C o n s c i o u s n e s s : It s

N e u ro b i o l o g y a n d
the Major Classes
of Impairment
a,b, a
Andrew M. Goldfine, MD *, Nicholas D. Schiff, MD

KEYWORDS
 Consciousness  Vegetative state  Minimally conscious state
 Traumatic brain injury  Arousal

Disorders of consciousness encompass a wide range of syndromes whereby patients

demonstrate a globally impaired ability to interact with the environment. We briefly
review the subset of disorders of consciousness that result from permanent brain
injury, such as ischemic stroke, global ischemia, and traumatic brain injury (TBI).
Disorders of consciousness may also arise as functional (rather than structural) distur-
bances of consciousness, including generalized and complex partial seizures as well
as metabolic and toxic delirium. These functional disturbances are not discussed here
but have been reviewed by Posner and colleagues.1
In this review, we first review brain structures that support the normal conscious
state to develop a framework to demonstrate how their dysfunction can lead to disor-
ders of consciousness. We then present the nosology of the different disorders of con-
sciousness, including coma, vegetative state (VS), the minimally conscious state, and
akinetic mutism. The pathology and brain imaging data that give insight into the path-
ophysiology associated with each diagnostic category are reviewed. Knowledge of
the underlying mechanisms of the disorders can enhance the ability to prognosticate
and promote recovery from these devastating conditions.

This work was supported by NIH-NICHD 51912, the James S McDonnell Foundation. AMG is
supported by grant KL2RR024997 of the Clinical & Translational Science Center at Weill Cornell
Medical College.
a
Department of Neurology and Neuroscience, Weill Cornell Medical College, LC 803, 1300
York Avenue, New York, NY 10065, USA
b
Burke Medical Research Institute, Weill Cornell Medical College, 785 Mamaroneck Avenue,
White Plains, NY 10605, USA
* Corresponding author. Burke Medical Research Institute, Weill Cornell Medical College, 785
Mamaroneck Avenue, White Plains, NY 10605.
E-mail address: [email protected]

Neurol Clin 29 (2011) 723–737

doi:10.1016/j.ncl.2011.08.001 neurologic.theclinics.com
0733-8619/11/$ – see front matter Ó 2011 Elsevier Inc. All rights reserved.
724 Goldfine & Schiff

BIOLOGIC BASIS OF CONSCIOUSNESS: MECHANISMS OF AROUSAL AND CEREBRAL

INTEGRATIVE FUNCTION
A Clinically Relevant Definition of Consciousness
Normal human consciousness is defined as the presence of a wakeful arousal state
and the awareness and motivation to respond to self or environmental events. In
the intact brain, arousal is the overall level of responsiveness to environmental stimuli.
Arousal has a physiologic range from stage 3 non–rapid eye movement (REM) sleep
during which strong stimuli are required to elicit a response, to states of high vigilance,
during which subtle stimuli can be detected and acted upon.2 Whereas arousal is the
global state of responsiveness, awareness is the brain’s ability to perceive specific
environmental stimuli in different domains, including visual, somatosensory, auditory,
and interoceptive (eg, visceral and body position). The focal loss of awareness, such
as language awareness in aphasia or spatial awareness in left-sided neglect, does not
significantly impair awareness in other modalities. Motivation is the drive to act on
internal or external stimuli that have entered conscious awareness. In the next section,
we describe the brain regions that support these three aspects of consciousness and
show that they are not independent, but rather interact extensively with each other.

Underlying Substrates of Arousal and Conscious Awareness

The initial discovery that specific brain areas could drive overall cerebral activity
appeared in the work of Moruzzi and Magoun.3 These investigators proposed the exis-
tence of an ascending reticular activating system (ARAS) in the upper brainstem
tegmentum (reticular formation) and central thalamus that promoted widespread
cortical activation.4 Subsequent work has revealed that the ARAS is not a monolithic
activating system, but a collection of interdependent subcortical and brainstem areas
that have specific roles in arousal and awareness.5 The core areas for maintaining an
awake state seem to be the glutamatergic and cholinergic neurons in the dorsal
tegmentum of the midbrain and pons.6 These areas activate the central thalamus
(primarily intralaminar nuclei) and basal forebrain. The central thalamus and basal fore-
brain subsequently activate the cortex through glutamatergic and cholinergic projec-
tions, respectively. In addition to supporting arousal, the basal forebrain is active
during REM sleep and the central thalamus plays a role in conscious awareness (below).
Other brain regions are also involved in arousal but have a more modulatory role,
including the nuclei in the upper brainstem that use norepinephrine, dopamine, sero-
tonin, and other neurotransmitters. These nuclei act on the basal forebrain, thalamus,
striatum, and cortex.2,5 The hypothalamus is also involved in the sleep-wake transi-
tion7 and its histaminergic outputs help maintain the awake state. Overall, the large
number of regions involved in arousal provide redundancy, so that selective damage
to one region, even if bilateral, only rarely results in permanent unconsciousness.
Whereas the level of arousal reflects the overall state of activity in the brain,
conscious awareness is a more dynamic and complex process involving various cere-
bral networks at any one time. There are several competing theories on how we
become aware of environmental and internal stimuli, although it is widely believed
to depend on interactions between the cortex and specific and nonspecific (eg, intra-
laminar) thalamic nuclei.8–10
Conscious awareness and arousal states also interact. Without arousal, there is no
awareness, and in states of high arousal, awareness can be focused on one modality
at the expense of others.11 For example, animal models have been used to demon-
strate that in addition to a core generalized arousal, there are also more specific forms
of arousal, such as hunger, sexual behavior, and fear, which enhance responses to
 Neurobiology of Consciousness 725

specific stimuli.12,13 Conversely, awareness also influences arousal, such as the

abrupt increase in arousal when an alarm goes off.
Stimuli are not acted on as reflexes, but typically require motivation to enter
conscious awareness through a process called intention or goal-directed be-
havior.14,15 Lesion and functional brain imaging studies demonstrate that goal-
directed behavior is primarily driven by the medial frontal and anterior cingulate
cortices.16–18 These cortical regions are supported in producing goal-directed
behavior by striatopallidal-thalamic loops as well as the ventral tegmental area and
the periaqueductal gray of the brainstem (Fig. 1).19 The arousal systems discussed
previously also act directly on the goal-directed behavior network, primarily through
innervation of the striatum and frontal cortex.18,20
In summary, studies indicate that the normal conscious state includes volition, pro-
cessing of sensory information, and a generalized level of arousal. As discussed later,
brain injury can produce disorders of consciousness from injury at any of these levels.

NOSOLOGY AND PATHOPHYSIOLOGY OF DISORDERS OF CONSCIOUSNESS

The disorders of consciousness discussed in this article are syndromes that are behav-
iorally defined, and each is thought to reflect a specific pathophysiologic model
(Table 1). However, the models are imprecise and do not apply in every case. As
such, we will begin with an overview of the behavioral assessment of levels of conscious-
ness, followed by more detailed descriptions for each syndrome. Pathology and imaging
data are used to support mechanistic models underlying each behavioral syndrome.

General Concepts in the Assessment of Consciousness

The determination of level of consciousness at the bedside is primarily a judgment of
responsiveness across multiple sensory modalities (eg, vision, somatosensation, and

Fig. 1. A network that drives goal-directed behavior together with targets for specific inter-
ventions. ACC, anterior cingulate cortex; GPi, globus pallidus pars interna; ILN, intralaminar
nuclei of the thalamus; MSN, medium spiny neurons; PFC, prefrontal cortex. Blue arrows repre-
sent glutamatergic synapses and red represents GABAergic synapses unless otherwise noted.
726 Goldfine & Schiff

Table 1
Summary of behavioral features and pathophysiologies of disorders of consciousness
syndromes from permanent brain injury

Syndrome Behavioral Description Pathophysiology

Coma Eyes closed, immobile, or reflex Global dysfunction of
movements corticothalamic loops from
diffuse cellular dysfunction,
disconnection, or loss of
upper brainstem arousal
tone. If the entire brain or
brainstem is permanently
nonfunctional, then
diagnosis is brain death
rather than coma
Vegetative state Alternating eyes-closed/ Same as coma, except that it
eyes-open states, reflex implies some functioning of
movements the upper brainstem
Minimally conscious state Low-level and typically Diverse but typically diffuse
intermittent interaction with injury to white matter and/or
the environment. thalamus. Varying degrees of
Emergence from MCS is cortical injury
defined as recovery of
functional object use or
consistent communication
Akinetic mutism Severe form has eye tracking Dysfunction of prefrontal
only (fits within MCS), cortex or its subcortical
whereas milder forms have connections (striatum,
decreased initiation of goal- globus pallidus, or central
directed behavior with thalamus) or of white matter
relatively retained response connecting these areas
to commands
Locked-in statea Complete or almost complete Classically the loss of
loss of motor output corticospinal tract in ventral
resulting in the appearance pons, but can also be from
of a disorder of diffuse white matter injury
consciousness in the setting of trauma
a
Not a disorder of consciousness.

auditory) and cognitive domains (eg, language and learned movements). The lowest
level of behavior to be documented is whether eye opening is spontaneous or requires
stimulation (eg, loud sounds or noxious touch). Higher-level behaviors include
responses that are contingent on sensory stimuli. These range from eyes tracking
a mirror and withdrawal from painful touch, to accurately following commands and
the use of objects (eg, a comb or toothbrush).21 The level of effort required to alert
the patient and the speed of their response should also be noted, because these
observations guide subjective and objective assessments of arousal. Inaccuracy in
specific cognitive domains (eg, aphasia and apraxia) reflects focal impairments in
awareness, rather than global disorders of consciousness.
One caveat to behavioral testing of arousal is that all of the patient responses require
a capacity for motor output and adequate arousal. Patients with functional or struc-
tural interruption of motor systems at any level may not be able to follow the
commands, despite full comprehension and intention. Patients with a minimal residual
ability to communicate (eg, eye blinks) but who have generally intact consciousness,
 Neurobiology of Consciousness 727

are deemed to be in the locked-in state (LIS).1 There are also patients with both
impaired motor output and arousal from diffuse brain injury, which contribute to
a high misdiagnosis rate in disorders of consciousness.22,23 To ensure accurate diag-
nosis in patients with diffuse brain injury, it is essential to examine patients at maximal
levels of arousal using techniques such as deep tendon massage or postural reposi-
tioning.24 Patients should also be examined at multiple time points or videotaped by
family to capture periods of high alertness.

Coma and VS Represent Loss of Corticothalamic Function

The most common disorder of consciousness that immediately follows severe brain
injury is coma. Coma is a state that is characterized by eyes-closed unresponsive-
ness: comatose patients fail to respond to even the most vigorous stimulation.1
When given noxious stimulation, patients may not move at all or may display stereo-
typed/reflexive movements only. The pathophysiology of coma is generally the same
as VS (discussed below), except that some patients have loss of some or all brainstem
function. For patients with loss of all brainstem and cerebral function, the diagnosis is
brain death. Coma prognosis is complex and depends on the causes and the severity
of injury as well as the multiple medical factors that led to the initial injury.1 Brain death
does not have a prognosis because it is simply equivalent to death.
If patients survive coma, they either recover consciousness within days or transition
to VS within 30 days after injury. VS is a behaviorally-defined state, similar to coma,
whereby patients show no evidence of self or environmental awareness.25 It is also
similar to coma because patients can have spontaneous or stimulus-induced, stereo-
typed movements, and may retain brainstem regulation of visceral autonomic function
that would suggest that the lower brainstem is intact. The only behaviorally salient
difference from coma is that VS patients cycle daily through eyes-open and eyes-
closed periods. This does not imply that VS patients have normal sleep-wake cycles;
rather, their electroencephalograms (EEGs) display a monotonous slow pattern regard-
less of whether the eyes are open or closed, or they only have fragmented components
of normal electrographic sleep-wake phenomenology.26,27 The periods of eye opening
reflect only a crude arousal pattern that involves upper brainstem nuclei.
VS may represent a transitional state on the way to recovery of consciousness or
could be a chronic condition in cases of more severe brain injuries. Persistent vegeta-
tive state (PVS)25 is a term used for patients who have remained in VS for an arbitrarily
defined duration of 30 days.28 Another commonly used term is permanent vegetative
state, which is applied to patients in VS after global ischemia for 3 months or TBI for 1
year.28 Permanent VS is more of a prognosis than a diagnosis, as these time durations
reflect only a reduced probability of recovery. We prefer to define patients in persistent
VS simply by the etiology and duration, avoiding the use of absolute terms, such as
permanent.
There are three main pathologic findings in patients with prolonged VS from struc-
tural injury. The most common is diffuse cortical and thalamic cell loss, which occurs
in the setting of global ischemia caused by cardiac arrest.29 The second is widespr-
ead damage to long axons, known as diffuse axonal injury (DAI), which occurs
from TBI.30 DAI has been shown in animal models to occur as a result of rapid
acceleration-deceleration injury of the axons, sometimes in conjunction with delayed
axonal disconnections.31 The third and least common pattern of injury is extensive
damage to the upper brainstem and thalamus, which usually occurs as a result of
basilar artery stroke.32,33 The common link between these three injury types and
VS is the loss of corticothalamic function, either from cell death, disconnection, or
loss of brainstem drive.
728 Goldfine & Schiff

In vivo imaging studies further support the model of VS that represents diffuse cortico-
thalamic dysfunction. Fluorodeoxyglucose (FDG)-positron emission tomography (PET)
is a measure of energy consumption, and in the brain it primarily represents the neuronal
firing rate at the synapse.34 Patients in PVS have been shown to have global metabolic
rates reduced by 50% or more compared to healthy controls.35 In general, metabolic
rates exhibit less reduction in the brainstem and more reduction in the cortex and
subcortical nuclei, with the most consistent reduction occurring in the medial parietal
and frontal areas.36 Comparable reductions in cerebral metabolic rate have been iden-
tified during generalized anesthesia37,38 and slow-wave sleep in healthy controls.39,40
To examine corticothalamic functioning more directly, investigators have used
H215O-PET, functional magnetic resonance imaging (fMRI), and event-related poten-
tial analysis to measure brain responses to sensory inputs.41 Studies using simple and
complex auditory stimuli42–44 and noxious stimuli45 have demonstrated a pattern of
activation of brainstem and primary sensory cortical regions in some patients with
VS without the activation of higher-order sensory or association areas. These results
suggest that patients with VS may have some residual thalamocortical activity, but do
not possess enough to produce the global integrative function that is required for
conscious awareness.
These imaging tools have also been used to provide insight into an ambiguous area
between VS and consciousness. Schiff and colleagues46 described 3 patients who
demonstrated complex motor behaviors but were still considered to be in VS. All were
found to have an overall low resting metabolism (20–50% of normal by FDG-PET), yet
had residual islands of cortical and subcortical higher metabolism in areas consistent
with their behaviors. In all patients, these brain structures showed marked abnormalities
at the level of response to simple sensory stimuli as measured by magnetoencephalog-
raphy, which demonstrated a loss of the integrity of even early cortical processing. These
patients, similar to those studied by Laureys and colleagues,44,47 revealed that some
preservation of basic corticothalamic processing may coexist with behavioral uncon-
sciousness and this does not contravene a clinical diagnosis of VS.

The Minimally Conscious State Represents a Low Level of Residual Corticothalamic

Integrity or an Inability to Maintain Cerebral Integrative Function
The next level of recovery on the continuum from VS to full consciousness is the mini-
mally conscious state (MCS). The Aspen Neurobehavioral Workgroup defined MCS in
2002 as “a condition of severely altered consciousness in which minimal but definite
behavioral evidence of self or environmental awareness is demonstrated.”48 This
condition has been operationally defined by a set of behavioral tests known as the
JFK Coma Recovery Scale Revised (CRS-R),21 and is discussed by Hirschberg and
Giacino elsewhere in this issue. MCS includes a more heterogeneous group of
patients than VS, because the operational definition allows for a wide range of behav-
iors, whereas VS only includes reflexive movements. In MCS, low-end behaviors
include visual tracking to a mirror, localization of noxious touch, and inaccurate verbal-
ization, whereas high-end behaviors include consistent movement to command and
choosing correctly between 2 objects. Patients with only low-end behaviors can be
difficult to differentiate from VS, because these behaviors may be subtle and infre-
quent.22,49,50 This differentiation is essential because patients in MCS have signifi-
cantly better prognoses for recovery than those in VS.51,52
Pathology and anatomic imaging literature have revealed that MCS is typically asso-
ciated with similar injury patterns as VS, but with sufficient surviving neurons and
connectivity between cortex, thalamus, and brainstem arousal centers to support
some level of behavioral responsiveness.53,54 In the setting of TBI, one study found
 Neurobiology of Consciousness 729

that across the continuum of VS to MCS to full consciousness, patients were less likely
to have severe DAI and more likely to have focal brain injuries, such as hematomas
and contusions.53 Notably, these investigators reported overlap in pathologic find-
ings across all levels of consciousness, which demonstrated that current anatomic
methods cannot completely account for the variances in behavior.
Functional imaging (fMRI and H215O-PET) and neurophysiologic methods have
proved to be more sensitive than anatomic methods in distinguishing patients in VS
from those in MCS, because they measure corticothalamic function. For example,
when presented with sensory stimuli, MCS patients activate higher-order association
cortices, similar to healthy controls, whereas VS patients, at best, activate primary
sensory cortices.55,56 However, compared to healthy controls, MCS patients require
a higher level of arousal (ie, more alerting stimuli) to produce similar patterns of acti-
vation.42 This requirement for a higher level of arousal is consistent with behavioral
data, which show that these patients fluctuate in their level of responsiveness57 and
suggest an underlying inability to maintain cerebral integrative functioning.

Akinetic Mutism and Related Syndromes are Disorders of Goal-Directed Behavior

Akinetic mutism, in its originally described form, fits in the category of MCS,58 although
milder variants, including abulia,59,60 are categorized as fully conscious states.61
Patients with these conditions have intact arousal and often the appearance of vigi-
lance, but have severe poverty of movement despite lack of damage to motor
systems. Severe cases can only be distinguished from VS by the preservation of visual
tracking through smooth pursuit eye movements. The underlying cause in most cases
is injury to the bilateral medial frontal lobes and anterior cingulate cortex from a mass
lesion or anterior cerebral artery infarct. These syndromes can also arise from bilateral
injury to the basal ganglia,62,63 dorsal and central thalamus, or midbrain,64 as these
areas are tightly integrated with the frontal lobes in the generation of goal-directed
behavior. As discussed below, the circuits involving these areas play a significant
role in recovery of consciousness from a wide range of injuries.

Patients with Severely Damaged Motor System may be Widely Miscategorized

Functional brain imaging studies have led to a new but currently undefined category of
disordered consciousness: patients who are behaviorally in VS or MCS, yet demon-
strate imaging evidence of high-level cognitive processes, including command
following and, in 2 instances, communication.65–67 These studies used fMRI (although
EEG may also be used68) to reveal changes in cortical activity when patients are asked
to imagine a motor performance or spatial navigation task (Fig. 2 shows example
results). The most striking example of covert conscious function came from a patient
who initially fulfilled the behavioral criteria for VS, but was able to answer 5 out of 6
autobiographical questions correctly using the mental imagery of playing tennis as
a ‘yes’ response and walking around his house as a ‘no’ response.66 Only a few
such patients have been identified, because there are no obvious historical or
anatomic imaging markers to predict covert consciousness. Furthermore, the
assessments currently used require levels of memory and attention not present
even in some fully conscious subjects.67 The clinical implications of these findings
are also not clear, because it is not yet possible to turn these fMRI or EEG paradigms
into a bedside communication device. Moreover, it is not known if the ability to follow
commands identified through fMRI predicts an emergence to full consciousness.
However, once these measurements are obtained, it is clear that the patients have
interacted with their environment, thereby placing them in a vague category between
high-level MCS and LIS.
730 Goldfine & Schiff
 Neurobiology of Consciousness 731

MECHANISTIC CONSIDERATIONS IN THE PROGNOSIS AND TREATMENT OF PATIENTS

WITH DISORDERS OF CONSCIOUSNESS
Prognosis from Disorders of Consciousness
The pathophysiologies described earlier help to explain the mechanisms by which
some patients recover and why others do not, and give an interpretive framework
for the successes of specific interventions in improving arousal. In brief, the three
types of pathophysiologies linked to disorders of consciousness from permanent
brain injury discussed earlier are: (1) loss of cortical and thalamic neurons from global
ischemia, (2) DAI in the setting of rapid acceleration/deceleration that leads to the
disconnection of corticothalamic loops, and (3) damage to the upper brainstem and
central thalamic neurons leading to loss of arousal tone for corticothalamic loops. In
addition, dysfunction of medial frontal systems from any of these three mechanisms,
as well as others, may result in MCS and globally impaired levels of function near the
operational criteria for MCS (ie, akinetic mutism).
Global ischemia generally has the worst prognosis of the injury types discussed
because of the marked sensitivity of cortical and thalamic neurons to hypoxia and
ischemia.29 In this setting, the key issue is typically the prediction of recovery to avoid
futile attempts at sustaining life in patients who are often otherwise quite ill.69 Previ-
ously, this declaration could be made purely on clinical grounds within 3 days after
an injury,70 but with the addition of therapeutic hypothermia,71,72 these criteria no
longer apply.73 Prognosis after hypothermia is difficult, most likely because the
neurons spared by hypothermia remain functionally impaired for long time periods,
leading to a later demonstration of recovery. As a result, new prognostic algorithms
need to be developed, which will likely require more time after injury as well as new
imaging and electrophysiological techniques. If patients survive and transition to
MCS, treatment strategies are similar to those discussed below.
Patients with DAI presenting with coma have a wide range of outcomes, from pro-
longed VS to independent functioning.28,69 The time course of recovery is also
variable, ranging from days to years. Interestingly, one patient regained full conscious-
ness and language after 19 years in MCS.74 There are no reliable predictors of
recovery in this population, although rough guidelines suggest that patients in MCS
have a higher likelihood of recovery than those in VS, especially if MCS occurs within
the first year.51,52 This is a better prognosis than for patients with global ischemia, for
whom recovery to independence is exceedingly rare if the patient remains in VS for 3
months. The mechanism by which the brain recovers from DAI is still not clear.75
Possible contributors to recovery include the regrowth of corticothalamic axons74–77
and the remapping of intracortical connections to maximize spared pathways.78

Fig. 2. Noninvasive imaging evidence of command following in a patient with severe brain
injury who was behaviorally locked in. (A) fMRI demonstrating increased activity (orange) in
supplementary motor and other cortical areas when the patient was asked to imagine swim-
ming versus a resting baseline. (B) Spectral analysis of EEG in the same patient performing
the imagination of the swimming task at a different time. Example power spectra for 2 channels
are on the right; the image on the left summarizes significant spectral changes across all chan-
nels and frequencies tested. Head maps below summarize amplitude of power change across all
channels at the frequencies listed directly above. (Adapted from Bardin JC, Fins JJ, Katz DI, et al.
Dissociations between behavioural and functional magnetic resonance imaging-based evalu-
ations of cognitive function after brain injury. Brain 2011;134(Pt 3):769–82; Goldfine AM,
Victor JD, Conte MM, et al. Determination of awareness in patients with severe brain injury
using EEG power spectral analysis. Clin Neurophysiol 2011. Available at: http://www.ncbi.
nlm.nih.gov/pubmed/21514214. Accessed July 17, 2011; with permission.)
732 Goldfine & Schiff

In cases of upper brainstem and central thalamic injury, recovery of function

depends on the ability of the remaining arousal centers to restore patterned cortico-
thalamic activity. If return of consciousness occurs, patients may be left with severe
cognitive deficits, depending on the degree of thalamic injury.79 Similar to DAI, there
are a wide range of reported outcomes, but anatomic and functional imaging tech-
niques do not allow prediction of the potential for recovery in most cases.

TREATMENT STRATEGIES FOR PATIENTS WITH DISORDERS OF CONSCIOUSNESS

Akinetic mutism offers a model for approaches that improve the level of conscious-
ness (see Fig. 1). In akinetic mutism, the injury to the cortico-striatopallidal-
thalamocortical circuit involving the medial frontal lobe can produce dysfunction as
severe as in patients with much more widespread injury.58,61 Increasing the function
of this circuit through medication or brain electrical stimulation can drive activity widely
through the cerebrum.80 For example, dopaminergic agents (eg, amantadine, levo-
dopa, bromocriptine, or apomorphine) that enhance striatal background activity,
have been shown to raise the level of consciousness and improve recovery rates in
patients with various severe brain injuries (reviewed by Hirschberg and Giacino else-
where in this issue). Zolpidem, an agonist of a subset of g-aminobutyric acid(A)
(GABAA) receptors, has also been demonstrated to dramatically improve conscious-
ness in patients with diffuse brain injury.81,82 The mechanism of action of zolpidem
is thought to occur through cortical activation, both directly83 and indirectly, by inhib-
iting the globus pallidus interna from inhibiting thalamocortical firing.84 Another
successful approach through the same network, although only reported in a single
patient, is direct activation central thalamic outflow via deep brain stimulation
(DBS).85,86
There are no clear guidelines for medical management to attempt to speed recovery
of consciousness, as almost all data are from case series. Accordingly, we offer some
approaches that have been proved to be successful in our experience. For a medically
stable patient with a disorder of consciousness, the first goal is to rule out potential
inhibitors of recovery. This includes undiagnosed seizure disorders, particularly
because they can be difficult to detect behaviorally in patients with impaired motor
output. Medications can also be culprits in worsening arousal, especially those with
anticholinergic, antihistaminergic, barbiturate, and benzodiazepine properties as
well as some antiepileptic and antispasticity agents.87
To promote recovery of consciousness, we recommend amantadine 200–400 mg,
split between early morning and early afternoon doses. Amantadine has a relatively
benign safety profile and is the only medication tested to date in patients in VS and
MCS in a well-powered, randomized, double-blind, clinical trial,88 although the
results have not yet been published. A selective serotonin reuptake inhibitor may
also be added, based on animal model89 and clinical trial90 evidence for enhancing
plasticity, although there is no strong evidence in patients with disorders of
consciousness. Zolpidem can be given as 5 or 10 mg doses with a response
expected within 1 hour, though only rarely.91 Zolpidem is apparently safe, though
there are no long-term data and the potential for habituation exists. Medications
should be trialed individually, with a gradual titration of doses. Patients should
have well-documented formal examinations using the CRS-R before and after initi-
ation and dose changes, and any side effects should be noted. In addition, physical,
occupational, and speech therapy should be used when appropriate, including daily
joint stretching to avoid contractures, which can severely limit movement when the
motor system recovers.
 Neurobiology of Consciousness 733

SUMMARY

Fins92 has argued against a nihilistic approach to patients with chronic disorders of
consciousness, as if the loss of function is invariably permanent and there is nothing
more to be gained from diagnostic testing and treatment. We agree that these patients
deserve a more systematic approach to assessment, prognosis, and treatment. The
evidence described in this review shows that these conditions include a wide range
of pathologies, causes, prognoses, and proven treatments. Diagnostic testing can
be used to determine the degree of injury and suggest residual capacity for cognitive
function. Future work will allow the use of imaging modalities to predict recovery and
development of tools to communicate with those who have lost all motor function.

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