Pupil dilation response elicited by violations of auditory regularities is a promising but challenging approach to probe consciousness at the bedside.

Pupil dilation response (PDR) has been proposed as a physiological marker of conscious access to a stimulus or its attributes, such as novelty. In a previous study on healthy volunteers, we adapted the auditory "local global" paradigm and showed that violations of global regularity elicited a PDR. Notably without instructions, this global effect was present only in participants who could consciously report violations of global regularities. In the present study, we used a similar approach in 24 non-communicating patients affected with a Disorder of Consciousness (DoC) and compared PDR to ERPs regarding diagnostic and prognostic performance. At the group level, global effect could not be detected in DoC patients. At the individual level, the only patient with a PDR global effect was in a MCS and recovered consciousness at 6 months. Contrasting the most regular trials to the most irregular ones improved PDR's diagnostic and prognostic power in DoC patients. Pupillometry is a promising tool but requires several methodological improvements to enhance the signal-to-noise ratio and make it more robust for probing consciousness and cognition in DoC patients.

Neural modulations in the auditory cortex during internal and external attention tasks: A single-patient intracranial recording study.

Brain sensory processing is not passive, but is rather modulated by our internal state. Different research methods such as non-invasive imaging methods and intracranial recording of the local field potential (LFP) have been used to study to what extent sensory processing and the auditory cortex in particular are modulated by selective attention. However, at the level of the single- or multi-units the selective attention in humans has not been tested. In addition, most previous research on selective attention has explored externally-oriented attention, but attention can be also directed inward (i.e., internal attention), like spontaneous self-generated thoughts and mind-wandering. In the present study we had a rare opportunity to record multi-unit activity (MUA) in the auditory cortex of a patient. To complement, we also analyzed the LFP signal of the macro-contact in the auditory cortex. Our experiment consisted of two conditions with periodic beeping sounds. The participants were asked either to count the beeps (i.e., an "external attention" condition) or to recall the events of the previous day (i.e., an "internal attention" condition). We found that the four out of seven recorded units in the auditory cortex showed increased firing rates in "external attention" compared to "internal attention" condition. The beginning of this attentional modulation varied across multi-units between 30-50 msec and 130-150 msec from stimulus onset, a result that is compatible with an early selection view. The LFP evoked potential and induced high gamma activity both showed attentional modulation starting at about 70-80 msec. As the control, for the same experiment we recorded MUA activity in the amygdala and hippocampus of two additional patients. No major attentional modulation was found in the control regions. Overall, we believe that our results provide new empirical information and support for existing theoretical views on selective attention and spontaneous self-generated cognition.

Predicting the loss of responsiveness when falling asleep in humans.

Falling asleep is a dynamical process that is poorly defined. The period preceding sleep, characterized by the progressive alteration of behavioral responses to the environment, which may last several minutes, has no electrophysiological definition, and is embedded in the first stage of sleep (N1). We aimed at better characterizing this drowsiness period looking for neurophysiological predictors of responsiveness using electro and magneto-encephalography. Healthy participants were recorded when falling asleep, while they were presented with continuous auditory stimulations and asked to respond to deviant sounds. We analysed brain responses to sounds and markers of ongoing activity, such as information and connectivity measures, in relation to rapid fluctuations of brain rhythms observed at sleep onset and participants' capabilities to respond. Results reveal a drowsiness period distinct from wakefulness and sleep, from alpha rhythms to the first sleep spindles, characterized by diverse and transient brain states that come on and off at the scale of a few seconds and closely reflects, mainly through neural processes in alpha and theta bands, decreasing probabilities to be responsive to external stimuli. Results also show that the global P300 was only present in responsive trials, regardless of vigilance states. A better consideration of the drowsiness period through a formalized classification and its specific brain markers such as described here should lead to significant advances in vigilance assessment in the future, in medicine and ecological environments.

Does adding <i>beer</i> to <i>coffee</i> enhance the activation of <i>drinks</i>? An ERP study of semantic category priming.

Categorization - whether of objects, ideas, or events - is a cognitive process that is essential for human thinking, reasoning, and making sense of everyday experiences. Categorization abilities are typically measured by the Wechsler Adult Intelligence Scale (WAIS) similarity subtest, which consists of naming the shared category of two items (e.g., 'How are beer and coffee alike'). Previous studies show that categorization, as measured by similarity tasks, requires executive control functions. However, other theories and studies indicate that semantic memory is organized into taxonomic and thematic categories that can be activated implicitly in semantic priming tasks. To explore whether categories can be primed during a similarity task, we developed a double semantic priming paradigm. We measured the priming effect of two primes on a target word that was taxonomically or thematically related to both primes (double priming) or only one of them (single priming). Our results show a larger and additive priming effect in the double priming condition compared to the single priming condition, as measured by both response times and, more consistently, event-related potentials. Our results support the view that taxonomic and thematic categorization can occur during a double priming task and contribute to improving our knowledge on the organization of semantic memory into categories. These findings show how abstract categories can be activated, which likely shapes the way we think and interact with our environment. Our study also provides a new cognitive tool that could be useful to understand the categorization difficulties of neurological patients.

Conscious processing of narrative stimuli synchronizes heart rate between individuals.

Heart rate has natural fluctuations that are typically ascribed to autonomic function. Recent evidence suggests that conscious processing can affect the timing of the heartbeat. We hypothesized that heart rate is modulated by conscious processing and therefore dependent on attentional focus. To test this, we leverage the observation that neural processes synchronize between subjects by presenting an identical narrative stimulus. As predicted, we find significant inter-subject correlation of heart rate (ISC-HR) when subjects are presented with an auditory or audiovisual narrative. Consistent with our hypothesis, we find that ISC-HR is reduced when subjects are distracted from the narrative, and higher ISC-HR predicts better recall of the narrative. Finally, patients with disorders of consciousness have lower ISC-HR, as compared to healthy individuals. We conclude that heart rate fluctuations are partially driven by conscious processing, depend on attentional state, and may represent a simple metric to assess conscious state in unresponsive patients.

Suggestion of self-(in)coherence modulates cognitive dissonance.

While cognitive dissonance is an influential concept of social psychology, its relations with consciousness and episodic memory remain strongly debated. We recently used the free-choice paradigm (FCP) to demonstrate the crucial role of conscious memory of previous choices on choice-induced preference change (CIPC). After choosing between two similarly rated items, subjects reevaluated chosen items as more attractive, and rejected items as less attractive. However such a CIPC was present exclusively for items that were correctly remembered as chosen or rejected during the choice stage, both in healthy controls and in amnesic patients. In the present work, we show that CIPC can be modulated by suggestive quotes promoting self-coherence or self-incoherence. In addition to the crucial role of memory of previous choices, we discovered that memory of the suggestive quotes was correlated to the modulation of CIPC. Taken together these results suggest that CIPC reflects a dynamic homeostatic regulation of self-coherence.

Brain-heart interactions reveal consciousness in noncommunicating patients.

OBJECTIVE: 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. METHODS: A cohort of 127 patients in vegetative state/unresponsive wakefulness syndrome (VS/UWS; n = 70) and minimally conscious state (MCS; n = 57) were presented with the local-global auditory oddball paradigm, which distinguishes 2 levels of processing: short-term deviation of local auditory regularities and global long-term rule violations. In addition to previously validated markers of consciousness extracted from electroencephalograms (EEG), we computed autonomic cardiac markers, such as heart rate (HR) and HR variability (HRV), and cardiac cycle phase shifts triggered by the processing of the auditory stimuli. RESULTS: HR and HRV were similar in patients across groups. The cardiac cycle was not sensitive to the processing of local regularities in either the VS/UWS or MCS patients. In contrast, global regularities induced a phase shift of the cardiac cycle exclusively in the MCS group. The interval between the auditory stimulation and the following R peak was significantly shortened in MCS when the auditory rule was violated. When the information for the cardiac cycle modulations and other consciousness-related EEG markers were combined, single patient classification performance was enhanced compared to classification with solely EEG markers. INTERPRETATION: Our work shows a link between residual cognitive processing and the modulation of autonomic somatic markers. These results open a new window to evaluate patients with disorders of consciousness via the embodied paradigm, according to which body-brain functions contribute to a holistic approach to conscious processing. Ann Neurol 2017;82:578-591.

Dissociating temporal attention from spatial attention and motor response preparation: A high-density EEG study.

Engagement of various forms of attention and response preparation determines behavioral performance during stimulus-response tasks. Many studies explored the respective properties and neural signatures of each of these processes. However, very few experiments were conceived to explore their interaction. In the present work we used an auditory target detection task during which both temporal attention on the one side, and spatial attention and motor response preparation on the other side could be explicitly cued. Both cueing effects speeded response times, and showed strictly additive effects. Target ERP analysis revealed modulations of N1 and P3 responses by these two forms of cueing. Cue-target interval analysis revealed two main effects paralleling behavior. First, a typical contingent negative variation (CNV), induced by the cue and resolved immediately after target onset, was found larger for temporal attention cueing than for spatial and motor response cueing. Second, a posterior and late cue-P3 complex showed the reverse profile. Analyses of lateralized readiness potentials (LRP) revealed both patterns of motor response inhibition and activation. Taken together these results help to clarify and disentangle the respective effects of temporal attention on the one hand, and of the combination of spatial attention and motor response preparation on the other hand on brain activity and behavior.

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.

Event-Related Potential, Time-frequency, and Functional Connectivity Facets of Local and Global Auditory Novelty Processing: An Intracranial Study in Humans.

Auditory novelty detection has been associated with different cognitive processes. Bekinschtein et al. (2009) developed an experimental paradigm to dissociate these processes, using local and global novelty, which were associated, respectively, with automatic versus strategic perceptual processing. They have mostly been studied using event-related potentials (ERPs), but local spiking activity as indexed by gamma (60-120 Hz) power and interactions between brain regions as indexed by modulations in beta-band (13-25 Hz) power and functional connectivity have not been explored. We thus recorded 9 epileptic patients with intracranial electrodes to compare the precise dynamics of the responses to local and global novelty. Local novelty triggered an early response observed as an intracranial mismatch negativity (MMN) contemporary with a strong power increase in the gamma band and an increase in connectivity in the beta band. Importantly, all these responses were strictly confined to the temporal auditory cortex. In contrast, global novelty gave rise to a late ERP response distributed across brain areas, contemporary with a sustained power decrease in the beta band (13-25 Hz) and an increase in connectivity in the alpha band (8-13 Hz) within the frontal lobe. We discuss these multi-facet signatures in terms of conscious access to perceptual information.

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

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.

Evidence for a hierarchy of predictions and prediction errors in human cortex.

According to hierarchical predictive coding models, the cortex constantly generates predictions of incoming stimuli at multiple levels of processing. Responses to auditory mismatches and omissions are interpreted as reflecting the prediction error when these predictions are violated. An alternative interpretation, however, is that neurons passively adapt to repeated stimuli. We separated these alternative interpretations by designing a hierarchical auditory novelty paradigm and recording human EEG and magnetoencephalographic (MEG) responses to mismatching or omitted stimuli. In the crucial condition, participants listened to frequent series of four identical tones followed by a fifth different tone, which generates a mismatch response. Because this response itself is frequent and expected, the hierarchical predictive coding hypothesis suggests that it should be cancelled out by a higher-order prediction. Three consequences ensue. First, the mismatch response should be larger when it is unexpected than when it is expected. Second, a perfectly monotonic sequence of five identical tones should now elicit a higher-order novelty response. Third, omitting the fifth tone should reveal the brain's hierarchical predictions. The rationale here is that, when a deviant tone is expected, its omission represents a violation of two expectations: a local prediction of a tone plus a hierarchically higher expectation of its deviancy. Thus, such an omission should induce a greater prediction error than when a standard tone is expected. Simultaneous EEE- magnetoencephalographic recordings verify those predictions and thus strongly support the predictive coding hypothesis. Higher-order predictions appear to be generated in multiple areas of frontal and associative cortices.

Probing the lifetimes of auditory novelty detection processes.

Auditory novelty detection can be fractionated into multiple cognitive processes associated with their respective neurophysiological signatures. In the present study we used high-density scalp event-related potentials (ERPs) during an active version of the auditory oddball paradigm to explore the lifetimes of these processes by varying the stimulus onset asynchrony (SOA). We observed that early MMN (90-160 ms) decreased when the SOA increased, confirming the evanescence of this echoic memory system. Subsequent neural events including late MMN (160-220 ms) and P3a/P3b components of the P3 complex (240-500 ms) did not decay with SOA, but showed a systematic delay effect supporting a two-stage model of accumulation of evidence. On the basis of these observations, we propose a distinction within the MMN complex of two distinct events: (1) an early, pre-attentive and fast-decaying MMN associated with generators located within superior temporal gyri (STG) and frontal cortex, and (2) a late MMN more resistant to SOA, corresponding to the activation of a distributed cortical network including fronto-parietal regions.

Impaired consciousness during temporal lobe seizures is related to increased long-distance cortical-subcortical synchronization.

Loss of consciousness (LOC) is a dramatic clinical manifestation of temporal lobe seizures. Its underlying mechanism could involve altered coordinated neuronal activity between the brain regions that support conscious information processing. The consciousness access hypothesis assumes the existence of a global workspace in which information becomes available via synchronized activity within neuronal modules, often widely distributed throughout the brain. Re-entry loops and, in particular, thalamo-cortical communication would be crucial to functionally bind different modules together. In the present investigation, we used intracranial recordings of cortical and subcortical structures in 12 patients, with intractable temporal lobe epilepsy (TLE), as part of their presurgical evaluation to investigate the relationship between states of consciousness and neuronal activity within the brain. The synchronization of electroencephalography signals between distant regions was estimated as a function of time by using non-linear regression analysis. We report that LOC occurring during temporal lobe seizures is characterized by increased long-distance synchronization between structures that are critical in processing awareness, including thalamus (Th) and parietal cortices. The degree of LOC was found to correlate with the amount of synchronization in thalamo-cortical systems. We suggest that excessive synchronization overloads the structures involved in consciousness processing, preventing them from treating incoming information, thus resulting in LOC.

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.