Background Given its emotional and autobiographical properties, music appears as a potential aid in diagnostic assessment and therapeutics in patients with disorders of consciousness (DOC). Several studies have shown boosting effects on behavior and brain functioning when patients were exposed to (their preferred) music. Objective To investigate if these effects on the brain’s spontaneous activity are dependent on the level of consciousness. Methods Nine post-comatose patients and eight healthy control subjects were assessed using fMRI 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 emotions 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 to rest. Voxel-to-voxel analyses showed stronger increases of intrinsic connectivity in the music condition compared to rest in regions previously related to music processing. There were consistently more regions with increased connectivity during the main effect of music compared to 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 to rest, pointing towards 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.

Background. Transcranial direct current stimulation (tDCS) over the left dorsolateral prefrontal cortex (lDLPFC) was reported to promote the recovery of signs of consciousness in some patients in a minimally conscious state (MCS), but its electrophysiological effects on brain activity remain poorly understood. Objective. We aimed to assess behavioral (using the Coma Recovery Scale—Revised; CRS-R) and neurophysiological effects (using high density electroencephalography; hdEEG) of lDLPFC-tDCS in patients with prolonged disorders of consciousness (DOC). Methods. In a double-blind, sham-controlled, crossover design, one active and one sham tDCS (2 mA, 20 min) were delivered in a randomized order. Directly before and after tDCS, 10 min of hdEEG were recorded and the CRS-R was administered. Results. Thirteen patients with severe brain injury were enrolled in the study. We found higher relative power at the group level after the active tDCS session in the alpha band in central regions and in the theta band over the frontal and posterior regions (uncorrected results). Higher weighted symbolic mutual information (wSMI) connectivity was found between left and right parietal regions, and higher fronto-parietal weighted phase lag index (wPLI) connectivity was found, both in the alpha band (uncorrected results). At the group level, no significant treatment effect was observed. Three patients showed behavioral improvement after the active session and one patient improved after the sham. Conclusion. We provide preliminary indications that neurophysiological changes can be observed after a single session of tDCS in patients with prolonged DOC, although they are not necessarily paralleled with significant behavioral improvements.

Motivation: Heart rate variability (HRV) reflects the heart-brain two-way dynamic interactions[1-5]. HRV entropy analysis quantifies the unpredictability and complexity of the heart rate beats intervals and over multiple time scales using multiscale entropy (MSE)[6-8]. The complexity index (CI) provides a score of a system’s complexity by aggregating the MSE measures over a range of time scales[8]. Most HRV entropy studies have focused on acute traumatic patients using task-based designs[9]. We here investigate the CI and its discriminative power in chronic patients with unresponsive wakefulness syndrome (UWS) and minimally conscious state (MCS) at rest, and its relation to brain functional connectivity. Methods: We investigated the CI in short (CIs) and long (CIl) time scales in 16 UWS and 17 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 12 UWS and 12 MCS patients with sufficient image quality. Results and Discussion: Significant differences were found between MCS and UWS for CIs and CIl (0.0001≤p≤0.006). Significant correlations were found between CRS-R and CIs and CIl (0.0001≤p≤0.026). The One-R classifier selected CIl as the best discriminator between UWS and MCS with 85% accuracy, 19% false positive rate and 12% false negative rate after a 10-fold cross-validation test. Positive correlations were observed between CI and brain areas belonging to the autonomic system. CI was found to be significantly higher in MCS compared to UWS patients, with high discriminative power and lower false negative rate than the reported misdiagnosis rate of human assessors, providing an easy, inexpensive and non-invasive diagnosis tool. CI is correlated to functional connectivity changes in brain regions belonging to the autonomic nervous system, suggesting that CI can provide an indirect way to screen and monitor connectivity changes in this neural system. Future studies should investigate further the extent of CI’s predictive power for other pathologies in the disorders of consciousness spectrum.

Introduction Currently, therapeutic options for severely brain-injured patients with disorders of consciousness (DOC), including patients in unresponsive wakefulness syndrome (UWS) and minimally conscious state (MCS), are limited and still need to be improved to influence long-term outcomes. Non-invasive brain stimulations (NIBS) techniques have recently shown promising results in DOC (1). Notably, transcranial direct current stimulation (tDCS) applied over the left dorsolateral prefrontal cortex has proved to be effective in improving signs of consciousness in 43% of patients in MCS either after a single stimulation (2) or after repeated sessions (3,4). However, brain mechanisms underlying tDCS effects remain poorly understood. In the present protocol, we aimed to assess the effects of prefrontal tDCS on neurophysiological (i.e., electroencephalography – EEG – primary outcome) and behavioral (secondary outcome) measures in severely brain-injured patients with DOC. Methods In a double-blind sham-controlled design, one anodal and one sham tDCS were delivered in a randomized order in 3 chronic (>28 days post-onset) severely brain-damaged patients (1 UWS, 1 MCS and 1 Locked-in-syndrome). The stimulation had an intensity of 2 mA and lasted 20 minutes. The anode was placed on the left dorsolateral prefrontal cortex and the cathode on the right supraorbital region. Patients were eligible for the study if they suffered from a traumatic or non-traumatic accident that occurred between 3 months and 1 year before the inclusion; and if they had been assessed with the CRS-R at least twice in the 2 weeks preceding the first session and diagnosed as UWS, MCS, emergence from MCS or LIS, with at least 1 subscale on which there was no sign of consciousness. Patients were excluded if there was any evidence of uncontrolled seizure, implanted electronic brain medical device or pacemaker, or history of recent craniotomy or cranioplasty in the frontal region. Ten minutes of high-density EEG (hd-EEG) were recorded using a 256-channel saline electrode net (Electrical Geodesics) directly before and after each tDCS session. Behavioral assessments were performed using the Coma Recovery Scale-Revised (CRS-R – 5) before and after each session by an investigator blinded to the treatment allocation. EEG data were first filtered from 1 Hz to 30 Hz and were further divided into 2-sec epochs. Eye blinks and muscle artifacts were removed using visual inspection and independent component analysis. Then, bad channels were interpolated by spherical interpolation and signals were re-referenced to the common average of all electrodes. Z-score normalization was further applied on each electrode. Multitapers method (6) was used to calculate power spectral density of each electrode and power analysis was performed for standard frequency bands of delta (0-4 Hz), theta (4-8 Hz), alpha (8-12 Hz), and beta (12-25 Hz). Non-parametric corrected two-tailed cluster permutation test (7) was performed to compare the significant difference of the power topographic maps before and after tDCS as compared to the sham ((post_tdcs – pre_tdcs) – (post_sham - pre_sham)). Electrode clusters with p-value less than 0.01 were considered as significant power changes. Given the small number of patients included so far, descriptive analyses were used for the behavioural data. Results and discussion The UWS patient showed significant power decrease in theta, alpha and beta bands and no significant change in the delta band after the active tDCS as compared to sham. For the MCS patient, a significant increase of power in the theta band and decrease of power in delta band were found after the active stimulation compared to sham. Finally, we found a significant global increase of power in alpha and beta bands for the LIS patient after tDCS as compared to the sham. This power increase was more dominant in frontal and parietal electrodes (see Figure 1). On the other hand, no global effect was observed in the theta and delta bands. Behaviorally, none of the 3 patients presented improvement of signs of consciousness as measured with the CRS-R after the active session, nor after the sham session. CRS-R sub-scores for each patient are shown in Table 1. The fact that the UWS patient did not show any new sign of consciousness after the tDCS is consistent with previous studies in which no treatment effect was observed in UWS patients (1). This absence of behavioral changes was supported by an absence of increase in any of the bandwidths as shown by the EEG results. The absence of behavioral improvement for the MCS patient is concordant with the EEG results which do not show significant power increase after tDCS in alpha and beta bands, as what is usually observed in healthy subjects following tDCS (8, 9, 10). However, an increase in theta power was found. Therefore, it could be speculated that an increase in theta is not sufficient to induce behavioral improvements and an effect on alpha and/or beta could be necessary to induce such clinical changes. On the other hand, it could also be hypothesized that one session, for this patient, was not sufficient to induce clinical enhancement and more sessions are required as it has been previously shown in DOC but also in other pathologies (4, 11, 12, 13). If this is confirmed, the change in theta could be a marker of further EEG and behavioral improvement after repetitive tDCS. For the LIS patient, the lack of behavioral improvement, together with an increase in alpha and beta power, could be explained by a ceiling effect on the CRS-R (except for the motor and oro-motor subscales that remained very low due to paralysis), therefore limiting the possibility to observe an improvement after treatment. However, tDCS might have led to attentional or arousal changes that could not be detected with the CRS-R. Henceforth, more sensitive scales should be employed with LIS or patients who have...