Brief Summary
Detecting preserved consciousness in brain-injured patients by traditional clinical means<br /> requires presence of motor function. Otherwise, patients may be erroneously classified as<br /> being in a vegetative state. In order to circumvent the need for motor function, paradigms<br /> using functional magnetic resonance imaging (fMRI) and electroencephalography (EEG) have been<br /> developed. According to a recent meta-analysis, 15% of patients with a clinical diagnosis of<br /> vegetative state can follow commands by performing mental imaginary tasks, strongly<br /> suggesting they are indeed conscious. This is of utmost importance for prognosis, treatment,<br /> and resource allocation. However, consciousness paradigms are usually employed in<br /> rehabilitation medicine. Therefore, opportunities to optimize patient outcome at an early<br /> stage may be lost. As a novel approach, the CONsciousness in NEurocritical Care cohorT study<br /> using fMRI and EEG (CONNECT-ME) will import the full range of consciousness paradigms into<br /> neurocritical care. The investigators aim to assess patients with acute brain injury for<br /> preserved consciousness by serial multimodal evaluations using active, passive and resting<br /> state fMRI- and EEG-based paradigms. A prospective longitudinal database and a biobank for<br /> genomic and metabolomic research will be established. This approach will add essential<br /> clinical information, including detection of preserved consciousness in patients previously<br /> thought of as unconscious. Due to its complexity, this project is divided into nine work<br /> packages. Eventually, the investigators will have established a clinical service for the<br /> systematic assessment of covert consciousness, as well as an interdisciplinary research group<br /> dedicated to the neuronal mechanisms by which consciousness recovers after acute brain<br /> injury.
Detailed Description
Searching for consciousness in non-communicating brain-injured patients by clinical
examination is essential, yet challenging. The origin of many clinical signs is not entirely
clear and their significance as to whether or not the patient is conscious is even less
certain. In addition, consciousness may wax and wane within seconds to hours and days to
months. Indeed, as many as 40% of patients with disorders of consciousness (DoC) are
misclassified as being in a vegetative state (VS). Although these patients may not show any
signs of consciousness during clinical examination because of lost motor output, some are
able to willfully modulate their brain activity on command, occasionally even answering yes
or no questions by performing mental imagery tasks. For patients with acute brain injury and
their caregivers, this has significant ethical and practical implications, not least for
prognostication, treatment decisions, resource allocation and end-of-life considerations.
Technologies based on functional Magnetic Resonance Imaging (fMRI) and electroencephalography
(EEG) have been developed during the last two decades to assist clinical evaluation of
patients in VS and minimal conscious states (MCS). There are three main approaches to test
for preserved consciousness: (i) Active paradigms in which patients are required to execute
cognitive tasks, as outlined above, (ii) passive paradigms relying on the documentation of
preserved large-scale functional cortical connectivity, following an external stimulus, and
(iii) resting state conditions in which assumptions about the patient's conscious state are
made by extrapolation from patterns of spontaneous brain activity. Consciousness paradigms
offer exciting opportunities but so far they have been almost exclusively employed in
rehabilitation medicine, addressing patients with chronic brain disorders, typically several
years following onset of the injury. Moreover, these studies have mainly been restricted to
spot assessments, not taking into account that consciousness fluctuates over time. In
addition, important methodological issues remain, including uncertainties about the
specificity and sensitivity of the different paradigms and about their applicability in brain
disorders of various etiologies. Lastly, almost all studies until now have employed either
fMRI- or EEG-based paradigms, although the two modalities do not necessarily yield identical
results in a given patient but rather complement each other. As the investigators have
recently pointed out in a review and meta-analysis, systematic evaluation of the similarities
and differences of these technologies is essential, preferentially by multimodal serial
assessments.
In the present protocol, as a novel approach the investigators will focus on the evaluation
of consciousness in patients in the acute phase of brain injury. The aim is to establish,
validate and improve fMRI- and EEG-based consciousness paradigms in intensive care (ICU) and
step down units. This will assist clinicians in more precisely estimating the level of
consciousness in various acute disorders of the brain. The project will comprise a
multidisciplinary approach including expertise from neurology, clinical neurophysiology,
anesthesiology and functional neuroimaging. The investigators hypothesize that serial
multimodal assessments better reflect changing levels of consciousness than single unimodal
evaluations. Within the next two to three years, the investigators wish to establish a full
clinical service and a fruitful research milieu covering the entire spectrum of fMRI- and
EEG-based consciousness paradigms in acute brain injury. The ability to identify preserved
cognitive abilities following acute brain injury is of utmost importance to improve
diagnosis, to guide therapeutic decisions and to better predict outcome in non-responsive
patients. Eventually, the present research project will lead to more efficient decision
making in neurocritical care, thereby optimizing resource allocation and improving quality of
life in survivors with acute brain injury.
Study Design:
Due to its complexity, this project is divided into 3 phases, including 9 work packages.
- During the first phase of the project the investigators aim to set up the different
parts of consciousness testing, that is, clinical rating scales; fMRI-based active,
passive and resting state paradigms; and EEG-based active, passive and resting state
paradigms. This will be done step by step and in a pragmatic manner according to local
requirements and resources. To this end, a prospective, longitudinal database will be
set up, collecting all relevant clinical, neurophysiological and imaging data, as well
as a biobank for cerebrospinal fluid and blood samples (work packages 1-7).
- During the second phase of the project the investigators wish to combine all diagnostic
parts and to implement them simultaneously using a convenience sample of suitable
non-communicating patients with acute brain injury (n=20) at the neurological and
neurosurgical ICU and step down units, Rigshospitalet, Copenhagen University Hospital.
These patients will be tested for the presence of preserved consciousness and cognitive
abilities with the full range of fMRI- and EEG-based consciousness paradigms, as well as
standardized bedside examination and clinical rating scales (work package 8).
- In the third phase of the project the investigators wish to develop a full clinical
service for the evaluation of patients with DoC following acute and sub-acute brain
injury, including comprehensive neurological evaluation and fMRI- and EEG-based
consciousness paradigms, and to build the infrastructure for a fruitful research
activity in the future (work package 9).
Detailed and regularly updated procedures for each work package are provided in the
Amendments to the Study Protocol (see below).
- Work package 1 (resting state fMRI; systematic clinical examination): The investigators
will start by evaluating a convenience sample of DoC patients with acute brain injury
(n=10), admitted to the ICU and/or neurological and neurosurgical step down units at
Rigshospitalet, using resting state fMRI, since a relevant protocol is already available
at the institution. A systems-level approach, including assessment of the auditory and
default mode networks, will be used as described earlier. At the same time, the
investigators will establish a systematic clinical examination protocol, including - but
not limited to - the Full Outline of UnResponsiveness (FOUR) and Coma Recovery
Scale-Revised (CRS-R). Exclusion criteria include contraindications for examination by
MRI, severe cardiorespiratory compromise and similar acutely life-threatening
conditions, evidence of severe pre-morbid neurological deficits such as aphasia or
deafness, lack of Danish or English language proficiency, age less than 16 years, and
patients without evidence of intact primary auditory and sensory cortex function as
revealed by pretest screening with brainstem auditory evoked potentials (BAEP) and
somatosensory evoked potentials (SSEP). The investigators will aim for un-sedated
patients; however, if patients cannot be weaned from sedation, the level of sedation
will be lowered to the lowest possible level in order to maximize the chance of
detecting the presence of consciousness.
- Work package 2 (clinical database): In order to maximize the learning effect at the
present institution and to facilitate research, all relevant clinical,
neurophysiological and imaging data will be collected in a comprehensive longitudinal
database. Clinical outcome data will be assessed, either by telephone interview or
during follow up visits, using established rating scales (e.g. modified Rankin Scale
(mRS), Barthel index) at hospital discharge and at 3, respectively, 12 months. Approval
to establish this database and to distribute information derived from it by means of
scientific publication will be obtained according to current legislation from the Danish
authorities Datatilsynet (The Danish Data Protection Agency) and Sundhedsstyrelsen (The
National Board of Health).
- Work package 3 (active fMRI paradigms): The investigators will establish an active fMRI
paradigm by means of visual imaginary tasks (playing tennis, navigating in a familiar
surrounding) as described earlier, using a similar convenience sample (n=5-10) as in
work package 1. Patients will be clinically evaluated on a daily basis, including 30 min
prior to and after each fMRI assessment, in order to capture fluctuations in
consciousness levels as accurately as possible. Prior to inclusion, patients will be
examined by brainstem auditory evoked potentials (BAEP) and somatosensory evoked
potentials (SSEP) in order to ensure intact primary auditory and sensory cortex
integrity.
- Work package 4 (passive fMRI paradigms): The investigators wish to set up a passive fMRI
paradigm using two oddball paradigms ("subject's own name", respectively, semantic
ambiguity), and we will assess patients (n=5-10) clinically and neurophysiologically
(BAEP, SSEP) as outlined above.
- Work package 5 (resting state EEG): In order to correlate resting state EEG with
clinical outcome data, the investigators will assess a historical EEG database,
available at the Department of Clinical Neurophysiology, Rigshospitalet, for EEG
complexity and other advanced EEG measures following acute brain injury 18.
- Work package 6 (active EEG paradigms): Similar to fMRI, the investigators will establish
an active EEG paradigm using visual imaginary tasks (playing tennis, navigating in a
familiar surrounding) as described earlier (Cruse et al. 2011). Clinical evaluation of
patients (n=5-10) will be performed as outlined previously.
- Work package 7 (passive EEG paradigms): The investigators will set up passive EEG
paradigms using oddball paradigms ("subject's own name", respectively, semantic
ambiguity) as described previously. As cognitive correlates we will accept P300 and more
prolonged evoked potentials, as well as more elaborate measures such as EEG complexity.
Clinical evaluation of patients (n=5-10) will be performed as previously described.
- Work package 8 (consecutive sample assessed by full range of fMRI- and EEG-paradigms):
In this work package, corresponding to the second phase of the project, the
investigators wish to combine all consciousness measures in order to systematically and
comprehensively evaluate consciousness in each acute brain injury patient, using the
full range of clinical assessments as well as active, passive and resting state fMRI-
and EEG-based paradigms. The investigators aim for 20 consecutive TBI and/or non-TBI
non-communicating DoC patients admitted to the neurological and neurosurgical ICU or
step down units (inclusion criteria). Prior to inclusion, primary auditory and sensory
cortex integrity will be verified using BAEP and SSEP. Exclusion criteria will include
those referred to in work package 1.
- Work package 9 (full clinical service; biobank): Once the investigators have shown that
comprehensive fMRI- and EEG-based consciousness paradigms are feasible in patients with
acute brain injury in the ICU and intermediate care units, they wish to establish a full
clinical service and a national referral center for the evaluation of DoC patients
following acute brain injury. In addition, the investigators will set up a biobank for
cerebrospinal fluid and blood samples for potential future studies related to genomics
and metabolomics. Together this will lay the foundation for a fruitful research milieu
(phase 3).