Abstract: Over the last few years, functional neuroimaging studies have provided new insights into cerebral activity in subjects with severe brain damage leading to coma and other clinical states characterized by unresponsiveness. The present paper introduces the clinical picture of patients with impaired consciousness, and reviews the nosological criteria and functional neuroanatomical basis for brain death, coma, vegetative state, minimally conscious state, and the locked-in syndrome. Converging evidence suggests that disrupted activity in higher-order association areas, especially prefrontal and posteromedial parietal regions, plays a pivotal role within the neural correlates of impaired consciousness in the unresponsive patient.
Consciousness is a multifaceted concept traditionally resistant to univocal definitions. However, from an operational perspective, consciousness can be identified with two separate functions, namely awareness (i.e., awareness of the environment and of the self; contents of consciousness) and arousal (wakefulness or vigilance; level of consciousness). These functions are dependent upon separate physiological and anatomical systems (Monaco and Cavanna, 2007). Although consciousness cannot be measured objectively by any means, over the last few years several scoring systems have been developed for the quantification and standardization of the assessment of consciousness across coma and neurological disorders (Cavanna et al., 2008). The estimation of the level and the contents of consciousness usually requires the interpretation of several clinical signs, and is hampered by the unresponsive state that characterizes coma and other conditions of impaired consciousness.
An accurate and reliable assessment of both arousal and awareness in patients with severe brain damage is of greatest importance for their management and prognosis. Clinical practice has shown the challenges of identifying signs of these patients’ conscious state, which entail perception of the environment and of themselves. Bedside assessment of residual brain function and consciousness in patients who are severely brain-damaged is difficult because motor and verbal responses may be quite limited. This paper describes the assessment of consciousness in unresponsive patients, reviews the main clinical notions of altered states of consciousness causing unresponsiveness after severe brain damage, and discusses recent functional neuroimaging findings in patients with these disorders.
The Unresponsive Patient
The assessment of consciousness necessarily relies on the responses that a patient might give, and the actions that he might undertake, either spontaneously or upon stimulation. Patients with profound impairment of consciousness can be assessed using specific tools, such as the Glasgow Coma Scale (Teasdale and Jennett, 1974) (Table 1). This scale was originally developed for the clinical assessment of post-traumatic unconsciousness, and arguably represents the best available method for the assessment of the general level of consciousness through its three components: eye, verbal, and motor response to external stimuli.
|Table 1. The Glasgow Coma Scale|
|Eye Opening||Motor Response||Verbal Response|
|1 - Absent||1 - Absent||1 - Absent|
|2 - To pain||2 - Abnormal extension||2 - Incomprehensible|
|3 - To verbal stimuli||3 - Abnormal flexion||3 - Comprehensible|
|4 - Spontaneous||4 - Weak flexion||4 - Confused|
|5 - Localization||5 - Fully orientated|
|6 - Obeys command|
The observation of spontaneous eye opening “indicates that the arousal mechanisms of the brainstem are active” (Teasdale and Jennett, 1974). The presence of verbal responses indicates the restoration of a sufficient degree of interaction with the environment. The motor response assesses whether the patient obeys simple commands.
A significant limitation of the Glasgow Coma Scale is its failure to incorporate brainstem reflexes, since spontaneous eye opening can be a poor indicator of brainstem arousal systems activity. Another scale, the Glasgow Liege Scale, was developed over 25 years ago to overcome this limitation (Born et al., 1982). This instrument combines the Glasgow Scale with a quantified analysis of five brainstem reflexes: fronto-orbicular, vertical oculo-cephalic, pupillary, horizontal oculo-cephalic, and oculo-cardiac reflexes. The best response determines the brainstem reflex score. These reflexes disappear in descending order during rostral-caudal deterioration: the disappearance of the oculo-cardiac reflex coincides with brain death.
Clinical Features of Impaired Consciousness
Brain death is defined by the absence of any clinical and neurophysiological sign of brain activity. Moreover, the diagnosis of irreversible loss of brainstem function is now considered as being synonymous with brain death.
Brainstem death is established by the following criteria (Medical Consultants on the Diagnosis of Death, 1981):
- The cause of coma must be ascertained and it must be known that the patient is suffering from irremediable structural brain damage.
- All complicating factors such as drug intoxication, metabolic unbalances, and hypothermia shall have been corrected or excluded.
- The loss of all brainstem reflexes and the demonstration of continuing apnea in a persistently comatose patient must be ascertained.
The main feature of coma is the absence of arousal and thus also of any content of consciousness. Coma is a pathological state of eyes-closed unconsciousness from which patients cannot be aroused to wakefulness by stimuli, and have no awareness of self and surroundings (Plum and Posner, 1983). It can be caused by a structural, metabolic, or toxic disturbance of the reticular system and its thalamic projections (Vigand and Vigand, 2000).
To be clearly distinguished from syncope, concussion, or other states of transient unconsciousness, coma must persist for at least one hour. However, true coma rarely persists for longer than a month in the absence of complicating metabolic, infectious, or toxic factors. In general, comatose patients who survive begin to awaken and recover gradually within 2-4 weeks. In most survivors of coma who do not spontaneously achieve awareness, coma usually progresses to a vegetative state or minimally conscious state, or there may be brief or prolonged stages before more complete recovery of consciousness (Vigand and Vigand, 2000).
Patients in a vegetative state are awake but, as far as can be determined, they are unaware of themselves or their environment (Jennett, 2002). They typically lie with their eyes open while awake and closed while asleep, breathe spontaneously, and have preserved autonomic function and intact limb tendon and cranial nerve-innervated reflexes. They can blink and show eye and facial movements (expressions). Despite eye opening, these patients have no voluntary movements and there is often evidence for sleep/wake cycles with either complete or partial preservation of brainstem functions. It is particularly important to assess whether any movements made by a patient thought to be in the vegetative state are reflex or under voluntary control. In particular, clinicians should carefully look for signs of conscious behavior in younger children presumed to be vegetative because of severe congenital brain damage (Ashwal, 2004). The pathological basis of the persistent vegetative state is usually a widespread cortical damage resulting from such causes as cerebral hypoxia or widespread subcortical damage resulting from severe head injury.
Persistent vegetative state has been defined as a vegetative state remaining for longer than one month after acute traumatic or non-traumatic brain damage (The Multi-Society Task Force on Persistent Vegetative State, 1994). It does not imply irreversibility, because it is a diagnostic, not a prognostic term. On the other hand, permanent vegetative state is irreversible (Medical Consultants on the Diagnosis of Death, 1981; Jennet, 2002).
In the 1990s two expert task forces (The Multi-Society Task Force on Persistent Vegetative State in U.S. and The Royal College of Physicians Working Group in U.K.) produced a series of clinical criteria for the definition of vegetative state (Royal College of Physicians Working Group, 1996; Bauby, 1997) in order to minimize the risk of neglecting the presence of their conscious experience simply because of the difficulties in measure it (McQuillen, 1991) (Table 2).
|Table 2. Clinical Criteria of Vegetative State Criteria|
|- No evidence of awareness of self or environment at any time.
- No volitional response to visual auditory, tactile, or noxious stimuli.
- No evidence of language comprehension or expression.
- Presence of cycles of eye closure and eye opening which may simulate sleep and wakening.
- Sufficiently preserved hypothalamic and brainstem function to ensure the maintenance of
respiration and circulation.
Minimally conscious state
The course of recovery from vegetative state is typically slow, with a gradual and subtle transition from unconsciousness to consciousness. Motor response to verbal command and discernible communication represent the clearest signs of re-emerging consciousness, but these behaviors can occur inconsistently during the early stages of recovery, and are often difficult to differentiate from random movements (Giacino and Zasler, 2005). Moreover, some patients fail to progress beyond this level of responsiveness and remain permanently incapable of consistently producing sentient behavior. These patients occupy an intermediate point along a continuum of consciousness that includes those in vegetative state on one pole, and those who consistently exhibit meaningful behavioral responses on the other. This intermediate subgroup of patients was indiscriminately lumped together with patients in vegetative state and coma, until the Aspen Neurobehavioral Conference expert panel formulated consensus-based diagnostic criteria on a specific clinical syndrome they termed the minimally conscious state (Giacino et al., 2002).
Minimally conscious state is defined as a condition of severely altered consciousness in which minimal but definite behavioral evidence of self or environmental awareness is demonstrated (Giacino et al., 2002). To be minimally conscious, patients have to show limited but clear evidence of awareness of themselves or their environment. The behavior of interest must be reproducible during the examination and must be representative of cognitive processing. What is clinically relevant is that further improvement is more likely than in patients in a vegetative state (Giacino et al., 1997), although some people remain in a minimally conscious state permanently.
The term locked-in syndrome was first introduced by Plum and Posner (1983) to describe the clinical picture of total paralysis (quadriplegia) and inability to speak (anarthria) resulting from the disruption of the brainstem’s corticospinal and corticobulbar descending pathways, respectively. Plum and Posner (1983) described the locked-in syndrome as “a state in which selective supranuclear motor de-efferentation produces paralysis of all four limbs and the last cranial nerves without interfering with consciousness. The voluntary motor paralysis prevents the subjects from communicating by word or body movement. Usually, but not always, the anatomy of the responsible lesion in the brainstem is such that locked-in patients are left with the capacity to use vertical eye movements and blinking to communicate their awareness of internal and external stimuli.” Consequently, eye or eyelid movements (e.g., blinking of the upper eyelid to signal yes/no responses) are the main method of conscious experience communication (American Congress of Rehabilitation Medicine, 1995).
The neuropathological basis for this condition is usually a bilateral lesion of the ventral pons and efferent motor tracks (e.g., Plum and Posner, 1983; Patterson and Grabois, 1986). In rarer instances, it can be the result of a mesencephalic lesion (e.g., Chia, 1991). The most common etiology of locked-in syndrome is vascular pathology, namely basilar artery occlusion. A similar clinical picture may sometimes be seen in patients with pontine tumors, pontine hemorrhage, central pontine myelinolysis, traumatic brain injury, or brainstem encephalitis (Golubovic et al., 2004). In all cases recovery is exceptional (Plum and Posner, 1983).
Table 3 summarizes and compares the behavioral characteristics of different unresponsive states, whereas Table 4 shows how the two dimensions of consciousness (arousal = level; awareness = contents) can vary across these states.
|Table 3. Comparison of Behavioral Features Across Unresponsive States|
|Behavior||Brain Death||Coma||Vegetative State||Minimally
|Spontaneous movement||Absent||Absent||Reflex/patterned||Automatic/object manipulation||Absent|
|Response to pain||Posturing/
|Visual response||Absent||Absent||Startle/pursuit (rare)||Object recognition/
|Verbalization||Absent||Absent||Random vocalization||Intelligible words||Absent|
|Table 4. Level and Contents of Consciousness in the Unresponsive Subject|
(level of consciousness)
(contents of consciousness)
|Minimally conscious state||+||+/-|
Neural Correlates of Impaired Consciousness
Neuroimaging studies with functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) have disclosed interesting findings that in some cases help discriminate vegetative state from coma, minimally conscious state, and other states of impaired consciousness (Laureys et al., 2004).
Brain death results from irreversible loss of brainstem function (Wijdicks, 2001). Functional imaging studies with cerebral perfusion and metabolism tracers (Facco et al., 1998) typically show a “hollow skull phenomenon” in patients who are brain dead, thus confirming the absence of neuronal activity in the whole brain.
Coma can result from diffuse cortical or white-matter damage after neuronal or axonal injury, or from focal brainstem lesions that affect the pontomesencephalic region or paramedian thalami bilaterally. According to PET studies, grey matter metabolism is 50-70% of the normal range in comatose patients of traumatic or hypoxic origin (Schaafsma et al., 2003). These metabolic rates are similar to levels of normal patients undergoing general anesthesia. On the other hand, in patients who recover from a postanoxic coma there is a reduction of cerebral metabolic rates to 75% of the normal range (DeVolder et al., 1990).
Overall, PET findings correlate poorly with the level of consciousness, as measured by the Glasgow Coma Scale (Hattori et al., 2003), in patients studied within the first month after head trauma (Bergsneider et al., 2000). New generation PET scanning of comatose and noncomatose survivors of brain trauma within 5 days of trauma has shown a correlation between the level of consciousness and the regional cerebral metabolism in the thalamus, brainstem, and cerebellar cortex (Hattori et al., 2003). At present, however, there is no established relation between cerebral metabolic rates of glucose or oxygen as measured by PET and patient outcome (Bergsneider et al., 2001).
In vegetative state the brainstem is mostly spared whereas both cerebral hemispheres are widely and severely damaged. Several studies of resting brain function in vegetative state by PET show a baseline decrease in cortical metabolism to 40-50% of the normal range of values (Boly et al., 2004). In “permanent” vegetative state, brain metabolism values drop to 30-40% of the normal range of values (Tommasino et al., 1995). The relative sparing of metabolism of the brainstem and allied structures maintains arousal and autonomic functions in these patients (Laureys et al., 2000a). Polymodal associative cortices (posterior parietal areas and precuneus, bilateral prefrontal regions, Broca’s area, and parietotemporal area) are particularly affected (Laureys et al., 2004) as is their connectivity (Laureys et al., 2002). These regions are important in various functions that are necessary for consciousness, such as attention, memory, and language (Baars et al., 2003). It is not known whether the observed metabolic impairment in this large cortical network reflects an irreversible structural neuronal loss (Rudolf et al., 2000) or functional and potentially reversible damage. However, in rare cases where patients in a vegetative state recover awareness of self and environment, PET shows a concomitant improvement in both cortical metabolism (Rudolf et al., 1999) and connectivity (Laureys et al., 2000b) in these same cortical regions. The resumption of functional connectivity between associative cortices and the intralaminar thalamic nuclei parallels the restoration of their functional integrity (Laureys et al., 1999; 2000c). These data suggest that the observed baseline reduction in resting cerebral metabolism represents a combination of potentially reversible neuronal metabolic dysfunction and irreversible neuronal death.
Minimally conscious state
There are very few functional neuroimaging studies of patients in this newly defined condition. Preliminary data show that overall cerebral metabolism is decreased to values slightly higher than those observed in the vegetative state. In a PET study, Laureys et al. (2000b) exposed a patient in minimally conscious state to four conditions: no sound, frequency-modulated noise, infant cries, and the patient’s own voice. Although global metabolism was significantly reduced relative to controls, activation spread to association cortices following presentation of the infant cries and the patient’s name. Functional connectivity analyses performed in other PET paradigms have also shown significantly greater activation of medial parietal, posterior cingulate, and secondary frontal and temporal cortices in minimally conscious state patients, relative to those in vegetative state (Laureys, 2003). In particular, the medial parietal cortex (precuneus) and adjacent posterior cingulate cortex seem to be crucial in differentiating patients in minimally conscious state from those in vegetative state (Laureys, 2003). Interestingly, these richly connected multimodal posteromedial associative areas are among the most active brain regions in the conscious waking state (Gusnard and Raichle, 2001) and are among the least active regions in altered states of consciousness (Cavanna, 2007). It has been suggested that they may play a key role in the neural network subserving general awareness (Cavanna and Trimble, 2006).
Classically, structural brain imaging (MRI) of locked-in patients shows isolated lesions (bilateral infarction, hemorrhage, or tumor) of the ventral portion of the basis pontis or midbrain (e.g., Leon-Carrion et al., 2002). While neurophysiological tests (electroencephalograms and evoked potentials) do not seem to reliably distinguish the locked-in syndrome from the vegetative state (Gutling et al., 1996), PET scanning has shown higher metabolic levels in the brains of patients in a locked-in syndrome compared to those in a vegetative state (Levy et al., 1987). Preliminary PET studies by Laureys (2003) indicate that no supra-tentorial cortical area shows significantly lower metabolism in locked-in syndrome patients when compared to healthy subjects (Laureys, 2003). The absence of metabolic signs of reduced activity in any cortical area emphasizes the fact that locked-in syndrome patients suffer from a pure motor de-efferentation and recover an entirely intact intellectual capacity. Moreover, locked-in patients displayed increased regional activity within the amygdalar nuclei. Several PET studies in normal volunteers have shown amygdalar activation in relation to negative emotions such as fear and anxiety. In the absence of decreased neural activity in any cortical region, it has been assumed that the increased amygdalar activity relates to the terrifying situation of an intact self-awareness in a sensitive being, experiencing frustration, stress, and anguish, locked in an immobile body.
Conclusions — The Functional Neuroanatomy of Impaired Consciousness
Subjects who are unresponsive due to impaired consciousness can present with the clinical picture of coma, vegetative state, minimally conscious state, or locked-in syndrome. At the patient’s bedside, assessment of the conscious state is difficult because voluntary movement/verbalization may be very small, inconsistent, and easily exhausted. Instruments such as the Glasgow Coma Scale and the Glasgow Liege Scale represent useful tools in the standardized assessment of unresponsive subjects.
In the last few years it has been shown that measurements of cerebral metabolism and brain activations in response to sensory stimuli with functional neuroimaging and electrophysiological methods can provide detailed information on the presence, degree, and location of any residual brain function. The use of these techniques in people with severe brain damage is methodologically complex and needs careful quantitative analysis and interpretation. In addition, neuroscientists should always be mindful of the limited spatial resolution allowed by current technology.
Despite these limitations, converging evidence from preliminary functional imaging studies seems to suggest that disrupted activity in cortical association areas, especially prefrontal and posteromedial parietal regions, plays a pivotal role within the neural correlates of impaired consciousness in the unresponsive patient. According to the “default mode” of brain function, these areas are among the most active cortical regions during the conscious resting state, whereas they selectively deactivate in a number of pathophysiological conditions (e.g., sleep, drug-induced anesthesia) and neurological disorders (e.g., epilepsy, Alzheimer’s disease), which are characterized by impaired consciousness (Cavanna and Trimble, 2006; Cavanna, 2007). Since these core regions have a widespread cortical and subcortical connectivity patterns, it is likely that brainstem/diencephalic damage can lead to unresponsive states by ultimately disrupting the physiological activity of higher-order fronto-parietal pathways.
In summary, the clinical assessment of unresponsive patients represents the gold standard in identifying nosological distinctions needed for accurate diagnosis and prognosis. Neuroimaging techniques help producing an informed guess as to the identity of the mechanisms underlying coma and unresponsive states associated with severe brain damage. Based on the preliminary findings reviewed in the present paper, we believe that functional neuroimaging will substantially increase our understanding of the pathophysiology of impaired consciousness.
(Corresponding author: Dr. Andrea E. Cavanna, Department of Neuropsychiatry, Birmingham and Solihull Mental Health NHS Foundation Trust, 25 Vincent Drive, Birmingham B152FG, United Kingdom.)
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[Discovery Medicine, 9(48):431-438, May 2010.]