Toward an interventional science of recovery after coma.

Recovery of consciousness after coma remains one of the most challenging areas for accurate diagnosis and effective therapeutic engagement in the clinical neurosciences. Recovery depends on preservation of neuronal integrity and evolving changes in network function that re-establish environmental responsiveness. It typically occurs in defined steps: it begins with eye opening and unresponsiveness in a vegetative state, then limited recovery of responsiveness characterizes the minimally conscious state, and this is followed by recovery of reliable communication. This review considers several points for novel interventions, for example, in persons with cognitive motor dissociation in whom a hidden cognitive reserve is revealed. Circuit mechanisms underlying restoration of behavioral responsiveness and communication are discussed. An emerging theme is the possibility to rescue latent capacities in partially damaged human networks across time. These opportunities should be exploited for therapeutic engagement to achieve individualized solutions for restoration of communication and environmental interaction across varying levels of recovery.

Single session of intermittent theta burst stimulation alters brain activity of patients in vegetative state.

BACKGROUND: Non-invasive brain stimulation is considered as a promising technology for treating patients with disorders of consciousness (DOC). Various approaches and protocols have been proposed; however, few of them have shown potential effects on patients with vegetative state (VS). This study aimed to explore the neuro-modulation effects of intermittent theta burst stimulation (iTBS) on the brains of patients with VS and to provide a pilot investigation into its possible role in treating such patients. METHODS: We conducted a sham-controlled crossover study, a real and a sham session of iTBS were delivered over the left dorsolateral prefrontal cortex of such patients. A measurement of an electroencephalography (EEG) and a behavioral assessment of the Coma Recovery Scale-Revised (CRS-R) were applied to evaluate the modulation effects of iTBS before and after stimulation. RESULTS: No meaningful changes of CRS-R were found. The iTBS altered the spectrum, complexity and functional connectivity of the patients. The real stimulation induced a trend of decreasing of delta power at T1 and T2 in the frontal region, significant increasing of permutation entropy at the T2 in the left frontal region. In addition, brain functional connectivity, particularly inter-hemispheric connectivity, was strengthened between the electrodes of the frontal region. The sham stimulation, however, did not induce any significant changes of the brain activity. CONCLUSIONS: One session of iTBS significantly altered the oscillation power, complexity and functional connectivity of brain activity of VS patients. It may be a valuable tool on modulating the brain activities of patients with VS.

Neurobehavioral Progress and Signs of Transition in Children With Prolonged Disorders of Consciousness: A Retrospective Longitudinal Study With the Coma Recovery Scale-Revised.

BACKGROUND: Research on disorders of consciousness in children is scarce and includes disparate and barely comparable participants and assessment instruments and therefore provides inconclusive information on the clinical progress and recovery in this population. This study retrospectively investigated the neurobehavioral progress and the signs of transition between states of consciousness in a group of children admitted to a rehabilitation program either with an unresponsive wakefulness syndrome (UWS) or in a minimally conscious state (MCS). METHODS: Systematic weekly assessments were conducted with the Coma Recovery Scale-Revised (CRS-R) until emergence from MCS, discharge, or death. RESULTS: Twenty-one children, nine admitted with a UWS and 12 admitted in an MCS, were included in the study. Four children with a UWS transitioned to an MCS with a CRS-R of 10 (9.2 to 12.2) by showing visual pursuit, visual fixation, or localization to noxious stimulation. Twelve children emerged from the MCS with a CRS-R of 20.5 (19 to 21.7). Children who emerged from the MCS had had a shorter time postinjury and higher CRS-R at admission, compared with those who did not emerge. CONCLUSIONS: Almost half of the children who were admitted with a UWS transitioned to an MCS, and almost all who were admitted in an MCS emerged from this state. Children who emerged had shorter times since injury and higher scores on the CRS-R at admission, compared with those who did not emerge.

Effects of different frequencies music on cortical responses and functional connectivity in patients with minimal conscious state.

The objective of this study was to investigate brain activation and functional network patterns during musical interventions in different frequency bands using functional near-infrared spectroscopy, and to provide a basis for more effective music therapy strategy selection for patients in minimally conscious state (MCS). Twenty six MCS patients and 20 healthy people were given music intervention with low frequency (31-180 Hz), medium frequency (180-4k Hz), and high frequency (4k-22k Hz) audio. In MCS patients, low frequency music intervention induced activation of left prefrontal cortex and left primary sensory cortex (S1), also a left-hemisphere lateralization effect of dorsolateral prefrontal cortex (DLPFC). And the functional connectivity of right DLPFC-right S1 was significantly improved by high frequency music intervention. The low frequency and high frequency music may contribute more than medium frequency music to the recovery of consciousness. This study also validated the effectiveness of fNIRS in studies of brain function in MCS patients.

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

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

Spatio-temporal analysis of EEG features during consciousness recovery in patients with disorders of consciousness.

OBJECTIVE: As consciousness recovery is not only dynamic but also involves interactions between various brain regions, elucidating the mechanism of recovery requires tracking cortical activity in spatio-temporal dimensions. METHODS: We tracked the cortical activities of 40 patients (mean age: 54.38 years; 28 males; 21 patients with minimally conscious states) with disorders of consciousness, and collected a total of 156 electroencephalographic signals. We investigated the longitudinal changes in EEG nonlinear dynamic features (i.e., approximate entropy, sample entropy, and Lempel-Ziv complexity) and relative wavelet energy along with consciousness recovery. RESULTS: Global EEG features showed a non-monotonic trend during consciousness recovery (P < 0.05). When the level of consciousness of patients was transferred to a minimally conscious state from an unresponsive wakefulness syndrome/ vegetative state, an inflection point appeared in the EEG features. The EEG feature change trends between the injured and uninjured areas were dissimilar (P < 0.05). Importantly, the degree of dissimilarity increased non-monotonically across the levels of consciousness (P < 0.05). CONCLUSIONS: EEG recovery was non-monotonic and dissimilar in spatio-temporal dimensions, with an inflection point. SIGNIFICANCE: These findings further clarify the process of consciousness recovery and provide assistance in exploring the mechanism of consciousness recovery.

Difference in the ascending reticular activating system between vegetative and minimally conscious states following traumatic brain injury.

OBJECTIVES: We investigated differences in the ascending reticular activating system (ARAS) between vegetative state (VS) and minimally conscious state (MCS) in patients with traumatic brain injury (TBI) by using diffusion tensor tractography. METHODS: We recruited TBI patients and normal subjects. We reconstructed the lower ARAS and five parts of upper ARAS [prefrontal cortex (PFC), premotor cortex, primary motor cortex, primary somatosensory cortex, and posterior parietal cortex]. RESULTS: Significant differences were observed in the fractional anisotropy (FA) and fiber number (FN) values of the five parts of upper ARAS between the VS and control groups and between the MCS and control groups (P < 0.05), but no differences were detected in the lower ARAS (P > 0.05). The FA and FN values of the PFC in the upper ARAS were significantly different between the VS and MCS groups (P < 0.05). No other significant differences in FA and FN values were detected among the other segments of the upper ARAS or in the lower ARAS (P > 0.05). CONCLUSION: The results indicate that the prefrontal portion of the upper ARAS is the critical area for distinguishing between VS and MCS in patients with TBI.

Improving motor and cognitive recovery following severe traumatic brain injury using advanced emotional audio-video stimulation: Lessons from a case report.

RATIONALE: It is estimated that about 6 million people suffer from severe traumatic brain injury (TBI) each year (73 cases per 100,000 people). TBI may affect emotional, sensory-motor, cognitive, and psychological functions with a consequent worsening of both patient and his/her caregiver's quality of life. In recent years, technological innovations allowed the development of new, advanced sensory stimulation systems, such as Neurowave, to further stimulate residual cognitive abilities and, at the same time, evaluate residual cognition. PATIENT CONCERN: An 69-year-old Italian man entered our neurorehabilitation unit with a diagnosis of minimally conscious state following severe TBI. He breathed spontaneously via tracheostomy and was fed via percutaneous gastrostomy. At the neurological examination, the patient showed severe tetraparesis as he showed fluctuating alertness and responsiveness to external stimuli and opened the eyes without stimulation. DIAGNOSIS: Patient was affected by subarachnoid hemorrhage and frontotemporal bilateral hematoma, which were surgically treated with decompressive craniotomy and subsequent cranioplasty about 6 months before. INTERVENTIONS: The patient underwent a neuropsychological and clinical evaluation before (T0) and after a conventional rehabilitation cycle (T1), and after a Neurowave emotional stimulation-supported rehabilitative cycle (T2). OUTCOMES: Following conventional rehabilitation (T1), the patient achieved a partial improvement in behavioral responsiveness; there was also a mild improvement in the caregiver's distress. Conversely, Neurowave emotional stimulation session determined (at T2) a significant improvement of the patient's behavioral responsiveness, cognition, and in the caregiver's distress. The P300 recording in response to the NES showed a significant change of P300 magnitude and latency. DISCUSSION: Our data suggest that emotional-integrated sensory stimulation using adequate visual stimuli represents a beneficial, complementary rehabilitative treatment for patients in minimally conscious state following a severe TBI. This may occur because stimuli with emotional salience can provide a reliable motivational resource to stimulate motor and cognitive recovery following severe TBI.

Spontaneous transient brain states in EEG source space in disorders of consciousness.

Spontaneous transient states were recently identified by functional magnetic resonance imaging and magnetoencephalography in healthy subjects. They organize and coordinate neural activity in brain networks. How spontaneous transient states are altered in abnormal brain conditions is unknown. Here, we conducted a transient state analysis on resting-state electroencephalography (EEG) source space and developed a state transfer analysis to patients with disorders of consciousness (DOC). They uncovered different neural coordination patterns, including spatial power patterns, temporal dynamics, spectral shifts, and connectivity construction varies at potentially very fast (millisecond) time scales, in groups with different consciousness levels: healthy subjects, patients in minimally conscious state (MCS), and patients with vegetative state/unresponsive wakefulness syndrome (VS/UWS). Machine learning based on transient state features reveal high classification accuracy between MCS and VS/UWS. This study developed methodology of transient states analysis on EEG source space and abnormal brain conditions. Findings correlate spontaneous transient states with human consciousness and suggest potential roles of transient states in brain disease assessment.

Preservation of Brain Activity in Unresponsive Patients Identifies MCS Star.

OBJECTIVE: Brain-injured patients who are unresponsive at the bedside (ie, vegetative state/unresponsive wakefulness syndrome - VS/UWS) may present brain activity similar to patients in minimally conscious state (MCS). This peculiar condition has been termed "non-behavioural MCS" or "MCS*". In the present study we aimed to investigate the proportion and underlying brain characteristics of patients in MCS*. METHODS: Brain 18 F-fluorodeoxyglucose Positron Emission Tomography (FDG-PET) was acquired on 135 brain-injured patients diagnosed in prolonged VS/UWS (n = 48) or MCS (n = 87). From an existing database, relative metabolic preservation in the fronto-parietal network (measured with standardized uptake value) was visually inspected by three experts. Patients with hypometabolism of the fronto-parietal network were labelled "VS/UWS", while its (partial) preservation either confirmed the behavioural diagnosis of "MCS" or, in absence of behavioural signs of consciousness, suggested a diagnosis of "MCS*". Clinical outcome at 1-year follow-up, functional connectivity, grey matter atrophy, and regional brain metabolic patterns were investigated in the three groups (VS/UWS, MCS* and MCS). RESULTS: 67% of behavioural VS/UWS presented a partial preservation of brain metabolism (ie, MCS*). Compared to VS/UWS patients, MCS* patients demonstrated a better outcome, global functional connectivity and grey matter preservation more compatible with the diagnosis of MCS. MCS* patients presented lower brain metabolism mostly in the posterior brain regions compared to MCS patients. INTERPRETATION: MCS* is a frequent phenomenon that is associated with better outcome and better brain preservation than the diagnosis of VS/UWS. Complementary exams should be provided to all unresponsive patients before taking medical decisions. ANN NEUROL 2021;90:89-100.

A novel closed-loop EEG-tDCS approach to promote responsiveness of patients in minimally conscious state: A study protocol.

Transcranial direct current stimulation (tDCS) applied over the prefrontal cortex has been shown to improve behavioral responsiveness in patients with disorders of consciousness following severe brain injury, especially those in minimally conscious state (MCS). However, one potential barrier of clinical response to tDCS is the timing of stimulation with regard to the fluctuations of vigilance that characterize this population. Indeed, a previous study showed that the vigilance of MCS patients has periodic average cycles of 70 min (range 57-80 min), potentially preventing them to be in an optimal neural state to benefit from tDCS when applied randomly. To tackle this issue, we propose a new protocol to optimize the application of tDCS by selectively stimulating at high and low vigilance states. Electroencephalography (EEG) real-time spectral entropy will be used as a marker of vigilance and to trigger tDCS, in a closed-loop fashion. We will conduct a randomized controlled crossover clinical trial on 16 patients in prolonged MCS who will undergo three EEG-tDCS sessions 5 days apart (1. tDCS applied at high vigilance; 2. tDCS applied at low vigilance; 3. tDCS applied at a random moment). Behavioral effects will be assessed using the Coma Recovery Scale-Revised at baseline and right after the stimulations. EEG will be recorded throughout the session and for 30 min after the end of the stimulation. This unique and novel approach will provide patients' tailored treatment options, currently lacking in the field of disorders of consciousness.

Neural Responses to Heartbeats Detect Residual Signs of Consciousness during Resting State in Postcomatose Patients.

The neural monitoring of visceral inputs might play a role in first-person perspective (i.e., the unified viewpoint of subjective experience). In healthy participants, how the brain responds to heartbeats, measured as the heartbeat-evoked response (HER), correlates with perceptual, bodily, and self-consciousness. Here we show that HERs in resting-state EEG data distinguishes between postcomatose male and female human patients (n = 68, split into training and validation samples) with the unresponsive wakefulness syndrome and in patients in a minimally conscious state with high accuracy (random forest classifier, 87% accuracy, 96% sensitivity, and 50% specificity in the validation sample). Random EEG segments not locked to heartbeats were useful to predict unconsciousness/consciousness, but HERs were more accurate, indicating that HERs provide specific information on consciousness. HERs also led to more accurate classification than heart rate variability. HER-based consciousness scores correlate with glucose metabolism in the default-mode network node located in the right superior temporal sulcus, as well as with the right ventral occipitotemporal cortex. These results were obtained when consciousness was inferred from brain glucose met`abolism measured with positron emission topography. HERs reflected the consciousness diagnosis based on brain metabolism better than the consciousness diagnosis based on behavior (Coma Recovery Scale-Revised, 77% validation accuracy). HERs thus seem to capture a capacity for consciousness that does not necessarily translate into intentional overt behavior. These results confirm the role of HERs in consciousness, offer new leads for future bedside testing, and highlight the importance of defining consciousness and its neural mechanisms independently from behavior.

Long-term recovery from a minimally responsive state with recovery of an injured ascending reticular activating system: A case report.

ABSTRACT: We report on a patient with hypoxic-ischemic brain injury (HI-BI) who showed recovery from a minimally consciousness state over 6 years concurrent with recovery of an injured ascending reticular activating system (ARAS), which was demonstrated on diffusion tensor tractography (DTT).A 31-year-old female patient, who suffered from HI-BI, showed impaired consciousness with a minimally conscious state: intermittently obeying simple motor tasks, such as "please grasp my hand." Her consciousness showed recovery with the passage of time; rapid recovery was observed during the recent 2 years.In the upper ARAS, the neural connectivity to both the basal forebrain and prefrontal cortex had increased on 8-year DTT compared with 1.5-year DTT. In the lower dorsal and ventral ARAS, no significant change was observed between 1.5 and 8 years DTTs.Recovery of an injured ARAS was demonstrated in a patient who showed recovery from a minimally consciousness state over 6 years following HI-BI. Our results suggest the brain target areas for recovery of impaired awareness in patients with disorders of consciousness.

Somatosensory evoked potential amplitudes correlate with long-term consciousness recovery in patients with unresponsive wakefulness syndrome.

OBJECTIVE: To prospectively investigate relationships of cortical somatosensory evoked potential (SEP) amplitudes with consciousness recovery and disability in the year following brain injury in patients with vegetative state/unresponsive wakefulness syndrome (VS/UWS). METHODS: SEPs of 42 patients with VS/UWS were recorded 51.7 ± 23.3 days post-injury. N20-P25 amplitudes were compared between patients with and without consciousness recovery at 6 months and 1 year post-injury. RESULTS: SEPs were present in 21 patients and bilaterally absent in 21 patients. N20-P25 amplitudes were significantly higher in patients who recovered consciousness than in those who died or did not recover consciousness at 6 months (median, 4.6 vs. 1.9 µV; P = 0.004) and 1 year (median, 4.6 vs. 2.1 µV; P = 0.02) after injury. The lowest N20-P25 amplitude in a patient who recovered consciousness was 2.15 µV. N20-P25 amplitudes correlated significantly with Coma Recovery Scale-Revised and Disability Rating Scale scores at 6 months and 1 year post-injury (both P < 0.05). CONCLUSIONS: In patients with VS/UWS, SEP amplitudes are related to consciousness recovery and disability at 6 months and 1 year post-injury. SIGNIFICANCE: The evaluation of SEP amplitudes can help to refine prognoses for patients with VS/UWS.

Swallowing in individuals with disorders of consciousness: A cohort study.

BACKGROUND: After a period of coma, a proportion of individuals with severe brain injury remain in an altered state of consciousness before regaining partial or complete recovery. Individuals with disorders of consciousness (DOC) classically receive hydration and nutrition through an enteral-feeding tube. However, the real impact of the level of consciousness on an individual's swallowing ability remains poorly investigated. OBJECTIVE: We aimed to document the incidence and characteristics of dysphagia in DOC individuals and to evaluate the link between different components of swallowing and the level of consciousness. METHODS: We analyzed clinical data on the respiratory status, oral feeding and otolaryngologic examination of swallowing in DOC individuals. We analyzed the association of components of swallowing and participant groups (i.e., unresponsive wakefulness syndrome [UWS] and minimally conscious state [MCS]). RESULTS: We included 92 individuals with DOC (26 UWS and 66 MCS). Overall, 99% of the participants showed deficits in the oral and/or pharyngeal phase of swallowing. As compared with the MCS group, the UWS group more frequently had a tracheostomy (69% vs 24%), with diminished cough reflex (27% vs 54%) and no effective oral phase (0% vs 21%). CONCLUSION: Almost all DOC participants had severe dysphagia. Some components of swallowing (i.e., tracheostomy, cough reflex and efficacy of the oral phase of swallowing) were related to consciousness. In particular, no UWS participant had an efficient oral phase, which suggests that its presence may be a sign of consciousness. In addition, no UWS participant could be fed entirely orally, whereas no MCS participant orally received ordinary food. Our study also confirms that objective swallowing assessment can be successfully completed in DOC individuals and that specific care is needed to treat severe dysphagia in DOC.

Are intrinsic neural timescales related to sensory processing? Evidence from abnormal behavioral states.

The brain exhibits a complex temporal structure which translates into a hierarchy of distinct neural timescales. An open question is how these intrinsic timescales are related to sensory or motor information processing and whether these dynamics have common patterns in different behavioral states. We address these questions by investigating the brain's intrinsic timescales in healthy controls, motor (amyotrophic lateral sclerosis, locked-in syndrome), sensory (anesthesia, unresponsive wakefulness syndrome), and progressive reduction of sensory processing (from awake states over N1, N2, N3). We employed a combination of measures from EEG resting-state data: auto-correlation window (ACW), power spectral density (PSD), and power-law exponent (PLE). Prolonged neural timescales accompanied by a shift towards slower frequencies were observed in the conditions with sensory deficits, but not in conditions with motor deficits. Our results establish that the spontaneous activity's intrinsic neural timescale is related to the neural capacity that specifically supports sensory rather than motor information processing in the healthy brain.

Intact Brain Network Function in an Unresponsive Patient with COVID-19.

Many patients with severe coronavirus disease 2019 (COVID-19) remain unresponsive after surviving critical illness. Although several structural brain abnormalities have been described, their impact on brain function and implications for prognosis are unknown. Functional neuroimaging, which has prognostic significance, has yet to be explored in this population. Here we describe a patient with severe COVID-19 who, despite prolonged unresponsiveness and structural brain abnormalities, demonstrated intact functional network connectivity, and weeks later recovered the ability to follow commands. When prognosticating for survivors of severe COVID-19, clinicians should consider that brain networks may remain functionally intact despite structural injury and prolonged unresponsiveness. ANN NEUROL 2020;88:851-854.

Habituation of auditory startle reflex is a new sign of minimally conscious state.

Neurological examination of non-communicating patients relies on a few decisive items that enable the crucial distinction between vegetative state (VS)-also coined unresponsive wakefulness syndrome (UWS)-and minimally conscious state. Over the past 10 years, this distinction has proven its diagnostic value as well as its important prognostic value on consciousness recovery. However, clinicians are currently limited by three factors: (i) the current behavioural repertoire of minimally conscious state items is limited and restricted to a few cognitive domains in the goldstandard revised version of the Coma Recovery Scale; (ii) a proportion of ∼15-20% clinically VS/UWS patients are actually in a richer state than VS/UWS as evidenced by functional brain imaging; and (iii) the neurophysiological and cognitive interpretation of each minimally conscious state item is still unclear and debated. In the current study we demonstrate that habituation of the auditory startle reflex (hASR) tested at bedside constitutes a novel, simple and powerful behavioural sign that can accurately distinguish minimally conscious state from VS/UWS. In addition to enlarging the minimally conscious state items repertoire, and therefore decreasing the low sensitivity of current behavioural measures, we also provide an original and rigorous description of the neurophysiological basis of hASR through a combination of functional (high density EEG and 18F-fluorodeoxyglucose PET imaging) and structural (diffusion tensor imaging MRI) measures. We show that preservation of hASR is associated with the functional and structural integrity of a brain-scale fronto-parietal network, including prefrontal regions related to control of action and inhibition, and meso-parietal areas associated with minimally conscious and conscious states. Lastly, we show that hASR predicts 6-month improvement of consciousness. Taken together, our results show that hASR is a cortically-mediated behaviour, and suggest that it could be a new clinical item to clearly and accurately identify non-communicating patients who are in the minimally conscious state.

Brain functional connectivity during the first day of coma reflects long-term outcome.

OBJECTIVE: In patients with disorders of consciousness (DOC), properties of functional brain networks at rest are informative of the degree of consciousness impairment and of long-term outcome. Here we investigate whether connectivity differences between patients with favorable and unfavorable outcome are already present within 24 h of coma onset. METHODS: We prospectively recorded 63-channel electroencephalography (EEG) at rest during the first day of coma after cardiac arrest. We analyzed 98 adults, of whom 57 survived beyond unresponsive wakefulness. Functional connectivity was estimated by computing the 'debiased weighted phase lag index' over epochs of five seconds duration. We evaluated the network's topological features, including clustering coefficient, path length, modularity and participation coefficient and computed their variance over time. Finally, we estimated the predictive value of these topological features for patients' outcomes by splitting the patient sample in training and test datasets. RESULTS: Group-level analysis revealed lower clustering coefficient, higher modularity and path length variance in patients with favorable compared to those with unfavorable outcomes (p < 0.01). Within all features, the path length variance in the network provided the best positive predictive value (PPV) for favorable outcome and specificity for unfavorable outcome in the test dataset (PPV: 0.83, p < 0.01; specificity: 0.86, p < 0.01) with above-chance negative predictive value and accuracy. Of note, the exclusion of patients with epileptiform activity (20 in total) eliminates all false positive predictions (n = 6) for path length variance. INTERPRETATION: Topological features of functional connectivity differ as a function of long-term outcome in patients on the first day of coma. These differences are not interpretable in terms of consciousness levels as all patients were in a deep unconscious state. The time variance of path length is informative of comatose patients' outcome, as patients with favorable outcome exhibit a richer repertoire of path length than those with unfavorable outcomes.