Propofol-induced unresponsiveness is associated with impaired feedforward connectivity in cortical hierarchy

Abstract

Background: Impaired consciousness has been associated with impaired cortical signal propagation after transcranial magnetic stimulation (TMS). We hypothesised that the reduced current propagation under propofol-induced unresponsiveness is associated with changes in both feedforward and feedback connectivity across the cortical hierarchy. Methods: Eight subjects underwent left occipital TMS coupled with high-density EEG recordings during wakefulness and propofol-induced unconsciousness. Spectral analysis was applied to responses recorded from sensors overlying six hierarchical cortical sources involved in visual processing. Dynamic causal modelling (DCM) of induced timeefrequency responses and evoked response potentials were used to investigate propofol's effects on connectivity between regions. Results: Sensor space analysis demonstrated that propofol reduced both induced and evoked power after TMS in occipital, parietal, and frontal electrodes. Bayesian model selection supported a DCM with hierarchical feedforward and feedback connections. DCM of induced EEG responses revealed that the primary effect of propofol was impaired feedforward responses in cross-frequency theta/alphaegamma coupling and within frequency theta coupling (F contrast, family-wise error corrected P<0.05). An exploratory analysis (thresholded at uncorrected P<0.001) also suggested that propofol impaired feedforward and feedback beta band coupling. Post hoc analyses showed impairments in all feedforward connections and one feedback connection from parietal to occipital cortex. DCM of the evoked response potential showed impaired feedforward connectivity between left-sided occipital and parietal cortex (T contrast P¼0.004, Bonferroni corrected).

Cortical functional connectivity indexes arousal state during sleep and anesthesia

“…For example, primary sensory cortex is still responsive to environmental stimuli, and basic organizational features such as frequency tuning in auditory cortex are preserved (Nir et al, 2015; Raz et al, 2014), while responses in higher order cortical sensory areas are largely suppressed (Liu et al, 2012; Wilf et al, 2016). In addition, cortical connectivity, which is central to leading theories of consciousness (Dehaene and Changeux, 2011; Friston, 2005; Tononi et al, 2016), is altered upon LOC during anesthesia (Boly et al, 2012a; Lee et al, 2017; Lee et al, 2013b; Murphy et al, 2011; Ranft et al, 2016; Sanders et al, 2018) and non-rapid eye movement (NREM) sleep (Boly et al, 2012b; Spoormaker et al, 2010).…”

Towards a Comprehensive Understanding of Anesthetic Mechanisms of Action: A Decade of Discovery

“…Accompanying TC disengagement, there is a corresponding reduction in anterior-to-posterior symbolic transfer entropy (STE) and global permutation entropy (where entropy is a surrogate marker of information transfer) as measured by EEG ( Figure 2B), consistent with reduced information processing in the cortex [81]. The loss of connectivity along the anteriorposterior axis in response to an appropriate dose/concentration of a general anesthetic, along with the accompanying loss of information transfer along that axis, both feedforward and feedback -( [82] and references therein), is associated with loss of consciousness. Whether the loss of such connectivity is necessary and sufficient to produce unconsciousness is an open question, hopefully one that can be answered given limits on appropriate assays and definitions of consciousness itself.…”

Robert D. Sanders, B.Sc., M.B.B.S., Ph.D., F.R.C.A., Recipient of the 2020 James E. Cottrell, M.D., Presidential Scholar Award

“…In his research at the University of Wisconsin, Rob confirmed that "connectedness" can indeed vary independently of consciousness and responsiveness, both under anesthesia and during sleep. 5 He also found that unresponsiveness is associated with changes in feed-forward cortical connectivity 6 -an intuitive contrast to the changes in feedback cortical connectivity that other investigators have associated with unconsciousness. This work adds substantially to our understanding of the brain, and how it can be impacted by drugs and disease.…”