The locus coeruleus–norepinephrine system as pacemaker of attention – a developmental mechanism of derailed attentional function in autism spectrum disorder

Abstract

Children with autism spectrum disorder (ASD) exhibit diminished visual engagement to environmental stimuli. Aberrant attentional function provides an explanation by reduced phasic alerting and orienting to exogenous stimuli. We review aberrant attentional function (alerting, orienting and attentional control) in children with ASD as studied by neurocognitive and neurophysiological tasks as well as magnetic resonance imaging studies. The locus coeruleus-norepinephrine (LC-NE) system is outlined as a pacemaker of attentional function. The LC-NE system regulates adaptive gain in synaptic signal transmission, which moderates phasic alerting ('promoting') and the activation of the ventral frontoparietal attention network within orienting ('permitting'). In children with ASD, atypical LC-NE activity is proposed as underlying mechanism of aberrant attentional function. It may manifest as (i) increased tonic activity with reduced phasic reactivity to exogenous stimuli, (ii) attenuated bottom-up signalling mitigating salience and predictive reward attribution during phasic alerting, and (iii) reduced activation of the ventral frontoparietal attention system attenuating orienting to exogenous stimuli. Increased tonic pupil dilation and aberrant pupil reactivity are discussed as indicators of atypical LC-NE activity. Pupillometry is outlined as feasible method to assess alerting, orienting and attentional control that can be dissected from the pupil dilation time course. In children with ASD, aberrant attentional function through atypical LC-NE activity is proposed as developmental mechanism leading to reduced social attention as well as social interaction and communication impairments.

Expectancy modulates pupil size both during endogenous orienting and during re‐orienting of spatial attention: A study with isoluminant stimuli

“…In both cases, these effects remained sustained for entire duration of the target period. In a recent investigation run with the Attention Network Task (Petersen and Posner, ) to explore the alerting, orienting and executive‐control components of attention (for a review on the relationship of these components with LC‐NE activity, see Bast et al., ), Geva et al. () have described PDil effects related to the attentional and control components of attention that have onset latencies similar to those of the PDil effects observed in our study.…”

“…In humans, a combined fMRI/PDil investigation has also highlighted a relationship between PDil and the BOLD activity in a dorsal pontine area that overlaps with the Locus Coeruleus (LC) (Murphy, Robertson, Balsters, & O'connell, ). Taken together, these findings suggest that PDil can be used as a non‐invasive index of LC‐NE activity (for review, see Bast, Poustka, & Freitag, ).…”

A genetically encoded fluorescent sensor for rapid and specificin vivodetection of norepinephrine

“…In the brain, NE is synthesized primarily in the locus coeruleus (LC), a small yet powerful nucleus located in the pons. Noradrenergic LC neurons project throughout the brain and exert a wide range of effects, including processing sensory information (Berridge and Waterhouse, 2003), regulating the sleep-wake/arousal state (Berridge et al, 2012), and mediating attentional function (Bast et al, 2018). Blocking noradrenergic transmission causes impaired cognition and arousal and is closely correlated with a variety of psychiatric conditions and neurodegenerative diseases, including stress (Chrousos, 2009), anxiety (Goddard et al, 2010), depression (Moret and Briley, 2011), attention-deficit hyperactivity disorder (ADHD) (Berridge and Spencer, 2016), and Parkinson’s disease (PD) (Espay et al, 2014).…”

Social scene perception in autism spectrum disorder: An eye-tracking and pupillometric study

“…The LC, a noradrenergic "hub" used in the brain as a pacemaker for attentional processes, also controls the muscles in the iris (Laeng et al, 2012), and changes in pupil diameter have been shown to directly correlate with activation changes in LC neurons that signify attentional shifts (Laeng et al, 2012;Rajkowski, Majczynski, Clayton & Aston-Jones, 2004). This psychophysiological signature is also presumed to reveal social processing development and differences, as social perception is a product of attentional shifts due to the prioritized attention placed on social stimuli (Bast, Poustka, & Freitag, 2018). Indeed, it has been shown that infants as young as one month show differential (larger) pupil dilation in response to social vs. non-social stimuli (Fitzgerald, 1968).…”