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Tracking the recovery of consciousness from coma
Steven Laureys, Mélanie Boly, and Pierre Maquet
Cyclotron Research Center and Department of Neurology, University of Liège, Liège, Belgium.
Address correspondence to: Steven Laureys, Cyclotron Research Center and Neurology Department, University of Liège, Sart Tilman B30, 4000 Liège, Belgium. Phone: 32-4-366-23-16; Fax: 32-4-366-29-46; E-mail: steven.laureys@ulg.ac.be .
Find articles by Laureys, S. in: JCI | PubMed | Google Scholar
Cyclotron Research Center and Department of Neurology, University of Liège, Liège, Belgium.
Address correspondence to: Steven Laureys, Cyclotron Research Center and Neurology Department, University of Liège, Sart Tilman B30, 4000 Liège, Belgium. Phone: 32-4-366-23-16; Fax: 32-4-366-29-46; E-mail: steven.laureys@ulg.ac.be .
Find articles by Boly, M. in: JCI | PubMed | Google Scholar
Cyclotron Research Center and Department of Neurology, University of Liège, Liège, Belgium.
Address correspondence to: Steven Laureys, Cyclotron Research Center and Neurology Department, University of Liège, Sart Tilman B30, 4000 Liège, Belgium. Phone: 32-4-366-23-16; Fax: 32-4-366-29-46; E-mail: steven.laureys@ulg.ac.be .
Find articles by Maquet, P. in: JCI | PubMed | Google Scholar
Published July 3, 2006 - More info
J Clin Invest. 2006;116(7):1823–1825. https://doi.org/10.1172/JCI29172.
© 2006 The American Society for Clinical Investigation
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Abstract
We used diffusion tensor imaging (DTI) to study 2 patients with traumatic brain injury. The first patient recovered reliable expressive language after 19 years in a minimally conscious state (MCS); the second had remained in MCS for 6 years. Comparison of white matter integrity in the patients and 20 normal subjects using histograms of apparent diffusion constants and diffusion anisotropy identified widespread altered diffusivity and decreased anisotropy in the damaged white matter. These findings remained unchanged over an 18-month interval between 2 studies in the first patient. In addition, in this patient, we identified large, bilateral regions of posterior white matter with significantly increased anisotropy that reduced over 18 months. In contrast, notable increases in anisotropy within the midline cerebellar white matter in the second study correlated with marked clinical improvements in motor functions. This finding was further correlated with an increase in resting metabolism measured by PET in this subregion. Aberrant white matter structures were evident in the second patient’s DTI images but were not clinically correlated. We propose that axonal regrowth may underlie these findings and provide a biological mechanism for late recovery. Our results are discussed in the context of recent experimental studies that support this inference.
Authors
Henning U. Voss, Aziz M. Uluç, Jonathan P. Dyke, Richard Watts, Erik J. Kobylarz, Bruce D. McCandliss, Linda A. Heier, Bradley J. Beattie, Klaus A. Hamacher, Shankar Vallabhajosula, Stanley J. Goldsmith, Douglas Ballon, Joseph T. Giacino, Nicholas D. Schiff
Forty years ago, Plum and Posner published the first edition of their landmark book, The diagnosis of stupor and coma (1). Since then, clinical research efforts in the field of acute brain damage and coma have increased nearly exponentially. Comatose patients who survive thanks to ever-improving intensive care medicine classically begin to awaken and recover consciousness within some days to weeks or will enter a vegetative state (VS). The clinical criteria of this diagnostic entity of “wakefulness without awareness” were first set out by Jennet and Plum in their 1972 milestone paper (2). The VS may be a transitional state on the route to further recovery or, unlike coma, which virtually never becomes chronic, the VS may progress to a long-standing, sometimes irreversible condition. Permanent VS, a prognostic term to be used with great caution, implies the prediction that the patient will not recover. It was introduced by the Multi-Society Task Force on PVS (persistent vegetative state) to denote irreversibility of the condition after 3 months following a nontraumatic brain injury and 12 months after traumatic injury (3). However, even after these long and arbitrary delays, some patients may exceptionally recover (4, 5). In 2002, the Aspen Neurobehavioral Conference Workgroup published the definition and diagnostic criteria of the minimally conscious state (MCS) (6). Patients in MCS will show more than the purely reflex or automatic behavior observed in VS survivors, but they will nevertheless be unable to communicate their thoughts and feelings. Recent preliminary evidence indicates that MCS patients demonstrate improvement over a longer period of time and attain better functional recovery as compared with VS patients (7, 8). At present, the vast majority of studies on traumatic or ischemic brain damage are focused on the acute phase of coma. This creates a silent epidemic in which there is only minute attention devoted to the long-term diagnostic, prognostic, therapeutic, and social problems of persistent (albeit sometimes transient) disorders of consciousness such as VSs and MCSs (9, 10). The number of scientific papers on acute comatose states is about 10-fold higher than the number of publications on chronic disorders of consciousness. Future research efforts should also address the silent epidemic of VS and MCS and so that these challenging neurological states can emerge from the current dark ages of therapeutic nihilism.
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Searching for the neural correlate of consciousness
Our center had the opportunity to study neuronal metabolic changes underlying recovery from VS. To date, of 60 patients studied using quantified fluorodeoxyglucose PET, 7 patients recovered consciousness and could be rescanned. In these patients, we localized the brain areas where metabolism was most impaired during the VS and returned to near-normal values after recovery (22, 23). Such analyses identified the precuneus (Brodmann areas 7 and 31) as the area showing the largest recovery-related metabolic changes (Figure 1), followed by a wide network of frontoparietal associative cortices. In some VS or MCS patients, the disorder of consciousness seems due to a functional “disconnection syndrome” (16, 24). Long-range corticocortical (between midline-posterior and latero-frontal areas) and corticothalamic (between midline-posterior cortices and nonspecific thalamic nuclei) disconnections could be identified in a cohort of VS patients, and the rare cases that recovered showed a partial functional restoration of these connections (22, 25). The fiber-tracking MRI studies reported by Voss et al. in this issue of the JCI (12) offer indications as to the cellular mechanisms underlying this functional normalization. Their quantification of white matter reorganization shows long-distance rewiring in posterior medial cortices, possibly reflecting axonal sprouting or neurite outgrowth, maybe even related to neurogenesis (known to occur primarily in associative cortices in normal primates) (26).
Figure 1PET studies show that in the rare patients who recover consciousness after being in a chronic VS, glucose metabolism is partially restored in discrete cortical regions. (A) The most significant restoration of glucose metabolism occurs in the posteromedial cortices (shown in white on a medial view of a 3D-rendered MRI). The arrows represent the corticocortical and corticothalamocortical functional disconnections observed in vegetative patients. MF, mesiofrontal cortex; P, precuneus; T, thalamus (nonspecific nuclei). (B) Metabolism in this area is significantly impaired during the VS (black) but resumes near-normal activity after recovery of consciousness (REC; gray). Normal resting metabolic rates of glucose as measured in healthy controls are shown for comparison (CON; white). In this issue of the JCI, Voss and coworkers report on their observation of intracortical connectivity changes in the same area of the brain, as assessed by diffusion tensor MRI, in an exceptional patient who emerged after spending 19 years in an MCS (12). This residual cerebral plasticity in chronic disorders of consciousness has been largely overlooked by the medical community and deserves further study to expose its underlying cellular mechanisms. Figure and data adapted with permission from the Journal of Neurology, Neurosurgery, and Psychiatry (22).
Severe brain damage represents an immense medical, social, and economic problem that warrants further research. Chronically unconscious or minimally conscious patients present unique problems for diagnosis, prognosis, treatment, and everyday management. They are vulnerable to being denied potentially life-saving therapy if clinical research remains solely focused on the acute stage of the disease. Current functional neuroimaging techniques can prospectively quantify residual neuronal plasticity and the challenging process of recovery. The findings of Voss and coworkers (12) will increase our understanding of severely brain-damaged patients and their “miracle” recovery of consciousness.
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