Cerebral responses to local and global auditory novelty under general anesthesia

Abstract

Primate brains can detect a variety of unexpected deviations in auditory sequences. The local-global paradigm dissociates two hierarchical levels of auditory predictive coding by examining the brain responses to first-order (local) and second-order (global) sequence violations. Using the macaque model, we previously demonstrated that, in the awake state, local violations cause focal auditory responses while global violations activate a brain circuit comprising prefrontal, parietal and cingulate cortices. Here we used the same local-global auditory paradigm to clarify the encoding of the hierarchical auditory regularities in anesthetized monkeys and compared their brain responses to those obtained in the awake state as measured with fMRI. Both, propofol, a GABAA-agonist, and ketamine, an NMDA-antagonist, left intact or even enhanced the cortical response to auditory inputs. The local effect vanished during propofol anesthesia and shifted spatially during ketamine anesthesia compared with wakefulness. Under increasing levels of propofol, we observed a progressive disorganization of the global effect in prefrontal, parietal and cingulate cortices and its complete suppression under ketamine anesthesia. Anesthesia also suppressed thalamic activations to the global effect. These results suggest that anesthesia preserves initial auditory processing, but disturbs both short-term and long-term auditory predictive coding mechanisms. The disorganization of auditory novelty processing under anesthesia relates to a loss of thalamic responses to novelty and to a disruption of higher-order functional cortical networks in parietal, prefrontal and cingular cortices.

Keywords: Anesthesia; Cortex; Primate; Sequence violation; Thalamus; fMRI.

Fig. 1

‘Local/global’ paradigm. a, Trial: short auditory sequences containing either 5 identical sounds (local standard, denoted as xxxxx), or 4 identical sounds followed by a distinct one (local deviant, denoted as xxxxY). b, Series: 24 trials with an initial 4 habituation trials, followed by 20 test-phase trials; 4 deviant trial and 16 standard trials. Stimuli presentation, one sequence served as the global standard and another as the global deviant. c, Run: initial period of rest (14.4 s), 5 series of 24 trials (36 s), period of rest (14.4 s) at the end of each trial, total duration of the run of 266.4 s. Adapted from Uhrig et al. (2014b).

Fig. 2

fMRI activations to all sounds relative to rest. fMRI activations to all sounds relative to rest (a–c) under moderate propofol sedation, deep propofol anesthesia and deep ketamine anesthesia. Panels d–f show the corresponding comparisons between the awake state and moderate propofol sedation, deep propofol anesthesia and deep ketamine anesthesia. SPM maps for all sounds overlying coronal T1-weighted images from the macaque MNI atlas. y, level of coronal section relative to the bregma in the Paxinos atlas. Group analysis, p < 0.05, FDR corrected. a, all sounds relative to rest for moderate propofol sedation; b, all sounds relative to rest for deep propofol anesthesia; c, all sounds relative to rest for deep ketamine anesthesia; d, stronger activations for all sounds during moderate propofol sedation compared to the awake state; e, stronger activations for all sounds during deep propofol anesthesia compared to awake state; f, stronger activations for all sounds during deep anesthesia sedation compared to the awake state; IC, inferior colliculus; Caudate, Caudate nucleus.

Fig. 3

Local novelty effect under anesthesia. a, Activation maps for the local novelty effect (local deviants minus local standards = (xxxxx rare + xxxxY frequent) – (xxxxx frequent + xxxxY rare)) under ketamine anesthesia. b, fMRI signal change in areas responsive to local novelty (blue cross on SPM maps) under ketamine anesthesia. Plots show signal change for habituation (hab), frequent (freq) and rare stimuli. y, level of coronal section relative to the bregma in the Paxinos atlas. Group analysis, p < 0.05, FDR corrected. We found no significant activations for the local novelty effect during moderate propofol sedation and deep propofol anesthesia. IPS, intraparietal sulcus; VIP, ventral intraparietal area.

Fig. 4

Comparison between the awake state and anesthesia states for the local novelty effect. a, Activation map for local novelty effect (local deviants minus local standards) showing stronger activations in the awake state compared to moderate propofol sedation; b, Activation map for local novelty effect showing stronger activations in the awake state compared to deep propofol anesthesia; c, Activation map for local novelty effect with stronger activations in the awake state compared to deep ketamine anesthesia. Group analysis, p < 0.05, FDR corrected. d, g fMRI signal change in areas responsive to local novelty effect (blue cross on SPM maps) in the awake state and under moderate propofol sedation. e, h fMRI signal change in areas responsive to local novelty effect (blue cross on SPM maps) in the awake state and under deep propofol anesthesia. f, i, fMRI signal change in areas responsive to local novelty effect (blue cross on SPM maps) in the awake state and under deep ketamine anesthesia. Plots show signal change for habituation (hab), frequent (freq) and rare stimuli in the auditory cortex and medial geniculate nucleus. y, level of coronal section relative to the bregma in the Paxinos atlas. MGN, medial geniculate nucleus.

Fig. 5

Global novelty effect under anesthesia. a, Activation maps for the global novelty effect (rare minus frequent sequences = (xxxxx rare global deviants + xxxxY rare global deviants) – (xxxxx frequent global standards + xxxxY frequent global standards)) under moderate propofol sedation. b, fMRI signal change in areas responsive to the global effect (blue cross on SPM maps) under moderate propofol sedation. Plots show signal change for habituation (hab), frequent (freq) and rare stimuli. c, Activation maps for the global novelty effect under deep propofol anesthesia. d, fMRI signal change in areas responsive to global effect (blue cross on SPM maps) under deep propofol anesthesia. Plots show signal change for habituation (hab), frequent (freq) and rare stimuli. y, level of coronal section relative to the bregma in the Paxinos atlas. y, level of coronal section relative to the bregma in the Paxinos atlas. 46, prefrontal cortex area 46; 8A/45, prefrontal cortex area 8A/45; ACC, anterior cingulate cortex; MGN, medial geniculate nucleus. We found no significant activations for the global novelty effect under ketamine anesthesia.

Fig. 6

Global novelty effect under anesthesia, individual results. Activation maps for rare minus frequent sequences (global novelty) under moderate and deep propofol anesthesia. fMRI signal change in areas responsive to global novelty. Plots show signal change for habituation (hab), frequent (freq) and rare stimuli. y, level of coronal section relative to the bregma in the Paxinos atlas. Individual results. p < 0.001 uncorrected Moderate propofol sedation. a, Monkey K: Activation map for the global effect in prefrontal cortex (PFC) and in the auditory cortex under moderate propofol sedation. b, Monkey R: Activation map for the global effect in prefrontal cortex (PFC) and in the auditory cortex under moderate propofol sedation. c, Monkey J: Activation map for the global effect in prefrontal cortex (PFC) and in the auditory cortex under moderate propofol sedation. Deep propofol anesthesia. d, Monkey K: Activation map for the global effect in prefrontal cortex (PFC) and in the auditory cortex under deep propofol anesthesia. e, Monkey R: Activation map for the global effect in prefrontal cortex (PFC) and in the auditory cortex under deep propofol anesthesia. f, Monkey J: Activation map for the global effect in prefrontal cortex (PFC) and in the auditory cortex under deep propofol anesthesia.

Fig. 7

Comparison between the awake state and anesthesia states for the global novelty effect. a, Activation map for the global novelty effect showing stronger activations in the awake state compared to moderate propofol sedation; b, Activation map for the global novelty effect with stronger activations in the awake state compared to deep propofol anesthesia; c, Activation map for the global novelty effect showing stronger activations in the awake state then under deep ketamine anesthesia. Group analysis, p < 0.05, FDR corrected. d, fMRI signal change in areas responsive to the global novelty effect for the awake state (red), moderate propofol sedation (light blue); deep propofol anesthesia (dark blue) and deep ketamine anesthesia (grey). * significant changes to global novelty between the awake state and the anesthesia states (moderate propofol sedation, deep propofol anesthesia, deep ketamine anesthesia). 8A/45, prefrontal cortex area 8A/45; 6V, premotor area 6V; IPS, intraparietal sulcus; PFC, prefrontal cortex; VIP, ventral intraparietal area; ACC, anterior cingulate cortex; PCC, posterior cingulate cortex.

Fig. 8

Task-evoked connectivity during the global novelty effect. a, Task-evoked connectivity during the global novelty effect in the macaque cortex under moderate propofol sedation, using a seed in the right auditory cortex and looking for psychophysiological interaction, i.e. increase in correlation with auditory cortex activation in response to rare than to frequent sequences. b, Task-evoked connectivity during the global novelty effect in the macaque cortex under deep propofol anesthesia, using a seed in the right auditory cortex and looking for psychophysiological interaction. Group analysis, p < 0.05, FDR corrected. 8A/45, prefrontal cortex area 8A/45; 46, prefrontal cortex area 46; 6V, premotor area 6V; ACC, anterior cingulate cortex; IPS, intraparietal sulcus; STS, superior temporal sulcus, PCC, posterior cingulate cortex, V4, visual areas V4. Functional connectivity analysis revealed no increase in functional correlation with auditory cortex (A1) during ketamine anesthesia.