Traveling waves shape neural population dynamics enabling predictions and internal model updating.

The brain generates predictions based on statistical regularities in our environment. However, it is unclear how predictions are optimized through iterative interactions with the environment. Because traveling waves (TWs) propagate across the cortex shaping neural excitability, they can carry information to serve predictive processing. Using human intracranial recordings, we show that anterior-to-posterior alpha TWs correlated with prediction strength. Learning about priors altered neural state space trajectories, and how much it altered correlated with trial-by-trial prediction strength. Learning involved mismatches between predictions and sensory evidence triggering alpha-phase resets in lateral temporal cortex, accompanied by stronger alpha phase-high gamma amplitude coupling and high-gamma power. The mismatch initiated posterior-to-anterior alpha TWs and change in the subsequent trial's state space trajectory, facilitating model updating. Our findings suggest a vital role of alpha TWs carrying both predictions to sensory cortex and mismatch signals to frontal cortex for trial-by-trial fine-tuning of predictive models.

Method for quantifying arousal and consciousness in healthy states and severe brain injury via EEG-based measures of corticothalamic physiology.

BACKGROUND: Characterization of normal arousal states has been achieved by fitting predictions of corticothalamic neural field theory (NFT) to electroencephalographic (EEG) spectra to yield relevant physiological parameters. NEW METHOD: A prior fitting method is extended to distinguish conscious and unconscious states in healthy and brain injured subjects by identifying additional parameters and clusters in parameter space. RESULTS: Fits of NFT predictions to EEG spectra are used to estimate neurophysiological parameters in healthy and brain injured subjects. Spectra are used from healthy subjects in wake and sleep and from patients with unresponsive wakefulness syndrome, in a minimally conscious state (MCS), and emerged from MCS. Subjects cluster into three groups in parameter space: conscious healthy (wake and REM), sleep, and brain injured. These are distinguished by the difference X-Y between corticocortical (X) and corticothalamic (Y) feedbacks, and by mean neural response rates α and ß to incoming spikes. X-Y tracks consciousness in healthy individuals, with smaller values in wake/REM than sleep, but cannot distinguish between brain injuries. Parameters α and ß differentiate deep sleep from wake/REM and brain injury. COMPARISON WITH EXISTING METHODS: Other methods typically rely on laborious clinical assessment, manual EEG scoring, or evaluation of measures like Φ from integrated information theory, for which no efficient method exists. In contrast, the present method can be automated on a personal computer. CONCLUSION: The method provides a means to quantify consciousness and arousal in healthy and brain injured subjects, but does not distinguish subtypes of brain injury.

Clinical and advanced neurophysiology in the prognostic and diagnostic evaluation of disorders of consciousness: review of an IFCN-endorsed expert group.

The analysis of spontaneous EEG activity and evoked potentialsis a cornerstone of the instrumental evaluation of patients with disorders of consciousness (DoC). Thepast few years have witnessed an unprecedented surge in EEG-related research applied to the prediction and detection of recovery of consciousness after severe brain injury,opening up the prospect that new concepts and tools may be available at the bedside. This paper provides a comprehensive, critical overview of bothconsolidated and investigational electrophysiological techniquesfor the prognostic and diagnostic assessment of DoC.We describe conventional clinical EEG approaches, then focus on evoked and event-related potentials, and finally we analyze the potential of novel research findings. In doing so, we (i) draw a distinction between acute, prolonged and chronic phases of DoC, (ii) attempt to relate both clinical and research findings to the underlying neuronal processes and (iii) discuss technical and conceptual caveats.The primary aim of this narrative review is to bridge the gap between standard and emerging electrophysiological measures for the detection and prediction of recovery of consciousness. The ultimate scope is to provide a reference and common ground for academic researchers active in the field of neurophysiology and clinicians engaged in intensive care unit and rehabilitation.

Optimization of the Cortical Traveling Wave Analysis framework for feasibility in Stereo-Electroencephalography.

The study of brain waves propagation is of interest to understand the neural involvement in both physiological and pathological events, such as interictal epileptic spikes (IES). The possibility to track the trajectory of IESs could be useful to better characterize the role of the involved structures in the epileptic network, adding valuable information to the epileptic focus localization. Methods for the cortical traveling wave analysis (CTWA) have been proposed to trace the preferred propagation path of sleep slow waves, using scalp high-density EEG and reconstructing the trajectories both in the sensors and in the sources space. In this work, we propose a feasibility study of the application of these concepts to Stereo-EEG (SEEG) data for the analysis of IES. Through simulations, we selected the best performing Electrical Source Imaging inverse solution for our purpose and illustrate the CTWA procedure. We further show an exemplary application on real data and discuss advantages and pitfalls of the application of CTWA in SEEG.

Propofol-induced unresponsiveness is associated with impaired feedforward connectivity in cortical hierarchy.

BACKGROUND: Impaired consciousness has been associated with impaired cortical signal propagation after transcranial magnetic stimulation (TMS). We hypothesised that the reduced current propagation under propofol-induced unresponsiveness is associated with changes in both feedforward and feedback connectivity across the cortical hierarchy. METHODS: Eight subjects underwent left occipital TMS coupled with high-density EEG recordings during wakefulness and propofol-induced unconsciousness. Spectral analysis was applied to responses recorded from sensors overlying six hierarchical cortical sources involved in visual processing. Dynamic causal modelling (DCM) of induced time-frequency responses and evoked response potentials were used to investigate propofol's effects on connectivity between regions. RESULTS: Sensor space analysis demonstrated that propofol reduced both induced and evoked power after TMS in occipital, parietal, and frontal electrodes. Bayesian model selection supported a DCM with hierarchical feedforward and feedback connections. DCM of induced EEG responses revealed that the primary effect of propofol was impaired feedforward responses in cross-frequency theta/alpha-gamma coupling and within frequency theta coupling (F contrast, family-wise error corrected P<0.05). An exploratory analysis (thresholded at uncorrected P<0.001) also suggested that propofol impaired feedforward and feedback beta band coupling. Post hoc analyses showed impairments in all feedforward connections and one feedback connection from parietal to occipital cortex. DCM of the evoked response potential showed impaired feedforward connectivity between left-sided occipital and parietal cortex (T contrast P=0.004, Bonferroni corrected). CONCLUSIONS: Propofol-induced loss of consciousness is associated with impaired hierarchical feedforward connectivity assessed by EEG after occipital TMS.

Sleep-like cortical OFF-periods disrupt causality and complexity in the brain of unresponsive wakefulness syndrome patients.

Unresponsive wakefulness syndrome (UWS) patients may retain intact portions of the thalamocortical system that are spontaneously active and reactive to sensory stimuli but fail to engage in complex causal interactions, resulting in loss of consciousness. Here, we show that loss of brain complexity after severe injuries is due to a pathological tendency of cortical circuits to fall into silence (OFF-period) upon receiving an input, a behavior typically observed during sleep. Spectral and phase domain analysis of EEG responses to transcranial magnetic stimulation reveals the occurrence of OFF-periods in the cortex of UWS patients (N = 16); these events never occur in healthy awake individuals (N = 20) but are similar to those detected in healthy sleeping subjects (N = 8). Crucially, OFF-periods impair local causal interactions, and prevent the build-up of global complexity in UWS. Our findings link potentially reversible local events to global brain dynamics that are relevant for pathological loss and recovery of consciousness.

Brain functional connectivity differentiates dexmedetomidine from propofol and natural sleep.

BACKGROUND: We used functional connectivity measures from brain resting state functional magnetic resonance imaging to identify human neural correlates of sedation with dexmedetomidine or propofol and their similarities with natural sleep. METHODS: Connectivity within the resting state networks that are proposed to sustain consciousness generation was compared between deep non-rapid-eye-movement (N3) sleep, dexmedetomidine sedation, and propofol sedation in volunteers who became unresponsive to verbal command. A newly acquired dexmedetomidine dataset was compared with our previously published propofol and N3 sleep datasets. RESULTS: In all three unresponsive states (dexmedetomidine sedation, propofol sedation, and N3 sleep), within-network functional connectivity, including thalamic functional connectivity in the higher-order (default mode, executive control, and salience) networks, was significantly reduced as compared with the wake state. Thalamic functional connectivity was not reduced for unresponsive states within lower-order (auditory, sensorimotor, and visual) networks. Voxel-wise statistical comparisons between the different unresponsive states revealed that thalamic functional connectivity with the medial prefrontal/anterior cingulate cortex and with the mesopontine area was reduced least during dexmedetomidine-induced unresponsiveness and most during propofol-induced unresponsiveness. The reduction seen during N3 sleep was intermediate between those of dexmedetomidine and propofol. CONCLUSIONS: Thalamic connectivity with key nodes of arousal and saliency detection networks was relatively preserved during N3 sleep and dexmedetomidine-induced unresponsiveness as compared to propofol. These network effects may explain the rapid recovery of oriented responsiveness to external stimulation seen under dexmedetomidine sedation. TRIAL REGISTRY NUMBER: Committee number: 'Comité d'Ethique Hospitalo-Facultaire Universitaire de Liège' (707); EudraCT number: 2012-003562-40; internal reference: 20121/135; accepted on August 31, 2012; Chair: Prof G. Rorive. As it was considered a phase I clinical trial, this protocol does not appear on the EudraCT public website.

Assessing consciousness in coma and related states using transcranial magnetic stimulation combined with electroencephalography.

Thanks to advances in medical care, an increased number of patients recover from coma. However, some remain in vegetative/unresponsive wakefulness syndrome or in a minimally conscious state. Detection of awareness in severely brain-injured patients is challenging because it relies on behavioral assessments, which can be affected by motor, sensory and cognitive impairments of the patients. Other means of evaluation are needed to improve the accuracy of the diagnosis in this challenging population. We will here review the different altered states of consciousness occurring after severe brain damage, and explain the difficulties associated with behavioral assessment of consciousness. We will then describe a non-invasive technique, transcranial magnetic stimulation combined with high-density electroencephalography (TMS-EEG), which has allowed us to detect the presence or absence of consciousness in different physiological, pathological and pharmacological states. Some potential underlying mechanisms of the loss of consciousness will then be discussed. In conclusion, TMS-EEG is highly promising in identifying markers of consciousness at the individual level and might be of great value for clinicians in the assessment of consciousness.

Unresponsive wakefulness syndrome.

Recent studies providing evidence for preserved awareness in some behaviorally unresponsive patients stress the need to improve diagnosis in patients with disorders of consciousness - and stress the possible dissociation between responsiveness and preserved consciousness. Because active paradigms can only bring information in the few cases where they return positive, a major effort is needed to setup ancillary markers evaluating the brain's ability to generate consciousness without requiring the patients' collaboration - in this context, research on neural correlates of consciousness and coma science progress hand in hand.

A default mode of brain function in altered states of consciousness.

Using modern brain imaging techniques, new discoveries are being made concerning the spontaneous activity of the brain when it is devoid of attention-demanding tasks. Spatially separated patches of neuronal assemblies have been found to show synchronized oscillatory activity behavior and are said to be functionally connected. One of the most robust of these is the default mode network, which is associated with intrinsic processes like mind wandering and self-projection. Furthermore, activity in this network is anticorrelated with activity in a network that is linked to attention to external stimuli. The integrity of both networks is disturbed in altered states of consciousness, like sleep, general anesthesia and hypnosis. In coma and related disorders of consciousness, encompassing the vegetative state (unresponsive wakefulness syndrome) and minimally conscious state, default mode network integrity correlates with the level of remaining consciousness, offering the possibility of using this information for diagnostic and prognostic purposes. Functional brain imaging is currently being validated as a valuable addition to the standardized behavioral assessments that are already in use.

Neural correlates of consciousness during general anesthesia using functional magnetic resonance imaging (fMRI).

This paper reviews the current knowledge about the mechanisms of anesthesia-induced alteration of consciousness. It is now evident that hypnotic anesthetic agents have specific brain targets whose function is hierarchically altered in a dose-dependent manner. Higher order networks, thought to be involved in mental content generation, as well as sub-cortical networks involved in thalamic activity regulation seems to be affected first by increasing concentrations of hypnotic agents that enhance inhibitory neurotransmission. Lower order sensory networks are preserved, including thalamo-cortical connectivity into those networks, even at concentrations that suppress responsiveness, but cross-modal sensory interactions are inhibited. Thalamo-cortical connectivity into the consciousness networks decreases with increasing concentrations of those agents, and is transformed into an anti-correlated activity between the thalamus and the cortex for the deepest levels of sedation, when the subject is non responsive. Future will tell us whether these brain function alterations are also observed with hypnotic agents that mainly inhibit excitatory neurotransmission. The link between the observations made using fMRI and the identified biochemical targets of hypnotic anesthetic agents still remains to be identified.

Modes and models in disorders of consciousness science.

The clinical assessment of non-communicative brain damaged patients is extremely difficult and there is a need for paraclinical diagnostic markers of the level of consciousness. In the last few years, progress within neuroimaging has led to a growing body of studies investigating vegetative state and minimally conscious state patients, which can be classified in two main approaches. Active neuroimaging paradigms search for a response to command without requiring a motor response. Passive neuroimaging paradigms investigate spontaneous brain activity and brain responses to external stimuli and aim at identifying neural correlates of consciousness. Other passive paradigms eschew neuroimaging in favour of behavioural markers which reliably distinguish conscious and unconscious conditions in healthy controls. In order to furnish accurate diagnostic criteria, a mechanistic explanation of how the brain gives rise to consciousness seems desirable. Mechanistic and theoretical approaches could also ultimately lead to a unification of passive and active paradigms in a coherent diagnostic approach. In this paper, we survey current passive and active paradigms available for diagnosis of residual consciousness in vegetative state and minimally conscious patients. We then review the current main theories of consciousness and see how they can apply in this context. Finally, we discuss some avenues for future research in this domain.

Linking sleep and general anesthesia mechanisms: this is no walkover.

This review aims at defining the link between physiological sleep and general anesthesia. Despite common behavioral and electrophysiological characteristics between both states, current literature suggests that the transition process between waking and sleep or anesthesia-induced alteration of consciousness is not driven by the same sequence of events. On the one hand, sleep originates in sub-cortical structures with subsequent repercussions on thalamo-cortical interactions and cortical activity. On the other hand, anesthesia seems to primarily affect the cortex with subsequent repercussions on the activity of sub-cortical networks. This discrepancy has yet to be confirmed by further functional brain imaging and electrophysiological experiments. The relationship between the observed functional modifications of brain activity during anesthesia and the known biochemical targets of hypnotic anesthetic agents also remains to be determined.

Multimodal neuroimaging in patients with disorders of consciousness showing "functional hemispherectomy".

Beside behavioral assessment of patients with disorders of consciousness, neuroimaging modalities may offer objective paraclinical markers important for diagnosis and prognosis. They provide information on the structural location and extent of brain lesions (e.g., morphometric MRI and diffusion tensor imaging (DTI-MRI) assessing structural connectivity) but also their functional impact (e.g., metabolic FDG-PET, hemodynamic fMRI, and EEG measurements obtained in "resting state" conditions). We here illustrate the role of multimodal imaging in severe brain injury, presenting a patient in unresponsive wakefulness syndrome (UWS; i.e., vegetative state, VS) and in a "fluctuating" minimally conscious state (MCS). In both cases, resting state FDG-PET, fMRI, and EEG showed a functionally preserved right hemisphere, while DTI showed underlying differences in structural connectivity highlighting the complementarities of these neuroimaging methods in the study of disorders of consciousness.

Primary diffuse leptomeningeal gliomatosis: an autopsy case and review of the literature.

We report a case of primary diffuse leptomeningeal gliomatosis (PDLG) in a 76-year-old male presenting with confusion, dysarthria, diplopia, lumbal pain and headaches of recent onset. Neurological examination revealed nuchal rigidity and bilateral sixth cranial nerve palsy. The cerebrospinal fluid showed a marked hyperproteinorachia (4711 mg/L) and mild cytorachia (5-10 leucocytes/mm3) with a few atypical lymphoid cells. On admission, brain CT scan and MRI demonstrated diffuse and nodular leptomeningeal contrast enhancement predominant at the skull base and several osteolytic lesions in the right parietal bone. Extensive serological studies for infectious, autoimmune or neoplastic diseases were negative. The work-up diagnosis was neurosarcoidosis or multiple meningeal and osseous metastases of an unknown primary cancer. Surgical biopsy of the right parietal bone lesion showed only fibrous tissue with no evidence of tumour or inflammation. The patient was treated with high dose corticosteroids but its neurological status progressively worsened and he died of aspiration pneumonia 35 days after admission. Post-mortem examination revealed a PDLG, a rare fatal tumour with about 60 cases reported. PDGL is characterized by the diffusion of neoplastic glial cells throughout the leptomeninges without evidence of a primary intra-parenchymal lesion. Recognition of this rare brain tumour is important as recent reports suggest that radiotherapy and chemotherapy can improve patient survival.

Disorders of consciousness: Moving from passive to resting state and active paradigms.

Following coma, some patients will recover wakefulness without signs of consciousness (i.e., vegetative state) or may show nonreflexive movements but with no ability for functional communication (i.e., minimally conscious state). Currently, there remains a high rate of misdiagnosis of the vegetative state. The increasing use of fMRI and EEG tools permits the clinical characterization of these patients to be improved. We first discuss "resting metabolism" and "passive activation" paradigms, used in neuroimaging and evoked potential studies, which merely identify neural activation reflecting "automatic" processing-that is, occurring without the patient's willful intervention. Secondly, we present an alternative approach consisting of instructing subjects to imagine well-defined sensory-motor or cognitive-mental actions. This strategy reflects volitional neural activation and, hence, witnesses awareness. Finally, we present results on blood-oxgen-level-dependent "default mode network"/resting state studies that might be a promising tool in the diagnosis of these challenging patients.

Different beliefs about pain perception in the vegetative and minimally conscious states: a European survey of medical and paramedical professionals.

Pain management in severely brain-damaged patients constitutes a clinical and ethical stake. At the bedside, assessing the presence of pain and suffering is challenging due to both patients' physical condition and inherent limitations of clinical assessment. Neuroimaging studies support the existence of distinct cerebral responses to noxious stimulation in brain death, vegetative state, and minimally conscious state. We here provide results from a European survey on 2059 medical and paramedical professionals' beliefs on possible pain perception in patients with disorders of consciousness. To the question "Do you think that patients in a vegetative state can feel pain?," 68% of the interviewed paramedical caregivers (n=538) and 56% of medical doctors (n=1166) answered "yes" (no data on exact profession in 17% of total sample). Logistic regression analysis showed that paramedical professionals, religious caregivers, and older caregivers reported more often that vegetative patients may experience pain. Following professional background, religion was the highest predictor of caregivers' opinion: 64% of religious (n=1009; 850 Christians) versus 52% of nonreligious respondents (n=830) answered positively (missing data on religion in 11% of total sample). To the question "Do you think that patients in a minimally conscious state can feel pain?" nearly all interviewed caregivers answered "yes" (96% of the medical doctors and 97% of the paramedical caregivers). Women and religious caregivers reported more often that minimally conscious patients may experience pain. These results are discussed in terms of existing definitions of pain and suffering, the remaining uncertainty on the clinical assessment of pain as a subjective first-person experience and recent functional neuroimaging findings on nociceptive processing in disorders of consciousness. In our view, more research is needed to increase our understanding of residual sensation in vegetative and minimally conscious patients and to propose evidence-based medical guidelines for the management of possible pain perception and suffering in these vulnerable patient populations.

Bispectral index correlates with regional cerebral blood flow during sleep in distinct cortical and subcortical structures in humans.

The relationship between the Bispectral Index (BIS), an EEG-based monitor of anesthesia, and brain activity is still unclear. This study aimed at investigating the relationship between changes in BIS values during natural sleep and regional cerebral blood flow (rCBF) variations, as measured by Positron Emission Tomography (PET). Data were obtained from six young, healthy, right-handed, male volunteers (20-30 years old) using the H2(15)O infusion method. PET scans were performed both during waking and various stages of sleep. BIS values were monitored continuously and recorded during each PET scan. Positive correlations were detected between BIS and rCBF values in dorsolateral prefontal, parietal, anterior and posterior cingulate, precuneal, mesiofrontal, mesiotemporal and insular cortices. These areas belong to a frontoparietal network known to be related to awareness of self conscious sensory perception, attention and memory. BIS values also positively correlated with activity in brainstem and thalami, both structures known to be involved in arousal and wakefulness. These results show that BIS changes associated with physiological sleep depth co-vary with the activity of specific cortical and subcortical areas. The latter are known to modulate arousal, which in turn allows sustained thalamo-cortical enhancement of activity in a specific frontoparietal network known to be related to the content of consciousness. Thus, although mainly derived from frontal EEG, BIS could represent a wider index of cerebral activity.

Pain and non-pain processing during hypnosis: a thulium-YAG event-related fMRI study.

The neural mechanisms underlying the antinociceptive effects of hypnosis still remain unclear. Using a parametric single-trial thulium-YAG laser fMRI paradigm, we assessed changes in brain activation and connectivity related to the hypnotic state as compared to normal wakefulness in 13 healthy volunteers. Behaviorally, a difference in subjective ratings was found between normal wakefulness and hypnotic state for both non-painful and painful intensity-matched stimuli applied to the left hand. In normal wakefulness, non-painful range stimuli activated brainstem, contralateral primary somatosensory (S1) and bilateral insular cortices. Painful stimuli activated additional areas encompassing thalamus, bilateral striatum, anterior cingulate (ACC), premotor and dorsolateral prefrontal cortices. In hypnosis, intensity-matched stimuli in both the non-painful and painful range failed to elicit any cerebral activation. The interaction analysis identified that contralateral thalamus, bilateral striatum and ACC activated more in normal wakefulness compared to hypnosis during painful versus non-painful stimulation. Finally, we demonstrated hypnosis-related increases in functional connectivity between S1 and distant anterior insular and prefrontal cortices, possibly reflecting top-down modulation.