Reward processing in autism: a thematic series

This thematic series presents theoretical and empirical papers focused on understanding autism from the perspective of reward processing deficits. Although the core symptoms of autism have not traditionally been conceptualized with respect to altered reward-based processes, it is clear that brain reward circuitry plays a critical role in guiding social and nonsocial learning and behavior throughout development. Additionally, brain reward circuitry may respond to social sources of information in ways that are similar to responses to primary rewards, and recent clinical data consistently suggest abnormal behavioral and neurobiologic responses to rewards in autism. This thematic series presents empirical data and review papers that highlight the utility of considering autism from the perspective of reward processing deficits. Our hope is that this novel framework may further elucidate autism pathophysiology, with the ultimate goal of yielding novel insights with potential therapeutic implications

Evidence for the role of EPHX2 gene variants in anorexia nervosa.

Anorexia nervosa (AN) and related eating disorders are complex, multifactorial neuropsychiatric conditions with likely rare and common genetic and environmental determinants. To identify genetic variants associated with AN, we pursued a series of sequencing and genotyping studies focusing on the coding regions and upstream sequence of 152 candidate genes in a total of 1205 AN cases and 1948 controls. We identified individual variant associations in the Estrogen Receptor-ß (ESR2) gene, as well as a set of rare and common variants in the Epoxide Hydrolase 2 (EPHX2) gene, in an initial sequencing study of 261 early-onset severe AN cases and 73 controls (P=0.0004). The association of EPHX2 variants was further delineated in: (1) a pooling-based replication study involving an additional 500 AN patients and 500 controls (replication set P=0.00000016); (2) single-locus studies in a cohort of 386 previously genotyped broadly defined AN cases and 295 female population controls from the Bogalusa Heart Study (BHS) and a cohort of 58 individuals with self-reported eating disturbances and 851 controls (combined smallest single locus P<0.01). As EPHX2 is known to influence cholesterol metabolism, and AN is often associated with elevated cholesterol levels, we also investigated the association of EPHX2 variants and longitudinal body mass index (BMI) and cholesterol in BHS female and male subjects (N=229) and found evidence for a modifying effect of a subset of variants on the relationship between cholesterol and BMI (P<0.01). These findings suggest a novel association of gene variants within EPHX2 to susceptibility to AN and provide a foundation for future study of this important yet poorly understood condition

Measuring the value of social engagement in adults with and without autism

Differences in social communication are commonly reported in autism spectrum condition (ASC). A recent theory attributes this to a reduced motivation to engage with others, that is, deficits in social motivation. However, there are currently few simple, direct, behavioural ways to test this claim. This study uses a new behavioural measure of social motivation to test if preferences for direct gaze and face stimuli are linked to autistic traits or an ASC diagnosis. Our novel choose-a-movie (CAM) paradigm measures the effort participants invest to see particular stimuli. This aspect of social motivation is also known as social seeking. Methods In experiment 1, 80 typical adults completed the CAM task and a measure of autistic traits. In experiment 2, 30 adults with ASC and 24 age/IQ-matched typical adults completed the CAM paradigm. Results The results from study one showed that typical adults prefer social stimuli over non-social, but this preference is weaker in those with higher levels of autistic traits. In study two, adults with ASC showed a significant reduction in their preference for direct gaze but little difference in their preference for faces without direct gaze. Conclusions These data show that social motivation can be measured in a simple, direct, behavioural paradigm. Furthermore, adults with ASC prefer direct gaze less than typical adults but may not avoid faces without direct gaze. This data advance our understanding of how social motivation may differ between those with and without autism

SHANK3 controls maturation of social reward circuits in the VTA.

Haploinsufficiency of SHANK3, encoding the synapse scaffolding protein SHANK3, leads to a highly penetrant form of autism spectrum disorder. How SHANK3 insufficiency affects specific neural circuits and how this is related to specific symptoms remains elusive. Here we used shRNA to model Shank3 insufficiency in the ventral tegmental area of mice. We identified dopamine (DA) and GABA cell-type-specific changes in excitatory synapse transmission that converge to reduce DA neuron activity and generate behavioral deficits, including impaired social preference. Administration of a positive allosteric modulator of the type 1 metabotropic glutamate receptors mGluR1 during the first postnatal week restored DA neuron excitatory synapse transmission and partially rescued the social preference defects, while optogenetic DA neuron stimulation was sufficient to enhance social preference. Collectively, these data reveal the contribution of impaired ventral tegmental area function to social behaviors and identify mGluR1 modulation during postnatal development as a potential treatment strategy

Reduced preference for social rewards in a novel tablet based task in young children with Autism Spectrum Disorders

Atypical responsivity to social rewards has been observed in young children with or at risk of Autism Spectrum Disorders (ASD). These observations contributed to the hypothesis of reduced social motivation in ASD. In the current study we develop a novel task to test social reward preference using a tablet computer (iPad), where two differently coloured buttons were associated with a social and a nonsocial rewarding image respectively. 63 young children, aged 14–68 months, with and without a diagnosis of ASD took part in the study. The experimental sessions were also recorded on video, using an in-built webcam on the tablet as well as an external camera. Children with ASD were found to show a reduced relative preference for social rewards, indexed by a lower proportion of touches for the button associated with the social reward image. Greater social preference as measured using the tablet-based task was associated with increased use of social communicative behaviour such as eye contact with the experimenter and social smile in response to the social reward image. These results are consistent with earlier findings from eye-tracking studies, and provide novel empirical insights into atypical social reward responsivity in ASD

Abnormal social reward processing in autism as indexed by pupillary responses to happy faces

Background: Individuals with Autism Spectrum Disorders (ASD) typically show impaired eye contact during social interactions. From a young age, they look less at faces than typically developing (TD) children and tend to avoid direct gaze. However, the reason for this behavior remains controversial; ASD children might avoid eye contact because they perceive the eyes as aversive or because they do not find social engagement through mutual gaze rewarding. Methods: We monitored pupillary diameter as a measure of autonomic response in children with ASD (n = 20, mean age = 12.4) and TD controls (n = 18, mean age = 13.7) while they looked at faces displaying different emotions. Each face displayed happy, fearful, angry or neutral emotions with the gaze either directed to or averted from the subjects. Results: Overall, children with ASD and TD controls showed similar pupillary responses; however, they differed significantly in their sensitivity to gaze direction for happy faces. Specifically, pupillary diameter increased among TD children when viewing happy faces with direct gaze as compared to those with averted gaze, whereas children with ASD did not show such sensitivity to gaze direction. We found no group differences in fixation that could explain the differential pupillary responses. There was no effect of gaze direction on pupil diameter for negative affect or neutral faces among either the TD or ASD group. Conclusions: We interpret the increased pupillary diameter to happy faces with direct gaze in TD children to reflect the intrinsic reward value of a smiling face looking directly at an individual. The lack of this effect in children with ASD is consistent with the hypothesis that individuals with ASD may have reduced sensitivity to the reward value of social stimuli

Lack of privileged access to awareness for rewarding social scenes in Autism Spectrum Disorder

Reduced social motivation is hypothesised to underlie social behavioural symptoms of Autism Spectrum Disorder (ASD). The extent to which rewarding social stimuli are granted privileged access to awareness in ASD is currently unknown. We use continuous flash suppression to investigate whether individuals with and without ASD show privileged access to awareness for social over nonsocial rewarding scenes that are closely matched for stimulus features. Strong evidence for a privileged access to awareness for rewarding social over nonsocial scenes was observed in neurotypical adults. No such privileged access was seen in ASD individuals, and moderate support for the null model was noted. These results suggest that the purported deficits in social motivation in ASD may extend to early processing mechanisms

Intertwining personal and reward relevance: evidence from the drift-diffusion model.

In their seminal paper 'Is our self nothing but reward', Northoff and Hayes (Biol Psychiatry 69(11):1019-1025, Northoff, Hayes, Biological Psychiatry 69(11):1019-1025, 2011) proposed three models of the relationship between self and reward and opened a continuing debate about how these different fields can be linked. To date, none of the proposed models received strong empirical support. The present study tested common and distinct effects of personal relevance and reward values by de-componenting different stages of perceptual decision making using a drift-diffusion approach. We employed a recently developed associative matching paradigm where participants (N = 40) formed mental associations between five geometric shapes and five labels referring personal relevance in the personal task, or five shape-label pairings with different reward values in the reward task and then performed a matching task by indicating whether a displayed shape-label pairing was correct or incorrect. We found that common effects of personal relevance and monetary reward were manifested in the facilitation of behavioural performance for high personal relevance and high reward value as socially important signals. The differential effects between personal and monetary relevance reflected non-decisional time in a perceptual decision process, and task-specific prioritization of stimuli. Our findings support the parallel processing model (Northoff & Hayes, Biol Psychiatry 69(11):1019-1025, Northoff, Hayes, Biological Psychiatry 69(11):1019-1025, 2011) and suggest that self-specific processing occurs in parallel with high reward processing. Limitations and further directions are discussed

Dissection of genetic associations with language-related traits in population-based cohorts

Recent advances in the field of language-related disorders have led to the identification of candidate genes for specific language impairment (SLI) and dyslexia. Replication studies have been conducted in independent samples including population-based cohorts, which can be characterised for a large number of relevant cognitive measures. The availability of a wide range of phenotypes allows us to not only identify the most suitable traits for replication of genetic association but also to refine the associated cognitive trait. In addition, it is possible to test for pleiotropic effects across multiple phenotypes which could explain the extensive comorbidity observed across SLI, dyslexia and other neurodevelopmental disorders. The availability of genome-wide genotype data for such cohorts will facilitate this kind of analysis but important issues, such as multiple test corrections, have to be taken into account considering that small effect sizes are expected to underlie such associations