Dr GOBERT, Florent
Assessment of disorders of consciousness
The anesthesia-reanimation team at the neurological hospital intervenes during the 4,500 procedures carried out each year by the establishment’s surgeons and radiologists. It supports more than 1,600 intensive care or post-interventional care stays/year. Specialized, it also provides plasmapheresis treatments for patients suffering from chronic dysimmune pathologies.
Project
Research axis
Multimodal evaluation of the prognosis of awakening in the acute phase of the disorder of consciousness in the neuro-intensive care department of Drs Dailler and Gobert (after prolonged cessation of sedation) using the tools available according to the state of the art (morphological MRI, neurophysiology, functional MRI, tractography), by adapting the use of tools with another indication (metabolic FDG PET in the acute phase by extrapolation of uses to the chronic phase) and by developing new biomarkers (stimulations visual autobiographical assessed by eye tracking and auditory assessed by evoked potentials)
– Clinical implementation for a prognostic evaluation of the disorder of consciousness and the functional reserve of rehabilitation to optimize the care pathway, in comparison of the new metrics with the current classic neurophysiological evaluation protocol (relationship with the electrophysiology theme of the IPW: Dr Nathalie André-Obadia and Dr Julien Jung) and radiological evaluation (Pr Yves Berthezène, Pr François Cotton).
– Exploration of the contribution for each biomarker of the simultaneity of functional explorations with comparison of functional connectivity EEG-MRI, anatomical connectivity, metabolism, perfusion, enabled by the LILI platform (PET-MRI research, in collaboration with CERMEP of Dr Nicolas Costes and Inès Merida and in nuclear medicine with Dr Anthime Flaus)
– Multimodal evaluation of the level of vigilance, the content of consciousness and the cognitive processes of patients with a chronic disorder of consciousness under evaluation in the post-intensive care rehabilitation department of Professor Luauté by implementation of clinical and paraclinical tools of the state of consciousness art and participation in a national research network
– Clinical trials on modulation of chronic phase arousal (electrical stimulation, behavioral stimulation)
– Evaluation of neurophysiological (EEG), physiological (actimetry, ECG, respiration, autonomic nervous system, eye tracking), hormonal (cortisol, melatonin, monoamines) rhythms in relation to pathological fluctuations in vigilance after acute and chronic brain injuries
– Evaluation of the genomic factors of variability of the consequences of brain lesions on the modification of biological rhythms, the return of consciousness and functional recovery (bioinformatics Dr Claire Bardel-Danjean; biostatistics: Dr Benjamin Riche and Pr Delphine Maucort-Boulch )
Links with nationals or internationals teams
– Collaboration within the local framework of the Lyon Michel Jouvet Neuroscience Research Center with:
. Dr Fabien Perrin on the behavioral and neurophysiological assessment of sub-conscious cognitive processes and their emotional modulation with the development of automated scoring tools (Dr Stefan Duffner, LIRIS)
. Dr. Maude Beaudoin on the oculometric exploration of the environment and images according to their emotional valence and exploration of the monoaminergic function in cognitive evolution after acute brain injury
. Dr Claude Gronfier on the evaluation of circadian rhythms and their differential modulation by injury and environmental factors
. Drs Jérémie Mattout and Perrine Seguin on infra-behavioral cognitive processes in patients with a chronic disorder of consciousness with validation in the context of communicating brain-injured patients (upper quadriplegia and locked-in syndrome with effective communication)
– Collaboration within the local framework of the Marc Jannerod Institute of Cognitive Sciences with Dr Léon Tremblay for the creation of a pre-clinical model of consciousness disorder by modulation of the mesocircuit with behavioral characterization and functional imaging
– Collaboration in the local setting of the CREATIS imaging laboratory with Dr. Carole Lartizien for the development of artificial intelligence tools promoting the automatic categorization of prognostic imaging markers.
– Collaboration in the local context with the University of Lyon 2 on socio-anthropological (Dr Anne-Sophie Haeringer), philosophical (Dr Julie Henry) and psychological (Pr Raphael Minjard, Dr Celine Racin) themes linked to disorder of conscience .
– Collaboration within the national framework:
. on connectivity in functional MRI with the team of Professor Stein Silva and Dr Patrice Péran (Inserm TONIC Team, Toulouse)
. on clinical neurophysiology with integration of a national network for the evaluation of disorders of consciousness with the team of Professor Lionel Naccache and Dr Benjamin Rohaut (ICM, Pitié-Salpêtrière, Paris)
– Collaboration on functional connectivity in coma (long-term analysis) with the team of Professor David Menon and Dr Srivas Chennu (Cambridge)
Publications
1. Twenty-four-hour rhythmicities in disorders of consciousness are associated with a favourable outcome.
Gobert F, Corneyllie A, Bastuji H, Berthomier Ch, Thevenet M, Abernot J, Raverot V, Dailler F, Guérin C, Gronfier C, Luauté J, and Perrin F (2023).
Communications Biology — Abstract
with a disorder of consciousness after acute brain injuries. 24-h assessment of brain (EEG),
behaviour (eye-opening), and circadian (clock-controlled hormones secretion from urine)
functions was performed in acute brain-injured patients. The distribution, long-term predictability,
and rhythmicity (circadian/ultradian) of various EEG features were compared with
the initial clinical status, the functional outcome, and the circadian rhythmicities of behaviour
and clock-controlled hormones. Here we show that more physiological and favourable patterns
of fluctuations are associated with a higher 24 h predictability and sharp up-and-down
shape of EEG switches, reminiscent of the Flip-Flop model of sleep. Multimodal rhythmic
analysis shows that patients with simultaneous circadian rhythmicity for brain, behaviour, and
hormones had a favourable outcome. Finally, both re-emerging EEG fluctuations and
homogeneous 24-h cycles for EEG, eye-opening, and hormones appeared as surrogates for
preserved functionality in brainstem and basal forebrain, which are key prognostic factors for
later improvement. While the recovery of consciousness has previously been related to a high
short-term complexity, we suggest in this exploratory study the importance of the high
predictability of the 24 h long-term generation of brain rhythms and highlight the importance
of circadian body-brain rhythms in awakening.No abstract available
2. Infraclinical detection of voluntary attention in coma and post-coma patients using electrophysiology.
Morlet D, Mattout J, Fischer C, Luaute J, Dailler F, Ruby, Andre-Obadia N. (2023)
Clin Neurophysiol. — Abstract
Objective: Early functional evaluation and prognosis of patients with disorders of consciousness is a major challenge that clinical assessments alone cannot solve. Objective measures of brain activity could help resolve this uncertainty. We used electroencephalogram at bedside to detect voluntary attention with a paradigm previously validated in healthy subjects.
Methods: Using auditory-oddball sequences, our approach rests on detecting known attentional modulations of Event Related Potentials that reflect compliance with verbal instructions. Sixty-eight unresponsive patients were tested in their first year after coma onset (37 coma and 31 first year post-coma patients). Their evolution 6 months after the test was considered.
Results: Fourteen of the 68 patients, showed a positive response. Nine were in a coma and 5 in a minimally conscious state (MCS). Except for one who died early, all responders evolved to exit-MCS within 6 months (93%), while 35 (65%) among non-responders only.
Conclusions: Among those patients for whom the outcome is highly uncertain, 21% responded positively to this simple but cognitively demanding test. Strikingly, some coma patients were among responders.
Significance: The proposed paradigm revealed cognitive-motor dissociation in some coma patients. This ability to sustain attention on demand predicted awakening within 6 months and represents an immediately useful information for relatives and caregivers.
Keywords: Active paradigm; Coma; Consciousness disorders; Electroencephalography; Event related potentials; Outcome.
3. Virtually spatialized sounds enhance auditory processing in healthy participants and patients with a disorder of consciousness.
Heine L, Corneyllie A, Gobert F, Luauté J, Lavandier M, Perrin F (2021)
Scientific Reports. — Abstract
Neuroscientific and clinical studies on auditory perception often use headphones to limit sound interference. In these conditions, sounds are perceived as internalized because they lack the sound-attributes that normally occur with a sound produced from a point in space around the listener. Without the spatial attention mechanisms that occur with localized sounds, auditory functional assessments could thus be underestimated. We hypothesize that adding virtually externalization and localization cues to sounds through headphones enhance sound discrimination in both healthy participants and patients with a disorder of consciousness (DOC). Hd-EEG was analyzed in 14 healthy participants and 18 patients while they listened to self-relevant and irrelevant stimuli in two forms: diotic (classic sound presentation with an “internalized” feeling) and convolved with a binaural room impulse response (to create an “externalized” feeling). Convolution enhanced the brains’ discriminative response as well as the processing of irrelevant sounds itself, in both healthy participants and DOC patients. For the healthy participants, these effects could be associated with enhanced activation of both the dorsal (where/how) and ventral (what) auditory streams, suggesting that spatial attributes support speech discrimination. Thus, virtually spatialized sounds might “call attention to the outside world” and improve the sensitivity of assessment of brain function in DOC patients.
4. Do not rely on imaging to predict awakening: The value of neurophysiology in a case of Weston-Hurst syndrome.
Gobert F, Ritzenthaler T, Dailler F (2019).
Clinical Neurophysiology — Abstract
No abstract available
5. Is circadian rhythmicity a prerequisite to coma recovery? Circadian recovery concomitant to cognitive improvement in two comatose patients.
Gobert F, Luauté J, Raverot V, Cotton F, Dailler F, Claustrat B, Perrin F* and Gronfier C* (2019)
J Pineal Res, — Abstract
Circadian rhythmicity (CR) is involved in the regulation of all integrated functions, from sleep-wake cycle regulation to metabolic function, mood and cognition. However, the interdependence of CR, cognition and consciousness has been poorly addressed. To clarify the state of CR in coma and to determine the chronological relationship between its recovery and consciousness after brain lesions, we conducted a longitudinal observational study investigating how the state of CR was chronologically related with the recovery of behavioural wakefulness, cognition and/or awareness. Among 16 acute comatose patients, we recruited two 37-year-old patients with a persistent disorder of consciousness, presenting diencephalic lesions caused by severe traumatic brain injuries. Two biological urinary markers of CR were explored every 2 hours during 24 hours (6-sulfatoxymelatonin, free cortisol) with a dedicated methodology to extract the endogenous component of rhythmicity (environmental light recording, near-constant-routine protocol, control of beta-blockers). They presented an initial absence of rhythmic secretions and a recovered CR 7-8 months later. This recovery was not associated with the restoration of behavioural wakefulness, but with an improvement of cognition and awareness (up to the minimally conscious state). MRI showed a lesion pattern compatible with the interruption of either the main hypothalamic-sympathetic pathway or the accessory habenular pathway. These results suggest that CR may be a prerequisite for coma recovery with a potential but still unproven favourable effect on brain function of the resorted circadian melatonin secretion and/or the functional recovery of the suprachiasmatic nucleus (SCN). Assessing circadian functions by urinary melatonin should be further explored as a biomarker of cognition reappearance and investigated to prognosticate functional recovery.
Keywords: biomarkers; circadian rhythm; cognition; coma; hypothalamus; melatonin; traumatic brain injury.
6. Restoring consciousness with vagus nerve stimulation.
Corazzol M, Lio G, Lefevre A, Deiana G, Tell L, Andre-Obadia N, Bourdillon P, Guenot M, Desmurget M, Luaute J, Sirigu A (2017)
Curr Biol. — Abstract
Patients lying in a vegetative state present severe impairments of consciousness [1] caused by lesions in the cortex, the brainstem, the thalamus and the white matter [2]. There is agreement that this condition may involve disconnections in long-range cortico-cortical and thalamo-cortical pathways [3]. Hence, in the vegetative state cortical activity is ‘deafferented’ from subcortical modulation and/or principally disrupted between fronto-parietal regions. Some patients in a vegetative state recover while others persistently remain in such a state. The neural signature of spontaneous recovery is linked to increased thalamo-cortical activity and improved fronto-parietal functional connectivity [3]. The likelihood of consciousness recovery depends on the extent of brain damage and patients’ etiology, but after one year of unresponsive behavior, chances become low [1]. There is thus a need to explore novel ways of repairing lost consciousness. Here we report beneficial effects of vagus nerve stimulation on consciousness level of a single patient in a vegetative state, including improved behavioral responsiveness and enhanced brain connectivity patterns.
7. Proving cortical death after vascular coma: Confrontation of evoked potentials, EEG and radiology.
Gobert F, Dailler F, Fischer C, André-Obadia N and Luauté J (2018)
Clin Neurophysiol — Abstract
Objectives: Several studies have shown that bilateral abolition of somatosensory evoked potentials after a nontraumatic coma has 100% specificity for nonawakening with ethical consequences for active care withdrawal. We propose to evaluate the prognostic value of bilateral abolished cortical components of SEPs in severe vascular coma.
Methods: A total of 144 comatose patients after subarachnoid haemorrhage were evaluated by multimodal evoked potentials (EPs); 7 patients presented a bilateral abolition of somatosensory and auditory EPs. Their prognosis value was interpreted with respect to brainstem auditory EPs, EEG, and structural imaging.
Results: One patient emerged from vegetative state during follow-up; 6 patients did not return to consciousness. The main neurophysiological difference was a cortical reactivity to pain preserved in the patient who returned to consciousness. This patient had focal sub-cortical lesions, which could explain the abolition of primary cortical components by a bilateral deafferentation of somatosensory and auditory pathways.
Conclusions: This is the first report of a favourable outcome after a multimodal abolition of primary cortex EPs in vascular coma. For the 3 cases of vascular coma with preserved brainstem function, EEG reactivity and cortical EPs were abolished by a diffuse ischaemia close to cerebral anoxia.
Significance: The complementarity of EPs, EEG, and imaging must be emphasised if therapeutic limitations are considered to avoid over-interpretation of the prognosis value of EPs.
Keywords: Coma; Critical care; EEG; Evoked potentials; Prognosis; Subarachnoid haemorrhage.
8. Diagnosing Kernohan-Woltman notch phenomenon by Somatosensory Evoked Potentials in ICU.
Gobert F, Baars J, Ritzenthaler T, Afathi M, Boulogne S, André-Obadia N and Dailler F (2017)
Clin Neurophysiol — Abstract
No abstract available
9. Buying time to save a life: A 3-month “call in the dark for awareness”. A moral dilemma in predicting consciousness recovery.
Gobert F, Le Cam P, Guérin C (2016)
Intensive Care Med. — Abstract
No abstract available
10. Long-term outcomes of chronic minimally conscious and vegetative states.
Luaute J, Maucort-Boulch D, Tell L, Quelard F, Sarraf T, Iwaz J, Boisson D, Fischer C (2010).
Neurology — Abstract
Adolescebat autem obstinatum propositum erga haec et similia multa scrutanda, stimulos admovente regina, quae abrupte mariti fortunas trudebat in exitium praeceps, cum eum potius lenitate feminea ad veritatis humanitatisque viam reducere utilia suadendo deberet, ut in Gordianorum actibus factitasse Maximini truculenti illius imperatoris rettulimus coniugem.
