Elsevier

Neuropsychologia

Volume 50, Issue 3, February 2012, Pages 403-418
Neuropsychologia

Event related potentials elicited by violations of auditory regularities in patients with impaired consciousness

https://doi.org/10.1016/j.neuropsychologia.2011.12.015Get rights and content

Abstract

Improving our ability to detect conscious processing in non communicating patients remains a major goal of clinical cognitive neurosciences. In this perspective, several functional brain imaging tools are currently under development. Bedside cognitive event-related potentials (ERPs) derived from the EEG signal are a good candidate to explore consciousness in these patients because: (1) they have an optimal time resolution within the millisecond range able to monitor the stream of consciousness, (2) they are fully non-invasive and relatively cheap, (3) they can be recorded continuously on dedicated individual systems to monitor consciousness and to communicate with patients, (4) and they can be used to enrich patients’ autonomy through brain–computer interfaces. We recently designed an original auditory rule extraction ERP test 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, while global violations led to a late and spatially distributed response that was only present when subjects were attentive and aware of the violations. In the present work, we report the results of this test in 65 successive recordings obtained at bedside from 49 non-communicating patients affected with various acute or chronic neurological disorders. At the individual level, we confirm the high specificity of the ‘global effect’: only conscious patients presented this proposed neural signature of conscious processing. Here, we also describe in details the respective neural responses elicited by violations of local and global auditory regularities, and we report two additional ERP effects related to stimuli expectancy and to task learning, and we discuss their relations to consciousness.

Highlights

► It is possible to probe consciousness at bedside with an auditory ERP test. ► Only conscious brains respond to violations of long-span auditory regularities. ► Violations of short-span auditory regularities elicit non-conscious responses. ► Clinically vegetative patients positive on this test are most probably conscious.

Introduction

Is he/she conscious?” Far from being a purely philosophical abyssal issue, this question is a daily interrogation for the caregivers and health professionals of acute or chronic non-communicating patients. Answers to this question are crucial to optimize the medical management of those patients, to specify the amount of efforts devoted to communicate with them, and to provide robust objective landmarks to the caregivers and close relatives of the patients in these extremely difficult situations where irrepressible emotions, subjective feelings and interpretative beliefs may be misleading and insufficient to guide medical strategy.

For many years, clinical examination and behavioral observation constituted the single approach to diagnose consciousness (Plum & Posner, 1972). Consciousness is clinically defined in relation to the diverse neurological conditions where it is impaired or absent. Major principles can be derived from clinical neurology.

First, a necessary but insufficient physiological condition to consciousness is wakefulness, that is to say the presence of waking periods during which the patient keeps his eyes open independently of external stimulations. Wakefulness is impaired in comatose states, in general anesthesia or in deep sleep stages in which patients are not conscious (Laureys, Owen, & Schiff, 2004). The neural bases of wakefulness mostly involve complex brainstem and thalamic networks often regrouped under the generic term of ascending reticular activating system (ARAS) (see Moruzzi and Magoun, 1949, Parvizi and Damasio, 2001 for a recent review).

A more subtle alteration of consciousness is the vegetative state (VS), which is characterized by preserved wakefulness (Jennett & Plum, 1972) – even if circadian rhythms may not be strictly normal (Bekinschtein, Golombek, Simonetta, Coleman, & Manes, 2009) – in the absence of any purposeful behavior and of any sign of intentional reactions to the external environment. Note that VS is, by definition, a clinical syndrome and not a specific condition. For this reason, and in order to avoid too radical interpretations of patient's cognitive state only based on behavioral observations, a group of experts recently proposed the ‘Unresponsive Wakefulness Syndrome’ expression to describe VS (Laureys et al., 2010).

The mere existence of VS demonstrates that wakefulness and consciousness can be dissociated, and therefore that they cannot be identified one with another (Bernat, 2006). While VS can have a highly variable duration, from several days to a whole lifetime, other neurological situations can be described as ‘transient VS’: during complex partial epileptic seizures or during “petit mal absence” seizures for instance, a comparable dissociation between consciousness and wakefulness occurs, but on a much shorter time-scale, usually from a few seconds to several minutes (Blumenfeld & Taylor, 2003).

Neurological observations revealed that many patients presented fluctuating states which could be identified neither as VS nor conscious states. These transitional states have recently been regrouped under the concept of minimally conscious states (MCS, Giacino et al., 2002). The behavioral distinction between VS and MCS requires an expertise in clinical assessment and can be based on the use of a dedicated scale: the revised version of the Coma Recovery Scale (CRS-R, see Kalmar & Giacino, 2005, adapted in many languages including French, Schnakers, Majerus, et al., 2008). For instance, while VS patients can show fast and transient saccadic responses to moving visual targets, the presence of sustained and reproducible visual pursuit is an index of MCS. Note that a recent work showed that the use of EMG signal in active motor paradigms is more sensitive than mere clinical examination of overt movements (Bekinschtein, Coleman, Niklison, Pickard, & Manes, 2008).

Prior to consciousness assessment, a detailed clinical checking of the functionality of motor pathways is absolutely necessary, as demonstrated by various clinical conditions in which a paralyzed but conscious patient can be misclassified as unconscious. “Locked in syndrome” usually secondary to brainstem strokes in the paramedian protuberance (Laureys et al., 2005), but also related conditions such as severe Guillain–Barré polyradiculoneuritis or severe amyotrophic lateral sclerosis are typical illustrations of this point.

Note also that the presence of massive cognitive impairments may be difficult to detect and may lead to an underestimation of consciousness. For instance, a non-communicating patient affected by a global aphasia (e.g.: massive left hemispheric lesion) will probably not demonstrate any adapted behavior even to basic verbal instructions. Similarly, massive impairments in anterograde memory, in working memory or executive functions can lead to an underestimation of the consciousness status.

In the light of these fundamental neurological principles, it is clear that purely behavioral observations have limited sensitivity, and only constitute indirect evidence of conscious processes. In some cases, the categorization of a patient as vegetative or minimally conscious is far from obvious. Thus, in many daily clinical situations, the inaugural question of this article is left unanswered: “Is he/she conscious?”

A complementary approach to clinical neurology originates from cognitive neurosciences of consciousness. Although the issue remains debated, two decades of experimental and theoretical works have led to the characterization of psychological and neurophysiological attributes that may be unique to conscious processing (Seth, Dienes, Cleeremans, Overgaard, & Pessoa, 2008). Many cognitive processes may occur unconsciously both in conscious subjects (Dehaene et al., 2006, Kouider and Dehaene, 2007), in visual neglect patients or related patients (Driver and Mattingley, 1998, Naccache, 2008), and in non conscious patients (Laureys, 2005, Owen et al., 2005), reaching such complex levels as abstract semantics, phonological or emotional processing. Still, three properties seem to be exclusively associated with conscious processing of reportable mental contents (Dehaene & Naccache, 2001): (i) active maintenance of mental representations in working memory; (ii) strategical processing; and (iii) spontaneous intentional behavior. Similarly, while unconscious processing may engage multiple isolated cortical areas, neural signatures of conscious processing are defined by late and long-lasting brain activations that mobilize long-distance coherent thalamo-cortical networks, particularly involving bilateral prefrontal, cingulate and parietal areas (Dehaene et al., 2006, Gaillard et al., 2009).

On the basis of these studies, original experimental paradigms can therefore be designed in order to improve our ability to diagnose consciousness in non-communicating patients, beyond clinical evaluations. For instance, at the behavioral level, Bekinschtein, Shalom, et al. (2009) capitalized on the working memory property mentioned above, and used an eyeblink conditioning paradigm in which a tone stimulus can be paired with an air-puff delivered on the cornea. Delay conditioning – where the conditioned stimulus and the unconditioned air-puff overlap in time – does not require conscious processing of the stimuli. In contrast, trace conditioning where a temporal gap is inserted between the two stimuli seems to require conscious processing in working memory (Clark & Squire, 1998). Interestingly, they showed that some clinically defined VS patients were able to demonstrate both conditioning and trace conditionings. Functional brain-imaging approaches are also emerging (Coleman et al., 2009). For instance, Owen et al. (2006) probed with fMRI the active maintenance of task-instructed cognitive tasks, such the ability to perform motor or spatial imagery tasks for a extended duration of 30 s. Using this approach on 54 patients, they could identify 5 patients able to willfully modulate their brain activity (Monti et al., 2010). Among these 5 patients, two were clinically classified as VS. In one clinically MCS patient, fMRI could be used to define an arbitrary code and communicate a single bit of information (a yes/no answer), while such a communication was not possible behaviorally.

In parallel to such fMRI experiments, EEG paradigms may constitute a highly promising research direction for at least two reasons. First, EEG is a time-resolved tool able to sample brain activity at the millisecond scale. This offers a unique opportunity to monitor the flow of consciousness and eventually to interact with the patient in real-time. Second, given that EEG is a non-invasive technique, has a relatively low-cost and can be recorded at bedside, one may ultimately design dedicated systems for recurrent and even continuous daily recording of brain activity in patients. In that respect, EEG monitoring seems more likely to truthfully reflect VS and MCS patients’ complex fluctuating states than a single fMRI scan lasting a few tens of minutes. Schnakers and her colleagues showed the utility of using active EEG paradigms to probe voluntary brain responses to stimuli. They could confirm the presence of conscious processing in a locked-in syndrome patient (Schnakers, Perrin, et al., 2009), and in clinically defined MCS patients (Schnakers, Perrin, et al., 2008).

We recently designed an auditory paradigm that evaluates the cerebral responses to violations of temporal regularities (Bekinschtein, Dehaene, et al., 2009). Local violations due to the unexpected occurrence of a single deviant sound among a repeated train of standard sounds led to an early response in auditory cortex, the mismatch negativity (MMN) ERP component, independent of attention and of the presence of a concurrent visual task. On the other hand, global violations, defined as the presentation of a rare and unexpected series of five sounds, led to a late and spatially distributed response that was only present when subjects were attentive and aware of the violations (P3b ERP component). We could detect the global effect in individual subjects using functional MRI and both scalp and intracerebral event-related potentials. The original publication (Bekinschtein, Dehaene, et al., 2009) reported the results from 8 non communicating patients with disorders of consciousness (4 MCS and 4 VS) and confirmed that only conscious individuals presented a global effect (3 MCS patients). In a more recent work focusing on a larger sample of clinically defined VS patients, we confirmed the absence of global effect in the vast majority of patients, and identified 2 patients showing this neural signature of consciousness (Faugeras et al., 2011). Interestingly, these 2 patients showed unequivocal clinical signs of consciousness within the 3–4 days following ERP recording, strongly suggesting they were misclassified as VS due to limitations of clinical examination. Taken together, these observations were highly suggestive that the global effect might be a signature of conscious processing, although it can be absent in conscious subjects who are not aware of the global auditory regularities.

In the present work, we prospectively explored the first 100 consecutive recordings obtained in 65 non-communicating patients (November 2008 to February 2010) with the ‘local global’ paradigm while recording their EEG activity with a high-density EEG system (see Fig. 1), subsequently to a detailed neurological examination, and to a behavioral scoring of consciousness with the CRS-R. Our objectives were fourfold: (i) probe the diagnostic reliability of our test at the individual-level on a large sample of well characterized non-communicating patients with various degrees of consciousness impairments, (ii) estimate its utility in extreme situations such as “locked in syndrome” and related conditions, and (iii) explore in details the distinct ERP correlates of the violations of local and global regularities, both at the group-level and at the individual level, (iv) report the ERP correlates of task learning and stimuli expectancy. Note that the main objective of this study being the validation of the specificity of the ERP “global effect” at the individual level, we deliberately included all ERP datasets originating from various etiologies, recorded either at acute or chronic stages, and we included repeated recordings of the same patients (11 patients with 2–4 recordings) to avoid arbitrary data selection. This study does not aim at reporting specific knowledge about a given disease, of about a specific group of patients, but rather aims at testing the value of our ERP test at individual level in regards to the clinical evaluation of consciousness.

Section snippets

Normal controls

Experiments were approved by the Ethical Committee of the Salpêtrière hospital. The 10 normal controls (mean age = 20.3 ± 0.7; sex-ratio (M/F) = 2.3) gave written informed consent. Data from two control subjects were discarded from the analysis due to excessive movement artifacts.

Patients

The clinical motivation for recording patients was to better assess their level of consciousness (Bekinschtein, Dehaene, et al., 2009), and to probe potential residual unconscious processing of the auditory environment

Behavioral assessment of consciousness

Among the 100 recordings, 65 were considered as valid on the basis of our procedure of EEG quality evaluation (see Section 2). These 65 correct recordings corresponded to 49 patients, some of whom were recorded several times (from 1 to 4). This heterogeneous collection of recordings included various levels of clinically assessed conscious states ranging from VS, MCS to overtly conscious, and conscious but paralyzed patients. More precisely, these 65 recordings corresponded to: 24 recordings

Discussion

In this work we prospectively recorded high-density scalp ERP in patients suffering from various disorders of consciousness, while they were instructed to perform an active version of the ‘local global test’. This test was recently designed to diagnose consciousness without relying on behavioral responses. Among these 100 recordings, 65 satisfied criteria of data quality, due to the large amount of motor and environment EEG artifacts. Both the clinical condition of patients who were recorded in

Acknowledgments

This work has been supported by the Fondation pour la Recherche Médicale (FRM) (PhD support to Frédéric Faugeras and ‘Equipe FRM 2010’ grant to Lionel Naccache), by the JNLF (Master 2 funding to Frédéric Faugeras), by the ERC (NeuroConsc grant supporting Stanislas Dehaene and Lionel Naccache), by the Institut pour le Cerveau et la Moëlle épinière (ICM Institute, Paris, France), by INSERM and by AP-HP. We thank Pr. Chastre, Pr. Similowski, Pr. Samson, Pr. Rouby and Dr. Patte-Karsenti for

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