Cognitive Motor Dissociation in Disorders of Consciousness.

BACKGROUND: Patients with brain injury who are unresponsive to commands may perform cognitive tasks that are detected on functional magnetic resonance imaging (fMRI) and electroencephalography (EEG). This phenomenon, known as cognitive motor dissociation, has not been systematically studied in a large cohort of persons with disorders of consciousness. METHODS: In this prospective cohort study conducted at six international centers, we collected clinical, behavioral, and task-based fMRI and EEG data from a convenience sample of 353 adults with disorders of consciousness. We assessed the response to commands on task-based fMRI or EEG in participants without an observable response to verbal commands (i.e., those with a behavioral diagnosis of coma, vegetative state, or minimally conscious state-minus) and in participants with an observable response to verbal commands. The presence or absence of an observable response to commands was assessed with the use of the Coma Recovery Scale-Revised (CRS-R). RESULTS: Data from fMRI only or EEG only were available for 65% of the participants, and data from both fMRI and EEG were available for 35%. The median age of the participants was 37.9 years, the median time between brain injury and assessment with the CRS-R was 7.9 months (25% of the participants were assessed with the CRS-R within 28 days after injury), and brain trauma was an etiologic factor in 50%. We detected cognitive motor dissociation in 60 of the 241 participants (25%) without an observable response to commands, of whom 11 had been assessed with the use of fMRI only, 13 with the use of EEG only, and 36 with the use of both techniques. Cognitive motor dissociation was associated with younger age, longer time since injury, and brain trauma as an etiologic factor. In contrast, responses on task-based fMRI or EEG occurred in 43 of 112 participants (38%) with an observable response to verbal commands. CONCLUSIONS: Approximately one in four participants without an observable response to commands performed a cognitive task on fMRI or EEG as compared with one in three participants with an observable response to commands. (Funded by the James S. McDonnell Foundation and others.).

Feedback information transfer in the human brain reflects bistable perception in the absence of report.

In the search for the neural basis of conscious experience, perception and the cognitive processes associated with reporting perception are typically confounded as neural activity is recorded while participants explicitly report what they experience. Here, we present a novel way to disentangle perception from report using eye movement analysis techniques based on convolutional neural networks and neurodynamical analyses based on information theory. We use a bistable visual stimulus that instantiates two well-known properties of conscious perception: integration and differentiation. At any given moment, observers either perceive the stimulus as one integrated unitary object or as two differentiated objects that are clearly distinct from each other. Using electroencephalography, we show that measures of integration and differentiation based on information theory closely follow participants' perceptual experience of those contents when switches were reported. We observed increased information integration between anterior to posterior electrodes (front to back) prior to a switch to the integrated percept, and higher information differentiation of anterior signals leading up to reporting the differentiated percept. Crucially, information integration was closely linked to perception and even observed in a no-report condition when perceptual transitions were inferred from eye movements alone. In contrast, the link between neural differentiation and perception was observed solely in the active report condition. Our results, therefore, suggest that perception and the processes associated with report require distinct amounts of anterior-posterior network communication and anterior information differentiation. While front-to-back directed information is associated with changes in the content of perception when viewing bistable visual stimuli, regardless of report, frontal information differentiation was absent in the no-report condition and therefore is not directly linked to perception per se.

Family caregivers' sense-making of the results of functional neurodiagnostics for patients with Prolonged Disorders of Consciousness.

Functional neuroimaging and electrophysiological assessments can identify evidence of residual consciousness and cognition in patients with prolonged disorders of consciousness (PDOC) who are otherwise behaviourally unresponsive. These functional neurodiagnostics are increasingly available in clinical settings and are recommended by international clinical guidelines to reduce diagnostic and prognostic uncertainty, and thereby assist family caregivers in their best-interests decision-making. Nevertheless, little is known about how family caregivers make sense of the results of these state-of-the-art functional neurodiagnostics. By applying Interpretative Phenomenological Analysis (IPA) to interviews with family caregivers of patients with diagnoses of PDOC who had received a functional neurodiagnostic assessment, we identify three primary themes of sense-making: The special significance of "brain scans"; A dynamic sense-making process; Holding on to hope and holding on to the person. These themes highlight the challenges of helping family caregivers to balance the relative importance of functional neurodiagnostic results with other clinical assessments and identify an ability of family caregivers to hold a contradiction in which they hope for recovery but simultaneously express a rational understanding of evidence to the contrary. We offer several recommendations for the ways in which family caregivers can be better supported to make sense of the results of functional neurodiagnostics.

Altered Brain Connectivity and Network Topological Organization in a Non-ordinary State of Consciousness Induced by Hypnosis.

Hypnosis has been shown to be of clinical utility; however, its underlying neural mechanisms remain unclear. This study aims to investigate altered brain dynamics during the non-ordinary state of consciousness induced by hypnosis. We studied high-density EEG in 9 healthy participants during eyes-closed wakefulness and during hypnosis, induced by a muscle relaxation and eyes fixation procedure. Using hypotheses based on internal and external awareness brain networks, we assessed region-wise brain connectivity between six ROIs (right and left frontal, right and left parietal, upper and lower midline regions) at the scalp level and compared across conditions. Data-driven, graph-theory analyses were also carried out to characterize brain network topology in terms of brain network segregation and integration. During hypnosis, we observed (1) increased delta connectivity between left and right frontal, as well as between right frontal and parietal regions; (2) decreased connectivity for alpha (between right frontal and parietal and between upper and lower midline regions) and beta-2 bands (between upper midline and right frontal, frontal and parietal, also between upper and lower midline regions); and (3) increased network segregation (short-range connections) in delta and alpha bands, and increased integration (long-range connections) in beta-2 band. This higher network integration and segregation was measured bilaterally in frontal and right parietal electrodes, which were identified as central hub regions during hypnosis. This modified connectivity and increased network integration-segregation properties suggest a modification of the internal and external awareness brain networks that may reflect efficient cognitive-processing and lower incidences of mind-wandering during hypnosis.

Exploring electrophysiological markers of auditory predictive processes and pathological ageing in adults with Down's syndrome.

Down's syndrome is associated with pathological ageing and a propensity for early-onset Alzheimer's disease. The early symptoms of dementia in people with Down's syndrome may reflect frontal lobe vulnerability to amyloid deposition. Auditory predictive processes rely on the bilateral auditory cortices with the recruitment of frontal cortices and appear to be impaired in pathologies characterized by compromised frontal lobe. Hence, auditory predictive processes were investigated to assess Down's syndrome pathology and its relationship with pathological ageing. An auditory electroencephalography (EEG) global-local paradigm was presented to the participants, in which oddball stimuli could either violate local or higher level global rules. We characterised predictive processes in individuals with Down's syndrome and their relationship with pathological ageing, with a focus on the EEG event-related potential called Mismatch Negativity (MMN) and the P300. In Down's syndrome, we also evaluated the EEG components as predictor of cognitive decline 1 year later. We found that predictive processes of detection of auditory violations are overall preserved in Down's syndrome but also that the amplitude of the MMN to local deviancies decreases with age. However, the 1-year follow-up of Down's syndrome found that none of the ERPs measures predicted subsequent cognitive decline. The present study provides a novel characterization of electrophysiological markers of local and global predictive processes in Down's syndrome.

How hot is the hot zone? Computational modelling clarifies the role of parietal and frontoparietal connectivity during anaesthetic-induced loss of consciousness.

In recent years, specific cortical networks have been proposed to be crucial for sustaining consciousness, including the posterior hot zone and frontoparietal resting state networks (RSN). Here, we computationally evaluate the relative contributions of three RSNs - the default mode network (DMN), the salience network (SAL), and the central executive network (CEN) - to consciousness and its loss during propofol anaesthesia. Specifically, we use dynamic causal modelling (DCM) of 10 min of high-density EEG recordings (N = 10, 4 males) obtained during behavioural responsiveness, unconsciousness and post-anaesthetic recovery to characterise differences in effective connectivity within frontal areas, the posterior 'hot zone', frontoparietal connections, and between-RSN connections. We estimate - for the first time - a large DCM model (LAR) of resting EEG, combining the three RSNs into a rich club of interconnectivity. Consistent with the hot zone theory, our findings demonstrate reductions in inter-RSN connectivity in the parietal cortex. Within the DMN itself, the strongest reductions are in feed-forward frontoparietal and parietal connections at the precuneus node. Within the SAL and CEN, loss of consciousness generates small increases in bidirectional connectivity. Using novel DCM leave-one-out cross-validation, we show that the most consistent out-of-sample predictions of the state of consciousness come from a key set of frontoparietal connections. This finding also generalises to unseen data collected during post-anaesthetic recovery. Our findings provide new, computational evidence for the importance of the posterior hot zone in explaining the loss of consciousness, highlighting also the distinct role of frontoparietal connectivity in underpinning conscious responsiveness, and consequently, suggest a dissociation between the mechanisms most prominently associated with explaining the contrast between conscious awareness and unconsciousness, and those maintaining consciousness.

Sedation Modulates Frontotemporal Predictive Coding Circuits and the Double Surprise Acceleration Effect.

Two important theories in cognitive neuroscience are predictive coding (PC) and the global workspace (GW) theory. A key research task is to understand how these two theories relate to one another, and particularly, how the brain transitions from a predictive early state to the eventual engagement of a brain-scale state (the GW). To address this question, we present a source-localization of EEG responses evoked by the local-global task-an experimental paradigm that engages a predictive hierarchy, which encompasses the GW. The results of our source reconstruction suggest three phases of processing. The first phase involves the sensory (here auditory) regions of the superior temporal lobe and predicts sensory regularities over a short timeframe (as per the local effect). The third phase is brain-scale, involving inferior frontal, as well as inferior and superior parietal regions, consistent with a global neuronal workspace (GNW; as per the global effect). Crucially, our analysis suggests that there is an intermediate (second) phase, involving modulatory interactions between inferior frontal and superior temporal regions. Furthermore, sedation with propofol reduces modulatory interactions in the second phase. This selective effect is consistent with a PC explanation of sedation, with propofol acting on descending predictions of the precision of prediction errors; thereby constraining access to the GNW.

Dissociable Neural Information Dynamics of Perceptual Integration and Differentiation during Bistable Perception.

At any given moment, we experience a perceptual scene as a single whole and yet we may distinguish a variety of objects within it. This phenomenon instantiates two properties of conscious perception: integration and differentiation. Integration is the property of experiencing a collection of objects as a unitary percept and differentiation is the property of experiencing these objects as distinct from each other. Here, we evaluated the neural information dynamics underlying integration and differentiation of perceptual contents during bistable perception. Participants listened to a sequence of tones (auditory bistable stimuli) experienced either as a single stream (perceptual integration) or as two parallel streams (perceptual differentiation) of sounds. We computed neurophysiological indices of information integration and information differentiation with electroencephalographic and intracranial recordings. When perceptual alternations were endogenously driven, the integrated percept was associated with an increase in neural information integration and a decrease in neural differentiation across frontoparietal regions, whereas the opposite pattern was observed for the differentiated percept. However, when perception was exogenously driven by a change in the sound stream (no bistability), neural oscillatory power distinguished between percepts but information measures did not. We demonstrate that perceptual integration and differentiation can be mapped to theoretically motivated neural information signatures, suggesting a direct relationship between phenomenology and neurophysiology.

Alertness fluctuations when performing a task modulate cortical evoked responses to transcranial magnetic stimulation.

Transcranial magnetic stimulation (TMS) has been widely used in human cognitive neuroscience to examine the causal role of distinct cortical areas in perceptual, cognitive and motor functions. However, it is widely acknowledged that the effects of focal cortical stimulation can vary substantially between participants and even from trial to trial within individuals. Recent work from resting state functional magnetic resonance imaging (fMRI) studies has suggested that spontaneous fluctuations in alertness over a testing session can modulate the neural dynamics of cortical processing, even when participants remain awake and responsive to the task at hand. Here we investigated the extent to which spontaneous fluctuations in alertness during wake-to-sleep transition can account for the variability in neurophysiological responses to TMS. We combined single-pulse TMS with neural recording via electroencephalography (EEG) to quantify changes in motor and cortical reactivity with fluctuating levels of alertness defined objectively on the basis of ongoing brain activity. We observed rapid, non-linear changes in TMS-evoked responses with decreasing levels of alertness, even while participants remained responsive in the behavioural task. Specifically, we found that the amplitude of motor evoked potentials peaked during periods of EEG flattening, whereas TMS-evoked potentials increased and remained stable during EEG flattening and the subsequent occurrence of theta ripples that indicate the onset of NREM stage 1 sleep. Our findings suggest a rapid and complex reorganization of active neural networks in response to spontaneous fluctuations of alertness over relatively short periods of behavioural testing during wake-to-sleep transition.

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.

Brain networks predict metabolism, diagnosis and prognosis at the bedside in disorders of consciousness.

Recent advances in functional neuroimaging have demonstrated novel potential for informing diagnosis and prognosis in the unresponsive wakeful syndrome and minimally conscious states. However, these technologies come with considerable expense and difficulty, limiting the possibility of wider clinical application in patients. Here, we show that high density electroencephalography, collected from 104 patients measured at rest, can provide valuable information about brain connectivity that correlates with behaviour and functional neuroimaging. Using graph theory, we visualize and quantify spectral connectivity estimated from electroencephalography as a dense brain network. Our findings demonstrate that key quantitative metrics of these networks correlate with the continuum of behavioural recovery in patients, ranging from those diagnosed as unresponsive, through those who have emerged from minimally conscious, to the fully conscious locked-in syndrome. In particular, a network metric indexing the presence of densely interconnected central hubs of connectivity discriminated behavioural consciousness with accuracy comparable to that achieved by expert assessment with positron emission tomography. We also show that this metric correlates strongly with brain metabolism. Further, with classification analysis, we predict the behavioural diagnosis, brain metabolism and 1-year clinical outcome of individual patients. Finally, we demonstrate that assessments of brain networks show robust connectivity in patients diagnosed as unresponsive by clinical consensus, but later rediagnosed as minimally conscious with the Coma Recovery Scale-Revised. Classification analysis of their brain network identified each of these misdiagnosed patients as minimally conscious, corroborating their behavioural diagnoses. If deployed at the bedside in the clinical context, such network measurements could complement systematic behavioural assessment and help reduce the high misdiagnosis rate reported in these patients. These metrics could also identify patients in whom further assessment is warranted using neuroimaging or conventional clinical evaluation. Finally, by providing objective characterization of states of consciousness, repeated assessments of network metrics could help track individual patients longitudinally, and also assess their neural responses to therapeutic and pharmacological interventions.

Placing meta-stable states of consciousness within the predictive coding hierarchy: The deceleration of the accelerated prediction error.

While many studies have linked prediction errors and event related potentials at a single processing level, few consider how these responses interact across levels. In response, we present a factorial analysis of a multi-level oddball task - the local-global task - and we explore it when participants are sedated versus recovered. We found that the local and global levels in fact interact. This is of considerable current interest, since it has recently been argued that the MEEG response evoked by the global effect corresponds to a distinct processing mode that moves beyond predictive coding. This interaction suggests that the two processing modes are not distinct. Additionally, we observed that sedation modulates this interaction, suggesting that conscious awareness may not be completely restricted to a single (global) processing level.

Silent Expectations: Dynamic Causal Modeling of Cortical Prediction and Attention to Sounds That Weren't.

UNLABELLED: There is increasing evidence that human perception is realized by a hierarchy of neural processes in which predictions sent backward from higher levels result in prediction errors that are fed forward from lower levels, to update the current model of the environment. Moreover, the precision of prediction errors is thought to be modulated by attention. Much of this evidence comes from paradigms in which a stimulus differs from that predicted by the recent history of other stimuli (generating a so-called "mismatch response"). There is less evidence from situations where a prediction is not fulfilled by any sensory input (an "omission" response). This situation arguably provides a more direct measure of "top-down" predictions in the absence of confounding "bottom-up" input. We applied Dynamic Causal Modeling of evoked electromagnetic responses recorded by EEG and MEG to an auditory paradigm in which we factorially crossed the presence versus absence of "bottom-up" stimuli with the presence versus absence of "top-down" attention. Model comparison revealed that both mismatch and omission responses were mediated by increased forward and backward connections, differing primarily in the driving input. In both responses, modeling results suggested that the presence of attention selectively modulated backward "prediction" connections. Our results provide new model-driven evidence of the pure top-down prediction signal posited in theories of hierarchical perception, and highlight the role of attentional precision in strengthening this prediction. SIGNIFICANCE STATEMENT: Human auditory perception is thought to be realized by a network of neurons that maintain a model of and predict future stimuli. Much of the evidence for this comes from experiments where a stimulus unexpectedly differs from previous ones, which generates a well-known "mismatch response." But what happens when a stimulus is unexpectedly omitted altogether? By measuring the brain's electromagnetic activity, we show that it also generates an "omission response" that is contingent on the presence of attention. We model these responses computationally, revealing that mismatch and omission responses only differ in the location of inputs into the same underlying neuronal network. In both cases, we show that attention selectively strengthens the brain's prediction of the future.

Somatosensory attention identifies both overt and covert awareness in disorders of consciousness.

OBJECTIVE: Some patients diagnosed with disorders of consciousness retain sensory and cognitive abilities beyond those apparent from their overt behavior. Characterizing these covert abilities is crucial for diagnosis, prognosis, and medical ethics. This multimodal study investigates the relationship between electroencephalographic evidence for perceptual/cognitive preservation and both overt and covert markers of awareness. METHODS: Fourteen patients with severe brain injuries were evaluated with an electroencephalographic vibrotactile attention task designed to identify a hierarchy of residual somatosensory and cognitive abilities: (1) somatosensory steady-state evoked responses, (2) bottom-up attention orienting (P3a event-related potential), and (3) top-down attention (P3b event-related potential). Each patient was also assessed with a clinical behavioral scale and 2 functional magnetic resonance imaging assessments of covert command following. RESULTS: Six patients produced only sensory responses, with no evidence of cognitive event-related potentials. A further 8 patients demonstrated reliable bottom-up attention-orienting responses (P3a). No patient showed evidence of top-down attention (P3b). Only those patients who followed commands, whether overtly with behavior or covertly with functional neuroimaging, also demonstrated event-related potential evidence of attentional orienting. INTERPRETATION: Somatosensory attention-orienting event-related potentials differentiated patients who could follow commands from those who could not. Crucially, this differentiation was irrespective of whether command following was evident through overt external behavior, or through covert functional neuroimaging methods. Bedside electroencephalographic methods may corroborate more expensive and challenging methods such as functional neuroimaging, and thereby assist in the accurate diagnosis of awareness. Ann Neurol 2016;80:412-423.

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.

Auditory Feedback Differentially Modulates Behavioral and Neural Markers of Objective and Subjective Performance When Tapping to Your Heartbeat.

Interoception, the perception of our body internal signals, plays a key role in maintaining homeostasis and guiding our behavior. Sometimes, we become aware of our body signals and use them in planning and strategic thinking. Here, we show behavioral and neural dissociations between learning to follow one's own heartbeat and metacognitive awareness of one's performance, in a heartbeat-tapping task performed before and after auditory feedback. The electroencephalography amplitude of the heartbeat-evoked potential in interoceptive learners, that is, participants whose accuracy of tapping to their heartbeat improved after auditory feedback, was higher compared with non-learners. However, an increase in gamma phase synchrony (30-45 Hz) after the heartbeat auditory feedback was present only in those participants showing agreement between objective interoceptive performance and metacognitive awareness. Source localization in a group of participants and direct cortical recordings in a single patient identified a network hub for interoceptive learning in the insular cortex. In summary, interoceptive learning may be mediated by the right insular response to the heartbeat, whereas metacognitive awareness of learning may be mediated by widespread cortical synchronization patterns.

Predictive coding in autism spectrum disorder and attention deficit hyperactivity disorder.

Predictive coding has been proposed as a framework to understand neural processes in neuropsychiatric disorders. We used this approach to describe mechanisms responsible for attentional abnormalities in autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD). We monitored brain dynamics of 59 children (8-15 yr old) who had ASD or ADHD or who were control participants via high-density electroencephalography. We performed analysis at the scalp and source-space levels while participants listened to standard and deviant tone sequences. Through task instructions, we manipulated top-down expectation by presenting expected and unexpected deviant sequences. Children with ASD showed reduced superior frontal cortex (FC) responses to unexpected events but increased dorsolateral prefrontal cortex (PFC) activation to expected events. In contrast, children with ADHD exhibited reduced cortical responses in superior FC to expected events but strong PFC activation to unexpected events. Moreover, neural abnormalities were associated with specific control mechanisms, namely, inhibitory control in ASD and set-shifting in ADHD. Based on the predictive coding account, top-down expectation abnormalities could be attributed to a disproportionate reliance (precision) allocated to prior beliefs in ASD and to sensory input in ADHD.

Spectral signatures of reorganised brain networks in disorders of consciousness.

Theoretical advances in the science of consciousness have proposed that it is concomitant with balanced cortical integration and differentiation, enabled by efficient networks of information transfer across multiple scales. Here, we apply graph theory to compare key signatures of such networks in high-density electroencephalographic data from 32 patients with chronic disorders of consciousness, against normative data from healthy controls. Based on connectivity within canonical frequency bands, we found that patient networks had reduced local and global efficiency, and fewer hubs in the alpha band. We devised a novel topographical metric, termed modular span, which showed that the alpha network modules in patients were also spatially circumscribed, lacking the structured long-distance interactions commonly observed in the healthy controls. Importantly however, these differences between graph-theoretic metrics were partially reversed in delta and theta band networks, which were also significantly more similar to each other in patients than controls. Going further, we found that metrics of alpha network efficiency also correlated with the degree of behavioural awareness. Intriguingly, some patients in behaviourally unresponsive vegetative states who demonstrated evidence of covert awareness with functional neuroimaging stood out from this trend: they had alpha networks that were remarkably well preserved and similar to those observed in the controls. Taken together, our findings inform current understanding of disorders of consciousness by highlighting the distinctive brain networks that characterise them. In the significant minority of vegetative patients who follow commands in neuroimaging tests, they point to putative network mechanisms that could support cognitive function and consciousness despite profound behavioural impairment.