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The Aging Brain and General Anesthesia

Emery N. Brown, M.D., Ph.D.

Warren M. Zapol Professor of AnaesthesiaDepartment of Anesthesia, Critical Care and Pain Medicine

Massachusetts General HospitalHarvard Medical School

Edward Hood Taplin Professor of Medical Engineering and Computational Neuroscience

Institute for Medical Engineering and ScienceDepartment of Brain and Cognitive Sciences

Massachusetts Institute of Technology

May 13, 2015

ANESTHESIOLOGY UPDATE 2015 HARVARD UNIVERSITY

BOSTON, MA Current Funding:

NIH Director’s Transformative Research Award GM104948-01

NSF 1159652

Other Financial Relationships:

Masimo has licensed our algorithms for EEG monitoring.

Conflicts of Interest: The relationship with Masimo is described above.

Disclosures

A. A Clinical Look at General Anesthesia

B. The Dynamics of Unconsciousness from Propofol

C. Defining the Anesthetic State as a Function of Age

D. Conclusion: The Anesthetic State of the Aging Brain

Outline What is General Anesthesia?

A drug-induced, reversible state comprised of

Unconsciousness

Amnesia (loss of memory)

Analgesia (loss of pain perception)

Akinesia (loss of movement)and

Stability and Control of the cardiovascular, respiratory thermoregulatory and autonomic nervous systems.

Brown, Lydic, Schiff, NEJM (2010)

How Do Drugs Cause General Anesthesia?

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Awake

Paradoxical Excitation

Sedation

Slow-Alpha Oscillations(<1 Hz) (8-12 Hz)

Induction Slow Oscillations(<1 Hz)

Burst Suppression

Isoelectric

EEG States of Propofol-Induced Unconsciousness

Propofol-Induced Unconsciousness

Slow Oscillation

Slow and Alpha Oscillation

Loss of Consciousness from Propofol

Emad Eskandar

Eric Pierce Laura Lewis

Syd Cash

ShiNung ChingPatrick Purdon

Nancy Kopell

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Cimenser et al PNAS, 2011

GABAA Inhibition at Inhibitory Interneurons

Mechanisms for Alpha and Slow Oscillations

Brown, Purdon, Van Dort, ARN 2011

Purdon et al. PNAS 2013; Cimenser et al. PNAS, 2011; Ching et al. PNAS, 2010

Alpha: Pathological Oscillation

Microelectrodes

Grid Electrodes

Lewis  et al. PNAS, 2012

SummaryWhy Does Propofol Make You Unconscious?

Cortex and Thalamusalpha (8-12 Hz) rhythms strongly couple the thalamus and

cortex restricting communication

slow-wave (< 1 Hz) rhythms create local islands preventing communication within the cortex

anteriorization as a mechanism for frontal-parietal disconnection

Brain Stemblocking the brain stem arousal pathways prevents

communication of the lower parts of the brain with thecortex

Our Aging Patients

• More likely to experience Post‐Operative Cognitive Dysfunction (POCD)– Memory impairment, reduced cognitive performance 

(Monk, et al., Anesthesiology 2008)

• More likely to experience delirium– Delirium is associated with lasting cognitive impairment (Saczynski et al., NEJM 2012)

• Patients with Mild Cognitive Impairment (MCI) have longer wake‐up times and lower anesthetic requirements (Erdogan et al., Eur J Anaes 2012)

We need to understand the aging brain!

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The Neurobiology of AgingLoss of synapses, not loss of neurons

(Morrison & Baxter, Nat Rev Neurosci 2012)

Young Old

The Neurobiology of AgingChanges in myelination

(Peters, Neurosci Brain Behav Rev, 2002)

Cortical Thinning

(McGinnis, et al., Brain Topography, 2011)

Post‐Natal DevelopmentLast to Develop, First to Go

Typical AgingDorsolateral Prefrontal CortexLateral Parietal CortexLateral Temporal CortexHippocampus

Cortical Thinning in Aging and Dementia

Thinning in specific cortical areas predicts later conversion to Alzheimer’s disease in otherwise asymptomatic patients

(Dickerson, et al., Neurology, 2011)

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Reductions in Grey Matter and White Matter Volume

(Fjell, et al., Cereb Cortex, 2009)

Anesthesia and Aging

(Akeju, et al., in review; Purdon, et al., in review)

Declining Frontal Coherence in the Elderly (Propofol)

Declining Frontal Power in the Elderly (Propofol)

(Purdon, et al., in review) (IARS Poster S‐195, PR02‐26, 10am Sunday)

Young (18 to 38 years) vs. Old (70 to 90 Years)

(Purdon, et al., in review) (IARS Poster S‐195, PR02‐26, 10am Sunday)

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Putting it All Together

Loss of Brain VolumeCortical ThinningIncreased CSF Space

Loss of synapses

Typical Aging Neurodegeneration

Looking at the EEG the right way

Adjusting The ScaleDefault Scale Settings

1 sec

50 uV

Adjusted Scale Settings

1 sec

10 uV

Each Patient is Different

• Age is just an number!

100 100

90

80

70

60

50 0

5

10

15

150

200

250

300

3504–6 4–13 30–59 60–9019–30+12–14 16–18 24–28

Age (months) Age (years) Age (years)

Beh

avio

ural

inde

x

Rats Monkeys Humans

Box 1 | ‘Successful ageing’ and individual dif ferences

Exercise, sleep well, and eat right!

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The Anesthetic State of the Aging Brain

1. Anesthetics act in the brain to create altered arousal states by inducing oscillations that are readily visible on the EEG.

2. The nature of the EEG oscillations change with molecular target of the anesthetics and the neural circuits in which the drug are acting. Hence, every anesthetic has a different signature.

3. The unprocessed EEG and its spectrogram can be used to track brainstates of patients, particularly ele

4. The brain response to anesthesia differs with age, most likely reflecting changes in the brain due to typical aging.

5. A rationale strategy for EEG-based brain monitoring must understandand take account of these aging differences.

Summary/Conclusion