Thalamic Control of Propofol Phase-amplitude Coupling

Austin Soplata, Boston University

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Background / Methods

Propofol Alpha and Slow Wave

From Fig 1 of Mukamel et al. (2014)
From Fig 1 of Mukamel et al. (2014)

Why do we care?

  • Better understanding of propofol mechanisms could lead to more targeted anesthetics

  • Clarify mechanistic differences between between anesthesia and sleep, including rhythms

  • Propofol coupling correlates with depth of anesthesia, as can be used in the Operating Room
    • Coupling mechanisms may tie to specific aspects of loss of consciousness

Sleep Spindles vs Propofol Alpha

From Fig 1 of Astori, Wimmer, and Lüthi (2013)
From Fig 1 of Astori, Wimmer, and Lüthi (2013)

Propofol Mechanisms of Action

  1. Increases GABAAGABA_A inhibition:
    • Increases max synaptic conductance (↑g‾GABAA\uparrow \bar g_{GABA_A} )
    • Increases decay time constant (↑τGABAA\uparrow \tau_{GABA_A} )

  2. Decreases thalamocortical (TC) cell H-current conductance (↓g‾H\downarrow \bar g_H )

  3. Decreases Excitation from brainstem (↓Iapplied\downarrow I_{applied})

Our Model Thalamus

From Fig 2 of Soplata et al. (2017)
From Fig 2 of Soplata et al. (2017)

Overview

Overview

  1. Increase of GABAAGABA_A and decrease of TC cell H-current are required for thalamic Alpha oscillations

  2. Thalamic Alpha oscillations are sustained spindles

  3. Interaction between thalamic Alpha and Slow Wave Activity can produce propofol phase-amplitude coupling regimes

GABAAGABA_A and H-current changes are required for thalamic Alpha oscillations

Native hyperpolarized thalamus cannot produce Alpha oscillations

From Fig 3 of Soplata et al. (2017)
From Fig 3 of Soplata et al. (2017)

Simulating GABAAGABA_A increase enables thalamic Alpha oscillations

From Fig 2 of Soplata et al. (2017)
From Fig 2 of Soplata et al. (2017)

Alpha requires H-current decrease

From Fig 4 of Soplata et al. (2017)
From Fig 4 of Soplata et al. (2017)

Summary So Far

  • Sustained Alpha does not occur normally

  • GABAAGABA_A increase is a necessary factor for sustained Alpha

  • TC cell H-current decrease is also a necessary factor for sustained Alpha

Overview So Far

  1. Increase of GABAAGABA_A and decrease of TC cell H-current are required for thalamic Alpha oscillations

  2. Thalamic Alpha oscillations are sustained spindles

  3. Interaction between thalamic Alpha and Slow Wave Activity can produce propofol phase-amplitude coupling regimes

Thalamic Alpha oscillations are sustained spindles

Sustained alpha emerges from Baseline spindles

From Fig 5 of Soplata et al. (2017)
From Fig 5 of Soplata et al. (2017)

Summary So Far

  • Propofol thalamic alpha takes advantage of thalamic spindle dynamics (e.g. TwindowT_{window})

  • Enhanced inhibition enables more spiking/oscillating due to T-current and H-current interplay

Overview So Far

  1. Increase of GABAAGABA_A and decrease of TC cell H-current are required for thalamic Alpha oscillations

  2. Thalamic Alpha oscillations are sustained spindles

  3. Interaction between thalamic Alpha and Slow Wave Activity can produce propofol phase-amplitude coupling regimes

Alpha-SWO Coupling

Slow Wave Oscillations

From Fig 1 of Crunelli and Hughes (2010)
From Fig 1 of Crunelli and Hughes (2010)

Phase-amplitude Coupling Switches

From Fig 1 of Mukamel et al. (2014)
From Fig 1 of Mukamel et al. (2014)

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