Functional and Structural Integrity of Frontoparietal Connectivity in Traumatic and Anoxic Coma.

OBJECTIVES: Recovery from coma might critically depend on the structural and functional integrity of frontoparietal networks. We aimed to measure this integrity in traumatic brain injury and anoxo-ischemic (cardiac arrest) coma patients by using an original multimodal MRI protocol. DESIGN: Prospective cohort study. SETTING: Three Intensive Critical Care Units affiliated to the University in Toulouse (France). PATIENTS: We longitudinally recruited 43 coma patients (Glasgow Coma Scale at the admission < 8; 29 cardiac arrest and 14 traumatic brain injury) and 34 age-matched healthy volunteers. Exclusion criteria were disorders of consciousness lasting more than 30 days and focal brain damage within the explored brain regions. Patient assessments were conducted at least 2 days (5 ± 2 d) after complete withdrawal of sedation. All patients were followed up (Coma Recovery Scale-Revised) 3 months after acute brain injury. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Functional and structural MRI data were recorded, and the analysis was targeted on the posteromedial cortex, the medial prefrontal cortex, and the cingulum. Univariate analyses and machine learning techniques were used to assess diagnostic and predictive values. Coma patients displayed significantly lower medial prefrontal cortex-posteromedial cortex functional connectivity (area under the curve, 0.94; 95% CI, 0.93-0.95). Cardiac arrest patients showed specific structural disturbances within posteromedial cortex. Significant cingulum architectural disturbances were observed in traumatic brain injury patients. The machine learning medial prefrontal cortex-posteromedial cortex multimodal classifier had a significant predictive value (area under the curve, 0.96; 95% CI, 0.95-0.97), best combination of subregions that discriminates a binary outcome based on Coma Recovery Scale-Revised). CONCLUSIONS: This exploratory study suggests that frontoparietal functional disconnections are specifically observed in coma and their structural counterpart provides information about brain injury mechanisms. Multimodal MRI biomarkers of frontoparietal disconnection predict 3-month outcome in our sample. These findings suggest that fronto-parietal disconnection might be particularly relevant for coma outcome prediction and could inspire innovative precision medicine approaches.

Deep coma does not always predict poor outcomes among patients with polytrauma.

PURPOSES: This study aimed to clarify the prognosis of polytrauma patients presenting to the emergency department (ED) with a Glasgow Coma Scale score (GCS) of 3. METHODS: A trauma registry system has been established at our institution since 2009. The current study reviewed patients in the registry who presented to the ED with a GCS of 3 from January 2011 to December 2015. Surviving and non-surviving patients were compared to identify the prognostic factors of patient survival. The study also aimed to determine the factors contributing to patients who survived with a GCS > 13 at discharge. RESULTS: During the study period, 145 patients were enrolled in the study, 119 of whom (82.1%) did not survive the traumatic insult. Of the 26 survivors, 13 (9.0%) had a GCS of 14 or 15 at discharge. The multiple logistic regression revealed that a lack of bilateral dilated and fixed pupils (BFDP) (OR 5.967, 95% CI 1.780-19.997, p = 0.004) and a GCS > 3 after resuscitation (OR 6.875, 95% CI 2.135-22.138, p = 0.001) were independent prognostic factors of survival. Based on the multiple logistic regression, an age under 40 years (OR 16.405, 95% CI 1.520-177.066, p = 0.021) and a GCS > 3 after resuscitation (OR 12.100, 95% CI 1.058-138.352, p = 0.045) were independent prognostic factors of a GCS > 13 at discharge. CONCLUSION: Aggressive resuscitation still provided benefit to polytrauma patients presenting with a GCS of 3, especially those with a rapid response to the resuscitation. Young patients with a deep coma on arrival had a higher probability of functional recovery after resuscitation in the ED.

Right median nerve electrical stimulation for acute traumatic coma (the Asia Coma Electrical Stimulation trial): study protocol for a randomised controlled trial.

BACKGROUND: Traumatic brain injury (TBI) has become the most common cause of death and disability in persons between 15 and 30 years of age, and about 10-15% of patients affected by TBI will end up in a coma. Coma caused by TBI presents a significant challenge to neuroscientists. Right median nerve electrical stimulation has been reported as a simple, inexpensive, non-invasive technique to speed recovery and improve outcomes for traumatic comatose patients. METHODS/DESIGN: This multicentre, prospective, randomised (1:1) controlled trial aims to demonstrate the efficacy and safety of electrical right median nerve stimulation (RMNS) in both accelerating emergence from coma and promoting long-term outcomes. This trial aims to enrol 380 TBI comatose patients to partake in either an electrical stimulation group or a non-stimulation group. Patients assigned to the stimulation group will receive RMNS in addition to standard treatment at an amplitude of 15-20 mA with a pulse width of 300 µs at 40 Hz ON for 20 s and OFF for 40 s. The electrical treatment will last for 8 h per day for 2 weeks. The primary endpoint will be the percentage of patients regaining consciousness 6 months after injury. The secondary endpoints will be Extended Glasgow Outcome Scale, Coma Recovery Scale-Revised and Disability Rating Scale scores at 28 days, 3 months and 6 months after injury; Glasgow Coma Scale, Glasgow Coma Scale Motor Part and Full Outline of Unresponsiveness scale scores on day 1 and day 7 after enrolment and 28 days, 3 months and 6 months after injury; duration of unconsciousness and mechanical ventilation; length of intensive care unit and hospital stays; and incidence of adverse events. DISCUSSION: Right median nerve electrical stimulation has been used as a safe, inexpensive, non-invasive therapy for neuroresuscitation of coma patients for more than two decades, yet no trial has robustly proven the efficacy and safety of this treatment. The Asia Coma Electrical Stimulation (ACES) trial has the following novel features compared with other major RMNS trials: (1) the ACES trial is an Asian multicentre randomised controlled trial; (2) RMNS therapy starts at an early stage 7-14 days after the injury; and (3) various assessment scales are used to evaluate the condition of patients. We hope the ACES trial will lead to optimal use of right median nerve electrical treatment. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02645578 . Registered on 23 December 2015.

Stability of auditory event-related potentials in coma research.

Patients with unresponsive wakefulness syndrome (UWS) or in minimally conscious state (MCS) after brain injury show significant fluctuations in their behavioural abilities over time. As the importance of event-related potentials (ERPs) in the detection of traces of consciousness increases, we investigated the retest reliability of ERPs with repeated tests at four different time points. Twelve healthy controls and 12 inpatients (8 UWS, 4 MCS; 6 traumatic, 6 non-traumatic) were tested twice a day (morning, afternoon) for 2 days with an auditory oddball task. ERPs were recorded with a 256-channel-EEG system, and correlated with behavioural test scores in the Coma Recovery Scale-revised (CRS-R). The number of identifiable P300 responses varied between zero and four in both groups. Reliabilities varied between Krippendorff's α = 0.43 for within-day comparison, and α = 0.25 for between-day comparison in the patient group. Retest reliability was strong for the CRS-R scores for all comparisons (α = 0.83-0.95). The stability of auditory information processing in patients with disorders of consciousness is the basis for other, even more demanding tasks and cognitive potentials. The relatively low ERP-retest reliability suggests that it is necessary to perform repeated tests, especially when probing for consciousness with ERPs. A single negative ERP test result may be mistaken for proof that a UWS patient truly is unresponsive.

Functional MRI and outcome in traumatic coma.

Advances in task-based functional MRI (fMRI), resting-state fMRI (rs-fMRI), and arterial spin labeling (ASL) perfusion MRI have occurred at a rapid pace in recent years. These techniques for measuring brain function have great potential to improve the accuracy of prognostication for civilian and military patients with traumatic coma. In addition, fMRI, rs-fMRI, and ASL perfusion MRI have provided novel insights into the pathophysiology of traumatic disorders of consciousness, as well as the mechanisms of recovery from coma. However, functional neuroimaging techniques have yet to achieve widespread clinical use as prognostic tests for patients with traumatic coma. Rather, a broad spectrum of methodological hurdles currently limits the feasibility of clinical implementation. In this review, we discuss the basic principles of fMRI, rs-fMRI, and ASL perfusion MRI and their potential applications as prognostic tools for patients with traumatic coma. We also discuss future strategies for overcoming the current barriers to clinical implementation.

Disconnection of the ascending arousal system in traumatic coma.

Traumatic coma is associated with disruption of axonal pathways throughout the brain, but the specific pathways involved in humans are incompletely understood. In this study, we used high angular resolution diffusion imaging to map the connectivity of axonal pathways that mediate the 2 critical components of consciousness-arousal and awareness-in the postmortem brain of a 62-year-old woman with acute traumatic coma and in 2 control brains. High angular resolution diffusion imaging tractography guided tissue sampling in the neuropathologic analysis. High angular resolution diffusion imaging tractography demonstrated complete disruption of white matter pathways connecting brainstem arousal nuclei to the basal forebrain and thalamic intralaminar and reticular nuclei. In contrast, hemispheric arousal pathways connecting the thalamus and basal forebrain to the cerebral cortex were only partially disrupted, as were the cortical "awareness pathways." Neuropathologic examination, which used ß-amyloid precursor protein and fractin immunomarkers, revealed axonal injury in the white matter of the brainstem and cerebral hemispheres that corresponded to sites of high angular resolution diffusion imaging tract disruption. Axonal injury was also present within the gray matter of the hypothalamus, thalamus, basal forebrain, and cerebral cortex. We propose that traumatic coma may be a subcortical disconnection syndrome related to the disconnection of specific brainstem arousal nuclei from the thalamus and basal forebrain.

[The value of bispectral index in the unconscious patients with acute brain injury due to different pathogenic factors].

OBJECTIVE: To observe the differences in bispectral index (BIS) in unconscious patients with acute brain injury due to different pathogenic factors, and approach its clinical significance. METHODS: A retrospective study was conducted. One hundred and twenty-two unconscious patients with acute brain injured admitted to the intensive care unit (ICU) from March 2009 to August 2012 were involved. According to the pathogenic factors, all patients were divided into direct injury group (n=66) and indirect injury group (n=56). Based on BIS value, all patients were divided into the BIS<60 group (n=80) and the BIS≥60 group (n=42). The BIS was continuously measured for 12 hours during the first 3 days, or 24 hours after stoppage of sedative after admission to ICU. The mean value of BIS (BISmean) was evaluated. The acute physiology and chronic health evaluationII (APACHEII) score, probability of survival (PS) and Glasgow coma score (GCS) were recorded. On the same day, the serum protein S100 and neuron-specific enolase (NSE) were determined. The mortality and the rate of the poor neurological outcome were analyzed. RESULTS: (1) There were no significant differences in the age, sex, APACHEII score, PS and days of stay in ICU between the direct and indirect injury groups. (2) BISmean and GCS in direct injury group were significantly lower than those of the indirect injury group [BISmean: 39.0 (2.5, 58.0) vs. 59.0 (42.0, 71.0), GCS score: 3 (3, 5) vs. 4 (3, 6), both P<0.01], while serum S100 levels was significantly higher [2.30 (0.75, 6.66) mg/L vs. 0.84 (0.40, 3.62) mg/L, P<0.01]. There was no significant difference in the NSE level between the direct and indirect injury groups. (3) The mortality rate and poor neurological outcome rate in BIS<60 group were significantly higher than the BIS≥60 group (mortality rate: 67.50% vs. 40.48%, poor neurological outcome rate: 86.25% vs. 66.67%, P<0.01 and P<0.05). In the BIS<60 group, there were no significant differences in the mortality and poor neurological outcome rate between direct and indirect injury group. CONCLUSIONS: There are differences in pathogenic factors, the injury mechanism, and the degree of the brain injury between the direct and indirect injury groups. BIS monitoring could help judge the degree of different kinds of brain injury. BIS<60 indicates poor prognosis and neurological outcome in spite of the inducing factor of brain injury.

Pain indicators in brain-injured critical care adults: an integrative review.

INTRODUCTION: Health professionals are confronted with the difficulty of adequately evaluating pain in critically ill, brain-injured patients, as these patients are often unable to self-report. In addition, their confused and stereotyped behaviours may change their responses to pain; the indicators and descriptors generally used to evaluate pain in the critically ill may therefore not be appropriate for brain-injured patients. AIM: The aim of this integrative review was to identify clinically measurable and observable pain indicators and descriptors for brain-injured, critically ill adults. METHOD: A search of electronic databases (Medline, CINAHL, Embase) combined with cross-referencing was performed. Articles were included if they described pain indicators in critically ill adults and included brain-injured patients in their population. RESULTS: Seven articles met the inclusion criteria. They were critically appraised for their quality and their relevance for the population of brain-injured patients. Behavioural pain indicators such as facial expressions, body movements and muscle tension were found in all of the articles. However, the descriptions of the indicators differ from one article to another. The intensity and nature of behavioural pain responses vary according to the level of consciousness. Changes in physiological parameters have also been reported, but these results are inconclusive. CONCLUSION: Additional research is needed to identify and better describe pain indicators that are specific to brain-injured patients in the ICU. Studies with large samples, different brain injury diagnoses and various levels of consciousness are warranted.

[Peculiarities of disorders of brain bioelectrical activity spatial-time organization in patients with different consciousness depression after severe head injury].

Specific changes of bioelectrical brain activity was found in 27 patients with different level of posttraumatic consciousness depression by the methods of crosscorrelation, coherence and factor analysis of EEG. The changes of activity of morphofunctional systems of intracerebral integrations were revealed partially by decreasing of unspecific activity from brainstem structures reflected with increasing of slow wave activity and decreasing of EEG coherence in alpha- and beta-range. Depression of system organization of interconnections of bioelectrical brain activity in frontal and occipital regions of both hemispheres was also detected, and testified about decreasing of intercortical and thalamocortical brain system action under brain dislocation. The changes of integrative brain system activity, provides interhemispheric interaction, had the specific characted. Our results propose a "facilitation" of activity of system, providing "direct" interhemispheric connections through corpus callosum and other commissural tracts of telencephalon as a sequel of mesodiencephalon structures depression with steady reciprocal, antiphase relations of slow weve activity in symmetrical areas of hemispheres in coma II patients. The data of our research had shown no complete disintegration of system brain activity in coma II patients in spite of consciousness and brainstem reflexes depression.

Acute management of acquired brain injury Part III: an evidence-based review of interventions used to promote arousal from coma.

PRIMARY OBJECTIVE: To review the literature regarding techniques used to promote arousal from coma following an acquired brain injury. MAIN OUTCOMES: A literature search of multiple databases (CINAHL, EMBASE, MEDLINE and PsycINFO) and hand searched articles covering the years 1980-2008 was performed. Peer reviewed articles were assessed for methodological quality using the PEDro scoring system for randomized controlled trials and the Downs and Black tool for RCTs and non-randomized trials. Levels of evidence were assigned and recommendations were made. RESULTS: Research into coma arousal has generally focused on the stimulation of neural pathways responsible for arousal. These pathways have been targeted using pharmacological and non-pharmacological techniques. This review reports the evidence surrounding agents targeting dopamine pathways (amantadine, bromocriptine and levodopa), sensory stimulation, music therapy and median nerve electrical stimulation. Each of these interventions has shown some degree of benefit in improving consciousness, but further research is necessary. CONCLUSIONS: Despite numerous studies, strong evidence was only found for one intervention (Amantadine use in children) and this was based on a single study. However, each of the interventions showed promise in some aspect of arousal and warrant further study. More methodologically rigorous study is needed before any definitive conclusions can be drawn.

Usefulness of functional MRI associated with PET scan and evoked potentials in the evaluation of brain functions after severe brain injury: preliminary results.

OBJECTIVE: To evaluate the feasability and the potential usefulness of functional MRI (fMRI) for the evaluation of brain functions after severe brain injury, when compared to a multimodal approach (evoked potentials [EP] and Positron Emission Tomography [PET] examinations). MATERIAL AND METHODS: Seven patients (mean age: 49 years [23-73], three males, four females) presenting with coma after acute severe brain injuries underwent fMRI (auditive, visual, somesthesic), (18)F-FDG PET and EP (auditive, visual, somesthesic) within a 3-day period of time in a mean of 120 days after initial brain injury. fMRI activations in somesthesic, visual and auditive cortical areas were compared to EP (28 possible comparisons) and to the metabolic activity on PET examination in the same anatomical areas (21 possible comparisons). RESULTS: In case of availability, results were concordant between fMRI and PET in 10 comparisons but not in one, and between fMRI and EP in 11 comparisons but not in four. CONCLUSIONS: In many patients, there is a good concordance between fMRI and brain functions suggested by EP and metabolic activity demonstrated with PET. In few others, fMRI can be integrated in the early evaluation of brain functions to further augment our capacity for a proper evaluation of brain functions in critically ill patients.

Recovery of consciousness after brain injury: a mesocircuit hypothesis.

Recovery of consciousness following severe brain injuries can occur over long time intervals. Importantly, evolving cognitive recovery can be strongly dissociated from motor recovery in some individuals, resulting in underestimation of cognitive capacities. Common mechanisms of cerebral dysfunction that arise at the neuronal population level may explain slow functional recoveries from severe brain injuries. This review proposes a "mesocircuit" model that predicts specific roles for different structural and dynamic changes that may occur gradually during recovery. Recent functional neuroimaging studies that operationally identify varying levels of awareness, memory and other higher brain functions in patients with no behavioral evidence of these cognitive capacities are discussed. Measuring evolving changes in underlying brain function and dynamics post-injury and post-treatment frames future investigative work.

Feasibility of instrumental swallowing assessments in patients with prolonged disordered consciousness while undergoing inpatient rehabilitation.

OBJECTIVE: To evaluate the feasibility, safety, and potential benefit of instrumental swallowing assessments for patients with prolonged disordered consciousness participating in rehabilitation. DESIGN: Case-control, retrospective. PARTICIPANTS: Thirty-five participants divided into 2 cohorts according to cognitive level at the time of baseline instrumental swallowing assessment. Group 1 (n = 17) participants were at Rancho Los Amigo (RLA) level II/III or RLA level III, while Group 2 (n = 18) participants were rated better than RLA level III. RESULTS: Aspiration and laryngeal penetration rates for both groups were similar (aspiration rate Group 1 = 41%, Group 2 = 39%; laryngeal penetration rate Group 1 = 59%, Group 2 = 61%). Overall, 76% (13/17) of Group 1 and 72% (13/18) of Group 2 were able to receive some type of oral feedings following baseline video fluoroscopic swallow study (VFSS) or endoscopic exam of the swallow (FEES). CONCLUSION: The majority of participants who underwent an instrumental swallowing examination while still functioning at RLA level II/III or RLA level III were able to return to some form of oral feedings immediately following their baseline examination. Swallowing as a treatment modality can be considered a part of the overall plan to facilitate neurobehavioral recovery for patients with prolonged disordered consciousness participating in rehabilitation.

Neuroimaging and the vegetative state: resolving the behavioral assessment dilemma?

The accurate assessment of patients with impaired consciousness following a brain injury often remains a challenge to the most experienced clinician. A diagnosis of vegetative or minimally conscious state is made on the basis of the patient's clinical history and detailed behavioral examinations, which rely upon the patient being able to move or speak in order to demonstrate residual cognitive function. Recently, the development of noninvasive neuroimaging techniques has fostered a rapid increase in the exploration of residual cognitive abilities in these patient populations. However, while this body of literature is growing rapidly, at present the enterprise remains one of scientific endeavor with no inclusion in standard clinical practice. Correctly administered behavioral testing in survivors of brain injury may provide sufficient information to identify patients who are aware and are able to signal that this is the case via a recognized motor output. However, it remains possible that a subgroup of these patients may retain some level of awareness, but lack the ability to produce any motor output and are therefore mistakenly diagnosed as vegetative. It is in this latter situation that functional neuroimaging may prove to be most valuable, as a unique clinical tool for probing volition and residual cognition without necessarily assuming that the patient is able to produce any motor output.

Diagnostic and prognostic use of bispectral index in coma, vegetative state and related disorders.

PRIMARY OBJECTIVE: This study investigates (1) the utility of the bispectral index (BIS) to distinguish levels of consciousness in severely brain damaged patients and, particularly, disentangle vegetative state (VS) from minimally conscious state (MCS), as compared to other EEG parameters; (2) the prognostic value of BIS with regards to recovery after 1 year. RESEARCH DESIGN: Multi-centric prospective study. METHOD AND PROCEDURES: Unsedated patients recovering from coma were followed until death or transferal. Automated electrophysiological and standardized behavioural assessments were carried out twice a week. EEG recordings were categorized according to level of consciousness (coma, VS, MCS and Exit MCS). Outcome was assessed at 1 year post-insult. MAIN OUTCOMES AND RESULTS: One hundred and fifty-six EEG epochs obtained in 43 patients were included in the analyses. BIS showed a higher correlation with behavioural scales as compared to other EEG parameters. Moreover, BIS values differentiated levels of consciousness and distinguished VS from MCS while other EEG parameters did not. Finally, higher BIS values were found in patients who recovered at 1 year post-insult as compared to patients who did not recover. CONCLUSION: EEG-BIS recording is an interesting additional method to help in the diagnosis as well as in the prognosis of severely brain injured patients recovering from coma.

Analysis of intracranial pressure changes during early versus late percutaneous tracheostomy in a neuro-intensive care unit.

BACKGROUND: We aimed to investigate intracranial pressure (ICP) changes during early versus late bedside percutaneous tracheostomy (PT) in a neuro-intensive care unit (NICU). METHODS: This study included 30 patients admitted to our NICU for head trauma, subarachnoid haemorrhage, intracerebral haematoma or brain tumour with a Glasgow Coma Score (GCS) less than 8. These patients also underwent ICP monitoring. Bedside PT was performed either early (within 7 days of ventilation) or late (after 7 days of ventilation) via the Griggs system. In all patients; ICP, systemic blood pressure, heart rate, oxygen saturation (Sat O(2)) and arterial blood gases were recorded 5 min before the procedure, during skin incision, during tracheal cannulation, as well as 5 min and 10 min after the procedure. FINDINGS: Thirty patients, 18 male and 12 female, with various intracranial pathologies between ages 18 and 78 (mean 38.7 +/- 20) were identified. The admission GCS ranged between 4 and 11 (median 7). Physiological variables did not differ significantly between the two groups. In the early group, ICP values measured 5 min before the procedure, during skin incision, during tracheal cannulation, as well as 5 min and 10 min after the procedure were 15.1 +/- 5.2, 22 +/- 10.1, 28.4 +/- 13.7, 17.3 +/- 7.1, 13.8 +/- 5.0 mmHg, respectively. In the late group, these values were 14.2 +/- 4.5, 17.2 +/- 5.5, 21.5 +/- 8.0, 15.1 +/- 5.3 and 12.4 +/- 4.1 mmHg. There was no significant difference between the early or late groups in terms of ICP increases during these predetermined 5 time points. CONCLUSIONS: In patients with decreased intracranial compliance, a relatively minimally invasive procedure such as PT may lead to significant increases in ICP. The timing of PT does not seem to influence ICP, mortality, pneumonia or early complications. During the PT procedure, ICP should be closely monitored and preventive strategies should be instituted in an attempt to prevent secondary insult to an already severely injured brain.