The vegetative state (VS), a disorder often observed after traumatic brain injury, is characterized by the absence of awareness of self or the environment and preserved autonomic functions (Multi-Society Task Force on PVS, 1994; Royal College of Physicians, 2003). To date, the diagnosis of VS has relied on behavioral assessment, most importantly, the lack of consistent signs of purposeful behavior in response to external stimulation. Yet, due to severe diffuse brain damage (Adams et al., 2000) these patients often exhibit fragmented movement patterns which may hinder the discrimination between reflexive and voluntary behavior (Schiff et al., 2002). On the other hand, some VS patients may retain partial levels of conscious processing, but be unable to reproducibly perform movements due to lesions at one or more levels of the motor system (Bekinschtein et al., 2008). Relying on the absence of overt behavior as the diagnostic criterion for VS may thus render the clinical assessment imprecise and subjective, leading to high error rates (Childs et al., 1993; Andrews et al., 1996; Gill-Thwaites, 2006). There is currently a need for greater diagnostic precision for patients in states of impaired consciousness as the diagnosis may have an impact on prognosis and treatment (Owen and Coleman, 2008); neurophysiological measures that may unveil voluntary responses to external stimuli should help to reduce the risk of misdiagnosis.

To date, only two studies have shown unequivocal, objective evidence of conscious awareness in clinically defined VS patients using functional magnetic resonance imaging (fMRI; Owen et al., 2006; Monti et al., 2010). Our group has previously demonstrated activation of two different functional networks when the patient is asked to imagine playing tennis (motor imagery) or walking throughout his/her apartment (spatial navigation; Owen et al., 2006). The brain pattern associated with these two tasks did not differ from that found in healthy volunteers. Nevertheless, the high cognitive demands associated with imagery (Guillot and Collet, 2005) may restrict its application to a subset of patients with relatively spared cognitive processing. In a recent study we demonstrated that, although movement may not be detectable in the behavioral assessment, it can be inferred from electromyographical recordings of hand muscles in response to a hand movement command (Bekinschtein et al., 2008). On this basis, it seems likely that there may be even more extreme cases where the motor system is insufficiently preserved to generate a movement. Here, we used a simple motor paradigm to objectively detect signs of residual purposeful behavior in VS patients by examining the neural correlates of movement preparation to command. We hypothesized that VS patients with residual voluntary processing would activate the dorsal premotor cortex contralateral to the specific hand command.

A wealth of neurophysiological and neuroimaging studies have demonstrated that movement preparation to externally triggered actions typically activates the dorsal premotor cortex (Wise et al., 1983; Passingham, 1985; Crammond and Kalaska, 1994, 2000; Toni et al., 1999; Thoenissen et al., 2002). Here, we showed that when instructed to move their right hand, two out of five vegetative patients with preserved auditory processing of basic speech characteristics, exhibited increased activity in the contralateral dorsal premotor cortex despite a lack of movement-related muscle activity. This predicted pattern of functional activation contralateral to the instructed hand movement strongly suggests movement preparation and/or planning, and thus, is consistent with a residual ability for conscious processing in these patients. Our findings are strengthened by the increment of activity in the contralateral posterior parietal cortex for both patients, a region involved in processing movement intention (Toni et al., 1999; Andersen and Buneo, 2002; Thoenissen et al., 2002).

It is important to remark that no significant activity was detected in premotor cortex in response to left-hand movement commands. This functional pattern may stem from anatomical lesions suffered during the accident or may be a consequence of subsequent atrophy or further tissue loss. The lack of activity for the left vs. right contrast in VS1 finds indirect support in his/her last behavioral assessment performed 34 months after the fMRI study: when pinched on the left arm, the patient crossed the body midline to reach it with his right arm but was unable to reach with the left arm when pinched on the right arm. Despite showing spontaneous EMG activity for the muscles of the right arm, this patients’ T1 image revealed severe callosal atrophy, commonly observed in TBI patients (e.g., Vuilleumier and Assal, 1995). Callosal atrophy may have interfered with interhemispheric processing affecting the right-hemisphere response to verbal commands of left-hand movements. As for VS2, the fact that no spontaneous EMG activity was detected for muscles of the right arm but withdrawal reflex was spared, suggests there was damage at the cerebral level of the motor (or sensory) system. The T1 image for this patient revealed no callosal damage, or any further atrophy in cortical motor/sensory cortex. This, however, does not rule out the existence of a cortical lesion that may have not been detectable at the low image resolution used (voxel size = 0.47 mm × 0.47 mm × 2.8 mm). New MRI quantitative methods are now available to characterise the degree of tissue damage (Fernandez-espejo et al.,2011).

A number of previous studies have used neuroimaging methods to unveil cognitive processing in VS patients. The capacity to process painful stimuli (Laureys et al., 2002; Boly et al., 2008), auditory stimuli (Boly et al., 2004), some features of speech (Owen et al., 2002; Bekinschtein et al., 2004; Kotchoubey et al., 2005), and visual stimuli (Menon et al., 1998) has been reported in clinically diagnosed VS patients. More recently, Coleman et al. (2007, 2009a) identified a subset of VS patients (7 out of 22) who exhibited a pattern of brain activity consistent with speech processing. Moreover, our group also demonstrated conscious processing in 5 out of 54 patients with disorder of consciousness from which two truly VS patients, as determined by behavioral assessment, showed modulation of BOLD activity in response to an imagery task (Monti et al., 2010). Although, as revealed by fMRI, speech perception can occur in healthy subjects in some unconscious states such as sleep (Portas et al., 2000), recent evidence from anesthetized volunteers suggests that speech comprehension does require conscious awareness (Davis et al., 2007). In the context of this finding we suggest that VS1 and VS2 were able to process semantic characteristics of speech and used that information to activate movement-related networks.

Given the small number of patients with residual consciousness detected with fMRI, one could argue that the technique is not efficient enough to implement as a standard routine in addition to the clinical assessment. Consciousness is assessed by measuring an active response to a command. Given that the paradigm we used required understanding of verbal instructions, only those patients with demonstrated preserved auditory processing for basic speech characteristics could be included. This reduced the original sample size from 24 to 5. Two out of these five patients showed signs of residual conscious processing. Thus, the small number is greatly explained by the relatively low proportion of patients with preserved speech processing after traumatic brain injury (Coleman et al., 2009), not by the low detection rate of our method. Considering these limitations, the identification of two patients with potential for recovery is of clinical relevance.

We have previously used fMRI to assess residual conscious awareness in clinically diagnosed VS patients (Owen et al., 2006; Monti et al., 2010). Nevertheless, the high cognitive demands associated with that experimental paradigm (Guillot and Collet, 2005) may restrict its application to high functioning patients in MCS or patients with relatively spared cognitive processing. Here, we showed that signs of purposeful behavior can be inferred with a much simpler motor paradigm based on movement preparatory activity in the absence of overt action. The overall pattern of brain activity observed for VS1 and VS2 was greater and more extended than that found for the other three patients. This is consistent with the observation that MCS patients exhibit a more extended pattern of brain activity than VS patients in a variety of tasks (Boly et al., 2004; Schnakers et al., 2008; Bekinschtein et al., 2009). The fact that behavioral re-assessment of VS1 3 years after fMRI scanning was compatible with a diagnosis of MCS, further suggests that signs of voluntary behavior may reflect residual conscious awareness. Importantly however, there was no evidence of volition from the first behavioral evaluation. Unfortunately, we were unable to carry out a full behavioral 2-year follow-up of VS2.

From a methodological point of view, the innovation of this paradigm lies in the use of a simple motor task that does not require high-level cognitive processing and therefore could be used to detect conscious awareness in a presumably larger VS patient population. We believe that functional imaging techniques should be used as a complementary test to confirm conscious awareness in patients who have already been through a comprehensive clinical assessment and several physiological tests using affordable and portable methods such as EMG and EEG to assess basic auditory, perception, and speech (Coleman et al., 2009b). In this manner fMRI could serve as an additional tool to detect signs of voluntary movement which may reflect residual conscious awareness in those patients that have been insensitive to other methods. It is important to keep in mind, however, that fMRI is limited in its interpretation: whereas positive results such as those shown here, are very informative and often straightforward to interpret, negative results are ambiguous as they can reflect true negative results, a drop in signal intensity, changes in wakefulness, lack of attention, etc.

In conclusion, we have used a simple motor preparation paradigm to objectively detect signs of purposeful behavior that were not evident from the clinical assessment in two of five patients who were presumed to be vegetative (and therefore unconscious). The current study argues for the use of functional MRI in the assessment and diagnosis of disorders of consciousness following severe brain injury. We believe that neurorehabilitation centers could benefit greatly from incorporating these and other objective tools such as electromyographic (Bekinschtein et al., 2008, 2009b) or electroencephalographic (e.g., Schnakers et al., 2008; Bekinschtein et al., 2009a) methods to identify those patients with potential for recovery. Moreover, recent advances in Brain Computer Interface paradigms, showing high accuracy of communication through EEG signals after very little training (Blankertz et al., 2008) may be adapted in the future to be used in patients with disorders of consciousness. A multimodal approach is desirable to minimize misdiagnosis of these patients as a result of a functional deficit in a particular perceptual domain, in the production of movement or due to low sensitivity of the tests performed (Coleman et al., 2009).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.