CRS-R score in disorders of consciousness is strongly related to spectral EEG at rest

Patients suffering from disorders of consciousness still present a diagnostic challenge due to the fact that their assessment is mainly based on behavioral scales with their motor responses often being strongly impaired. We therefore focused on resting electroencephalography (EEG) in order to reveal potential alternative measures of the patient’s current state independent of rather complex abilities (e.g., language comprehension). Resting EEG was recorded in nine minimally conscious state (MCS) and eight vegetative state/unresponsive wakefulness syndrome (VS/UWS) patients. Behavioral assessments were conducted using the Coma-Recovery Scale—Revised (CRS-R). The signal was analyzed in the frequency domain and association between resting EEG and CRS-R score as well as clinical diagnosis were calculated using Pearson correlation and repeated-measures ANOVAs. The analyses revealed robust positive correlations between CRS-R score and ratios between frequencies above 8 Hz and frequencies below 8 Hz. Furthermore, the frequency of the spectral peak was also highly indicative of the patient’s CRS-R score. Concerning differences between clinical diagnosis and healthy controls, it could be revealed that while VS/UWS patients showed higher delta and theta activity than controls, MCS did not differ from controls in this frequency range. Alpha activity, on the other hand, was strongly decreased in both patient groups as compared to controls. The strong relationship between various resting EEG parameters and CRS-R score provides significant clinical relevance. Not only is resting activity easily acquired at bedside, but furthermore, it does not depend on explicit cooperation of the patient. Especially in cases where behavioral assessment is difficult or ambiguous, spectral analysis of resting EEG can therefore complement clinical diagnosis.     

Electroencephalography quadratic phase self-coupling correlates with consciousness states and restoration in patients with disorders of consciousness

ObjectiveThe objective of this study was to explore the role for quadratic phase coupling within electroencephalography (EEG) oscillations in the diagnosis of consciousness and consciousness restoration for disorders of consciousness (DOC).MethodsFifty-one DOC patients were enrolled in this study. For each patient, a Coma Recovery Scale-Revised (CRS-R) score and 20-min resting-state EEG were recorded. Consciousness recovery was assessed with a CRS-R score at a three-month follow-up. Twenty healthy subjects were included as controls. General harmonic wavelet transform-based bicoherence was used to quantify the quadratic phase coupling characteristics of the EEG oscillations.ResultsQuadratic phase self-coupling (QPSC) at the delta (QPSC_delta), theta (QPSC_theta) and alpha (QPSC_alpha) bands were closely correlated with patient CRS-R scores. Particularly, the QPSC_theta value could significantly differentiate between vegetative state (VS) patients, minimally conscious state (MCS) patients and healthy control subjects. As compared to VS patients, patients with MCS had a lower QPSC_theta value on the left as well as a higher QPSC_alpha value in right frontal regions. The frontal QPSC_theta value showed significant differences between recovered and unrecovered patients.ConclusionQPSC characteristics could differentiate between consciousness states and show a predictive ability for the recovery of consciousness in DOC patients.SignificanceChanges in QPSC accompany consciousness injury and restoration in DOC patients. A QPSC assessment is helpful in the diagnosis and prognosis of DOC patients.     

Validez actual del diagnóstico de «estado vegetativo permanente»: estudio longitudinal en una muestra clínica de pacientes en estados alterados de conciencia

IntroductionAltered states of consciousness have traditionally been associated with poor prognosis. At present, clinical differences between these entities are beginning to be established.MethodOur study included 37 patients diagnosed with vegetative state/unresponsive wakefulness syndrome (UWS) and 43 in a minimally conscious state (MCS) according to the Coma Recovery Scale–Revised (CRS-R). All patients were followed up each month for at least 6 months using the CRS-R. We recorded the time points when vegetative state progressed from ‘persistent’ to ‘permanent’ based on the cut-off points established by the Multi-Society-Task-Force: 12 months in patients with traumatic injury and 3 months in those with non-traumatic injury. A logistic regression model was used to determine the factors potentially predicting which patients will emerge from MCS.ResultsIn the UWS group, 23 patients emerged from UWS but only 9 emerged from MCS. Of the 43 patients in the MCS group, 26 patients emerged from that state during follow-up. Eight of the 23 patients (34.7%) who emerged from UWS and 17 of the 35 (48.6%) who emerged from MCS recovered after the time points proposed by the Multi-Society-Task-Force. According to the multivariate regression analysis, aetiology (P < .01), chronicity (P = .01), and CRS-R scores at admission (P < .001) correctly predicted emergence from MCS in 77.5% of the cases.ConclusionsUWS and MCS are different clinical entities in terms of diagnosis and outcomes. Some of the factors traditionally associated with poor prognosis, such as time from injury and likelihood of recovery, should be revaluated.     

Quantitative rates of brain glucose metabolism distinguish minimally conscious from vegetative state patients

The differentiation of the vegetative or unresponsive wakefulness syndrome (VS/UWS) from the minimally conscious state (MCS) is an important clinical issue. The cerebral metabolic rate of glucose (CMRglc) declines when consciousness is lost, and may reveal the residual cognitive function of these patients. However, no quantitative comparisons of cerebral glucose metabolism in VS/UWS and MCS have yet been reported. We calculated the regional and whole-brain CMRglc of 41 patients in the states of VS/UWS (n=14), MCS (n=21) or emergence from MCS (EMCS, n=6), and healthy volunteers (n=29). Global cortical CMRglc in VS/UWS and MCS averaged 42% and 55% of normal, respectively. Differences between VS/UWS and MCS were most pronounced in the frontoparietal cortex, at 42% and 60% of normal. In brainstem and thalamus, metabolism declined equally in the two conditions. In EMCS, metabolic rates were indistinguishable from those of MCS. Ordinal logistic regression predicted that patients are likely to emerge into MCS at CMRglc above 45% of normal. Receiver-operating characteristics showed that patients in MCS and VS/UWS can be differentiated with 82% accuracy, based on cortical metabolism. Together these results reveal a significant correlation between whole-brain energy metabolism and level of consciousness, suggesting that quantitative values of CMRglc reveal consciousness in severely brain-injured patients.     

Cardiac autonomic responses to nociceptive stimuli in patients with chronic disorders of consciousness

Objectives

Patients with chronic disorders of consciousness (DOC) may show alterations of autonomic function; however, in this clinical population, no data are available on the specific effects of nociceptive stimuli on cardiac autonomic control. Thus, we aimed at investigating the effects of a noxious stimulation on heart rate variability (HRV) in a population of patients with chronic DOC, taking into account different states of consciousness (vegetative state/unresponsive wakefulness syndrome, VS/UWS and minimally conscious state, MCS).

The vegetative state/unresponsive wakefulness syndrome: a systematic review of prevalence studies

One of the worst outcomes of acquired brain injury is the vegetative state, recently renamed ‘unresponsive wakefulness syndrome’ (VS/UWS). A patient in VS/UWS shows reflexive behaviour such as spontaneous eye opening and breathing, but no signs of awareness of the self or the environment. We performed a systematic review of VS/UWS prevalence studies and assessed their reliability. Medline, Embase, the Cochrane Library, CINAHL and PsycINFO were searched in April 2013 for cross‐sectional point or period prevalence studies explicitly stating the prevalence of VS/UWS due to acute causes within the general population. We additionally checked bibliographies and consulted experts in the field to obtain ‘grey data’ like government reports. Relevant publications underwent quality assessment and data‐extraction. We retrieved 1032 papers out of which 14 met the inclusion criteria. Prevalence figures varied from 0.2 to 6.1 VS/UWS patients per 100 000 members of the population. However, the publications’ methodological quality differed substantially, in particular with regards to inclusion criteria and diagnosis verification. The reliability of VS/UWS prevalence figures is poor. Methodological flaws in available prevalence studies, the fact that 5/14 of the studies predate the identification of the minimally conscious state (MCS) as a distinct entity in 2002, and insufficient verification of included cases may lead to both overestimation and underestimation of the actual number of patients in VS/UWS.     

Altered resting state effective connectivity in long-standing vegetative state patients: An EEG study

ObjectiveRecent evidence mainly based on hemodynamic measures suggests that the impairment of functional connections between different brain areas may help to clarify the neuronal dysfunction occurring in patients with disorders of consciousness (DOC).The aim of this study was to evaluate effective EEG connectivity in a cohort of 18 patients in a chronic vegetative state (VS) observed years after the occurrence of hypoxic (eight) and traumatic or hemorrhagic brain insult.Methodswe analysed the EEG signals recorded under resting conditions using a frequency domain linear index of connectivity (partial directed coherence: PDC) estimated from a multivariate autoregressive model. The results were compared with those obtained in ten healthy controls.ResultsOur findings indicated significant connectivity changes in EEG activities in delta and alpha bands. The VS patients showed a significant and widespread decrease in delta band connectivity, whereas the alpha activity was hyper-connected in the central and posterior cortical regions.ConclusionThese changes suggest the occurrence of severe circuitry derangements probably due to the loose control of the subcortical connections. The alpha hyper-synchronisation may be due to simplified networks mainly involving the short-range connections between intrinsically oscillatory cortical neurons that generate aberrant EEG alpha sources. This increased connectivity may be interpreted as a reduction in information capacity, implying an increasing prevalence of stereotypic activity patterns.SignificanceOur observations suggest a remarkable rearrangement of connectivity in patients with long-standing VS. We hypothesize that in persistent VS, after a first period characterized by a breakdown of cortical connectivity, neurodegenerative processes, largely independent from the type of initial insult, lead to cortex de-afferentation and to a severe reduction of possible cortical activity patterns and states.     

脑室线性结构变化与严重意识障碍疾病的相关性研究

目的评价脑室线性结构在意识障碍(DOC)患者诊断和分级中的应用价值。方法收集2015年1月至2015年12月就诊于中国人民解放军陆军总医院的20例DOC患者,由两名主治医师根据CRS-R评分量表将患者分为无反应觉醒综合征组(UWS)和微意识状态组(MCS)。另选10例健康志愿者作为对照组。分析患者MRI T_1图像的结果,测量数据并探索这些测量指标与CRS-R评分之间的相关性。结果 UWS组和MCS组的Huckman值和第三脑室宽度明显高于对照组(均P0.05),而PDI指数和脑室指数则低于对照组(均P0.05),除Evans值外其余各指标在UWS组和MCS组之间差别也具有统计学意义(均P0.05)。Huckman值和第三脑室宽度与CRS-R评分呈负相关,而PDI指数和脑室指数则相反。结论脑室线性结构测量可以用于DOC患者意识水平的评估。     

Fronto-parietal coherence response to tDCS modulation in patients with disorders of consciousness

Aim of the study: A transcranial direct current stimulation (tDCS) protocol (20 min, 2 mA, anodal electrode at the left dorsolateral prefrontal cortex and cathodal electrode at the right supraorbital area) was applied in patients with different degrees of disorders of consciousness (DoC). Although previous research indicates that it could improve patients’ coma recovery scale-revised (CRS-R) scores, the brain's electrophysiological responses to tDCS are still unclear. Therefore, the present study was performed to explore the underlying brain responses of patients in a minimally conscious state (MCS) and an unresponsive wakefulness syndrome (UWS) to tDCS modulation.

Materials and methods: Seventeen patients with DoC were recruited in a sham controlled crossover study receiving real and sham tDCS. EEG coherence was used to measure functional connectivity changes induced by the tDCS modulation.

Results: After real tDCS modulation, the fronto-parietal coherence significantly increased in the theta band and decreased in the gamma band in the MCS group. No significant changes were found in the UWS group. The coherence responses significantly correlated with the patients’ baseline CRS-R scores. No distinct alteration occurred in the sham session for either the MCS or UWS patients.

Conclusions: The coherence responses to the present tDCS protocol may be a tool for diagnosing MCS versus UWS, as they may be a crucial cause of the different clinical effects in the two states.     

Behavioural and electrophysiological effects of tDCS to prefrontal cortex in patients with disorders of consciousness

ObjectivesLeft dorsolateral prefrontal cortex anodal transcranial direct current stimulation (tDCS) was applied in a group of patients with disorders of consciousness to determine the effects of modulation of spontaneous oscillatory brain activity.Methods12 patients in an unresponsive wakefulness syndrome (UWS) and 12 in a minimally conscious state (MCS) underwent 2-weeks active and 2-weeks sham tDCS. Neurophysiological assessment was performed with EEG power spectra and coherence analysis directly before and after each session.ResultsAn increase of power and coherence of the frontal and parietal alpha and beta frequency bands and significant clinical improvements were seen after the active tDCS in MCS patients. In contrast, UWS patients showed some local frontal changes in the slow frequencies. No treatment effect was observed after sham.ConclusionstDCS could induce changes in cortical EEG oscillations, modulating the travel of alpha and beta waves between anterior and posterior brain areas when some cognitive functions were preserved. This plays an important role in consciousness by integrating cognitive-emotional processing with the state of arousal. In unresponsive people, brain integration seems to be lost.SignificanceOur results further support the critical role of long-range fronto-parietal connections in consciousness and show the potential therapeutic utility of tDCS.     

Sleep patterns associated with the severity of impairment in a large cohort of patients with chronic disorders of consciousness

Objective

We assessed sleep patterns in 85 patients with chronic disorders of consciousness (DOC) in order to reveal any relationship with the degree of the impairment.

Global functional connectivity reveals highly significant differences between the vegetative and the minimally conscious state

A major challenge in the diagnosis of disorders of consciousness is the differential diagnosis between the vegetative state (VS) and the minimally conscious state (MCS). Clinically, VS is defined by complete unawareness, whereas MCS is defined by the presence of inconsistent but clearly discernible behavioural signs of consciousness. In healthy individuals, pain cries have been reported to elicit functional activation within the pain matrix of the brain, which may be interpreted as empathic reaction. In this study, pain cries were presented to six VS patients, six MCS patients, and 17 age-matched healthy controls. Conventional task-related functional magnetic resonance imaging (fMRI) showed no significant differences in functional activation between the VS and MCS groups. In contrast to this negative finding, the application of a novel data-driven technique for the analysis of the brain’s global functional connectivity yielded a positive result. The weighted global connectivity (WGC) was significantly greater in the MCS group compared to the VS group (p < 0.05, family-wise error corrected). Using areas of significant WGC differences as ‘seed regions’ in a secondary connectivity analysis revealed extended functional networks in both MCS and healthy groups, whereas no such long-range functional connections were observed in the VS group. These results demonstrate the potential of functional connectivity MRI (fcMRI) as a clinical tool for differential diagnosis in disorders of consciousness.     

弥散张量成像对意识障碍患者诊断与预后评估的作用

目的探讨弥散张量成像（DTI）对意识障碍（DOC）患者的临床应用价值及其各指标变化规律。 方法选取自2014年1月至2015年12月陆军总医院附属八一脑科医院临床诊断为DOC的患者[植物状态（VS）患者56例,微意识状态（MCS）患者19例]进行弥散张量扫描,分别收集脑干、丘脑、皮层下三个相关的感兴趣区域评价FA、MD等指标数据。对不同意识状态的两组的参数值进行统计学分析,并将感兴趣区的各向异性（FA）、平均弥散率（MD）均值与临床昏迷恢复量表（CRS-R）评分进行相关性分析。 结果VS组FA值明显低于MCS组,差异具有统计学意义（P<0.05）;MD值则高于MCS组,差异具有统计学意义（P<0.05）;感兴趣区（脑干、皮层下,丘脑）FA值和MD值与CRS-R评分具有较好相关性,尤其是丘脑部。 结论DTI对于DOC影像学分级具有一定的临床参考价值。意识障碍程度越重,MD值越高,FA值越低。     

Analysis of Wessex Head Injury Matrix (WHIM) scores in consecutive vegetative and minimally conscious state patients

Consensus guidelines defining minimally conscious state (MCS) have been available for some years. However, to date, few measures have been developed that are particularly suited to monitoring MCS patients and there are limited clinical outcome data. The objective of the study was to determine the value of serial repeated assessments using the Wessex Head Injury Matrix (WHIM) to identify changes in vegetative state (VS) and MCS patients. Twenty consecutive VS/MCS patients admitted to a post-acute regional neurorehabilitation unit were assessed using WHIM. Significant differences in both total number of behaviours observed (p < .001) and highest rank behaviour were observed (p = .001) between initial and final WHIM assessments. Preliminary findings suggest that the WHIM is a sensitive measure of subtle changes in VS and MCS patients.     

脑机接口技术在慢性意识障碍诊疗中的应用进展

慢性意识障碍(DOC)包括植物状态(VS)或无反应觉醒综合征(UWS)和微意识状态(MCS),目前临床鉴别诊断以及治疗仍是难题。慢性意识障碍评估,目前临床使用较多的是量表,但存在误判。为了提高诊断准确率,出现一些基于神经影像学的辅助检测方法,如脑机接口(BCI)技术。BCI主要通过脑电信号的处理用人机对话的方法检测患者是否存在指令跟随,被用于意识障碍患者意识状态的检测及康复治疗的评价。本文简述BCI技术特点及在慢性意识障碍中的应用前景。     

Disentangling disorders of consciousness: Insights from diffusion tensor imaging and machine learning

Previous studies have suggested that disorders of consciousness (DOC) after severe brain injury may result from disconnections of the thalamo‐cortical system. However, thalamo‐cortical connectivity differences between vegetative state (VS), minimally conscious state minus (MCS?, i.e., low‐level behavior such as visual pursuit), and minimally conscious state plus (MCS+, i.e., high‐level behavior such as language processing) remain unclear. Probabilistic tractography in a sample of 25 DOC patients was employed to assess whether structural connectivity in various thalamo‐cortical circuits could differentiate between VS, MCS?, and MCS+ patients. First, the thalamus was individually segmented into seven clusters based on patterns of cortical connectivity and tested for univariate differences across groups. Second, reconstructed whole‐brain thalamic tracks were used as features in a multivariate searchlight analysis to identify regions along the tracks that were most informative in distinguishing among groups. At the univariate level, it was found that VS patients displayed reduced connectivity in most thalamo‐cortical circuits of interest, including frontal, temporal, and sensorimotor connections, as compared with MCS+, but showed more pulvinar‐occipital connections when compared with MCS?. Moreover, MCS? exhibited significantly less thalamo‐premotor and thalamo‐temporal connectivity than MCS+. At the multivariate level, it was found that thalamic tracks reaching frontal, parietal, and sensorimotor regions, could discriminate, up to 100% accuracy, across each pairwise group comparison. Together, these findings highlight the role of thalamo‐cortical connections in patients' behavioral profile and level of consciousness. Diffusion tensor imaging combined with machine learning algorithms could thus potentially facilitate diagnostic distinctions in DOC and shed light on the neural correlates of consciousness. Hum Brain Mapp 38:431–443, 2017 . © 2016 Wiley Periodicals, Inc.     

Brain function in the minimally conscious state: a quantitative neurophysiological study.

OBJECTIVE: To explore possible EEG power spectrum and coherence differences between patients in minimally conscious state (MCS) and patients with severe neurocognitive disorders (SND), who show signs of awareness. We also try to find EEG cortical sources that differentiate between both conditions using LORETA source analysis. METHODS: We studied 16 patients with traumatic brain injury (7 MCS, 9 SND; aged 18-49) and compared EEG power spectra, coherence, and LORETA sources at rest for both groups. RESULTS: EEG power spectra revealed significant differences in the delta range of both conditions. Patients in MCS showed a notably increased power in this band, compared to SND patients. LORETA analysis showed that posterior sources of delta and theta frequencies had higher amplitude in MCS patients than in SND patients. Regarding fast frequencies, lower source magnitudes in temporal and frontal lobes were found for MCS patients. CONCLUSIONS: Our results stress the importance of fronto-temporal-parietal associative cortices within the "awareness-regions" model. Our results also suggest a relation between excess of slow wave activity and diminished level of awareness in brain injury population. SIGNIFICANCE: Neurophysiological correlates in brain damaged patients who are severely impaired could be used to assess the integrity of brain areas responsible for awareness.     

Resistance to eye opening in patients with disorders of consciousness

Introduction

Resistance to eye opening (REO) is a commonly encountered phenomenon in clinical practice. We aim to investigate whether REO is a sign of consciousness or a reflex in severely brain-injured patients.

Methods

We recorded REO in chronic patients with disorders of consciousness during a multimodal diagnostic assessment. REO evaluations were performed daily in each patient and clinical diagnosis of unresponsive wakefulness syndrome (UWS), minimally conscious state with (MCS+) or without (MCS?) preserved language processing was made using the Coma Recovery Scale-Revised (CRS-R).

Results

Out of 150 consecutive patients, 79 patients fit inclusion criteria. REO was seen in 19 patients (24.1%). At the group level, there was a significant relationship between the presence of REO and the level of consciousness. We also observed a difference in the repeatability of REO between patients in UWS, MCS? and MCS+. Out of 23 patients in UWS, six showed REO, in whom five showed atypical brain patterns activation.

Conclusion

Our findings suggest a voluntary basis for REO and stress the need for multiple serial assessments of REO in these patients, especially since most patients show fluctuating levels of consciousness.

     

视觉威胁反应在判断严重意识障碍程度的应用

目的用强弱光源作为视觉威胁刺激物,与CRS-R量表中以手指为刺激物的视觉威胁反应进行对比,比较严重意识障碍患者对不同视觉威胁刺激物的敏感性差异;在此基础上研究视觉威胁反应能否作为意识的指标。方法随机选择89例严重意识障碍(DOC)患者,采用The JFK Coma Recovery Scale-Revise(JFK改进的昏迷恢复量表,以下简称CRS-R)对其进行床边测量。对于视觉威胁反应项,分别对患者采取手指、弱光、强光刺激物进行刺激,比较反应的差异。结果植物状态(VS)和最小意识状态(MCS)患者对手指视觉威胁刺激的反应具有显著的差异(P0.001),植物状态和最小意识状态患者对强光视觉威胁刺激的反应具有显著的差异(P0.001)。最小意识障碍患者对手指、强光两种视觉威胁刺激的反应没有显著性的差异(P0.05),植物状态患者对手指、强光两种视觉威胁刺激的反应没有显著性的差异(P0.05)。结论严重意识障碍患者(n=89)对不同刺激物(手指、弱光、强光)的反应无显著性差异;视觉威胁反应(手指和光)能反映意识。     

Pain Perception in Disorders of Consciousness: Neuroscience, Clinical Care, and Ethics in Dialogue

Pain, suffering and positive emotions in patients in vegetative state/unresponsive wakefulness syndrome (VS/UWS) and minimally conscious states (MCS) pose clinical and ethical challenges. Clinically, we evaluate behavioural responses after painful stimulation and also emotionally-contingent behaviours (e.g., smiling). Using stimuli with emotional valence, neuroimaging and electrophysiology technologies can detect subclinical remnants of preserved capacities for pain which might influence decisions about treatment limitation. To date, no data exist as to how healthcare providers think about end-of-life options (e.g., withdrawal of artificial nutrition and hydration) in the presence or absence of pain in non-communicative patients. Here, we aimed to better clarify this issue by re-analyzing previously published data on pain perception (Prog Brain Res 2009 177, 329–38) and end-of-life decisions (J Neurol 2010 258, 1058–65) in patients with disorders of consciousness. In a sample of 2259 European healthcare professionals we found that, for VS/UWS more respondents agreed with treatment withdrawal when they considered that VS/UWS patients did not feel pain (77%) as compared to those who thought VS/UWS did feel pain (59%). This interaction was influenced by religiosity and professional background. For MCS, end-of-life attitudes were not influenced by opinions on pain perception. Within a contemporary ethical context we discuss (1) the evolving scientific understandings of pain perception and their relationship to existing clinical and ethical guidelines; (2) the discrepancies of attitudes within (and between) healthcare providers and their consequences for treatment approaches, and (3) the implicit but complex relationship between pain perception and attitudes toward life-sustaining treatments.