Locus coeruleus tonic upregulation increases selectivity to inconspicuous auditory information in autistic compared to non-autistic individuals: a combined pupillometry and electroencephalography study

Abstract

Background: Sensory processing requires selectivity to salient sensory input. Many autistic individuals report different sensory processing, which has been associated with altered sensory selectivity. The locus-coeruleus norepinephrine (LC-NE) system modulates the neuronal gain of sensory input, which represents a neurophysiological mechanism of sensory selectivity. In autistic individuals, we hypothesized that LC-NE tonic upregulation reduces sensory selectivity and underlies different sensory processing.

Methods: Autistic (n = 139) and non-autistic (n = 98) individuals were assessed during a passive auditory oddball task with pupillometry and electroencephalography. For every trial, a baseline pupil size (BPS) assessed LC-NE tonic activity that coincides with current arousal, while a stimulus-evoked pupillary response (SEPR) assessed LC-NE phasic activity that estimated sensory selectivity. Electroencephalography assessed amplitudes of mismatch negativity (MMN-amp) that estimated pre-attentive change detection as a brain-activity readout of sensory selectivity. Measures were modeled between groups within the task by combining Frequentist and Bayesian approaches.

Results: Across groups, higher BPS was associated with more negative MMN-amp to standards and oddballs. A more negative MMN-amp to standards was associated with a higher SEPR to standards. Controlling for these associations, autistic versus non-autistic individuals showed a higher SEPR in response to standards. In addition, a positive association of BPS and SEPR to standards was specific to autistic individuals. With task progression, autistic versus non-autistic individuals showed a higher initial increase and subsequently steeper decrease of BPS. This was supported by Bayesian posterior distribution estimates.

Limitations: A short trial duration required concatenating trials to epochs and applying a linear-time invariant filter to capture the slow pupil changes. Without an LC-NE manipulation, we cannot rule out that pupil changes are evoked by other cortical pathways than the LC-NE.

Conclusions: Across groups, LC-NE tonic upregulation is emphasized as a general mechanism that un-specifically increases pre-attentive change detection to all sensory stimuli, which then increases sensory selectivity to frequent stimuli. In autistic individuals, different sensory processing is characterized by increased sensory selectivity to frequent stimuli. This is likely caused by an LC-NE tonic upregulation. It associates autistic sensory processing with increased arousal upregulation that increases sensory selectivity to inconspicuous auditory information.

Keywords: Arousal; Auditory oddball paradigm; Autism spectrum condition; Mismatch negativity; Predictive coding; Pupillometry.

Fig. 1

Task description of the passive auditory oddball task. The auditory oddball tasks include the four conditions of standards, pitch oddballs, length oddballs, and pitch & length oddballs

Fig. 2

Dependent variables are calculated by pupil size changes (BPS, SEPR) and Fz-electrode amplitude changes (MMN-amp) within trials. A. Pupil size change within epoch by stimulus (shaded area = 95% CI), which was applied to estimate baseline pupil size (BPS, mean of epoch corrected for all stimulus effect, see data preprocessing) and stimulus-evoked pupillary response (SEPR, mean of epoch between 750 and 1750 ms retaining the stimulus effect of the first trial). B. Amplitude changes of the Fz electrode within trials were applied to estimate MMN-associated amplitude (negative peak between 50 and 350 ms, shaded area = 95% CI) similarly across and within the task. Inlay: Scalp topography of electrode amplitudes between stimuli within 150-250 ms after stimulus onset. The Fz electrode marked in magenta was utilized to estimate MMN-associated amplitude

Fig. 3

Effect of stimulus and task progression across groups. Effect of stimulus (A–C) and task progression (D–F) on baseline pupil size (BPS, left), stimulus-evoked pupillary response (SEPR, middle), and mismatch-negativity-associated amplitude (MMN-amp, right) across groups. All variables were z-standardized (z)

Fig. 4

Group differences of changes in baseline pupil size (BPS). Group differences in BPS with progression of the oddball task by stimulus between autistic (green) and non-autistic (orange) individuals. Top panels show estimated means of linear mixed models; boxplots indicate a + / − 1 standard-error margin and 95% confidence interval of the estimated means for binned trials (each 10%). Bottom panels show posterior distribution estimates of Bayesian sampling; boxplots plots indicate the interquartile range and 89% credible intervals. All variables were z-standardized (z)