MINI REVIEW ARTICLE

published: 03 September 2013

HUMAN NEUROSCIENCE doi: 10.3389/fnhum.2013.00538

Looking for the self in pathological unconsciousness

Athena Demertzi 1 *, Audrey Vanhaudenhuyse 1 , Serge Brédart 2 , Lizette Heine 1 , Carol di Perri 3 and
Steven Laureys 1
1
Coma Science Group, Cyclotron Research Center and Neurology Department, University of Liège, Liège, Belgium
2
Department of Psychology, Behavior, and Cognition, University of Liège, Liège, Belgium
3
Department of Neuroradiology, National Neurological Institute C. Mondino, Pavia, Italy

Edited by: There is an intimate relationship between consciousness and the notion of self. By studying
Pengmin Qin, Univeristy of Ottawa
patients with disorders of consciousness, we are offered with a unique lesion approach to
Institute of Mental Health Research,
Canada tackle the neural correlates of self in the absence of subjective reports. Studies employing
Reviewed by: neuroimaging techniques point to the critical involvement of midline anterior and poste-
Alexander Fingelkurts, BM-Science rior cortices in response to the passive presentation of self-referential stimuli, such as
Brain & Mind Technologies Research the patient’s own name and own face. Also, resting state studies show that these mid-
Centre, Finland
line regions are severely impaired as a function of the level of consciousness. Theoretical
Andrew Fingelkurts, BM-Science
Brain & Mind Technologies Research frameworks combining all this progress surpass the functional localization of self-related
Centre, Finland cognition and suggest a dynamic system-level approach to the phenomenological complex-
Pawel Tacikowski, Karolinska Institute, ity of subjectivity. Importantly for non-communicating patients suffering from disorders
Sweden
of consciousness, the clinical translation of these technologies will allow medical pro-
*Correspondence:
fessionals and families to better comprehend these disorders and plan efficient medical
Athena Demertzi , Coma Science
Group, Cyclotron Research Center management for these patients.
and Neurology Department,
Keywords: consciousness, self, neuroimaging, disorders of consciousness, default mode network, external
University of Liège, Allée du 6 août no
awareness
8, Sart Tilman B30, 4000 Liège,
Belgium
e-mail: [email protected]

(SELF) CONSCIOUSNESS IN NON-COMMUNICATING other words, can one claim that these patients retain a type of “core
CONDITIONS consciousness,” which provides them with a sense of self about
The scientific study of consciousness dictates that there is an inti- here and now? (Damasio and Meyer, 2009). We think that the
mate relationship between the mind and the brain (Feinberg, 2000; study of patients with disorders of consciousness offers a unique
John, 2002; Freeman, 2007; Tononi and Laureys, 2009; Fingelkurts lesion approach to tackle the necessary neural correlates of self-
et al., 2013). Nevertheless, besides several attempts to define it, con- consciousness. Our rationale lies on the argument that since clin-
sciousness remains a difficult term to describe and different people ical diagnosis shows that patients hold no subjective experience,
may think differently about it (Demertzi et al., 2009). Here, we will the absence of subjective identity will be eventually reflected in
define consciousness in an operational manner, namely conscious- patients’ brain function. As these patients are not able to commu-
ness is what is lost during dreamless sleep (Tononi, 2004). As such, nicate or show high-level cognitive function, we will here refer to
consciousness is a matter of both waking states and experience, self-consciousness as to its basic expression. In other words, as self-
so that the less awake we get the less aware we become of our detection, namely when an organism can respond to stimuli with
surroundings and ourselves. which is directly implicated or modify its behavior in ways which
Based on this definition, patients in coma are not conscious imply awareness of its own actions (Zeman, 2001). Accordingly,
because they cannot be awakened. The linear relationship between the employed experimental paradigms refer to the administration
wakefulness and awareness is violated in cases of severely brain- of self-referential stimuli (patients’ own name and own face) and
damaged patients who are in a vegetative state (VS) and minimally the subsequent measure of brain responses to these stimuli with
conscious state (MCS). Indeed, patients is VS, also coined as neuroimaging and electrophysiological techniques. The excellent
unresponsive wakefulness syndrome (UWS; Laureys et al., 2010), spatial resolution which is offered by functional magnetic reso-
maintain awaking periods as evidenced by eye-opening and they nance imaging (fMRI) and positron emission tomography (PET),
will never respond to any visual, somatosensory, or auditory stimu- permits to better “localize” self-referential brain activity. There-
lation indicative of preserved awareness (Jennett and Plum, 1972). fore, we will here focus on studies employing these neuroimaging
On the other hand, patients in MCS show fluctuating signs of methods to study residual self-consciousness in patients with dis-
awareness and non-reflex behaviors, such as visual pursuit and orders of consciousness. To date, such functional neuroimaging
command following (Giacino et al., 2002). Importantly, in both studies point to the critical recruitment of anterior and poste-
clinical conditions patients remain unable to communicate with rior midline cerebral areas in experimental paradigms employing
their environment in a functional manner. In the absence of sub- self-referential stimuli. Activation of these midline regions is fur-
jective reports, how can one know whether patients in VS/UWS ther observed during resting state conditions in healthy volunteers.
and MCS experience something and what these experiences are? In This has led to the suggestion of a link between resting state activity

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Demertzi et al. The self in pathological unconsciousness

and unconstraint self-related mentation. We will review these areas, such as precuneus and anterior cingulate/mesiofrontal cor-
studies in patients and healthy controls, discuss the involvement of tex next to lateral parietal areas including language-related regions,
midline areas to the notion of self in patients and will propose that such as Broca’s and Wernicke’s. Another n = 1 study with a patient
self-related cognition might be a matter of a system-level dynamic in VS/UWS utilizing fMRI also showed that passive listening to the
activity rather than activation of specific brain areas. own name compared to other names, encompassed the activation
of the medial prefrontal cortex bilaterally in parallel to temporo-
ASSESSING SELF-CONSCIOUSNESS IN parietal and superior frontal cortices (Staffen et al., 2006). Includ-
NON-COMMUNICATING PATIENTS ing more patients (n = 11), it was shown that all four patients in
Clinicians are offered with various clinical scales to detect sings of MCS and six patients in VS/UWS showed cerebral responses to
awareness at the bedside (Majerus et al., 2005). The Coma Recov- their own names either in the anterior cingulate cortex (ACC) or
ery Scale-Revised (Giacino et al., 2004) is one of the most sensitive in the caudal part of the ACC or the supplementary motor area
tool to diagnose and differentiate between patients in VS/UWS (predefined regions based on brain responses of healthy controls)
and MCS because it assesses all the defining criteria for MCS, such (Qin et al., 2010). Interestingly, those two patients in VS/UWS
as visual pursuit (Seel et al., 2010). Nonetheless, it is not only a cer- who exhibited activity in the caudal ACC evolved to a MCS at
tain behavior that needs to be detected, but the way this is assessed a 3-month follow up. Similarly, two patients in VS/UWS when
seems to be equally important. For example, when visual pursuit listening to their own name showed cerebral activation extend-
was tested by means of a moving object, a moving person, and a ing to associative auditory cortex and also recovered to MCS (Di
moving mirror, more patients tracked their image in the mirror et al., 2007). Such brain activations, however, are atypical of the
compared the other two stimuli and were hence considered as in VS/UWS. Indeed, it has been shown that auditory processing of
a MCS (Vanhaudenhuyse et al., 2008). Similarly, to score sound simple stimuli in VS/UWS refers to the activation of only auditory
localization with the Coma Recovery Scale-Revised, patients need primary cortices whereas hierarchically higher-order multi-modal
to orient their head or eyes toward the source of the sound. When association areas are not activated (Laureys et al., 2000; Boly et al.,
the patients’ own names were used, more oriented their head or 2004). Although caution should be paid on the accurate behav-
eyes toward the examiner compared to the meaningless sound of ioral evaluation of these patients with standardized tools, like the
a ringing bell (Cheng et al., 2013). These studies imply that self- Coma Recovery Scale-Revised (Table 1), there are cases of unre-
referential stimuli are more effective to explore patients’ respon- sponsive patients where functional neuroimaging can precede the
siveness and can influence the diagnostic process (also, see Laureys clinic (e.g., Owen et al., 2006). Taken together, these studies suggest
et al., 2007). To what degree, however, can one claim that these that when activity of the anterior midline areas is recruited using
paradigms also reflect the, indirect, assessment of residual self- the own name paradigm, this can work as prognostic marker (for
consciousness in this non-communicating clinical population? a review, see Di et al., 2008).
One way to approach the answer is to measure patients’ brain Apart from activation studies utilizing self-referential stimuli,
responses and activation during sensitive experimental manipu- increasing attention has been paid to spontaneous brain activ-
lations and compare them with that of healthy controls. If the ity and its significance to self-related cognition. During resting
cerebral pattern is indistinguishable between the two groups, state, a set of brain areas encompassing precuneus, medial pre-
then one has good reasons to believe that the extracted statisti- frontal cortex and bilateral temporo-parietal junctions have been
cal maps reflect the same construct (Owen, 2013). Naturally, there shown to work by default, when subjects do not perform any
are emerging legitimate concerns about the degree of confidence task (Gusnard and Raichle, 2001). This default mode network
one can have on functional neuroimaging results, especially in (DMN) of areas in healthy controls has been related to inter-
the absence of subjective reports (e.g., Fins and Schiff, 2010). nally oriented cognitive content, such as self-referential or social
In addition, our limited understanding of the dynamic neural cognition, mind-wandering, and autobiographical memory recall
complexity underlying consciousness and its resistance to quantifi- (e.g., D’Argembeau et al., 2005; Mason et al., 2007; Buckner et al.,
cation in the absence of communication (Seth et al., 2008) makes 2008; Schilbach et al., 2008; Vanhaudenhuyse et al., 2011). Such
it difficult to establish strong claims about self-consciousness in intrinsic cerebral activity also seems to be implicated in conscious-
non-communicating patients. Nevertheless, the use of these tech- ness processes. For example, in brain death, where all brainstem
nologies have shed light on the gray zones between the different reflexes are lost parallel to continuous cessation of respiration,
clinical entities of consciousness and have revealed that not all functional connectivity in the DMN is absent (Boly et al., 2009),
patients can be considered unresponsive (Laureys and Boly, 2008; or attributed merely to motion artifacts (Soddu et al., 2011). Coma
Gantner et al., 2012). For example, fMRI has been used to assist the patients show no identifiable fMRI DMN connectivity and in those
diagnosis of patients with disorders of consciousness (Coleman patients where such connectivity can be detected may indicate sub-
et al., 2009), to detect preserved awareness in behaviorally unre- sequent recovery of consciousness (Norton et al., 2012). In patients
sponsive patients (Owen et al., 2006), and even to communicate with disorders of consciousness, such fMRI DMN connectivity is
with them (Monti et al., 2010). partially preserved yet severely disrupted, showing consciousness
Due to the difficulty to control voluntary eye-opening of level-dependent decreases when moving from healthy controls to
patients, most neuroimaging studies employing self-referential patients in MCS, VS/UWS, and coma (Vanhaudenhuyse et al.,
stimuli restrict to the auditory modality (Table 1). In a PET study 2010). Interestingly, EEG studies have corroborated these findings:
with one patient in MCS, the patient’s own name was presented it has been shown that the strength of DMN EEG synchrony
next to baby cries and meaningless noise (Laureys et al., 2004). Pas- was smallest or even absent in patients in VS/UWS, intermedi-
sive listening to the own name recruited the activation of midline ate in patients in MCS, and highest in healthy fully self-conscious

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Demertzi et al. The self in pathological unconsciousness

Table 1 | Studies showing brain responses to the presentation of self-referential stimuli in patients in vegetative state/unresponsive
wakefulness syndrome (UWS) and minimally conscious state (MCS) by means of positron emission tomography (PET) and functional magnetic
resonance imaging (fMRI) techniques (*indicates prognostic value).

Technique Patients Coma recovery Experimental contrast Implicated brain regions Reference
scale-revised
assessment?

fMRI 4 MCS, Yes Passive listening to own In predefined regions of ACC, cACC, and SMA: Qin et al.
7 UWS name by familiar voice • In all 4 MCS and six UWS: signal changes in at least one (2010)
the three regions
• In 2 UWS: activity in cACC (clinical improvement to MCS
at three-month follow up)*

fMRI 4 MCS, Yes Passive listening to own • In all 4 MCS: primary auditory cortex extending to Di et al.
7 UWS name by familiar voice vs. associative auditory cortex (2007)
baseline (machine noise) • In 2 UWS: no activation
In 3 UWS: primary auditory cortex
In 2 UWS: primary auditory cortex extending to
associative auditory cortex (clinical improvement to MCS
at three-month follow up)*

fMRI 1 UWS No Passive listening to own vs. Medial prefrontal cortex bilaterally (also activation in L Staffen
other names temporo-parietal and superior frontal cortices) et al. (2006)

PET 1 MCS Yes Passive listening to own name Precuneus and anterior cingulate/mesiofrontal cortex (also Laureys
activation in bilateral angular gyri, R temporo-parietal et al. (2004)
junction, L dorsal prefrontal regions and Broca’s area,
bilateral posterior superior temporal sulci and dorsal superior
temporal gyri, encompassing Wernicke’s area)

ACC, anterior cingulate cortex; cACC, caudal part of the anterior cingulate cortex; SMA, supplementary motor area.

subjects (Fingelkurts et al., 2012). Similarly, brain metabolism

in these midline structures is severely disrupted in patients in
VS/UWS and MCS compared to patients who have emerged from
the MCS or are in a locked-in syndrome (Figure 1; Thibaut et al.,
2012). It has been further proposed that deactivation of the DMN
is supposed to reflect interruptions of introspective processes.
Such investigation in patients showed that, compared to healthy
controls, deactivation in medial regions of the DMN was absent
in patients in VS/UWS and reduced in patients in MCS (Crone
et al., 2011). Taken together, studies of spontaneous activity in
patients suggest that changes in the DMN functional connectivity
FIGURE 1 | Metabolic activity in medial precuneus (MP) and
could suggest modified self-related conscious mentation. Indeed,
mesiofrontal (MF) cortex is severely impaired in patients with
it has been suggested that in normal waking conditions, resting disorders of consciousness, such as in vegetative state/unresponsive
state activity in the posterior cingulate, and frontal areas accounts wakefulness syndrome and minimally conscious state. Of note is that
for self-referential thoughts (Whitfield-Gabrieli et al., 2011; Fin- patients who have emerged from the minimally conscious state (who yet
gelkurts et al., 2012). Therefore, it could be inferred that decreased experience confusion and amnesia syndromes) show metabolic
dysfunction only in the posterior cingulate and adjacent retrosplenial cortex
connectivity in these midline regions of the DMN reflects, at least but not in the lateral frontoparietal network (see text). Finally, fully
to certain degree, restricted abilities for self-referential processing conscious yet severely paralyzed patients with locked-in syndrome do not
in patients with disorders of consciousness. show metabolic impairment in any of these areas, suggesting a critical
involvement of midline regions in supporting self-related cognition (figure
THE SELF AS A PRODUCT OF A DYNAMIC SYSTEM adapted from Thibaut et al., 2012).
APPROACH
Since the early studies of resting state, it has been suggested that the
brain’s baseline activity can be organized in two brain networks with the DMN and is involved in the same cognitive processes as
showing anticorrelated activity to each other: an “intrinsic” and the DMN. The “extrinsic” system encompasses lateral frontopari-
an “extrinsic” network (Fox et al., 2005; Fransson, 2005; Golland etal areas resembling the brain activations during goal-directed
et al., 2007; Tian et al., 2007). The “intrinsic” network coincides behavior and it has been linked to cognitive processes of external

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Demertzi et al. The self in pathological unconsciousness

sensory input, such as somatosensory (e.g., Boly et al., 2007), visual in a hyperfunctional state, while the other is hypoactive. Extrinsic
(e.g., Dehaene and Changeux, 2005), and auditory (e.g., Brunetti system hyperfunction is expected to lead to a state of total senso-
et al., 2008). Previous studies showed that these two systems are of rimotor absorption or “lost self.” In contrast, intrinsic or default
a competing character in the sense that they can disturb or even system hyperfunction is expected to lead to a state of complete
interrupt each other (e.g., Tian et al., 2007). Such anticorrelated detachment from the external world. A state where both extrin-
pattern is also illustrated in activation studies on motor perfor- sic and intrinsic systems are hypofunctional is predicted to lead
mance (Fox et al., 2007), perceptual discrimination (Sapir et al., to markedly impaired consciousness as seen in disorders of con-
2005), attentional lapses (Weissman et al., 2006), and somatosen- sciousness (Soddu et al., 2009). A more recent proposal, adopting
sory perception of stimuli close to somatosensory threshold (Boly a similar system-level approach, points to the functional separa-
et al., 2007). tion of the dorsal and ventral subcomponents of the posterior
We have recently proposed that these two systems may account cingulate cortex (PCC): the ventral PCC appears to be highly inte-
for the phenomenological complexity of awareness. In particular, grated within the DMN, and is involved in internally directed
it is proposed that awareness, or the contents of consciousness, cognition (e.g., memory retrieval and planning) whereas the dor-
can be reduced to two components, namely the “external” aware- sal PCC shows a highly complex pattern of connectivity, with
ness or everything we perceive through our senses (what we see, prominent connections to the frontal lobes (Leech et al., 2012).
hear, feel, smell, and taste) and “internal” awareness or stimulus- According to the suggested model, differential regional activity
independent thoughts (Demertzi et al., 2013). Interestingly, the can be explained by considering the arousal state, the milieu of
switch between the external and internal milieu was found not attention (internal vs. external) and the breadth of attention (nar-
only to characterize overt behavioral reports but also had a cerebral row vs. broad) (Leech and Sharp, 2013). The model proposes that
correlate (Vanhaudenhuyse et al., 2011). More particularly, it was through its interactions with the prefrontal cortex, the dorsal PCC
shown that behavioral reports of internal awareness were linked is involved in controlling attentional focus. Hence, interactions of
to the activity of midline anterior cingulate/mesiofrontal areas as these PCC sub-regions with other intrinsic connectivity networks
well as posterior cingulate/precuneal cortices. Conversely, subjec- are then involved in shifting the balance of attention along an
tive ratings for external awareness correlated with the activity of internal/external and broad/narrow dimension (Leech and Sharp,
lateral fronto-parieto-temporal regions. These findings highlight 2013).
that the anticorrelated pattern between the internal and external Taken together these studies indicate that DMN and anti-
awareness system is of functional relevance to conscious cognition. correlated external awareness system activity underlies (at least
Indeed, in an altered conscious state like hypnosis, where subjects partially) conscious ongoing mentation. It should be mentioned
report awareness alterations but remain fully responsive, hypnosis- that fMRI anticorrelations were previously subject to debate in
related reductions in functional connectivity were shown in the the literature. It has been argued, for instance, that fMRI func-
external awareness system parallel to subjective ratings of increased tional anticorrelations are nothing more than noise in the signal
sense of dissociation from the environment and reduced intensity due to regression of the brain’s global activity during data pre-
of thoughts about external events (Demertzi et al., 2011). Similar processing (Anderson et al., 2011). Other data, however, suggest
reductions in external awareness systems have been also shown for that the anticorrelations persist both with and without global sig-
non-responsive conditions, such as deep sleep and anesthesia (for nal regression, suggesting some underlying biological origins for
a review, see Heine et al., 2012). this anticorrelated pattern (Fox et al., 2009; Chai et al., 2012). We
Analysis of metabolic activity obtained in VS/UWS patients would agree with the latter evidence which is supported by studies
compared to healthy controls or comparisons with recovery of in unconscious conditions, such as anesthesia, sleep, and in unre-
awareness (i.e., within-subject), have highlighted the critical role sponsive patients (Boly et al., 2009) where these anticorrelations
of a widespread fronto-temporo-parietal associative cortical net- generally reduce or even disappear, accounting for their functional
work (Thibaut et al., 2012). Recent PET data indicate that recovery contribution to conscious cognition.
of MCS patients seems to be accompanied by a right-lateralized
recovery of the external awareness network whereas the presence of CONCLUSION
command following, defining the MCS plus (Bruno et al., 2011), Neuroimaging activation and resting state studies indicate an
classically parallels the recovery of the dominant left-lateralized indirect measure of self-related cognition encompassing midline
language network (Bruno et al., 2012). Similar results have been and lateral frontoparietal areas. Furthermore, such studies have
observed in slow wave sleep and general anesthesia (for review, recently shown a much more complex, dynamic, and multifac-
see Boveroux et al., 2008). Interestingly, these findings are also eted architecture of brain functional connectivity in the emergence
confirmed in transient dissociative states of unresponsive wakeful- of consciousness than previously thought. Importantly for non-
ness, such as absence seizures, complex partial seizures, or sleep- communicating patients suffering from disorders of conscious-
walking – all characterized by preserved automatic reflex motor ness, such neuroimaging measurements are of medical and ethical
behavior in the absence of response to commands and show- importance (Jox et al., 2012). What remains to be determined
ing transient impaired activity in these fronto-temporo-parietal is the clinical translation of these technologies which will allow
associative areas (Laureys, 2005; Blumenfeld, 2012). medical professionals and families to better comprehend these
According to a suggested framework taking the external and disorders, plan efficient medical management, and in a far reach-
internal awareness systems into account, two complementary ing perspective, to acquire new opportunities to restore their brain
states of system imbalance are possible, where one system can be functions.

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Demertzi et al. The self in pathological unconsciousness

ACKNOWLEDGMENTS “Université Européenne du Travail,” “Fondazione Europea di

This work was supported by the Belgian National Funds for Ricerca Biomedica,” and the University Hospital of Liège. Athena
Scientific Research (FNRS), tinnitus Prize 2011, the European Demertzi and Audrey Vanhaudenhuyse are FNRS Postdoc-
Commission, the James McDonnell Foundation, the Euro- toral Researchers, Serge Brédart is a Full Professor of Cog-
pean Space Agency, Mind Science Foundation, the French nitive Psychology at the University of Liège, Lizette Heine is
Speaking Community Concerted Research Action, the Belgian FNRS Research fellow and Steven Laureys is FNRS Research
Interuniversity Attraction Pole, the Public Utility Foundation Director.

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communicative patients. Conscious. Sci. U.S.A. 102, 17810–17815. “The neurology of consciousness: nal author(s) or licensor are credited and
Cogn. 16, 722–741. doi:10.1016/j. doi:10.1073/pnas.0504678102 an overview,” in The Neurology that the original publication in this jour-
concog.2007.04.004 Schilbach, L., Eickhoff, S. B., Rotarska- of Consciousness: Cognitive Neuro- nal is cited, in accordance with accepted
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