A – 61 Neural Mechanisms of Social Cognition in Autism Spectrum Disorder and Phelan-McDermid Syndrome: A Quantitative and Comparative Review

Abstract Objective This review explores neural activation patterns underlying social cognition in Autism Spectrum Disorder (ASD) and Phelan-McDermid Syndrome (PMS), a monogenic disorder involving SHANK3 gene mutations or deletions (Leblond et al., 2014). While both are marked by social-communication deficits, PMS offers a genetically defined lens to examine neural mechanisms underlying ASD. This review aimed to compare social processing-related neural activity patterns and connectivity across ASD and PMS. Method A systematic review of PubMed and PsycINFO databases was conducted for studies published between 2005-2024 using terms such as “autism,” “Phelan-McDermid syndrome,” “SHANK3,” “social cognition” and “fMRI.” Thirty-two fMRI studies (resting-state or task-based) were selected. Results ASD-related studies showed consistent hypoactivation in the amygdala, medial prefrontal cortex, and posterior superior temporal sulcus across social processing tasks targeting emotion recognition, face processing, and theory of mind (Gotts et al., 2021; Sugranyes et al., 2011). PMS studies revealed widespread cortical underconnectivity, specifically within the default mode and salience networks, with reduced superior temporal sulcus and amygdala-prefrontal connectivity (Chenausky et al., 2018). Despite social-processing deficit overlap, PMS showed greater neural coherence disorganization (Zwanenburg et al., 2016). Conclusion While ASD and PMS overlap in core social impairments, neural connectivity differences suggest condition-specific neurobiological mechanisms. PMS, as a genetically defined subtype of ASD, highlights SHANK3’s impact on social brain circuitry. These findings emphasize gene-informed neuroimaging to understand ASD heterogeneity and develop tailored interventions. Future research should explore whether connectivity changes following social skills interventions could serve as treatment response biomarkers.