Altered states of consciousness

Laszlo Vutskits MD, PhDDepartment of Anesthesiology, Pharmacology and Intensive Care, University Hospital of GenevaDepartment of Neuroscience, University of Geneva Medical School

objective: give some functional and mechanistic insights into biological processes and substrates underlying consciousness

plandefinition(s) of consciousnessstudying consciousness through altered states of consciousness

sleepgeneral anesthesiacoma, vegetative and minimal mental statesepilepsy

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Definitions of Consciousness

“the perception of what passes in a man’s own mind”(Locke 1690)

“anything that we are aware of at a given moment forms part of our consciousness, making conscious experience at once the most familiar and most mysterious aspect of our lives” (Welmans & Schneider 2008)

“quality or state of being aware of an external subject or something within oneself”

(Merriam-Webster 2012)

“consciousness is synonymous with experience - any experience - of shapes, sounds, thoughts or emotions about the world or about the self”

(Tononi 2012)

How to study consciousness in neuroscience?

explore changes in the level of consciousnessconsider conditions in which consciousness is globally diminished, and ask what has changed in the brain

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investigate changes in the content of consciousness☞examine how and where brain activity changes when, everything else is being as equal as possible, a stimulus is experienced or not

develop theoretical framework☞clarify what consciousness is; how it can be generated in a physical system; how it can be measured; test the obtained theoretical predictions against biological data

Sleep: a physiologically altered state of consciousness

453 hours in humans

Sleep: a physiologically altered state of consciousness

physiological rhythm of waking /sleeping in

humans

Cortical scalp EEG patterns during sleep

Neural circuits governing sleep

first steps ....

Functional neuroimaging of human sleep usingpositron emission tomography

brain areas with significant reduction of rCBF during slow wave NREM sleep

(compared to awake)

Functional neuroimaging of human sleep usingpositron emission tomography - REM phase

brain areas with significant increase in rCBF (compared to awake)

Neural circuits governing sleep

cholinergic nuclei

raphe nuclei(serotonin)

locus coeruleus(noradrenalin)

tuberomamillary n.(histamine)

cholinergic nuclei locus coeruleus raphe nuclei

brainstem nuclei

tuberomamillarynucleus

hypothalamus

orexin neurons

+ +

Cerebral cortex

Subcortex

Thalamus

+

+

+

ventrolateral preopticnucleus

-

-

circadian oscillator(suprachiasmatic n.)

integration of homeostatic and circadian inputs

retina

environmental light

homeostasis

Summary of the cellular mechanisms that govern sleep and wakefulness

Brainstem/hypoth nuclei responsible

Neurotransmitter involved

Activity state of neurons

Wakefulnesscholinergic nuclei

locus coeruleus

raphe nuclei

tuberomamillary nucleus

Acetylcholine

activeNorepinephrine

Serotonin

Histamine / Orexin

active

active

active

Non-REM sleep

cholinergic nuclei

locus coeruleus

raphe nuclei

tuberomamillary nucleus

Acetylcholine

decreasedNorepinephrine

Serotonin

Histamine / Orexin

decreased

decreased

decreased

REM sleepAcetylcholine

decreased

activecholinergic nuclei

others

General anesthesia

Is this pharmacologically-induced physiological sleep?

EEG patterns in sleep vs general anesthesia

Characteristic differences between anesthesia and sleep

Anesthesia Sleep

Ons

etM

aint

enan

ceOff

set

Drug-inducedNo homeostatic controlFailure to initiate is non-existentNot altered by environmental factors

Endogenously generatedHomeostatic and circadian regulationFailure to initiate is a recognized pathologySignificantly modulated by environmental factors

Duration dependent on doseDepth at a given anesthetic dose is constantFailure to maintain is non-existentAltered minimally by environmental factors

Duration function of homeostatic and circadian factorsDepth fluctuates rhythmically and spontaneouslyFailure to maintain is a recognized pathologySignificantly altered by environmental factors

Returns to normal wakefulness in hours to daysDuration of anesthesia and elimination of agent governs timing of wakefulness

Return to normal wakefulness within minutesTiming of wakefulness governed by environment, sleep duration, and circadian rhythm

some definitions related to general anesthesia ...

Amnesiapartial or complete loss of memory

Sedationdecreased level of arousal

Hypnosisimpairment of neural functions that are required to respond to verbal commands

Immobilitylack of movements in response to noxious stimuli

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Neuroanatomical substrates for anesthetics

5 right-handed volunteers

propofol infusion titrated to (i) mild sedation, (ii) deep sedation; (iii) no response to verbal commands (defined as unconsciousness...)evaluate global and regional cerebral blood flow using PET

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Neuroanatomical substrates for anesthetics

Alkire & Miller 2005

20 right-handed volunteers☞dexmedetomidine infusion titrated to loss of response to verbal commands (LOC)and then tactile stimuli for return of consciousness (ROC) at the same drug concentration

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imaging ROC with propofol☞

dexmedetomidine propofol

Unconsciousness is associated with a loss of information (integration) capacity

breakdown of efficient cortical connectivity

control isoflurane (1.1%)

flash light at 0.2 Hz flash light at 0.2 Hz

Alkire et al. 2008

Loss of consciousness is associated with the breakdown of efficient cortical connectivity

Alkire et al. 2008

Neuroanatomical substrates for anesthesia

Molecular mechanisms of actions of anesthesia

first hypothesis: Meyer-Overton rule

Nicotinic receptor superfamilyNicotinic receptor superfamilyNicotinic receptor superfamilyNicotinic receptor superfamily Ionotropic glutamate receptors

Ionotropic glutamate receptors

Ionotropic glutamate receptors

GABAA Glycine nACh 5-HT3 AMPA kainate NMDA

Etomidate ++ + - 0 ND ND ND

Propofol ++ + - - - 0 -Barbiturates ++ + -- -- -- -- -Ketamine + 0 -- -- 0 0 --Isoflurane ++ ++ -- -- -- ++ -Sevoflurane ++ ++ -- -- ND ND ND

Nitrous oxide + + -- -- - -- --

Effects of currently used anesthetics on ligand-gated ion channels

++: significant potentiation; +: weak potentiation; --: significant inhibition; -: weak inhibition; 0: no effect; ND: remains to be determined.

Functional switch in GABAergic neurotransmission during development

Na+, K+

Cl-

NKCC1

Cl-GABAAR

GLU-R

Cl-

Na+

excitation

Na+, K+

Cl-

NKCC1

K+

Cl-

KCC2

GABAAR Cl-

Cl-

hyperpolarization

GLU-R

How to study efficacy of anesthesia in laboratory animals?

tail clamp test (classic for MAC determination)

locomotor activity (i.e. sedation)

righting reflex / sedation score (hypnotic activity)

hindlimb withdrawal reflex (immobilizing action)

How to study receptors and receptor subtypes mediating anesthesia effects?

receptor knock-out mice

knock-in transgenic approach (point mutations)

Diego Pandolfo

Adenosine receptors

How to ascertain that our patient sleeps during anesthesia?

EEG

BIS (and related qEEG)

physiological signs (BP, HR, RR)

isolated arm test (“Gold Standard”)

Arthur Guedel M.D.

EEG monitoring and anesthesia (I)

scalp EEG: voltage detected on the scalp

measure mean dendritic currents (post-synaptic potential) of hundreds to millions of cortical neurons that underlie the active electrode

EEG monitoring and anesthesia (II)

Bispectral index (BIS) monitoring

Memory formation during anesthesia

Explicit: awareness

Implicit: unconscious (but detectable/testable)Memory for mock crisis - Levinson 1965

Explicit memory formation during anesthesia (II)

Incidence (prospective studies are the only valid methodology

Overall: 1960-70: > 1.2% 1990-2000: 0.1-0.2%

Cardiac surgery: 0.5-23% (type of anesthesia, commorbidities)

Obstetrical surgery: 1960-70: > 1.2% 1990-2000: 0.4%

Explicit memory formation during anesthesia (I)

Explicit recall of events during general anesthesia is detected by direct (non-suggestive) questioning:

What was the last thing you remember before you went to sleep?What was the first thing you remember when you woke up?Can you remember anything in between these periods?Did you dream during your operation?

More than one interview is needed

Credibility of reports should always be verified

Explicit memory formation during anesthesia (III)

Implicit memory formation during anesthesia (II)

Occurence: strong association with BIS>50(studies were conducted under anesthesia in the absence of surgery! )

Does implicit memory matter?

Research in psychology suggests that even this very rudimentary activity may have profound effects on behaviour and emotion

Priming does not induce novel behaviours; it enhances existing tendencies

Bispectral index (BIS) monitoring

Memory formation during anesthesia

Explicit: awareness

Implicit: unconscious (but detectable/testable)Memory for mock crisis - Levinson 1965

Explicit memory formation during anesthesia (II)

Incidence (prospective studies are the only valid methodology

Overall: 1960-70: > 1.2% 1990-2000: 0.1-0.2%

Cardiac surgery: 0.5-23% (type of anesthesia, commorbidities)

Obstetrical surgery: 1960-70: > 1.2% 1990-2000: 0.4%

Explicit memory formation during anesthesia (I)

Explicit recall of events during general anesthesia is detected by direct (non-suggestive) questioning:

What was the last thing you remember before you went to sleep?What was the first thing you remember when you woke up?Can you remember anything in between these periods?Did you dream during your operation?

More than one interview is needed

Credibility of reports should always be verified

Explicit memory formation during anesthesia (III)

Implicit memory formation during anesthesia (II)

Occurence: strong association with BIS>50(studies were conducted under anesthesia in the absence of surgery! )

Does implicit memory matter?

Research in psychology suggests that even this very rudimentary activity may have profound effects on behaviour and emotion

Priming does not induce novel behaviours; it enhances existing tendencies

Implicit memory formation during anesthesia (I)

(Memory for mock crisis - Levinson 1965 )

Methods to test:

Hypnosis

Perceptual primingdef.: perceptual priming represent temporarily increased activation of a word or idea in memorymethod: word stem completion (eg. “tractor” per-op then asscociation tra- (traffic, tractor, travail etc.......) post-op

Conceptual primingdef.: conceptual priming refers to activation of related knowledge

method: e.g. Robinson Crusoe test (“Friday”)

Dreaming during anesthesia

Incidence : 1-81%

Predictors :patient factors : women > men young > old

anesthetics : ketamine-based*

opioid-based**

propofol-based**volatiles**>

* bizarre, hallucinating** pleasant (family, work, recreation, sexual)

depth of anesthesia : light > heavy

Consequences?

Pathologically-altered states of consciousness

Pathologically-altered states of consciousness

Pathologically-altered states of consciousness

Monti et al. 2010

Anatomo-pathological correlates

diffuse damage to subcortical white matter (diffuse axonal injury) - traumatic injury

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extensive cortical necrosis - non-traumatic injury☞thalamic damage - non-traumatic & traumatic injury☞

brainstem damage - mainly in locked-in syndrome☞

One of the major challenge in pathologically-altered states of consciousness

AVOID MISDIAGNOSIS

vegetative state vs minimally conscious state vs locked-in syndrome

Difficulties in diagnosis- based nearly entirely on clinical assessment- needs lots of experience (awareness vs wakefulness)- confusion between definitions/terminology- place for functional tools?

an intriguing example ........

- 23-year-old woman - severe traumatic brain injury in road accident - remained unresponsive 5 month later with preserved sleep-wake cycles - fulfilled the criteria of vegetative state according to international guidelinesunderwent fMRI imaging when asked to imagine to play tennis

- 54 patients with diagnosis of vegetative state

- fMRI to assess each patient’s ability to generate willful, neuroanatomically specific, blood-oxygenation-level-dependent responses during two established mental-imagery tasks- 5 patients were able to willfully modulate their brain activity

in 3 pts, additional bedside tests revealed some signs of awareness in 2 pts, further clinical assessment did not reveal signs of awareness

- 16 patients with diagnosis of vegetative state vs 12 healthy controls

- EEG task involving motor imagery

3 of 16 patients (19%) could repeatedly and reliably generate appropriate EEG responses to two distinct commands

6-month double-blind alternating crossover study

bilateral deep brain stimulation (DBS) of the central thalamus

one patient with the diagnosis of minimally conscious state for 6 years following traumatic brain injury

Schiff 2009

Conclusions

multiple underlying anatomical substrates☞

loss of efficient cerebral connectivity☞

general anesthesia as a model to study consciousness and neuronal plasticity

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pathologically-altered states of consciousness: challenges for appropriate diagnosis and potential therapy

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Readings

1. Purves, Neuroscience 4th edition, Chapter 28: Sleep and Wakefulness

2. Monti et al.,: The vegetative state. BMJ 2010, 341:c3765

3. Rudolph & Antkowiak: Molecular and neuronal substrates for general anesthetics. Nature Reviews Neuroscience 2004, 5:709