With use of an EEG motor imagery paradigm, 22% (5 of 23) of a group of MCS patients were able to produce ~100 responses to command without exhibiting any external behavior (). When separated according to etiology, a greater proportion of TBI patients returned positive EEG outcomes (33%, 5 of 15) compared with non-TBI patients (0%, 0 of 8). This pattern was also mirrored in the patients' behavioral profiles, with non-TBI patients returning significantly lower scores on behavioral assessments of consciousness (CRS-R score). Crucially, the effect of etiology on the ability to successfully complete this EEG task was statistically robust after these differential behavioral abilities were factored out, indicating that the relatively fewer behavioral markers of consciousness displayed by non-TBI patients are likely to be accurate reflections of their covert cognitive capacities. Conversely, and more remarkably, one-third of the TBI MCS patients possessed a range of high-level cognitive abilities that were not evident from their external behavior, but which were required to complete this EEG task. These include extensive sustained attention, language comprehension, working memory, and response selection, all high-level functions that are commonly associated with normal consciousness (for a full description of these arguments, see Cruse et al.8
As a result of the strains of rapid acceleration and deceleration on the brain, the most common neuropathologic changes after TBI are diffuse axonal injury,19,20
which predominantly affects both hemispheres, the corpus callosum, brainstem, and cerebellum in the VS and MCS.21–23
Conversely, when these conditions are caused by a nontraumatic injury, such as hypoxic-ischemic encephalopathy, selective and widespread damage to the neocortex and thalamus is observed, possibly due to the differences in the oxygen requirements of these structures.24–26
In the broadest sense then, what is known about the neuropathologic mechanisms underlying TBI and non-TBI, particularly in relation to the relative preservation of the cortex after TBI, is reflected here in the differential degree of functional deficit observed across the 2 groups.
The adverse effect of nontraumatic etiology on covert command-following abilities is consistent with that found in other functional neuroimaging studies of covert cognition. None of a group of 22 non-TBI VS and MCS patients were capable of successfully following commands during an fMRI mental imagery task.10
Indeed, this difference relative to TBI patients (16%, 5 of 32) approached statistical significance (Fisher exact test, one-tailed, p
= 0.058). An investigation of whether a group of 41 VS and MCS patients could produce appropriate fMRI activations when passively listening to speech, compared with nonspeech, found that significantly more TBI patients showed appropriate activations in this contrast (57%, 15 of 26), compared with non-TBI patients (20%, 3 of 15; Fisher exact test, one-tailed, p
In an event-related potential study, which required patients to count the occurrences of a target word in a stream of distractor words, a small effect of etiology was reported, with 71% of TBI MCS patients (5 of 7) appearing to follow command, albeit inconsistently, compared with 57% of non-TBI MCS patients (4 of 7).27
In the assessment of one TBI MCS patient and one non-TBI MCS patient, evidence for covert command-following was reported in the EEG response of the TBI patient only,28
whereas similar signs of command-following were observed in the fMRI responses of 1 of 3 TBI MCS patients and 1 of 4 non-TBI patients.29
The Multi-Society Task Force on Persistent Vegetative State11
reviewed the outcome of 754 published cases of VS and found that an adult patient who is in a VS within 1 month of a TBI has a 52% chance of recovering consciousness within 1 year, whereas a non-TBI patient has only a 15% chance of doing so. With regard to prognosis from the MCS, however, little is known. In one report, of the 16 TBI MCS patients assessed, 6 regained functional communication at the 5-year follow-up (38%) compared with only 1 of the 7 patients who were in an MCS as a result of anoxic-ischemic injury (14%).14
Although prognosis for VS and MCS patients was not reported separately, a further study found that 77% of 22 TBI patients had emerged from the MCS at long-term follow-up (1–4 years) compared with only 57% of 14 non-TBI patients and that 77% of TBI patients were capable of interactive communication at that time, whereas only 29% of non-TBI patients were able to do so.15,16
Despite the introduction of the MCS diagnostic category almost 10 years ago,2
to date there have been no large-scale epidemiologic studies of prognosis from this state. As a result, it is not known how often MCS patients recover and to what degree. For example, in one notable case, Terry Wallis was in an MCS for 19 years before emerging to a level at which functional and expressive communication was possible, yet the frequency with which such cases occur has not been systematically investigated.30
Indeed, in contrast to the VS, a diagnosis of permanent MCS cannot currently be made. Nevertheless, the data reported here suggest that there is a decreased likelihood that non-TBI MCS patients will possess high-level cognitive faculties, whether these may be expressed overtly or not, convergent with the general consensus within the wider literature on this topic. In this context, our results show that etiologic factors produce a clearly measurable difference in remarkably high-level, demanding cognitive functions that subserve awareness, including language, attention, working memory, task orientation, and decision making.
The current data also reemphasize the disparity between behavioral signs of awareness and those that may be detected with functional neuroimaging. Thirty-eight percent of the 8 MCS patients who were incapable of following commands with their behavior, i.e., those producing only low-level nonreflexive behaviors such as visual pursuit, were nevertheless capable of following-command with this EEG paradigm (, , and ). Indeed, 75% of TBI MCS patients who could not follow commands behaviorally (3 of 4) were capable of returning a positive EEG outcome, compared with none of the non-TBI MCS patients. This result adds to the significant body of evidence that an apparent inability to follow commands with external responses does not necessarily reflect the true absence of the cognitive capability to do so.8–10,27
Rather, a significant proportion of behaviorally nonresponsive patients retain a range of high-level cognitive capacities beyond those indicated by their behavior.
We have shown that patients who progress to the MCS after a non-TBI are significantly less likely to produce evidence of high-level cognitive functioning than traumatically injured MCS patients. This finding holds true for the conventionally used externally observable signs of cognition, as assessed by behavioral scales (e.g., CRS-R), as well as for covert faculties as determined by the current EEG motor-imagery assessment. Evidence for the differential effect of etiology on the behavior of MCS patients is sparse, and future large-scale epidemiologic studies are required to fully characterize this challenging diagnostic category.31