Detecting Autism Spectrum Disorder and Attention Deficit Hyperactivity Disorder Using Multimodal Time-Frequency Analysis with Machine Learning Using the Electroretinogram from Two Flash Strengths.

PURPOSE: Autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) are conditions that similarly alter cognitive functioning ability and challenge the social interaction, attention, and communication skills of affected individuals. Yet these are distinct neurological conditions that can exhibit diverse characteristics which require different management strategies. It is desirable to develop tools to assist with early distinction so that appropriate early interventions and support may be tailored to an individual's specific requirements. The current diagnostic procedures for ASD and ADHD require a multidisciplinary approach and can be lengthy. This study investigated the potential of electroretinogram (ERG), an eye test measuring retinal responses to light, for rapid screening of ASD and ADHD. METHODS: Previous studies identified differences in ERG amplitude between ASD and ADHD, but this study explored time-frequency analysis (TFS) to capture dynamic changes in the signal. ERG data from 286 subjects (146 control, 94 ASD, 46 ADHD) was analyzed using two TFS techniques. RESULTS: Key features were selected, and machine learning models were trained to classify individuals based on their ERG response. The best model achieved 70% overall accuracy in distinguishing control, ASD, and ADHD groups. CONCLUSION: The ERG to the stronger flash strength provided better separation and the high frequency dynamics (80-300 Hz) were more informative features than lower frequency components. To further improve classification a greater number of different flash strengths may be required along with a discrimination comparison to participants who meet both ASD and ADHD classifications and carry both diagnoses.

Detecting Autism Spectrum Disorder Using Spectral Analysis of Electroretinogram and Machine Learning: Preliminary results.

Autism spectrum disorder (ASD) is a neurodevelopmental condition that impacts language, communication and social interactions. The current diagnostic process for ASD is based upon a detailed multidisciplinary assessment. Currently no clinical biomarker exists to help in the diagnosis and monitoring of this condition that has a prevalence of approximately 1%. The electroretinogram (ERG), is a clinical test that records the electrical response of the retina to light. The ERG is a promising way to study different neurodevelopmental and neurodegenerative disorders, including ASD. In this study, we have proposed a machine learning based method to detect ASD from control subjects using the ERG waveform. We collected ERG signals from 47 control (CO) and 96 ASD individuals. We analyzed ERG signals both in the time and the spectral domain to gain insight into the statistically significant discriminating features between CO and ASD individuals. We evaluated the machine learning (ML) models using a subject independent cross validation-based approach. Time-domain features were able to detect ASD with a maximum 65% accuracy. The classification accuracy of our best ML model using time-domain and spectral features was 86%, with 98% sensitivity. Our preliminary results indicate that spectral analysis of ERG provides helpful information for the classification of ASD.

Discrete Wavelet Transform Analysis of the Electroretinogram in Autism Spectrum Disorder and Attention Deficit Hyperactivity Disorder.

Background: To evaluate the electroretinogram waveform in autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) using a discrete wavelet transform (DWT) approach. Methods: A total of 55 ASD, 15 ADHD and 156 control individuals took part in this study. Full field light-adapted electroretinograms (ERGs) were recorded using a Troland protocol, accounting for pupil size, with five flash strengths ranging from -0.12 to 1.20 log photopic cd.s.m-2. A DWT analysis was performed using the Haar wavelet on the waveforms to examine the energy within the time windows of the a- and b-waves and the oscillatory potentials (OPs) which yielded six DWT coefficients related to these parameters. The central frequency bands were from 20-160 Hz relating to the a-wave, b-wave and OPs represented by the coefficients: a20, a40, b20, b40, op80, and op160, respectively. In addition, the b-wave amplitude and percentage energy contribution of the OPs (%OPs) in the total ERG broadband energy was evaluated. Results: There were significant group differences (p < 0.001) in the coefficients corresponding to energies in the b-wave (b20, b40) and OPs (op80 and op160) as well as the b-wave amplitude. Notable differences between the ADHD and control groups were found in the b20 and b40 coefficients. In contrast, the greatest differences between the ASD and control group were found in the op80 and op160 coefficients. The b-wave amplitude showed both ASD and ADHD significant group differences from the control participants, for flash strengths greater than 0.4 log photopic cd.s.m-2 (p < 0.001). Conclusion: This methodological approach may provide insights about neuronal activity in studies investigating group differences where retinal signaling may be altered through neurodevelopment or neurodegenerative conditions. However, further work will be required to determine if retinal signal analysis can offer a classification model for neurodevelopmental conditions in which there is a co-occurrence such as ASD and ADHD.

Education in psychiatry: the art of getting published.

Getting an article published in a scientific journal requires skills that are rarely taught, but are almost invariably learned by (bitter) experience. Yet, there are generally applicable guidelines that facilitate the process. This article summarises them.

The electroretinogram b-wave amplitude: a differential physiological measure for Attention Deficit Hyperactivity Disorder and Autism Spectrum Disorder.

BACKGROUND: Attention Deficit Hyperactivity Disorder (ADHD) is the most prevalent childhood neurodevelopmental disorder. It shares some genetic risk with Autism Spectrum Disorder (ASD), and the conditions often occur together. Both are potentially associated with abnormal glutamate and GABA neurotransmission, which can be modelled by measuring the synaptic activity in the retina with an electroretinogram (ERG). Reduction of retinal responses in ASD has been reported, but little is known about retinal activity in ADHD. In this study, we compared the light-adapted ERGs of individuals with ADHD, ASD and controls to investigate whether retinal responses differ between these neurodevelopmental conditions. METHODS: Full field light-adapted ERGs were recorded from 15 ADHD, 57 ASD (without ADHD) and 59 control participants, aged from 5.4 to 27.3 years old. A Troland protocol was used with a random series of nine flash strengths from -0.367 to 1.204 log photopic cd.s.m-2. The time-to-peak and amplitude of the a- and b-waves and the parameters of the Photopic Negative Response (PhNR) were compared amongst the three groups of participants, using generalised estimating equations. RESULTS: Statistically significant elevations of the ERG b-wave amplitudes, PhNR responses and faster timings of the b-wave time-to-peak were found in those with ADHD compared with both the control and ASD groups. The greatest elevation in the b-wave amplitudes associated with ADHD were observed at 1.204 log phot cd.s.m-2 flash strength (p < .0001), at which the b-wave amplitude in ASD was significantly lower than that in the controls. Using this measure, ADHD could be distinguished from ASD with an area under the curve of 0.88. CONCLUSIONS: The ERG b-wave amplitude appears to be a distinctive differential feature for both ADHD and ASD, which produced a reversed pattern of b-wave responses. These findings imply imbalances between glutamate and GABA neurotransmission which primarily regulate the b-wave formation. Abnormalities in the b-wave amplitude could provisionally serve as a biomarker for both neurodevelopmental conditions.

The photopic negative response in autism spectrum disorder.

CLINICAL RELEVANCE: To ascertain if the photopic negative response of the electroretinogram is different in autism spectrum disorder as a potential clinical marker. BACKGROUND: Visual function can be atypical in autism spectrum disorder and structural imaging of the ganglion cell layers has been reported to differ in these individuals. Therefore, we sought to investigate if the photopic negative response of the full field electroretinograms, a measure of ganglion cell function, could help explain the visual perceptual differences in autism spectrum disorder and support the structural changes observed. METHODS: Participants (n = 55 autism spectrum disorder, aged 5.4-26.7 years) and control (n = 87, aged 5.4-27.3 years) were recruited for the study. Full-field light-adapted electroretinograms using a Troland protocol with 10 flash strengths from -0.367 to 1.204 log photopic cd.s.m-2 were recorded in each eye. The photopic negative response amplitudes at Tmin and at t = 72 ms were compared between groups along with the a- and b-wave values. RESULTS: There were no significant interactions between groups for the Photopic Negative Response measures of amplitude or time (p > 0.30). There was a group interaction between groups and flash strengths for the b-wave amplitude as previously reported (p < 0.001). CONCLUSION: The photopic negative response results suggest that there are no significant differences in the summed retinal ganglion cell responses produced by a full-field stimulus.

A framework for an evidence-based gene list relevant to autism spectrum disorder.

Autism spectrum disorder (ASD) is often grouped with other brain-related phenotypes into a broader category of neurodevelopmental disorders (NDDs). In clinical practice, providers need to decide which genes to test in individuals with ASD phenotypes, which requires an understanding of the level of evidence for individual NDD genes that supports an association with ASD. Consensus is currently lacking about which NDD genes have sufficient evidence to support a relationship to ASD. Estimates of the number of genes relevant to ASD differ greatly among research groups and clinical sequencing panels, varying from a few to several hundred. This Roadmap discusses important considerations necessary to provide an evidence-based framework for the curation of NDD genes based on the level of information supporting a clinically relevant relationship between a given gene and ASD.

Light-Adapted Electroretinogram Differences in Autism Spectrum Disorder.

Light-adapted (LA) electroretinograms (ERGs) from 90 individuals with autism spectrum disorder (ASD), mean age (13.0 ± 4.2), were compared to 87 control subjects, mean age (13.8 ± 4.8). LA-ERGs were produced by a random series of nine different Troland based, full-field flash strengths and the ISCEV standard flash at 2/s on a 30 cd m-2 white background. A random effects mixed model analysis showed the ASD group had smaller b- and a-wave amplitudes at high flash strengths (p < .001) and slower b-wave peak times (p < .001). Photopic hill models showed the peaks of the component Gaussian (p = .035) and logistic functions (p = .014) differed significantly between groups. Retinal neurophysiology assessed by LA-ERG provides insight into neural development in ASD.

Associations between cooperation, reactive aggression and social impairments among boys with autism spectrum disorder.

Cooperation is a fundamental human ability that seems to be inversely related to aggressive behaviour in typical development. However, there is no knowledge whether similar association holds for children with autism spectrum disorder. A total of 27 boys with autism spectrum disorder and their gender, age and total score intelligence matched controls were studied in order to determine associations between cooperation, reactive aggression and autism spectrum disorder-related social impairments. The participants performed a modified version of the Prisoner's Dilemma task and the Pulkkinen Aggression Machine which measure dimensions of trust, trustworthiness and self-sacrifice in predisposition to cooperate, and inhibition of reactive aggression in the absence and presence of situational cues, respectively. Autism spectrum disorder severity-related Autism Diagnostic Interview-algorithm scores were ascertained by interviewing the parents of the participants with a semi-structured parental interview (Developmental, Dimensional and Diagnostic Interview). The results showed that albeit the boys with autism spectrum disorder were able to engage in reciprocation and cooperation regardless of their social impairments, their cooperativeness was positively associated with lower levels of reactive aggression and older age. Thus, strengthening inhibition mechanisms that regulate reactive aggression might make boys with autism spectrum disorder more likely to prefer mutual gain over self-interest in cooperation.

Structural connectivity of the amygdala in young adults with autism spectrum disorder.

Autism spectrum disorder (ASD) is characterized by impairments in social cognition, a function associated with the amygdala. Subdivisions of the amygdala have been identified which show specificity of structure, connectivity, and function. Little is known about amygdala connectivity in ASD. The aim of this study was to investigate the microstructural properties of amygdala-cortical connections and their association with ASD behaviours, and whether connectivity of specific amygdala subregions is associated with particular ASD traits. The brains of 51 high-functioning young adults (25 with ASD; 26 controls) were scanned using MRI. Amygdala volume was measured, and amygdala-cortical connectivity estimated using probabilistic tractography. An iterative 'winner takes all' algorithm was used to parcellate the amygdala based on its primary cortical connections. Measures of amygdala connectivity were correlated with clinical scores. In comparison with controls, amygdala volume was greater in ASD (F(1,94) = 4.19; p = .04). In white matter (WM) tracts connecting the right amygdala to the right cortex, ASD subjects showed increased mean diffusivity (t = 2.35; p = .05), which correlated with the severity of emotion recognition deficits (rho = -0.53; p = .01). Following amygdala parcellation, in ASD subjects reduced fractional anisotropy in WM connecting the left amygdala to the temporal cortex was associated with with greater attention switching impairment (rho = -0.61; p = .02). This study demonstrates that both amygdala volume and the microstructure of connections between the amygdala and the cortex are altered in ASD. Findings indicate that the microstructure of right amygdala WM tracts are associated with overall ASD severity, but that investigation of amygdala subregions can identify more specific associations.

Shared genetic influences between dimensional ASD and ADHD symptoms during child and adolescent development.

BACKGROUND: Shared genetic influences between attention-deficit/hyperactivity disorder (ADHD) symptoms and autism spectrum disorder (ASD) symptoms have been reported. Cross-trait genetic relationships are, however, subject to dynamic changes during development. We investigated the continuity of genetic overlap between ASD and ADHD symptoms in a general population sample during childhood and adolescence. We also studied uni- and cross-dimensional trait-disorder links with respect to genetic ADHD and ASD risk. METHODS: Social-communication difficulties (N ≤ 5551, Social and Communication Disorders Checklist, SCDC) and combined hyperactive-impulsive/inattentive ADHD symptoms (N ≤ 5678, Strengths and Difficulties Questionnaire, SDQ-ADHD) were repeatedly measured in a UK birth cohort (ALSPAC, age 7 to 17 years). Genome-wide summary statistics on clinical ASD (5305 cases; 5305 pseudo-controls) and ADHD (4163 cases; 12,040 controls/pseudo-controls) were available from the Psychiatric Genomics Consortium. Genetic trait variances and genetic overlap between phenotypes were estimated using genome-wide data. RESULTS: In the general population, genetic influences for SCDC and SDQ-ADHD scores were shared throughout development. Genetic correlations across traits reached a similar strength and magnitude (cross-trait rg ≤ 1, pmin = 3 × 10-4) as those between repeated measures of the same trait (within-trait rg ≤ 0.94, pmin = 7 × 10-4). Shared genetic influences between traits, especially during later adolescence, may implicate variants in K-RAS signalling upregulated genes (p-meta = 6.4 × 10-4). Uni-dimensionally, each population-based trait mapped to the expected behavioural continuum: risk-increasing alleles for clinical ADHD were persistently associated with SDQ-ADHD scores throughout development (marginal regression R2 = 0.084%). An age-specific genetic overlap between clinical ASD and social-communication difficulties during childhood was also shown, as per previous reports. Cross-dimensionally, however, neither SCDC nor SDQ-ADHD scores were linked to genetic risk for disorder. CONCLUSIONS: In the general population, genetic aetiologies between social-communication difficulties and ADHD symptoms are shared throughout child and adolescent development and may implicate similar biological pathways that co-vary during development. Within both the ASD and the ADHD dimension, population-based traits are also linked to clinical disorder, although much larger clinical discovery samples are required to reliably detect cross-dimensional trait-disorder relationships.

Cognitive, behavioral, and neural consequences of sex chromosome aneuploidy.

The X chromosome has played a critical role in the development of sexually selected characteristics for over 300 million years, and during that time it has accumulated a disproportionate number of genes concerned with mental functions. There are relatively specific effects of X-linked genes on social cognition, language, emotional regulation, visuospatial, and numerical skills. Many human X-linked genes outside the X-Y pairing pseudoautosomal regions escape X-inactivation. Dosage differences in the expression of such genes (which constitute at least 15% of the total) are likely to play an important role in male-female neural differentiation, and in cognitive deficits and behavioral characteristics, particularly in the realm of social communication, that are associated with sex chromosome aneuploidies. © 2016 Wiley Periodicals, Inc.

Neurodevelopmental, emotional, and behavioural problems in Duchenne muscular dystrophy in relation to underlying dystrophin gene mutations.

AIM: Duchenne muscular dystrophy (DMD) is associated with neuropsychiatric disorders. The aim of the study was to characterize the DMD neuropsychiatric profile fully and to explore underlying genotype/phenotype associations. METHOD: One hundred and thirty males with DMD (mean age 9y 10mo, range 5-17y) in four European centres were included and completed IQ assessment and a neurodevelopmental-screening questionnaire. Of these, 87 underwent comprehensive neuropsychiatric assessment using structured diagnostic interview and parent-reported questionnaires. RESULTS: The overall mean score on the neurodevelopmental questionnaire was significantly abnormal compared with the general population of children (p<0.001). On average, intelligence was below the population mean, with intellectual disability observed in 34 males (26%). Autistic spectrum disorder was identified in 18 (21%), hyperactivity in 21 (24%), and inattention in 38 (44%). Clinical levels of internalizing and externalizing problems were observed in 21 (24%) and 13 (15%) respectively. Over a third of males scored more than two measures of emotional, behavioural, or neurodevelopmental problems. Males with mutations at the 3' end of the DMD gene affecting all protein isoforms had higher rates of intellectual disability and clusters of symptoms. INTERPRETATION: Males with DMD are at very high risk of neuropsychiatric disturbance, and this risk appears to increase with mutations at the 3' end of the gene. Patterns of symptom clusters suggest a DMD neuropsychiatric syndrome, which may require prompt evaluation and early intervention.

Variation in the X-linked EFHC2 gene is associated with social cognitive abilities in males.

Females outperform males on many social cognitive tasks. X-linked genes may contribute to this sex difference. Males possess one X chromosome, while females possess two X chromosomes. Functional variations in X-linked genes are therefore likely to impact more on males than females. Previous studies of X-monosomic women with Turner syndrome suggest a genetic association with facial fear recognition abilities at Xp11.3, specifically at a single nucleotide polymorphism (SNP rs7055196) within the EFHC2 gene. Based on a strong hypothesis, we investigated an association between variation at SNP rs7055196 and facial fear recognition and theory of mind abilities in males. As predicted, males possessing the G allele had significantly poorer facial fear detection accuracy and theory of mind abilities than males possessing the A allele (with SNP variant accounting for up to 4.6% of variance). Variation in the X-linked EFHC2 gene at SNP rs7055196 is therefore associated with social cognitive abilities in males.

Variability in the common genetic architecture of social-communication spectrum phenotypes during childhood and adolescence.

BACKGROUND: Social-communication abilities are heritable traits, and their impairments overlap with the autism continuum. To characterise the genetic architecture of social-communication difficulties developmentally and identify genetic links with the autistic dimension, we conducted a genome-wide screen of social-communication problems at multiple time-points during childhood and adolescence. METHODS: Social-communication difficulties were ascertained at ages 8, 11, 14 and 17 years in a UK population-based birth cohort (Avon Longitudinal Study of Parents and Children; N ≤ 5,628) using mother-reported Social Communication Disorder Checklist scores. Genome-wide Complex Trait Analysis (GCTA) was conducted for all phenotypes. The time-points with the highest GCTA heritability were subsequently analysed for single SNP association genome-wide. Type I error in the presence of measurement relatedness and the likelihood of observing SNP signals near known autism susceptibility loci (co-location) were assessed via large-scale, genome-wide permutations. Association signals (P ≤ 10-5) were also followed up in Autism Genetic Resource Exchange pedigrees (N = 793) and the Autism Case Control cohort (Ncases/Ncontrols = 1,204/6,491). RESULTS: GCTA heritability was strongest in childhood (h2(8 years) = 0.24) and especially in later adolescence (h2(17 years) = 0.45), with a marked drop during early to middle adolescence (h2(11 years) = 0.16 and h2(14 years) = 0.08). Genome-wide screens at ages 8 and 17 years identified for the latter time-point evidence for association at 3p22.2 near SCN11A (rs4453791, P = 9.3 × 10-9; genome-wide empirical P = 0.011) and suggestive evidence at 20p12.3 at PLCB1 (rs3761168, P = 7.9 × 10-8; genome-wide empirical P = 0.085). None of these signals contributed to risk for autism. However, the co-location of population-based signals and autism susceptibility loci harbouring rare mutations, such as PLCB1, is unlikely to be due to chance (genome-wide empirical Pco-location = 0.007). CONCLUSIONS: Our findings suggest that measurable common genetic effects for social-communication difficulties vary developmentally and that these changes may affect detectable overlaps with the autism spectrum.

Common polymorphism in the oxytocin receptor gene (OXTR) is associated with human social recognition skills.

The neuropeptides oxytocin and vasopressin are evolutionarily conserved regulators of social perception and behavior. Evidence is building that they are critically involved in the development of social recognition skills within rodent species, primates, and humans. We investigated whether common polymorphisms in the genes encoding the oxytocin and vasopressin 1a receptors influence social memory for faces. Our sample comprised 198 families, from the United Kingdom and Finland, in whom a single child had been diagnosed with high-functioning autism. Previous research has shown that impaired social perception, characteristic of autism, extends to the first-degree relatives of autistic individuals, implying heritable risk. Assessments of face recognition memory, discrimination of facial emotions, and direction of gaze detection were standardized for age (7-60 y) and sex. A common SNP in the oxytocin receptor (rs237887) was strongly associated with recognition memory in combined probands, parents, and siblings after correction for multiple comparisons. Homozygotes for the ancestral A allele had impairments in the range -0.6 to -1.15 SD scores, irrespective of their diagnostic status. Our findings imply that a critical role for the oxytocin system in social recognition has been conserved across perceptual boundaries through evolution, from olfaction in rodents to visual memory in humans.

White matter microstructure correlates with autism trait severity in a combined clinical-control sample of high-functioning adults.

Diffusion tensor imaging (DTI) studies have demonstrated white matter (WM) abnormalities in tracts involved in emotion processing in autism spectrum disorder (ASD), but little is known regarding the nature and distribution of WM anomalies in relation to ASD trait severity in adults. Increasing evidence suggests that ASD occurs at the extreme of a distribution of social abilities. We aimed to examine WM microstructure as a potential marker for ASD symptom severity in a combined clinical-neurotypical population. SIENAX was used to estimate whole brain volume. Tract-based spatial statistics (TBSS) was used to provide a voxel-wise comparison of WM microstructure in 50 high-functioning young adults: 25 ASD and 25 neurotypical. The severity of ASD traits was measured by autism quotient (AQ); we examined regressions between DTI markers of WM microstructure and ASD trait severity. Cognitive abilities, measured by intelligence quotient, were well-matched between the groups and were controlled in all analyses. There were no significant group differences in whole brain volume. TBSS showed widespread regions of significantly reduced fractional anisotropy (FA) and increased mean diffusivity (MD) and radial diffusivity (RD) in ASD compared with controls. Linear regression analyses in the combined sample showed that average whole WM skeleton FA was negatively influenced by AQ (p = 0.004), whilst MD and RD were positively related to AQ (p = 0.002; p = 0.001). Regression slopes were similar within both groups and strongest for AQ social, communication and attention switching scores. In conclusion, similar regression characteristics were found between WM microstructure and ASD trait severity in a combined sample of ASD and neurotypical adults. WM anomalies were relatively more severe in the clinically diagnosed sample. Both findings suggest that there is a dimensional relationship between WM microstructure and severity of ASD traits from neurotypical subjects through to clinical ASD, with reduced coherence of WM associated with greater ASD symptoms. General cognitive abilities were independent of the relationship between WM indices and ASD traits.

Recognition of face and non-face stimuli in autistic spectrum disorder.

The ability to remember faces is critical for the development of social competence. From childhood to adulthood, we acquire a high level of expertise in the recognition of facial images, and neural processes become dedicated to sustaining competence. Many people with autism spectrum disorder (ASD) have poor face recognition memory; changes in hairstyle or other non-facial features in an otherwise familiar person affect their recollection skills. The observation implies that they may not use the configuration of the inner face to achieve memory competence, but bolster performance in other ways. We aimed to test this hypothesis by comparing the performance of a group of high-functioning unmedicated adolescents with ASD and a matched control group on a "surprise" face recognition memory task. We compared their memory for unfamiliar faces with their memory for images of houses. To evaluate the role that is played by peripheral cues in assisting recognition memory, we cropped both sets of pictures, retaining only the most salient central features. ASD adolescents had poorer recognition memory for faces than typical controls, but their recognition memory for houses was unimpaired. Cropping images of faces did not disproportionately influence their recall accuracy, relative to controls. House recognition skills (cropped and uncropped) were similar in both groups. In the ASD group only, performance on both sets of task was closely correlated, implying that memory for faces and other complex pictorial stimuli is achieved by domain-general (non-dedicated) cognitive mechanisms. Adolescents with ASD apparently do not use domain-specialized processing of inner facial cues to support face recognition memory.

Specific neural correlates of successful learning and adaptation during social exchanges.

Cooperation and betrayal are universal features of social interactions, and knowing who to trust is vital in human society. Previous studies have identified brain regions engaged by decision making during social encounters, but the mechanisms supporting modification of future behaviour by utilizing social experience are not well characterized. Using functional magnetic resonance imaging (fMRI), we show that cooperation and betrayal during social exchanges elicit specific patterns of neural activity associated with future behaviour. Unanticipated cooperation leads to greater behavioural adaptation than unexpected betrayal, and is signalled by specific neural responses in the striatum and midbrain. Neural responses to betrayal and willingness to trust novel partners both decrease as the number of individuals encountered during repeated social encounters increases. We propose that, as social groups increase in size, uncooperative or untrustworthy behaviour becomes progressively less surprising, with cooperation becoming increasingly important as a stimulus for social learning. Effects on reputation of non-trusting decisions may also act to drive pro-social behaviour. Our findings characterize the dynamic neural processes underlying social adaptation, and suggest that the brain is optimized to cooperate with trustworthy partners, rather than avoiding those who might betray us.