M. Boly, A.M. Owen, and S. Laureys
Introduction: What is the Vegetative State
The vegetative state is a clinical diagnosis first defined by Jennett and Plum in 1972 [1]. It is a diagnosis based on the absence of clinical signs of awareness of self or environment despite preserved arousal. That is, if a patient repeatedly fails to answer to commands and if all observed behavior is considered reflexive, the patient is con- sidered to be unconscious.
Patients in a minimally conscious state [2] will show more than the mere reflex behavior observed in vegetative state survivors, but they are unable to effectively communicate. However, these distinctions are complicated by the fact that there is no universally-accepted definition of consciousness [3]. Existing definitions often invoke the importance of ‘purposeful’ or ‘meaningful’ behavior, but it is not clear
Table 1. Clinical features of the vegetative state according to the report of a working party of the Royal College of Physicians [6].
Compatible features
) Signs of a cycle of sleep and wakefulness.
) Spontaneous movements (made for no discernible reason) including :chewing, teeth grinding, swal- lowing, roving eye movements, purposeless limb movements; smiling grimacing, shedding tears, grunting, groaning (it would be unusual for a patient to display the entire range of movements).
) Variously preserved brainstem reflexes including: pupillary, oculocephalic (doll’s eye), corneal, oculo- vestibular (caloric), and gag reflex
) Noxious or noisy stimuli may excite a generalized arousal response including: quickening of respira- tion, grimaces or limb movements, extensor or flexor withdrawal of a limb.
) Patients’ eyes may turn fleetingly to follow a moving object or towards a loud sound.
) Grasp reflexes may be present.
Compatible but atypical features (prompting careful reassessment but not negating the diagnosis) ) follow a moving target for more than a fraction of a second
) fixate a target ) react to visual menace
) utterance of a single inappropriate word Incompatible features
) evidence of discriminative perception ) purposeful actions
) communicative acts
) a smile in response to the arrival of a friend or relative ) an attempt to reach out for an object
) appropriate use of language
what type of evidence is sufficient to demonstrate that a specific motor action is imbued with purpose or meaning [4]. Until an objective index is found, the bound- ary separating consciousness and unconsciousness remains arbitrary [5]. Recently, diagnostic schemes built around the presence or absence of criterion behaviors have been developed to distinguish minimally conscious state from vegetative state [2, 6, 7]. While behavior-based diagnostic criteria are useful for characterizing patients clinically, they are inherently flawed because motor responsiveness is often an unre- liable proxy for consciousness. Movements that appear to be volitional may actually be reflexive in nature and vice versa. Complicating matters further, patients may exhibit behavioral signs of awareness during one examination and fail to do so on the next. Fluctuations in arousal and motor responsiveness commonly occur in dis- orders of consciousness and may result in diagnostic instability [8, 9]. These factors have conspired to produce high rates of misdiagnosis in vegetative state, especially if the diagnosis is not made by trained physicians with the necessary expertise; pre- vious studies have reported diagnostic error in 18 % [10], 37 % [11] and 43 % [12] of patients considered ‘vegetative’.
Complimentary Examinations in Vegetative State
Structural imaging such as computed tomography (CT) and magnetic resonance imaging (MRI) are non-specific for the diagnosis of vegetative state. With regard to outcome, corpus callosum and brainstem lesions, identified with MRI, are associated with non-recovery in post-traumatic vegetative state [13, 14]. Post-trauma metabolic (brainstem spectroscopy) and morphological (T2 star and Flair) MRI studies also correlate with long-term neurological outcome, especially in vegetative state and minimally conscious state [15]. In vegetative state of non-traumatic origin, there is no established correlation between structural imaging data and the development of vegetative state or the potential for recovery [16].
Electroencephalography (EEG) is not specific for the diagnosis of vegetative state and classically shows a diffuse slowing of the electrocortical activity (general- ized polymorphic delta or theta rhythm) [17]. Background activity only occasion- ally shows reactivity to sensory (noxious) stimulation [18, 19]. In most patients, transition from wakefulness to sleep is accompanied by changes in the EEG pat- tern. However, some patients show persistent very low voltage activity and sporadi- cally isoelectric EEGs have been reported [16]. In approximately 10 % of long- standing vegetative state patients, a non-reactive alpha rhythm has been observed [18]. The transition from coma to vegetative state is not accompanied by any nota- ble changes in the EEG. In contrast, transition from vegetative state to awareness has sometimes been accompanied by the reappearance of a reactive alpha rhythm [18, 20].
Evoked potentials are a valid tool for assessing the prognosis of patients who are in a coma but are not helpful in confirming the diagnosis of vegetateive state [21].
Somatosensory evoked potentials (SEP) are the most helpful: bilateral absence of cortical responses three days after the insult is highly predictive of failure to regain consciousness (i.e., death or survival in vegetative state). However, patients with normal SEPs may enter a vegetative state and remain in it and visual evoked poten- tials (VEP), brainstem auditory evoked potentials (BAEP), and passive auditory oddball paradigm are not specific for vegetative state, niether do they help in pre- dicting the outcome [22].
Functional neuroimaging studies in vegetative state have shown that cerebral metabolic activity decreases to about 50 % of normal levels [23, 24]. However, in one group of patients who subsequently recovered, global metabolic rates for glucose metabolism did not show substantial changes [25]. Moreover, some awake healthy volunteers have global brain metabolism values comparable to those observed in some patients in a vegetative state [26] and inversely, some well documented vegeta- tive patients have shown close to normal global cortical metabolism [23]. The most characteristic feature of vegetative state is a dysfunction in the frontoparietal net- work encompassing the polymodal associative cortices: bilateral lateral frontal regions, parieto-temporal and posterior parietal areas, mesiofrontal, posterior cin- gulate and precuneal cortices [24, 26]. But neither global nor regional measures of resting cerebral metabolism dissociate vegetative state from minimally conscious state at the individual patient level [27].
In response to external sensory stimuli, functional neuroimaging studies have shown that vegetative patients show cerebral activation, but this activation is usually limited to subcortical and ‘low-level’ primary cortical areas, disconnected from the cortical network considered necessary for conscious perception. Studies using pain- ful stimulation have shown activation in brainstem, thalamus, and primary somato- sensory cortex in vegetative state patients, while hierarchically higher-order areas of the pain matrix (that is, secondary somatosensory, insular, posterior parietal, and anterior cingulate cortices) failed to activate [28]. Moreover, the activated primary somatosensory cortex was isolated and dissociated from the frontoparietal network, thought to be required for conscious perception. Similarly, auditory stimulation in vegetative patients activates primary auditory cortices, but usually not higher-order multi-modal areas from which they were disconnected [29, 30].
Surprising Results in Vegetative State: Signs of Consciousness?
Some electrophysiological and functional neuroimaging studies have shown surpris- ing results in patients diagnosed as vegetative. Hinterberger et al. [31] reported results of a five stage electrophysiological assessment of five patients diagnosed as vegetative and five healthy volunteers. Several of the patients showed normal or near-normal event-related brain potential (ERP) responses to some of the tasks, although results were most constant at the lower levels of the suggested processing hierarchy (e.g., semantic oddball). On the basis of these findings, two of the patients were selected for training on a brain computer interface (also called ‘thought trans- lation device’) with some success in one of these cases. Similarly, Kotchoubey [32]
has reported that some patients diagnosed as vegetative may be capable of process- ing semantic stimuli indicating some comprehension of meaning. Thus, P3 and N400 components were observed but were often abnormal (e.g., slow negative response instead of a P300) in patients considered to be in a vegetative state [33].
Perrin and co-workers [34] have reported a P300 response to salient stimuli such as the patient’s own name as compared to other names in minimally conscious state, but also in some vegetative state patients.
Similarly, several case studies using functional MRI (fMRI) have also provided evidence of preserved high-level cortical processing in some patients reported to be in a vegetative state. An auditory paradigm was used in the first oxygen-15-labelled positron emission tomography (PET) study of a patient in a vegetative state. The authors observed activation in the anterior cingulate and temporal cortices when
this patient (in a post-traumatic vegetative state) was told a story by his mother compared with when he heard nonsense words [35]. These authors interpreted this activation as the processing of the emotional attributes of speech or sound. In another widely discussed PET study of a patient in an upper boundary vegetative state after encephalitis (and before subsequent recovery), activation during presen- tation of photographs of familiar faces was compared with that during meaningless pictures. Although there was no evidence of behavioral responsiveness during pre- sentation of the familiar-face photographs, except occasional visual tracking, the visual association areas encompassing the fusiform face area showed significant activation [36]. Evidence is also building up indicating that non-communicative patients usually respond more to complex emotionally salient stimuli than to simple stimuli, suggesting some response to meaningfulness of information even in these disorders of consciousness [37]. None of these studies, however, demonstrate that finding evidence of residual complex processing predicts further recovery.
In order to most effectively define the degree and extent of preserved cognitive function in vegetative state, Owen et al. [38] have argued that a hierarchical approach to cognition is required; beginning with the simplest form of processing within a particular domain (e.g., auditory) and then progressing sequentially through more complex cognitive functions. To illustrate this point, a series of para- digms in the auditory domain were investigated, which systematically increase in complexity in terms of the auditory and/or linguistic processes required and, there- fore, the degree of preserved cognition that can be inferred from ‘normal’ patterns of activation in disorders of consciousness. For example, speech perception was assessed by comparing cortical responses to spoken sentences with those to acousti- cally-matched noise sequences. At the next level, phonological processing of speech was assessed by comparing responses to degraded (‘less intelligible’) sentences ver- sus normal (intelligible) sentences. Finally, speech comprehension was tested by comparing cortical responses to sentences containing ambiguous words (e.g., “the creak/creek came from a beam in the ceiling”) and matched unambiguous sen- tences. Increases in neural activity during ambiguous sentences reflect the operation of semantic processes that are critical for speech comprehension. The authors illus- trated this approach in a patient diagnosed as vegetative who showed activation in response to speech relative to signal correlated noise, potentially reflecting some perception of speech. A significant response was also observed to speech of increas- ing intelligibility suggesting that these perceptual processes are recruited more strongly for speech that can be more readily understood. Finally, ambiguous sen- tences yielded a partially normal response, interpreted as evidence that some semantic aspect of sentence processing was intact; in other words, not only did the patient’s brain recognize speech as speech, but it seemingly was being processed at a level which, in the healthy brain, is equated with comprehension [38].
Rarely, patients meeting the diagnostic criteria for vegetative state have behav- ioral features that seem to contravene the diagnosis [27]. From a series of multi- modal imaging studies of patients in a vegetative state, three with unusual behav- ioral fragments were identified. Preserved areas of high resting brain metabolism (measured with fluorine-18-labelled deoxyglucose PET) and incompletely preserved gamma-band responses (measured with magnetoencephalography) were fitted to structural data from an MRI and correlated with the behaviors of the patients [39].
Among those studied was a patient who had been in a vegetative state for 20 years who infrequently expressed single words unrelated to any environmental stimuli [40]. MRI images showed severe subcortical damage. Resting 18F-fluorodeoxyglu-
cose-PET measurements of the patient’s brain showed a global cerebral metabolic rate of ‹ 50 % of the normal range across most brain regions, with small regions in the left hemisphere expressing higher levels of metabolism. Magnetoencephalogra- phy responses to bilateral auditory stimulation were confined to the left hemisphere and localized to primary auditory areas. Taken together, the imaging and neuro- physiological data seemed to show that the left sided thalamocortical-basal ganglia loops (that support language function in Heschl’s gyrus, Broca’s area, and Wer- nicke’s area) were partially preserved. Similar observations in two other patients in chronic vegetative state provide evidence that isolated cerebral networks may remain active in rare cases. The preservation of these isolated behaviors does not indicate further recovery in patients in chronic vegetative state who have been repeatedly examined and carefully studied with imaging tools. Reliable observations of such unusual features should prompt further investigation in individual cases [27].
In several of the EEG [31, 34, 41] and functional imaging [38] studies described above, ‘normal’ evoked potentials or activation patterns in predicted regions of cor- tex have been used to infer residual cognitive processing in patients diagnosed as vegetative. The question that invariably arises is whether such signs indicate aware- ness. It is important to stress that there is a wealth of data in healthy volunteers, from studies of implicit learning and the effects of priming, to studies of learning during anesthesia that have demonstrated that many aspects of human cognition can go on in the absence of awareness. In the examples discussed above (including speech perception and the detection of semantic ambiguous sentences), under nor- mal circumstances cognitive processing is relatively automatic. That is to say, it occurs without the need for willful intervention – you cannot choose to not under- stand speech that is presented clearly in your native language.
A New Paradigm to Assess Consciousness in Vegetative State
Owen et al. [42] have recently addressed this concern by applying an fMRI paradigm where non-communicative patients are asked to perform mental imagery tasks at specific points during scanning. In one exceptional vegetative state patient studied five months after a traumatic brain insult, activation was observed in the supple- mentary motor area after she was asked to imagine playing tennis. In contrast, when asked to imagine visiting all of the rooms of her house, activation was observed in premotor cortex, parahippocampal gyrus, and posterior parietal cortex (Fig. 1).
Similar activation patterns were seen in 34 healthy volunteers studied in Cambridge and Li`ege. Importantly, because the only difference between the conditions that elic- ited task-specific activation was in the instruction given at the beginning of each scanning session, the activation observed can only reflect the intentions of the patient (which were, of course, based on the remembered instruction), rather than some altered property of the outside world. In this sense, the decision to ‘imagine playing tennis’ rather than simply ‘rest’ is an act of willed intention and, therefore, clear evidence for awareness and command-following in the absence of voluntary motor responsiveness. Of course, negative findings in such patients cannot be used as evidence for lack of awareness, as false negative findings in functional neuroima- ging studies are common, even in healthy volunteers. However, in the case described here, the presence of reproducible and robust task-dependent responses to com- mand without the need for any practice or training suggests a novel method by which some non-communicative patients, including those diagnosed as vegetative,
Fig. 1. Supplementary motor area (SMA) activity during tennis imagery in the patient and a group of 12 healthy volunteers (left panel). Parahippocampal gyrus (PPA), posterior parietal-lobe (PPC), and lateral pre- motor cortex (PMC) activity while imagining moving around a house in the patient and in the same group of volunteers (right panel). Adapted from [42] with permission.
minimally conscious or locked in, may be able to use their residual cognitive capa- bilities to communicate their thoughts to those around them by modulating their own neural activity [42].
Where Do We Go from Here?
Though enhancing the potential role that functional neuroimaging techniques can play in differential diagnosis in disorders of consciousness, the study by Owen et al.
[42] will not challenge current practice in therapeutic decision making. Indeed, the patient studied was in vegetative state following a traumatic brain injury, and at 5 months post injury had a 20 % chance of some recovery. Concerns about end-of-life decisions, treatment withdrawal or ending of artificial hydration and nutrition were, therefore, never applicable to this patient. Furthermore, this patient, though meeting established criteria for vegetative state at the time of scanning, showed an atypical clinical presentation. When re-examined six months later she showed inconsistent visual tracking – the most frequently encountered preliminary clinical sign of recov- ery from vegetative state.
The electrophysiological and functional neuroimaging studies described here fur- ther demonstrate the great need to increase research efforts to improve diagnosis in disorders of consciousness and better understand borderline behavior such as fixa- tion, eye tracking, and orientation to pain. In the current context, functional neuroi-
maging can improve our understanding of the neural correlates of these behaviors, as well as their significance in terms of awareness. A transition from case reports to multicenter studies enrolling large number of patients is also crucial.
Like brain death, vegetative state is a clinical diagnosis. In brain death, comple- mentary examinations are used to confirm clinical diagnosis [43]. At present, in veg- etative state no such ancillary objective measurements exist. They are, however, needed, given the clinical difficulties of quantifying consciousness based on behav- ior [44] and the known problem of clinical misdiagnosis.
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