What awareness in coma?What awareness in coma?
Faculty of health medicine and life sciencesFaculty of health medicine and life sciencesMaastricht University
March 15 2010, Maastricht, The Netherlands
Athena Demertzi MScAthena Demertzi, MScNeuropsychologist, PhD candidate medical sciences
Coma Science GroupCentre de Recherches du Cyclotron &CHU N l D t t Liè U i it H it lCHU Neurology Department, Liège University HospitalBELGIUM
www.comascience.org
Overview
DefinitionsDefinitionsScientific perspective
Neural correlate of consciousness
Clinical interestDiagnosis, prognosis, treatment
Ethical issuesEthical issuesEnd-of-lifeQuality of life
Conclusions‘Le scaphandre et le papillon’ (2007)Direction: Julian Schnabel
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Definitions
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Reducing consciousness to 2DDefinitions | Scientific perspective | Clinical interest| Ethical issues | Conclusions
g
g
Conscious
nd
fo
llo
win
g
Locked-in syndrome
Conscious Wakefulness
Drowsiness
LucidDreaming
s=
co
mm
an
St I-II Sleep
REM Sleep
Aw
aren
ess
General
Minimally Conscious State- more than reflex movements
- no communicationSt III-IV Sleep
Coma
General Anesthesia
Vegetative state
www.comascience.orgLaureys, Trends in Cognitive Sciences 2005
= eyes opening
disorders of consciousness | behavioural evaluation | electrophysiology | neuroimaging | methods, ethics & quality of life | perspectives
Locked-in syndrome (LIS)Definitions | Scientific perspective | Clinical perspective| Ethical issues | Conclusions
y ( )
Presence of sustained eye opening
Aphonia or severe hypophonia
Ocular mode of communication
Quadriplegia or quadriparesis-Types:
Cl i l Classical
Incomplete
TotalTotal
Preserved cognitive abilities
www.comascience.orgAmercian Congress of Rehabilitation Medicine 1995Laureys et al, Prog in Brain Resc 2005Bauer et al, J Neurol 1979
QuestionnaireDefinitions | Scientific perspective | Clinical interest| Ethical issues | Conclusions
Q
Age categoryg g y Gender Nationality (NL, BE..) P f i Oth ( ) Profession Other (...)
Would you like to ke kept alive if you were in:Would you like to ke kept alive if you were in:1. Vegetative state (> 1year)? 2. Minimally conscious state (> 1year)? 3. Locked-in syndrome (> 1year)?
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Scientific perspectiveScientific perspective
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disorders of consciousness | behavioural evaluation | electrophysiology | neuroimaging | methods, ethics & quality of life | perspectives
Consciousness ≠ whole brainDefinitions | Scientific perspective | Clinical interest| Ethical issues | Conclusions
www.comascience.orgLaureys et al, Lancet Neurology 2004
disorders of consciousness | behavioural evaluation | electrophysiology | neuroimaging | methods, ethics & quality of life | perspectives
Consciousness ≈ frontoparietal Definitions | Scientific perspective | Clinical interest| Ethical issues | Conclusions
p
areas systematically dysfunctional in the areas resuming metabolism after areas systematically dysfunctional in the vegetative state
areas resuming metabolism after recovery from the vegetative state
Laureys et al, Neuroimage 1999 Laureys et al, J Neurol Neurosurg Psychiatry, 1999
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disorders of consciousness | behavioural evaluation | electrophysiology | neuroimaging | methods, ethics & quality of life | perspectives
Two awareness networksDefinitions | Scientific perspective | Clinical interest| Ethical issues | Conclusions
Two awareness networks
GLOBAL NEURONAL WORKSPACE
INTERNAL AWARENESSNETWORK
EXTERNAL AWARENESSNETWORK
www.comascience.orgBoly et al., Human Brain Mapping 2008
disorders of consciousness | behavioural evaluation | electrophysiology | neuroimaging | methods, ethics & quality of life | perspectives
External and internal awarenessDefinitions | Scientific perspective | Clinical interest| Ethical issues | Conclusions
NEURAL CORRELATE OF EXTERNAL (SENSORY) AWARENESS
NEURAL CORRELATE OF INTERNAL (SELF) AWARENESSEXTERNAL (SENSORY) AWARENESS
Peri-luminal laser stimulation on h d (N 24)
INTERNAL (SELF) AWARENESS
Self-referential stimulihand (N=24)
i d (433 23 J) i d(438 21 J)
Boly et al, PNAS 2007( l D h t l N t R N i 2001
Laureys et al, Consciousness & Cognition 2007( l M t l S i 2007
perceived (433±23 mJ) > unperceived(438±21 mJ)
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(also Dehaene et al, Nat Rev Neuroci 2001; Rees et al, Nat Rev Neuroci 2001)
(also Mason et al, Science, 2007; Golland et al, Neuropsychologia 2008)
disorders of consciousness | behavioural evaluation | electrophysiology | neuroimaging | methods, ethics & quality of life | perspectives
“Resting state” default brain activityDefinitions | Scientific perspective | Clinical interest| Ethical issues | Conclusions
g
Anti-correlation of internal and external awareness networks
Spontaneous brain fluctuations predict conscious perception of external stimuliexternal awareness networks conscious perception of external stimuli
fore
stim
ula
tion
Precuneus
MEDIAL NETWORK
BO
LD 3
s bef
LATERAL NETWORK
fore
stim
ula
tion
IPS DLPF
)
BO
LD 3
s bef
Switching 1/20s (0.05 Hz)
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Boly et al, Ann NY Acad Sci 2009 Boly et al, PNAS 2007
External vs internal awarenessDefinitions | Scientific perspective | Clinical interest| Ethical issues | Conclusions
Anti-correlated
Switching 0.05 Hz (range 0.01-0.1Hz)
/20 s (range 10-100 s)(range 10 100 s)
www.comascience.orgVanhaudenhuyse & Demertzi, J Cogn Neurosci in press
disorders of consciousness | behavioural evaluation | electrophysiology | neuroimaging | methods, ethics & quality of life | perspectives
“Resting state” default brain activityDefinitions | Scientific perspective | Clinical interest| Ethical issues | Conclusions
g
vity
k"al
connec
tiv
ult n
etw
ork
locked-insyndrome
Funct
iona
in "
def
a
www.comascience.orgVanhaudenhuyse et al, Brain, 2010
QuestionnaireDefinitions | Scientific perspective | Clinical interest| Ethical issues | Conclusions
Q
4A D thi k f ti l i i diff ti t 4A. Do you think functional neuroimaging can differentiate between the vegetative and minimally conscious states?
4B. If a behaviorally vegetative patient would show normal activation of functional neuroimaging would this change your diagnosis? your diagnosis?
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Clinical interest
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OutcomeDefinitions | Scientific perspective | Clinical interest| Ethical issues | Conclusions
P tPermanentMinimally Conscious
State
?
www.comascience.orgLaureys, Scientific American 2007
disorders of consciousness | behavioural evaluation | electrophysiology | neuroimaging | methods, ethics & quality of life | perspectives
Assessing consciousnessDefinitions | Scientific perspective | Clinical interest| Ethical issues | Conclusions
g
live professional reinsertion
EN
ES
S
severe di bilit
moderate disability
goodrecovery
independently
PO
NS
IVE
MCSdisability
communication
TO
R R
ES
VSawareness
MO
comaarousal
www.comascience.orgLaureys et al., Current Opinion in Neurology 2005
COGNITIVE CAPACITY
Misdiagnosis of vegetative stateDefinitions | Scientific perspective | Clinical interest| Ethical issues | Conclusions
g g
n=103 post comatose patientsn=103 post-comatose patients
45 li i l di i ‘ t ti t t ’ 45 clinical consensus diagnosis ‘vegetative state’ 18 signs of awareness (Coma Recovery Scale)
40% potential misdiagnoses
www.comascience.orgSchnakers et al., BMC Neurology 2009
Eye tracking : use a mirror!Definitions | Scientific perspective | Clinical interest| Ethical issues | Conclusions
y g
n=52
www.comascience.orgVanhaudenhuyse et al., J Neurol Neurosurg Psychiatry 2008
‘Self’ processing in MCSDefinitions | Scientific perspective | Clinical interest| Ethical issues | Conclusions
p g
www.comascience.orgLaureys et al., Neurology 2004
fMRI: predictor of outcome?Definitions | Scientific perspective | Clinical interest| Ethical issues | Conclusions
pvegetative minimally conscious
ATYPICAL ‘HIGH LEVEL’ ‘HIGH LEVEL’ CORTICAL ACTIVATION
www.comascience.orgDi et al., Neurology 2007Coleman et al., Brain 2008
disorders of consciousness | behavioural evaluation | electrophysiology | neuroimaging | methods, ethics & quality of life | perspectives
P300 to the own nameDefinitions | Scientific perspective | Clinical interest| Ethical issues | Conclusions
n=4n=5
n=5n=6
www.comascience.orgPerrin et al., Archives in Neurology 2006
disorders of consciousness | behavioural evaluation | electrophysiology | neuroimaging | methods, ethics & quality of life | perspectives
“Mindreading”Definitions | Scientific perspective | Clinical interest| Ethical issues | Conclusions
Sg
EN
NIS
TE
NA
TIO
NN
AV
IGA
www.comascience.orgBoly et al, NeuroImage 2007
N
Signs of consciousness on fMRIDefinitions | Scientific perspective | Clinical interest| Ethical issues | Conclusions
g
www.comascience.orgOwen, Coleman, Boly, Davis, Laureys & Pickard, Science 2006
≠ “automatic” brain responseDefinitions | Scientific perspective | Clinical interest| Ethical issues | Conclusions
www.comascience.orgSoddu et al, Prog Brain Res 2009
disorders of consciousness | behavioural evaluation | electrophysiology | neuroimaging | methods, ethics & quality of life | perspectives
Yes-No communication with fMRI Definitions | Scientific perspective | Clinical interest| Ethical issues | Conclusions
www.comascience.orgMonti & Vanhaudenhuyse, Coleman, Boly, Pickard, Tshibanda, Owen, LaureysNew England J Med 2010
Communication via fMRIDefinitions | Scientific perspective | Clinical interest| Ethical issues | Conclusions
www.comascience.orgSorger et al, Prog Brain Res 2009
disorders of consciousness | behavioural evaluation | electrophysiology | neuroimaging | methods, ethics & quality of life | perspectives
EEG-based Brain Computer InterfacesDefinitions | Scientific perspective | Clinical interest| Ethical issues | Conclusions
Coma or total locked in syndrome?
-15-20-25Pz (µV)
Coma or total locked-in syndrome?
21-y old woman basilar artery thrombosis - day 49
ms-200 50 300 550 800 1050 1300
-5-10
5
basilar artery thrombosis day 49
ms200 50 300 550 800 1050 13005101520
Other names PASSIVE
Count TARGET (other name)25
Count TARGET (own name)
Count TARGET (other name)
Own name PASSIVE
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Count TARGET (own name)
Schnakers et al, Neurology, 2008Schnakers et al, Neurocase, 2009
QuestionnaireDefinitions | Scientific perspective | Clinical interest| Ethical issues | Conclusions
Q Do you think that: 5A. Patients in a VS can feel pain?p
5B. Patients in a VS should receive pain medication?
6A. Patients in a MCS can feel pain? 6B. Patients in a MCS should receive pain medication?
7A. Patients in a LIS can feel pain? 7B. Patients in a LIS should receive pain medication?
Assuming surrogate informed consent, is it acceptable to do functional neuroimaging g g p g gstudies on: 8A. Pain perception in the VS? 8B. Perception of thirst and hunger in the VS?
9A Pain perception in the MCS? 9A. Pain perception in the MCS? 9B. Perception of thirst and hunger in the MCS?
Do you think invasive interventions are justified to...10A. Diagnose and study disorders of consciousness or to provide prognostic information?
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10B. Develop treatments for disorders of consciousness?
TreatmentTreatment
- symptomatic- curative
"…a (woman’s) brain is a mystery...and even more so in this state”
Talk to her - Almodovar
www.comascience.orgPedro Almodovar - Hable con ella
disorders of consciousness | behavioural evaluation | electrophysiology | neuroimaging | methods, ethics & quality of life | perspectives
Nociception and painDefinitions | Scientific perspective | Clinical interest| Ethical issues | Conclusions
p p
Nociception Coma Scale
www.comascience.org
Demertzi et al, Prog Brain Res, 2009 Schnakers et al, Pain, in press
disorders of consciousness | behavioural evaluation | electrophysiology | neuroimaging | methods, ethics & quality of life | perspectives
Do they feel pain ?Definitions | Scientific perspective | Clinical interest| Ethical issues | Conclusions
y p
Noxious electrical stimulationNoxious electrical stimulation
Low level disconnected disconnected cortical activation
www.comascience.orgLaureys et al., Neuroimage 2002Laureys, Nature Reviews Neuroscience 2006
disorders of consciousness | behavioural evaluation | electrophysiology | neuroimaging | methods, ethics & quality of life | perspectives
Pain in minimally conscious stateDefinitions | Scientific perspective | Clinical interest| Ethical issues | Conclusions
y
www.comascience.orgBoly et al., Lancet Neurology 2008
Curative treatment: Drugs? id b d h
Definitions | Scientific perspective | Clinical interest| Ethical issues | Conclusions
no evidence based therapy
www.comascience.orgDemertzi et al., Expert Rev Neurotherapeutics 2008Schnakers et al., J Neurol Neurosurg Psychiatry 2008
disorders of consciousness | behavioural evaluation | electrophysiology | neuroimaging | methods, ethics & quality of life | perspectives
Curative treatment: Deep brain stimulation?Definitions | Scientific perspective | Clinical interest| Ethical issues | Conclusions
www.comascience.orgSchiff et al., Nature 2007
QuestionnaireDefinitions | Scientific perspective | Clinical interest| Ethical issues | Conclusions
Q
Do you think it is acceptable to withhold or withdraw o you s accep a e o o d o d atreatment in patients:
11. In the vegetative state? 12 I th i i ll i t t ? 12. In the minimally conscious state? 13. In the locked-in syndrome?
Are you religious? If yes, please state your affilitation
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Ethicalchallenges
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Quality of lifeDefinitions | Scientific perspective | Clinical interest| Ethical issues | Conclusions
Short Form-36 in brainstem stroke LIS patients
Reintegration to Normal Living Indexin ALS patients
Q y
brainstem stroke LIS patients(n=17; duration 6±4 y)
in ALS patients(n=30; duration 6±5 y)
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Laureys et al., Prog Brain Res, 2005 Lulé et al., Prog Brain Res, 2009
disorders of consciousness | behavioural evaluation | electrophysiology | neuroimaging | methods, ethics & quality of life | perspectives
Quality of LifeDefinitions | Scientific perspective | Clinical interest| Ethical issues | Conclusions
Q y
Case 1
24-year-old girl
LIS for 6 years
Good social interactions
Occasionally depressed
●X
No suicidal thoughts
Never considered euthanasia
No Reanimation in case of cardiac arrest
● Control subjects n=820
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Control subjects n 820X Locked-in patients n=65
Bruno et al., in preparationBruno et al., Pediatic Neurology 2009
disorders of consciousness | behavioural evaluation | electrophysiology | neuroimaging | methods, ethics & quality of life | perspectives
Quality of LifeDefinitions | Scientific perspective | Clinical interest| Ethical issues | Conclusions
Q y
Case 2
17-year-old girl
X●LIS for 1 year
Good social interactions
Occasionally depressed
No suicidal thoughts
Never considered euthanasia
Reanimation in case of cardiac arrest
● Control subjects n=820
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Control subjects n 820X Locked-in patients n=65
Bruno et al., in preparationBruno et al., Pediatic Neurology 2009
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ConclusionsConclusions
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Translational research Definitions | Scientific perspective | Clinical interest| Ethical issues | Conclusions
INTERNAL AWARENESSNeural correlates of conscious awareness
EXTERNALAWARENESS
AWARENESSNeural correlates of conscious awareness≈ fronto-parietal neuronal ‘global workspace’≈ cortico-thalamo-cortical functional connectivity
AWARENESSDiagnostic use ≈ 40% signs of consciousness in vegetative state
Prognostic usePrognostic use(f)MRI prospective multicenter studies
Therapeutic uset & i t t t / ti th l i DBSsymptom & pain treatment / curative thalamic DBS
Ethical issues
www.comascience.orgTononi & Laureys, The Neurology of Consciousness 2009Laureys & Boly, Nature Clinical Practice 2008Owen, Schiff & Laureys, Prog Brain Res 2009
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THANK YOUSlides can be downloaded from www.comascience.org
PhD candidates:Audrey Vanhaudenhuyse ARCMarie Aurélie Bruno FNRS
Collaborations:NY J Giacino, N Schiff, J Fins Cambridge A OwenMarie-Aurélie Bruno FNRS
Athena Demertzi, Marie-Curie Olivia Gosseries FNRSCamille Chatelle FNRSMarie Thonnard non-FRIAVictor Cologan FRIA
Cambridge A OwenMilano M MassiminiWisconsin G TononiTubingen & Wurzburg A KüblerParis L Puybasset Hangzou China H DiVictor Cologan FRIA
Jean-Floris Tshibanda MDPierre Boveroux MD CHUMuriel Kirsch MDAudrey Maudoux MD FNRSIsabelle Lutte MD ULB
Hangzou China H DiSalzburg M SchabusLyon F Perrin
PhDs:Melanie Boly MDDidier Ledoux MD Caroline Schnakers Quentin Noirhomme EngineeringQ g gAndrea Soddu PhysicsBetina Sorger MaastrichtDorothée Lulé Tubingen
Visiting fellows: Natalia Lapitskaia, Remy L h b J th O b
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Lehembre, Jonathan Orban, Francisco Gomez…