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 domai

Consciousness and responsiveness: Lessons from anaesthesia and the vegetative state

peer reviewedPURPOSE OF REVIEW: The aim of this article is to review recent behavioural and neuroimaging studies in anaesthesia and the vegetative state. RECENT FINDINGS: These studies highlight possible dissociations between consciousness and responsiveness in both these states. SUMMARY: We discuss future avenues of research in the field, in order to improve the detection of awareness during anaesthesia and the vegetative state using neuroimaging and neurophysiologic techniques

Detecting Awareness in the Vegetative State

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Neuroimaging after coma.

Following coma, some patients will recover wakefulness without signs of consciousness (only showing reflex movements, i.e., the vegetative state) or may show non-reflex movements but remain without functional communication (i.e., the minimally conscious state). Currently, there remains a high rate of misdiagnosis of the vegetative state (Schnakers et. al. BMC Neurol, 9:35, 8) and the clinical and electrophysiological markers of outcome from the vegetative and minimally conscious states remain unsatisfactory. This should incite clinicians to use multimodal assessment to detect objective signs of consciousness and validate para-clinical prognostic markers in these challenging patients. This review will focus on advanced magnetic resonance imaging (MRI) techniques such as magnetic resonance spectroscopy, diffusion tensor imaging, and functional MRI (fMRI studies in both "activation" and "resting state" conditions) that were recently introduced in the assessment of patients with chronic disorders of consciousness

Brain Connectivity in Pathological and Pharmacological Coma

Recent studies in patients with disorders of consciousness (DOC) tend to support the view that awareness is not related to activity in a single brain region but to thalamo-cortical connectivity in the frontoparietal network. Functional neuroimaging studies have shown preserved albeit disconnected low-level cortical activation in response to external stimulation in patients in a “vegetative state” or unresponsive wakefulness syndrome. While activation of these “primary” sensory cortices does not necessarily reflect conscious awareness, activation in higher-order associative cortices in minimally conscious state patients seems to herald some residual perceptual awareness. PET studies have identified a metabolic dysfunction in a widespread frontoparietal “global neuronal workspace” in DOC patients including the midline default mode network (“intrinsic” system) and the lateral frontoparietal cortices or “extrinsic system.” Recent studies have investigated the relation of awareness to the functional connectivity within intrinsic and extrinsic networks, and with the thalami in both pathological and pharmacological coma. In brain damaged patients, connectivity in all default network areas was found to be non-linearly correlated with the degree of clinical consciousness impairment, ranging from healthy controls and locked-in syndrome to minimally conscious, vegetative, coma, and brain dead patients. Anesthesia-induced loss of consciousness was also shown to correlate with a global decrease in cortico-cortical and thalamo-cortical connectivity in both intrinsic and extrinsic networks, but not in auditory, or visual networks. In anesthesia, unconsciousness was also associated with a loss of cross-modal interactions between networks. These results suggest that conscious awareness critically depends on the functional integrity of thalamo-cortical and cortico-cortical frontoparietal connectivity within and between “intrinsic” and “extrinsic” brain networks

Functional neuroanatomy underlying the clinical subcategorization of minimally conscious state patients.

Patients in a minimally conscious state (MCS) show restricted signs of awareness but are unable to communicate. We assessed cerebral glucose metabolism in MCS patients and tested the hypothesis that this entity can be subcategorized into MCS- (i.e., patients only showing nonreflex behavior such as visual pursuit, localization of noxious stimulation and/or contingent behavior) and MCS+ (i.e., patients showing command following).Patterns of cerebral glucose metabolism were studied using [(18)F]-fluorodeoxyglucose-PET in 39 healthy volunteers (aged 46 +/- 18 years) and 27 MCS patients of whom 13 were MCS- (aged 49 +/- 19 years; 4 traumatic; 21 +/- 23 months post injury) and 14 MCS+ (aged 43 +/- 19 years; 5 traumatic; 19 +/- 26 months post injury). Results were thresholded for significance at false discovery rate corrected p < 0.05.We observed a metabolic impairment in a bilateral subcortical (thalamus and caudate) and cortical (fronto-temporo-parietal) network in nontraumatic and traumatic MCS patients. Compared to MCS-, patients in MCS+ showed higher cerebral metabolism in left-sided cortical areas encompassing the language network, premotor, presupplementary motor, and sensorimotor cortices. A functional connectivity study showed that Broca's region was disconnected from the rest of the language network, mesiofrontal and cerebellar areas in MCS- as compared to MCS+ patients.The proposed subcategorization of MCS based on the presence or absence of command following showed a different functional neuroanatomy. MCS- is characterized by preserved right hemispheric cortical metabolism interpreted as evidence of residual sensory consciousness. MCS+ patients showed preserved metabolism and functional connectivity in language networks arguably reflecting some additional higher order or extended consciousness albeit devoid of clinical verbal or nonverbal expression

Propofol-Induced Frontal Cortex Disconnection: A Study of Resting-State Networks, Total Brain Connectivity, and Mean BOLD Signal Oscillation Frequencies.

Propofol is one of the most commonly used anesthetics in the world, but much remains unknown about the mechanisms by which it induces loss of consciousness. In this resting-state functional magnetic resonance imaging study, we examined qualitative and quantitative changes of resting-state networks (RSNs), total brain connectivity, and mean oscillation frequencies of the regional blood oxygenation level-dependent (BOLD) signal, associated with propofol-induced mild sedation and loss of responsiveness in healthy subjects. We found that detectability of RSNs diminished significantly with loss of responsiveness, and total brain connectivity decreased strongly in the frontal cortex, which was associated with increased mean oscillation frequencies of the BOLD signal. Our results suggest a pivotal role of the frontal cortex in propofol-induced loss of responsiveness

Global structural integrity and effective connectivity in patients with disorders of consciousness

peer reviewedBackground Previous studies have separately reported impaired functional, structural, and effective connectivity in patients with disorders of consciousness (DOC). The perturbational complexity index (PCI) is a transcranial magnetic stimulation (TMS) derived marker of effective connectivity. The global fractional anisotropy (FA) is a marker of structural integrity. Little is known about how these parameters are related to each other. Objective We aimed at testing the relationship between structural integrity and effective connectivity. Methods We assessed 23 patients with severe brain injury more than 4 weeks post-onset, leading to DOC or locked-in syndrome, and 14 healthy subjects. We calculated PCI using repeated single pulse TMS coupled with high-density electroencephalography, and used it as a surrogate of effective connectivity. Structural integrity was measured using the global FA, derived from diffusion weighted imaging. We used linear regression modelling to test our hypothesis, and computed the correlation between PCI and FA in different groups. Results Global FA could predict 74% of PCI variance in the whole sample and 56% in the patients' group. No other predictors (age, gender, time since onset, behavioural score) improved the models. FA and PCI were correlated in the whole population (r = 0.86, p < 0.0001), the patients, and the healthy subjects subgroups. Conclusion We here demonstrated that effective connectivity correlates with structural integrity in brain-injured patients. Increased structural damage level decreases effective connectivity, which could prevent the emergence of consciousness

The spectral exponent of the resting EEG indexes the presence of consciousness during unresponsiveness induced by propofol, xenon, and ketamine

peer reviewedDespite the absence of responsiveness during anesthesia, conscious experience may persist. However, reliable, easily acquirable and interpretable neurophysiological markers of the presence of consciousness in unresponsive states are still missing. A promising marker is based on the decay-rate of the power spectral density (PSD) of the resting EEG. We acquired resting electroencephalogram (EEG) in three groups of healthy participants (n = 5 each), before and during anesthesia induced by either xenon, propofol or ketamine. Dosage of each anesthetic agent was tailored to yield unresponsiveness (Ramsay score = 6). Delayed subjective reports assessed whether conscious experience was present (‘Conscious report’) or absent/inaccessible to recall (‘No Report’). We estimated the decay of the PSD of the resting EEG—after removing oscillatory peaks—via the spectral exponent β, for a broad band (1–40 Hz) and narrower sub-bands (1–20 Hz, 20–40 Hz). Within-subject anesthetic changes in β were assessed. Furthermore, based on β, ‘Conscious report’ states were discriminated against ‘no report’ states. Finally, we evaluated the correlation of the resting spectral exponent with a recently proposed index of consciousness, the Perturbational Complexity Index (PCI), derived from a previous TMS-EEG study. The spectral exponent of the resting EEG discriminated states in which consciousness was present (wakefulness, ketamine) from states where consciousness was reduced or abolished (xenon, propofol). Loss of consciousness substantially decreased the (negative) broad-band spectral exponent in each subject undergoing xenon or propofol anesthesia—indexing an overall steeper PSD decay. Conversely, ketamine displayed an overall PSD decay similar to that of wakefulness—consistent with the preservation of consciousness—yet it showed a flattening of the decay in the high-frequencies (20–40 Hz)—consistent with its specific mechanism of action. The spectral exponent was highly correlated to PCI, corroborating its interpretation as a marker of the presence of consciousness. A steeper PSD of the resting EEG reliably indexed unconsciousness in anesthesia, beyond sheer unresponsiveness. © 2019 The Author

Functional neuroimaging (fMRI, PET and MEG): what do we measure?

peer reviewedFunctional cerebral imaging techniques allow the in vivo study of human cognitive and sensorimotor functions in physiological or pathological conditions. In this paper, we review the advantages and limitations of functional magnetic resonance imaging (fMRI), positron emission tomography (PET) and magnetoencephalography (MEG). fMRI and PET measure haemodynamic changes induced by regional changes in neuronal activity. These techniques have a high spatial resolution (a few millimeters), but a poor temporal resolution (a few seconds to several minutes). Electroencephalogram (EEG) and MEG measure the neuronal electrical or magnetic activity with a high temporal resolution (i.e., milliseconds) albeit with a poorer spatial resolution (i.e., a few millimeters to one centimeter). The combination of these different neuroimaging techniques allows studying different components of the brain's activity (e.g., neurovascular coupling, electromagnetic activity) with both a high temporal and spatial resolution