Journal of Neurology

, Volume 259, Issue 6, pp 1087–1098 | Cite as

Functional neuroanatomy underlying the clinical subcategorization of minimally conscious state patients

  • Marie-Aurélie Bruno
  • Steve Majerus
  • Mélanie Boly
  • Audrey Vanhaudenhuyse
  • Caroline Schnakers
  • Olivia Gosseries
  • Pierre Boveroux
  • Murielle Kirsch
  • Athena Demertzi
  • Claire Bernard
  • Roland Hustinx
  • Gustave Moonen
  • Steven Laureys
Original Communication

Abstract

Patients in a minimally conscious state (MCS) show restricted signs of awareness but are unable to communicate. We assessed cerebral glucose metabolism in MCS patients and tested the hypothesis that this entity can be subcategorized into MCS− (i.e., patients only showing nonreflex behavior such as visual pursuit, localization of noxious stimulation and/or contingent behavior) and MCS+ (i.e., patients showing command following).

Patterns of cerebral glucose metabolism were studied using [18F]-fluorodeoxyglucose-PET in 39 healthy volunteers (aged 46 ± 18 years) and 27 MCS patients of whom 13 were MCS− (aged 49 ± 19 years; 4 traumatic; 21 ± 23 months post injury) and 14 MCS+ (aged 43 ± 19 years; 5 traumatic; 19 ± 26 months post injury). Results were thresholded for significance at false discovery rate corrected p < 0.05.

We observed a metabolic impairment in a bilateral subcortical (thalamus and caudate) and cortical (fronto-temporo-parietal) network in nontraumatic and traumatic MCS patients. Compared to MCS−, patients in MCS+ showed higher cerebral metabolism in left-sided cortical areas encompassing the language network, premotor, presupplementary motor, and sensorimotor cortices. A functional connectivity study showed that Broca’s region was disconnected from the rest of the language network, mesiofrontal and cerebellar areas in MCS− as compared to MCS+ patients.

The proposed subcategorization of MCS based on the presence or absence of command following showed a different functional neuroanatomy. MCS− is characterized by preserved right hemispheric cortical metabolism interpreted as evidence of residual sensory consciousness. MCS+ patients showed preserved metabolism and functional connectivity in language networks arguably reflecting some additional higher order or extended consciousness albeit devoid of clinical verbal or nonverbal expression.

Keywords

Coma Consciousness Minimally conscious state Positron-emission tomography Neuroanatomy 

Introduction

The minimally conscious state (MCS) describes a condition of severely altered consciousness in which patients demonstrate minimal but definite behavioral evidence of awareness but are, by definition, unable to effectively communicate [1]. We recently propose to subcategorize MCS patients based on the complexity of their behavior into two entities: “MCS minus” (MCS−) and “MCS plus” (MCS+) [2]. MCS− describes patients with minimal level of behavioral interactions without command following (e.g., visual pursuit, localization of noxious stimulation and/or smiling/crying in contingent relationship to external stimuli). MCS+ patients show higher-level behavioral responses such as command following (Figure 1). Since the subcategorization of MCS is based on the complexity of behavior as previously proposed [2], the aim of this study was to characterize the integrity of residual cortical networks in MCS patients using [18F]-fluorodeoxyglucose-PET (FDG-PET) testing the hypothesis that this heterogeneous clinical entity can be subcategorized into MCS− and MCS+, each subcategory characterized by its own functional neuroanatomy.
Fig. 1

Clinical criteria of disorders of consciousness illustrating the proposed difference between MCS− and MCS+. MCS− describes patients with minimal level of behavioral interactions such as visual pursuit, localization of noxious stimulation and/or appropriate smiling/crying. MCS+ is characterized by the presence of high-level behavioral responses as command following

Methods

Cerebral metabolic rates for glucose (CMRGlu) [3] were studied by means of FDG-PET in 27 subacute and chronic MCS patients (10 women; aged 45 ± 16 years) and 39 age-matched healthy controls (21 women; aged 46 ± 18 years). Inclusion criteria were the presence of acute brain damage, coma on admission, absence of sedation, and the presence of operational criteria for MCS (i.e., patients showing minimal but definite behavioral evidence of awareness). Exclusion criteria were patients with extremely vast structural damage encompassing more than two-thirds of one hemisphere in order to allow for reliable spatial normalization of brain images. Table 1 shows the patients’ demographic and clinical data. Patients were diagnosed as being in a MCS according to the Aspen Neurobehavioral Conference Workgroup clinical criteria [1] and had repeated Coma Recovery Scale-Revised (CRS-R) [4] assessments (day of scanning, and in the week before and the week after) performed by an experienced multidisciplinary team (i.e., neurologists MB and SL and neuropsychologists MAB, AV, CS, OG, and AD). Given the known behavioral variability in this pathology, the diagnosis of MCS− was made if the patient repeatedly failed to show command following on all CRS-R assessments. Thirteen patients were classified as MCS− (6 women; aged 49 ± 19 years; 4 traumatic; 21 ± 23 months post injury) meaning they did not show command following but presented clearly discernible evidence of nonreflex “purposeful” behavior. Nonreflex behavior included (1) localization to noxious stimulation, (2) visual pursuit movements, (3) “automatic” motor responses (e.g., mouth opening to an approaching spoon, nose scratching, grasping the bedrail), (4) object manipulation (i.e., nongrasp reflex hand movements), (5) affective behaviors occurring in contingent relation to relevant environmental stimuli and are not due to reflexive activity (e.g., smiling in response to a specific eliciting stimulus such as the patient’s mother) as defined by CRS-R criteria [4]. Fourteen patients were classified as MCS+ (4 women; aged 43 ± 19 years; 5 traumatic; 19 ± 26 months post injury) meaning they showed reproducible command following (i.e., at least three correct responses out of four identical commands) as defined by CRS-R criteria. Commands were presented verbally and in written form. All patients were studied free of sedative drugs and following administration of a standardized arousal facilitation protocol [4]. MCS− and MCS+ groups were matched for age, etiology, and time since insult.
Table 1

Demographic and clinical data of patients in minimally conscious state

Clinical features

Age (years) (gender)

Cause

Time of PET-scan (months after insult)

Auditory functiona

Visual functiona

Motor functiona

Oromotor/verbal functiona

Communicationa

Arousala

Structural lesions on MRI/CT

MCS−1

66 (M)

Anoxia

3.2

Auditory startle

Visual pursuit

Flexion withdrawal

Vocalization/oral movement

None

Eyes open without stimulation

NA

MCS−2

56 (M)

CVA

2.4

Auditory startle

Visual pursuit

None

Oral reflexive movement

None

Eyes open without stimulation

Left frontal sub-cortical

MCS−3

72 (M)

Encephalitis

1.4

Localization to sound

Visual pursuit

Localization to noxious stimulation

Oral reflexive movement

None

Eyes open without stimulation

Cortico-sub-cortical cerebellum

MCS−4

33 (M)

Anoxia

38.2

Auditory startle

Visual pursuit

Abnormal posturing

Vocalization/oral movement

None

Eyes open without stimulation

Diffuse atrophy, bilateral fronto-parietal, periventricular, left temporal, brainstem

MCS−5

44 (F)

Hypoglycemia

2.5

Auditory startle

Visual pursuit

Flexion withdrawal

Vocalization/oral movement

None

Eyes open without stimulation

NA

MCS−6

46 (F)

Anoxia

62.6

Localization to sound

Visual pursuit

Abnormal posturing

Vocalization/oral movement

None

Eyes open without stimulation

Diffuse atrophy, periventricular, left fronto-parietal, mesencephalon

MCS−7

48 (F)

Hypoglycemia

1.2

Auditory startle

Visual pursuit

Localization to noxious stimulation

Oral reflexive movement

None

Eyes open without stimulation

Diffuse atrophy, bifrontal, periventricular, cerebellum, pontomesencephalic

MCS−8

88 (M)

Subarachnoid hemorrhage

1.2

Auditory startle

Visual pursuit

Flexion withdrawal

None

None

Eyes open with stimulation

Bilateral fronto-parieto-occipital, left temporal, pontomesencephalic

Mcs−9

31 (M)

Trauma

35.2

Auditory startle

Visual pursuit

Flexion withdrawal

Oral reflexive movement

None

Eyes open without stimulation

Left frontoparietal, periventricular, cerebellum

Mcs−10

44 (F)

Trauma

22.4

Auditory startle

Visual pursuit

Flexion withdrawal

Oral reflexive movement

None

Eyes open without stimulation

Bilateral temporal

Mcs−11

24 (F)

Trauma

61.8

Localization to sound

Visual pursuit

Automatic motor response

Vocalization/oral movement

None

Eyes open without stimulation

NA

Mcs−12

22 (F)

Trauma

29.3

None

Visual pursuit

Flexion withdrawal

Vocalization/oral movement

None

Eyes open without stimulation

Bifronto-temporal,

diffuse axonal,

cerebellum, right brainstem

Mcs−13

64 (M)

Anoxia

1.2

Localization to sound

Visual pursuit

Automatic motor response

Vocalization/oral movement

None

Eyes open without stimulation

No focal lesions

MCS+1

50 (F)

Anoxia

82

Reproducible movement to command

Object localization : reaching

Automatic motor response

None

Non-functional : Intentional

Eyes open with stimulation

No focal lesions

MCS+2

59 (M)

Anoxia

6.5

Reproducible movement to command

Object localization : reaching

Automatic motor response

Intelligible verbalization

Non-functional : Intentional

Eyes open without stimulation

Diffuse leucoencephalopathy and cortico-sub-cortical atrophy

MCS+3

64 (M)

Subarachnoid hemorrhage

5.6

Reproducible movement to command

Object recognition

Automatic motor response

Intelligible verbalization

Non-functional : Intentional

Eyes open with stimulation

Diffuse atrophy, left cerebellar, right frontal

MCS+4

76 (F)

CVA

1.4

Reproducible movement to command

Object localization : reaching

Automatic motor response

Vocalization/oral movement

Non-functional : Intentional

Eyes open without stimulation

Right temporal

MCS+5

32 (M)

Anoxia

14.3

Reproducible movement to command

Visual pursuit

Abnormal posturing

Oral reflexive movement

None

Eyes open without stimulation

NA

MCS+6

38 (M)

Anoxia

3.6

Reproducible movement to command

Visual pursuit

Flexion withdrawal

Oral reflexive movement

None

Eyes open without stimulation

No focal lesion

MCS+7

71 (F)

Encephalitis

9

Reproducible movement to command

Object recognition

Flexion withdrawal

Vocalization/oral movement

None

Eyes open with stimulation

Bifronto-temporal

MCS+8

46 (M)

Subarachnoid hemorrhage

18

Reproducible movement to command

Object recognition

Automatic motor response

Intelligible verbalization

Non-functional : Intentional

Attention

NA

MCS+9

17 (F)

Trauma

4

Reproducible movement to command

Visual fixation

Localization to noxious stimulation

Oral reflexive movement

None

Eyes open without stimulation

Diffuse edema, bifrontal

MCS+10

27 (M)

Trauma

41

Reproducible movement to command

Visual pursuit

Flexion withdrawal

Vocalization/oral movement

None

Eyes open without stimulation

Diffuse atrophy

MCS+11

40 (M)

Trauma

2

Reproducible movement to command

Visual fixation

Localization to noxious stimulation

None

None

Eyes open without stimulation

Bitemporo-occipital

MCS+12

23 (M)

Trauma

70

Reproducible movement to command

Object recognition

Automatic motor response

Intelligible verbalization

Non-functional : Intentional

Eyes open without stimulation

NA

MCS+13

37 (M)

Trauma

4

Reproducible movement to command

Visual pursuit

Flexion withdrawal

Oral reflexive movement

None

Eyes open without stimulation

Biparietal, right cerebellum, brainstem

MCS+14

27 (M)

Anoxia

4

Reproducible movement to command

Visual pursuit

Automatic motor response

Vocalization/oral movement

None

Eyes open with stimulation

Diffuse atrophy

NA not available

a As defined by Coma Recovery Scale-Revised criteria

FDG-PET data were acquired after intravenous injection of 300 MBq of FDG on a Philips Gemini TF PET-CT scanner [5]. Patients were monitored by two anesthesiologists throughout the procedure. PET data were spatially normalized, smoothed (14 mm full width at a half maximum) and analyzed using Statistical Parametric Mapping (SPM8; www.fil.ion.ucl.ac.uk/spm). The first analysis identified brain regions with significant decreased metabolism in the following: (1) MCS patients as compared to controls, (2) MCS− compared to control subjects, (3) MCS+ compared to control subjects, (4) MCS+ compared to MCS−. The design matrix included 13 MCS−, 14 MCS+, and 39 control subjects’ scans and global normalization was performed by proportional scaling. A second analysis looked for differences in brain metabolism between MCS of traumatic (n = 9) and nontraumatic (n = 18) origin, taking into account age and duration since onset as confounding factors. A third analysis identified brain regions where residual metabolism correlated with the time spent since onset. We also identified areas showing a correlation with the CRS-R total scores. Next, a psychophysiological interaction analysis [3] tested the hypothesis on altered functional cortical connectivity in MCS− as compared to MCS+ and control subjects. This design matrix included the same scans as described above and took into account group differences in mean levels of glucose consumption. Now the analysis looked for brain regions that experienced a significant difference in reciprocal modulation with/from the cortical area that most differentiated MCS− from MCS+ (i.e., Broca’s area; stereotaxic coordinates −44, 22, 4 mm). It assessed the difference in modulation of Broca’s area depending on the condition MCS− versus MCS+ or control subjects. A conjunction analysis [6] identified areas showing functional connectivity (i.e., cross-correlation in metabolic activity) with the seed voxel (Broca’s area) in healthy controls which also showed higher connectivity in MCS+ as compared to MCS−.

All results were corrected for multiple comparisons and considered significant at false discovery rate corrected p < 0.05 [7]. The study was approved by the Ethics Committee of the Faculty of Medicine of the University of Liege and written informed consent was obtained from all healthy controls and the patients’ legal representatives.

Results

Patients in MCS (as compared to healthy controls) showed hypometabolism in bilateral thalamus, caudate, posterior cingulate and precuneal, anterior cingulate and mesiofrontal, posterior parietal, temporal, and dorsolateral prefrontal cortices. Patients in MCS− showed metabolic dysfunction in bilateral thalami, caudate, posterior cingulate and precuneal, anterior cingulate and mesiofrontal, angular gyrus, left posterior parietal and bilateral temporal and dorsolateral prefrontal cortices. Patients in MCS+ showed hypometabolism in right thalamus, bilateral caudate, posterior cingulate and precuneal, anterior cingulate and mesiofrontal, right posterior parietal, temporal, and premotor cortices. Finally, MCS+ patients showed significant higher metabolism as compared to MCS− in Broca’s and Wernicke’s regions, left premotor, left caudate, and post- and precentral cortices (Table 2; Fig. 2). No differences were observed between traumatic and nontraumatic etiology.
Table 2

Statistical results and localization of peak voxels where cerebral metabolism was impaired in patients in a minimally conscious state (MCS), MCS− (showing non-reflex behavior without command following) and MCS+ (showing command following)

Brain region (area)

Side

x (mm)

y (mm)

z (mm)

z-value

Corrected p-value

MCS

 Caudate

L

−8

12

10

6.15

<0.001

R

14

14

8

7.6

<0.001

 Bilateral thalamus

 

6

−16

8

7.24

<0.001

 Posterior cingulate/precuneus (31/7)

 

0

−30

32

Inf

<0.001

 Anterior cingulate (24/31)

R

4

12

24

5.83

<0.001

 Premotor (6)

L

−30

6

52

5.26

<0.001

 Middle frontal gyrus (9)

L

−44

12

34

4.66

<0.001

 Superior frontal gyrus (10)

L

−32

54

14

3.73

0.001

 Inferior frontal gyrus (47)

L

−40

20

−4

4.69

<0.001

 Premotor cortex (6)

R

38

4

50

4.50

<0.001

 Superior frontal gyrus (8)

R

2

18

50

4.64

<0.001

 Superior temporal gyrus (38)

R

42

24

−22

4.5

<0.001

 Inferior temporal gyrus (20)

L

−62

−26

−16

2.88

0.013

R

64

−18

−18

2.95

0.011

 Angular gyrus (39/40)

L

−44

−70

42

3.68

0.001

R

54

−52

52

2.99

0.010

MCS−

 Caudate

L

−8

12

8

5.75

<0.001

R

14

14

8

6.44

<0.001

 Bilateral thalamus

 

0

−18

6

5.82

<0.001

 Posterior cingulate/precuneus  (31/7)

 

0

−26

32

6.93

<0.001

 Anterior cingulate (33)

R

4

12

24

5.5

<0.001

 Premotor (6)

L

−30

8

54

5.96

<0.001

 Middle frontal gyrus (9/6)

L

−44

14

32

5.61

<0.001

R

36

4

62

4.18

<0.001

 Inferior frontal gyrus (47)

L

−40

20

−2

5.49

<0.001

 Inferior temporal gyrus (20)

L

−60

−22

−16

3.96

0.001

R

62

−20

−18

2.42

0.008

 Angular gyrus (39/38)

L

−46

−68

40

4.58

<0.001

R

42

24

−22

3.18

0.006

MCS+

 Caudate

L

−8

10

12

4.48

<0.001

R

14

14

6

6.53

<0.001

 Right thalamus

R

10

−16

10

6.86

<0.001

 Posterior cingulate/precuneus (31/7)

 

0

−36

32

7.04

<0.001

 Anterior cingulate (32)

R

8

12

38

4.21

<0.001

 Middle frontal gyrus (9)

R

46

12

30

4.3

<0.001

 Middle temporal gyrus (21)

R

68

−50

−2

2.67

0.033

 Superior temporal gyrus (22)

R

52

12

−4

4.89

<0.001

 Postcentral gyrus (7)

R

38

−70

52

2.69

0.031

 Angular gyrus (39/40)

R

54

−50

52

3.08

0.012

 Right premotor gyrus

R

48

10

48

3.85

<0.001

Preserved area in MCS+ as compared to MCS−

 Caudate

L

−8

8

−6

2.62

0.048

 Sensory-motor area (4/3)

L

−60

−8

26

3.37

0.023

 Premotor (6)

L

−30

8

56

3.76

0.023

 Inferior frontal gyrus (45)

L

−44

22

4

3.99

0.023

 Middle frontal gyrus (9)

L

−42

14

30

3.87

0.023

 Superior temporal gyrus (39)

L

−58

−56

26

3.19

0.024

 Middle temporal gyrus (21)

L

−54

−8

−14

3.77

0.023

Coordinates are in standardized stereotaxic Montreal Neurological Institute space

Fig. 2

Areas with impaired metabolism (shown in blue) in patients in a minimally conscious state (MCS), MCS− (showing nonreflex behavior) and MCS+ (showing command following). The lowest panel shows areas with higher metabolism in MCS+ as compared to MCS− (shown in orange). All results are shown on a 3D MRI template and thresholded at false discovery rate corrected p < 0.05

This analysis as a function of lesion type was also performed for each MCS group separately (MCS− traumatic versus MCS− nontraumatic; MCS+ traumatic versus MCS+ nontraumatic). No differences were found between traumatic and nontraumatic groups within each subcategory. Time since onset showed no negative correlation with brain metabolism (similar results were observed when acute (<3 months) and subacute/chronic patients were compared). Conversely, a positive correlation was observed with precuneus—albeit at a less conservative threshold (coordinates x = 10 y = −58 z = 48 mm, z value = 3.72; small volume corrected p < 0.05).

CRS-R total scores showed a linear correlation with metabolism in the left thalamus, precuneus, posterior parietal, left primary and associative auditory cortices, bilateral premotor cortex, frontal eye field, insula, dorsolateral prefrontal and anterior cingulate cortices (Table 3; Fig. 3).
Table 3

Peak voxels showing linear correlation between regional metabolism and Coma Recovery Scale-Revised total scores

Brain region (area)

Side

x (mm)

y (mm)

z (mm)

z-value

Corrected p-value

Left caudate

L

−10

12

8

6.60

<0.001

R

14

14

8

6.63

<0.001

Left thalamus

L

−2

−18

6

6.76

<0.001

Insula

L

−38

20

−4

5.59

<0.001

R

38

24

−2

3.33

<0.001

Posterior cingulate (31)

 

0

−28

34

7.71

<0.001

Precuneus (7)

L

−2

−70

38

4.27

<0.001

Anterior cingulate (33)

R

4

12

24

5.82

<0.001

Mesiofrontal (10)

 

0

52

0

3.46

0.002

Premotor (6)

L

−30

8

52

6.21

<0.001

R

34

6

64

4.09

<0.001

Superior frontal gyrus (8)

L

−4

48

42

4.31

<0.001

R

26

28

54

3.76

0.001

Middle frontal gyrus (9/10)

L

−44

14

30

5.92

<0.001

L

−36

52

12

4.70

<0.001

Inferior parietal gyrus (39)

L

−46

−68

42

5.01

<0.001

Middle temporal gyrus (21)/Primary auditory area

L

−62

−26

−14

3.68

0.001

Fig. 3

Areas showing linear correlation of metabolism with Coma Recovery Scale-Revised (CRS-R) total scores (shown in red) shown on a 3D MRI template and thresholded at false discovery rate corrected p < 0.05. The lower panel graphically illustrates that CRS-R scores increase as metabolic activity becomes more robust

The connectivity study showed that Broca’s area was functionally connected with the language network, mesiofrontal and cerebellar areas in controls and that this connectivity was significantly higher in MCS+ as compared to MCS− patients (Table 4; Fig. 4).
Table 4

Peak voxels of functional connectivity assessment with Broca’s area (peak voxel identified in MCS+ > MCS− comparison) identifying areas with higher connectivity in MCS+ as compared to MCS− patients

Brain region (area)

Side

x (mm)

y (mm)

z (mm)

z-value

Corrected p-value

Posterior cingulate (30)

L

−14

−46

6

3.37

0.029

Middle frontal gyrus (10)

L

−42

52

6

4.46

0.003

Mesiofrontal (10)

R

8

64

0

4.77

0.001

Superior frontal gyrus (10)

R

30

54

16

3.49

0.023

Inferior frontal gyrus (44)

R

64

14

16

3.09

0.048

Middle temporal gyrus (22)

L

−60

−40

6

3.56

0.020

Cerebellum

L

−52

−54

−46

4.15

0.005

Fig. 4

Functional disconnections with Broca’s area in MCS− as compared to MCS+ showing the language network, mesiofrontal and cerebellar areas (thresholded at false discovery rate corrected p < 0.05; transparency denotes uncorrected p < 0.05)

Discussion

Metabolic impairment in a bilateral subcortical (thalamus and caudate) and cortical (fronto-temporo-parietal) network in nontraumatic and traumatic MCS patients, comparable but less widespread than previously shown in the vegetative state [3], was shown with this research. These results are in line and extend a previous FDG-PET study in 13 MCS patients of traumatic origin [8]. We observed no differences in residual brain function depending on etiology of MCS. In the vegetative state, a progressive loss of cortical metabolic function was reported as a function of the duration of the condition. The absence of such decreased brain metabolism with time in our MCS cohort might illustrate the absence of progressive Wallerian and transsynaptic degeneration characterizing the chronic vegetative state [9]. In contrast, an increase in metabolism seemed present in some areas such as the precuneus in our subacute and chronic MCS patients. This can be interpreted as a sign of residual cortical plasticity in areas previously identified by means of diffusion tensor MRI techniques in exceptional cases of recovery from longstanding MCS [10].

We found a positive linear correlation between metabolism in frontoparietal cortices and the CRS-R total scores, in line with our previous study showing a correlation between this behavioral score and spontaneous “default network” brain activity as measured by functional MRI in “resting state” conditions [11]. The identified polymodal frontoparietal network is considered critical for the emergence of conscious awareness [12]. These results corroborate previous findings on pain [13, 14], auditory [15, 16], and emotional [17, 18] processing showing that MCS patients demonstrate a more elaborated and integrated level of noxious, auditory, and emotional processing than vegetative state patients who only showed activation of primary “lower level” sensory cortices which are disconnected from “higher order” associative cortical networks [5, 14].

Clinically, the MCS entity regroups patients with different degrees of cognitive dysfunction or disability. We here propose to subcategorize MCS in patients showing only minimal levels of nonreflex behavioral responses (coined MCS−) and patients showing higher levels of behavioral interactions such as command following (MCS+). Our FDG-PET results showed a different functional neuroanatomy for both groups. MCS− seems characterized by a partially preserved functioning brainstem and right hemisphere with impaired left cortical networks encompassing Broca’s and Wernicke’s regions, posterior parietal, presupplementary motor, sensorimotor and premotor cortices. Phylogenetically, the midbrain is capable of driving the eyes to track objects [19, 20], and the human phenomenon of blindsight in the absence of occipital lobe function suggests that tracking could be coordinated in the optic tectum [21]. Command following requires a series of cognitive and motor skills, including language comprehension, memory, volition, and motor execution, each depending on the functional integrity of multiple neuronal networks. Given that the vast majority of the patients sample had nonlateralizing injury etiologies, our observation that the syndrome lateralizes points to the critical role of the dominant hemisphere and language functions. These results are in line with a recent fMRI study in disorders of consciousness and locked-in patients suggesting that activity of the language network may serve as an indicator of high-level cognition and possibly volitional processes that cannot be discerned through conventional behavioral assessment alone [22]. Understanding spoken language requires a complex series of processing stages to translate speech sounds into meaning encompassing left-lateralized frontal and temporal cortical regions [23, 24, 25] shown to be dysfunctional in MCS−. Moreover, our functional connectivity analysis identified corticocortical disconnections within these networks and with speech motor production networks also involving the cerebellum [26, 27]. This functional connectivity analysis was also performed on patients without left focal lesions and showed the same results. Previous work suggested that complementary analyses should be used in studies comprising of traumatic patients. Some of these patients may exhibit extreme focal lesions and, as a result, any statistical inference could be driven by such outliers [28]. Previous studies have located various subprocesses of verbal working memory in structures of the left inferior frontal gyrus [29]. The capacity for voluntary action is thought to depend on the functional integrity of presupplementary motor area, anterior prefrontal, and parietal cortices [30]. Finally, limb praxis control and motor sequencing are considered to depend mainly upon left frontoparietal circuits [31]. All the aforementioned areas were observed to be highly dysfunctional in MCS− but showed near-normal metabolism in MCS+ patients characterized by the clinical demonstration of reproducible but inconsistent command following.

Our findings on MCS− suggest that the metabolically functionally preserved but isolated right hemisphere function might permit these patients to show nonreflex behaviors such as visual pursuit, localization to pain, “automatic” movements such as scratching or affective behaviors contingent upon emotionally relevant stimuli [32], while remaining unable to show command following as an unambiguous clinical proof of consciousness [31, 33]. Split-brain research has previously identified different cognitive processing styles for each cerebral hemisphere [34]. The right hemisphere appears to process what it perceives and no more, while the left hemisphere is considered to make elaborations above the level of minimal sensory consciousness [35]. It should be noted that MCS− patients also showed more frequently left-sided damage on structural MRI scans (5 out of 10 patients), while MCS+ patients had most frequently right hemispheric lesions (3 out of 10 patients). Structural and metabolic functions are obviously linked. These findings can also be seen in light of Damasio’s [36] prelinguistic core consciousness seemingly present in both MCS− and MCS+ patients. Core consciousness corresponds to the transient process that is incessantly generated relative to any external stimulation without requiring language. Similarly, Edelman has differentiated “primary” from “higher order” consciousness, the latter considered to require language for its most developed expression [37]. Damasio’s extended consciousness is a more complex process depending on an autobiographical self and is enhanced by language, possibly partially preserved in MCS+. However, both MCS− and MCS+ patients showed a functional impairment in midline cortices (mesiofrontal and precuneus) considered critical for the emergence of self consciousness [38]. Our limited understanding of the dynamical neural complexity underlying consciousness and its resistance to quantification in the absence of communication [39] makes it difficult to establish strong claims about the self-consciousness in MCS patients. In our view, even MCS patients lacking clinical proof of consciousness in terms of command following (here coined MCS−) show a functional neuroanatomy reflecting the presence of preserved sensory, core, or primary consciousness. An alternative explanation might be that MCS− patients have a comparable level of consciousness as MCS+ patients but that they fail to understand verbal or written commands due to a selective impairment of language function [40]. This may also explain why some MCS patients fail to show activations during fMRI active paradigms [22, 41]. As discussed elsewhere since language function may impact CRS-R scores, detecting impaired language networks may represent an important factor to consider for the clinical evaluation of patients with disorders of consciousness. This result emphasizes the importance of language independent assessment [42].

Notes

Acknowledgments

The funding sources had no role in the study design, data collection, data analysis, data interpretation, or writing of this report. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication. This research was funded by the Belgian National Funds for Scientific Research (FNRS), the European Commission (Mindbridge, DISCOS, Marie-Curie Actions, DECODER & COST), the James McDonnell Foundation, the Mind Science Foundation, the French Speaking Community Concerted Research Action (ARC-06/11-340), the Fondation Médicale Reine Elisabeth, and the University of Liège. SL and MAB participated in the conception and design of this study. MAB, AV, CS, OG, PB, and MK acquired the data. SL, MAB, and MB analyzed and interpreted the data. MAB and SL drafted the manuscript. AV, CS, AD, OG, MS, GM, and RH revised the manuscript for intellectual content. SL and GM obtained funding. RH and GM provided administrative, technical, or material support, and SL supervised the study.

Conflict of interest

The authors declare that they have no competing interests.

References

  1. 1.
    Giacino JT, Ashwal S, Childs N et al (2002) The minimally conscious state: definition and diagnostic criteria. Neurology 58:349–353PubMedCrossRefGoogle Scholar
  2. 2.
    Bruno MA, Vanhaudenhuyse A, Thibaut A et al (2011) From unresponsive wakefulness to minimally conscious PLUS and functional locked-in syndromes: recent advances in our understanding of disorders of consciousness. J NeurolGoogle Scholar
  3. 3.
    Laureys S, Goldman S, Phillips C et al (1999) Impaired effective cortical connectivity in vegetative state: preliminary investigation using PET. Neuroimage 9:377–382PubMedCrossRefGoogle Scholar
  4. 4.
    Giacino JT, Kalmar K, Whyte J (2004) The JFK Coma Recovery Scale-Revised: measurement characteristics and diagnostic utility. Arch Phys Med Rehabil 85:2020–2029PubMedCrossRefGoogle Scholar
  5. 5.
    Laureys S, Faymonville ME, Degueldre C et al (2000) Auditory processing in the vegetative state. Brain 123:1589–1601PubMedCrossRefGoogle Scholar
  6. 6.
    Friston KJ, Penny WD, Glaser DE (2005) Conjunction revisited. Neuroimage 25:661–667PubMedCrossRefGoogle Scholar
  7. 7.
    Genovese CR, Lazar NA, Nichols T (2002) Thresholding of statistical maps in functional neuroimaging using the false discovery rate. Neuroimage 15:870–878PubMedCrossRefGoogle Scholar
  8. 8.
    Nakayama N, Okumura A, Shinoda J et al (2006) Relationship between regional cerebral metabolism and consciousness disturbance in traumatic diffuse brain injury without large focal lesions: an FDG-PET study with statistical parametric mapping analysis. J Neurol Neurosurg Psychiatr 77:856–862PubMedCrossRefGoogle Scholar
  9. 9.
    Rudolf J, Ghaemi M, Ghaemi M et al (1999) Cerebral glucose metabolism in acute and persistent vegetative state. J Neurosurg Anesthesiol 11:17–24PubMedCrossRefGoogle Scholar
  10. 10.
    Voss HU, Uluc AM, Dyke JP et al (2006) Possible axonal regrowth in late recovery from the minimally conscious state. J Clin Invest 116:2005–2011PubMedCrossRefGoogle Scholar
  11. 11.
    Vanhaudenhuyse A, Noirhomme Q, Tshibanda LJ et al (2010) Default network connectivity reflects the level of consciousness in non-communicative brain-damaged patients. Brain 133:161–171PubMedCrossRefGoogle Scholar
  12. 12.
    Laureys S (2005) The neural correlate of (un)awareness: lessons from the vegetative state. Trends Cogn Sci 9:556–559PubMedCrossRefGoogle Scholar
  13. 13.
    Boly M, Faymonville ME, Schnakers C et al (2008) Perception of pain in the minimally conscious state with PET activation: an observational study. Lancet Neurol 7:1013–1020PubMedCrossRefGoogle Scholar
  14. 14.
    Laureys S, Faymonville ME, Peigneux P et al (2002) Cortical processing of noxious somatosensory stimuli in the persistent vegetative state. Neuroimage 17:732–741PubMedCrossRefGoogle Scholar
  15. 15.
    Boly M, Faymonville ME, Peigneux P et al (2004) Auditory processing in severely brain injured patients: differences between the minimally conscious state and the persistent vegetative state. Arch Neurol 61:233–238PubMedCrossRefGoogle Scholar
  16. 16.
    Coleman MR, Rodd JM, Davis MH et al (2007) Do vegetative patients retain aspects of language comprehension? Evidence from fMRI. Brain 130:2494–2507PubMedCrossRefGoogle Scholar
  17. 17.
    Laureys S, Perrin F, Faymonville ME et al (2004) Cerebral processing in the minimally conscious state. Neurology 63:916–918PubMedCrossRefGoogle Scholar
  18. 18.
    Schiff ND, Rodriguez-Moreno D, Kamal A et al (2005) fMRI reveals large-scale network activation in minimally conscious patients. Neurology 64:514–523PubMedCrossRefGoogle Scholar
  19. 19.
    Bruno MA, Vanhaudenhuyse A, Schnakers C et al (2010) Visual fixation in the vegetative state: an observational case series PET study. BMC Neurol 10:35PubMedCrossRefGoogle Scholar
  20. 20.
    Kentridge RW, Nijboer TC, Heywood CA (2008) Attended but unseen: visual attention is not sufficient for visual awareness. Neuropsychologia 46:864–869PubMedCrossRefGoogle Scholar
  21. 21.
    Tamietto M, Cauda F, Corazzini LL et al (2009) Collicular vision guides nonconscious behavior. J Cogn Neurosci 22:888–902CrossRefGoogle Scholar
  22. 22.
    Moreno DR, Schiff ND, Giacino J et al (2010) A network approach to assessing cognition in disorders of consciousness. Neurology 75:1871–1878CrossRefGoogle Scholar
  23. 23.
    Longoni F, Grande M, Hendrich V et al (2005) An fMRI study on conceptual, grammatical, and morpho-phonological processing. Brain Cogn 57:131–134PubMedCrossRefGoogle Scholar
  24. 24.
    Vigneau M, Beaucousin V, Herve PY et al (2006) Meta-analyzing left hemisphere language areas: phonology, semantics, and sentence processing. Neuroimage 30:1414–1432PubMedCrossRefGoogle Scholar
  25. 25.
    Davis MH, Johnsrude IS (2003) Hierarchical processing in spoken language comprehension. J Neurosci 23:3423–3431PubMedGoogle Scholar
  26. 26.
    Hickok G, Poeppel D (2007) The cortical organization of speech processing. Nat Rev Neurosci 8:393–402PubMedCrossRefGoogle Scholar
  27. 27.
    Riecker A, Mathiak K, Wildgruber D et al (2005) fMRI reveals two distinct cerebral networks subserving speech motor control. Neurology 64:700–706PubMedCrossRefGoogle Scholar
  28. 28.
    Zhang J, Mitsis EM, Chu K, Newmark RE et al (2010) Statistical parametric mapping and cluster counting analysis of [18F] FDG-PET imaging in traumatic brain injury. J Neurotrauma 27(1):35–49PubMedCrossRefGoogle Scholar
  29. 29.
    Gabrieli JD, Poldrack RA, Desmond JE (1998) The role of left prefrontal cortex in language and memory. Proc Natl Acad Sci USA. 95:906–913PubMedCrossRefGoogle Scholar
  30. 30.
    Haggard P (2008) Human volition: towards a neuroscience of will. Nat Rev Neurosci 9:934–946PubMedCrossRefGoogle Scholar
  31. 31.
    Haaland KY, Elsinger CL, Mayer AR et al (2004) Motor sequence complexity and performing hand produce differential patterns of hemispheric lateralization. J Cogn Neurosci 16:621–636PubMedCrossRefGoogle Scholar
  32. 32.
    Gainotti G (2001) Disorders of emotional behaviour. J Neurol 248:743–749PubMedCrossRefGoogle Scholar
  33. 33.
    Rushworth MF, Johansen-Berg H, Gobel SM et al (2003) The left parietal and premotor cortices: motor attention and selection. Neuroimage 20(Suppl 1):S89–S100PubMedCrossRefGoogle Scholar
  34. 34.
    Gazzaniga MS (2000) Cerebral specialization and interhemispheric communication: does the corpus callosum enable the human condition? Brain 123(Pt 7):1293–1326PubMedCrossRefGoogle Scholar
  35. 35.
    Turk DJ, Heatherton TF, Macrae CN et al (2003) Out of contact, out of mind: the distributed nature of the self. Ann NY Acad Sci 1001:65–78PubMedCrossRefGoogle Scholar
  36. 36.
    Damasio AR (1998) Investigating the biology of consciousness. Philos Trans R Soc Lond B Biol Sci 353:1879–1882PubMedCrossRefGoogle Scholar
  37. 37.
    Edelman GM (2004) Wider than the sky: The phenomenal gift of consciousness. Yale University Press, New Haven and LondonGoogle Scholar
  38. 38.
    Laureys S, Perrin F, Bredart S (2007) Self-consciousness in non-communicative patients. Conscious Cogn 16:722–741 (discussion 742–745)PubMedCrossRefGoogle Scholar
  39. 39.
    Seth AK, Dienes Z, Cleeremans A et al (2008) Measuring consciousness: relating behavioural and neurophysiological approaches. Trends Cogn Sci 12:314–321PubMedCrossRefGoogle Scholar
  40. 40.
    Majerus S, Bruno MA, Schnakers C et al (2009) The problem of aphasia in the assessment of consciousness in brain-damaged patients. Prog Brain Res 177:49–61PubMedCrossRefGoogle Scholar
  41. 41.
    Monti MM, Vanhaudenhuyse A, Coleman MR et al (2010) Willful modulation of brain activity in disorders of consciousness. N. Engl J Med 362(7):579–589PubMedCrossRefGoogle Scholar
  42. 42.
    Boly M, Garrido MA, Gosseries O et al (2011) Preserved feedforward but impaired top-down processes in the vegetative state. Science 332:858–862PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Marie-Aurélie Bruno
    • 1
    • 5
  • Steve Majerus
    • 3
    • 5
  • Mélanie Boly
    • 1
    • 2
    • 5
  • Audrey Vanhaudenhuyse
    • 1
    • 5
  • Caroline Schnakers
    • 1
    • 5
  • Olivia Gosseries
    • 1
    • 5
  • Pierre Boveroux
    • 1
  • Murielle Kirsch
    • 1
  • Athena Demertzi
    • 1
  • Claire Bernard
    • 4
  • Roland Hustinx
    • 4
  • Gustave Moonen
    • 1
    • 2
  • Steven Laureys
    • 1
    • 2
    • 5
  1. 1.Coma Science Group, Cyclotron Research CenterUniversity of LiègeLiègeBelgium
  2. 2.Department of NeurologyUniversity Hospital of LiègeLiègeBelgium
  3. 3.Research Center for Cognitive and Behavioral NeuroscienceUniversity of LiègeLiègeBelgium
  4. 4.Department of Nuclear MedicineUniversity Hospital of LiègeLiègeBelgium
  5. 5.Fund for Scientific Research FNRSBrusselsBelgium

Personalised recommendations