Deep brain stimulation of the thalamus restores signatures of consciousness in a nonhuman primate model.

Loss of consciousness is associated with the disruption of long-range thalamocortical and corticocortical brain communication. We tested the hypothesis that deep brain stimulation (DBS) of central thalamus might restore both arousal and awareness following consciousness loss. We applied anesthesia to suppress consciousness in nonhuman primates. During anesthesia, central thalamic stimulation induced arousal in an on-off manner and increased functional magnetic resonance imaging activity in prefrontal, parietal, and cingulate cortices. Moreover, DBS restored a broad dynamic repertoire of spontaneous resting-state activity, previously described as a signature of consciousness. None of these effects were obtained during the stimulation of a control site in the ventrolateral thalamus. Last, DBS restored a broad hierarchical response to auditory violations that was disrupted under anesthesia. Thus, DBS restored the two dimensions of consciousness, arousal and conscious access, following consciousness loss, paving the way to its therapeutical translation in patients with disorders of consciousness.

Assessing the depth of language processing in patients with disorders of consciousness.

Assessing residual consciousness and cognitive abilities in unresponsive patients is a major clinical concern and a challenge for cognitive neuroscience. Although neuroimaging studies have demonstrated a potential for informing diagnosis and prognosis in unresponsive patients, these methods involve sophisticated brain imaging technologies, which limit their clinical application. In this study, we adopted a new language paradigm that elicited rhythmic brain responses tracking the single-word, phrase and sentence rhythms in speech, to examine whether bedside electroencephalography (EEG) recordings can help inform diagnosis and prognosis. EEG-derived neural signals, including both speech-tracking responses and temporal dynamics of global brain states, were associated with behavioral diagnosis of consciousness. Crucially, multiple EEG measures in the language paradigm were robust to predict future outcomes in individual patients. Thus, EEG-based language assessment provides a new and reliable approach to objectively characterize and predict states of consciousness and to longitudinally track individual patients' language processing abilities at the bedside.

Brain signatures of a multiscale process of sequence learning in humans.

Extracting the temporal structure of sequences of events is crucial for perception, decision-making, and language processing. Here, we investigate the mechanisms by which the brain acquires knowledge of sequences and the possibility that successive brain responses reflect the progressive extraction of sequence statistics at different timescales. We measured brain activity using magnetoencephalography in humans exposed to auditory sequences with various statistical regularities, and we modeled this activity as theoretical surprise levels using several learning models. Successive brain waves related to different types of statistical inferences. Early post-stimulus brain waves denoted a sensitivity to a simple statistic, the frequency of items estimated over a long timescale (habituation). Mid-latency and late brain waves conformed qualitatively and quantitatively to the computational properties of a more complex inference: the learning of recent transition probabilities. Our findings thus support the existence of multiple computational systems for sequence processing involving statistical inferences at multiple scales.

A distinct cortical network for mathematical knowledge in the human brain.

How does the brain represent and manipulate abstract mathematical concepts? Recent evidence suggests that mathematical processing relies on specific brain areas and dissociates from language. Here, we investigate this dissociation in two fMRI experiments in which professional mathematicians had to judge the truth value of mathematical and nonmathematical spoken statements. Sentences with mathematical content systematically activated bilateral intraparietal sulci and inferior temporal regions, regardless of math domain, problem difficulty, and strategy for judging truth value (memory retrieval, calculation or mental imagery). Second, classical language areas were only involved in the parsing of both nonmathematical and mathematical statements, and their activation correlated with syntactic complexity, not mathematical content. Third, the mere presence, within a sentence, of elementary logical operators such as quantifiers or negation did not suffice to activate math-responsive areas. Instead, quantifiers and negation impacted on activity in right angular gyrus and left inferior frontal gyrus, respectively. Overall, these results support the existence of a distinct, non-linguistic cortical network for mathematical knowledge in the human brain.

Detection of arithmetic violations during sleep.

Can the sleeping brain develop predictions of future auditory stimuli? Past research demonstrated disrupted prediction capabilities during sleep in the context of novel, arbitrary auditory sequences, but the availability of overlearned knowledge already stored in long-term memory could still be preserved. We tested the sleeping brain capabilities to detect violations of simple arithmetic facts. Sleeping participants were presented with spoken arithmetic facts such as "two plus two is nine" and brain responses to correct or incorrect results were recorded in electro and magneto-encephalography. Sleep responses were compared to both attentive and inattentive wakefulness. During attentive wakefulness, arithmetic violations elicited a succession of N400 and P600 effects, whereas no such activations could be recorded in sleep or in inattentive wakefulness. Still, small but significant effects remained in sleep, advocating for a preserved but partial accessibility to arithmetic facts stored in long-term memory and preserved predictions of low-level and already learned knowledge. Those effects were very different from residual activities seen in inattention, highlighting the differences of information processing between the sleeping and the inattentive brain.

Large-Scale Cortical Networks for Hierarchical Prediction and Prediction Error in the Primate Brain.

According to predictive-coding theory, cortical areas continuously generate and update predictions of sensory inputs at different hierarchical levels and emit prediction errors when the predicted and actual inputs differ. However, predictions and prediction errors are simultaneous and interdependent processes, making it difficult to disentangle their constituent neural network organization. Here, we test the theory by using high-density electrocorticography (ECoG) in monkeys during an auditory "local-global" paradigm in which the temporal regularities of the stimuli were controlled at two hierarchical levels. We decomposed the broadband data and identified lower- and higher-level prediction-error signals in early auditory cortex and anterior temporal cortex, respectively, and a prediction-update signal sent from prefrontal cortex back to temporal cortex. The prediction-error and prediction-update signals were transmitted via γ (>40 Hz) and α/ß (<30 Hz) oscillations, respectively. Our findings provide strong support for hierarchical predictive coding and outline how it is dynamically implemented using distinct cortical areas and frequencies.

On the role of visual experience in mathematical development: Evidence from blind mathematicians.

Advanced mathematical reasoning, regardless of domain or difficulty, activates a reproducible set of bilateral brain areas including intraparietal, inferior temporal and dorsal prefrontal cortex. The respective roles of genetics, experience and education in the development of this math-responsive network, however, remain unresolved. Here, we investigate the role of visual experience by studying the exceptional case of three professional mathematicians who were blind from birth (n=1) or became blind during childhood (n=2). Subjects were scanned with fMRI while they judged the truth value of spoken mathematical and nonmathematical statements. Blind mathematicians activated the classical network of math-related areas during mathematical reflection, similar to that found in a group of sighted professional mathematicians. Thus, brain networks for advanced mathematical reasoning can develop in the absence of visual experience. Additional activations were found in occipital cortex, even in individuals who became blind during childhood, suggesting that either mental imagery or a more radical repurposing of visual cortex may occur in blind mathematicians.

Time-Resolved Decoding of Two Processing Chains during Dual-Task Interference.

The human brain exhibits fundamental limitations in multitasking. When subjects engage in a primary task, their ability to respond to a second stimulus is degraded. Two competing models of multitasking have been proposed: either cognitive resources are shared between tasks, or they are allocated to each task serially. Using a novel combination of magneto-encephalography and multivariate pattern analyses, we obtained a precise spatio-temporal decomposition of the brain processes at work during multitasking. We discovered that each task relies on a sequence of brain processes. These sequences can operate in parallel for several hundred milliseconds but beyond ∼ 500 ms, they repel each other: processes evoked by the first task are shortened, while processes of the second task are either lengthened or postponed. These results contradict the resource-sharing model and further demonstrate that the serial model is incomplete. We therefore propose a new theoretical framework for the computational architecture underlying multitasking.

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.

A hierarchy of cortical responses to sequence violations in three-month-old infants.

The adult human brain quickly adapts to regular temporal sequences, and emits a sequence of novelty responses when these regularities are violated. These novelty responses have been interpreted as error signals that reflect the difference between the incoming signal and predictions generated at multiple cortical levels. Do infants already possess such a hierarchy of violation-detection mechanisms? Using high-density recordings of event-related potentials during an auditory local-global violation paradigm, we show that three-month-old infants process novelty in temporal sequences at two distinct levels. Violations of local expectancies, such as perceiving a deviant vowel "a" after repeated presentation of another vowel i-i-i, elicited an early auditory mismatch response. Conversely, violations of global expectancies, such as hearing the rare sequence a-a-a-a instead of the frequent sequence a-a-a-i, modulated this early mismatch response and led to a late frontal negative slow wave, whose cortical sources included the left inferior frontal region. These results suggest that the infant brain already possesses two dissociable systems for temporal sequence learning.

Reading with sounds: sensory substitution selectively activates the visual word form area in the blind.

Using a visual-to-auditory sensory-substitution algorithm, congenitally fully blind adults were taught to read and recognize complex images using "soundscapes"--sounds topographically representing images. fMRI was used to examine key questions regarding the visual word form area (VWFA): its selectivity for letters over other visual categories without visual experience, its feature tolerance for reading in a novel sensory modality, and its plasticity for scripts learned in adulthood. The blind activated the VWFA specifically and selectively during the processing of letter soundscapes relative to both textures and visually complex object categories and relative to mental imagery and semantic-content controls. Further, VWFA recruitment for reading soundscapes emerged after 2 hr of training in a blind adult on a novel script. Therefore, the VWFA shows category selectivity regardless of input sensory modality, visual experience, and long-term familiarity or expertise with the script. The VWFA may perform a flexible task-specific rather than sensory-specific computation, possibly linking letter shapes to phonology.

A temporal bottleneck in the language comprehension network.

Humans can understand spoken or written sentences presented at extremely fast rates of ∼400 wpm, far exceeding the normal speech rate (∼150 wpm). How does the brain cope with speeded language? And what processing bottlenecks eventually make language incomprehensible above a certain presentation rate? We used time-resolved fMRI to probe the brain responses to spoken and written sentences presented at five compression rates, ranging from intelligible (60-100% of the natural duration) to challenging (40%) and unintelligible (20%). The results show that cortical areas differ sharply in their activation speed and amplitude. In modality-specific sensory areas, activation varies linearly with stimulus duration. However, a large modality-independent left-hemispheric language network, including the inferior frontal gyrus (pars orbitalis and triangularis) and the superior temporal sulcus, shows a remarkably time-invariant response, followed by a sudden collapse for unintelligible stimuli. Finally, linear and nonlinear responses, reflecting a greater effort as compression increases, are seen at various prefrontal and parietal sites. We show that these profiles fit with a simple model according to which the higher stages of language processing operate at a fixed speed and thus impose a temporal bottleneck on sentence comprehension. At presentation rates faster than this internal processing speed, incoming words must be buffered, and intelligibility vanishes when buffer storage and retrieval operations are saturated. Based on their temporal and amplitude profiles, buffer regions can be identified with the left inferior frontal/anterior insula, precentral cortex, and mesial frontal cortex.

Cortical networks for vision and language in dyslexic and normal children of variable socio-economic status.

In dyslexia, anomalous activations have been described in both left temporo-parietal language cortices and in left ventral visual occipito-temporal cortex. However, the reproducibility, task-dependency, and presence of these brain anomalies in childhood rather than adulthood remain debated. We probed the large-scale organization of ventral visual and spoken language areas in dyslexic children using minimal target-detection tasks that were performed equally well by all groups. In 23 normal and 23 dyslexic 10-year-old children from two different socio-economic status (SES) backgrounds, we compared fMRI activity to visually presented houses, faces, and written strings, and to spoken sentences in the native or in a foreign language. Our results confirm a disorganization of both ventral visual and spoken language areas in dyslexic children. Visually, dyslexic children showed a normal lateral-to-medial mosaic of preferences, as well as normal responses to houses and checkerboards, but a reduced activation to words in the visual word form area (VWFA) and to faces in the right fusiform face area (FFA). Auditorily, dyslexic children exhibited reduced responses to speech in posterior temporal cortex, left insula and supplementary motor area, as well as reduced responses to maternal language in subparts of the planum temporale, left basal language area and VWFA. By correlating these two findings, we identify spoken-language predictors of VWFA activation to written words, which differ for dyslexic and normal readers. Similarities in fMRI deficits in both SES groups emphasize the existence of a core set of brain activation anomalies in dyslexia, regardless of culture, language and SES, without however resolving whether these anomalies are a cause or a consequence of impaired reading.

A neuronal model of predictive coding accounting for the mismatch negativity.

The mismatch negativity (MMN) is thought to index the activation of specialized neural networks for active prediction and deviance detection. However, a detailed neuronal model of the neurobiological mechanisms underlying the MMN is still lacking, and its computational foundations remain debated. We propose here a detailed neuronal model of auditory cortex, based on predictive coding, that accounts for the critical features of MMN. The model is entirely composed of spiking excitatory and inhibitory neurons interconnected in a layered cortical architecture with distinct input, predictive, and prediction error units. A spike-timing dependent learning rule, relying upon NMDA receptor synaptic transmission, allows the network to adjust its internal predictions and use a memory of the recent past inputs to anticipate on future stimuli based on transition statistics. We demonstrate that this simple architecture can account for the major empirical properties of the MMN. These include a frequency-dependent response to rare deviants, a response to unexpected repeats in alternating sequences (ABABAA…), a lack of consideration of the global sequence context, a response to sound omission, and a sensitivity of the MMN to NMDA receptor antagonists. Novel predictions are presented, and a new magnetoencephalography experiment in healthy human subjects is presented that validates our key hypothesis: the MMN results from active cortical prediction rather than passive synaptic habituation.

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.

A shared cortical bottleneck underlying Attentional Blink and Psychological Refractory Period.

Doing two things at once is difficult. When two tasks have to be performed within a short interval, the second is sharply delayed, an effect called the Psychological Refractory Period (PRP). Similarly, when two successive visual targets are briefly flashed, people may fail to detect the second target (Attentional Blink or AB). Although AB and PRP are typically studied in very different paradigms, a recent detailed neuromimetic model suggests that both might arise from the same serial stage during which stimuli gain access to consciousness and, as a result, can be arbitrarily routed to any other appropriate processor. Here, in agreement with this model, we demonstrate that AB and PRP can be obtained on alternate trials of the same cross-modal paradigm and result from limitations in the same brain mechanisms. We asked participants to respond as fast as possible to an auditory target T1 and then to a visual target T2 embedded in a series of distractors, while brain activity was recorded with magneto-encephalography (MEG). For identical stimuli, we observed a mixture of blinked trials, where T2 was entirely missed, and PRP trials, where T2 processing was delayed. MEG recordings showed that PRP and blinked trials underwent identical sensory processing in visual occipito-temporal cortices, even including the non-conscious separation of targets from distractors. However, late activations in frontal cortex (>350 ms), strongly influenced by the speed of task-1 execution, were delayed in PRP trials and absent in blinked trials. Our findings suggest that PRP and AB arise from similar cortical stages, can occur with the same exact stimuli, and are merely distinguished by trial-by-trial fluctuations in task processing.

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.

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.

Sentence syntax and content in the human temporal lobe: an fMRI adaptation study in auditory and visual modalities.

Priming effects have been well documented in behavioral psycholinguistics experiments: The processing of a word or a sentence is typically facilitated when it shares lexico-semantic or syntactic features with a previously encountered stimulus. Here, we used fMRI priming to investigate which brain areas show adaptation to the repetition of a sentence's content or syntax. Participants read or listened to sentences organized in series which could or not share similar syntactic constructions and/or lexico-semantic content. The repetition of lexico-semantic content yielded adaptation in most of the temporal and frontal sentence processing network, both in the visual and the auditory modalities, even when the same lexico-semantic content was expressed using variable syntactic constructions. No fMRI adaptation effect was observed when the same syntactic construction was repeated. Yet behavioral priming was observed at both syntactic and semantic levels in a separate experiment where participants detected sentence endings. We discuss a number of possible explanations for the absence of syntactic priming in the fMRI experiments, including the possibility that the conglomerate of syntactic properties defining "a construction" is not an actual object assembled during parsing.