Benjamin Rohaut

Neural signature of the conscious processing of auditory regularities

Can conscious processing be inferred from neurophysiological measurements? Some models stipulate that the active maintenance of perceptual representations across time requires consciousness. Capitalizing on this assumption, we designed an auditory paradigm that evaluates cerebral responses to violations of temporal regularities that are either local in time or global across several seconds. Local violations led to an early response in auditory cortex, independent of attention or the presence of a concurrent visual task, whereas global violations led to a late and spatially distributed response that was only present when subjects were attentive and aware of the violations. We could detect the global effect in individual subjects using functional MRI and both scalp and intracerebral event-related potentials. Recordings from 8 noncommunicating patients with disorders of consciousness confirmed that only conscious individuals presented a global effect. Taken together these observations suggest that the presence of the global effect is a signature of conscious processing, although it can be absent in conscious subjects who are not aware of the global auditory regularities. This simple electrophysiological marker could thus serve as a useful clinical tool.

Probing ERP correlates of verbal semantic processing in patients with impaired consciousness

Our ability to identify covert cognitive abilities in non-communicating patients is of prime importance to improve diagnosis, to guide therapeutic decisions and to better predict their cognitive outcome. In the present study, we used a basic and rigorous paradigm contrasting pairs of words orthogonally. This paradigm enables the probing of semantic processing by comparing neural activity elicited by similar words delivered in various combinations. We describe the respective timing, topography and estimated cortical sources of two successive event-related potentials (ERP) components (N400 and late positive component (LPC)) using high-density EEG in conscious controls (N=20) and in minimally conscious (MCS; N=15) and vegetative states (VS; N=15) patients recorded at bedside. Whereas N400-like ERP components could be observed in the VS, MCS and conscious groups, only MCS and conscious groups showed a LPC response, suggesting that this late effect could be a potential specific marker of conscious semantic processing. This result is coherent with recent findings disentangling early and local non-conscious responses (e.g.: MMN in odd-ball paradigms, N400 in semantic violation paradigms) from late, distributed and conscious responses (e.g.: P3b to auditory rule violation) in controls and in patients with disorders of consciousness. However, N400 and LPC responses were not easily observed at the individual level, - even in conscious controls - , with standard ERP analyses, which is a limiting factor for its clinical use. Of potential interest, the only 3 patients presenting both significant N400 and LPC effects were MCS, and 2 of them regained consciousness and functional language abilities.

Multidimensional cognitive evaluation of patients with disorders of consciousness using EEG: A proof of concept study

The use of cognitive evoked potentials in EEG is now part of the routine evaluation of non-communicating patients with disorders of consciousness in several specialized medical centers around the world. They typically focus on one or two cognitive markers, such as the mismatch negativity or the P3 to global auditory regularity. However it has become clear that none of these markers in isolation is at the same time sufficiently specific and sufficiently sensitive to be taken as the unique gold standard for diagnosing consciousness. A good way forward would be to combine several cognitive markers within the same test to improve evaluation. Furthermore, given the diversity of lesions leading to disorders of consciousness, it is important not only to probe whether a patient is conscious or not, but also to establish a more general and nuanced profile of the residual cognitive capacities of each patient using a combination of markers. In the present study we built a unique EEG protocol that probed 8 dimensions of cognitive processing in a single 1.5 h session. This protocol probed variants of classical markers together with new markers of spatial attention, which has not yet been studied in these patients. The eight dimensions were: (1) own name recognition, (2) temporal attention, (3) spatial attention, (4) detection of spatial incongruence (5) motor planning, and (6,7,8) modulations of these effects by the global context, reflecting higher-level functions. This protocol was tested in 15 healthy control subjects and in 17 patients with various etiologies, among which 13 could be included in the analysis. The results in the control group allowed a validation and a specific description of the cognitive levels probed by each marker. At the single-subject level, this combined protocol allowed assessing the presence of both classical and newly introduced markers for each patient and control, and revealed that the combination of several markers increased diagnostic sensitivity. The presence of a high-level effect in any of the three tested domains distinguished between minimally conscious and vegetative patients, while the presence of low-level effects was similar in both groups. In summary, this study constitutes a validated proof of concept in favor of probing multiple cognitive dimensions to improve the evaluation of non-communicating patients. At a more conceptual level, this EEG tool can help achieve a better understanding of disorders of consciousness by exploring consciousness in its multiple cognitive facets.

Neural detection of complex sound sequences or of statistical regularities in the absence of consciousness

Sir, We read with interest the article by Tzovara et al. (2015), recently published in Brain . In this study the authors adapted a paradigm we previously designed (Bekinschtein et al. , 2009) to probe the EEG of comatose patients in response to two types of violations of auditory regularities. Unfortunately, several important problems mitigate the reliability of their conclusions. In the local-global paradigm, local auditory irregularities correspond to a change of sound within a trial, whereas global irregularities correspond to a change of sound sequence across trials. The authors showed with a decoding algorithm a significant difference in EEG responses to global violations in 10 of 24 comatose patients. Observing such a global effect in unconscious subjects challenges our previous conclusion that this global effect can only be observed in conscious and attentive subjects (Bekinschtein et al. , 2009; Wacongne et al. , 2012; El Karoui et al. , 2014) and systematically disappears in inattentive subjects (Bekinschtein et al. , 2009; King et al. , 2013), sleeping subjects (Strauss et al. , 2015), and clinically unconscious patients in vegetative state (Faugeras et al. , 2011, 2012). Converging findings from multiple functional brain imaging tools [high-density EEG, magnetoencephalography (MEG), intracranial stereoelectroencephalography (SEEG), functional MRI] demonstrated that the global effect is characterized by a late (>300 ms after violation onset) and sustained brain response (King et al. , 2014) typical of conscious access (Dehaene and Naccache 2001; Dehaene et al. , 2011). In our data, the only two patients in a vegetative state showing a late global effect recovered clinical signs of minimally conscious state within the next …

Reply: Replicability and impact of statistics in the detection of neural responses of consciousness

Sir, We read with interest the letter by Gabriel and colleagues (2016) addressing the major issue of replicability when probing conscious processing in non-communicating patients. This question—as well as the choice of the optimal statistical methodology—concerns the whole field of functional brain imaging in cognitive neuroscience (Kriegeskorte et al. , 2009), but its importance obviously culminates in single-subject analyses of non-communicating patients (see for instance the recent debate in Cruse et al. , 2011, 2013; Goldfine et al. , 2012). Gabriel et al. reacted to a recent discussion (Naccache et al. , 2015; Tzovara et al. , 2015 a , b ) following a report by Tzovara et al. (2015 a ), who adapted our auditory ‘local-global’ bedside EEG test (Bekinschtein et al. , 2009) to test comatose patients. Briefly, in the local-global paradigm two levels of regularities are manipulated: local auditory irregularities correspond to a change of sound within a trial, whereas global irregularities correspond to a change of sound sequence across trials. When analysing data according to the local irregularities, one can typically extract a mismatch negativity response observable even in unconscious states. In sharp contrast, when analysing event-related potentials (ERPs) to violations of global irregularities, we previously showed that a late global effect was present only in conscious or minimally conscious patients (Bekinschtein et al. , 2009; Faugeras et al. , 2011, 2012). Two problems emerged from the study of Tzovara et al. (2015 a ), first, this ERP global effect was found positive in the vast majority of conscious controls we tested at two distinct sites using high-density EEG: 18/18 (100%) in Paris, France (with 256 electrodes), and 7 to 10/10 (70 to 100%) with the monaural and binaural versions of the task, respectively in Cambridge, UK …

Status dissociatus and disturbed dreaming in a patient with Morvan syndrome plus myasthenia gravis

A 52-year-old patient suffered from myasthenia gravis with antibodies against acetylcholine receptors and a thymoma, and was successfully treated with surgery, radiotherapy, and azathioprine. At age 60, he experienced non-painful cramps and myokymia in the calves, which progressively spread to the whole body, associated with profuse sweating, non-restorative sleep, and dream-enacting behaviors. Because of dysphagia and dysarthria, he was admitted to the intensive care unit. As there were continuous resting activities with fasciculations andmyokymia but no myasthenia decrement in the electromyography, no malignant thymoma, and no paraneoplastic antibodies, Morvan syndromewas suspected and later confirmed by positive antibodies against contactin-associated protein-like 2. His wife reported that he displayed continuous motor restlessness during the night for the past year. The patient slept on average for 7 h at night and had two 30-min-long naps per day. He always felt “mid-water, neither awake nor asleep,” being conscious throughout the night and yet experiencing an intense and continuous dreaming activity, including epic dreaming (eg, fantastic, prolonged rides in a hot air balloon with gypsies), vivid dreaming (eg, he repeatedly dreamt that his son was cheating on his wife; the dreams seemed so real that he felt obliged to inquire from his son), lucid dreaming (he knew sometimes that he was dreaming), and recurrent contextual dreams. As he was scheduled for a brain scan, he vividly dreamt that the nurses entered his hospital room to bring him to the scanner. As he stood up and put his slippers, he realized that it was 3 am, resumed sleep, and dreamt again, but this time the nurses were coming into the room to warn him that the scanner has been rescheduled another day, and so on. During daytime, he felt sleepy needing four to five naps of 30 min each per day, during which dreaming was less vivid than during nighttime. During nighttime videopolysomnography, the electroencephalographic (EEG) activity contained a continuous, diffuse 9-Hz alpha rhythm (as duringwakefulnesswith eye closed) all night long, without any conventional sleep features (theta activity, spindles, * Corresponding author. Service des Pathologies du Sommeil, Hopital PitieSalpetriere, 47-83 Boulevard de l’Hopital, 75651 Paris Cedex 13, France. Tel.: +33 142 16 77 02; fax: +33 142 16 77 00. E-mail address: isabelle.arnulf@psl.aphp.fr (I. Arnulf).

Post-traumatic stress symptoms in Guillain–Barré syndrome patients after prolonged mechanical ventilation in ICU: a preliminary report

Thirty percent of Guillain–Barré syndrome (GBS) patients require mechanical ventilation (MV) in intensive care unit (ICU). Post‐traumatic stress disorder (PTSD) is found in ICU survivors, and the traumatic aspects of intubation and MV have been previously reported as risk factors for PTSD after ICU. Our objective was to determine long‐term PTSD or post‐traumatic stress symptoms (PTSS) in GBS patients after prolonged MV in ICU. We assessed GBS patients who had MV for more than 2 months. PTSD was assessed using Horowitz Impact of Event Scale (IES), IES‐Revisited (IES‐R), and the Post‐traumatic CheckList Scale; functional outcome using Rankin and Barthel scales; quality of life (QoL) using Nottingham Health Profile (NHP) and 36‐Item Short Form Health Survey (SF‐36) and depression using Hospital Anxiety and Depression Scale (HAD) and Beck questionnaire. Thirteen patients could be identified and analyzed. They had only mild disability. They were neither anxious nor depressed with an anxiety HAD at 5 (4–11.5), a depression HAD at 1 (0–3.5) and a Beck at 1 (0–5). QoL was mildly decreased in our population with a NHP at 78.5 (12.8–178.8) and mild decreased SF‐36. Compared with the French population, the SF‐36 sub‐categories were, however, not statistically different. Twenty‐two percentage of our 13 patients had PTSD and PTSS with a Horowitz IES at 12 (2–29), and an IES‐R at 16 (2–34.5). Although severe GBS patients requiring prolonged MV had good functional recovery and no difference in QoL, they had a high incidence of PTSS.

Brain-heart interactions reveal consciousness in non-communicating patients

We here aimed at characterizing heart–brain interactions in patients with disorders of consciousness. We tested how this information impacts data‐driven classification between unresponsive and minimally conscious patients.

Survival and consciousness recovery are better in the minimally conscious state than in the vegetative state

ABSTRACT Background: The prognosis value of early clinical diagnosis of consciousness impairment is documented by an extremely limited number of studies, whereas it may convey important information to guide medical decisions. Objective: We aimed at determining if patients diagnosed at an early stage (<90 days after brain injury) as being in the minimally conscious state (MCS) have a better prognosis than patients in the vegetative state/Unresponsive Wakefulness syndrome (VS/UWS), independent of care limitations or withdrawal decisions. Methods: Patients hospitalized in ICUs of the Pitié-Salpêtrière Hospital (Paris, France) from November 2008 to January 2011 were included and evaluated behaviourally with standardized assessment and with the Coma Recovery Scale-Revised as being either in the VS/UWS or in the MCS. They were then prospectively followed until 1July 2011 to evaluate their outcome with the GOSE. We compared survival function and outcomes of these two groups. Results: Both survival function and outcomes, including consciousness recovery, were significantly better in the MCS group. This difference of outcome still holds when considering only patients still alive at the end of the study. Conclusions: Early accurate clinical diagnosis of VS/UWS or MCS conveys a strong prognostic value of survival and of consciousness recovery.