An Echo of Consciousness: Brain Function During Preferred Music.

Background: Given its emotional and autobiographical properties, music appears as a potential aid in diagnostic assessment and therapeutics in patients with disorders of consciousness (DOCs). Several studies have shown boosting effects on behavior and brain functioning when patients were exposed to (their preferred) music. Objective: The aim of this study was to investigate if these effects on the brain's spontaneous activity are dependent on the level of consciousness. Methods: Nine postcomatose patients and eight healthy control subjects were assessed using functional magnetic resonance imaging in two conditions: rest (without stimulation) and music. All patients presented at least an auditory startle, thereby suggesting the presence of residual auditory function. A gradient of consciousness (from unresponsive wakefulness syndrome to healthy subjects) was formulated to evaluate consciousness-level-dependent increases in brain activity and connectivity. Network-based functional connectivity assessed auditory, default-mode, frontoparietal, and music-evoked emotion networks. Furthermore, exploratory voxel-to-voxel analyses were performed at the whole brain level using intrinsic connectivity contrast and (fractional) amplitude of low-frequency fluctuations. Results: Stronger consciousness-level-dependent increases within network-to-voxel analysis of connectivity were found in the frontoparietal network with the precuneus during music stimulation compared with rest. Voxel-to-voxel analyses showed stronger increases of intrinsic connectivity in the music condition compared with rest in regions previously related to music processing. There were consistently more regions with increased connectivity during the main effect of music compared with rest. These increases of connectivity during music were observed in brain regions involved in consciousness, language, emotion, and memory processing. Conclusions: Our results show that music seems to trigger more substantial connectivity changes compared with rest, pointing toward the potential ability of music to stimulate patients' brain function. Further research should focus on effects of music in general, its specific acoustical features, and the effects of simple auditory stimuli, as well as the possible therapeutic and diagnostic effects of music in well-controlled clinical trials. Impact statement Due to its emotional and autobiographical properties, music is a particularly salient stimulus. A few studies using musical stimuli have shown promising results in terms of behavioral responsiveness in patients with disorders of consciousness (Magee, 2005; Raglio et al., 2014; Verger et al., 2014). Our study confirms the presence of a beneficial effect of music on brain connectivity in these severely brain-injured patients, which moreover seems to be dependent on the level of consciousness. Our findings therefore strengthen the hypothesis that music could play a role from a diagnostic and therapeutic standpoint in this population, paving the way for future well-controlled clinical trials.

Brain Metabolism but Not Gray Matter Volume Underlies the Presence of Language Function in the Minimally Conscious State (MCS): MCS+ Versus MCS- Neuroimaging Differences.

Background. The minimally conscious state (MCS) is subcategorized into MCS- and MCS+, depending on the absence or presence, respectively, of high-level behavioral responses such as command-following. Objective. We aim to investigate the functional and structural neuroanatomy underlying the presence of these responses in MCS- and MCS+ patients. Methods. In this cross-sectional retrospective study, chronic MCS patients were diagnosed using repeated Coma Recovery Scale-Revised assessments. Fluorodeoxyglucose-positron emission tomography data were acquired on 57 patients (16 MCS-; 41 MCS+) and magnetic resonance imaging with voxel-based morphometry analysis was performed on 66 patients (17 MCS-; 49 MCS+). Brain glucose metabolism and gray matter integrity were compared between patient groups and control groups. A metabolic functional connectivity analysis testing the hypothesis of preserved language network in MCS+ compared with MCS- was also done. Results. Patients in MCS+ presented higher metabolism mainly in the left middle temporal cortex, known to be important for semantic processing, compared with the MCS- group. The left angular gyrus was also functionally disconnected from the left prefrontal cortex in MCS- compared with MCS+ group. No significant differences were found in gray matter volume between patient groups. Conclusions. The clinical subcategorization of MCS is supported by differences in brain metabolism but not in gray matter structure, suggesting that brain function in the language network is the main support for recovery of command-following, intelligible verbalization and/or intentional communication in the MCS. Better characterizing the neural correlates of residual cognitive abilities of MCS patients contributes to reduce their misdiagnosis and to adapt therapeutic approaches.

General Anesthesia: A Probe to Explore Consciousness.

General anesthesia reversibly alters consciousness, without shutting down the brain globally. Depending on the anesthetic agent and dose, it may produce different consciousness states including a complete absence of subjective experience (unconsciousness), a conscious experience without perception of the environment (disconnected consciousness, like during dreaming), or episodes of oriented consciousness with awareness of the environment (connected consciousness). Each consciousness state may potentially be followed by explicit or implicit memories after the procedure. In this respect, anesthesia can be considered as a proxy to explore consciousness. During the recent years, progress in the exploration of brain function has allowed a better understanding of the neural correlates of consciousness, and of their alterations during anesthesia. Several changes in functional and effective between-region brain connectivity, consciousness network topology, and spatio-temporal dynamics of between-region interactions have been evidenced during anesthesia. Despite a set of effects that are common to many anesthetic agents, it is still uneasy to draw a comprehensive picture of the precise cascades during general anesthesia. Several questions remain unsolved, including the exact identification of the neural substrate of consciousness and its components, the detection of specific consciousness states in unresponsive patients and their associated memory processes, the processing of sensory information during anesthesia, the pharmacodynamic interactions between anesthetic agents, the direction-dependent hysteresis phenomenon during the transitions between consciousness states, the mechanisms of cognitive alterations that follow an anesthetic procedure, the identification of an eventual unitary mechanism of anesthesia-induced alteration of consciousness, the relationship between network effects and the biochemical or sleep-wake cycle targets of anesthetic agents, as well as the vast between-studies variations in dose and administration mode, leading to difficulties in between-studies comparisons. In this narrative review, we draw the picture of the current state of knowledge in anesthesia-induced unconsciousness, from insights gathered on propofol, halogenated vapors, ketamine, dexmedetomidine, benzodiazepines and xenon. We also describe how anesthesia can help understanding consciousness, we develop the above-mentioned unresolved questions, and propose tracks for future research.

Resting-state functional connectivity and cortical thickness characterization of a patient with Charles Bonnet syndrome.

Charles Bonnet syndrome (CBS) is a rare condition characterized by visual impairment associated with complex visual hallucinations in elderly people. Although studies suggested that visual hallucinations may be caused by brain damage in the visual system in CBS patients, alterations in specific brain regions in the occipital cortex have not been studied. Functional connectivity during resting-state functional magnetic resonance imaging (rs-fMRI; without hallucinations) in CBS patients, has never been explored. We aimed to investigate brain structural and functional changes in a patient with CBS, as compared with late blind (LB) and normally sighted subjects. We employed voxel-based morphometry and cortical thickness analyses to investigate alterations in grey matter characteristics, and rs-fMRI to study changes in functional brain connectivity. Decreased grey matter volume was observed in the middle occipital gyrus and in the cuneus in the CBS patient, and in the middle occipital gyrus and in the lingual gyrus within LB subjects, compared to their respective control groups. Reductions in cortical thickness in associative and multimodal cortices were observed in the CBS patient when comparing with LB subjects. The precuneus exhibited increased functional connectivity with the secondary visual cortex in the CBS patient compared to the controls. In contrast, LB patients showed decreased functional connectivity compared to sighted controls between the DMN and the temporo-occipital fusiform gyrus, a region known to support hallucinations. Our findings suggest a reorganization of the functional connectivity between regions involved in self-awareness and in visual and salience processing in CBS that may contribute to the appearance of visual hallucinations.

Measures of CNS-Autonomic Interaction and Responsiveness in Disorder of Consciousness.

Neuroimaging studies have demonstrated functional interactions between autonomic (ANS) and brain (CNS) structures involved in higher brain functions, including attention and conscious processes. These interactions have been described by the Central Autonomic Network (CAN), a concept model based on the brain-heart two-way integrated interaction. Heart rate variability (HRV) measures proved reliable as non-invasive descriptors of the ANS-CNS function setup and are thought to reflect higher brain functions. Autonomic function, ANS-mediated responsiveness and the ANS-CNS interaction qualify as possible independent indicators for clinical functional assessment and prognosis in Disorders of Consciousness (DoC). HRV has proved helpful to investigate residual responsiveness in DoC and predict clinical recovery. Variability due to internal (e.g., homeostatic and circadian processes) and environmental factors remains a key independent variable and systematic research with this regard is warranted. The interest in bidirectional ANS-CNS interactions in a variety of physiopathological conditions is growing, however, these interactions have not been extensively investigated in DoC. In this brief review we illustrate the potentiality of brain-heart investigation by means of HRV analysis in assessing patients with DoC. The authors' opinion is that this easy, inexpensive and non-invasive approach may provide useful information in the clinical assessment of this challenging patient population.

Changes in Whole Brain Dynamics and Connectivity Patterns during Sevoflurane- and Propofol-induced Unconsciousness Identified by Functional Magnetic Resonance Imaging.

BACKGROUND: A key feature of the human brain is its capability to adapt flexibly to changing external stimuli. This capability can be eliminated by general anesthesia, a state characterized by unresponsiveness, amnesia, and (most likely) unconsciousness. Previous studies demonstrated decreased connectivity within the thalamus, frontoparietal, and default mode networks during general anesthesia. We hypothesized that these alterations within specific brain networks lead to a change of communication between networks and their temporal dynamics. METHODS: We conducted a pooled spatial independent component analysis of resting-state functional magnetic resonance imaging data obtained from 16 volunteers during propofol and 14 volunteers during sevoflurane general anesthesia that have been previously published. Similar to previous studies, mean z-scores of the resulting spatial maps served as a measure of the activity within a network. Additionally, correlations of associated time courses served as a measure of the connectivity between networks. To analyze the temporal dynamics of between-network connectivity, we computed the correlation matrices during sliding windows of 1 min and applied k-means clustering to the matrices during both general anesthesia and wakefulness. RESULTS: Within-network activity was decreased in the default mode, attentional, and salience networks during general anesthesia (P < 0.001, range of median changes: -0.34, -0.13). Average between-network connectivity was reduced during general anesthesia (P < 0.001, median change: -0.031). Distinct between-network connectivity patterns for both wakefulness and general anesthesia were observed irrespective of the anesthetic agent (P < 0.001), and there were fewer transitions in between-network connectivity patterns during general anesthesia (P < 0.001, median number of transitions during wakefulness: 4 and during general anesthesia: 0). CONCLUSIONS: These results suggest that (1) higher-order brain regions play a crucial role in the generation of specific between-network connectivity patterns and their dynamics, and (2) the capability to interact with external stimuli is represented by complex between-network connectivity patterns.

Reappearance of Command-Following Is Associated With the Recovery of Language and Internal-Awareness Networks: A Longitudinal Multiple-Case Report.

The recovery of patients with disorders of consciousness is a real challenge, especially at the chronic stage. After a severe brain injury, patients can regain some slight signs of consciousness, while not being able to functionally communicate. This entity is called the minimally conscious state (MCS), which has been divided into MCS- and MCS+, respectively based on the absence or presence of language-related signs of consciousness. In this series of cases we aimed to describe retrospectively the longitudinal recovery of specific language-related behaviors using neuroimaging measurement in severely brain-injured patients. Among 209 chronic MCS patients admitted to our center from 2008 to 2018, 19 were assessed at two time points by means of behavioral and neuroimaging assessments. Three of them met our inclusion criteria and were diagnosed as MCS- during their first stay and had recovered command-following when they were reassessed (i.e., MCS+). As compared to their first assessments, when the three patients were in a MCS+, they showed less hypometabolism and/or higher gray matter volume in brain regions such as the precuneus and thalamus, as well as the left caudate and temporal/angular cortices known to be involved in various aspects of semantics. According to these preliminary results, the reappearance of language-related behaviors was concomitant with the recovery of metabolism and gray matter in neural regions that have been associated with self-consciousness and language processing. Prospective studies should be conducted to deepen our understanding of the neural correlates of the recovery of language-related behaviors in chronic MCS.

A Heartbeat Away From Consciousness: Heart Rate Variability Entropy Can Discriminate Disorders of Consciousness and Is Correlated With Resting-State fMRI Brain Connectivity of the Central Autonomic Network.

Background: Disorders of consciousness are challenging to diagnose, with inconsistent behavioral responses, motor and cognitive disabilities, leading to approximately 40% misdiagnoses. Heart rate variability (HRV) reflects the complexity of the heart-brain two-way dynamic interactions. HRV entropy analysis quantifies the unpredictability and complexity of the heart rate beats intervals. We here investigate the complexity index (CI), a score of HRV complexity by aggregating the non-linear multi-scale entropies over a range of time scales, and its discriminative power in chronic patients with unresponsive wakefulness syndrome (UWS) and minimally conscious state (MCS), and its relation to brain functional connectivity. Methods: We investigated the CI in short (CIs) and long (CIl) time scales in 14 UWS and 16 MCS sedated. CI for MCS and UWS groups were compared using a Mann-Whitney exact test. Spearman's correlation tests were conducted between the Coma Recovery Scale-revised (CRS-R) and both CI. Discriminative power of both CI was assessed with One-R machine learning model. Correlation between CI and brain connectivity (detected with functional magnetic resonance imagery using seed-based and hypothesis-free intrinsic connectivity) was investigated using a linear regression in a subgroup of 10 UWS and 11 MCS patients with sufficient image quality. Results: Higher CIs and CIl values were observed in MCS compared to UWS. Positive correlations were found between CRS-R and both CI. The One-R classifier selected CIl as the best discriminator between UWS and MCS with 90% accuracy, 7% false positive and 13% false negative rates after a 10-fold cross-validation test. Positive correlations were observed between both CI and the recovery of functional connectivity of brain areas belonging to the central autonomic networks (CAN). Conclusion: CI of MCS compared to UWS patients has high discriminative power and low false negative rate at one third of the estimated human assessors' misdiagnosis, providing an easy, inexpensive and non-invasive diagnostic tool. CI reflects functional connectivity changes in the CAN, suggesting that CI can provide an indirect way to screen and monitor connectivity changes in this neural system. Future studies should assess the extent of CI's predictive power in a larger cohort of patients and prognostic power in acute patients.

Clinical subcategorization of minimally conscious state according to resting functional connectivity.

Patients in minimally conscious state (MCS) have been subcategorized in MCS plus and MCS minus, based on command-following, intelligible verbalization or intentional communication. We here aimed to better characterize the functional neuroanatomy of MCS based on this clinical subcategorization by means of resting state functional magnetic resonance imaging (fMRI). Resting state fMRI was acquired in 292 MCS patients and a seed-based analysis was conducted on a convenience sample of 10 MCS plus patients, 9 MCS minus patients and 35 healthy subjects. We investigated the left and right frontoparietal networks (FPN), auditory network, default mode network (DMN), thalamocortical connectivity and DMN between-network anticorrelations. We also employed an analysis based on regions of interest (ROI) to examine interhemispheric connectivity and investigated intergroup differences in gray/white matter volume by means of voxel-based morphometry. We found a higher connectivity in MCS plus as compared to MCS minus in the left FPN, specifically between the left dorso-lateral prefrontal cortex and left temporo-occipital fusiform cortex. No differences between patient groups were observed in the auditory network, right FPN, DMN, thalamocortical and interhemispheric connectivity, between-network anticorrelations and gray/white matter volume. Our preliminary group-level results suggest that the clinical subcategorization of MCS may involve functional connectivity differences in a language-related executive control network. MCS plus and minus patients are seemingly not differentiated by networks associated to auditory processing, perception of surroundings and internal awareness/self-mentation, nor by interhemispheric integration and structural brain damage.

Is oral feeding compatible with an unresponsive wakefulness syndrome?

OBJECTIVE: The aim of the study is to explore the possibility of oral feeding in unresponsive wakefulness syndrome/vegetative state (UWS/VS) patients. METHOD: We reviewed the clinical information of 68 UWS/VS patients (mean age 45 ± 11; range 16-79 years) searching for mention of oral feeding. UWS/VS diagnosis was made after repeated behavioural assessments using the Coma Recovery Scale-Revised. Patients also had complementary neuroimaging evaluations (positron emission tomography, functional magnetic resonance imaging and electroencephalography and diffusion tensor imaging). RESULTS: Out of the 68 UWS/VS patients, only two could resume oral feeding (3%). The first patient had oral feeding (only liquid and semi liquid) in addition to gastrostomy feeding and the second one could achieve full oral feeding (liquid and mixed solid food). Clinical assessments concluded that they fulfilled the criteria for a diagnosis of UWS/VS. Results from neuroimaging and neurophysiology were typical for the first patient with regard to the diagnosis of UWS/VS but atypical for the second patient. CONCLUSION: Oral feeding that implies a full and complex oral phase could probably be considered as a sign of consciousness. However, we actually do not know which components are necessary to consider the swallowing conscious as compared to reflex. We also discussed the importance of swallowing assessment and management in all patients with altered state of consciousness.

Multifaceted brain networks reconfiguration in disorders of consciousness uncovered by co-activation patterns.

INTRODUCTION: Given that recent research has shown that functional connectivity is not a static phenomenon, we aim to investigate the dynamic properties of the default mode network's (DMN) connectivity in patients with disorders of consciousness. METHODS: Resting-state fMRI volumes of a convenience sample of 17 patients in unresponsive wakefulness syndrome (UWS) and controls were reduced to a spatiotemporal point process by selecting critical time points in the posterior cingulate cortex (PCC). Spatial clustering was performed on the extracted PCC time frames to obtain 8 different co-activation patterns (CAPs). We investigated spatial connectivity patterns positively and negatively correlated with PCC using both CAPs and standard stationary method. We calculated CAPs occurrences and the total number of frames. RESULTS: Compared to controls, patients showed (i) decreased within-network positive correlations and between-network negative correlations, (ii) emergence of "pathological" within-network negative correlations and between-network positive correlations (better defined with CAPs), and (iii) "pathological" increases in within-network positive correlations and between-network negative correlations (only detectable using CAPs). Patients showed decreased occurrence of DMN-like CAPs (1-2) compared to controls. No between-group differences were observed in the total number of frames CONCLUSION: CAPs reveal at a more fine-grained level the multifaceted spatial connectivity reconfiguration following the DMN disruption in UWS patients, which is more complex than previously thought and suggests alternative anatomical substrates for consciousness. BOLD fluctuations do not seem to differ between patients and controls, suggesting that BOLD response represents an intrinsic feature of the signal, and therefore that spatial configuration is more important for consciousness than BOLD activation itself. Hum Brain Mapp 39:89-103, 2018. © 2017 Wiley Periodicals, Inc.