The Neuroethics of Disorders of Consciousness

A Brief History of Evolving Ideas

Michael J. Young; Yelena G. Bodien; Joseph T. Giacino; Joseph J. Fins; Robert D. Truog; Leigh R. Hochberg; Brian L. Edlow


Brain. 2021;144(11):3291-3310. 

In This Article

Consciousness and its Disorders: Epistemic and Historical Considerations

How is consciousness defined? Philosophers and other theorists have debated this topic for centuries. Table 1 takes stock of a range of different theories and definitions proposed by key thinkers and neuroscientists over the years, beginning with Hippocrates. In addition to Western conceptions of consciousness, varied conceptions of consciousness are apparent cross-culturally in both historical non-Western philosophic tracts and in the modern psychological literature.[40–46] While it is beyond the present scope to delve into each of these positions and their history or to provide a comprehensive account of all theories of consciousness, the juxtaposition of these definitions highlights their heterogeneity and underscores the inherently elastic and ill-defined nature of the concept of consciousness, alluded to by Cheyne, Plum and Posner. Surveying the landscape of what we have come to learn about consciousness, it becomes clear that it is not a unitary state but rather a cluster concept that includes a number of interdigitated ingredients; in isolation, each is not sufficient but when variably combined produce a range of states that fall on a spectrum of what we call consciousness, and each of which might be variably disordered across the spectrum of conditions that neurologists are called upon to evaluate.[7] Across definitions, consciousness appears to be subjective, related to experience and serves as a grounds for the possibility of other capacities.

An area of philosophical investigation orthogonal to the question of how to characterize consciousness surrounds how to understand the unity of consciousness; that is, how the individual contents of representational experience are joined (temporally and qualitatively) into a coherent whole.[47] Approaches to this question have emphasized the importance of self-consciousness and cognate theories of personal identity to explain the pervasively conjoint phenomenology of consciousness.[48] Pathological alterations in this remarkable capacity for unified experience through consciousness may be occasionally observed in a range of neurological and psychiatric conditions, including anosognosia for hemiplegia, Anton's syndrome, delusional misidentification syndrome, amnestic syndromes, dissociative and dysmorphic disorders, neurodegenerative conditions, neurodevelopmental conditions, epilepsy, traumatic brain injury and sleep-behaviour disorders, highlighting the relevance of this empirically underexplored concept to clinical practice and neuroscientific inquiry.[49–52]

In examining these widely varied perspectives on the character of consciousness, it becomes apparent that rather than a monotonic, fixed entity, consciousness is more aptly characterized as a cluster concept that consists in a wide array of criss-crossing and malleable dimensions and grounds for experience. While many of these dimensions exist on a continuum, in the process of diagnosis and neuroscientific research, clinicians and researchers require discrete categories as instruments for progress, efficient communication and knowledge-generation.[53–55] Despite its practical necessity, creating instrumental categories of consciousness in the derivation of DoC nosology thus carries the epistemic risk of misleading end-users about the nature of the natural phenomena being described; indeed, rather than 'carving nature at its joints',[56] the process of DoC classification is often normatively and pragmatically laden, as is the case with many other diseases.[7,53,54,57–60]

In clinical neurology, consciousness is conceptualized as encompassing two cardinal elements: wakefulness and awareness. 'Wakefulness' refers to the level of arousal, which is often manifested clinically by eye opening. 'Awareness' refers to the 'contents' of consciousness and is clinically assessed by looking for intentional responses to external stimuli; these responses are taken to be our best surrogate measure for some purposeful internal experience. Different states of the brain, both normal and pathological, can be described with respect to these two elements. These ingredients can become dissociated from one another, as in the vegetative state/unresponsive wakefulness syndrome, where there is wakefulness without awareness, and in the case of rapid eye movement sleep, where there may be awareness without wakefulness. Different clinical entities are encountered in mapping the gradual recovery from coma, and may be illustrated as a function of cognitive and motor capacities.

The return of wakefulness, in the absence of volitional motor behaviour, marks the transition from coma to vegetative state/unresponsive wakefulness syndrome. Passage from vegetative state/unresponsive wakefulness syndrome to the MCS is evidenced by reproducible evidence of voluntary behaviour, which has been operationally defined as including: (i) simple command following; (ii) yes/no responses (regardless of the accuracy thereof); (iii) intelligible verbalization; or (iv) motor or emotional responses occurring in contingent relation to relevant stimuli (such as appropriate visual tracking, sustained fixation, hand squeezing, crying, smiling or laughing in contingent relation to appropriate environmental triggers).[61,62] Emergence from the MCS is marked by the return of functional communication or object use. The confusional state is a condition marked by impairments in attention, memory, orientation and symptom fluctuation and may be accompanied by emotional/behavioural dysregulation, disrupted sleep-wake cycling, and confabulation, delusions and perceptual disturbances.[63,64] We will next examine each of these categories (Figure 1) in greater detail.

Figure 1.

An operational approach to classifying DoC following brain injury in clinical practice. Boxes with dashed outline represent decision points in assessment before arriving at a diagnosis. CCP = covert cortical processing; CMD = cognitive motor dissociation; CS = confusional state; LIS = locked-in syndrome; MCS− = minimally conscious state without language function; MCS+ = minimally conscious state with language function; UWS = unresponsive wakefulness syndrome; VS = vegetative state


Coma derives from the Greek term kōma meaning trance or deep sleep.[65] It is an unconscious state characterized by lack of both wakefulness and awareness. As Posner observed, 'very few surviving patients … remain in eyes-closed coma for more than 10 to 30 days';[34] however, cases of longer-lasting coma have been reported, and in one instance lasting up to 1 year.[66] Those who recover from coma may enter or pass through a vegetative state/unresponsive wakefulness syndrome, a MCS or locked-in syndrome. Multiple scales have been devised for classifying patients with coma.[67–70] The value of these is in providing a simple estimate of a person's level of consciousness. The Glasgow Coma Scale (GCS) was devised to categorize patients with head trauma;[67] however, when used by emergency department physicians, inter-rater agreement is only moderate, and so a detailed qualitative description of neurological exam findings may be of greater utility in tracking a patient's course of recovery.[71] The ascending arousal network, also known as the ascending reticular activating system, is instrumental in maintaining arousal, and when disturbed, coma or other DoC ensue.[72,73] The network is composed of key subcortical neurons and their axonal projections in the rostral brainstem tegmentum, diencephalon, basal forebrain and associated cortical networks, which notably exhibit redundancy,[74,75] a characteristic that permits recovery of consciousness depending on lesion location, extent and severity.[76]

Distinguishing Coma From Brain Death

Importantly, coma should be distinguished from the state of brain death, which in addition to the absence of wakefulness and awareness entails the irreversible cessation of all brainstem functions, including respiratory drive. As such, the state of brain death has been conceptualized by some as an 'irreversible apneic coma'.[77–79] Areas of ongoing ethical and policy debate include whether the diagnosis of brain death requires demonstrable absence of all functions of the brainstem or the entire brain (including neurohormonal functions of the hypothalamus and pituitary gland), whether to distinguish permanent from irreversible dysfunction,[80,81] how to achieve consistency between prevailing definitions and diagnostic schemata and whether brain death should be regarded as biological death or legal death of the human organism in the presence of ongoing cardiopulmonary function supported by mechanical ventilation or extracorporeal membrane oxygenation.[77–79,82,83]

The Uniform Law Commission is meeting in 2021 to decide whether to recommend that the Uniform Determination of Death Act (UDDA), which was approved as model legislation governing death determination in the USA in 1981, should be revised in response to current controversies.[84,85] While the UDDA currently requires the irreversible cessation of all brain function, the AAN guidelines on brain death do not require the loss of hypothalamic function, which is sometimes present in patients who meet the AAN brain death criteria. Likewise, the Academy of Medical Royal Colleges (UK) standards do not require absence of neurohormonal function for declaration of brain death.[86] There is increasing recognition that these possible discrepancies between or within law and clinical guidelines should be addressed.[77–79,82,83]

From the Vegetative State to Unresponsive Wakefulness Syndrome

The vegetative state is one of preserved wakefulness without awareness. It is characterized by recovery of apparent sleep-wake cycles and signalled by the appearance of periods of eye-opening in an unresponsive patient. The use of the term vegetative in this context has been traced to Aristotle's De Anima, where a tripartite distinction is drawn between the faculty of organisms that subserve basic physiological functions (vegetative element), the faculty that subserves emotions and desires (appetitive element) and the faculty that subserves reason (rational element).[53,87] Two milestones in our understanding of vegetative state have been the publication by neurologist Fred Plum and neurosurgeon Bryan Jennett in 1972 that first coined the term vegetative state and the Multi-Society Task Force (MSTF) that in 1994 proposed a consensus definition of vegetative state and its prognosis. The term 'permanent' has now been abandoned, based upon a growing number of reports of late recovery of consciousness in patients who were previously believed to meet criteria for permanent vegetative state.[88–91]

Before 1972, several other terms were used in the medical literature to describe the state of wakefulness without awareness. Beyond mere linguistic preference, choice of language can make profound differences in enabling informed decisions about how to proceed with care.[92] The term apallic syndrome, which is still used in some German-speaking regions[93] (das apallische syndrome), traces back to an article published by German psychiatrist Ernst Kretschmer (1888–1964) in 1940 and derives from 'pallium', meaning cortex.[94,95] This paper suggested that a complete cortical loss is the pathological substrate of this condition (though neuropathological[96] and imaging studies suggest that thalamic injury may also contribute to its pathogenesis).[96–98] Kretschmer described eight patients who had all been exposed to severe cerebral anoxia and survived for varying periods of time. All showed a uniform clinical symptomatology with complete loss of higher capacities but with retention of brainstem functions, including spontaneous breathing. On autopsy, all were found to have widespread cortical atrophy and severe gliosis.[95] In 2010, the European Task Force on DoC, recognizing the possibly misleading connotation of the term vegetative state, proposed a new name for this condition: unresponsive wakefulness syndrome.[99] The task force suggested removing the term 'vegetative', which carries a spuriously pejorative connotation, as well as the term 'state', which erroneously implies a static, immutable condition, when many of these patients may substantially recover.[22,53,89,100–106] Although use of unresponsive wakefulness syndrome in lieu of vegetative state has grown in popularity, it has been suggested that the unresponsive wakefulness syndrome descriptor may be misplaced insofar as it implies absolute unresponsiveness when some patients who appear unresponsive may covertly harbour responsiveness revealed by neuroimaging or electrophysiological tasks,[22] as we examine below. Furthermore, even in the absence of awareness, patients may have stereotyped, reflexive motor responses to noxious or other stimuli. Contrary to what was initially thought to be the neuropathological basis for the vegetative state, many patients who are clinically unresponsive but awake do not suffer complete cortical necrosis as posited by Kretschmer but rather seem to exhibit disconnection of key modules that are part of a widespread cortical network encompassing medial and lateral prefrontal cortices and parietal multimodal associative areas.[107–112]

The Minimally Conscious State

Patients in an MCS exhibit preserved wakefulness and reproducible, often fluctuating, signs of awareness. These patients can manifest, albeit inconsistently, behavioural and emotional responses such as responding correctly to verbal commands, manipulating objects, localizing responses to noxious stimulation, visually tracking objects or fixating.[61] In 2002, the Aspen Neurobehavioral Conference Workgroup led by Giacino and colleagues proposed the first consensus based criteria for the diagnosis of MCS, as well as criteria for emergence from the MCS.[61] According to the Aspen criteria, the diagnosis of MCS requires 'clearly discernible evidence of self or environmental awareness' as evidenced by simple command following, gestural or verbal responses, intelligible verbalization and/or purposeful behaviour.[61] Recognizing the 'high rate of misdiagnosis', the Aspen Workgroup recommended that someone 'with experience in neurological assessment of patients with impaired consciousness should be primarily responsible for establishing the diagnosis and prognosis and for coordinating clinical management, [and an] additional opinion of a physician or other professional with particular expertise in the evaluation, diagnosis and prognosis of patients in the vegetative state and MCS is recommended when the assessment will impact critical management decisions.'[61] Given substantial clinical heterogeneity within the population of patients with MCS, Bruno and colleagues in 2011 proposed subcategorizing MCS into MCS+ and MCS−.[113] Patients in an MCS are subdivided into these categories depending on the presence of intelligible speech or intentional communication (MCS+) or absence thereof (MCS−).[114] Some have proposed revising MCS terminology to a 'cortically-mediated state' as a potentially more accurate way to characterize the impairments of patients meeting these criteria.[115] Importantly, vegetative state and MCS differ not only in behavioural criteria but also in the prognosis for recovery that is informed by being in either state.[116,117]

The Confusional State

The confusional state, termed PTCS when following traumatic brain injury, is a condition of disordered neurocognitive functioning with intact wakefulness and awareness that may be observed during transitions to levels of consciousness higher than MCS. Recovery of object use or functional communication indicate emergence from MCS and thus constitutes the lower boundary of PTCS. PTCS is marked by impairments in attention, memory, orientation and cognitive-behavioural consistency. PTCS may be further accompanied by emotional or behavioural dysregulation, disrupted sleep-wake cycling, confabulation, delusions or perceptual disturbances.[63,64] The term PTCS was coined by Stuss and colleagues in 1999[118] and in June 2020 was refined and codified by an ACRM Evidence and Practice Committee.[63,64] In contrast to the historical term 'post-traumatic amnesia', the domain-general term PTCS was formulated to inclusively denote the broader range of multidimensional neurocognitive changes observed during recovery from brain injury. Acute confusional state or delirium are diagnostic categories used to describe non-traumatic cases of confusional emergence from MCS.

Covert Consciousness and the Complete Locked-in Syndrome

Covert consciousness refers to a state of dissociation between cognitive and motor functions, also referred to as cognitive motor dissociation.[21] Despite the absence of overt signs of self-expression or purposeful motoric responses, an individual may still harbour preserved cognition to varying degrees, which are often suggested or detected through task-based functional MRI or EEG paradigms. Odorant-dependent sniff responses have more recently been described as a tool to aid in identifying covert processing and potentially improve diagnosis and prognosis in unresponsive patients with DoC.[119]

The phenomenological significance of intact electrophysiological or neuroimaging responses to tasks is poorly understood, and important questions surround how different forms of subjective experience and processing of stimuli may variably correspond to signatures of neural activity detected through these advanced techniques.[112] Indeed, in many (if not most) cases of cognitive motor dissociation, functional MRI or EEG data may only indicate a binary state of awareness (with the upper limit of cognitive assessment achievable consisting of answering factual/autobiographical yes/no questions)[120,121] without clearly providing immediate information about the subjective state of the individual. The level of subjective experience or qualia implied by different patterns of neural activity may conceivably range from (i) rudimentary subcortical responses; to (ii) primary sensory cortical responses (e.g. Heschl's gyrus response to language); to (iii) association cortex responses disconnected from subjective experience (e.g. Wernicke's area response to language) also known as covert cortical processing;[122,123] to (iv) volitional modulation of thoughts and possible states of locked-in awareness.[124–126] Importantly, the absence of demonstrable brain activity in response to task-based paradigms does not entail evidence of absence of cognitive abilities queried, as highlighted by substantial false negative rates among normal control subjects in functional MRI and EEG studies.[127–129] While the phenomenological significance of individual patterns of covert consciousness remains to be understood, the presence of covert brain activation by EEG portends substantially improved outcomes for behaviourally unresponsive patients after acute brain injury,[130–132] highlighting the potential prognostic relevance of brain activity detected by these advanced neurotechnologies. Efforts to detect covert consciousness have been identified as a moral imperative in light of the consequential impact that this finding may have on clinical decision making, prognosis, family perceptions and neurorehabilitation.[22,106,133,134]