Putative Neural Substrates of Social Cognition in Adults with Autism or Lesch-Nyhan Disease Compared to Healthy Controls Mark Varvaris,1 Rebecca Ward, 1 Barry Gordon,3 James C. Harris,1 H.A. Jinnah,4 David J. Schretlen1,2 Departments of 1Psychiatry, 2Radiology, and 3Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD USA 4Departments of Neurology and Human Genetics, Emory University School of Medicine, Atlanta, Georgia USA Background and Objectives Lesch-Nyhan disease (LND) and autism spectrum disorder (ASD) are both characterized by varying degrees of cognitive dysfunction, aberrant behaviors, and motor neurological abnormalities. However, while persons with ASD exhibit challenges in social settings, frequently opting to avoid human interaction, those with LND are often gregarious and eager to engage with others, to the point of appearing disinhibited. Individuals with ASD are typically avoid social contact while those with LND will actively seek out interactions (O’Hearn, et al., 2008; Schretlen, et. al., 2005). However, few studies of personality from a dimensional perspective have been reported for either population, nor have the two been compared directly. Instead, most studies of personality in ASD have focused on “autistic traits,” which essentially constitute the typically defined behavioral phenotype. Often these studies will compare individuals with ASD to a typically devolving community which may be problematic as ASD represents a constellation of symptoms rather than a single deficit. Given the similarity of ASD and LND outside of social interactions, the goal of this study was to compare gray matter volume (GMV) in established neural regions related to aspects of social cognition. Method Participants. As part of a larger cognitive battery that included general IQ testing, 8 adults with LND, 10 with ASD, and 11 healthy controls completed the Benton Facial Recognition Test (BFRT) and a brain MRI scan. The BFRT was administered under the guidance of a board- certified neuropsychologist (DJS) who has experience with Lesch-Nyhan disease and autism spectrum disorders. Imaging. The brain MRI scan included an anatomical T1 magnetization prepared rapid gradient echo sequence (TR: 2300ms; TE: 2.9ms, FOV: 256mm, 1.0x1.0x1.2mm). The voxel-based morphometric (VBM) analysis pipeline was followed using the VBM8 toolbox within the SPM8 software in order to create segmented gray matter volumes. Before automated segmentation and modulation, images were manually aligned to the anterior-poster commissure line to prevent possible warping due to the microcephaly observed in LND patients. Finally, segmentation and normalization were carried out using Jacobian modulation. Data analysis. Masks of the amygdala, fusiform, and superior temporal region were created using the WFU PickAtlas (Maldijan, et al., 2003). These masks were then used to extract gray matter volume for each participant in these three regions for comparison based on univariate ANCOVAS (as the relationship between GMV violates the assumption of multivariate statistics). Table 1: Participant Characteristics by Group Results Characteristic LND ASD HC Age: Mean (SD) 26.5 32.2 29.0 Race: n (Wht/Blk/Other) 7/1/0 8/1/1 9/2/0 IQ estimate: Mean (SD) 64.2 70.4 113.9 Education: Mean (SD) NA* 12.3 13.7 Cognitive. Overall, the group differed in facial discrimination (F=11.06, p<0.001). Adults with LND performed more poorly than HCs (d=2.09) and those with ASD (d=1.53). The ASD group performed worse than the HCs, but not significantly. Imaging. Three ANCOVAs (co-varying for total gray matter) revealed group differences for the amygdala (F=4.97, p=0.015) and fusiform (F=4.39, p=0.023) but not the superior temporal region (p>0.05). Post hoc comparisons showed the same pattern of group differences (HC>ASD=LND) for the amygdala and fusiform gyrus, but a different pattern for the superior temporal cortex, in which participants with ASD showed the greatest volumetric deficit. *Years of schooling is not a meaningful measure of education in LND Conclusions Table 2: Results GMV Both LND and ASD groups showed significantly reduced GMVs in regions that contribute to social cognition (Pelphrey, et al., 2004). Specifically, the LND and ASD patients showed reduced amygdala and fusiform GMV. Persons with ASD also exhibited slightly smaller superior temporal GMVs. The superior temporal region is particularly relevant to social attention and directed eye contact, impairments of which are more characteristic of ASD than LND. Thus, while abnormalities of facial processing, social perception, and fear response might represent common features of the phenotypes, the mechanism by which these phenotypes arise may differ. An LND individual’s overly gregarious disposition and disinhibition in social situations might be the function of global GMV atrophy. By contrast, an autistic person’s elevated sensitivity and reservation in social settings could be explained by localized atrophy in regions such as the superior temporal gyrus, leading to diverted eye gaze and subsequent socially isolating behaviors. References Examined brain regions linked to social cognition Maldjian JA, et al. (2003) An Automated Method for Neuroanatomic and Cytoarchitectonic Atlas-based Interrogation of fMRI Data Sets. NeuroImage, 19(3), 1233-1239. O'Hearn K, et al. (2008). Neurodevelopment and executive function in autism. Development and Psychopathology, 20(4), 1103-1132. Pelphrey K, et al. (2004). Neuroanatomical Substrates of Social Cognition Dysfunction in Autism. Mental Retardation and Developmental Disabilities Research Reviews, 10(4), 259- 271. Schretlen DJ, et al. (2005). Behavioral aspects of Lesch-Nyhan disease and its variants. Developmental Medicine and Child Neurology, 47(10), 673-677. Notes and Acknowledgements This work was supported by grant R01 HD53312 from the NICHHD/NIH (DS, JH, HJ), the Therapeutic Cognitive Neuroscience Endowment (BG), the Therapeutic Cognitive Neuroscience Fund (BG), and the Benjamin and Adith Miller Family Endowment on Aging, Alzheimer’s, and Autism Research (BG). Red corresponds to the amygdala, blue to the fusiform area, and green to the superior temporal region. Presented at the 17th SSBP International Research Symposium in New York, USA (10-13th October 2014)