Brain Function in Disorders of Consciousness

By: Steven Laureys MD, PhD

The evaluation of residual cerebral function in severely brain damaged patients is of major medical importance. We will here briefly review some recent studies on bedside behavioral evaluation scales, electrophysiology and functional neuroimaging in post-coma disorders of consciousness (DOC).

Behavioral evaluation of consciousness

Bedside clinical evaluation of consciousness in non-communicative severely brain-damaged patients is extremely difficult. It is known that if inadequately assessed, about a third of patients considered vegetative actually are minimally conscious or conscious [for recent discussion see 1]. Wijdicks et al. [2] have recently presented the Full Outline of UnResponsiveness (FOUR) scale as an alternative to the Glasgow Coma Scale (GCS) in the evaluation of consciousness in severely brain-damaged patients.

In collaboration with Giacino et al. we tested the accuracy of the FOUR in the differential diagnosis of the vegetative state (VS) versus the minimally conscious state (MCS) [3]. It was shown that the FOUR does better than the Glasgow Coma Scale (GCS) in diagnosing VS but more than a quarter of acute and chronic patients considered vegetative by use of the FOUR scale actually were MCS based on Coma Recovery Scale [CRS-R, 4] assessments. Prior to performing any neuroimaging or electrophysiological measurements in DOC, it is crucial to obtain accurate clinical assessments using standardized and validated behavioral scales.

Electrophysiological studies

The electroencephalogram (EEG) is an objective tool that permits continuous and online monitoring of brain function. Because interpretation of the raw EEG signal requires considerable expertise and specialized training, simpler, more standardized measures of brain function are desired. The bispectral index (BIS) of the EEG is an empirical, statistically derived variable [ranging from 0 (isoelectric) to 100 (“fully conscious”)] designed as a measure of depth of anesthesia. Our group recently tested the usefulness of the BIS to monitor consciousness in comatose, VS, MCS and locked-in syndrome (LIS) patients [5]. It was shown that the BIS correlated with the level of consciousness as assessed by means of the Glasgow Liège Scale [GLS, 6] and the Wessex Head Injury Matrix [WHIM, 7]. An empirically defined BIS cut-off value of 50 differentiated unconscious patients (coma or VS) from conscious patients (MCS or emergence from MCS) with a sensitivity of 75% and specificity of 75%.
Using event related potentials (ERPs), we recently investigated the integrity of detection of the patients’ own name - a potent ‘attention-grabbing’ self-referential stimulus - in VS, MCS and LIS patients [8]. To our surprise, 3 out of 5 behaviorally well-documented VS patients who failed to subsequently recover, emitted a differential P300 potential to their own name and not to other names. Hence, a P300 response does not necessarily reflect conscious perception and cannot be used to reliably differentiate individuals in VS from MCS.

Functional neuroimaging

Few studies to date have used functional magnetic resonance imaging (fMRI) or positron emission tomography (PET) to monitor and record the recovery of consciousness in VS and MCS. Beckinschtein et al. [9] described an interesting case who, after 2 months in a VS, progressed to MCS and then, over the next 18 months, to partial independence. An fMRI was performed involving passive listening blocks of real words, white noise or silence. During VS, the word versus silence comparison revealed small clusters of activity in temporal-lobe regions, although activity was increased significantly in speech and auditory areas following recovery.

Among the most challenging problems in DOC are the sporadic reports of late recovery following stable behavioural levels consistent with MCS that continue to arise, although few of these patients receive careful evaluation. The team led by Schiff et al. [10] presented remarkable findings in an unusual case of late emergence from MCS using a combination of diffusion tensor MRI and PET techniques.

A 40 year-old male who fully recovered expressive and receptive language after remaining in MCS for 19 years following a severe traumatic brain injury showed very severe diffuse axonal injury along with unusual large regions of increased connectivity (as measured by fractional anisotropy) in posterior medial brain structures not seen in normal subjects.

These same areas showed increased glucose metabolism as studied by PET, likely reflecting the neuronal re-growth paralleling clinical recovery. It shows that old dogmas need to be oppugned as recovery with meaningful reduction in disability here continued for nearly two decades after extremely severe traumatic brain injury [see commentary in 11].

Their findings also stress the importance of the posterior medial structures in consciousness of self and interaction with the environment. The medial parietal cortices (encompassing the precuneus) seem to be the brain regions that best differentiates MCS from VS patients [12]. Interestingly, these areas are among the most active brain regions in conscious waking and are among the least active regions in altered states of consciousness such as pharmacological coma, sleep, dementia and Wernicke-Korsakoff's or post-anoxic amnesia [discussed in 13].

So far, functional neuroimaging in cohort studies of patients unequivocally meeting the clinical diagnosis of the VS, external stimulation using for example noxious or auditory stimuli have classically shown systematic activation of primary sensory cortices disconnected from higher order associative cortices considered necessary for conscious perception [e.g., see reviews in 12,13,14]. However, anecdotal but increasing evidence from functional neuroimaging and ERP [e.g., the above discussed study 8] shows ‘preserved’ cerebral activation in patients diagnosed as VS .

A recent fMRI study for example, has reported selective medial prefrontal activation to the patient’s own name as compared to other names in a VS case studied 10 months after cardiac arrest [15]. The patient died 1 year later without ever showing signs of awareness. The question that arises is whether the observed brain activation indicates awareness. It is important to emphasize that studies of implicit learning, priming and anesthesia have shown that many brain processes go on in the absence of awareness.

How can we disentangle automatic from conscious brain activation. Owen et al. [in collaboration with our group, 16] have recently addressed this issue by asking non-communicative patients to actively perform mental imagery tasks. In one exceptional VS patient studied five months after a cerebral trauma, activation was observed in the supplementary motor area after being asked to imagine playing tennis.

When asked to imagine visiting the rooms of her house, activation was seen in premotor cortex, parahippocampal gyrus and posterior parietal cortex. Near identical activation was observed in the 34 healthy volunteers studied in Cambridge and Liège. The patient’s decision to ‘imagine playing tennis’ rather than simply ‘rest’ must here be seen as an act of willed intention and, therefore, clear evidence for awareness. Interestingly, later evolved to a MCS.

Functional imaging studies in MCS patients using auditory stimuli with emotional valence (i.e., personalized narratives [17] or infant cries and the patient's own name [18]) induced a much more widespread activation than did meaningless stimuli. The observed context-dependent higher-order auditory processing in MCS, not necessarily assessable at the patient’s bedside, indicates that content does matter when talking to MCS patients.

What do we go from here? Complimentary tests such as functional neuroimaging will never replace our clinical assessment but can, as for the diagnosis of brain death, objectively confirm our clinical findings in VS and MCS [for a review on the functional neuroanatomy of brain death as compared to the VS, see 19].

At present, however, much more experimental evidence and the elucidation of methodological and ethical controversies are awaited prior to their routine clinical use. With regard to neuro-rehabilitation, despite the fact that ERP and functional neuroimaging studies could in principle allow an objective quantification of the putative cerebral effect of rehabilitative treatment in DOC, they have so far not been used in this context [discussed in 20]. It is our hope that the increasing use (and funding) of multi-modal complimentary examinations will eventually improve our ability to disentangle differences in diagnosis, outcome and therapy on the basis of underlying cerebral mechanisms in these challenging patient populations.

 

Figure 1.
 
Preserved P300 response to patient’s own name (thick line) as compared to  other names (thin line) identified in (a) a locked-in patient post-basilar artery dissection; (b) a post-traumatic vegetative state (VS) patient, studied 2 weeks after injury, who failed to recover consciousness at 1 year follow-up; and in (c) a VS patient following cardio-respiratory arrest who died 8 months later without ever showing signs of recovery. Adapted from Archives of Neurology – American Medical Association [8].

 

Figure 2.
 
Supplementary motor area (SMA) activation during tennis imagery and parahippocampal area (PPA), posterior parietal cortex (PPC) and lateral pre-motor cortex (PMC) activation while imagining moving around the house in a patient clinically considered vegetative and in healthy volunteers. Adapted from Science [16].

Steven Laureys MD, PhD, steven.laureys@ulg.ac.be 
Research Associate Belgian National Fund for Scientific Research, 
Cyclotron Research Center, 
University of Liège and Head of Clinics, Dept of Neurology, 
Liège University Hospital, Belgium

References

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