Author: C. Schnakers
Introduction: in the past
Fifty years ago, scientific research on disorders of consciousness was very limited. Patients with severe brain injury, who are most likely to present with impaired consciousness during recovery, often died. In the fifties, the introduction of artificial breathing changed everything. The lives of these patients could be extended even in cases of severe lesions to brain areas supporting vital functions. Clinicians started to face patients who were “alive” but not reactive to their surroundings. In this context, a new categorization emerged for such patients, namely, the disorders of consciousness (DOC) (see figure 1). In the sixties, Plum and Posner defined for the first time a clinical entity called “coma” as a pathological state marked by severe and prolonged dysfunction of vigilance and consciousness . In 1972, the term “vegetative state” (VS) was first introduced by Jennet and Plum to describe those patients who were awake (eye opening) but not conscious (no oriented or voluntary response) . A few years later, Jennett and Teasdale developed the well-known Glasgow Coma Scale for assessing the progress of patients with severe brain injury in intensive care units . Finally, in 2002, formal diagnostic criteria for the “minimally conscious state” (MCS) and emergence from MCS were published in the journal Neurology to account for those patients who start to show signs of consciousness in a reproducible but fluctuant way . Since the definition of these clinical entities, the number of scientific studies performed on patients with DOC has dramatically increased (see figure 2). For example, only 15 articles were published about VS from 1975 to 1985 as compared to 446 articles in the last five years.
Figure 1 – The main clinical entities encountered in patients recovering from coma, illustrated as a function of two main components: arousal and consciousness.
Figure legend. VS=vegetative state, MCS=minimally conscious state and EMCS=emergence from MCS.
Figure 2 – Publications on disorders of consciousness between 1975 and 2015
Figure legend. Pubmed search using the terms: vegetative state, minimally conscious state, consciousness and awareness. The results for the vegetative state are presented in light grey while the results for the minimally conscious state are presented in dark grey.
The emergence of functional neuroimaging techniques (such as positron emission tomography – PET and functional magnetic resonance imaging – fMRI) opened new opportunities to study brain activity in patients with DOC. The use of those techniques allowed to improved ability to delineate neural processes linked to consciousness. We know now that most patients in VS present with partial activation of sensory networks and impaired functional connectivity contrary to patients in MCS. Low-level primary cortical activity seems to be isolated from higher-level associative cortical activity, and recent findings suggest that long distance connectivity (e.g., between frontal and temporal areas) is more impaired than short distance connectivity (e.g., areas within the temporal gyrus) . The reemergence of thalamo-cortical connections has also been associated with recovery of consciousness; whereas, thalamic atrophy has been associated to chronic DOC [5, 6] (see figure 3). The brain activity in some patients with VS may nevertheless differ from findings suggesting altered brain activity. In 2006, Owen and colleagues reported the landmark case of a young woman who was clinically diagnosed as being in a VS. Yet, when performing a mental imagery task during an fMRI scan, her brain activity was similar to the pattern of activity observed in healthy controls . Since then, other case studies have reported similar observations suggesting an underestimation of cognitive processing and the existence of a “covert cognition” in a minority of patients diagnosed as being in a VS.
Figure 3 – Residual brain activity in disorders of consciousness
Residual brain activity at rest (within the default network) (A) and in response to noxious stimulation (B) in patients in a vegetative state (VS) versus in a minimally conscious state (MCS) (adapted from [15-16]). Panel C illustrates the deficit in connectivity (particularly, long distance backward connectivity) in patients in VS versus MCS (adapted from ). Panel D illustrates the thalamic atrophy linked to prolonged disorders of consciousness at 6 months post-injury (adapted from ).
Recent findings on assessment and treatment
Thanks to all those findings, new techniques and paradigms aiming to improve the assessment and the treatment of patients with DOC started to emerge. With regards to assessment, Stender and colleagues have demonstrated, in a large sample, the utility of PET scan when detecting conscious brain activity based on the preservation of fronto-parietal networks. The technique allowed these researchers to correctly identify 93% of patients in MCS and to correctly predict consciousness recovery in 74% of patients with DOC .
Based on previous findings on functional connectivity, Casali and colleagues proposed the perturbational complexity index (PCI) as a measure of effective connectivity by calculating the spatial and temporal response of the brain to a perturbation induced by transcranial magnetic stimulation. The PCI distinguishes alert, healthy volunteers from volunteers who were anesthetized, sedated and asleep, and differentiated patients who were conscious (locked-in syndrome, MCS and emerged from MCS) from those who were unconscious (VS) . Finally, a series of fMRI and electroencephalography-based brain computer Interfaces are under development to detect “VS” patients with covert cognition . Brain computer interfaces are motor-independent systems that use brain activity to drive external devices or computer interfaces. These systems could represent a complementary tool for detecting command-following and for allowing complex ideas to be communicated to the outside world despite severe motor dysfunctions. The development of these interfaces is based on the idea that patients in VS who respond to active paradigms have preserved cognition. Such an idea has recently been challenged and should be further investigated .
With regards to treatment, Giacino, Whyte and colleagues have recently demonstrated the efficacy of a pharmacological treatment with amantadine (a dopaminergic agent), which seems to modulate cortico-cortical (e.g., fronto-parietal) network. In the context of this 11-site international, multicenter, randomized and controlled trial, rate of recovery in both VS and MCS was significantly faster in the amantadine group as compared to those who received placebo . There is also a growing interest in the use of invasive and non-invasive brain stimulation techniques to restore cortico-cortical but also thalamo-cortical connections in patients with prolonged DOC. The central premise used to guide these therapies is that electrical or magnetic stimulation elicits action potentials and depolarization of target neurons in cortical networks that underlie key functional systems (e.g., arousal, drive, language) responsible for behavioral initiation and control. Using a blinded alternating crossover design, Schiff, Giacino and colleagues observed treatment-related behavioral improvements in a patient with TBI in MCS who was treated with deep brain stimulation of the thalamic intralaminar nuclei more than six years post-onset .
The use of non-invasive brain stimulation techniques such as transcranial direct current stimulation has also been investigated in the context of treatment of persons in DOC. Thibaut and colleagues administered this technique in 55 patients with DOC using a double-blind sham-controlled crossover design. In each patient, a single stimulation and sham session were applied over the left dorsolateral prefrontal cortex. Behavioral improvements have been observed in patients in MCS directly after the stimulation session; whereas, such improvements were not observed after the sham session .
Conclusion: in the future
Even though it remains difficult to manage patients with severe brain injury, the field is in a rapid state of evolution. Ten years ago, everything was about characterizing and understanding consciousness processing. Clinicians would mainly collaborate with neuroscientists and help them to recruit to improve theoretical understanding, knowing it would not directly impact their practice. Now, the knowledge we have accumulated (and that we are still accumulating) is starting to have real translational ability to patient assessment and treatment. If this exponential increase of publication and interest continues (see figure 2), it will soon lead to even more substantial changes in the way we perceive the role of neurorehabilitation in those patients with DOC. In this context, recent initiatives have been created to develop international networks of collaboration, i.e., the American Congress of Rehabilitation Medicine has created a special interest group on DOC and the International Brain Injury Association is currently doing the same to expend such networks worldwide. This is truly an exciting time for the field, full of hope but also full of challenges. Assessment and treatment options need a lot more development and validation to be able to one day be implemented in clinical practice. In an experimental setting, the study of this population is also extremely challenging. These patients are sometimes difficult to recruit and retain, often easily exhausted and agitated, limiting the sample size, the assessment window and the data quality. The development of a research environment adapted to the scientific investigation of these patients is time consuming and requests important clinical and scientific expertise. Coordinating multidisciplinary resources and knowledge (particularly between clinicians and neuroscientists) is therefore more than ever needed. Such collaboration will certainly help to overcome those complications and will lead, on the long term, to significant improvements in the care of patients with severe brain injury.
Dr Schnakers’ work is currently supported by the Dana Foundation.
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About the Author
Dr. Schnakers is from the Dpartment of Neurosurgery, University of California Los Angeles, Los Angeles, CA.
Caroline Schnakers, PhD
Department of Neurosurgery,
University of California, Los Angeles
Los Angeles, CA 90095-1563