http://www.jsmf.org/meetings/2003/nov/LaureysANB2002.pdf
Acta neurol. belg., 2002, 102, 177-185
Abstract
Positron emission tomography (PET) techniques represent
a useful tool to better understand the residual
brain function in vegetative state patients. It has been
shown that overall cerebral metabolic rates for glucose
are massively reduced in this condition. However, the
recovery of consciousness from vegetative state is not
always associated with substantial changes in global
metabolism. This finding led us to hypothesize that some
vegetative patients are unconscious not just because of a
global loss of neuronal function, but rather due to an
altered activity in some critical brain regions and to the
abolished functional connections between them. We used
voxel-based Statistical Parametric Mapping (SPM)
approaches to characterize the functional neuroanatomy
of the vegetative state. The most dysfunctional brain
regions were bilateral frontal and parieto-temporal
associative cortices. Despite the metabolic impairment,
external stimulation still induced a significant neuronal
activation (i.e., change in blood flow) in vegetative
patients as shown by both auditory click stimuli and
noxious somatosensory stimuli. However, this activation
was limited to primary cortices and dissociated from
higher-order associative cortices, thought to be necessary
for conscious perception. Finally, we demonstrated
that vegetative patients have impaired functional connections
between distant cortical areas and between the
thalami and the cortex and, more importantly, that
recovery of consciousness is paralleled by a restoration
of this cortico-thalamo-cortical interaction.
Key words : Vegetative state ; consciousness ; functional
neuroimaging ; positron emission tomography ; brain
metabolism, cerebral blood flow ; functional connectivity
; brain plasticity.
Introduction
Progress of medicine in general and intensive
care in particular has increased the number of
patients who survive severe acute brain injury.
Some of these patients recover from their coma
within the first days after the insult, others will take
more time and go through different stages before
fully or partially recovering awareness (e.g., minimally
conscious state, vegetative state) or will permanently
lose all brain functions (i.e., brain death).
Clinical practice shows how puzzling it is to recognize
unambiguous signs of conscious perception of
the environment and of the self in these patients.
This difficulty is reflected by frequent misdiagnoses
of locked-in syndrome, coma, minimally
conscious state and vegetative state (Childs et al.,
1993 ; Andrews et al., 1996). Objective assessment
of residual brain function is difficult in patients
with severe brain injury because their motor
responses may be limited or inconsistent (Laureys
et al., 2002b). In addition, consciousness is not an
all-or-none phenomenon but should rather be conceptualized
as a continuum between different states
(Wade and Johnston, 1999). There is also a theoretical
limitation to the certainty of our clinical diagnosis,
since we can only infer the presence or
absence of conscious experience in another person
(Bernat, 1992).
In 1972, Jennet and Plum defined the vegetative
state as a clinical condition of "wakefulness without
awareness". They cited the Oxford English
Dictionary to clarify their choice of the term "vegetative"
as : "to vegetate is to live a merely physical
life devoid of intellectual activity or social
intercourse" and "vegetative describes an organic
body capable of growth and development but
devoid of sensation and thought". Table 1 summarizes
the criteria for the diagnosis of vegetative
state (The Multi-Society Task Force on PVS,
1994). It is important to distinguish between persistent
and permanent vegetative state. A vegetative
state is said persistent when it persists after an arbitrary
period of one month after acute traumatic or
Brain function in the vegetative state
Steven LAUREYS1,2,6, Sylvie ANTOINE5, Melanie BOLY1,2, Sandra ELINCX6,
Marie-Elisabeth FAYMONVILLE3, Jacques BERRÉ7,
Bernard SADZOT2, Martine FERRING7, Xavier DE TIÈGE6, Patrick VAN
BOGAERT6, Isabelle HANSEN2, Pierre DAMAS3,
Nicolas MAVROUDAKIS8, Bernard LAMBERMONT4, Guy DEL FIORE1, Joël
AERTS1, Christian DEGUELDRE1,
Christophe PHILLIPS1, George FRANCK2, Jean-Louis VINCENT7, Maurice
LAMY3, André LUXEN1, Gustave MOONEN2,
Serge GOLDMAN6 and Pierre MAQUET1,2
1Cyclotron Research Center, 2Department of Neurology, 3Anesthesiology
and Intensive Care Medicine and 4Internal Medicine, CHU Sart Tilman,
University of Liège, Liège, 5Department of Neurology, AZ-VUB,
Brussels, 6PET/Biomedical Cyclotron Unit and 7Department of Intensive
Care
and 8Neurology, ULB Erasme, Brussels, Belgium
————
178 S. LAUREYS ET AL.
non-traumatic brain injury (The Multi-Society Task
Force on PVS, 1994) but this does not imply irreversibility.
A vegetative state is said permanent
when one predicts that the patient will not recover.
This distinction was introduced by the American
Multi-Society Task Force on PVS in 1994 to denote
irreversibility after three months following a nontraumatic
brain injury and twelve months after
traumatic injury (Fig. 1). However, even after these
long and arbitrary delays, some patients may
exceptionally recover. Hence, the American
Congress of Rehabilitation Medicine advocated to
abandon the term "permanent" in favor of simply
defining the duration of the vegetative state
(American Congress of Rehabilitation Medicine,
1995).
Patients in a vegetative state usually show reflex
or spontaneous eye opening and breathing. At
times they seem to be awake with their eyes open,
sometimes showing spontaneous roving eye movements
and occasionally moving trunk or limbs in
meaningless ways. At other times they may keep
their eyes shut and appear to be asleep. They may
be aroused by painful or prominent stimuli opening
their eyes if they are closed, increasing their respiratory
rate, heart rate and blood pressure and occasionally
grimacing or moving. Pupillary, corneal,
oculocephalic and gag reflexes are often preserved.
Vegetative patients can make a range of spontaneous
movements including chewing, teeth-grinding
and swallowing. More distressingly, they can
even show rage, cry, grunt, moan, scream or smile
reactions spontaneously or to non-verbal sounds.
Their head and eyes sometimes, inconsistently, turn
fleetingly towards new sounds or sights. These
abilities are also seen in another group of patients
showing preserved wakefulness without awareness
– namely, infants with anencephaly – and are considered
to be of subcortical origin (The Medical
Task Force on Anencephaly, 1990). The diagnosis
of vegetative state should be questioned when there
is any degree of sustained visual pursuit, consistent
and reproducible visual fixation, or response to
threatening gestures. When patients undergo a transition
from the vegetative state to a state of awareness,
one of the first and most readily observed
clinical signs of this transition is the appearance of
sustained visual pursuit. The crucial element to
ascertain is the formal absence of any sign of conscious
perception or deliberate action. Any evidence
of communication, including a consistent
response to command, or any purposeful movement
rules out the diagnosis. This evidence can
easily be missed, especially in patients whose senses
and motor capacities are severely impaired and
in whom a blink of an eye (e.g., locked-in syndrome)
or the subtle movement of a finger (e.g.
minimally conscious state) may provide the only
evidence of awareness. Careful and prolonged
observation is indispensable as fluctuating arousal
or motivation can prevent the assessment of minimal
yet present awareness in these patients.
Apallic state or syndrome is an archaic term for
a condition that is now considered equivalent to
vegetative state. The term neocortical death has
been used differently by various authors. Some
refer to it as a vegetative state with absence or substantial
slowing of electrocortical activity on electroencephalography
(EEG), in addition to the characteristics
of vegetative state. Others equate neocortical
death with the ostensible death of all neurons
of the cerebral cortex. It is not clear whether
this term denotes a clinical syndrome or its electrical,
pathologic, or anatomical features (The Multi-
Society Task Force on PVS, 1994). The American
Neurological Association has suggested abandoning
the terms apallic state or syndrome, neocortical
death, coma vigile, alpha coma and permanent
unconsciousness (ANA Committee on Ethical
Affairs, 1993).
Three factors clearly influence the chances of
recovery from vegetative state : age, etiology, and
time already spent in a vegetative state. The outcome
is better after traumatic than non-traumatic
Table 1
Criteria of vegetative state
– No evidence of awareness of self or environment and an
inability to interact with others.
– No evidence of sustained, reproducible, purposeful, or
voluntary behavioral responses to visual, auditory, tactile,
or noxious stimuli.
– No evidence of language comprehension or expression.
– Intermittent wakefulness manifested by the presence of
sleep-wake cycles.
– Sufficiently preserved hypothalamic and brainstem autonomic
functions to permit survival with medical and
nursing care.
– Bowel and bladder incontinence.
– Variably preserved cranial-nerve and spinal reflexes.
>From the Multi-Society Task Force on PVS (1994). FIG. 1. — Flow chart
of the different clinical conditions that
follow a severe brain lesion.
BRAIN FUNCTION IN THE VEGETATIVE STATE 179
brain injury, better in children, and worse as time
passes (The Multi-Society Task Force on PVS,
1994). Clinical, EEG, evoked potentials (EP), or
structural imaging data do not permit to reliably
predict the prognosis of individual vegetative
patients (Jennett, 2002).
The interest of functional imaging in the vegetative
state is twofold. First, vegetative patients represent
an important clinical problem, in terms of
diagnosis, prognosis, treatment and everyday management.
Second, it offers a lesional approach to
the study of human consciousness and adds to the
international research effort on identifying the
neural correlate of consciousness. Indeed, these
patients represent genuine cases of abolition of
consciousness but, contrary to comatose patients,
with preserved arousal.
Resting brain metabolism
CHANGES IN GLOBAL CEREBRAL METABOLISM
Positron emission tomography (PET) has shown
a substantial reduction in global brain metabolism
in vegetative patients (Table 2). Studies from our
group and others have shown a 50 to 60% decrease
in brain metabolism in vegetative state of different
etiology and duration. In patients with a locked-in
syndrome, overall supratentorial cerebral metabolism
has been shown to be preserved partially
(Levy et al., 1987) or fully (Laureys et al., 2001b),
whereas in comatose patients a 45% decrease in
cerebral metabolism has been observed
(Tommasino, 1994 ; Laureys et al., 2001a). De
Volder and co-workers have shown that patients
regaining consciousness after post-anoxic coma
show cerebral metabolic rates for glucose
(CMRGlu) that remain 25% below normal (De
Volder et al., 1990). Compared to cerebral glucose
metabolism, cerebral blood flow seems to have a
larger inter-patient variability in the vegetative state
(Levy et al., 1987). CMRGlu is lower in persistent
vegetative state than in acute vegetative state
(Tommasino et al., 1995). Progressive Wallerian
and transsynaptic degeneration could be responsible
for this progressive loss of metabolic functioning
over time. At present, there is no established
correlation between CMRGlu depression and
patient outcome.
A global depression of cerebral metabolism is
not unique to vegetative state or coma (see Table 2).
In slow wave sleep overall brain metabolism
decreases 44% below normal waking values
(Buchsbaum et al., 1989 ; Maquet et al., 1997).
Another example of transient metabolic depression
is observed during general anesthesia. Indeed,
when different anesthetics are titrated to the point
of unresponsiveness, the resulting reduction in
CMRGlu is comparable to that observed in vegetative
patients (Alkire et al., 1995 ; 1997 ; 1999).
CHANGES IN REGIONAL CEREBRAL METABOLISM
Using ROI (region of interest) analysis, previous
PET studies have showed overall reduction in cortical
metabolism (Levy et al., 1987 ; De Volder et
al., 1990 ; Tommasino et al., 1995 ; Rudolf et al.,
1999) with most profound reductions in the parieto-
occipital and mesiofrontal cortices (De Volder
et al., 1990). By means of a voxel-based Statistical
Parametric Mapping analysis (SPM ; Friston,
1997), we have been able to identify a common
Table 2
Whole-brain averaged global metabolism levels in vegetative state,
anaesthesia and deep sleep (% decrease from normal)
Reference Condition Decrease in metabolism Number of subjects
(mean ± SD and range)
Vegetative state (aetiology, duration)
Levy et al. (1987) Hypoxic/Traumatic, 3 weeks-68 months 60% (53-67%)a 7
De Volder et al. (1990) Hypoxic, 5.5 weeks-16 weeks 53% (43-65%)b 7
Tommasino et al. (1995) Hypoxic/Traumatic,
< 3 months (hypoxic) < 12 months (traumatic) 48% 6
> 3 months (hypoxic) > 12 months (traumatic) 65% 4
Rudolf et al. (1999b) Hypoxic
< 3 months 17%a,c 11
> 3 months 33%a,c 13
Our data Hypoxic / Toxic / Traumatic, 0.5 weeks-18 weeks 56 ± 15% (37-72%)b 30
Non-REM Sleep
Buchsbaum et al. (1989) (stages II and III) 32% 12
Maquet et al. (1990a) (stages III and IV) 44 ± 14% 4
General anaesthesia
(agent titrated to the point of unresponsiveness)
Alkire et al. (1999) Halothane 40 ± 9% (28-53%) 5
Alkire et al. (1997) Isoflurane 46 ± 11% (29-55%) 5
Alkire et al. (1995) Propofol 55% (35-72%) 6
acortical metabolism ; bgray matter metabolism ; cno arterial blood sampling.
180 S. LAUREYS ET AL.
regional pattern of metabolic impairment in a set of
vegetative state patients (Laureys et al., 1999a).
The prefrontal, premotor and parietotemporal association
cortices and the posterior cingulate/precuneus
region showed the most severe functional
impairment (Fig. 2A). This pattern is in agreement
with postmortem findings where involvement of
the association cortices is frequently encountered
(Kinney and Samuels, 1994). These associative
cortices are known to be involved in various consciousness-
related functions such as attention
(Posner, 1994), working memory (Courtney et al.,
1998), episodic memory (Shallice et al., 1994), language
(Mesulam, 1990) and conscious perception
(Lumer et al., 1998),
Interestingly, the precuneus and adjacent posterior
cingulate cortex are one of the most active
cerebral regions (together with the anterior cingulate
and mesiofrontal cortex) in conscious waking
(Andreasen et al., 1995 ; Maquet et al., 1997 ;
Gusnard and Raichle, 2001). Moreover, it is one of
the least active regions in unconscious or minimally
conscious states such as such as halothane anesthesia
(Alkire et al., 1999), slow wave sleep
(Maquet et al., 1997), rapid eye movement sleep
(Maquet et al., 1996) and Wernicke-Korsakoff's or
post-anoxic amnesia (Aupee et al., 2001). The precuneus
is also the site of earliest reduction in glucose
metabolism in Alzheimer's disease
(Minoshima et al., 1997). These observations suggest
that the precuneus and posterior cingulate cortex
represent part of the critical neural network
subserving conscious experience.
Another hallmark of the vegetative state is the
relative preservation of metabolism in the brainstem
(encompassing the mesopontine reticular formation),
basal forebrain, and posterior hypothalamus
(Fig. 2B) (Laureys et al., 2000d). This allows
for the maintenance of vegetative functions in these
patients such as : sleep-wake cycles, autonomic
and ventilatory control, and cranial nerve reflexes.
This finding is in line with the post-mortem neuropathological
observations that these structures
are relatively preserved in the vegetative state
(Kinney and Samuels, 1994).
CHANGES IN CEREBRAL METABOLISM AFTER RECOVERY
OF CONSCIOUSNESS
More interestingly, we have had the opportunity to
scan a patient during vegetative state and after
recovery of consciousness (Laureys et al., 1999b).
Global gray matter CMRGlu did not show a substantial
increase after recovery (4.5 mg/100g.min
versus 4.7 mg/100g.min). In this patient, the recovery
of consciousness seemed related to a modification
of the regional distribution of brain function
rather than to the global resumption of cerebral
metabolism. Using SPM (Friston, 1997), we identified
the most important decreases in metabolism,
seen during vegetative state but not after recovery,
in the bilateral parietal associative cortices at the
convexity and at the midline (precuneus and posterior
cingulate cortex ; Laureys et al., 1999b). To
our knowledge there is only one other case report
of PET scanning during vegetative state and after
FIG. 2. — The common pattern of altered cerebral metabolism
characterizing vegetative state patients : A schematic representation
of areas where metabolism is (A) relatively most impaired and (B)
relatively spared. From Laureys et al. (2000d).
BRAIN FUNCTION IN THE VEGETATIVE STATE 181
recovery of consciousness (De Volder et al., 1990).
In this case also, global gray matter CMRGlu did
not show a substantial increase after recovery
(5.0 mg/100 g.min versus 5.2 mg/100 g.min).
Although no SPM analysis was performed, ROI
analysis showed the largest regional increase in
parieto-occipital cortices. Again, these data point to
a critical role for the posterior associative cortices
in the emergence of consciousness.
It remains controversial whether the observed
metabolic impairment in the vegetative state
reflects functional and potentially reversible
damage or irreversible structural neuronal loss.
Rudolf and co-workers argued for the latter, using
11C-flumazenil as a marker of neuronal integrity in
evaluating acute post-anoxic vegetative patients
(Rudolf et al., 2000). We hypothesize that an
impairment in cortico-cortical and thalamo-cortical
modulation (i.e., functional connectivity) may at
least in part explain the cerebral impairment in the
vegetative state. The cellular mechanisms which
underlie this functional normalization remain putative
: axonal sprouting, neurite outgrowth, cell division
(known to occur predominantly in associative
cortices in normal primates ; Gould et al., 1999) or
even apoptosis. In our opinion, the residual cerebral
plasticity of some vegetative patients has been
largely overlooked by the medical community and
deserves further investigation (Laureys et al.,
2000f). The challenge is now to identify the conditions
in which, and the mechanisms by which,
some vegetative patients may recover consciousness.
CHANGES IN FUNCTIONAL CEREBRAL CONNECTIVITY
The functional role played by any component
(e.g., neuronal population) of a connected system
(e.g., the brain) is largely defined by its connections.
It is only since recently that we have an analytical
tool to assess the functional or effective connectivity
between distant cerebral areas in functional
imaging (Friston et al., 1997). Functional
connectivity is defined as the temporal correlation
of a neurophysiological index (i.e., rCMRGlu or
rCBF) measured in different remote brain areas,
whereas effective connectivity is defined as the
influence one neural system exerts over another
(Buchel and Friston, 1997). A psychophysiological
interaction analysis explains the activity in one cortical
area in terms of an interaction between the
influence of another area and some experimental
condition (i.e., being a vegetative patient or a conscious
control). A psychophysiological interaction
means that the contribution (i.e., regression slope)
of one area to another changes significantly with
the experimental context assessed with the general
linear model as employed by statistical parametric
mapping (Friston et al., 1997). The statistical
analysis will identify brain regions that show condition-
dependent differences in modulation with
another (chosen) area (Fig. 3). It is important to
stress that one cannot guarantee that these connections
are direct (i.e., they may be mediated through
other areas) and that the two regions can have a
common input (a third area, which shows contextsensitive
responses, may be providing input to the
two areas implicated in the psychophysiological
interaction).
Using such psychophysiological interaction
analyses, we could demonstrate 'functional disconnections'
between distal cortical areas (left prefrontal
cortices and posterior cingulate cortex ;
Laureys, et al. 1999a) and between the thalami and
the cortex (intralaminar nuclei and precuneus ;
Laureys et al., 2000c) when patients in a vegetative
state were compared to healthy controls (Fig. 4).
The observed impairment in fronto-parietal connectivity
in the vegetative state is in accordance
with experiments in non-human primates where the
functional integrity of the prefrontal cortex and its
interactions with modality specific posterior brain
regions is considered critically dependant for working
memory (Goldman-Rakic, 1988). The altered
thalamo-cortical modulation in vegetative patients
is in line with the role of high frequency oscillatory
thalamocortical circuitry underlying human consciousness
in healthy volunteers (Llinas et al.,
1998). Finally, we could show that these altered
cortico-thalamo-cortical loops restored near normal
values after recovery of consciousness
(Laureys et al., 2000e).
FIG. 3. — Schematic representation of a cerebral connectivity
study in functional imaging. The graph shows the difference
in modulation between the thalami and prefrontal cortices
depending on the condition vegetative state, recovery of consciousness,
and healthy control. Put simply, in controls an
increase in activity in the thalami increases activity in the prefrontal
cortices (full line), whereas in the vegetative state this
functional relationship no longer exists (dotted line). Recovery
of consciousness is paralleled by a return to near normal
thalamo-cortical modulation (dashed line).
182 S. LAUREYS ET AL.
Cerebral activation during external stimulation
In 1989, Momose and co-workers described a
vegetative patient who increased CMRGlu after
cervical spinal cord stimulation (Momose et al.,
1989). More recently, the H2
15O infusion technique
has been used to study changes in regional cerebral
blood flow during auditory (de Jong et al., 1997)
and visual (Menon et al., 1998) stimulation.
Compared to non-word sounds, de Jong and coworkers
observed an activation in anterior cingulate
and temporal cortices when their post-traumatic
vegetative patient was presented a story told by
his mother. They interpreted this finding as possibly
reflecting the processing of emotional attributes
of speech or sound (de Jong et al., 1997). Menon
and co-workers presented photographs of familiar
faces and meaningless pictures to a vegetative
patient who subsequently recovered. The visual
association areas showed significant activation
when faces were compared to meaningless stimuli
(Menon et al., 1998).
Our group was the first to study pain perception
in persistent vegetative state patients (Laureys et
al., 2002a). Using PET, we measured changes in
regional cerebral blood flow during high intensity
electrical stimulation of the median nerve at the
wrist compared to rest in fifteen non-sedated
patients and in fifteen healthy controls. Evoked
potentials were recorded simultaneously. Brain
glucose metabolism was also quantified in each
patient. The stimuli were experienced as highly
unpleasant to painful in controls. In patients, overall
cerebral metabolism was 40% of normal values.
Nevertheless, noxious somatosensory stimulation
activated midbrain, contralateral thalamus and primary
somatosensory cortex in each and every vegetative
patient, even in the absence of detectable
cortical evoked potentials. Secondary somatosensory,
bilateral insular, posterior parietal and anterior
cingulate cortices did not show activation in any
patient. Moreover, in patients in a persistent vegetative
state, as compared to controls, the activated
primary somatosensory cortex was functionally
disconnected from higher-order associative cortices.
Similarly, auditory stimulation (95 dB clicks)
activated bilateral primary, but not associative,
auditory cortices in vegetative patients (Laureys et
al., 2000b). Functional connectivity assessment
revealed that the auditory association cortex was
'disconnected' from posterior parietal cortex, anterior
cingulate cortex and hippocampus (Laureys et
al., 2000a). Thus, despite an altered resting metabolism,
primary cortices still seem to activate during
external stimulation in vegetative patients whereas
hierarchically higher-order multimodal association
areas do not. The observed cortical activation is
isolated and dissociated from higher-order associative
cortices, suggesting that the observed residual
cortical processing in the vegetative state is insufficient
to lead to integrative processes thought to be
necessary to attain the normal level of awareness
(Schiff et al., 2002). It is important to stress that
these results should be interpreted at the 'population-
level' and must be used with great caution
regarding clinical or ethical decisions in individual
persons in a vegetative state. Future studies, using
more powerful techniques such as functional MRI,
are needed to assess noxious and cognitive processing
of individual patients studied over time.
Finally, apart from their clinical interest, these data
complement to the current debate among neuroscientists
concerning the relationship between neuronal
activity in the nervous system (especially in
primary cortex) and human consciousness (Crick
and Koch, 1995 ; Tononi and Edelman, 1998).
Conclusion
The vegetative state is a devastating medical
condition of wakefulness unaccompanied by any
evidence of awareness. It represents a problem in
terms of diagnosis, prognosis, treatment and everyday
management. At the patient's bedside, the evaluation
of possible cognitive function in severely
brain-injured patients is difficult because voluntary
movements may be very limited, inconsistent and
easily exhausted. Functional neuroimaging cannot
replace the clinical assessment of patients with
altered states of consciousness. Nevertheless, it can
describe objectively how deviant from normal is
the cerebral activity and its regional distribution, at
rest and under various conditions of stimulation. In
our opinion, the use of PET on growing scale and
the future use of functional MRI will substantially
FIG. 4. — Simplified representation of the altered thalamocortical
and cortico-cortical networks in the vegetative state.
Compared to normal controls, vegetative patients suffer from
an altered modulation between the thalami (1) and the prefrontal
cortices (2) and between the latter and the medial parietal
cortex (i.e., precuneus) and posterior cingulate cortex (3).
BRAIN FUNCTION IN THE VEGETATIVE STATE 183
increase our understanding of severely braininjured
patients. Past studies from our own and
other centers have used PET to study brain metabolism
in such patients during wakeful periods.
Those efforts identified a decrease in global metabolism
of 50 to 60%. However, some patients who
recovered from a vegetative state, improved their
regional distribution of brain function rather than
showing a resumption of global metabolism. This
led us to postulate that certain vegetative patients
remain unconscious not because of a widespread
neuronal loss, but due to the impaired activity in
some critical brain areas and to an altered functional
relationship between them. Using voxel-based
Statistical Parametric Mapping techniques we were
able to identify the common neural correlate of
vegetative patients. The most severely affected
brain regions were localized in the frontal and parieto-
temporal associative cortices. On the contrary,
brainstem, posterior hypothalamus, and basal forebrain
were the most spared brain regions. By means
of functional connectivity analyses we further
demonstrated that patients in a vegetative state suffer
from thalamo-cortical and cortico-cortical
'functional disconnections'. Moreover, in the rare
patients who recovered consciousness, we
observed a restoration of regional metabolic brain
function and resumption of cortico-thalamo-cortical
functional connectivity. Finally, using cerebral
activation paradigms, we have shown a preserved
neural reactivity to auditory and noxious
somatosensory stimuli (despite the well-known
massive metabolic cortical depression). This cerebral
activation, however, was limited to subcortical
and primary cortical areas but seemed isolated and
disconnected from the higher-order cortices considered
to be necessary for conscious perception. In
the absence of a generally accepted neural correlate
of human consciousness, it remains difficult to
interpret functional neuroimaging data from
severely brain-injured patients as a proof or disproof
of their 'unconsciousness'. We hope that further
research efforts will more closely correlate
functional imaging with behavioral assessment,
electrophysiological findings, and possibly outcome
in these challenging neurological patients.
Acknowledgements
The present work is part of an ongoing multi-center
and inter-university collaboration. It is supported by
grants from the Fonds National de la Recherche
Scientifique de Belgique (FNRS), the Special Funds for
Scientific Research of the University of Liège, the
Queen Elisabeth Medical Foundation and by the Funds
for Scientific Research of the Erasme University
Hospital. SL and PM are supported by FNRS. We thank
Bernard Rogister, Gaetan Garraux, Alain Maertens de
Noordhout (Neurology), Nathalie Janssens (Anesthesiology),
Patrick Hawotte, Jean-Luc Génon, Christiane
Meesters, Jeanine and Georges Hodiaumont (PET unit)
from the ULg ; Jean-Christophe Bier (Neurology),
Emmanuel Bartolomé (Neurorevalidation), David
Wikler, Philippe Damhaut, John Van Namen, Stéphane
Coppens, Mohammed Tahare, Pascale Cornet, Corrine
Tinant, Eric Mulleneers (PET unit) from the ULB ; Guy
Ebinger and Jen Maes (Neurology) from the VUB ;
Peter Diels and Erica Peters (Revalidation Center, De
Bijtjes, Brussels) and Manfredi Ventura (Centre de
Traumatologie et Réadaptation, Brussels) for their kind
and much valued collaboration. Richard Frackowiak and
Karl Friston (Welcome Department of Cognitive
Neurology, Institute of Neurology, London, UK) kindly
provided the SPM software. Finally, we thank the family
of the patients and the patients who subsequently
recovered for their indispensable collaboration to the
PET studies.
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