on the slippery slope to legalize euthanasia. Given the observed individual variability, we stress the importance of advance directives and identification of proxies when discussing end-of-life issues in patients with disorders of consciousness. [less ▲]Detailed reference viewed: 256 (11 ULg)
Electrophysiological correlates of behavioural changes in vigilance in vegetative state and minimally conscious state.
; Bruno, Marie-Aurélie ; Noirhomme, Quentin et al
in Brain : A Journal of Neurology (2011), 134(Pt 8), 2222-32
The existence of normal sleep in patients in a vegetative state is still a matter of debate. Previous electrophysiological sleep studies in patients with disorders of consciousness did not differentiate ... [more ▼]
The existence of normal sleep in patients in a vegetative state is still a matter of debate. Previous electrophysiological sleep studies in patients with disorders of consciousness did not differentiate patients in a vegetative state from patients in a minimally conscious state. Using high-density electroencephalographic sleep recordings, 11 patients with disorders of consciousness (six in a minimally conscious state, five in a vegetative state) were studied to correlate the electrophysiological changes associated with sleep to behavioural changes in vigilance (sustained eye closure and muscle inactivity). All minimally conscious patients showed clear electroencephalographic changes associated with decreases in behavioural vigilance. In the five minimally conscious patients showing sustained behavioural sleep periods, we identified several electrophysiological characteristics typical of normal sleep. In particular, all minimally conscious patients showed an alternating non-rapid eye movement/rapid eye movement sleep pattern and a homoeostatic decline of electroencephalographic slow wave activity through the night. In contrast, for most patients in a vegetative state, while preserved behavioural sleep was observed, the electroencephalographic patterns remained virtually unchanged during periods with the eyes closed compared to periods of behavioural wakefulness (eyes open and muscle activity). No slow wave sleep or rapid eye movement sleep stages could be identified and no homoeostatic regulation of sleep-related slow wave activity was observed over the night-time period. In conclusion, we observed behavioural, but no electrophysiological, sleep wake patterns in patients in a vegetative state, while there were near-to-normal patterns of sleep in patients in a minimally conscious state. These results shed light on the relationship between sleep electrophysiology and the level of consciousness in severely brain-damaged patients. We suggest that the study of sleep and homoeostatic regulation of slow wave activity may provide a complementary tool for the assessment of brain function in minimally conscious state and vegetative state patients. [less ▲]Detailed reference viewed: 35 (2 ULg)
Preserved feedforward but impaired top-down processes in the vegetative state.
Boly, Mélanie ; ; Gosseries, Olivia et al
in Science (2011), 332(6031), 858-62
Frontoparietal cortex is involved in the explicit processing (awareness) of stimuli. Frontoparietal activation has also been found in studies of subliminal stimulus processing. We hypothesized that an ... [more ▼]
Frontoparietal cortex is involved in the explicit processing (awareness) of stimuli. Frontoparietal activation has also been found in studies of subliminal stimulus processing. We hypothesized that an impairment of top-down processes, involved in recurrent neuronal message-passing and the generation of long-latency electrophysiological responses, might provide a more reliable correlate of consciousness in severely brain-damaged patients, than frontoparietal responses. We measured effective connectivity during a mismatch negativity paradigm and found that the only significant difference between patients in a vegetative state and controls was an impairment of backward connectivity from frontal to temporal cortices. This result emphasizes the importance of top-down projections in recurrent processing that involve high-order associative cortices for conscious perception. [less ▲]Detailed reference viewed: 51 (12 ULg)
Two distinct neuronal networks mediate the awareness of environment and of self
Vanhaudenhuyse, Audrey ; Demertzi, Athina ; et al
in Journal of Cognitive Neuroscience (2011), 23(3), 570-578
Evidence from functional neuroimaging studies on resting state suggests that there are two distinct anticorrelated cortical systems that mediate conscious awareness: an "extrinsic" system that encompasses ... [more ▼]
Evidence from functional neuroimaging studies on resting state suggests that there are two distinct anticorrelated cortical systems that mediate conscious awareness: an "extrinsic" system that encompasses lateral fronto-parietal areas and has been linked with processes of external input (external awareness), and an "intrinsic" system which encompasses mainly medial brain areas and has been associated with internal processes (internal awareness). The aim of our study was to explore the neural correlates of resting state by providing behavioral and neuroimaging data from healthy volunteers. With no a priori assumptions, we first determined behaviorally the relationship between external and internal awareness in 31 subjects. We found a significant anticorrelation between external and internal awareness with a mean switching frequency of 0.05 Hz (range: 0.01-0.1 Hz). Interestingly, this frequency is similar to BOLD fMRI slow oscillations. We then evaluated 22 healthy volunteers in an fMRI paradigm looking for brain areas where BOLD activity correlated with "internal" and "external" scores. Activation of precuneus/posterior cingulate, anterior cingulate/mesiofrontal cortices, and parahippocampal areas ("intrinsic system") was linearly linked to intensity of internal awareness, whereas activation of lateral fronto-parietal cortices ("extrinsic system") was linearly associated with intensity of external awareness. [less ▲]Detailed reference viewed: 165 (23 ULg)
Linking sleep and general anesthesia mechanisms: this is no walkover
BONHOMME, Vincent ; BOVEROUX, Pierre ; Vanhaudenhuyse, Audrey et al
in Acta Anaesthesiologica Belgica (2011), 62(3), 161-171Detailed reference viewed: 150 (17 ULg)
Response to comment on "preserved feedforward but impaired top-down processes in the vegetative state".
Boly, Mélanie ; ; Gosseries, Olivia et al
in Science (2011), 334(6060), 1203
King et al. raise some technical issues about our recent study showing impaired top-down processes in the vegetative state. We welcome the opportunity to provide more details about our methods and results ... [more ▼]
King et al. raise some technical issues about our recent study showing impaired top-down processes in the vegetative state. We welcome the opportunity to provide more details about our methods and results and to resolve their concerns. We substantiate our interpretation of the results and provide a point-by-point response to the issues raised. [less ▲]Detailed reference viewed: 31 (2 ULg)
Multimodal neuroimaging in patients with disorders of consciousness showing "functional hemispherectomy".
Bruno, Marie-Aurélie ; ; Lehembre, Remy et al
in Progress in Brain Research (2011), 193
Beside behavioral assessment of patients with disorders of consciousness, neuroimaging modalities may offer objective paraclinical markers important for diagnosis and prognosis. They provide information ... [more ▼]
Beside behavioral assessment of patients with disorders of consciousness, neuroimaging modalities may offer objective paraclinical markers important for diagnosis and prognosis. They provide information on the structural location and extent of brain lesions (e.g., morphometric MRI and diffusion tensor imaging (DTI-MRI) assessing structural connectivity) but also their functional impact (e.g., metabolic FDG-PET, hemodynamic fMRI, and EEG measurements obtained in "resting state" conditions). We here illustrate the role of multimodal imaging in severe brain injury, presenting a patient in unresponsive wakefulness syndrome (UWS; i.e., vegetative state, VS) and in a "fluctuating" minimally conscious state (MCS). In both cases, resting state FDG-PET, fMRI, and EEG showed a functionally preserved right hemisphere, while DTI showed underlying differences in structural connectivity highlighting the complementarities of these neuroimaging methods in the study of disorders of consciousness. [less ▲]Detailed reference viewed: 67 (5 ULg)
Disorders of consciousness: coma, vegetative and minimally conscious states
Gosseries, Olivia ; Vanhaudenhuyse, Audrey ; Bruno, Marie-Aurélie et al
in D. Cvetkovic & I. Cosic (Ed.) States of Consciousness: Experimental Insights into Meditation, Waking, Sleep and Dreams (2011)Detailed reference viewed: 54 (3 ULg)
Comment évaluer la conscience chez des patients sévèrement cérébro-lésés ?
Gosseries, Olivia ; Laureys, Steven ; Vanhaudenhuyse, Audrey
in Lutte, Isabelle (Ed.) L’évaluation du traumatisme crânien (2011)Detailed reference viewed: 85 (9 ULg)
Les traitements pharmacologiques chez les patients récupérant du coma
Gosseries, Olivia ; Thonnard, Marie ; Laureys, Steven
in C Schnakers & S Laureys (Ed.) Comas et états de conscience altérée (2011)Detailed reference viewed: 17 (1 ULg)
From armchair to wheelchair: How patients with a locked-in syndrome integrate bodily changes in experienced identity.
; Demertzi, Athina ; Gosseries, Olivia et al
in Consciousness & Cognition (2011)
Different sort of people are interested in personal identity. Philosophers frequently ask what it takes to remain oneself. Caregivers imagine their patients' experience. But both philosophers and ... [more ▼]
Different sort of people are interested in personal identity. Philosophers frequently ask what it takes to remain oneself. Caregivers imagine their patients' experience. But both philosophers and caregivers think from the armchair: they can only make assumptions about what it would be like to wake up with massive bodily changes. Patients with a locked-in syndrome (LIS) suffer a full body paralysis without cognitive impairment. They can tell us what it is like. Forty-four chronic LIS patients and 20 age-matched healthy medical professionals answered a 15-items questionnaire targeting: (A) global evaluation of identity, (B) body representation and (C) experienced meaning in life. In patients, self-reported identity was correlated with B and C. Patients differed with controls in C. These results suggest that the paralyzed body remains a strong component of patients' experienced identity, that patients can adjust to objectives changes perceived as meaningful and that caregivers fail in predicting patients' experience. [less ▲]Detailed reference viewed: 32 (1 ULg)
Influence of anesthesia on cerebral blood flow, cerebral metabolic rate, and brain functional connectivity.
BONHOMME, Vincent ; BOVEROUX, Pierre ; HANS, Pol et al
in Current Opinion in Anaesthesiology (2011), 24(5), 474-9
PURPOSE OF REVIEW: To describe recent studies exploring brain function under the influence of hypnotic anesthetic agents, and their implications on the understanding of consciousness physiology and ... [more ▼]
PURPOSE OF REVIEW: To describe recent studies exploring brain function under the influence of hypnotic anesthetic agents, and their implications on the understanding of consciousness physiology and anesthesia-induced alteration of consciousness. RECENT FINDINGS: Cerebral cortex is the primary target of the hypnotic effect of anesthetic agents, and higher-order association areas are more sensitive to this effect than lower-order processing regions. Increasing concentration of anesthetic agents progressively attenuates connectivity in the consciousness networks, while connectivity in lower-order sensory and motor networks is preserved. Alteration of thalamic sub-cortical regulation could compromise the cortical integration of information despite preserved thalamic activation by external stimuli. At concentrations producing unresponsiveness, the activity of consciousness networks becomes anticorrelated with thalamic activity, while connectivity in lower-order sensory networks persists, although with cross-modal interaction alterations. SUMMARY: Accumulating evidence suggests that hypnotic anesthetic agents disrupt large-scale cerebral connectivity. This would result in an inability of the brain to generate and integrate information, while external sensory information is still processed at a lower order of complexity. [less ▲]Detailed reference viewed: 63 (12 ULg)
Identifying the default-mode component in spatial IC analyses of patients with disorders of consciousness.
Soddu, Andrea ; Vanhaudenhuyse, Audrey ; Bahri, Mohamed Ali et al
in Human Brain Mapping (2011)
Objectives:Recent fMRI studies have shown that it is possible to reliably identify the default-mode network (DMN) in the absence of any task, by resting-state connectivity analyses in healthy volunteers ... [more ▼]
Objectives:Recent fMRI studies have shown that it is possible to reliably identify the default-mode network (DMN) in the absence of any task, by resting-state connectivity analyses in healthy volunteers. We here aimed to identify the DMN in the challenging patient population of disorders of consciousness encountered following coma. Experimental design: A spatial independent component analysis-based methodology permitted DMN assessment, decomposing connectivity in all its different sources either neuronal or artifactual. Three different selection criteria were introduced assessing anticorrelation-corrected connectivity with or without an automatic masking procedure and calculating connectivity scores encompassing both spatial and temporal properties. These three methods were validated on 10 healthy controls and applied to an independent group of 8 healthy controls and 11 severely brain-damaged patients [locked-in syndrome (n = 2), minimally conscious (n = 1), and vegetative state (n = 8)]. Principal observations: All vegetative patients showed fewer connections in the default-mode areas, when compared with controls, contrary to locked-in patients who showed near-normal connectivity. In the minimally conscious-state patient, only the two selection criteria considering both spatial and temporal properties were able to identify an intact right lateralized BOLD connectivity pattern, and metabolic PET data suggested its neuronal origin. Conclusions: When assessing resting-state connectivity in patients with disorders of consciousness, it is important to use a methodology excluding non-neuronal contributions caused by head motion, respiration, and heart rate artifacts encountered in all studied patients. Hum Brain Mapp, 2011. (c) 2011 Wiley-Liss, Inc. [less ▲]Detailed reference viewed: 63 (5 ULg)
Disorders of consciousness: What's in a name?
Gosseries, Olivia ; Bruno, Marie-Aurélie ; Chatelle, Camille et al
in NeuroRehabilitation (2011), 28
Following a coma, some patients may “awaken” without voluntary interaction or communication with the environment. More than 40 years ago this condition was coined coma vigil or apallic syndrome and later ... [more ▼]
Following a coma, some patients may “awaken” without voluntary interaction or communication with the environment. More than 40 years ago this condition was coined coma vigil or apallic syndrome and later became worldwide known as “persistent vegetative state”. About 10 years ago it became clear that some of these patients who failed to recover verbal or nonverbal communication did show some degree of consciousness – a condition called “minimally conscious state”. Some authors questioned the usefulness of differentiating unresponsive “vegetative” from minimally conscious patients but subsequent functional neuroimaging studies have since objectively demonstrated differences in residual cerebral processing and hence, we think, conscious awareness. These neuroimaging studies have also demonstrated that a small subset of unresponsive “vegetative” patients may show unambiguous signs of consciousness and command following inaccessible to bedside clinical examination. These findings, together with negative associations intrinsic to the term “vegetative state” as well as the diagnostic errors and their potential effect on the treatment and care for these patients gave rise to the recent proposal for an alternative neutral and more descriptive name: unresponsive wakefulness syndrome. We here give an overview of PET and (functional) MRI studies performed in these challenging patients and stress the need for a separate ICD9CM diagnosis code and MEDLINEMeSH entry for “minimally conscious state” as the lack of clear distinction between vegetative state/unresponsive wakefulness syndrome and minimally conscious state may encumber scientific studies in the field of disorders of consciousness. [less ▲]Detailed reference viewed: 106 (2 ULg)
Assessment of consciousness with electrophysiological and neurological imaging techniques.
Bruno, Marie-Aurélie ; Gosseries, Olivia ; Ledoux, Didier et al
in Current Opinion in Critical Care (2011)
PURPOSE OF REVIEW: Brain MRI (diffusion tensor imaging and spectroscopy) and functional neuroimaging (PET, functional MRI, EEG and evoked potential studies) are changing our understanding of patients with ... [more ▼]
PURPOSE OF REVIEW: Brain MRI (diffusion tensor imaging and spectroscopy) and functional neuroimaging (PET, functional MRI, EEG and evoked potential studies) are changing our understanding of patients with disorders of consciousness encountered after coma such as the 'vegetative' or minimally conscious states. RECENT FINDINGS: Increasing evidence from functional neuroimaging and electrophysiology demonstrates some residual cognitive processing in a subgroup of patients who clinically fail to show any response to commands, leading to the recent proposal of 'unresponsive wakefulness syndrome' as an alternative name for patients previously coined 'vegetative' or 'apallic'. SUMMARY: Consciousness can be viewed as the emergent property of the collective behavior of widespread thalamocortical frontoparietal network connectivity. Data from physiological, pharmacological and pathological alterations of consciousness provide evidence in favor of this hypothesis. Increasing our understanding of the neural correlates of consciousness is helping clinicians to do a better job in terms of diagnosis, prognosis and finally treatment and drug development for these severely brain-damaged patients. The current challenge remains to continue translating this research from the bench to the bedside. Only well controlled large multicentric neuroimaging and electrophysiology studies will enable to identify which paraclinical diagnostic or prognostic test is necessary for our routine evidence-based assessment of individuals with disorders of consciousness. [less ▲]Detailed reference viewed: 150 (10 ULg)
Brain connectivity in pathological and pharmacological coma
Noirhomme, Quentin ; Soddu, Andrea ; Lehembre, Remy et al
in Frontiers in Systems Neuroscience [=FNSYS] (2010), 4
Recent studies in patients with disorders of consciousness (DOC) tend to support the view that awareness is not related to activity in a single brain region but to thalamo-cortical connectivity in the ... [more ▼]
Recent studies in patients with disorders of consciousness (DOC) tend to support the view that awareness is not related to activity in a single brain region but to thalamo-cortical connectivity in the frontoparietal network. Functional neuroimaging studies have shown preserved albeit disconnected low-level cortical activation in response to external stimulation in patients in a “vegetative state” or unresponsive wakefulness syndrome. While activation of these “primary” sensory cortices does not necessarily reflect conscious awareness, activation in higher-order associative cortices in minimally conscious state patients seems to herald some residual perceptual awareness. PET studies have identified a metabolic dysfunction in a widespread frontoparietal “global neuronal workspace” in DOC patients including the midline default mode network (“intrinsic” system) and the lateral frontoparietal cortices or “extrinsic system.” Recent studies have investigated the relation of awareness to the functional connectivity within intrinsic and extrinsic networks, and with the thalami in both pathological and pharmacological coma. In brain damaged patients, connectivity in all default network areas was found to be non-linearly correlated with the degree of clinical consciousness impairment, ranging from healthy controls and locked-in syndrome to minimally conscious, vegetative, coma, and brain dead patients. Anesthesia-induced loss of consciousness was also shown to correlate with a global decrease in cortico-cortical and thalamo-cortical connectivity in both intrinsic and extrinsic networks, but not in auditory, or visual networks. In anesthesia, unconsciousness was also associated with a loss of cross-modal interactions between networks. These results suggest that conscious awareness critically depends on the functional integrity of thalamo-cortical and cortico-cortical frontoparietal connectivity within and between “intrinsic” and “extrinsic” brain networks. [less ▲]Detailed reference viewed: 63 (5 ULg)