Effect of acoustic stimuli in patients with disorders of consciousness: a quantitative electroencephalography study

Auditory stimuli are proposed as beneficial neurorehabilitation methods in patients with disorders of consciousness. However, precise and accurate quantitative indices to estimate their potential effect remain scarce. Fourteen patients were recruited from the Neuro-Rehabilitation Unit of Hangzhou Hospital of Zhejiang Armed Police Corps of China. Altogether, there were seven cases of unresponsive wakefulness syndrome（five males and two females, aged 45.7 ± 16.8 years） and seven cases of minimally conscious state（six males and one female, aged 42.3 ± 20.8 years）. Simultaneously, fourteen healthy controls（10 males and 4 females, aged 51.7 ± 9.7 years） also participated in this case-control experiment. Brain response to music, subjects＇ own name, and noise was monitored by quantitative electroencephalography（QEEG） in the resting state and with acoustic stimulation. Predictive QEEG values in various brain regions were investigated. Our results show that cerebral activation was high in subjects stimulated by their own name, especially in the temporal lobe in patients with disorders of consciousness, and the frontal lobe in the control group. Further, during resting and stimulation, QEEG index（δ ＋ θ/α ＋ β ratio） negatively correlated with the Coma Recovery Scale-Revised score in traumatic disorders of consciousness patients. Hence, we speculate that a subject＇s own name might be an effective awakening therapy for patients with disorders of consciousness. Moreover, QEEG index in specific stimulation states may be used as a prognostic indicator for disorders of consciousness patients（sensitivity, 75%; specificity, 50%）.

Recovery from prolonged disorders of consciousness:A dual-center prospective cohort study in China

BACKGROUND Recent innovations in intensive care have improved the prognosis of patients with severe brain injuries and brought more patients with disorders of consciousness(DoC).Data are lacking regarding the long-term outcomes of those patients in China.It is necessary to study the long-term outcomes of patients with prolonged DoC in light of many factors likely to influence crucial decisions about their care and their life.AIM To present the preliminary results of a DoC cohort.METHODS This was a two-center prospective cohort study of inpatients with vegetative state(VS)/unresponsive wakefulness syndrome(UWS).The study outcomes were the recovery from VS/UWS to minimally conscious state(MCS)and the long-term status of patients with prolonged DoC considered in VS/UWS or MCS for up to 6 years.The patients were evaluated using the Glasgow coma scale,coma recovery scale-revised,and Glasgow outcome scale.The endpoint of follow-up was recovery of full consciousness or death.The changes in the primary clinical outcome improvement in clinical diagnosis were evaluated at 12 mo compared with baseline.RESULTS The study population included 93 patients(62 VS/UWS and 31 MCS).The postinjury interval range was 28-634 d.Median follow-up was 20 mo(interquartile range,12-37 mo).At the endpoint,33 transitioned to an emergence from MCS or full consciousness,eight had a locked-in syndrome,and there were 35 patients remaining in a VS/UWS and 11 in an MCS.Seven(including one locked-in syndrome)patients(7.5%)died within 12 mo of injury.Compared with the unresponsive group(n=52)at 12 mo,the responsive group(n=41)had a higher proportion of males(87.8%vs 63.5%,P=0.008),shorter time from injury(median,40.0 d vs 65.5 d,P=0.006),higher frequency of vascular etiology(68.3%vs 38.5%,P=0.007),higher Glasgow coma scale score at admission(median,9 vs 6,P<0.001),higher coma recovery scale-revised score at admission(median,9 vs 2.5,P<0.001),at 1 mo(median,14 vs 5,P<0.001),and at 3 mo(median,20 vs 6,P<0.001),lower frequency of VS/UWS(36.6%vs 90.0%,P<0.001),and more favorable Glasgow outcome scale outcome(P<0.001).CONCLUSION Patients with severe DoC,despite having strong predictors of poor prognosis,might recover consciousness after a prolonged time of rehabilitation.An accurate initial diagnosis of patients with DoC is critical for predicting outcome and a long-term regular follow-up is also important.

Non-invasive EEG-based brain-computer interfaces in patients with disorders of consciousness

Disorders of consciousness(DoCs) are chronic conditions resulting usually from severe neurological deficits. The limitations of the existing diagnosis systems and methodologies cause a need for additional tools for relevant patients with DoCs assessment, including brain-computer interfaces(BCIs). Recent progress in BCIs' clinical applications may offer important breakthroughs in the diagnosis and therapy of patients with DoCs. Thus the clinical significance of BCI applications in the diagnosis of patients with DoCs is hard to overestimate. One of them may be brain-computer interfaces. The aim of this study is to evaluate possibility of non-invasive EEG-based brain-computer interfaces in diagnosis of patients with DOCs in post-acute and long-term care institutions.

Positive effects of music therapist's selected auditory stimulation on the autonomic nervous system of patients with disorder of consciousness: a randomized controlled trial

The current randomized controlled trial was performed at the China Rehabilitation Science Institute, China to test the hypothesis that musical auditory stimulation has positive effects on the autonomic nervous system of patients with disorder of consciousness.Although past studies have recommended that patients with disorder of consciousness listen to patient-preferred music, this practice is not universally accepted by researchers.Twenty patients with severe disorder of consciousness listened to either therapist-selected(n = 10, 6 males and 4 females;43.33 ± 18.76 years old) or patient-preferred(n = 10, 5 males and 5 females, 48.83 ± 18.79 years old) musical therapy, 30 minutes/day, 5 times/week for 6 weeks.The results showed no obvious differences in heart rate variability-related parameters including heart rate, standard deviation of normal-to-normal R-R intervals, and the root-mean-square of successive heartbeat interval differences of successive heartbeat intervals between the two groups of patients.However, percentage of differences exceeding 50 ms between adjacent normal number of intervals, low-frequency power/high-frequency power, high-frequency power norm, low-frequency power norm, and total power were higher in patients receiving therapist-selected music than in patients receiving their own preferred music.In contrast, this relationship was reversed for the high-frequency power and very-low-frequency band.These results suggest that compared with preferred musical stimulation, therapist-selected musical stimulation resulted in higher interactive activity of the autonomic nervous system.Therefore, therapist-selected musical stimulation should be used to arouse the autonomic nervous system of patients with disorder of consciousness.This study was approved by the Institutional Ethics Committee of China Rehabilitation Research Center, China(approval No.2018-022-1) on March 12, 2018 and registered with the Chinese Clinical Trial Registry(registration number Chi CTR1800017809) on August 15, 2018.

Neuronal activation by acupuncture at Yongquan(KI1) and sham acupoints in patients with disorder of consciousness: a positron emission tomography study

Disorder of consciousness （DOC） is one of the most serious sequelae of brain injury, and is challenging for neurologists and rehabilitation special- ists to manage because of its refractory nature （Whyte et al., 2013）. Acu- puncture is a traditional Chinese medicine technique that is often used to help improve the level of consciousness in patients with DOC. However, the responses to stimulation of acupoints in patients with DOC are not fully understood.

Cognitive Neurobiology of Consciousness and Memory during Anesthesia Awareness—Scientific Possibilities and Clinical Implications

The condition of pharmacologically induced unconsciousness that renders a patient unresponsive to uncomfortable surgical stimuli is known as general anesthesia. When it is used for surgery, a fairly rare but traumatizing state known as anesthesia awareness might develop. What is the probability that a patient can be awake, conscious, and able to hear the surroundings and experience excruciating pain but be immobilized to communicate it during surgery? According to estimates, there are 1 to 2 cases for every 1000 patients who experience this phenomenon and retain various sensory information after general anesthesia was applied. Even with seemingly effective anesthetic care, emerging consciousness states during anesthesia are reported and often come with various degrees of memory loss mechanisms. Some researchers and the experiments covered in this paper suggest anesthesia is merely a memory loss or poorly understood neurological form of amnesia induced during the event itself and not a loss of consciousness per se during the traumatic event, as suggested by studies described in this article. In some instances, the agony may be unbearable, with long-term neuropsychiatric effects such as post-traumatic stress disorder. Although the neurobiological phenomenon of consciousness regained during anesthesia is still poorly understood, these continuously reported events carry significant medical and legal ramifications. The numerous contributing elements that may increase the risk of intraoperative raised levels of consciousness are gathered, analyzed, and discussed in this research study. Preventive methods for both preinduction and intraoperative usage, as well as corrective actions to take after such occurrences, are also discussed.

Clinical Decision on Disorders of Consciousness After Acquired Brain Injury:Stepping Forward

Major advances have been made over the past few decades in identifying and managing disorders of consciousness(DOC)in patients with acquired brain injury(ABI),bringing the transformation from a conceptualized definition to a complex clinical scenario worthy of scientific exploration.Given the continuously-evolving framework of precision medicine that integrates valuable behavioral assessment tools,sophisticated neuroimaging,and electrophysiological techniques,a considerably higher diagnostic accuracy rate of DOC may now be reached.During the treatment of patients with DOC,a variety of intervention methods are available,including amantadine and transcranial direct current stimulation,which have both provided class II evidence,zolpidem,which is also of high quality,and non-invasive stimulation,which appears to be more encouraging than pharmacological therapy.However,heterogeneity is profoundly ingrained in study designs,and only rare schemes have been recommended by authoritative institutions.There is still a lack of an effective clinical protocol for managing patients with DOC following ABI.To advance future clinical studies on DOC,we present a comprehensive review of the progress in clinical identification and management as well as some challenges in the pathophysiology of DOC.We propose a preliminary clinical decision protocol,which could serve as an ideal reference tool for many medical institutions.

Transcutaneous auricular vague nerve stimulation improved brain connection activity on patients of disorders of consciousness: a pilot study

OBJECTIVE:To evaluate the clinical effect of transcutaneous auricular vagus nerve nerve stimulation(ta VNS)on disorders of consciousness(DOC)patients with Coma Recovery Scale-Revised(CRS-R)and cerebral cortex activity by electroencephalogram(EEG)detection.METHODS:Randomized controlled methods were used to evaluate the clinical effect of ta VNS on patients with DOC.Twelve patients with initial CRS-R of 6-10 were randomly divided into the treatment group of ta VNS and control group of transcutaneous non-auricular vague nerve stimulation(tn VNS).According to clinical diagnosis,the treatment group was divided into vegetative state(VS)group and minimally conscious state(MCS)group.RESULTS:The energy of delta and beta bands is positively correlated with the brain activity of patients.ta VNS has different regulatory effects on patients with different conscious States.In ta VNS group,the energy of delta band in local brain regions changed significantly.Significant changes in brain connection activity were limited to local brain regions.While in patients with MCS in the ta VNS group,delta and beta band energy significantly changed in multiple brain regions and crossbrain connection activity also changed significantly.CONCLUSION:These findings suggest that ta VNS may be a related extra method for arousing patients’awakening by improving brain connection activity.And the effect is remarkable in MCS patients.

Disorders of Consciousness in China

With the development of modern international medicine, the subject of disorders of consciousness （DOCs） has begun to be raised in China's Mainland. Much progress has been made to date in several specialties related to the management of chronic DOC patients in China. In this article, we briefly review the present status of DOC studies in China, specifically concerning diagnosis, prognosis, therapy, and rehabilitation. The development of DOC- related scientific organizations and activities in China are introduced. Some weaknesses that need improvement are also noted. The current program provides a good foundation for future development.

Brain Network Studies in Chronic Disorders of Consciousness:Advances and Perspectives

Neuroimaging has opened new opportunities to study the neural correlates of consciousness, and provided additional information concerning diagnosis, prognosis, and therapeutic interventions in patients with disorders of consciousness. Here, we aim to review neuroimaging studies in chronic disorders of consciousness from the viewpoint of the brain network, focusing on positron emission tomogra- phy, functional MRI, functional near-infrared spectroscopy, electrophysiology, and diffusion MRI. To accelerate basic research on disorders of consciousness and provide a panoramic view of unconsciousness, we propose that it is urgent to integrate different techniques at various spatiotemporal scales, and to merge fragmented findings into a uniform ＂Brainnetome＂ （Brain-net-ome） research framework.

Visual Fixation Assessment in Patients with Disorders of Consciousness Based on Brain-Computer Interface

Visual fixation is an item in the visual function subscale of the Coma Recovery Scale-Revised （CRS-R）. Sometimes clinicians using the behavioral scales find it difficult to detect because of the motor impairment in patients with disorders of consciousness （DOCs）. Brain- computer interface （BCI） can be used to improve clinical assessment because it directly detects the brain response to an external stimulus in the absence of behavioral expres- sion. In this study, we designed a BCI system to assist the visual fixation assessment of DOC patients. The results from 15 patients indicated that three showed visual fixation in both CRS-R and BCI assessments and one did not show such behavior in the CRS-R assessment but achieved significant online accuracy in the BCI assessment. The results revealed that electroencephalography-based BCI can detect the brain response for visual fixation. Therefore, the proposed BCI may provide a promising method for assisting behavioral assessment using the CRS-R.

Current Status of Neuromodulatory Therapies for Disorders of Consciousness

Treatment for disorders of consciousness （DOCs） is still a Gordian knot. Evidence-based guidelines on the treatment of DOC patients are not currently available, while neuromodulation techniques are seen as a potential treatment. Multiple neuromodulation therapies have been applied. This article reviews the most relevant studies in the literature in order to describe a clear picture of the current state of neuromodulation therapies that could be used to treat DOC patients. Both invasive and noninvasive brain stimulation is discussed. Significant behavioral improvements in prolonged DOCs under neuromodulation therapies are rare. The efficacy of various such therapies remains a matter of debate. Further clinical investigations of existing techniques in larger samples properly controlling for spontaneous recovery are needed, and new approaches are awaited.

Responses of Patients with Disorders of Consciousness to Habit Stimulation:A Quantitative EEG Study

Whether habit stimulation is effective in DOC patient arousal has not been reported. In this paper, we analyzed the responses of DOC patients to habit stimulation. Nineteen DOC patients with alcohol consumption or smoking habits were recruited and 64-channel EEG signals were acquired both at the resting state and at three stimulation states. Wavelet transformation and nonlinear dynamics were used to extract the features of EEG signals and four brain lobes were selected to investigate the degree of EEG response to habit stimulation. Results showed that the highest degree of EEG response was from the callname stimulation, followed by habit and music stimulations. Significant differences in EEG wavelet energy and response coefficient were found both between habit and music stimulation, and between habit and call-name stimulation. These findings prove that habit stimulation induces relatively more intense EEG responses in DOC patients than music stimulation, suggesting that it may be a relevant additional method for eliciting patient arousal.

Spinal Cord Stimulation Frequency Influences the Hemodynamic Response in Patients with Disorders of Consciousness

Spinal cord stimulation （SCS） is a promising technique for treating disorders of consciousness （DOCs）. However, differences in the spatio-temporal responsiveness of the brain under varied SCS parameters remain unclear. In this pilot study, functional near-infrared spectroscopy was used to measure the hemodynamic responses of 10 DOC patients to different SCS frequencies （5 Hz, 10 Hz, 50 Hz, 70 Hz, and 100 Hz）. In the prefrontal cortex, a key area in consciousness circuits, we found significantly increased hemodynamic responses at 70 Hz and 100 Hz, and significantly different hemodynamic responses between 50 Hz and 70 Hz/100 Hz. In addition, the functional connectivity between prefrontal and occipital areas was significantly improved with SCS at 70 Hz. These results demonstrated that SCS modulates the hemodynamic responses and long-range connectivity in a frequency-specific manner （with 70 Hz apparently better）, perhaps by improving the cerebral blood volume and information transmission through the reticular formation-thalamus-cortex pathway.

White Matter Deficits Underlying the Impaired Consciousness Level in Patients with Disorders of Consciousness

In this study, we aimed to （1） identify white matter （WM） deficits underlying the consciousness level in patients with disorders of consciousness （DOCs） using diffusion tensor imaging （DTI）, and （2） evaluate the relationship between DTI metrics and clinical measures of the consciousness level in DOC patients. With a cohort of 8 comatose, 8 unresponsive wakefulness syndrome/ vegetative state, and 14 minimally conscious state patients and 25 patient controls, we performed group comparisons of the DTI metrics in 48 core WM regions of interest （ROIs）, and examined the clinical relevance using correlation analysis. We identified multiple abnormal WM ROIs in DOC patients compared with normal controls, and the DTI metrics in these ROIs were significantly correlated with clinical measures of the consciousness level. Therefore, our findings suggested that multiple WM tracts are involved in the impaired consciousness levels in DOC patients and demonstrated the clinical relevance of DTI for DOC patients.

Connecting the P300 to the diagnosis and prognosis of unconscious patients

The residual consciousness of unconscious patients can be detected by studying the P300, a wave among event-related potentials. Previous studies have applied tones, the subject＇s name and other names as stimuli. However, the results were not satisfactory. In this study, we changed the constituent order of subjects＇ two-character names to create derived names. The subject＇s derived names, together with tones and their own names, were used as auditory stimuli in event-related potential experiments. Healthy controls and unconscious patients were included in this study and made to listen to these auditory stimuli. In the two paradigms, a sine tone followed by the subject＇s own name and the subject＇s derived name followed by the subject＇s own name were used as standard and deviant stimuli, respectively. The results showed that all healthy controls had the P300 using both paradigms, and that the P300 in the second paradigm had a longer latency and two peaks. All minimally conscious state patients had the P300 in the first paradigm and the majority of them had the P300 in the second paradigm. Most vegetative state patients had no P300. Patients who showed the P300 in the two paradigms had more residual consciousness, and patients with the two-peak P300 had a higher probability of awakening within a short time. Our experimental findings suggest that the P300 event-related potential could reflect the conscious state of unconscious patients.

Recent Progress in Basic and Clinical Research on Disorders of Consciousness

Severe brain injury can lead to disorders of consciousness （DOCs）. Since DOC patients cannot communicate functionally or behave purposefully, most remain bedridden and require laborious care. The medical community is often confronted with the expectations of the families of chronic DOC patients, and the social, economic, and ethical consequences are tremendous. Research on DOCs is attracting increasing attention from scientists and physicians in various fields. With the development of modern neuroimaging and neuromodulation techniques, much progress has been made in the diagnosis, prognosis, treatment, and rehabilitation of DOCs in the last decade.

Finger or Light:Stimulation Sensitivity of Visual Startle in the Coma Recovery Scale-Revised for Disorders of Consciousness

Dear Editor,Coma, the vegetative state （VS）, and the minimally- conscious state （MCS）, often collectively referred to as disorders of consciousness （DOCs）, typically occur after severe traumatic or non-traumatic brain injury [1]. The boundary between awareness and unawareness remains elusive, making it difficult to correctly distinguish MCS from VS patients. It is possible to employ noninvasive neuroimaging techniques, such as functional MRI （fMRI） [2] to assess residual cognitive processing as well as consciousness. However, the causal link between neural activity in specific brain areas and specific behavioral tasks is hard to dissect using fMRI [3]. Therefore, detecting residual cognitive function and consciousness in patients surviving severe brain injury remains extremely challenging.

Neuromodulatory therapies for patients with prolonged disorders of consciousness

Background:Reviving patients with prolonged disorders of consciousness(DOCs)has always been focused and challenging in medical research.Owing to the limited effectiveness of available medicine,recent research has increasingly turned towards neuromodulatory therapies,involving the stimulation of neural circuits.We summarised the progression of research regarding neuromodulatory therapies in the field of DOCs,compared the differences among different studies,in an attempt to explore optimal stimulation patterns and parameters,and analyzed the major limitations of the relevant studies to facilitate future research.Methods:We performed a search in the PubMed database,using the concepts of DOCs and neuromodulation.Inclusion criteria were:articles in English,published after 2002,and reporting clinical trials of neuromodulatory therapies in human patients with DOCs.Results:Overall,187 published articles met the search criteria,and 60 articles met the inclusion criteria.There are differences among these studies regarding the clinical efficacies of neurostimulation techniques for patients with DOCs,and large-sample studies are still lacking.Conclusions:Neuromodulatory techniques were used as trial therapies for DOCs wherein their curative effects were controversial.The difficulties in detecting residual consciousness,the confounding effect between the natural course of the disease and therapeutic effect,and the heterogeneity across patients are the major limitations.Large-sample,well-designed studies,and innovations for both treatment and assessment are anticipated in future research.

Risk factors for brain injury in patients with exertional heatstroke:A 5-year experience

Purpose:Minimal data exist on brain injury in patients with exertional heatstroke(EHS)in developing country.In this study,we explored the risk factors for brain injury induced by EHS 90-day after onset.Methods:A retrospective cohort study of patients with EHS was conducted in the intensive care unit of the General Hospital of Southern Theater Command of PLA in China from April 2014 to June 2019.Patients were divided into non-brain injury(fully recovered)and brain injury groups(comprising deceased patients or those with neurological sequelae).The brain injury group was further subdivided into a death group and a sequela group for detailed analysis.General information,neurological performance and information on important organ injuries in the acute stage were recorded and analysed.Multivariable logistic regression was used to identify risk factors for brain injury after EHS and mortality risk factors for brain injury,and Kaplan-Meier survival curve was used to evaluate the effect of the neurological dysfunction on survival.Results:Out of the 147 EHS patients,117 were enrolled,of which 96(82.1%)recovered,13(11.1%)died,and 8(6.8%)experienced neurological sequelae.Statistically significant differences were found between non-brain injury and brain injury groups in age,hypotension,duration of consciousness disorders,time to drop core body temperature below 38.5℃,lymphocyte counts,platelet counts,procalcitonin,alanine aminotransferase,aspartate aminotransferase,creatinine,cystatin C,coagulation parameters,international normalized ratio,acute physiology and chronic health evaluation II scores,sequential organ failure assessment(SOFA)scores,and Glasgow coma scale scores(all p<0.05).Multivariate logistic regression showed that age(OR=1.090,95%CI:1.02-1.17,p=0.008),time to drop core temperature(OR=8.223,95%CI:2.30-29.40,p=0.001),and SOFA scores(OR=1.676,95%CI:1.29-2.18,p<0.001)are independent risk factors for brain injury induced by EHS.The Kaplan-Meier curves suggest significantly prolonged survival(p<0.001)in patients with early Glasgow coma scale score>8 and duration of consciousness disorders≤24 h.Conclusions:Advanced age,delayed cooling,and higher SOFA scores significantly increase the risk of brain injury post-EHS.These findings underscore the importance of rapid cooling and early assessment of organ failure to improve outcomes in EHS patients.