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.

European Academy of Neurology guideline on the diagnosis of coma and other disorders of consciousness.

BACKGROUND AND PURPOSE: Patients with acquired brain injury and acute or prolonged disorders of consciousness (DoC) are challenging. Evidence to support diagnostic decisions on coma and other DoC is limited but accumulating. This guideline provides the state-of-the-art evidence regarding the diagnosis of DoC, summarizing data from bedside examination techniques, functional neuroimaging and electroencephalography (EEG). METHODS: Sixteen members of the European Academy of Neurology (EAN) Scientific Panel on Coma and Chronic Disorders of Consciousness, representing 10 European countries, reviewed the scientific evidence for the evaluation of coma and other DoC using standard bibliographic measures. Recommendations followed the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. The guideline was endorsed by the EAN. RESULTS: Besides a comprehensive neurological examination, the following suggestions are made: probe for voluntary eye movements using a mirror; repeat clinical assessments in the subacute and chronic setting, using the Coma Recovery Scale - Revised; use the Full Outline of Unresponsiveness score instead of the Glasgow Coma Scale in the acute setting; obtain clinical standard EEG; search for sleep patterns on EEG, particularly rapid eye movement sleep and slow-wave sleep; and, whenever feasible, consider positron emission tomography, resting state functional magnetic resonance imaging (fMRI), active fMRI or EEG paradigms and quantitative analysis of high-density EEG to complement behavioral assessment in patients without command following at the bedside. CONCLUSIONS: Standardized clinical evaluation, EEG-based techniques and functional neuroimaging should be integrated for multimodal evaluation of patients with DoC. The state of consciousness should be classified according to the highest level revealed by any of these three approaches.

Fractal dimension analysis of states of consciousness and unconsciousness using transcranial magnetic stimulation.

BACKGROUND AND OBJECTIVE: Knowing whether a subject is conscious or not is a current challenge with a deep potential clinical impact. Recent theoretical considerations suggest that consciousness is linked to the complexity of distributed interactions within the corticothalamic system. The fractal dimension (FD) is a quantitative parameter that has been extensively used to analyse the complexity of structural and functional patterns of the human brain. In this study we investigate FD to assess whether it can discriminate between consciousness and different states of unconsciousness in healthy individuals. METHODS: We study 69 high-density electroencephalogram (hd-EEG) measurements after transcranial magnetic stimulation (TMS) in 18 healthy subjects progressing from wakefulness to non-rapid eye movement (NREM) sleep and sedation induced by different anaesthetic agents (xenon and propofol). We quantify the integration of thalamocortical networks by calculating the FD of a spatiotemporal voxelization obtained from the locations of all sources that are significantly activated by the perturbation (4DFD). Moreover, we study the temporal evolution of the evoked spatial distributions and compute a measure of the differentiation of the response by means of the Higuchi FD (HFD). Finally, a Fractal Dimension Index (FDI) of perturbational complexity is computed as the product of both quantities: integration FD (4DFD) and differentiation FD (HFD). RESULTS: We found that FDI is significantly lower in sleep and sedation when compared to wakefulness and provides an almost perfect intra-subject discrimination between conscious and unconscious states. CONCLUSIONS: These results support the combination of FD measures of cortical integration and cortical differentiation as a novel paradigm of tracking complex spatiotemporal dynamics in the brain that could provide further insights into the link between complexity and the brain's capacity to sustain consciousness.

Memories of near-death experiences: are they self-defining?

Some people report memories of near-death experiences (NDEs) after facing situations of impending death and these memories appear to have significant consequences on their lives (here referred to as "real NDE experiencers"; real NDErs). We assessed to what extent NDE memories are considered self-defining: memories that help people to define clearly how they see themselves. We screened 71 participants using the Greyson NDE scale (48 real NDErs and 23 NDErs-like who had lived a similar experience in absence of a threat to their life). Participants described their two main self-defining memories (SDMs). For each SDM, they completed the Centrality of Event Scale (CES) to assess how central the event is to their identity. The two subgroups did not differ regarding the proportion of NDErs who recalled their NDE (30 real NDErs out of 48 and 11 NDErs-like out of 23). Real NDErs and NDErs-like who recalled their NDE (n = 41) reported richer experiences as assessed by the Greyson NDE scale. Furthermore, these participants rated their NDE memory as more central to their identity as compared to other SDMs, and the richness of the NDE memory was positively associated to its centrality (CES scores). Overall, these findings suggest that the self-defining aspect of the experience might be related to its phenomenological content rather than its circumstances of occurrence. The self-defining status of NDE memories confirms that they constitute an important part of NDErs' personal identity and highlights the importance for clinicians to facilitate their integration within the self.

Human consciousness is supported by dynamic complex patterns of brain signal coordination.

Adopting the framework of brain dynamics as a cornerstone of human consciousness, we determined whether dynamic signal coordination provides specific and generalizable patterns pertaining to conscious and unconscious states after brain damage. A dynamic pattern of coordinated and anticoordinated functional magnetic resonance imaging signals characterized healthy individuals and minimally conscious patients. The brains of unresponsive patients showed primarily a pattern of low interareal phase coherence mainly mediated by structural connectivity, and had smaller chances to transition between patterns. The complex pattern was further corroborated in patients with covert cognition, who could perform neuroimaging mental imagery tasks, validating this pattern's implication in consciousness. Anesthesia increased the probability of the less complex pattern to equal levels, validating its implication in unconsciousness. Our results establish that consciousness rests on the brain's ability to sustain rich brain dynamics and pave the way for determining specific and generalizable fingerprints of conscious and unconscious states.

Clinical and electrophysiological investigation of spastic muscle overactivity in patients with disorders of consciousness following severe brain injury.

OBJECTIVE: The clinical and electrophysiological profile of spastic muscle overactivity (SMO) is poorly documented in patients with disorders of consciousness (DOC) following severe cortical and subcortical injury. We aim at investigating the link between the clinical observations of SMO and the electrophysiological spastic over-reactivity in patients with prolonged DOC. METHODS: We prospectively enrolled adult patients with DOC at least 3 months post traumatic or non-traumatic brain injury. The spastic profile was investigated using the Modified Ashworth Scale and the Hmax/Mmax ratio. T1 MRI data and impact of medication were analyzed as well. RESULTS: 21 patients were included (mean age: 41 ±â€¯11 years; time since injury: 4 ±â€¯5 years; 9 women; 10 traumatic etiologies). Eighteen patients presented signs of SMO and 11 had an increased ratio. Eight patients presented signs of SMO but no increased ratio. We did not find any significant correlation between the ratio and the MAS score for each limb (all ps > 0.05). The presence of medication was not significantly associated with a reduction in MAS scores or Hmax/Mmax ratios. CONCLUSIONS: In this preliminary study, the Hmax/Mmax ratio does not seem to reflect the clinical MAS scores in patients with DOC. This supports the fact they do not only present spasticity but other forms of SMO and contracture. SIGNIFICANCE: Patients with DOC are still in need of optimized tools to evaluate their spastic profile and therapeutic approaches should be adapted accordingly.

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.

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.

Correction to: Actigraphy assessments of circadian sleep-wake cycles in the Vegetative and Minimally Conscious States.

The original article [1] contains an error affecting the actigraphy time-stamps throughout the article, particularly in Table 1.

Ultra-slow mechanical stimulation of olfactory epithelium modulates consciousness by slowing cerebral rhythms in humans.

The coupling between respiration and neural activity within olfactory areas and hippocampus has recently been unambiguously demonstrated, its neurophysiological basis sustained by the well-assessed mechanical sensitivity of the olfactory epithelium. We herein hypothesize that this coupling reverberates to the whole brain, possibly modulating the subject's behavior and state of consciousness. The olfactory epithelium of 12 healthy subjects was stimulated with periodical odorless air-delivery (frequency 0.05 Hz, 8 s on, 12 off). Cortical electrical activity (High Density-EEG) and perceived state of consciousness have been studied. The stimulation induced i) an enhancement of delta-theta EEG activity over the whole cortex mainly involving the Limbic System and Default Mode Network structures, ii) a reversal of the overall information flow directionality from wake-like postero-anterior to NREM sleep-like antero-posterior, iii) the perception of having experienced an Altered State of Consciousness. These findings could shed further light via a neurophenomenological approach on the links between respiration, cerebral activity and subjective experience, suggesting a plausible neurophysiological basis for interpreting altered states of consciousness induced by respiration-based meditative practices.

Physical therapy in patients with disorders of consciousness: Impact on spasticity and muscle contracture.

BACKGROUND: Spasticity is a frequent complication after severe brain injury, which may prevent the rehabilitation process and worsen the patients' quality of life. OBJECTIVES: In this study, we investigated the correlation between spasticity, muscle contracture, and the frequency of physical therapy (PT) in subacute and chronic patients with disorders of consciousness (DOC). METHODS: 109 patients with subacute and chronic disorders of consciousness (Vegetative state/Unresponsive wakefulness syndrome - VS/UWS; minimally conscious state - MCS and patients who emerged from MCS - EMCS) were included in the study (39 female; mean age: 40±13.5y; 60 with traumatic etiology; 35 VS/UWS, 68 MCS, 6 EMCS; time since insult: 38±42months). The number of PT sessions (i.e., 20 to 30 minutes of conventional stretching of the four limbs) was collected based on patients' medical record and varied between 0 to 6 times per week (low PT = 0-3 and high PT = 4-6 sessions per week). Spasticity was measured with the Modified Ashworth Scale (MAS) on every segment for both upper (UL) and lower limbs (LL). The presence of muscle contracture was assessed in every joint. We tested the relationship between spasticity and muscle contracture with the frequency of PT as well as other potential confounders such as time since injury or anti-spastic medication intake. RESULTS: We identified a negative correlation between the frequency of PT and MAS scores as well as the presence of muscle contracture. We also identified that patients who received less than four sessions per week were more likely to be spastic and suffer from muscle contracture than patients receiving 4 sessions or more. When separating subacute (3 to 12 months post-insult) and chronic (>12months post-insult) patients, these negative correlations were only observed in chronic patients. A logit regression model showed that frequency of PT influenced spasticity, whereas neither time since insult nor medication had a significant impact on the presence of spasticity. On the other hand, PT, time since injury and medication seemed to be associated with the presence of muscle contracture. CONCLUSION: Our results suggest that, in subacute and chronic patients with DOC, PT could have an impact on patients' spasticity and muscles contractures. Beside PT, other factors such as time since onset and medication seem to influence the development of muscle contractures. These findings support the need for frequent PT sessions and regular re-evaluation of the overall spastic treatment for patients with DOC.

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.

Effects of preference and sensory modality on behavioural reaction in patients with disorders of consciousness.

BACKGROUND: Reliable evaluation of patients with unresponsive wakefulness syndrome (UWS) or in a minimally conscious state (MCS) remains a major challenge. It has been suggested that the expression of residual cerebral function could be improved by allowing patients to listen to their favourite music. However, the potential effect of music on behavioural responsiveness, as well as the effect of preferred stimuli in other sensory modalities (e.g. olfaction), remain poorly understood. OBJECTIVE: The aim of our study was to investigate the effect of sensory modality (auditory versus olfactory) and preference (preferred versus neutral) of the test stimuli on patients' subsequent performance on the Coma Recovery Scale-Revised (CRS-R). RESEARCH DESIGN: Within-subject design because of inter-individual differences between patients. METHODS AND PROCEDURES: We studied four items from the CRS-R (visual pursuit using a mirror, auditory localization of the own name and two movements to command) in 13 patients (7 MCS; 6 UWS). MAIN OUTCOMES AND RESULTS: Auditory stimuli triggered higher responsiveness compared to olfactory stimuli, and preferred stimuli were followed by higher scores than did neutral stimuli. CONCLUSIONS: Findings suggest that preferred auditory stimuli at the bedside contribute to the expression of residual function and could improve the diagnostic assessment.

Ising model with conserved magnetization on the human connectome: Implications on the relation structure-function in wakefulness and anesthesia.

Dynamical models implemented on the large scale architecture of the human brain may shed light on how a function arises from the underlying structure. This is the case notably for simple abstract models, such as the Ising model. We compare the spin correlations of the Ising model and the empirical functional brain correlations, both at the single link level and at the modular level, and show that their match increases at the modular level in anesthesia, in line with recent results and theories. Moreover, we show that at the peak of the specific heat (the critical state), the spin correlations are minimally shaped by the underlying structural network, explaining how the best match between the structure and function is obtained at the onset of criticality, as previously observed. These findings confirm that brain dynamics under anesthesia shows a departure from criticality and could open the way to novel perspectives when the conserved magnetization is interpreted in terms of a homeostatic principle imposed to neural activity.

Function-structure connectivity in patients with severe brain injury as measured by MRI-DWI and FDG-PET.

A vast body of literature exists showing functional and structural dysfunction within the brains of patients with disorders of consciousness. However, the function (fluorodeoxyglucose FDG-PET metabolism)-structure (MRI-diffusion-weighted images; DWI) relationship and how it is affected in severely brain injured patients remains ill-defined. FDG-PET and MRI-DWI in 25 severely brain injured patients (19 Disorders of Consciousness of which 7 unresponsive wakefulness syndrome, 12 minimally conscious; 6 emergence from minimally conscious state) and 25 healthy control subjects were acquired here. Default mode network (DMN) function-structure connectivity was assessed by fractional anisotropy (FA) and metabolic standardized uptake value (SUV). As expected, a profound decline in regional metabolism and white matter integrity was found in patients as compared with healthy subjects. Furthermore, a function-structure relationship was present in brain-damaged patients between functional metabolism of inferior-parietal, precuneus, and frontal regions and structural integrity of the frontal-inferiorparietal, precuneus-inferiorparietal, thalamo-inferioparietal, and thalamofrontal tracts. When focusing on patients, a stronger relationship between structural integrity of thalamo-inferiorparietal tracts and thalamic metabolism in patients who have emerged from the minimally conscious state as compared with patients with disorders of consciousness was found. The latter finding was in line with the mesocircuit hypothesis for the emergence of consciousness. The findings showed a positive function-structure relationship within most regions of the DMN. Hum Brain Mapp 37:3707-3720, 2016. © 2016 Wiley Periodicals, Inc.

Spasticity in disorders of consciousness: a behavioral study.

BACKGROUND: Spasticity is a frequent complication after severe brain injury, which may impede the rehabilitation process and diminish the patients' quality of life. AIM: We here investigate the presence of spasticity in a population of non-communicative patients with disorders of consciousness. We also evaluate the correlation between spasticity and potential factors of co-morbidity, frequency of physical therapy, time since insult, presence of pain, presence of tendon retraction, etiology and diagnosis. DESIGN: Cross-sectional study. SETTING: University Hospital of Liège, Belgium. POPULATION: Sixty-five patients with chronic (>3 months post insult) disorders of consciousness were included (22 women; mean age: 44±14 y; 40 with traumatic etiology; 40 in a minimally conscious state; time since insult: 39±37 months). METHODS: Spasticity was measured with the Modified Ashworth Scale (MAS) and pain was assessed using the Nociception Coma Scale-Revised (NCS-R). RESULTS: Out of 65 patients, 58 demonstrated signs of spasticity (89%; MAS≥1), including 40 who showed severe spasticity (61.5%; MAS≥3). Patients with spasticity receiving anti-spastic medication were more spastic than unmedicated patients. A negative correlation was observed between the severity of spasticity and the frequency of physical therapy. MAS scores correlated positively with time since injury and NCS-R scores. We did not observe a difference of spasticity between the diagnoses. CONCLUSION: A large proportion of patients with disorders of consciousness develop severe spasticity, possibly affecting their functional recovery and their quality of life. The observed correlation between degrees of spasticity and pain scores highlights the importance of pain management in these patients with altered states of consciousness. Finally, the relationship between spasticity and treatment (i.e., pharmacological and physical therapy) should be further investigated in order to improve clinical care. CLINICAL REHABILITATION IMPACT: Managing spasticity at first signs could improve rehabilitation of patients with disorders of consciousness and maximize their chances of recovery. In addition, decreasing this trouble could allow a better quality of life for these non-communicative patients.

Neurophysiology of hypnosis.

We here review behavioral, neuroimaging and electrophysiological studies of hypnosis as a state, as well as hypnosis as a tool to modulate brain responses to painful stimulations. Studies have shown that hypnotic processes modify internal (self awareness) as well as external (environmental awareness) brain networks. Brain mechanisms underlying the modulation of pain perception under hypnotic conditions involve cortical as well as subcortical areas including anterior cingulate and prefrontal cortices, basal ganglia and thalami. Combined with local anesthesia and conscious sedation in patients undergoing surgery, hypnosis is associated with improved peri- and postoperative comfort of patients and surgeons. Finally, hypnosis can be considered as a useful analogue for simulating conversion and dissociation symptoms in healthy subjects, permitting better characterization of these challenging disorders by producing clinically similar experiences.