Spatiotemporal brain dynamics induced by propofol and ketamine in humans

Thesis

Human brain dynamics are radically altered under the influence of anaesthetics. However, despite their widespread clinical use, the whole-brain mechanisms by which anaesthetics alter consciousness are still not fully understood and clinical translation of existing insights is limited. This thesis presents several lines of investigation aimed to improve our understanding of spatiotemporal brain states under the anaesthetics propofol and ketamine.

First, slow-wave activity saturation (SWAS) was studied across the brain and in relation to existing depth of anaesthesia markers. Local propofol concentration needed to achieve SWAS in healthy volunteers correlated with GABA-A receptor density (Spearman ρ=-0.69, P=0.0018), providing more evidence for the importance of the neurophysiological state of SWAS. The average Bispectral Index at SWAS across volunteers was 49±4, but its value varied significantly over time.

Second, relevant cortico-cardiac interactions were studied. A slow propofol infusion increased heart rate in a dose-dependent manner (increase of +4.2±1.5 bpm / (μg ml-1), P<0.001). Individual cortical slow waves were coupled to the heartbeat (P<0.001), with heartbeat incidence peaking about 450ms before slow-wave onset. A ketamine case study showed decreased amplitude of heartbeat-evoked potentials, suggesting impaired interoceptive signalling may have a part in dissociative phenomenology.

Third, novel methodology was developed, validated, and applied throughout the thesis. Iterated Masking Empirical Mode Decomposition was used to identify three types of low-frequency propofol waves with different spatiotemporal maps and dose-responses. Hidden Markov Modelling of propofol showed a shift to anterior alpha states and a reduced switching rate (P<0.01); with ketamine states exhibiting low alpha power and decreased connectivity became more prominent (P<0.001).

Fourth, the potential of translating electroencephalographic markers from high- to low- density montages was studied. Posterior montages were best at capturing the reduced state switching under propofol. A patient study of antidepressant ketamine treatment demonstrated reduced temporal lobe alpha and theta power were associated with dissociation (P=0.0109).

Authors: Fabus, M

• DOI: 10.5287/ora-n1arpmab4
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: EEG; propofol; anaesthesia; ketamine
• Subjects: Anesthesia; Electroencephalography