Brandon M. Keehn, Ph.D. - US grants

Project Summary / Abstract Strengths and weaknesses in non-social attention have been identified as among the earliest features that distinguish infants who develop autism spectrum disorder (ASD), and may play a critical role in the emergence of core ASD symptoms. The seemingly paradoxical co-existence of enhanced and impaired attentional abilities in ASD has thus far evaded scientific explanation. The locus coeruleus-norepinephrine (LC-NE) system, which is known to play an important role in arousal regulation and selective attention, has been shown to function atypically in ASD. However, exactly how LC-NE activity relates to attentional strengths and weaknesses in ASD has not been determined. Thus, a critical gap remains in our knowledge of the neurofunctional mechanisms underlying these non-social attentional atypicalities. The objectives in this R21 application are to determine (1) relationship between attentional strengths and weaknesses and LC-NE activity in ASD, and (2) the neural circuits involved in these processes in ASD. The central hypothesis is that atypical function of the LC-NE system, as manifest through tonic and phasic activities, will correlate closely with enhanced visual search and inefficient attentional disengagement in ASD. The rationale for this research is that the ability to distinguish the underlying factors associated with attentional strengths and weaknesses in ASD can be expected to provide new insights into how lower-level attentional processes contribute to the emergence of higher-level sociocommunicative dysfunction in ASD, thus providing novel behavioral and/or pharmacological targets for intervention. We propose two specific aims: 1) Identify the relationship between attentional strengths and weaknesses and LC-NE activity in ASD; 2) Determine the extent of the association between the neurofunctional indices of attentional strengths and weaknesses and ASD symptom severity. Under the first aim, tonic and phasic indices of LC-NE activity (pupil dilation and P3 ERP amplitude) will be analyzed and related to behavioral and eye-tracking measures from visual search (strength) and gap-overlap (weakness) paradigms. Under the second aim, levels of symptom severity will be correlated with tonic and phasic activation of the LC-NE system. The approach is innovative because it will depart significantly from the status quo by examining strengths and weaknesses in parallel in a single cohort using a multimodal approach. Since processing strengths may be more likely to arise via a distinct mechanism and, therefore, should be more easily traced to their neurofunctional origin, investigating strengths and weaknesses in parallel will provide a more direct rendering of atypical brain architecture and neurocognitive function in ASD. The proposed research is significant because it is expected to lead to the identification of the neurofunctional mechanisms underlying these strengths and weaknesses. Such knowledge can be expected to provide insights into how these processes contribute to development of sociocommunicative deficits, and, ultimately inform early biomedical and behavioral markers and/or interventions that may ameliorate core symptoms of ASD.