Dynamic Reconfiguration, Fragmentation, and Integration of Whole-Brain Modular Structure across Depths of Unconsciousness

Abstract

General anesthetics are routinely used to induce unconsciousness, and much is known about their effects on receptor function and single neuron activity. Much less is known about how these local effects are manifest at the whole-brain level nor how they influence network dynamics, especially past the point of induced unconsciousness. Using resting-state functional magnetic resonance imaging (fMRI) with nonhuman primates, we investigated the dose-dependent effects of anesthesia on whole-brain temporal modular structure, following loss of consciousness. We found that higher isoflurane dose was associated with an increase in both the number and isolation of whole-brain modules, as well as an increase in the uncoordinated movement of brain regions between those modules. Conversely, we found that higher dose was associated with a decrease in the cohesive movement of brain regions between modules, as well as a decrease in the proportion of modules in which brain regions participated. Moreover, higher dose was associated with a decrease in the overall integrity of networks derived from the temporal modules, with the exception of a single, sensory-motor network. Together, these findings suggest that anesthesia-induced unconsciousness results from the hierarchical fragmentation of dynamic whole-brain network structure, leading to the discoordination of temporal interactions between cortical modules.

Muting, not fragmentation, of functional brain networks under general anesthesia

“…Consistent with this interpretation, decreases in local and global efficiency have also been observed in patients with consciousness disorders, such as unresponsive wakefulness syndrome and the minimally conscious state, and such decreases have been shown to correlate with reductions in patient awareness(Chennu et al 2014). Likewise, increases in whole-brain modularity and the number of network communities have been observed during both non-rapid eye movement sleep(Boly et al 2012b) and isoflurane-induced anesthesia(Hutchison et al 2014, Standage et al 2019, which has been interpreted as reflecting a literal fragmentation of brain networks into smaller, more isolated processing units. These interpretations are understandably compelling, as graph measures are thought to quantify key aspects of information transmission in the brain, and many of them, such as modularity and efficiency, neatly map onto existing frameworks and hypotheses concerning theories of consciousness (and disruptions thereof).…”

“…Several authors (e.g. Boly et al 2012b, Hutchison et al 2014, Standage et al 2019 have, implicitly or explicitly, interpreted these findings through the lens of various neurobiological theories of consciousness, which posit that conscious experience arises through the distributed processing of information throughout the neocortex. For example, the global neuronal workspace theory (Mashour et al 2020) submits that information is made consciously accessible when it is broadcast widely throughout the cortex by a set of diffusely connected control regions in the prefrontal and parietal cortices.…”

On the importance of being flexible: dynamic brain networks and their potential functional significances

“…One fascinating study applied flexibility analyses to investigate dynamic alterations in the modular structure of nervous systems with varying depths of unconsciousness (Standage et al, 2020). In this investigation, the anesthetic isoflurane was used to modulate consciousness level in rhesus macaques measured with high-field strength fMRI.…”

Using non-invasive neuroimaging to enhance the care, well-being and experimental outcomes of laboratory non-human primates (monkeys)

“…Using ultra-high field MRI, it has been demonstrated that the T2*-oxygenation-ratio varied as a function of the anesthetic agent, showing a higher T2*-oxygenation-ratio under volatile anesthetics (isoflurane, sevoflurane) compared to intravenous anesthetics (propofol, ketamine, midazolam) ( Uhrig et al, 2014a ). However, while both anesthetics are safe to use in repetitive studies in the same animal, they suppress neuronal activity and decrease functional brain connectivity ( Ranft et al, 2016 ; Standage et al, 2020 ; Wu et al, 2016 ) in a dose-dependent manner ( Hutchison et al, 2014 ; Li et al, 2013 ; Lv et al, 2016 ). In particular, both high and low concentrations of isoflurane were found to profoundly affect vertebral blood flow, cerebrovascular tone, and cerebrovascular reactivity ( Li et al, 2013 ; Li et al, 2014 ; Li and Zhang, 2017 ) with complex interactions.…”