Propofol-Induced Unresponsiveness is Associated with Impaired Feedforward Connectivity in the Cortical Hierarchy

Sanders, Robert D.; Banks, Matthew I.; Darracq, Matthieu; Moran, Rosalyn J.; Sleigh, Jamie; Gosseries, Olivia; Bonhomme, Vincent; Brichant, Jean-François; Rosanova, Mario; Raz, Aeyal; Tononi, Giulio; Massimini, Marcello; Laureys, Steven; Boly, Mélanie

doi:10.1101/213504

Cited by 5 publications

(5 citation statements)

References 57 publications

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“…Feedforward pathways carry sensory information from superficial layers to superficial and middle layers of higher-order cortical areas, whereas feedback pathways carry priorities and predictions from deep layers to either superficial or deep layers of lower-order cortical areas (Markov et al, 2014;Mejias et al, 2016). Reports of the contribution of feedforward (Maksimow et al, 2014;Sanders et al, 2018;van Vugt et al, 2018) and feedback (Boly et al, 2011;Lee et al, 2009Lee et al, , 2013Raz et al, 2014;Uhrig et al, 2018) pathways to consciousness have varied. However, previous studies did not have the spatial resolution to determine transmission along paths between specific layers-in particular, whether feedback paths to superficial or deep cortical layers, or both, contribute to consciousness.…”

Section: Introductionmentioning

confidence: 99%

Thalamus Modulates Consciousness via Layer-Specific Control of Cortex

Redinbaugh

Phillips

Kambi

et al. 2020

Neuron

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284

209

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Section: Introductionmentioning

confidence: 99%

Thalamus Modulates Consciousness via Layer-Specific Control of Cortex

Redinbaugh

Phillips

Kambi

et al. 2020

Neuron

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284

209

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“…L4 pyramidal cells are typically considered mediators for propagating feedforward information, receiving sensory-specific information from thalamus and lower areas 31,[40][41][42][43] and targeting L2/3 for output to higher areas 44,45 . Feedforward circuits are relatively resistant to anaesthetics 10,11,46 (though, see 47,48 ), and we show here that extracellular recordings of current sinks evoked by activation of TC afferents were not affected by isoflurane (Figure 1). Yet, interestingly, our results show that both TC and CC inputs to L4 cells are preferentially suppressed by isoflurane (Figure 2), suggesting that suppression of either afferent pathway may disrupt feedforward signaling.…”

Section: Suppression Of L4 Pyramidal Cells During Isoflurane May Disrmentioning

confidence: 68%

Cell type-specific effects of isoflurane on two distinct afferent inputs to cortical layer 1

Murphy

Banks

2020

Preprint

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18While their behavioral effects are well-characterized, the mechanisms by which anesthetics 19 induce loss of consciousness are largely unknown. Anesthetics may disrupt integration and 20 propagation of information in corticothalamic networks. Recent studies have shown that 21 isoflurane diminishes synaptic responses of thalamocortical (TC) and corticocortical (CC) 22 afferents in a pathway-specific manner. However, whether the synaptic effects of isoflurane 23 observed in extracellular recordings persist at the cellular level has yet to be explored. Here, 24we activate TC and CC layer 1 inputs in non-primary mouse neocortex in ex vivo brain slices 25 and explore the degree to which isoflurane modulates synaptic responses in pyramidal cells 26 and in two inhibitory cell populations, somatostatin-positive (SOM+) and parvalbumin-positive 27 (PV+) interneurons. We show that the effects of isoflurane on synaptic responses and intrinsic 28 properties of these cells varies among cell type and by cortical layer. Layer 1 inputs to L4 29 pyramidal cells were suppressed by isoflurane at both TC and CC synapses, while those to 30 L2/3 pyramidal cells and PV+ interneurons were not. TC inputs to SOM+ cells were rarely 31 observed at all, while CC inputs to SOM+ interneurons were robustly suppressed by isoflurane. 32These results suggest a mechanism by which isoflurane disrupts integration and propagation 33 of incoming cortical signals.Anesthetics may ultimately influence both the level and contents of consciousness via actions 36 on corticothalamic circuits, disrupting integration of information throughout the cortical 37 hierarchy (Crick and Koch, 2003; Dehaene and Changeux, 2011; Koch et al., 2016). Activity in 38 higher order cortical areas is particularly sensitive to anesthetics (Nourski et al., 2017; Nourski 39 et al., 2018), as is corticocortical (CC) feedback connectivity (Ferrarelli et al., 2010; Boly et al., 40 2012; Liu et al., 2012; Raz et al., 2014; Mashour and Hudetz, 2017; Murphy et al., 2019). In 41 addition to cortical effects, higher order thalamocortical (TC) connectivity is suppressed during 42 both sleep (Picchioni et al., 2014) and anesthesia (Langsjo et al., 2012; Liu et al., 2013; Akeju 43 et al., 2014). Activation of non-specific thalamic nuclei during anesthetic-induced 44 unconsciousness (Redinbaugh et al., 2020) and non-REM sleep (Honjoh et al., 2018) 45 promotes behavioral arousal, implicating higher order thalamic centers as enablers of 46 consciousness. 47Recent studies from our lab have shown that in ex vivo slices, isoflurane diminishes 48 synaptic responses in a pathway-specific manner (Raz et al., 2014; Murphy et al., 2019). 49Despite overlapping terminal fields in layer 1, CC feedback afferents to a non-primary cortical 50 area were preferentially suppressed by isoflurane compared to non-primary TC inputs. 51 However, extracellular recordings used in these investigations capture summed effects across 52 all synapses, leaving open questions as to whether observed effects are con...

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“…They also support a model based on predictive processing in which consciousness relies on active comparisons between internally-generated expectations and observed sensory information 62,63 . However, several findings are not easily reconciled with these models, including reports of increases in connectivity [25][26][27] and the reported suppression of feedforward connectivity 29 .…”

Section: Theories Of Consciousnessmentioning

confidence: 97%

“…For example, although altered network connectivity is observed consistently during both anesthesia and sleep, some studies report that connectivity is decreased [18][19][20][21][22][23][24] and others that it is increased [25][26][27] . Furthermore, selective effects of anesthesia have been reported on both feedback 19,28 and feedforward 29 connectivity. Decreased thalamocortical connectivity has been reported for both anesthesia and sleep 30,31 , but at least for anesthesia this change is unlikely to be causal for LOC 11 .…”

Section: Introductionmentioning

confidence: 99%

Consciousness is indexed by analogous cortical reorganization during sleep and anesthesia

Krause

Campbell

Kovach

et al. 2022

Preprint

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Although sleep and anesthesia are predicted to share common neural signatures of transitions into and out of unconsciousness, supportive evidence has been elusive. We identified these signatures using intracranial electroencephalography in neurosurgical patients. We applied diffusion map embedding to map cortical location into a space where proximity indicates functional similarity using a normalized connectivity ('diffusion') matrix, itself a rich source of information about network properties. During reduced consciousness, diffusion matrices exhibited decreased effective dimensionality, reflecting reduced network entropy. Furthermore, functional brain regions exhibited tighter clustering in embedding space with greater distances between regions, corresponding to decreased differentiation and functional integration. These changes were not region-specific, suggesting global network reorganization. These results strongly suggest common neural substrates for loss and recovery of consciousness during anesthesia and sleep, providing a systems-level mechanistic understanding within an intuitive geometric context and laying the foundation for evaluation of cortical state transitions in clinical settings.

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Propofol-Induced Unresponsiveness is Associated with Impaired Feedforward Connectivity in the Cortical Hierarchy

Abstract: Background: Impaired consciousness has been associated with impaired cortical signal

Cited by 5 publications

References 57 publications

Thalamus Modulates Consciousness via Layer-Specific Control of Cortex

Thalamus Modulates Consciousness via Layer-Specific Control of Cortex

Cell type-specific effects of isoflurane on two distinct afferent inputs to cortical layer 1

Consciousness is indexed by analogous cortical reorganization during sleep and anesthesia

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