Atypical sensory selectivity and neural gain adaptation in Autism Spectrum Disorder

• Applicants: Dr. Nico Bast; Dr. Christina Luckhardt
• Subject Area: Clinical Psychiatry, Psychotherapy, Child and Adolescent Psychiatry ; Biological Psychiatry
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 492582254

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder associated with atypical brain function that alters social behavior, but also perception, attention, and motor execution. The underlying mechanisms of this atypical brain function are not well understood. A central function of the brain is sensory processing that raised research interest by introducing altered sensory reactivity as ASD symptom with the latest revision of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). Sensory processing serves as a pre-attentive input filter also known as sensory selectivity, which has primarily been investigated in electroencephalography (EEG) by event-related potentials during the oddball paradigm. In ASD, altered sensory selectivity has been indicated in meta-analyses by attenuated P3b and Mismatch Negativity (MMN) to oddballs that suggest decreased sensory selectivity to salient stimuli. We aim to assess the underlying mechanisms of decreased sensory selectivity in ASD.The Locus-Coeruleus-Norepinephrine (LC-NE) system provides a mechanism to explain sensory selectivity on the cortical neuronal level by changing the input-output relationship of neuronal signaling (‘neural gain adaptation’). LC-NE phasic activity causes NE release that increases the synaptic signal-to-noise ratio (‘high gain’), which leads to a positive feedback loop of NE and glutamate release in local circuits that amplifies sensory processing of salient stimuli. LC-NE phasic activity is further moderated by cortical evaluations of salience and task utility. Interestingly, LC-NE phasic activity is reliably indexed by task-evoked pupillary responses (TEPR). Based on our previous publications, we hypothesize attenuated LC-NE phasic activity to underly decreased sensory selectivity in ASD.We want to operationalize the effects of LC-NE phasic activity on sensory selectivity in a group comparison of ASD and neurotypical controls. This is achieved by a concurrent assessment of pupillometry (LC-NE phasic activity = TEPR) and EEG during the oddball paradigm (sensory selectivity = P3b, MMN). We completed a preliminary study (n=13) that suggested the feasibility of concurrent pupillometry and EEG in the target samples. No previous ASD study assessed TEPR within the oddball task in order to relate LC-NE phasic activity to sensory selectivity. We want to investigate this in a passive auditory and an active visual oddball task.We further implement experimental manipulations of LC-NE phasic activity, salience attribution, and task-utility attribution. As a secondary aim of the study, this will allow us to investigate whether the expected effects of attenuated LC-NE phasic activity and decreased sensory selectivity in ASD are due to a genuine deficit of LC-NE functioning or based on altered salience and task utility attribution. Our proposed study could provide empirical evidence for impaired neural gain adaptation as a key mechanism of atypical brain function in ASD.

• DFG Programme: Research Grants