Background Resting-state functional magnetic resonance imaging provides insight into brain function in patients with consciousness disorders.We investigated the variability in functional brain networks in consciousnes...Background Resting-state functional magnetic resonance imaging provides insight into brain function in patients with consciousness disorders.We investigated the variability in functional brain networks in consciousness disorders with different etiologies and identified potential correlations with recovery.Methods In this single-center prospective observational study,we included seven patients with traumatic brain injury,seven with cerebrovascular accidents,and a healthy control group of eight participants with intraspinal space-occupying lesions.All participants underwent resting-state functional magnetic resonance imaging and were assessed using the Coma Recovery Scale-Revised.Regional homogeneity values were compared across groups to evaluate differences in functional brain activity.Results Patients with traumatic brain injury demonstrated increased regional homogeneity values in the right fusiform gyrus,left middle cingulum,and right inferior frontal gyrus and reduced values in the left middle temporal gyrus,right supramarginal gyrus,right supplementary motor area,right precentral gyrus,and inferior frontal gyrus.Both groups exhibited higher regional homogeneity values in subcortical nuclei compared with the healthy control group.Patients with traumatic brain injury had reduced regional homogeneity in the paracentral lobule and frontal,temporal,and supramarginal regions compared with patients with cerebrovascular accidents.Preoperative Coma Recovery Scale-Revised scores were positively correlated with regional homogeneity in the hippocampus and negatively correlated with regional homogeneity in the midline temporal region.For 3 months,both groups showed improved consciousness.Conclusions Regional homogeneity analysis can identify alterations in functional brain activity associated with recovery of consciousness,offering potential neuroimaging biomarkers for clinical assessment and prognosis for consciousness disorders.展开更多
Among the existing research on the treatment of disorders of consciousness(DOC),deep brain stimulation(DBS)offers a highly promising therapeutic approach.This comprehensive review documents the historical development ...Among the existing research on the treatment of disorders of consciousness(DOC),deep brain stimulation(DBS)offers a highly promising therapeutic approach.This comprehensive review documents the historical development of DBS and its role in the treatment of DOC,tracing its progression from an experimental therapy to a detailed modulation approach based on the mesocircuit model hypothesis.The mesocircuit model hypothesis suggests that DOC arises from disruptions in a critical network of brain regions,providing a framework for refining DBS targets.We also discuss the multimodal approaches for assessing patients with DOC,encompassing clinical behavioral scales,electrophysiological assessment,and neuroimaging techniques methods.During the evolution of DOC therapy,the segmentation of central nuclei,the recording of single-neurons,and the analysis of local field potentials have emerged as favorable technical factors that enhance the efficacy of DBS treatment.Advances in computational models have also facilitated a deeper exploration of the neural dynamics associated with DOC,linking neuron-level dynamics with macroscopic behavioral changes.Despite showing promising outcomes,challenges remain in patient selection,precise target localization,and the determination of optimal stimulation parameters.Future research should focus on conducting large-scale controlled studies to delve into the pathophysiological mechanisms of DOC.It is imperative to further elucidate the precise modulatory effects of DBS on thalamo-cortical and cortico-cortical functional connectivity networks.Ultimately,by optimizing neuromodulation strategies,we aim to substantially enhance therapeutic outcomes and greatly expedite the process of consciousness recovery in patients.展开更多
Disorders of consciousness (DOC) are neuropsychiatric disorders with causes that include traumatic brain injury, hypoxia, and stroke. The possibility of spontaneous recovery is low, and treatment remains a difficult p...Disorders of consciousness (DOC) are neuropsychiatric disorders with causes that include traumatic brain injury, hypoxia, and stroke. The possibility of spontaneous recovery is low, and treatment remains a difficult problem in the frontier challenge of neuroscience and medicine. With progress in neurocritical care, the number of patients with DOC is growing. Spinal cord stimulation (SCS) can improve the level of consciousness in patients with DOC. The present article reviews the current research status and development trends of SCS in promoting consciousness recovery in patients with DOC. It also seeks to identify the frontier problems and challenges associated with this neuroregulatory technology. Through a systematic review of the relevant literature, criteria for inclusion and exclusion in SCS therapy were established, suitable patients with DOC were identified, and the effects of different stimulation frequencies on consciousness and motor function were examined. Additionally, the optimal SCS mode was investigated, and evaluation criteria, treatment mechanisms, and factors influencing effectiveness were summarized. The present review aims to guide the clinical application and research development of SCS. Although SCS has demonstrated efficacy in the treatment of DOC, responses to SCS exhibit significant individual variation. Consequently, further studies are necessary to expand the sample size for continued exploration and enhancement.展开更多
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...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.展开更多
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 ...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.展开更多
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 rela...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.展开更多
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 ...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.展开更多
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 potenti...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.展开更多
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 definiti...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.展开更多
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...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.展开更多
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 smo...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.展开更多
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 unc...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.展开更多
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....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%）.展开更多
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-ter...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.展开更多
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 i...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.展开更多
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...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.展开更多
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 re...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.展开更多
A 38-year-old male patient with disorders of consciousness(DOC)successfully recovered consciousness and get obvious motor function improvements through three stages of cervical spinal cord stimulation(SCS)treatment(6 ...A 38-year-old male patient with disorders of consciousness(DOC)successfully recovered consciousness and get obvious motor function improvements through three stages of cervical spinal cord stimulation(SCS)treatment(6 Hz,40 Hz,and combined frequency stimulation).We used the Coma Recovery ScaleRevised(CRS-R),FugleMeyer Assessment Scale,activities of daily living,and Berg Balance Scale to detect changes in consciousness and motor function during the 7-month postoperative follow-up.Electroencephalography-based individual alpha frequency(IAF)and relative power spectral density(RP)were used to assess changes in cognitive function and brain network function before and after the combined stimulation.The results revealed a gradually increased patient's CRS-R score after stimulation at 6 Hz,and the patient recovered consciousness 12 weeks postoperatively.The patient's motor function score gradually increased after adjusting the stimulation frequency to 40 Hz.However,the patient regressed in motor function when the stimulation frequency was decreased to 2 Hz.The patient's fine motor control of both hands significantly improved,accompanied by an increased RP in the beta band but the IAF decreased,after combined stimulation(40 Hz and 6 Hz).Then,motor function continued to improve with an increased IAF and RP in the alpha band after switching the stimulation order to 6 Hz and 40 Hz.Our results demonstrated that different frequency stimulations of cervical SCS may improve consciousness and motor function in patients with DOC.展开更多
Objective To investigate the clinical effects of time window on hyperbaric oxygen treatment(HBOT)in patients with disorders of consciousness(DOC).Methods All the clinical research literature regarding HBOT for DOC pub...Objective To investigate the clinical effects of time window on hyperbaric oxygen treatment(HBOT)in patients with disorders of consciousness(DOC).Methods All the clinical research literature regarding HBOT for DOC published between January 2000 and November 2020 were retrieved from China National Knowledge Infrastructure(CNKI),Wanfang Standards Database(WFSD)and VIP Database using Chinese key words vegetative state,disorders of consciousness,and hyperbaric oxygen followed by a comprehensive meta-analysis.Results The query gave rise to 348 results,in which 21 articles were eventually selected for meta-analysis.Among the selected 21 articles,18 articles involved a time window comparison.All the patients were classified into<60-(718 patients)and≥60-(374 patients)day groups depending on the number of days from HBOT initiation.The Jadad scores for the included datasets were relatively low in general with 2 points as the highest score.Comparable baseline data were demonstrated in all of the articles.Datasets from different sources were pooled and analyzed,and the results suggested that the clinical curative effect rate in the treatment group was significantly higher compared with that in the control group(curative effect rate:69.86%versus 42.30%;Z=11.28,P=0.000,odds ratio=3.80,95%CI=3.02-4.80).Additionally,the adverse reaction rate of the<60-day group was found to be significantly lower compared with that of the≥60-day group(Z=10.01,P=0.000,odds ratio=4.82,95%CI=3.54-6.56).The funnel diagram in articles related to curative effect analysis and time window evaluation is inverted and symmetrical,indicating that publication bias was not significant.Conclusions The clinical curative effect of the HBOT group is higher compared with that of the control group.However,the conclusions based on meta-analysis are limited because of the methodological problems of some studies.Therefore,the clinical efficacy needs to be further tested using carefully designed large sample trials(multicenter,randomized,controlled,and double-blind).展开更多
Chronic disorders of consciousness(DOC)include the vegetative state and the minimally consciousness state.The DOC diagnosis mainly relies on the evaluation of clinical behavioral scales,electrophysiological testing,an...Chronic disorders of consciousness(DOC)include the vegetative state and the minimally consciousness state.The DOC diagnosis mainly relies on the evaluation of clinical behavioral scales,electrophysiological testing,and neuroimaging examinations.No specifically effective neurorestorative methods for chronic DOC currently exist.Any valuable exploration therapies of being able to repair functions and/or structures in the consciousness loop(e.g.,drugs,hyperbaric medicines,noninvasive neurostimulation,sensory and environmental stimulation,invasive neuromodulation therapy,and cell transplantation)may become effective neurorestorative strategies for chronic DOC.In the viewpoint of Neurorestoratology,this guideline proposes the diagnostic and neurorestorative therapeutic suggestions and future exploration direction for this disease following the review of the existing treatment exploration achievements for chronic DOC.展开更多
基金funded by a grant from the STI 2030 Major Projects,grant number 2021ZD0204300.
文摘Background Resting-state functional magnetic resonance imaging provides insight into brain function in patients with consciousness disorders.We investigated the variability in functional brain networks in consciousness disorders with different etiologies and identified potential correlations with recovery.Methods In this single-center prospective observational study,we included seven patients with traumatic brain injury,seven with cerebrovascular accidents,and a healthy control group of eight participants with intraspinal space-occupying lesions.All participants underwent resting-state functional magnetic resonance imaging and were assessed using the Coma Recovery Scale-Revised.Regional homogeneity values were compared across groups to evaluate differences in functional brain activity.Results Patients with traumatic brain injury demonstrated increased regional homogeneity values in the right fusiform gyrus,left middle cingulum,and right inferior frontal gyrus and reduced values in the left middle temporal gyrus,right supramarginal gyrus,right supplementary motor area,right precentral gyrus,and inferior frontal gyrus.Both groups exhibited higher regional homogeneity values in subcortical nuclei compared with the healthy control group.Patients with traumatic brain injury had reduced regional homogeneity in the paracentral lobule and frontal,temporal,and supramarginal regions compared with patients with cerebrovascular accidents.Preoperative Coma Recovery Scale-Revised scores were positively correlated with regional homogeneity in the hippocampus and negatively correlated with regional homogeneity in the midline temporal region.For 3 months,both groups showed improved consciousness.Conclusions Regional homogeneity analysis can identify alterations in functional brain activity associated with recovery of consciousness,offering potential neuroimaging biomarkers for clinical assessment and prognosis for consciousness disorders.
基金supported by the Science and Technology Innovation 2030(2022ZD0205300)the International(Hong Kong,Macao,and Taiwan)Science and Technology Cooperation Project(Z221100002722014)+5 种基金the 2022 Open Project of Key Laboratory and Engineering Technology Research of the Ministry of Civil Affairs(2022GKZS0003)the Chinese Institute for Brain Research Youth Scholar Program(2022-NKX-XM-02)the Natural Science Foundation of Beijing municipality(7232049)the General Program of National Natural Science Foundation of China(82371197)the FundRef Organization name of Guarantors of Brain(HMR04170)the Royal Society(IES\R3\213123).
文摘Among the existing research on the treatment of disorders of consciousness(DOC),deep brain stimulation(DBS)offers a highly promising therapeutic approach.This comprehensive review documents the historical development of DBS and its role in the treatment of DOC,tracing its progression from an experimental therapy to a detailed modulation approach based on the mesocircuit model hypothesis.The mesocircuit model hypothesis suggests that DOC arises from disruptions in a critical network of brain regions,providing a framework for refining DBS targets.We also discuss the multimodal approaches for assessing patients with DOC,encompassing clinical behavioral scales,electrophysiological assessment,and neuroimaging techniques methods.During the evolution of DOC therapy,the segmentation of central nuclei,the recording of single-neurons,and the analysis of local field potentials have emerged as favorable technical factors that enhance the efficacy of DBS treatment.Advances in computational models have also facilitated a deeper exploration of the neural dynamics associated with DOC,linking neuron-level dynamics with macroscopic behavioral changes.Despite showing promising outcomes,challenges remain in patient selection,precise target localization,and the determination of optimal stimulation parameters.Future research should focus on conducting large-scale controlled studies to delve into the pathophysiological mechanisms of DOC.It is imperative to further elucidate the precise modulatory effects of DBS on thalamo-cortical and cortico-cortical functional connectivity networks.Ultimately,by optimizing neuromodulation strategies,we aim to substantially enhance therapeutic outcomes and greatly expedite the process of consciousness recovery in patients.
基金funded by the 2023 Hebei Provincial Key R&D Program Project“Research and Development of Brain Health Assessment and Auxiliary Intervention Technology and Its Application in Beidaihe Health Care Industry”(No.23377709D).
文摘Disorders of consciousness (DOC) are neuropsychiatric disorders with causes that include traumatic brain injury, hypoxia, and stroke. The possibility of spontaneous recovery is low, and treatment remains a difficult problem in the frontier challenge of neuroscience and medicine. With progress in neurocritical care, the number of patients with DOC is growing. Spinal cord stimulation (SCS) can improve the level of consciousness in patients with DOC. The present article reviews the current research status and development trends of SCS in promoting consciousness recovery in patients with DOC. It also seeks to identify the frontier problems and challenges associated with this neuroregulatory technology. Through a systematic review of the relevant literature, criteria for inclusion and exclusion in SCS therapy were established, suitable patients with DOC were identified, and the effects of different stimulation frequencies on consciousness and motor function were examined. Additionally, the optimal SCS mode was investigated, and evaluation criteria, treatment mechanisms, and factors influencing effectiveness were summarized. The present review aims to guide the clinical application and research development of SCS. Although SCS has demonstrated efficacy in the treatment of DOC, responses to SCS exhibit significant individual variation. Consequently, further studies are necessary to expand the sample size for continued exploration and enhancement.
基金Supported by the Fundamental Research Funds for the Central Public Welfare Research Institutes:Brain Effects and Multimodal Imaging Mechanism of Transcutaneous Auricular Vagus Nerve Stimulation in Patients with Disorder of Consciousness(No.CI2021A03305)
文摘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.
基金supported by the National Natural Science Foundation of China(81471380,31771076,81501550,91432302,31620103905,and 81501179)the Science Frontier Program of the Chinese Academy of Sciences(QYZDJSSW-SMC019)+4 种基金National Key R&D Program of China(2017YFA0105203,2017YFB1002502)Beijing Municipal Science and Technology Commission(Z161100000216152,Z161100000216139,Z171100000117002,and Z161100000516165)the Shenzhen Peacock Plan(KQTD2015033016104926)the Guangdong Pearl River Talents Plan(2016ZT06S220)Youth Innovation Promotion Association,CAS,China
文摘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.
文摘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.
基金supported by the National Key Research and Development Program of China (2017YFB1002505)the National Natural Science Foundation of China (61633010, 91420302, and 61503143)+1 种基金the Natural Science Foundation of Guangdong Province, China (2014A030312005 and 2014A030310244)the Pearl River S&T Nova Program of Guangzhou Municipality, China (201710010038)
文摘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.
基金supported by the National Natural Science Foundation of China (81771128)the Beijing Municipal Science & Technology Commission (Z171100001017162 and Z161100000516165)
文摘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.
基金supported by the Shanghai Municipal Science and Technology Major Project(2018SHZDZX01)ZJ Lab,Shanghai Center for Brain Science and Brain-Inspired Technology,and National Major Pre-Research Project(pilot project)(IDF151042).
文摘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.
基金supported by the Natural Science Foundation of China (81571025)International Cooperation Project from Shanghai Science Foundation (18410711300)+13 种基金the National Science Foundation for Distinguished Young Scholars of China (81025013)National Basic Research Development Program (973 Program) of China (2012CB720700, 2010CB945500, 2012CB966300, and 2009CB941100)the National Natural Science Foundation of China (81322021)the Beijing Nova Program (Z121110002512032)the Project for National 985 Engineering of China (985III-YFX0102)the ‘‘Dawn Tracking’’ Program of Shanghai Education Commission (10GG01)the Shanghai Natural Science Foundation (08411952000 and 10ZR1405400)the National Natural Science Young Foundation in China (81201033)the grants of Shanghai Health Bureau (20114358)the National High-Technology Development Project (863 Project) of China (2015AA020501)the Program for New Century Excellent Talents in University of China (NCET-10-0356)the National Program for the Support of TopNotch Young Professionalssupported by the Michael Smith Foundation, the CRC, and the CIHRsupported by the China Scholarship Council
文摘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.
基金supported by the National Natural Science Foundation of China(81671038)
文摘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.
基金supported by the National Key Research and Development Program of China (2017YFB1002502)the National Natural Science Foundation of China (81501550, 81600919, and 31771076)+5 种基金the Cross Training (Shipei) Project of High-Caliber Talents in Beijing Municipal Institutions (2017–2018)the Supplementary and Supportive Project for Teachers at Beijing Information Science and Technology University (2018–2020, 5029011103)the School Scientific Research Project at Beijing Information Science and Technology University (1825010) the Beijing Municipal Science and Technology Commission (Z161100000516165) the Shenzhen Peacock Plan (KQTD2015033016104926)the Guangdong Pearl River Talents Plan Innovative and Entrepreneurial Team grant (2016ZT06S220)
文摘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.
基金supported by grants from the General Project Plan of Zhejiang Medical Technology of China,No.2014RCA007the Medical Science and Technology Project Co-founded by Zhejiang Province and the Ministry of Health of China,No.2016152769
文摘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%）.
基金Supported by the National Natural Science Foundation of China,No.81371194 and No.81873723.
文摘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.
文摘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.
基金supported by the Guangdong Provincial Natural Science Foundation(2015A030313609)the Guangzhou Municipal Project for Science and Technology Foundation(201508020253)
文摘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.
文摘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.
基金supported by the National Natural Science Foundation of China(Grant Nos.82272118 and 81771128).
文摘A 38-year-old male patient with disorders of consciousness(DOC)successfully recovered consciousness and get obvious motor function improvements through three stages of cervical spinal cord stimulation(SCS)treatment(6 Hz,40 Hz,and combined frequency stimulation).We used the Coma Recovery ScaleRevised(CRS-R),FugleMeyer Assessment Scale,activities of daily living,and Berg Balance Scale to detect changes in consciousness and motor function during the 7-month postoperative follow-up.Electroencephalography-based individual alpha frequency(IAF)and relative power spectral density(RP)were used to assess changes in cognitive function and brain network function before and after the combined stimulation.The results revealed a gradually increased patient's CRS-R score after stimulation at 6 Hz,and the patient recovered consciousness 12 weeks postoperatively.The patient's motor function score gradually increased after adjusting the stimulation frequency to 40 Hz.However,the patient regressed in motor function when the stimulation frequency was decreased to 2 Hz.The patient's fine motor control of both hands significantly improved,accompanied by an increased RP in the beta band but the IAF decreased,after combined stimulation(40 Hz and 6 Hz).Then,motor function continued to improve with an increased IAF and RP in the alpha band after switching the stimulation order to 6 Hz and 40 Hz.Our results demonstrated that different frequency stimulations of cervical SCS may improve consciousness and motor function in patients with DOC.
文摘Objective To investigate the clinical effects of time window on hyperbaric oxygen treatment(HBOT)in patients with disorders of consciousness(DOC).Methods All the clinical research literature regarding HBOT for DOC published between January 2000 and November 2020 were retrieved from China National Knowledge Infrastructure(CNKI),Wanfang Standards Database(WFSD)and VIP Database using Chinese key words vegetative state,disorders of consciousness,and hyperbaric oxygen followed by a comprehensive meta-analysis.Results The query gave rise to 348 results,in which 21 articles were eventually selected for meta-analysis.Among the selected 21 articles,18 articles involved a time window comparison.All the patients were classified into<60-(718 patients)and≥60-(374 patients)day groups depending on the number of days from HBOT initiation.The Jadad scores for the included datasets were relatively low in general with 2 points as the highest score.Comparable baseline data were demonstrated in all of the articles.Datasets from different sources were pooled and analyzed,and the results suggested that the clinical curative effect rate in the treatment group was significantly higher compared with that in the control group(curative effect rate:69.86%versus 42.30%;Z=11.28,P=0.000,odds ratio=3.80,95%CI=3.02-4.80).Additionally,the adverse reaction rate of the<60-day group was found to be significantly lower compared with that of the≥60-day group(Z=10.01,P=0.000,odds ratio=4.82,95%CI=3.54-6.56).The funnel diagram in articles related to curative effect analysis and time window evaluation is inverted and symmetrical,indicating that publication bias was not significant.Conclusions The clinical curative effect of the HBOT group is higher compared with that of the control group.However,the conclusions based on meta-analysis are limited because of the methodological problems of some studies.Therefore,the clinical efficacy needs to be further tested using carefully designed large sample trials(multicenter,randomized,controlled,and double-blind).
文摘Chronic disorders of consciousness(DOC)include the vegetative state and the minimally consciousness state.The DOC diagnosis mainly relies on the evaluation of clinical behavioral scales,electrophysiological testing,and neuroimaging examinations.No specifically effective neurorestorative methods for chronic DOC currently exist.Any valuable exploration therapies of being able to repair functions and/or structures in the consciousness loop(e.g.,drugs,hyperbaric medicines,noninvasive neurostimulation,sensory and environmental stimulation,invasive neuromodulation therapy,and cell transplantation)may become effective neurorestorative strategies for chronic DOC.In the viewpoint of Neurorestoratology,this guideline proposes the diagnostic and neurorestorative therapeutic suggestions and future exploration direction for this disease following the review of the existing treatment exploration achievements for chronic DOC.
