Consciousness in Neurocritical Care Cohort Study Using fMRI and EEG (CONNECT-ME): Protocol for a Longitudinal Prospective Study and a Tertiary Clinical Care Service

Aims and Objectives: To facilitate individualized assessment of unresponsive patients in the intensive care unit for signs of preserved consciousness after acute brain injury.Background: Physicians and neuroscientists are increasingly recognizing a disturbing dilemma: Brain-injured patients who appear entirely unresponsive at the bedside may show signs of covert consciousness when examined by functional MRI (fMRI) or electroencephalography (EEG). According to a recent meta-analysis, roughly 15% of behaviorally unresponsive brain-injured patients can participate in mental tasks by modifying their brain activity during EEG- or fMRI-based paradigms, suggesting that they are conscious and misdiagnosed. This has major ethical and practical implications, including prognosis, treatment, resource allocation, and end-of-life decisions. However, EEG- or fMRI-based paradigms have so far typically been tested in chronic brain injury. Hence, as a novel approach, CONNECT-ME will import the full range of consciousness paradigms into neurocritical care.Methods: We will assess intensive care patients with acute brain injury for preserved consciousness by serial and multimodal evaluation using active, passive and resting state fMRI and EEG paradigms, as well as state-of-the-art clinical techniques including pupillometry and sophisticated clinical rating scales such as the Coma Recovery Scale-Revised. In addition, we are establishing a biobank (blood, cerebrospinal fluid and brain tissue, where available) to facilitate future genomic and microbiomic research to search for signatures of consciousness recovery.Discussion: We anticipate that this multimodal approach will add vital clinical information, including detection of preserved consciousness in patients previously thought of as unconscious, and improved (i.e., personalized) prognostication of individual patients. Our aim is two-fold: We wish to establish a cutting-edge tertiary care clinical service for unresponsive patients in the intensive care unit and lay the foundation for a fruitful multidisciplinary research environment for the study of consciousness in acute brain injury. Of note, CONNECT-ME will not only enhance our understanding of consciousness disorders in acute brain injury but it will also raise awareness for these patients who, for obvious reasons, have lacked a voice so far.Trial registration: The study is registered with clinicaltrials.org (ClinicalTrials.gov Identifier: NCT02644265)

MRI in Severe Traumatic Brain Injury: Micro- and Macrostructural Changes

The principal aim of the present PhD project was to study quantitatively the long-term microand macrostructural brain changes in survivors from severe traumatic brain injury (TBI). A total of 31 patients admitted for early rehabilitation following severe TBI were included and underwent magnetic resonance imaging (MRI), including Diffusion Tensor Imaging (DTI), at mean 8 weeks post-injury. Follow-up MRI at mean 12 months post-injury was acquired in 25 of the patients. For comparison, healthy matched controls were scanned twice with a similar time interval. Clinical rating during rehabilitation and at 1-year follow-up was performed by experienced staff. Two papers make up the basis of this thesis. Paper I considers the DTI results. This MRI modality was chosen in order to evaluate diffusional changes in brain tissue, potentially useful for characterising the extent of microscopic white matter injury, as well as for tracking microstructural changes during recovery. Using a region-of-interest approach, four white matter regions were studied with additional regions in grey matter and CSF. At the initial scan, patients had abnormal fractional anisotropy (FA) in all white matter regions, which in the cerebral peduncle correlated with 1-year outcome, suggesting that DTI may have prognostic value. At follow-up, FA had partly normalised in some white matter regions, but deviated even more from normal values in other regions. Although these longitudinal findings warrant cautious interpretation, they might indicate microstructural reorganization. Paper II describes a study on the macrostructural brain changes during recovery. Global and regional brain volume changes between the two scan time points were investigated using voxelwise analyses. Despite remarkable clinical improvement in most patients, they all exhibited continued brain volume loss during the scan interval. Global volume change correlated with clinical injury severity, functional status at both scans, and with 1-year outcome. The areas which underwent the most change were structures particularly susceptible to traumatic axonal injury and consequent Wallerian degeneration, indicating that the long-term atrophy is attributable to consequences of axonal injury. Together, these MRI analyses complemented each other in the quantitative assessment of structural brain changes following severe TBI. Applied in the late subacute/early chronic phase of TBI, DTI may capture biological severity at the microstructural level and provide prognostic information. Serial application of the MRI techniques applied in this study enables the monitoring of the extent and distribution of micro- and macrostructural changes during TBI rehabilitation

Diffusion tensor imaging during recovery from severe traumatic brain injury and relation to clinical outcome: a longitudinal study.

Diffusion tensor imaging (DTI) has been proposed as a sensitive biomarker of traumatic white matter injury, which could potentially serve as a tool for prognostic assessment and for studying microstructural changes during recovery from traumatic brain injury (TBI). However, there is a lack of longitudinal studies on TBI that follow DTI changes over time and correlate findings with long-term clinical outcome. We performed a prospective longitudinal study of 30 adult patients admitted for subacute rehabilitation following severe traumatic brain injury. DTI and conventional MRI were acquired at mean 8 weeks (5-11 weeks), and repeated in 23 of the patients at mean 12 months (9-15 months) post-trauma. Using a region-of-interest-based approach, DTI parameters were compared to those of healthy matched controls, scanned during the same time period and rescanned with a similar interval as that of patients. At the initial scan, fractional anisotropy was reduced in all the investigated white matter regions in patients compared to controls (

Long-term global and regional brain volume changes following severe traumatic brain injury: A longitudinal study with clinical correlates

Traumatic brain injury (TBI) results in neurodegenerative changes that progress for months, perhaps even years post-injury. However, there is little information on the spatial distribution and the clinical significance of this late atrophy. In 24 patients who had sustained severe TBI we acquired 3D T1-weighted MRIs about 8 weeks and 12 months post-injury. For comparison, 14 healthy controls with similar distribution of age, gender and education were scanned with a similar time interval. For each subject, longitudinal atrophy was estimated using SIENA, and atrophy occurring before the first scan time point using SIENAX. Regional distribution of atrophy was evaluated using tensor-based morphometry (TBM). At the first scan time point, brain parenchymal volume was reduced by mean 8.4% in patients as compared to controls. During the scan interval, patients exhibited continued atrophy with percent brain volume change (%BVC) ranging between -0.6% and -9.4% (mean -4.0%). %BVC correlated significantly with injury severity, functional status at both scans, and with 1-year outcome. Moreover, %BVC improved prediction of long-term functional status over and above what could be predicted using functional status at approximately 8 weeks. In patients as compared to controls, TBM (permutation test, FDR 0.05) revealed a large coherent cluster of significant atrophy in the brain stem and cerebellar peduncles extending bilaterally through the thalamus, internal and external capsules, putamen, inferior and superior longitudinal fasciculus, corpus callosum and corona radiata. This indicates that the long-term atrophy is attributable to consequences of traumatic axonal injury. Despite progressive atrophy, remarkable clinical improvement occurred in most patients