Granger Causality Analysis of Steady-State Electroencephalographic Signals during Propofol-Induced Anaesthesia

Changes in conscious level have been associated with changes in dynamical integration and segregation among distributed brain regions. Recent theoretical developments emphasize changes in directed functional (i.e., causal) connectivity as reflected in quantities such as ‘integrated information’ and ‘causal density’. Here we develop and illustrate a rigorous methodology for assessing causal connectivity from electroencephalographic (EEG) signals using Granger causality (GC). Our method addresses the challenges of non-stationarity and bias by dividing data into short segments and applying permutation analysis. We apply the method to EEG data obtained from subjects undergoing propofol-induced anaesthesia, with signals source-localized to the anterior and posterior cingulate cortices. We found significant increases in bidirectional GC in most subjects during loss-of-consciousness, especially in the beta and gamma frequency ranges. Corroborating a previous analysis we also found increases in synchrony in these ranges; importantly, the Granger causality analysis showed higher inter-subject consistency than the synchrony analysis. Finally, we validate our method using simulated data generated from a model for which GC values can be analytically derived. In summary, our findings advance the methodology of Granger causality analysis of EEG data and carry implications for integrated information and causal density theories of consciousness

Lack of effect of ketamine on cortical glutamate and glutamine in healthy volunteers: a proton magnetic resonance spectroscopy study

Ketamine is a N-methyl-D-aspartic acid (NMDA) antagonist that has been associated with temporary clinical improvement in patients with depression. Studies using magnetic resonance spectroscopy (MRS) have shown that major depression is associated with decreased levels of glutamate and glutamine (Glx) in the anterior cingulate cortex, which normalize with clinical recovery. The present study aimed to test whether a ketamine infusion would increase cortical Glx levels in healthy volunteers. Healthy volunteers received an intravenous infusion of ketamine (0.5 mg kg⁻¹, n = 8) or saline (n = 9) over 40 minutes. MRS measurements were obtained at baseline, during, and at the end of the infusion. The infusion of ketamine had significant effects on mental state but there was no effect of ketamine on the levels of Glx (F (3,39) = 1.70, p = 0.18) or glutamate (F (3,39) = 48, p = 0.70). This study suggests that the gradual infusion of low-dose ketamine in antidepressant doses not cause changes in cortical glutamate or glutamine in healthy volunteers that are visible by proton MRS

Cortical and subcortical connectivity changes during decreasing levels of consciousness in humans: a functional magnetic resonance imaging study using propofol.

While ubiquitous, pharmacological manipulation of consciousness remains poorly defined and incompletely understood (Prys-Roberts, 1987). This retards anesthetic drug development, confounds interpretation of animal studies conducted under anesthesia, and limits the sensitivity of clinical monitors of cerebral function to intact perception. Animal and human studies propose a functional "switch" at the level of the thalamus, with inhibition of thalamo-cortical transmission characterizing loss of consciousness (Alkire et al., 2000; Mashour, 2006). We investigated the effects of propofol, widely used for anesthesia and sedation, on spontaneous and evoked cerebral activity using functional magnetic resonance imaging (fMRI). A series of auditory and noxious stimuli was presented to eight healthy volunteers at three behavioral states: awake, "sedated" and "unresponsive." Performance in a verbal task and the absence of a response to verbal stimulation, rather than propofol concentrations, were used to define these states clinically. Analysis of stimulus-related blood oxygenation level-dependent signal changes identified reductions in cortical and subcortical responses to auditory and noxious stimuli in sedated and unresponsive states. A specific reduction in activity within the putamen was noted and further investigated with functional connectivity analysis. Progressive failure to perceive or respond to auditory or noxious stimuli was associated with a reduction in the functional connectivity between the putamen and other brain regions, while thalamo-cortical connectivity was relatively preserved. This result has not been previously described and suggests that disruption of subcortical thalamo-regulatory systems may occur before, or even precipitate, failure of thalamo-cortical transmission with the induction of unconsciousness

Intravenous Hypnotic Agents: From Binding Sites to Loss of Consciousness

All the intravenous hypnotic drugs important for clinical anesthesiology reversibly unsettle functional brain networks, in order to undermine the information transfer on which consciousness depends. Three classes of intravenous hypnotic drugs are the most used nowadays: the carboxylated imidazole derivate propofol, the short-acting benzodiazepine midazolam, and the barbiturates, which show action on GABAA Receptors, potentiating gamma-aminobutyric acid (GABA) action. The dissociative agent ketamine, instead, mainly exerts its effects by reversibly blocking the activity of N-methyl-D-aspartate receptors while the most recent dexmedetomidine is an alpha-2 adrenergic receptor agonist. Nevertheless, other receptors are also involved in anesthesia determining, that is voltage-gated and ligand-gated ion channels and it is probable that each intravenous hypnotic agent alters neuronal activity acting at different levels and at multiple sites in a way not yet entirely clear