Tristan A. Bekinschtein

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.

A neuropsychological battery to detect specific executive and social cognitive impairments in early frontotemporal dementia

Traditional cognitive tests may not be sensitive for the early detection of executive and social cognitive impairments in the behavioural variant of frontotemporal dementia. The aim of this study was to detect specific executive and social cognitive deficits in patients with early behavioural variant frontotemporal dementia using a battery of tests previously shown to be sensitive to frontal lobe dysfunction. Behavioural variant frontotemporal dementia patients and paired controls were assessed with a complete standard neuropsychological battery evaluating attention, memory, visuospatial abilities, language and executive functions. All participants were then assessed with our Executive and Social Cognition Battery, which included Theory of Mind tests (Mind in the Eyes, Faux Pas), the Hotel Task, Multiple Errands Task-hospital version and the Iowa Gambling Task for complex decision-making. Patients were divided into two groups according to their Addenbrookes Cognitive Examination scores, a measure of general cognitive status. Low Addenbrookes Cognitive Examination patients differed from controls on most tasks of the standard battery and the Executive and Social Cognition Battery. While high Addenbrookes Cognitive Examination patients did not differ from controls on most traditional neuropsychological tests, significant differences were found between this high-functioning behavioural variant of frontotemporal dementia group and controls on most measures of our Executive and Social Cognition Battery. Our results suggest that the Executive and Social Cognition Battery used in this study is more sensitive in detecting executive and social cognitive impairment deficits in early behavioural variant of frontotemporal dementia than the classical cognitive measures.

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 brains 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.

Diffusion weighted imaging distinguishes the vegetative state from the minimally conscious state

The vegetative (VS) and minimally conscious (MCS) states are currently distinguished on the basis of exhibited behaviour rather than underlying pathology. Although previous histopathological studies have documented different degrees of diffuse axonal injury as well as damage to the thalami and brainstem regions in VS and MCS, these differences have not been assessed in vivo, and therefore, do not provide a measurable pathological marker to aid clinical diagnosis. Currently, the diagnostic decision-making process is highly subjective and prone to error. Indeed, previous work has suggested that up to 43% of patients in this group may be misdiagnosed. We used diffusion tensor imaging (DTI) to study the neuropathology of 25 vegetative and minimally conscious patients in vivo and to identify measures that could potentially distinguish the patients in these two groups. Mean diffusivity (MD) maps of the subcortical white matter, brainstem and thalami were generated. The MCS and VS patients differed significantly in subcortical white matter and thalamic regions, but appeared not to differ in the brainstem. Moreover, the DTI results predicted scores on the Coma Recovery Scale (p<0.001) and successfully classified the patients in to their appropriate diagnostic categories with an accuracy of 95%. The results suggest that this method may provide an objective and highly accurate method for classifying these challenging patient populations and may therefore complement the behavioural assessment to inform the diagnostic decision making process.

Probing consciousness with event-related potentials in the vegetative state

Objective: Probing consciousness in noncommunicating patients is a major medical and neuroscientific challenge. While standardized and expert behavioral assessment of patients constitutes a mandatory step, this clinical evaluation stage is often difficult and doubtful, and calls for complementary measures which may overcome its inherent limitations. Several functional brain imaging methods are currently being developed within this perspective, including fMRI and cognitive event-related potentials (ERPs). We recently designed an original rule extraction ERP test that is positive only in subjects who are conscious of the long-term regularity of auditory stimuli. Methods: In the present work, we report the results of this test in a population of 22 patients who met clinical criteria for vegetative state. Results: We identified 2 patients showing this neural signature of consciousness. Interestingly, these 2 patients showed unequivocal clinical signs of consciousness within the 3 to 4 days following ERP recording. Conclusions: Taken together, these results strengthen the relevance of bedside neurophysiological tools to improve diagnosis of consciousness in noncommunicating patients.

Expectation and Attention in Hierarchical Auditory Prediction

Hierarchical predictive coding suggests that attention in humans emerges from increased precision in probabilistic inference, whereas expectation biases attention in favor of contextually anticipated stimuli. We test these notions within auditory perception by independently manipulating top-down expectation and attentional precision alongside bottom-up stimulus predictability. Our findings support an integrative interpretation of commonly observed electrophysiological signatures of neurodynamics, namely mismatch negativity (MMN), P300, and contingent negative variation (CNV), as manifestations along successive levels of predictive complexity. Early first-level processing indexed by the MMN was sensitive to stimulus predictability: here, attentional precision enhanced early responses, but explicit top-down expectation diminished it. This pattern was in contrast to later, second-level processing indexed by the P300: although sensitive to the degree of predictability, responses at this level were contingent on attentional engagement and in fact sharpened by top-down expectation. At the highest level, the drift of the CNV was a fine-grained marker of top-down expectation itself. Source reconstruction of high-density EEG, supported by intracranial recordings, implicated temporal and frontal regions differentially active at early and late levels. The cortical generators of the CNV suggested that it might be involved in facilitating the consolidation of context-salient stimuli into conscious perception. These results provide convergent empirical support to promising recent accounts of attention and expectation in predictive coding.

Emotion processing in the minimally conscious state

As a newly described condition distinct from coma or the vegetative state, minimally conscious state (MCS) is characterised by a threshold level of consciousness, and diagnostic criteria have recently been proposed.1 In MCS, cognitively mediated behaviour occurs inconsistently, but is reproducible or sustained enough to be differentiated from reflexive behaviour. It is clinically essential to distinguish this condition from persistent vegetative state (PVS), due to a potentially more favourable outcome.1 So far, whether patients in MCS can process emotion is unknown. Cortical processing has been described in PVS using auditory and visual functional paradigms with positron emission tomography.2,3 However, to date hardly any functional imaging studies are available in patients in MCS.4 We used fMRI to assess brain activity induced by an emotional stimulus in a patient in MCS. A 17 year old man was riding his bicycle when he was hit by a train. The accident …

Classical conditioning in the vegetative and minimally conscious state

Pavlovian trace conditioning depends on the temporal gap between the conditioned and unconditioned stimuli. It requires, in mammals, functional medial temporal lobe structures and, in humans, explicit knowledge of the temporal contingency. It is therefore considered to be a plausible objective test to assess awareness without relying on explicit reports. We found that individuals with disorders of consciousness (DOCs), despite being unable to report awareness explicitly, were able to learn this procedure. Learning was specific and showed an anticipatory electromyographic response to the aversive conditioning stimulus, which was substantially stronger than to the control stimulus and was augmented as the aversive stimulus approached. The amount of learning correlated with the degree of cortical atrophy and was a good indicator of recovery. None of these effects were observed in control subjects under the effect of anesthesia (propofol). Our results suggest that individuals with DOCs might have partially preserved conscious processing, which cannot be mediated by explicit reports and is not detected by behavioral assessment.

Motor-language coupling: direct evidence from early Parkinson’s disease and intracranial cortical recordings

Language and action systems are functionally coupled in the brain as demonstrated by converging evidence using Functional magnetic resonance imaging (fMRI), electroencephalography (EEG), transcranial magnetic stimulation (TMS), and lesion studies. In particular, this coupling has been demonstrated using the action-sentence compatibility effect (ACE) in which motor activity and language interact. The ACE task requires participants to listen to sentences that described actions typically performed with an open hand (e.g., clapping), a closed hand (e.g., hammering), or without any hand action (neutral); and to press a large button with either an open hand position or closed hand position immediately upon comprehending each sentence. The ACE is defined as a longer reaction time (RT) in the action-sentence incompatible conditions than in the compatible conditions. Here we investigated direct motor-language coupling in two novel and uniquely informative ways. First, we measured the behavioural ACE in patients with motor impairment (early Parkinsons disease - EPD), and second, in epileptic patients with direct electrocorticography (ECoG) recordings. In experiment 1, EPD participants with preserved general cognitive repertoire, showed a much diminished ACE relative to non-EPD volunteers. Moreover, a correlation between ACE performance and action-verb processing (kissing and dancing test - KDT) was observed. Direct cortical recordings (ECoG) in motor and language areas (experiment 2) demonstrated simultaneous bidirectional effects: motor preparation affected language processing (N400 at left inferior frontal gyrus and middle/superior temporal gyrus), and language processing affected activity in movement-related areas (motor potential at premotor and M1). Our findings show that the ACE paradigm requires ongoing integration of preserved motor and language coupling (abolished in EPD) and engages motor-temporal cortices in a bidirectional way. In addition, both experiments suggest the presence of a motor-language network which is not restricted to somatotopically defined brain areas. These results open new pathways in the fields of motor diseases, theoretical approaches to language understanding, and models of action-perception coupling.

Circadian responses to endotoxin treatment in mice

We tested the ability of Escherichia coli lipopolysaccharide (LPS) to phase-shift the activity circadian rhythm in C57Bl/6J mice. Intraperitoneal administration of 25 microg/kg LPS induced photic-like phase delays (-43+/-10 min) during the early subjective night. These delays were non-additive to those induced by light at CT 15, and were reduced by the previous administration of sulfasalazine, a NF-kappaB activation inhibitor. At CT 15, LPS induced c-Fos expression in the dorsal area of the suprachiasmatic nuclei (SCN). Our results suggest that the activation of the immune system should be considered an entraining signal for the murine circadian clock.