Isoflurane-Induced Burst Suppression Increases Intrinsic Functional Connectivity of the Monkey Brain

Abstract

Animal functional magnetic resonance imaging (fMRI) has provided key insights into the physiological mechanisms underlying healthy and diseased brain states. In non-human primates, resting-state fMRI studies are commonly conducted under isoflurane anesthesia, where anesthetic concentration is used to roughly infer anesthesia depth. However, within the recommended isoflurane concentration range (1.00–1.50%), the brain state can switch from moderate anesthesia characterized by stable slow wave (SW) electroencephalogram (EEG) signals to deep anesthesia characterized by burst suppression (BS), which is electrophysiologically distinct from the resting state. To confirm the occurrence rate of BS activity in common setting of animal fMRI study, we conducted simultaneous resting-state EEG and fMRI experiments on 16 monkeys anesthetized using 0.80–1.30% isoflurane, and detected BS activity in two of them. Datasets either featured with BS or SW activity from these two monkeys were analyzed to investigate the intrinsic functional connectivity (FC) patterns during BS. In datasets with BS activity, we observed robust coupling between the BS pattern (the binary alternation between burst and suppression activity in EEG signal) and filtered BOLD signals in most brain areas, which was associated with a non-specific enhancement in whole brain connectivity. After eliminating the BS coupling effect by regressing out the BS pattern, we detected an overall increase in FC with a few decreased connectivity compared to datasets with SW activity. These affected connections were preferentially distributed within orbitofrontal cortex, between orbitofrontal and prefrontal/cingulate/occipital cortex, and between temporal and parietal cortex. Persistence of the default mode network and recovery of thalamocortical connections were also detected under deep anesthesia with BS activity. Taken together, the observed spatially specific alterations in BS activity induced by isoflurane not only highlight the necessity of EEG monitoring and careful data preprocessing in fMRI studies on anesthetized animals, but also advance our understanding of the underlying multi-phased mechanisms of anesthesia.

Brain states govern the spatio-temporal dynamics of resting-state functional connectivity

“…The possibility to combine resting-state fMRI with invasive recordings of brain activity constitutes a pivotal branch of translational research (2018). Despite evidence of subtle changes in anesthesia level being able to dramatically change brain connectivity ( Grandjean et al, 2014 ; Hutchison et al, 2014 ; Zhang et al, 2019 ), little has been investigated on how the brain’s current state impacts functional connectivity derived from blood oxygenation level-dependent (BOLD) activity. While variations in functional connectivity have been related to cognitive state in humans ( Finn et al, 2017 ), the effect of neurophysiologically defined states on functional connectivity in the cortex remains unknown.…”

Brain states govern the spatio-temporal dynamics of resting state functional connectivity

“…The possibility to combine task-free fMRI with invasive recordings of brain activity constitutes a pivotal branch of translational research 39 . Surprisingly, in rodents as in humans, little has been investigated on how the brain's current state impacts functional connectivity derived from BOLD activity, despite evidence that, for instance, small changes in anesthesia can dramatically change brain connectivity 40,41 . While variations in functional connectivity have been related to cognitive state 42 in humans, the effect of neurophysiologically defined states on functional connectivity in the cortex remains unknown.…”

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

“…Functional interactions between distributed brain areas within specific neural networks give rise to coherent patterns of hemodynamic signals, measured as BOLD activity. Covariant relations of spontaneous BOLD signals in the resting state have been reported in humans ( Arcaro et al, 2015a ; Biswal et al, 1995 ; Fox et al, 2009 ; Power et al, 2011 ; Sporns and Honey, 2013 ) and awake NHPs ( Belcher et al, 2016 ; Ghahremani et al, 2017 ; Hori et al, 2020a ; Leopold et al, 2003 ; Liu et al, 2013 ; Logothetis, 2003b ; Silva, 2017 ; Wang et al, 2012 ) as well as in anesthetized NHPs ( Hori et al, 2020a , b ; Hutchison et al, 2012 ; Hutchison et al, 2013 ; Mantini et al, 2012a ; Vincent et al, 2007 ; Wu et al, 2016 ; Wu et al, 2017 ; Zhang et al, 2019 ). These studies have revealed that specialized cognitive and sensory networks retain their basic functional connectivity, even when not specifically engaged in task-relevant operations.…”

“…The volatile anesthetics isoflurane ( Hori et al, 2020a ; Hutchison et al, 2014 ; Li et al, 2013 ; Li et al, 2014 ; Li and Zhang, 2017 ; Vincent et al, 2007 ; Wu et al, 2016 ; Zhang et al, 2019 ) and sevoflurane ( Pró-Sistiaga et al, 2012 ; Uhrig et al, 2018 ) are attractive in that they can be safely administered to provide satisfactory depth of anesthesia, with relatively quick onset of action, and smooth recovery of the animals upon withdrawal of the anesthetic. 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 ).…”