Anterior insula regulates brain network transitions that gate conscious access

Abstract

Conscious access to sensory information is likely gated at an intermediate site between primary sensory and transmodal association cortices, but the structure responsible remains unknown. We perform functional neuroimaging to determine the neural correlates of conscious access using a volitional mental imagery task, a report paradigm not confounded by motor behavior. Titrating propofol to loss of behavioral responsiveness in healthy volunteers creates dysfunction of the anterior insular cortex (AIC) in association with an impairment of dynamic transitions of default-mode and dorsal attention networks. Candidate subcortical regions mediating sensory gating or arousal (thalamus, basal forebrain) fail to show this association. The gating role of the AIC is consistent with findings in awake participants, whose conscious access is predicted by pre-stimulus AIC activity near perceptual threshold. These data support the hypothesis that AIC, situated at an intermediate position of the cortical hierarchy, regulates brain network transitions that gate conscious access.

Keywords: anesthesia; anterior insular cortex; conscious access; consciousness; cortical gradients; default-mode network; fMRI; functional hierarchy; perceptual awareness; prestimulus activity.

Figure 1.. Experimental design

Schematic of the experimental protocol for stepwise intravenous infusion of propofol and fMRI tasks. The infusion rate was adjusted to achieve stepwise increasing target effect-site concentrations (ESCs) in 0.4-μg/ml increments. The final target concentration was one increment above that which first resulted in loss of behavioral responsiveness. The final target was then maintained at this level for approximately 22 min. After that, the infusion was terminated to allow for spontaneous recovery. Mental imagery and motor response tasks were tested before, during, and after propofol infusion. Subjects were asked to perform three imagery tasks (tennis, navigation, and hand squeeze) plus a motor response task (actual hand squeeze). The timing of “action” instructions and the actual motor response were used to determine the periods during which a participant retained responsiveness (PreLOR), loss of responsiveness (LOR), and recovery of responsiveness (ROR). Two 10-min resting-state baseline and two 15-min task baseline recordings were done before (Rest1 and Base1) and after (Base2 and Rest2) propofol infusion.

Figure 2.. Task-induced brain activity

Group-level z-maps are shown for tennis imagery (Tennis; 15-s duration), navigation imagery (Navigation; 15-s duration), squeeze imagery (Squeeze; 10-s duration), actual hand squeeze (Action; 2-s duration), and verbal instruction (Instruction; 2-s duration) during Base1 (n = 26), PreLOR (n = 26), LOR (n = 26), ROR (n = 16), and Base2 (n = 25). All z-maps (one sample t test against zero) were corrected at the cluster level α < 0.05. During LOR, mental-imagery-related activations were absent. Verbal-instruction-evoked activations were attenuated and constrained within the Thal and A1, and deactivations were seen in bilateral AIC. SMA, supplementary motor area; PreCu, precuneus; PPA, parahippocampal place area; M1, primary motor cortex; MPFC, medial prefrontal cortex; PCC, posterior cingulate cortex; Vis, visual cortex; PostC, postcentral gyrus; Thal, thalamus; A1, auditory cortex; AIC, anterior insular cortex; DLPFC, dorsal lateral PFC.

Figure 3.. Cortical gradients of functional organization

(A) Topographic profiles of the first two gradients along the cortex during the baseline condition (Base1). See Figure S1 for other conditions. (B) The two gradients are projected into a two-dimensional gradient space. The axes represent each gradient and separate distinct functional poles of cortical organization (i.e., unimodal to transmodal regions in gradient one and visual to somatomotor regions in gradient two). (C) The distribution of gradient eigenvector loading values are shown for Base1 (n = 26), PreLOR (n = 26), LOR (n = 26), ROR (n = 16), and Base2 (n = 25) in seven pre-defined functional networks including the default-mode network (DMN), frontoparietal network (FPN), limbic network (LIM), ventral attention/salience network (VAT), dorsal attention network (DAT), somatomotor network (SMN), and visual network (VIS). Error bars indicate ± SEM across subjects. (D) The locations (cluster peaks; Table S1) of ROIs during the task are marked within these networks.

Figure 4.. Time course of fMRI signal change in ROIs

Each time course includes 4.0-s pre-stimulus baseline and 29.6-s post-stimulus period (step: 0.8 s). The fMRI signal is corrected by subtracting the mean value of the pre-stimulus baseline. Time courses are plotted for Base1 (n = 26), PreLOR (n = 26), LOR (n = 26), ROR (n = 16), and Base2 (n = 25). Shaded areas indicate ± SEM across subjects. Brown arrows versus gray arrows on the left indicate preserved versus disrupted cognitive processing pathways during LOR. The deactivations in the AIC represent a functional failure at an intermediate position in the brain’s functional hierarchy. The ROIs are mapped on the inflated and flattened cortical surface (except for Thal and Ch4; see small horizontal sections in the middle). The +Resp. and –Resp. indicate regions showing activation and deactivation, respectively.

Figure 5.. Time course of spatial similarity of eight CAPs

Each plot includes 4.0-s pre-stimulus baseline and 29.6-s post-stimulus period (step: 0.8 s). The spatial similarity values were corrected by subtracting the mean value of the pre-stimulus baseline. Time courses are plotted for Base1 (n = 26), PreLOR (n = 26), LOR (n = 26), ROR (n = 16), and Base2 (n = 25). Shaded areas indicate ± SEM across subjects. The CAPs include the DMN+, DAT+, FPN+, SMN+, VIS+, VAT+, and global network of activation and deactivation (GN+ and GN–). During conscious conditions (Base1, PreLOR, ROR, and Base2), there were positive (and negative) modulations in the DAT+ (and DMN+) for all imagery tasks. Other CAPs were less engaged in mental imagery tasks, expect for the VAT+ and VIS+ during squeeze imagery. The DMN-DAT switch was abolished during LOR.

Figure 6.. AIC controls the DMN-DAT switches

(A) Modulation indices were plotted for DMN+ and DAT+. Instruction-evoked activation estimated from general linear model was plotted for the AIC. Each gray dot represents an individual participant during Base1 (n = 26), PreLOR (n = 26), LOR (n = 26), ROR (n = 16), or Base2 (n = 25) connected by gray lines across conditions. Bars represent the group averages for each condition. Asterisk indicates statistical significance (one sample t test against zero) at false discovery rate (FDR)-corrected alpha < 0.05. Pearson correlation was performed between instruction-evoked activation in the AIC and DAT-DMN modulation index across subjects and conditions (n = 119). (B) Voxel-wise correlation between whole-brain instruction-evoked activation and DAT-DMN modulation index. (C) Voxel-wise partial correlation between whole-brain instruction-evoked activation and DAT-DMN modulation index by including the activations of A1, Ch4, and Thal as covariates. (D) Schematic illustration of hypothesized conscious processing. The AIC initiates a large-scale network transition by activating the DAT and suppressing the DMN. The group-averaged time courses are shown as an example for the AIC’s activity (arbitrary unit on y axis for illustrative purpose) and DMN+ and DAT+ spatial similarity during tennis imagery in the baseline condition.

Figure 7.. Testing conscious access in a psychological setting

(A) A face or a scrambled face was briefly displayed and then masked with a high-contrast image. Display duration of 200 ms was used for supraliminal presentation. The near-threshold face presentation was individualized by an adaptive staircase procedure. The threshold duration was 33 ms in 17 out of 19 participants (see Method details). (B) Each trial started with a brief flash of face or scrambled face image. Participants were instructed to view the stimuli but not respond until a red fixation cross prompt appeared on the screen. They were required to report whether they had seen a face or not. After their button press response, an unpredictably long rest period with a white fixation cross was used to separate trials (19.5-s mean duration; 1.5-s steps). (C) The duration of the rest periods followed an exponential distribution. (D) Behavioral results. The hit rates (p[present|present]) and correct rejections (p[absent|absent]) of a face were 91% (SD = 5.9%) and 96% (SD = 8.5%) in supraliminal conditions and 60% (SD = 19.3%) and 96% (SD = 8.8%) in near-threshold conditions. Significant differences in those rates were found between the near-threshold face and all other conditions (*p < 0.001). (E) Group-level z-maps of stimulus-induced activity for near-threshold seen versus unseen of a face. The z-maps were thresholded at cluster level α< 0.05. (F) Time courses of fMRI signal change for near-threshold seen versus unseen in the AIC, DLPFC, ACC, and Thal. (G) Time courses of spatial similarity for DAT+ and DMN+. *p < 0.01 (paired sample t tests); n.s., non-significance. Shaded areas and error bars indicate ± SEM across subjects (n = 19).