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

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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…