Cortical responses to auditory stimulation predict the prognosis of patients with disorders of consciousness.

OBJECTIVE: This study aimed to assess the prognosis of patients with disorders of consciousness (DoC) using auditory stimulation with electroencephalogram (EEG) recordings. METHODS: We enrolled 72 patients with DoC in the study, which involved subjecting patients to auditory stimulation while EEG responses were recorded. Coma Recovery Scale-Revised (CRS-R) scores and Glasgow Outcome Scale (GOS) were determined for each patient and followed up for three months. A frequency spectrum analysis was performed on the EEG recordings. Finally, the power spectral density (PSD) index was used to predict the prognosis of patients with DoC based on a support vector machine (SVM) model. RESULTS: Power spectral analyses revealed that the cortical response to auditory stimulation showed a decreasing trend with decreasing consciousness levels. Auditory stimulation-induced changes in absolute PSD at the delta and theta bands were positively correlated with the CRS-R and GOS scores. Furthermore, these cortical responses to auditory stimulation had a good ability to discriminate between good and poor prognoses of patients with DoC. CONCLUSIONS: Auditory stimulation-induced changes in the PSD were highly predictive of DoC outcomes. SIGNIFICANCE: Our findings showed that cortical responses to auditory stimulation may be an important electrophysiological indicator of prognosis in patients with DoC.

Auditory steady-state response to chirp-modulated tones: A pilot study in patients with disorders of consciousness.

OBJECTIVE: Due to the problems with behavioral diagnosis of patients with prolonged DOC (disorders of consciousness), complementary approaches based on objective measurement of neural function are necessary. In this pilot study, we assessed the sensitivity of auditory chirp-evoked responses to the state of patients with severe brain injury as measured with CRS-R (Coma Recovery Scale - Revised). METHODS: A convenience sample of fifteen DOC patients was included in the study. Auditory stimuli, chirp-modulated at 1-120 Hz were used to evoke auditory steady-state response (ASSR). Phase-locking index (PLI) estimates within low gamma and high gamma windows were evaluated. RESULTS: The PLI estimates within a narrow low gamma 38-42 Hz window positively correlated with the CRS-R total score and with the scores of the Auditory and Visual Function subscales. In the same low gamma window, significant difference in the PLIs was found between minimally conscious (MCS) and vegetative state (VS) patients. We did not observe any between-group differences nor any significant correlations with CRS-R scores in the high gamma window (80-110 Hz). CONCLUSIONS: Our results support the notion that the activity around 40 Hz may serve as a possible marker of the integrity of thalamocortical networks in prolonged DOC patients. SIGNIFICANCE: Auditory steady-state responses at gamma-band frequencies highlight the role of upper parts of auditory system in evaluation of the level of consciousness in DOC patients.

Animal-assisted therapy for patients in a minimally conscious state: A randomized two treatment multi-period crossover trial.

OBJECTIVE: To investigate if animal-assisted therapy (AAT) leads to higher consciousness in patients in a minimally conscious state during a therapy session, measured via behavioral reactions, heart rate and heart rate variability. METHODS: In a randomized two treatment multi-period crossover trial, 10 patients in a minimally conscious state participated in eight AAT sessions and eight paralleled conventional therapy sessions, leading to 78 AAT and 73 analyzed control sessions. Patients' responses during sessions were assessed via behavioral video coding and the Basler Vegetative State Assessment (BAVESTA), heart rate and heart rate variability (SDNN, RMSSD, HF and LF). Data were analyzed with generalized linear mixed models. RESULTS: Patients showed more eye movements (IRR = 1.31, 95% CI: 1.23 to 1.40, p < 0.001) and active movements per tactile input during AAT compared to control sessions (IRR = 1.13, 95% CI: 1.02 to 1.25, p = 0.018). No difference was found for positive emotions. With BAVESTA, patients' overall behavioral reactions were rated higher during AAT (b = 0.11, 95% CI: 0.01 to 0.22, p = 0.038). AAT led to significantly higher LF (b = 5.82, 95% CI: 0.55 to 11.08, p = 0.031) and lower HF (b = -5.80, 95% CI: -11.06 to -0.57, p = 0.030), while heart rate, SDNN, RMSSD did not differ. CONCLUSIONS: Patients in a minimally conscious state showed more behavioral reactions and increased physiological arousal during AAT compared to control sessions. This might indicate increased consciousness during therapeutic sessions in the presence of an animal. TRIAL REGISTRATION: ClinicalTrials.gov NCT02629302.

Low- and medium-rate auditory steady-state responses in patients with prolonged disorders of consciousness correlate with Coma Recovery Scale - Revised score.

Diagnosis of consciousness in patients with prolonged disorders of consciousness (PDOC) remains challenging since their responsiveness is often very impaired, while their assessment depends on observable behavior. The aim of this proof-of-concept study was to evaluate whether low- and medium-rate amplitude-modulated (AM) auditory steady-state responses (ASSRs) can be sensitive to the state of PDOC patients and may thus serve as a diagnostic tool which does not explicitly depend on a patient's cooperation. EEG was recorded from nine unresponsive wakefulness syndrome/vegetative state (UWS/VS) and eight minimally conscious state (MCS)/emergence from MCS patients during stimulation with two-minute trains of simple tones, amplitude modulated (AM) by 4 Hz, 6 Hz, 8 Hz, 12 Hz, 20 Hz, 40 Hz. The obtained ASSRs were then related to the Coma Recovery Scale - Revised (CRS-R) diagnosis and its total score. We observed significant correlations between mean inter-trial phase coherence (PC) (averaged across all stimulation frequencies) and total CRS-R score, as well as between 40 Hz relative power (RP) and total CRS-R score. Moreover, both parameters significantly differed between the patient groups. Our preliminary results suggest that a passive auditory stimulation protocol consisting of low- and medium-rate ASSRs might be used as an objective estimate of the level of neural dysfunction in PDOC patients. Consequently, the integrity of the auditory system appears to be an important predictor of the actual state of consciousness in PDOC patients.

Spatially Overlapping Regions Show Abnormal Thalamo-frontal Circuit and Abnormal Precuneus in Disorders of Consciousness.

Understanding the neural mechanisms of disorders of consciousness (DOC) is essential for estimating the conscious level and diagnosing DOC patients. Although previous studies reported brain functional connectivity (FC) and spontaneous neural activity patterns associated with consciousness, the relationship between them remains unclear. In this study, we identified the abnormal brain regions in DOC patients by performing voxel-wise FC strength (FCS) and fractional amplitude of low-frequency fluctuations (fALFF) analyses on resting-state functional magnetic resonance imaging data of 15 DOC patients and 24 healthy controls. Furthermore, we detected spatial intersections between two measures and estimated the correlations between either the FCS or the fALFF and the subscales of the Coma Recovery Scale-Revised (CRS-R). We found that the right superior frontal gyrus, left thalamus and right precuneus in which the DOC patients had a lower local FCS and fALFF than healthy controls, are coincident with regions of the mesocircuit model. In the right precuneus, the local FCS/fALFF was significantly positively correlated with the oromotor and motor scores/motor score of the CRS-R. Our findings may indicate that the co-occurrent pattern of spontaneous neural activity and functional connectivity in the thalamo-frontal circuit and the precuneus are associated with motor function in DOC patients.

Event-related potentials in the odd-ball paradigm and behavioral scales for the assessment of children and adolescents with disorders of consciousness: A proof of concept study.

OBJECTIVE: Quantification of signatures of conscious processing in children with disorders of consciousness (DoC) using odd-ball paradigms in multiple modalities. METHOD: We review the diagnostic approaches available in the field, from clinical scales to neuroimaging methods, and concentrate upon measures derived from electroencephalographic event related potentials. RESULTS: Evoked potentials were recorded in five procedures, encompassing visual, auditory and tactile modalities, from ten pediatric DoC patients-six in a minimally conscious state (MCS), three in unresponsive wakefulness syndrome (UWS) and one who emerged from MCS (eMCS)-and the control group of 10 healthy children. In almost all the eMCS and MCS patients, higher amplitude of P300 was observed and the effect was statistically significant in at least one out of the five performed procedures. Additionally, signs of conscious information processing were detected in one UWS patient. CONCLUSION: The presented results provide a proof of concept for the possibility of applying ERP-derived electrophysiological measures as an aid in the assessment of children and adolescents in DoC.

Single unit activities recorded in the thalamus and the overlying parietal cortex of subjects affected by disorders of consciousness.

The lack of direct neurophysiological recordings from the thalamus and the cortex hampers our understanding of vegetative state/unresponsive wakefulness syndrome and minimally conscious state in humans. We obtained microelectrode recordings from the thalami and the homolateral parietal cortex of two vegetative state/unresponsive wakefulness syndrome and one minimally conscious state patients during surgery for implantation of electrodes in both thalami for chronic deep brain stimulation. We found that activity of the thalamo-cortical networks differed among the two conditions. There were half the number of active neurons in the thalami of patients in vegetative state/unresponsive wakefulness syndrome than in minimally conscious state. Coupling of thalamic neuron discharge with EEG phases also differed in the two conditions and thalamo-cortical cross-frequency coupling was limited to the minimally conscious state patient. When consciousness is physiologically or pharmacologically reversibly suspended there is a significant increase in bursting activity of the thalamic neurons. By contrast, in the thalami of our patients in both conditions fewer than 17% of the recorded neurons showed bursting activity. This indicates that these conditions differ from physiological suspension of consciousness and that increased thalamic inhibition is not prominent. Our findings, albeit obtained in a limited number of patients, unveil the neurophysiology of these conditions at single unit resolution and might be relevant for inspiring novel therapeutic options.

Evaluation of induced and evoked changes in EEG during selective attention to verbal stimuli.

BACKGROUND: Two challenges need to be addressed before bringing non-motor mental tasks for brain-computer interface (BCI) control to persons in a minimally conscious state (MCS), who can be behaviorally unresponsive even when proven to be consciously aware: first, keeping the cognitive demands as low as possible so that they could be fulfilled by persons with MCS. Second, increasing the control of experimental protocol (i.e. type and timing of the task performance). NEW METHOD: The goal of this study is twofold: first goal is to develop an experimental paradigm that can facilitate the performance of brain-teasers (e.g. mental subtraction and word generation) on the one hand, and can increase the control of experimental protocol on the other hand. The second goal of this study is to exploit the similar findings for mentally attending to someone else's verbal performance of brain-teaser tasks and self-performing the same tasks to setup an online BCI, and to compare it in healthy participants to the current "state-of-the-art" motor imagery (MI, sports). RESULTS: The response accuracies for the best performing healthy participants indicate that selective attention to verbal performance of mental subtraction (SUB) is a viable alternative to the MI. Time-frequency analysis of the SUB task in one participant with MCS did not reveal any significant (p<0.05) EEG changes, whereas imagined performance of one sport of participants' choice (SPORT) revealed task-related EEG changes over neurophysiological plausible cortical areas. COMPARISON WITH EXISTING METHODS: We found that mentally attending to someone else's verbal performance of brain-teaser tasks leads to similar results as in self-performing the same tasks. CONCLUSIONS: In this work we demonstrated that a single auditory selective attention task (i.e. mentally attending to someone else's verbal performance of mental subtraction) can modulate both induced and evoked changes in EEG, and be used for yes/no communication in an auditory scanning paradigm.

Immediate responses to individual dialogic music therapy in patients in low awareness states.

OBJECTIVE: The aim of this study was to analyse immediate responses to individual dialogic music therapy (IDMT) of patients with unresponsive wakefulness syndrome (UWS) and individuals in a minimally conscious state (MCS) and to develop an assessment tool for IDMT. METHODS: Seven patients were subjected to three conditions: (1) sounds and stimuli of the daily environment immediately before IDMT, (2) specific improvisational music therapy intended to establish a dialogue with the patient (IDMT) and (3) sounds and stimuli of the daily environment immediately after IDMT. Video recordings were analysed by six independent assessors using 'Music Therapy in a Vegetative or Minimally Conscious State (MUVES)', an assessment tool developed in this study. Diagnosis of UWS or MCS was established using the coma recovery scale-revised (CRS-R). RESULTS: During IDMT, MUVES total score was higher than during the other conditions (mean difference = 3.36; p = 0.02). During IDMT, there was no significant difference in MUVES total score between the UWS and MCS sub-groups (p = 0.29). Mean inter-rater-reliability of MUVES total score was 0.76. CONCLUSIONS: IDMT may induce immediate responses in patients in low awareness states, particularly also in patients with UWS. MUVES appears to be an acceptably reliable assessment tool for IDMT.

Information processing in patients in vegetative and minimally conscious states.

OBJECTIVE: Evaluation of a short two-tone oddball paradigm to discriminate between the vegetative state (VS) and minimal consciousness state (MCS) in a sample of patients with severe disorders of consciousness (DOC). METHOD: EEG was recorded from 45 DOC patients and 14 healthy participants while listening to an auditory oddball paradigm presented in a passive - just listen - and an active - count the odd tones - condition. In patients, the experiment was repeated after a minimum of one week. RESULTS: Prevalence of the P300 was higher in healthy participants (71%) than in patients, but did not discriminate between VS (T1: ∼10%; T2: ∼11%) and MCS (T1: ∼13%; T2: 25%) patients. CONCLUSION: Results cast doubt on whether this simple auditory stimulation paradigm, which requires cognitive action from the listener, is sensitive enough to discriminate between patients with DOC. SIGNIFICANCE: The sensitivity of the P300 ERP obtained in a short two-tone oddball paradigm presented in a passive and an active condition appears to be too low for routine application in a clinical setting aiming at distinguishing between VS and MCS patients.

EEG entropy measures indicate decrease of cortical information processing in Disorders of Consciousness.

OBJECTIVE: Clinical assessments that rely on behavioral responses to differentiate Disorders of Consciousness are at times inapt because of some patients' motor disabilities. To objectify patients' conditions of reduced consciousness the present study evaluated the use of electroencephalography to measure residual brain activity. METHODS: We analyzed entropy values of 18 scalp EEG channels of 15 severely brain-damaged patients with clinically diagnosed Minimally-Conscious-State (MCS) or Unresponsive-Wakefulness-Syndrome (UWS) and compared the results to a sample of 24 control subjects. Permutation entropy (PeEn) and symbolic transfer entropy (STEn), reflecting information processes in the EEG, were calculated for all subjects. Participants were tested on a modified active own-name paradigm to identify correlates of active instruction following. RESULTS: PeEn showed reduced local information content in the EEG in patients, that was most pronounced in UWS. STEn analysis revealed altered directed information flow in the EEG of patients, indicating impaired feed-backward connectivity. Responses to auditory stimulation yielded differences in entropy measures, indicating reduced information processing in MCS and UWS. CONCLUSIONS: Local EEG information content and information flow are affected in Disorders of Consciousness. This suggests local cortical information capacity and feedback information transfer as neural correlates of consciousness. SIGNIFICANCE: The utilized EEG entropy analyses were able to relate to patient groups with different Disorders of Consciousness.

Neurophysiological Indicators of Residual Cognitive Capacity in the Minimally Conscious State.

BACKGROUND: The diagnostic usefulness of electrophysiological methods in assessing disorders of consciousness (DoC) remains to be established on an individual patient level, and there is need to determine what constitutes robust experimental paradigm to elicit electrophysiological indices of covert cognitive capacity. OBJECTIVES: Two tasks encompassing active and passive conditions were explored in an event-related potentials (ERP) study. The task robustness was studied in healthy controls, and their utility to detect covert signs of command-following on an individual patient level was investigated in patients in a minimally conscious state (MCS). METHODS: Twenty healthy controls and 20 MCS patients participated. The active tasks included (1) listening for a change of pitch in the subject's own name (SON) and (2) counting SON, both contrasted to passive conditions. Midline ERPs are reported. RESULTS: A larger P3 response was detected in the counting task compared to active listening to pitch change in the healthy controls. On an individual level, the counting task revealed a higher rate of responders among both healthy subjects and MCS patients. CONCLUSION: ERP paradigms involving actively counting SON represent a robust paradigm in probing for volitional cognition in minimally conscious patients and add important diagnostic information in some patients.

Repetitive transcranial magnetic stimulation induced slow wave activity modification: A possible role in disorder of consciousness differential diagnosis?

Slow wave activity (SWA) generation depends on cortico-thalamo-cortical loops that are disrupted in patients with chronic Disorders of Consciousness (DOC), including the Unresponsive Wakefulness Syndrome (UWS) and the Minimally Conscious State (MCS). We hypothesized that the modulation of SWA by means of a repetitive transcranial magnetic stimulation (rTMS) could reveal residual patterns of connectivity, thus supporting the DOC clinical differential diagnosis. We enrolled 10 DOC individuals who underwent a 24hh polysomnography followed by a real or sham 5Hz-rTMS over left primary motor area, and a second polysomnographic recording. A preserved sleep-wake cycle, a standard temporal progression of sleep stages, and a SWA perturbation were found in all of the MCS patients and in none of the UWS individuals, only following the real-rTMS. In conclusion, our combined approach may improve the differential diagnosis between MCS patients, who show a partial preservation of cortical plasticity, and UWS individuals, who lack such properties.

Cerebral response to subject's own name showed high prognostic value in traumatic vegetative state.

BACKGROUND: Previous studies have shown the prognostic value of stimulation elicited blood-oxygen-level-dependent (BOLD) signal in traumatic patients in vegetative state/unresponsive wakefulness syndrome (VS/UWS). However, to the best of our knowledge, no studies have focused on the relevance of etiology and level of consciousness in patients with disorders of consciousness (DOC) when explaining the relationship between BOLD signal and both outcome and signal variability. We herein propose a study in a large sample of traumatic and non-traumatic DOC patients in order to ascertain the relevance of etiology and level of consciousness in the variability and prognostic value of a stimulation-elicited BOLD signal. METHODS: 66 patients were included, and the response of each subject to his/her own name said by a familiar voice (SON-FV) was recorded using fMRI; 13 patients were scanned twice in the same day, respecting the exact same conditions in both cases. A behavioral follow-up program was carried out at 3, 6, and 12 months after scanning. RESULTS: Of the 39 VS/UWS patients, 12 (75%) out of 16 patients with higher level activation patterns recovered to minimally conscious state (MCS) or emergence from MCS (EMCS) and 17 (74%) out of 23 patients with lower level activation patterns or no activation had a negative outcome. Taking etiology into account for VS/UWS patients, a higher positive predictive value was assigned to traumatic patients, i.e., up to 92% (12/13) patients with higher level activation pattern achieved good recovery whereas 11 out of 13 (85%) non-traumatic patients with lower level activation or without activation had a negative clinical outcome. The reported data from visual analysis of fMRI activation patterns were corroborated using ROC curve analysis, which supported the correlation between auditory cortex activation volume and VS/UWS patients' recovery. The average brain activity overlap in primary and secondary auditory cortices in patients scanned twice was 52%. CONCLUSIONS: The activation type and volume in auditory cortex elicited by SON-FV significantly correlated with VS/UWS patients' prognosis, particularly in patients with traumatic etiology, however, this could not be established in MCS patients. Repeated use of this simple fMRI task might help obtain more reliable prognostic information.

Thalamic and extrathalamic mechanisms of consciousness after severe brain injury.

OBJECTIVE: What mechanisms underlie the loss and recovery of consciousness after severe brain injury? We sought to establish, in the largest cohort of patients with disorders of consciousness (DOC) to date, the link between gold standard clinical measures of awareness and wakefulness, and specific patterns of local brain pathology-thereby possibly providing a mechanistic framework for patient diagnosis, prognosis, and treatment development. METHODS: Structural T1-weighted magnetic resonance images were collected, in a continuous sample of 143 severely brain-injured patients with DOC (and 96 volunteers), across 2 tertiary expert centers. Brain atrophy in subcortical regions (bilateral thalamus, basal ganglia, hippocampus, basal forebrain, and brainstem) was assessed across (1) healthy volunteers and patients, (2) clinical entities (eg, vegetative state, minimally conscious state), (3) clinical measures of consciousness (Coma Recovery Scale-Revised), and (4) injury etiology. RESULTS: Compared to volunteers, patients exhibited significant atrophy across all structures (p < 0.05, corrected). Strikingly, we found almost no significant differences across clinical entities. Nonetheless, the clinical measures of awareness and wakefulness upon which differential diagnosis rely were systematically associated with tissue atrophy within thalamic and basal ganglia nuclei, respectively; the basal forebrain was atrophied in proportion to patients' response to sensory stimulation. In addition, nontraumatic injuries exhibited more extensive thalamic atrophy. INTERPRETATION: These findings provide, for the first time, a grounding in pathology for gold standard behavior-based clinical measures of consciousness, and reframe our current models of DOC by stressing the different links tying thalamic mechanisms to willful behavior and extrathalamic mechanisms to behavioral (and electrocortical) arousal.

Shaping thalamo-cortical plasticity: a marker of cortical pain integration in patients with post-anoxic unresponsive wakefulness syndrome?

BACKGROUND: The distinctive feature of unresponsive wakefulness syndrome (UWS) is the dissociation between arousal and awareness. Cortico-cortical and thalamo-cortical connectivity and plasticity play a key role in consciousness. UWS patients do not usually show any "cortical" behavioral sign in response to painful stimulation. Nevertheless a "focal conscious" pain perception has been hypothesized. HYPOTHESIS: Since defective plasticity and connectivity within pain matrix could be striking mechanisms of non-conscious pain perception and, consequently, of non-cortical responses in UWS subjects, aim of our study was to investigate pain-motor plasticity in such patients through a specific paired laser associative stimulation protocol (L-PAS). METHODS: We enrolled 10 post-anoxic subjects and 10 healthy controls evaluating clinical and electrophysiological parameters before and after the application of such protocol. RESULTS: Some patient showed a restored pain-motor integration with a partial motor cortex excitability modification. CONCLUSIONS: Although we studied a small cohort of post-anoxic UWS patients and the results obtained were short-lasting, L-PAS seems a feasible and suitable technique in order to induce plastic change within pain matrix in some UWS patients, allowing the production of "cortical" responses to painful stimuli, which are signs of at least partially ("focal") preserved consciousness. Cortico-thalamic plasticity could have also an important role in the emergence of pain perception as compared to other sensory modalities.

Thalamo-frontal connectivity mediates top-down cognitive functions in disorders of consciousness.

OBJECTIVE: We employed functional MRI (fMRI) to assess whether (1) patients with disorders of consciousness (DOC) retain the ability to willfully engage in top-down processing and (2) what neurophysiologic factors distinguish patients who can demonstrate this ability from patients who cannot. METHODS: Sixteen volunteers, 8 patients in vegetative state (VS), 16 minimally conscious patients (MCS), and 4 exit from MCS (eMCS) patients were enrolled in a prospective cross-sectional fMRI study. Participants performed a target detection task in which they counted the number of times a (changing) target word was presented amidst a set of distractors. RESULTS: Three of 8 patients diagnosed as being in a VS exhibited significant activations in response to the task, thereby demonstrating a state of consciousness. Differential activations across tasks were also observed in 6 MCS patients and 1 eMCS patient. A psycho-physiologic interaction analysis revealed that the main factor distinguishing patients who responded to the task from those who did not was a greater connectivity between the anterior section of thalamus and prefrontal cortex. CONCLUSIONS: In our sample of patients, the dissociation between overt behavior observable in clinical assessments and residual cognitive faculties is prevalent among DOC patients (37%). A substantial number of patients, including some diagnosed with VS, can demonstrate willful engagement in top-down cognition. While neuroimaging data are not the same as observable behavior, this suggests that the mental status of some VS patients exceeds what can be appreciated clinically. Furthermore, thalamo-frontal circuits might be crucial to sustaining top-down functions.

P300 latency Jitter occurrence in patients with disorders of consciousness: Toward a better design for Brain Computer Interface applications.

In this study the P300 latency jitter has been explored in an EEG data set collected from a group of patients with disorders of consciousness (DOC; n=13) that was administered with an auditory Oddball paradigm under passive and active conditions. A method based on wavelet transform was applied to estimate single trial P300 waveforms. Preliminary results showed that 5 Vegetative State (VS) and 8 Minimally Conscious Staten (MCS) patients exhibited significantly higher values of P300 latency jitter as compared to those obtained from a control group of 12 healthy subjects. In addition, the magnitude of the P300 latency jitter negatively correlated with patients' clinical status. The existence of such phenomenon might substantially limit an effective use of Brain Computer Interface systems for communication.