Sea Slugs, Subliminal Pictures, and Vegetative State Patients: Boundaries of Consciousness in Classical Conditioning

Classical (trace) conditioning is a specific variant of associative learning in which a neutral stimulus leads to the subsequent prediction of an emotionally charged or noxious stimulus after a temporal gap. When conditioning is concurrent with a distraction task, only participants who can report the relationship (the contingency) between stimuli explicitly show associative learning. This suggests that consciousness is a prerequisite for trace conditioning. We review and question three main controversies concerning this view. Firstly, virtually all animals, even invertebrate sea slugs, show this type of learning; secondly, unconsciously perceived stimuli may elicit trace conditioning; and thirdly, some vegetative state patients show trace learning. We discuss and analyze these seemingly contradictory arguments to find the theoretical boundaries of consciousness in classical conditioning. We conclude that trace conditioning remains one of the best measures to test conscious processing in the absence of explicit reports

Functional Imaging Reveals Movement Preparatory Activity in the Vegetative State

The vegetative state (VS) is characterized by the absence of awareness of self or the environment and preserved autonomic functions. The diagnosis relies critically on the lack of consistent signs of purposeful behavior in response to external stimulation. Yet, given that patients with disorders of consciousness often exhibit fragmented movement patterns, voluntary actions may go unnoticed. Here we designed a simple motor paradigm that could potentially detect signs of purposeful behavior in VS patients with mild to severe brain damage by examining the neural correlates of motor preparation in response to verbal commands. Twenty-four patients who met the diagnostic criteria for VS were recruited for this study. Eleven of these patients showing preserved auditory evoked potentials underwent functional magnetic resonance imaging (fMRI) to test for basic speech processing. Five of these patients, who showed word related activity, were included in a second fMRI study aimed at detecting functional changes in premotor cortex elicited by specific verbal instructions to move either their left or their right hand. Despite the lack of overt muscle activity, two patients out of five activated the dorsal premotor cortex contralateral to the instructed hand, consistent with movement preparation. Our results may reflect residual voluntary processing in these two patients. We believe that the identification of positive results with fMRI using this simple task, may complement the clinical assessment by helping attain a more precise diagnosis in patients with disorders of consciousness

Transient Topographical Dynamics of the Electroencephalogram Predict Brain Connectivity and Behavioural Responsiveness During Drowsiness.

As we fall sleep, our brain traverses a series of gradual changes at physiological, behavioural and cognitive levels, which are not yet fully understood. The loss of responsiveness is a critical event in the transition from wakefulness to sleep. Here we seek to understand the electrophysiological signatures that reflect the loss of capacity to respond to external stimuli during drowsiness using two complementary methods: spectral connectivity and EEG microstates. Furthermore, we integrate these two methods for the first time by investigating the connectivity patterns captured during individual microstate lifetimes. While participants performed an auditory semantic classification task, we allowed them to become drowsy and unresponsive. As they stopped responding to the stimuli, we report the breakdown of alpha networks and the emergence of theta connectivity. Further, we show that the temporal dynamics of all canonical EEG microstates slow down during unresponsiveness. We identify a specific microstate (D) whose occurrence and duration are prominently increased during this period. Employing machine learning, we show that the temporal properties of microstate D, particularly its prolonged duration, predicts the response likelihood to individual stimuli. Finally, we find a novel relationship between microstates and brain networks as we show that microstate D uniquely indexes significantly stronger theta connectivity during unresponsiveness. Our findings demonstrate that the transition to unconsciousness is not linear, but rather consists of an interplay between transient brain networks reflecting different degrees of sleep depth

Arousal modulates auditory attention and awareness: insights from sleep, sedation, and disorders of consciousness.

The interplay between attention and consciousness is frequently tested in altered states of consciousness, including transitions between stages of sleep and sedation, and in pathological disorders of consciousness (DoC; the vegetative and minimally conscious states; VS and MCS). One of the most widely used tasks to assess cognitive processing in this context is the auditory oddball paradigm, where an infrequent change in a sequence of sounds elicits, in awake subjects, a characteristic EEG event-related potential called the mismatch negativity, followed by the classic P300 wave. The latter is further separable into the slightly earlier, anterior P3a and the later, posterior P3b, thought to be linked to task-irrelevant "bottom-up" and task-oriented "top-down" attention, respectively. We discuss here the putative dissociations between attention and awareness in DoC, sedation and sleep, bearing in mind the recently emerging evidence from healthy volunteers and patients. These findings highlight the neurophysiological and cognitive parallels (and differences) across these three distinct variations in levels of consciousness, and inform the theoretical framework for interpreting the role of attention therein.This research was supported by generous funding from the Medical Research Council (U.1055.01.002.00001.01), the James S. McDonnell Foundation, and the Wellcome Trust Biomedical Research Fellowship awarded to Tristan A. Bekinschtein

Does left-handedness confer resistance to spatial bias?

We recently demonstrated that drowsiness, indexed using EEG, was associated with left-inattention in a group of 26 healthy right-handers. This has been linked to alertness-related modulation of spatial bias in left neglect patients and the greater persistence of left, compared with right, neglect following injury. Despite handedness being among the most overt aspects of human lateralization, studies of this healthy analogue of left neglect have only been conducted with predominantly or exclusively right-handed individuals. Here, with a group of 26 healthy non-right-handers we demonstrate that, unlike right-handers who showed a rightward shift in attention with drowsiness, non-right-handers showed the opposite pattern on an auditory spatial localization task. The current results are the first indication that factors linked to handedness can affect the development and extremity of spatial biases, potentially conferring resilience to clinical symptoms in non-right-handers and, given that 90% of us are right-handed, why left neglect is disproportionately persistent

Neural Signal to Violations of Abstract Rules Using Speech-Like Stimuli.

As the evidence of predictive processes playing a role in a wide variety of cognitive domains increases, the brain as a predictive machine becomes a central idea in neuroscience. In auditory processing, a considerable amount of progress has been made using variations of the Oddball design, but most of the existing work seems restricted to predictions based on physical features or conditional rules linking successive stimuli. To characterize the predictive capacity of the brain to abstract rules, we present here two experiments that use speech-like stimuli to overcome limitations and avoid common confounds. Pseudowords were presented in isolation, intermixed with infrequent deviants that contained unexpected phoneme sequences. As hypothesized, the occurrence of unexpected sequences of phonemes reliably elicited an early prediction error signal. These prediction error signals do not seemed to be modulated by attentional manipulations due to different task instructions, suggesting that the predictions are deployed even when the task at hand does not volitionally involve error detection. In contrast, the amount of syllables congruent with a standard pseudoword presented before the point of deviance exerted a strong modulation. Prediction error's amplitude doubled when two congruent syllables were presented instead of one, despite keeping local transitional probabilities constant. This suggests that auditory predictions can be built integrating information beyond the immediate past. In sum, the results presented here further contribute to the understanding of the predictive capabilities of the human auditory system when facing complex stimuli and abstract rules

Why Clowns Taste Funny: The Relationship between Humor and Semantic Ambiguity

What makes us laugh? One crucial component of many jokes is the disambiguation of words with multiple meanings. In this functional MRI study of normal participants, the neural mechanisms that underlie our experience of getting a joke that depends on the resolution of semantically ambiguous words were explored. Jokes that contained ambiguous words were compared with sentences that contained ambiguous words but were not funny, as well as to matched verbal jokes that did not depend on semantic ambiguity. The results confirm that both the left inferior temporal gyrus and left inferior frontal gyrus are involved in processing the semantic aspects of language comprehension, while a more widespread network that includes both of these regions and the temporoparietal junction bilaterally is involved in processing humorous verbal jokes when compared with matched nonhumorous material. In addition, hearing jokes was associated with increased activity in a network of subcortical regions, including the amygdala, the ventral striatum, and the midbrain, that have been implicated in experiencing positive reward. Moreover, activity in these regions correlated with the subjective ratings of funniness of the presented material. These results allow a more precise account of how the neural and cognitive processes that are involved in ambiguity resolution contribute to the appreciation of jokes that depend on semantic ambiguity

Brain Connectivity Dissociates Responsiveness from Drug Exposure during Propofol-Induced Transitions of Consciousness.

Accurately measuring the neural correlates of consciousness is a grand challenge for neuroscience. Despite theoretical advances, developing reliable brain measures to track the loss of reportable consciousness during sedation is hampered by significant individual variability in susceptibility to anaesthetics. We addressed this challenge using high-density electroencephalography to characterise changes in brain networks during propofol sedation. Assessments of spectral connectivity networks before, during and after sedation were combined with measurements of behavioural responsiveness and drug concentrations in blood. Strikingly, we found that participants who had weaker alpha band networks at baseline were more likely to become unresponsive during sedation, despite registering similar levels of drug in blood. In contrast, phase-amplitude coupling between slow and alpha oscillations correlated with drug concentrations in blood. Our findings highlight novel markers that prognosticate individual differences in susceptibility to propofol and track drug exposure. These advances could inform accurate drug titration and brain state monitoring during anaesthesia.This work was supported by grants from the James S. McDonnell Foundation, the Wellcome Trust [WT093811MA to TAB], and the British Oxygen Professorship from the Royal College of Anaesthetists [to DKM]. The research was also supported by the NIHR Brain Injury Healthcare Technology Co-operative based at Cambridge University Hospitals NHS Foundation Trust and University of Cambridge. The views expressed are those of the authors and not necessarily those of the UK National Health Service, the NIHR or the UK Department of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.This is the final version of the article. It was first available from PLOS via http://dx.doi.org/10.1371/journal.pcbi.100466

Inducing Task-Relevant Responses to Speech in the Sleeping Brain

Falling asleep leads to a loss of sensory awareness and to the inability to interact with the environment [1]. While this was traditionally thought as a consequence of the brain shutting down to external inputs, it is now acknowledged that incoming stimuli can still be processed, at least to some extent, during sleep [2]. For instance, sleeping participants can create novel sensory associations between tones and odors [3] or reactivate existing semantic associations, as evidenced by event-related potentials [4; 5; 6 ; 7]. Yet, the extent to which the brain continues to process external stimuli remains largely unknown. In particular, it remains unclear whether sensory information can be processed in a flexible and task-dependent manner by the sleeping brain, all the way up to the preparation of relevant actions. Here, using semantic categorization and lexical decision tasks, we studied task-relevant responses triggered by spoken stimuli in the sleeping brain. Awake participants classified words as either animals or objects (experiment 1) or as either words or pseudowords (experiment 2) by pressing a button with their right or left hand, while transitioning toward sleep. The lateralized readiness potential (LRP), an electrophysiological index of response preparation, revealed that task-specific preparatory responses are preserved during sleep. These findings demonstrate that despite the absence of awareness and behavioral responsiveness, sleepers can still extract task-relevant information from external stimuli and covertly prepare for appropriate motor responses

Delta band activity contributes to the identification of command following in disorder of consciousness.

The overt or covert ability to follow commands in patients with disorders of consciousness is considered a sign of awareness and has recently been defined as cortically mediated behaviour. Despite its clinical relevance, the brain signatures of the perceptual processing supporting command following have been elusive. This multimodal study investigates the temporal spectral pattern of electrical brain activity to identify features that differentiated healthy controls from patients both able and unable to follow commands. We combined evidence from behavioural assessment, functional neuroimaging during mental imagery and high-density electroencephalography collected during auditory prediction, from 21 patients and 10 controls. We used a penalised regression model to identify command following using features from electroencephalography. We identified seven well-defined spatiotemporal signatures in the delta, theta and alpha bands that together contribute to identify DoC subjects with and without the ability to follow command, and further distinguished these groups of patients from controls. A fine-grained analysis of these seven signatures enabled us to determine that increased delta modulation at the frontal sensors was the main feature in command following patients. In contrast, higher frequency theta and alpha modulations differentiated controls from both groups of patients. Our findings highlight a key role of spatiotemporally specific delta modulation in supporting cortically mediated behaviour including the ability to follow command. However, patients able to follow commands nevertheless have marked differences in brain activity in comparison with healthy volunteers