Wakefulness Syndrome Patients Research Articles

Conscious processing of global and local auditory irregularities causes differentiated heartbeat-evoked responses.

Recent research suggests that brain-heart interactions are associated with perceptual and self-consciousness. In this line, the neural responses to visceral inputs have been hypothesized to play a leading role in shaping our subjective experience. This study aims to investigate whether the contextual processing of auditory irregularities modulates both direct neuronal responses to the auditory stimuli (ERPs) and the neural responses to heartbeats, as measured with heartbeat-evoked responses (HERs). HERs were computed in patients with disorders of consciousness, diagnosed with a minimally conscious state or unresponsive wakefulness syndrome. We tested whether HERs reflect conscious auditory perception, which can potentially provide additional information for the consciousness diagnosis. EEG recordings were taken during the local-global paradigm, which evaluates the capacity of a patient to detect the appearance of auditory irregularities at local (short-term) and global (long-term) levels. The results show that local and global effects produce distinct ERPs and HERs, which can help distinguish between the minimally conscious state and unresponsive wakefulness syndrome patients. Furthermore, we found that ERP and HER responses were not correlated suggesting that independent neuronal mechanisms are behind them. These findings suggest that HER modulations in response to auditory irregularities, especially local irregularities, may be used as a novel neural marker of consciousness and may aid in the bedside diagnosis of disorders of consciousness with a more cost-effective option than neuroimaging methods.

Detecting passive and active response in patients with behaviourally diagnosed unresponsive wakefulness syndrome

The diagnosis of unresponsive wakefulness syndrome depends mostly on the motor response following verbal commands. However, there is a potential for misdiagnosis in patients who understand verbal commands (passive response) but cannot perform voluntary movements (active response). To evaluate passive and active responses in such patients, this study used an approach combining functional magnetic resonance imaging and passive listening tasks to evaluate the level of speech comprehension, with portable brain–computer interface modalities that were applied to elicit an active response to attentional modulation tasks at the bedside. We included ten patients who were clinically diagnosed as unresponsive wakefulness syndrome. Two of ten patients showed no significant activation, while limited activation in the auditory cortex was found in six patients. The remaining two patients showed significant activation in language areas, and were able to control the brain–computer interface with reliable accuracy. Using a combined passive/active approach, we identified unresponsive wakefulness syndrome patients who showed both active and passive neural responses. This suggests that some patients with unresponsive wakefulness syndrome diagnosed behaviourally are both wakeful and responsive, and the combined approach is useful for distinguishing a minimally conscious state from unresponsive wakefulness syndrome physiologically.

Altered functional connectivity and regional brain activity in a triple-network model in minimally conscious state and vegetative-state/unresponsive wakefulness syndrome patients: A resting-state functional magnetic resonance imaging study.

The purpose of this study was to investigate changes in functional connectivity and regional brain activity between and within the default mode network (DMN), salience network (SN), and executive control network (ECN) among individuals with disorders of consciousness (DOC) in the conditions of minimally conscious state (MCS) and vegetative-state/unresponsive wakefulness syndrome (VS/UWS). Twenty-five VS/UWS patients, 14 MCS patients, and 30 healthy individuals as normal control, completed resting-state fMRI scans. ROI-wise functional connectivity and fractional amplitude of low-frequency fluctuation (fALFF) were implemented to examine group differences. All ROI-wise and fALFF analyses masks were identified from the triple-network model. ROI-wise analyses indicated significantly decreased functional connectivity between posterior cingulate cortex (DMN)-left anterior insula (SN), right anterior insula (SN)-left dorsolateral prefrontal cortex (ECN), and right anterior insula (SN)-right amygdala (SN) in VS/UWS patients compared to MCS patients. Moreover, fALFF were observed reduced in the triple-network across all DOC patients, and as the clinical manifestations of DOC deteriorated from MCS to VS/UWS, fALFF in dorsal DMN, anterior/posterior SN, and left ECN became significantly reduced. Moreover, a positive correlation between fALFF of the left ECN and Coma Recovery Scale-Revised (CRS-R) total scores was found across all DOC patients. These findings contribute to a better understanding of the underlying neural mechanism of functional connectivity and regional brain activity in DOC patients, and this triple-network model provides new connectivity pattern changes that may be integrated in future diagnostic tools based on the neural signatures of conscious states.

Nociceptive Response Is a Possible Marker of Evolution in the Level of Consciousness in Unresponsive Wakefulness Syndrome Patients.

The Nociception Coma Scale (NCS) and its revised version (NCS-R) were used to evaluate behavioral responses to pain in non-communicative patients. We hypothesized that if patients demonstrate changes to their NCS(-R) scores over time, their evolving behavioral abilities could indicate a forthcoming diagnostic improvement with the Coma Recovery Scale-Revised (CRS-R). Forty-three Vegetative State/Unresponsive Wakefulness Syndrome (VS/UWS) patients were enrolled in the study. The patients were assessed weekly using the CRS-R and NCS(-R) for four consecutive weeks. The first assessment was within 10 days after hospitalization. The assessments were performed between 09:30 and 11:30 AM in a room with constant levels of humidity, light and temperature, as well as an absence of transient noise. Noxious stimuli were administered using a Newton-meter, with pressure applied to the fingernail bed for a maximum of 5 s unless interrupted by a behavioral response from subjects. Seventeen patients demonstrated improvements in their level of consciousness, 13 of whom showed significant behavioral changes through the NCS(-R) before being diagnosed with a Minimally Conscious State (MCS) according to the CRS-R. The behavioral changes observed using the NCS(-R) corresponded to a high probability of observing an improvement from VS/UWS to MCS. To characterize the increased likelihood of this transition, our results present threshold scores of ≥5 for the NCS (accuracy 86%, sensitivity 87%, and specificity 86%) and ≥3 for the NCS-R (accuracy 77%, sensitivity 89%, and specificity 73%). In conclusion, a careful evaluation of responses to nociceptive stimuli in DOC patients could constitute an effective procedure in assessing their evolving conscious state.

Auditory Stimulation Modulates Resting-State Functional Connectivity in Unresponsive Wakefulness Syndrome Patients.

Passive listening to music is associated with several psychological and physical benefits in both, healthy and diseased populations. In this fMRI study, we examined whether preferred music has effects on the functional connectivity within resting-state networks related to consciousness. Thirteen patients in unresponsive wakefulness syndrome (UWS) and 18 healthy controls (HC) were enrolled. Both groups were exposed to different auditory stimulation (scanner noise, preferred music, and aversive auditory stimulation). Functional connectivity was analyzed using a seed-based approach. In HC, no differences were found between the three conditions, indicating that their networks are already working at high level. UWS patients showed impaired functional connectivity within all resting-state networks. In addition, functional connectivity of the auditory network was modulated by preferred music and aversive auditory stimulation. Hence, both conditions have the potential to modulate brain activity of UWS patients.

Prognosis for patients with cognitive motor dissociation identified by brain-computer interface.

Cognitive motor dissociation describes a subset of patients with disorders of consciousness who show neuroimaging evidence of consciousness but no detectable command-following behaviours. Although essential for family counselling, decision-making, and the design of rehabilitation programmes, the prognosis for patients with cognitive motor dissociation remains under-investigated. The current study included 78 patients with disorders of consciousness who showed no detectable command-following behaviours. These patients included 45 patients with unresponsive wakefulness syndrome and 33 patients in a minimally conscious state, as diagnosed using the Coma Recovery Scale-Revised. Each patient underwent an EEG-based brain-computer interface experiment, in which he or she was instructed to perform an item-selection task (i.e. select a photograph or a number from two candidates). Patients who achieved statistically significant brain-computer interface accuracies were identified as cognitive motor dissociation. Two evaluations using the Coma Recovery Scale-Revised, one before the experiment and the other 3 months later, were carried out to measure the patients' behavioural improvements. Among the 78 patients with disorders of consciousness, our results showed that within the unresponsive wakefulness syndrome patient group, 15 of 18 patients with cognitive motor dissociation (83.33%) regained consciousness, while only five of the other 27 unresponsive wakefulness syndrome patients without significant brain-computer interface accuracies (18.52%) regained consciousness. Furthermore, within the minimally conscious state patient group, 14 of 16 patients with cognitive motor dissociation (87.5%) showed improvements in their Coma Recovery Scale-Revised scores, whereas only four of the other 17 minimally conscious state patients without significant brain-computer interface accuracies (23.53%) had improved Coma Recovery Scale-Revised scores. Our results suggest that patients with cognitive motor dissociation have a better outcome than other patients. Our findings extend current knowledge of the prognosis for patients with cognitive motor dissociation and have important implications for brain-computer interface-based clinical diagnosis and prognosis for patients with disorders of consciousness.

Sleep-like bistability, loss of causality and complexity in the cerebral cortex of unresponsive wakefulness syndrome patients

Unresponsiveness Wakefulness Syndrome (UWS) patients may retain intact portions of the thalamocortical system that are spontaneously active and responsive to sensory stimuli. In most of these patients, Transcranial Magnetic Stimulation combined with electroencephalography (TMS/EEG) shows that structurally preserved cortical areas react to TMS, but fail to engage complex patterns of effective interactions, as assessed by the perturbational complexity index (PCI). Another condition during which thalamocortical circuits are intact, active and reactive, yet unable to generate complex responses, is non-rapid eye movement (NREM) sleep, in which cortical neurons become bistable and tend to fall into a silent state (OFF-period) upon receiving an input. Here we tested whether a pathological form of bistability may be responsible for the loss of cortical complexity in UWS patients. In eyes-open UWS patients (n=16) TMS evoked a slow wave-like EEG response that was associated with a suppression of high-frequency (above 20Hz) oscillations suggesting the occurrence of OFF-periods similar to the ones observed in healthy subjects (n=8) during NREM sleep. Crucially, this phenomenon was never detected in healthy awake subjects (n=20). In all targeted cortical areas (Brodmann areas 6 and 7, bilaterally) of UWS patients, pathological OFF-periods significantly impaired local causal interactions (as measured by the phase-locking factor) and prevented the build-up of global complexity (as measured by PCI). Our results draw a first link between neuronal events (OFF-periods) and global brain dynamics (complexity) in UWS patients. Detecting the presence of sleep-like bistability and tracking its evolution over time, may offer a valuable read-out to devise, guide and titrate therapeutic strategies aimed at restoring consciousness.

Sleep-like cortical OFF-periods disrupt causality and complexity in the brain of unresponsive wakefulness syndrome patients

Unresponsive wakefulness syndrome (UWS) patients may retain intact portions of the thalamocortical system that are spontaneously active and reactive to sensory stimuli but fail to engage in complex causal interactions, resulting in loss of consciousness. Here, we show that loss of brain complexity after severe injuries is due to a pathological tendency of cortical circuits to fall into silence (OFF-period) upon receiving an input, a behavior typically observed during sleep. Spectral and phase domain analysis of EEG responses to transcranial magnetic stimulation reveals the occurrence of OFF-periods in the cortex of UWS patients (N = 16); these events never occur in healthy awake individuals (N = 20) but are similar to those detected in healthy sleeping subjects (N = 8). Crucially, OFF-periods impair local causal interactions, and prevent the build-up of global complexity in UWS. Our findings link potentially reversible local events to global brain dynamics that are relevant for pathological loss and recovery of consciousness.

Emerging Ethical Issues Related to the Use of Brain-Computer Interfaces for Patients with Total Locked-in Syndrome

New brain-computer interface and neuroimaging techniques are making differentiation less ambiguous and more accurate between unresponsive wakefulness syndrome patients and patients with higher cognitive function and awareness. As research into these areas continues to progress, new ethical issues will face physicians of patients suffering from total locked-in syndrome (total LIS), characterized by complete loss of voluntary muscle control, with retention of cognitive function and awareness detectable only with neuroimaging and brain-computer interfaces. Physicians, researchers, ethicists and hospital ethics committees should be aware of and prepared to handle ethical issues unique to these totally locked-in patients. Several thought experiments are discussed, to highlight potential ethical dilemmas surrounding surrogate decision-making, autonomy, end-of-life care, and pediatric care, which will be unique to total LIS patients. These, along with other ethical problems especially relevant to total LIS patients, merit further discussion among physicians, researchers, ethicists and hospital ethics committees, to facilitate consensus regarding these issues, and improve patient care.

Do unresponsive wakefulness syndrome patients feel pain? Role of laser-evoked potential-induced gamma-band oscillations in detecting cortical pain processing

It has been proposed that a neural signature of aware pain perception could be represented by the modulation of gamma-band oscillation (GBO) power induced by nociceptive repetitive laser stimulation (RLS). The aim of our study was to correlate the RLS-induced GBO modulation with the Nociception Coma Scale-Revised (NCS-R) scores (a validated scale assessing possible aware pain perception in patients with chronic disorders of consciousness), in an attempt to differentiate unresponsive wakefulness syndrome (UWS) patients from minimally conscious state (MCS) ones (both of them are awake but exhibit no or limited and fluctuant behavioral signs of awareness and mentation, and low and high NCS-R scores, respectively). In addition, we attempted to identify those among UWS patients who probably experienced pain at covert level (i.e. being aware but unable to show pain-related purposeful behaviors, which are those sustained, reproducible, and voluntary behavioral responses to nociceptive stimuli). Notably, the possibility of clearly differentiating UWS from MCS patients has outmost consequences concerning prognosis (worse in UWS) and adequate pain treatment. RLS consisted in 80 trains of three laser stimuli (delivered at 1Hz), at four different energies, able to evoke Aδ-fiber related laser evoked potentials. After each train, we assessed the NCS-R score. EEG was divided into epochs according to the laser trains, and the obtained epochs were classified in four categories according to the NCS-R score magnitude. We quantified the GBO absolute power for each category. RLS protocol induced a strongly correlated increase in GBO power and NCS-R score (the higher the laser stimulation intensity, the higher the NCS-R, independently of stimulus repetition) in all the MCS patients, thus confirming the presence of aware pain processing. Nonetheless, such findings were present even in five UWS individuals. This could suggest the presence of covert pain processing in such subjects, despite the low NCS-R scores. In conclusion, RSL-induced GBO power evaluation could be helpful in the differential diagnosis between MCS and UWS patients, besides the clinical assessment, and in identifying covert pain perception in some UWS individuals.

Correlation between resting state fMRI total neuronal activity and PET metabolism in healthy controls and patients with disorders of consciousness.

IntroductionThe mildly invasive 18F‐fluorodeoxyglucose positron emission tomography (FDG‐PET) is a well‐established imaging technique to measure ‘resting state’ cerebral metabolism. This technique made it possible to assess changes in metabolic activity in clinical applications, such as the study of severe brain injury and disorders of consciousness.ObjectiveWe assessed the possibility of creating functional MRI activity maps, which could estimate the relative levels of activity in FDG‐PET cerebral metabolic maps. If no metabolic absolute measures can be extracted, our approach may still be of clinical use in centers without access to FDG‐PET. It also overcomes the problem of recognizing individual networks of independent component selection in functional magnetic resonance imaging (fMRI) resting state analysis.MethodsWe extracted resting state fMRI functional connectivity maps using independent component analysis and combined only components of neuronal origin. To assess neuronality of components a classification based on support vector machine (SVM) was used. We compared the generated maps with the FDG‐PET maps in 16 healthy controls, 11 vegetative state/unresponsive wakefulness syndrome patients and four locked‐in patients.ResultsThe results show a significant similarity with ρ = 0.75 ± 0.05 for healthy controls and ρ = 0.58 ± 0.09 for vegetative state/unresponsive wakefulness syndrome patients between the FDG‐PET and the fMRI based maps. FDG‐PET, fMRI neuronal maps, and the conjunction analysis show decreases in frontoparietal and medial regions in vegetative patients with respect to controls. Subsequent analysis in locked‐in syndrome patients produced also consistent maps with healthy controls.ConclusionsThe constructed resting state fMRI functional connectivity map points toward the possibility for fMRI resting state to estimate relative levels of activity in a metabolic map.

Central olfactory processing in patients with disorders of consciousness.

Previous studies have demonstrated that individuals suffering from disorder of consciousness (DOC) maintain some minor neural processing of percepts mediated by senses that early in their pathway intersect the thalamus, a key dysfunctional area in DOC patients. Here the degree of sensory preservation within the olfactory system, a system that lacks an obligatory thalamic relay, and its relationship to the consciousness level in DOC patients of various etiologies was assessed. Clinical Coma Recovery Scale - Revised (CRS-R) as well as cerebral responses to odors by means of functional magnetic resonance were obtained in a group of vegetative state/unresponsive wakefulness syndrome (n = 26) patients, minimally conscious state (n = 7) patients and healthy controls (n = 25). A majority of vegetative state/unresponsive wakefulness syndrome patients (58%) and 100% of minimally conscious state patients demonstrated a significant preservation of olfactory neural processing, manifested by activation within the piriform cortex, an area considered as a primary olfactory region. Degree of preservation of olfactory processing differed linearly in line with the patients' etiologies where groups demonstrating greater conscious awareness demonstrated more significant processing. Viewed over all DOC patients, there was a significant negative association between odor-related activity in the orbitofrontal cortex and CRS-R scores. It is demonstrated that DOC patients exhibit a significant preservation of olfactory neural processing with a clear relationship to etiopathologies and clinical measures even years after of chronification of DOC.