Marie-Aurélie Bruno

Breakdown of within- and between-network Resting State Functional Magnetic Resonance Imaging Connectivity during Propofol-induced Loss of Consciousness

Background:Mechanisms of anesthesia-induced loss of consciousness remain poorly understood. Resting-state functional magnetic resonance imaging allows investigating whole-brain connectivity changes during pharmacological modulation of the level of consciousness. Methods:Low-frequency spontaneous blood oxygen level-dependent fluctuations were measured in 19 healthy volunteers during wakefulness, mild sedation, deep sedation with clinical unconsciousness, and subsequent recovery of consciousness. Results:Propofol-induced decrease in consciousness linearly correlates with decreased corticocortical and thalamocortical connectivity in frontoparietal networks (i.e., default- and executive-control networks). Furthermore, during propofol-induced unconsciousness, a negative correlation was identified between thalamic and cortical activity in these networks. Finally, negative correlations between default network and lateral frontoparietal cortices activity, present during wakefulness, decreased proportionally to propofol-induced loss of consciousness. In contrast, connectivity was globally preserved in low-level sensory cortices, (i.e., in auditory and visual networks across sedation stages). This was paired with preserved thalamocortical connectivity in these networks. Rather, waning of consciousness was associated with a loss of cross-modal interactions between visual and auditory networks. Conclusions:Our results shed light on the functional significance of spontaneous brain activity fluctuations observed in functional magnetic resonance imaging. They suggest that propofol-induced unconsciousness could be linked to a breakdown of cerebral temporal architecture that modifies both within- and between-network connectivity and thus prevents communication between low-level sensory and higher-order frontoparietal cortices, thought to be necessary for perception of external stimuli. They emphasize the importance of thalamocortical connectivity in higher-order cognitive brain networks in the genesis of conscious perception.

From unresponsive wakefulness to minimally conscious PLUS and functional locked-in syndromes: recent advances in our understanding of disorders of consciousness.

Functional neuroimaging and electrophysiology studies are changing our understanding of patients with coma and related states. Some severely brain damaged patients may show residual cortical processing in the absence of behavioural signs of consciousness. Given these new findings, the diagnostic errors and their potential effects on treatment as well as concerns regarding the negative associations intrinsic to the term vegetative state, the European Task Force on Disorders of Consciousness has recently proposed the more neutral and descriptive term unresponsive wakefulness syndrome. When vegetative/unresponsive patients show minimal signs of consciousness but are unable to reliably communicate the term minimally responsive or minimally conscious state (MCS) is used. MCS was recently subcategorized based on the complexity of patients’ behaviours: MCS+ describes high-level behavioural responses (i.e., command following, intelligible verbalizations or non-functional communication) and MCS− describes low-level behavioural responses (i.e., visual pursuit, localization of noxious stimulation or contingent behaviour such as appropriate smiling or crying to emotional stimuli). Finally, patients who show non-behavioural evidence of consciousness or communication only measurable via para-clinical testing (i.e., functional MRI, positron emission tomography, EEG or evoked potentials) can be considered to be in a functional locked-in syndrome. An improved assessment of brain function in coma and related states is not only changing nosology and medical care but also offers a better-documented diagnosis and prognosis and helps to further identify the neural correlates of human consciousness.

VOLUNTARY BRAIN PROCESSING IN DISORDERS OF CONSCIOUSNESS

Background: Disentangling the vegetative state from the minimally conscious state is often difficult when relying only on behavioral observation. In this study, we explored a new active evoked-related potentials paradigm as an alternative method for the detection of voluntary brain activity. Methods: The participants were 22 right-handed patients (10 traumatic) diagnosed as being in a vegetative state (VS) (n = 8) or in a minimally conscious state (MCS) (n = 14). They were presented sequences of names containing the patient’s own name or other names, in both passive and active conditions. In the active condition, the patients were instructed to count her or his own name or to count another target name. Results: Like controls, MCS patients presented a larger P3 to the patient’s own name, in the passive and in the active conditions. Moreover, the P3 to target stimuli was higher in the active than in the passive condition, suggesting voluntary compliance to task instructions like controls. These responses were even observed in patients with low behavioral responses (e.g., visual fixation and pursuit). In contrast, no P3 differences between passive and active conditions were observed for VS patients. Conclusions: The present results suggest that active evoked-related potentials paradigms may permit detection of voluntary brain function in patients with severe brain damage who present with a disorder of consciousness, even when the patient may present with very limited to questionably any signs of awareness.

Connectivity Changes Underlying Spectral EEG Changes during Propofol-Induced Loss of Consciousness

The mechanisms underlying anesthesia-induced loss of consciousness remain a matter of debate. Recent electrophysiological reports suggest that while initial propofol infusion provokes an increase in fast rhythms (from beta to gamma range), slow activity (from delta to alpha range) rises selectively during loss of consciousness. Dynamic causal modeling was used to investigate the neural mechanisms mediating these changes in spectral power in humans. We analyzed source-reconstructed data from frontal and parietal cortices during normal wakefulness, propofol-induced mild sedation, and loss of consciousness. Bayesian model selection revealed that the best model for explaining spectral changes across the three states involved changes in corticothalamic interactions. Compared with wakefulness, mild sedation was accounted for by an increase in thalamic excitability, which did not further increase during loss of consciousness. In contrast, loss of consciousness per se was accompanied by a decrease in backward corticocortical connectivity from frontal to parietal cortices, while thalamocortical connectivity remained unchanged. These results emphasize the importance of recurrent corticocortical communication in the maintenance of consciousness and suggest a direct effect of propofol on cortical dynamics.

Brain functional integration decreases during propofol-induced loss of consciousness

Consciousness has been related to the amount of integrated information that the brain is able to generate. In this paper, we tested the hypothesis that the loss of consciousness caused by propofol anesthesia is associated with a significant reduction in the capacity of the brain to integrate information. To assess the functional structure of the whole brain, functional integration and partial correlations were computed from fMRI data acquired from 18 healthy volunteers during resting wakefulness and propofol-induced deep sedation. Total integration was significantly reduced from wakefulness to deep sedation in the whole brain as well as within and between its constituent networks (or systems). Integration was systematically reduced within each system (i.e., brain or networks), as well as between networks. However, the ventral attentional network maintained interactions with most other networks during deep sedation. Partial correlations further suggested that functional connectivity was particularly affected between parietal areas and frontal or temporal regions during deep sedation. Our findings suggest that the breakdown in brain integration is the neural correlate of the loss of consciousness induced by propofol. They stress the important role played by parietal and frontal areas in the generation of consciousness.

A survey on self-assessed well-being in a cohort of chronic locked-in syndrome patients: happy majority, miserable minority

Objectives Locked-in syndrome (LIS) consists of anarthria and quadriplegia while consciousness is preserved. Classically, vertical eye movements or blinking allow coded communication. Given appropriate medical care, patients can survive for decades. We studied the self-reported quality of life in chronic LIS patients. Design 168 LIS members of the French Association for LIS were invited to answer a questionnaire on medical history, current status and end-of-life issues. They self-assessed their global subjective well-being with the Anamnestic Comparative Self-Assessment (ACSA) scale, whose +5 and −5 anchors were their memories of the best period in their life before LIS and their worst period ever, respectively. Results 91 patients (54%) responded and 26 were excluded because of missing data on quality of life. 47 patients professed happiness (median ACSA +3) and 18 unhappiness (median ACSA −4). Variables associated with unhappiness included anxiety and dissatisfaction with mobility in the community, recreational activities and recovery of speech production. A longer time in LIS was correlated with happiness. 58% declared they did not wish to be resuscitated in case of cardiac arrest and 7% expressed a wish for euthanasia. Conclusions Our data stress the need for extra palliative efforts directed at mobility and recreational activities in LIS and the importance of anxiolytic therapy. Recently affected LIS patients who wish to die should be assured that there is a high chance they will regain a happy meaningful life. End-of-life decisions, including euthanasia, should not be avoided, but a moratorium to allow a steady state to be reached should be proposed.

Detecting consciousness in a total locked-in syndrome: An active event-related paradigm

Total locked-in syndrome is characterized by tetraplegia, anarthria and paralysis of eye motility. In this study, consciousness was detected in a 21-year-old woman who presented a total locked-in syndrome after a basilar artery thrombosis (49 days post-injury) using an active event-related paradigm. The patient was presented sequences of names containing the patients own name and other names. The patient was instructed to count her own name or to count another target name. Similar to 4 age- and gender-matched healthy controls, the P3 response recorded for the voluntarily counted own name was larger than while passively listening. This P3 response was observed 14 days before the first behavioral signs of consciousness. This study shows that our active event-related paradigm allowed to identify voluntary brain activity in a patient who would behaviorally be diagnosed as comatose.

The nociception coma scale: A new tool to assess nociception in disorders of consciousness.

&NA; Assessing behavioral responses to nociception is difficult in severely brain‐injured patients recovering from coma. We here propose a new scale developed for assessing nociception in vegetative (VS) and minimally conscious (MCS) coma survivors, the Nociception Coma Scale (NCS), and explore its concurrent validity, inter‐rater agreement and sensitivity. Concurrent validity was assessed by analyzing behavioral responses of 48 post‐comatose patients to a noxious stimulation (pressure applied to the fingernail) (28 VS and 20 MCS; age range 20–82 years; 17 of traumatic etiology). Patients’ were assessed using the NCS and four other scales employed in non‐communicative patients: the ‘Neonatal Infant Pain Scale’ (NIPS) and the ‘Faces, Legs, Activity, Cry, Consolability’ (FLACC) used in newborns; and the ‘Pain Assessment In Advanced Dementia Scale’ (PAINAD) and the ‘Checklist of Non‐verbal Pain Indicators’ (CNPI) used in dementia. For the establishment of inter‐rater agreement, fifteen patients were concurrently assessed by two examiners. Concurrent validity, assessed by Spearman rank order correlations between the NCS and the four other validated scales, was good. Cohens kappa analyses revealed a good to excellent inter‐rater agreement for the NCS total and subscore measures, indicating that the scale yields reproducible findings across examiners. Finally, a significant difference between NCS total scores was observed as a function of diagnosis (i.e., VS or MCS). The NCS constitutes a sensitive clinical tool for assessing nociception in severely brain‐injured patients. This scale constitutes the first step to a better management of patients recovering from coma.

Identifying the default‐mode component in spatial IC analyses of patients with disorders of consciousness

Objectives:Recent fMRI studies have shown that it is possible to reliably identify the default‐mode network (DMN) in the absence of any task, by resting‐state connectivity analyses in healthy volunteers. We here aimed to identify the DMN in the challenging patient population of disorders of consciousness encountered following coma. Experimental design: A spatial independent component analysis‐based methodology permitted DMN assessment, decomposing connectivity in all its different sources either neuronal or artifactual. Three different selection criteria were introduced assessing anticorrelation‐corrected connectivity with or without an automatic masking procedure and calculating connectivity scores encompassing both spatial and temporal properties. These three methods were validated on 10 healthy controls and applied to an independent group of 8 healthy controls and 11 severely brain‐damaged patients [locked‐in syndrome (n = 2), minimally conscious (n = 1), and vegetative state (n = 8)]. Principal observations: All vegetative patients showed fewer connections in the default‐mode areas, when compared with controls, contrary to locked‐in patients who showed near‐normal connectivity. In the minimally conscious‐state patient, only the two selection criteria considering both spatial and temporal properties were able to identify an intact right lateralized BOLD connectivity pattern, and metabolic PET data suggested its neuronal origin. Conclusions: When assessing resting‐state connectivity in patients with disorders of consciousness, it is important to use a methodology excluding non‐neuronal contributions caused by head motion, respiration, and heart rate artifacts encountered in all studied patients. Hum Brain Mapp, 2012.

Spasticity after stroke: physiology, assessment and treatment.

Abstract Background: Spasticity following a stroke occurs in about 30% of patients. The mechanisms underlying this disorder, however, are not well understood. Method: This review aims to define spasticity, describe hypotheses explaining its development after a stroke, give an overview of related neuroimaging studies as well as a description of the most common scales used to quantify the degree of spasticity and finally explore which treatments are currently being used to treat this disorder. Results: The lack of consensus is highlighted on the basis of spasticity and the associated absence of guidelines for treatment, use of drugs and rehabilitation programmes. Conclusions: Future studies require controlled protocols to determine the efficiency of pharmacological and non-pharmacological treatments for spasticity. Neuroimaging may help predict the occurrence of spasticity and could provide insight into its neurological basis.