The multiplicity of caregiving burden: a qualitative analysis of families with prolonged disorders of consciousness.

Objective: To understand the multiple and sometimes conflicting roles substitute decision makers (SDMs) of individuals in a vegetative state (VS), minimally conscious state (MCS), or with locked-in syndrome (LIS) perform while caring for a loved one and the competing priorities derived from these roles.Methods: We conducted semi-structured qualitative interviews using a constructive-grounded theory design. Twelve SDMs, who were also family members for 11 patients, were interviewed at two time points (except one) for a total of 21 in-depth interviews.Results: Participants described that caregiving is often the central role which they identify as their top priority and around which they coordinate and to some extent subordinate their other roles. In addition to caregiving, they participated in a wide variety of roles, which were sometimes in conflict, as they became caregivers for a loved one with chronic and complex needs. SDMs described the caregiver role as complex and intense that lead to physical, emotional, social, and economic burdens.Conclusion: SDMs report high levels of burdens in caring for a person with a prolonged disorder of consciousness. Lack of health system support that recognized the broader context of SDMs lives, including their multiple competing priorities, was a major contributing factor.

Experiences of family of individuals in a locked in, minimally conscious state, or vegetative state with the health care system.

Primary Objective: To understand the experiences of family members of individuals in a locked-in state (LIS), minimally conscious state (MCS), or vegetative state (VS) with the health-care system when caring for their family member.Research Design: The study adopted a qualitative descriptive approach drawing on central tenets of constructivist grounded theory described by Charmaz. Our analysis drew on emphasizing connections between theory, concepts, and empirical data using a constant comparative method.Methods and Procedures: Semi-structured interviews were conducted with family members of individuals in a LIS, MCS, or VS. Participants were recruited between June 2014 and December 2016.Main Outcomes and Results: 22 interviews were conducted, which comprised interviews with 12 family members. The following themes were identified: care coordination challenges, lack of flexibility in health-care policies, and inappropriate care settings.Conclusions: Family members of individuals in a LIS, MCS, or VS described playing a significant role in the lives of their family member. Based on the results of this study, flexibility in health-care policies and/or programming should be adopted in the face of the challenges identified. Implementation of interventions to support caregivers and transitions is increasingly important.

Individualized assessment of residual cognition in patients with disorders of consciousness.

Patients diagnosed with disorders of consciousness show minimal or inconsistent behavioural evidence of conscious awareness. However, using functional neuroimaging, recent research in clinical neuroscience has identified a subpopulation of these patients who reliably produce neural markers indicative of awareness. In this study, we recorded electroencephalograms during a response-free movie task to assess narrative processing in patients with disorders of consciousness. Thirteen patients diagnosed with a disorder of consciousness and 28 healthy controls participated in this study. We designed a movie-watching/listening paradigm involving two suspenseful movie clips, one audiovisual and one audio-only, and used electroencephalography to extract patterns of brain activity that were maximally correlated between subjects. These activity patterns served as electrophysiological indices of narrative processing, which were compared to the neural responses of patients during the same movies. Our analysis revealed two patterns of neural activity, one for each movie condition, that were significantly and reliably correlated between healthy participants. Of the twelve patients who watched the audiovisual movie, 25% produced a pattern of activity that was significantly correlated with the healthy group, while of the ten who listened to the audio narrative, 30% produced electrophysiological patterns similar to controls (one patient responded appropriately to both). The method presented here allows for rapid bedside assessment of higher-order cognitive processing in patients with disorders of consciousness. By leveraging the common neural response to movie stimuli, we were able to identify comparable patterns of brain activity in individual, behaviourally non-responsive patients, reflecting a capacity for narrative processing.

Towards the assessment of quality of life in patients with disorders of consciousness.

PURPOSE: To generate foundational knowledge in the creation of a quality-of-life instrument for patients who are clinically diagnosed as being in a vegetative or minimally conscious state but are able to communicate by modulating their brain activity (i.e., behaviourally nonresponsive and covertly aware). The study aimed to identify a short list of key domains that could be used to formulate questions for an instrument that determines their self-reported quality of life. METHODS: A novel two-pronged strategy was employed: (i) a scoping review of quality-of-life instruments created for patient populations sharing some characteristics with patients who are behaviourally nonresponsive and covertly aware was done to compile a set of potentially relevant domains of quality of life; and (ii) a three-round Delphi consensus process with a multidisciplinary panel of experts was done to determine which of the identified domains of quality of life are most important to those who are behaviourally nonresponsive and covertly aware. Five expert groups were recruited for this study including healthcare workers, neuroscientists, bioethicists, quality-of-life methodologists, and patient advocates. RESULTS: Thirty-five individuals participated in the study with an average response rate of 95% per round. Over the three rounds, experts reached consensus on 34 of 44 domains (42 domains were identified in the scoping review and two new domains were added based on suggestions by experts). 22 domains were rated as being important for inclusion in a quality-of-life instrument and 12 domains were deemed to be of less importance. Participants agreed that domains related to physical pain, communication, and personal relationships were of primary importance. Based on subgroup analyses, there was a high degree of consistency among expert groups. CONCLUSIONS: Quality of life should be a central patient-reported outcome in all patient populations regardless of patients' ability to communicate. It remains to be determined how covertly aware patients perceive their circumstances and quality of life after suffering a life-altering injury. Nonetheless, it is important that any further dialogue on what constitutes a life worth living should not occur without direct patient input.

Feasibility of a web-based neurocognitive battery for assessing cognitive function in critical illness survivors.

PURPOSE: To assess the feasibility of using a widely validated, web-based neurocognitive test battery (Cambridge Brain Sciences, CBS) in a cohort of critical illness survivors. METHODS: We conducted a prospective observational study in two intensive care units (ICUs) at two tertiary care hospitals. Twenty non-delirious ICU patients who were mechanically ventilated for a minimum of 24 hours underwent cognitive testing using the CBS battery. The CBS consists of 12 cognitive tests that assess a broad range of cognitive abilities that can be categorized into three cognitive domains: reasoning skills, short-term memory, and verbal processing. Patients underwent cognitive assessment while still in the ICU (n = 13) or shortly after discharge to ward (n = 7). Cognitive impairment on each test was defined as a raw score that was 1.5 or more standard deviations below age- and sex-matched norms from healthy controls. RESULTS: We found that all patients were impaired on at least two tests and 18 patients were impaired on at least three tests. ICU patients had poorer performance on all three cognitive domains relative to healthy controls. We identified testing related fatigue due to battery length as a feasibility issue of the CBS test battery. CONCLUSIONS: Use of a web-based patient-administered cognitive test battery is feasible and can be used in large-scale studies to identify domain-specific cognitive impairment in critical illness survivors and the temporal course of recovery over time.

Functional diversity of brain networks supports consciousness and verbal intelligence.

How are the myriad stimuli arriving at our senses transformed into conscious thought? To address this question, in a series of studies, we asked whether a common mechanism underlies loss of information processing in unconscious states across different conditions, which could shed light on the brain mechanisms of conscious cognition. With a novel approach, we brought together for the first time, data from the same paradigm-a highly engaging auditory-only narrative-in three independent domains: anesthesia-induced unconsciousness, unconsciousness after brain injury, and individual differences in intellectual abilities during conscious cognition. During external stimulation in the unconscious state, the functional differentiation between the auditory and fronto-parietal systems decreased significantly relatively to the conscious state. Conversely, we found that stronger functional differentiation between these systems in response to external stimulation predicted higher intellectual abilities during conscious cognition, in particular higher verbal acuity scores in independent cognitive testing battery. These convergent findings suggest that the responsivity of sensory and higher-order brain systems to external stimulation, especially through the diversification of their functional responses is an essential feature of conscious cognition and verbal intelligence.

Do Patients Thought to Lack Consciousness Retain the Capacity for Internal as Well as External Awareness?

It is well established that some patients, who are deemed to have disorders of consciousness, remain entirely behaviorally non-responsive and are diagnosed as being in a vegetative state, yet can nevertheless demonstrate covert awareness of their external environment by modulating their brain activity, a phenomenon known as cognitive-motor dissociation. However, the extent to which these patients retain internal awareness remains unknown. To investigate the potential for internal and external awareness in patients with chronic disorders of consciousness (DoC), we asked whether the pattern of juxtaposition between the functional time-courses of the default mode (DMN) and fronto-parietal networks, shown in healthy individuals to mediate the naturally occurring dominance switching between internal and external aspects of consciousness, was present in these patients. We used a highly engaging movie by Alfred Hitchcock to drive the recruitment of the fronto-parietal networks, including the dorsal attention (DAN) and executive control (ECN) networks, and their maximal juxtaposition to the DMN in response to the complex stimulus, relative to rest and a scrambled, meaningless movie baseline condition. We tested a control group of healthy participants (N = 13/12) and two groups of patients with disorders of consciousness, one comprised of patients who demonstrated independent, neuroimaging-based evidence of covert external awareness (N = 8), and the other of those who did not (N = 8). Similarly to the healthy controls, only the group of patients with overt and, critically, covert external awareness showed significantly heightened differentiation between the DMN and the DAN in response to movie viewing relative to their resting state time-courses, which was driven by the movie's narrative. This result suggested the presence of functional integrity in the DMN and fronto-parietal networks and their relationship to one another in patients with covert external awareness. Similar to the effect in healthy controls, these networks became more strongly juxtaposed to one another in response to movie viewing relative to the baseline conditions, suggesting the potential for internal and external awareness during complex stimulus processing. Furthermore, our results suggest that naturalistic paradigms can dissociate between groups of DoC patients with and without covert awareness based on the functional integrity of brain networks.

A hierarchy of event-related potential markers of auditory processing in disorders of consciousness.

Functional neuroimaging of covert perceptual and cognitive processes can inform the diagnoses and prognoses of patients with disorders of consciousness, such as the vegetative and minimally conscious states (VS;MCS). Here we report an event-related potential (ERP) paradigm for detecting a hierarchy of auditory processes in a group of healthy individuals and patients with disorders of consciousness. Simple cortical responses to sounds were observed in all 16 patients; 7/16 (44%) patients exhibited markers of the differential processing of speech and noise; and 1 patient produced evidence of the semantic processing of speech (i.e. the N400 effect). In several patients, the level of auditory processing that was evident from ERPs was higher than the abilities that were evident from behavioural assessment, indicating a greater sensitivity of ERPs in some cases. However, there were no differences in auditory processing between VS and MCS patient groups, indicating a lack of diagnostic specificity for this paradigm. Reliably detecting semantic processing by means of the N400 effect in passively listening single-subjects is a challenge. Multiple assessment methods are needed in order to fully characterise the abilities of patients with disorders of consciousness.

Relationship between the anterior forebrain mesocircuit and the default mode network in the structural bases of disorders of consciousness.

The specific neural bases of disorders of consciousness (DOC) are still not well understood. Some studies have suggested that functional and structural impairments in the default mode network may play a role in explaining these disorders. In contrast, others have proposed that dysfunctions in the anterior forebrain mesocircuit involving striatum, globus pallidus, and thalamus may be the main underlying mechanism. Here, we provide the first report of structural integrity of fiber tracts connecting the nodes of the mesocircuit and the default mode network in 8 patients with DOC. We found evidence of significant damage to subcortico-cortical and cortico-cortical fibers, which were more severe in vegetative state patients and correlated with clinical severity as determined by Coma Recovery Scale-Revised (CRS-R) scores. In contrast, fiber tracts interconnecting subcortical nodes were not significantly impaired. Lastly, we found significant damage in all fiber tracts connecting the precuneus with cortical and subcortical areas. Our results suggest a strong relationship between the default mode network - and most importantly the precuneus - and the anterior forebrain mesocircuit in the neural basis of the DOC.

Pre-Labeling of Immune Cells in Normal Bone Marrow and Spleen for Subsequent Cell Tracking by MRI.

Iron particles are intravenously (IV) administered to label cells in vivo during magnetic resonance imaging. This technique has been extensively used to monitor immune cells in the context of inflammatory diseases. Here, we have investigated whether resting immune cells can be labeled in vivo in healthy mice before disease onset or injury, thus allowing visualization of critical early cellular events. Using 1.5 T magnetic resonance imaging, we were able to detect signal loss in bone marrow, liver, and spleen as early as 1 hour after the IV injection of superparamagnetic iron oxide nanoparticles (Feridex; 80 to 120 nm in diameter) or larger micron-sized iron oxide particles (Bangs; 0.9 µm in diameter). Results were confirmed via histology. Further, flow cytometric analysis confirmed the presence of iron-labeled CD19+ B cells, CD3+ T cells, and CD11b + myeloid cells within the spleen and the bone marrow. Extending this work to a murine model of multiple sclerosis, we IV administered superparamagnetic iron oxide to healthy mice 1 week before inducing experimental autoimmune encephalomyelitis. Images acquired 1 week after the onset of hindlimb paralysis showed regions of signal hypointensity in the mouse brain that corresponded with iron-labeled macrophages. In summary, we show that resting immune cells in the healthy mouse liver, spleen, and bone marrow can be prelabeled with iron oxide nanoparticles. Furthermore, iron oxide preloading of immune cells in the reticuloendothelial system can be used to detect cellular infiltration in the brains of experimental autoimmune encephalomyelitis mice.

Multiple tasks and neuroimaging modalities increase the likelihood of detecting covert awareness in patients with disorders of consciousness.

Minimal or inconsistent behavioral responses to command make it challenging to accurately diagnose the level of awareness of a patient with a Disorder of consciousness (DOC). By identifying markers of mental imagery being covertly performed to command, functional neuroimaging (fMRI), electroencephalography (EEG) has shown that some of these patients are aware despite their lack of behavioral responsiveness. We report the findings of behavioral, fMRI, and EEG approaches to detecting command-following in a group of patients with DOC. From an initial sample of 14 patients, complete data across all tasks was obtained in six cases. Behavioral evaluations were performed with the Coma Recovery Scale-Revised. Both fMRI and EEG evaluations involved the completion of previously validated mental imagery tasks-i.e., motor imagery (EEG and fMRI) and spatial navigation imagery (fMRI). One patient exhibited statistically significant evidence of motor imagery in both the fMRI and EEG tasks, despite being unable to follow commands behaviorally. Two behaviorally non-responsive patients produced appropriate activation during the spatial navigation fMRI task. However, neither of these patients successfully completed the motor imagery tasks, likely due to specific motor area damage in at least one of these cases. A further patient demonstrated command following only in the EEG motor imagery task, and two patients did not demonstrate command following in any of the behavioral, EEG, or fMRI assessments. Due to the heterogeneity of etiology and pathology in this group, DOC patients vary in terms of their suitability for some forms of neuroimaging, the preservation of specific neural structures, and the cognitive resources that may be available to them. Assessments of a range of cognitive abilities supported by spatially-distinct brain regions and indexed by multiple neural signatures are therefore required in order to accurately characterize a patient's level of residual cognition and awareness.

Ethics of neuroimaging after serious brain injury.

BACKGROUND: Patient outcome after serious brain injury is highly variable. Following a period of coma, some patients recover while others progress into a vegetative state (unresponsive wakefulness syndrome) or minimally conscious state. In both cases, assessment is difficult and misdiagnosis may be as high as 43%. Recent advances in neuroimaging suggest a solution. Both functional magnetic resonance imaging and electroencephalography have been used to detect residual cognitive function in vegetative and minimally conscious patients. Neuroimaging may improve diagnosis and prognostication. These techniques are beginning to be applied to comatose patients soon after injury. Evidence of preserved cognitive function may predict recovery, and this information would help families and health providers. Complex ethical issues arise due to the vulnerability of patients and families, difficulties interpreting negative results, restriction of communication to "yes" or "no" answers, and cost. We seek to investigate ethical issues in the use of neuroimaging in behaviorally nonresponsive patients who have suffered serious brain injury. The objectives of this research are to: (1) create an approach to capacity assessment using neuroimaging; (2) develop an ethics of welfare framework to guide considerations of quality of life; (3) explore the impact of neuroimaging on families; and, (4) analyze the ethics of the use of neuroimaging in comatose patients. METHODS/DESIGN: Our research program encompasses four projects and uses a mixed methods approach. Project 1 asks whether decision making capacity can be assessed in behaviorally nonresponsive patients. We will specify cognitive functions required for capacity and detail their assessment. Further, we will develop and pilot a series of scenarios and questions suitable for assessing capacity. Project 2 examines the ethics of welfare as a guide for neuroimaging. It grounds an obligation to explore patients' interests, and we explore conceptual issues in the development of a quality of life instrument adapted for neuroimaging. Project 3 will use grounded theory interviews to document families' understanding of the patient's condition, expectations of neuroimaging, and the impact of the results of neuroimaging. Project 4 will provide an ethical analysis of neuroimaging to investigate residual cognitive function in comatose patients within days of serious brain injury.

MRI tracking of transplanted iron-labeled mesenchymal stromal cells in an immune-compromised mouse model of critical limb ischemia.

Peripheral arterial disease is a clinical problem in which mesenchymal stromal cell (MSC) transplantation may offer substantial benefit by promoting the generation of new blood vessels and improving limb ischemia and wound healing via their potent paracrine activities. MRI allows for the noninvasive tracking of cells over time using iron oxide contrast agents to label cells before they are injected or transplanted. However, a major limitation of the tracking of iron oxide-labeled cells with MRI is the possibility that dead or dying cells will transfer the iron oxide label to local bystander macrophages, making it very difficult to distinguish between viable transplanted cells and endogenous macrophages in the images. In this study, a severely immune-compromised mouse, with limited macrophage activity, was investigated to examine cell tracking in a system in which bystander cell uptake of dead, iron-labeled cells or free iron particles was minimized. MRI was used to track the fate of MSCs over 21 days after their intramuscular transplantation in mice with a femoral artery ligation. In all mice, a region of signal loss was observed at the injection site and the volume of signal hypointensity diminished over time. Fluorescence and light microscopy showed that iron-positive MSCs persisted at the transplant site and often appeared to be integrated in perivascular niches. This was compared with MSC transplantation in immune-competent mice with femoral artery ligation. In these mice, the regions of signal loss caused by iron-labeled MSC cleared more slowly, and histology revealed iron particles trapped at the site of cell transplantation and associated with areas of inflammation.

The use of cellular magnetic resonance imaging to track the fate of iron-labeled multipotent stromal cells after direct transplantation in a mouse model of spinal cord injury.

PURPOSE: The objective of this study was to track the fate of iron-labeled, multipotent stromal cells (MSC) after their direct transplantation into mice with spinal cord injuries using magnetic resonance imaging (MRI). PROCEDURES: Mice with spinal cord injuries received a direct transplant of (1) live MSC labeled with micron-sized iron oxide particles (MPIO); (2) dead, MPIO-labeled MSC; (3) unlabeled MSC; or (4) free MPIO and were imaged at 3 T for 6 weeks after transplantation. RESULTS: Live, iron-labeled MSC appeared as a well-defined region of signal loss in the mouse spinal cord at the site of transplant. However, the MR appearance of dead, iron-labeled MSC and free iron particles was similar and persisted for the 6 weeks of the study. CONCLUSIONS: Iron-labeled stem cells can be detected and monitored in vivo after direct transplantation into the injured spinal cord of mice. However, the fate of the iron label is not clear. Our investigation indicates that caution should be taken when interpreting MR images after direct transplantation of iron-labeled cells.

Timing and duration of anti-alpha4beta1 integrin treatment after spinal cord injury: effect on therapeutic efficacy.

OBJECT: After spinal cord injury (SCI) leukocytes infiltrate the injured cord, causing significant damage and further impairment of functional recovery. The leukocyte integrin alpha4beta1 is crucial for their entry. The authors previously demonstrated that an anti-alpha4 monoclonal antibody (mAb) treatment attenuates leukocyte infiltration, improves motor and autonomic function, and reduces neuropathic pain when administered at 2 hours and 24 hours after SCI. METHODS: The authors conducted 2 preclinical studies: the first determined effects of treatment commencing at 6 hours, a clinically relevant time after injury, and the second examined effects of long-lasting treatment (28 days) on neurological recovery after SCI, as current clinically used anti-inflammatory monoclonal antibodies have such longevity. In the first study (timing study), rats were treated with anti-alpha4 or control mAb (intravenously) at 6 hours and 48 hours after moderate (35 g) thoracic compression SCI. Effects on intraspinal inflammation and oxidative injury were assessed at 3 and 7 days after SCI; motor function and pain were examined for 6 weeks. In the second study (duration study), anti-alpha4 mAb was administered starting 2 hours after SCI and subsequently every 3 days for 4 weeks (total of 8 doses), using a schedule of decreasing doses to resemble the pharmacodynamics of long-lasting antibodies used clinically. Motor function and pain were examined for 6 weeks. Lesions were assessed for tissue sparing and inflammation at 6 weeks by histological examination and MR imaging. RESULTS: Anti-alpha4 mAb treatment at 6 hours and 48 hours after SCI (timing study) significantly decreased neutrophil and monocyte/macrophage influx at 3 days by 36% and 20%, respectively, but had no effect by at 7 days after SCI. Antibody treatment significantly reduced intraspinal myeloperoxidase activity by 48% and lipid peroxidation by 27% at 3 days post-injury. The treatment did not improve locomotor function but reduced mechanical allodynia elicited from the trunk and hind paw by ~50% at 3-6 weeks after SCI. In contrast, long-term mAb treatment commencing at 2 hours after SCI (duration study) significantly improved locomotor function at 2-6 weeks after SCI, (mean BBB scores +/- SE: treated rats, 8.3 +/- 0.16; controls, 7.3 +/- 0.2 at 6 weeks). At 3-6 weeks, mAb treatment decreased mechanical allodynia elicited from the trunk and hind paw by ~55%. This recovery correlated with 30% more myelin-containing white matter in treated rats than controls at 6 weeks. The lesion cavity was smaller in the treated rats when assessed by both histological (-37%) and imaging (-50%) methods. The accumulation of ED1-immunoreactive microglia/macrophages at the lesion was similar in treated and control rats. CONCLUSIONS: Although delayed treatment reduced intraspinal inflammation and pain, motor function was not improved, revealing decreased efficacy at the more clinically feasibly treatment onset. Long-term anti-alpha4 mAb treatment starting 2 hours after SCI improved neurological outcomes, with tissue sparing near the lesion and no impairment of the late immune response to injury. These findings reveal no disadvantage of long-lasting immunosuppression by the treatment but show that efficacy depends upon very early delivery.

In vivo magnetic resonance imaging of spinal cord injury in the mouse.

The feasibility of performing high-resolution in vivo magnetic resonance imaging (MRI) to visualize the injured mouse spinal cord using a three-dimensional (3D)-FIESTA (fast imaging employing steady state acquisition) pulse sequence, in a clip compression injury model, is presented. Images were acquired using a 3-Tesla clinical whole-body MR system equipped with a high-performance gradient coil insert. High-resolution mouse cord images were used to detect and monitor the cord lesions for 6 weeks after spinal cord injury (SCI). The epicenter of the injury appeared as a region of mixed signal intensities on day 2 post-SCI. Regions of signal hypointensity appeared at the lesion site by 2 weeks post-SCI and became more apparent with time. In some mice, large cyst-like lesions were detected rostral to the lesion epicenter, as early as 2 weeks post-SCI, and increased in volume with time. In addition, MRI was used to detect and monitor iron-labeled mesenchymal stem cells (MSCs) after their transplantation into the injured cord. MSCs appeared as large, obvious regions of signal loss in the cord, which decreased in size over time.