Changing perspectives on autism: Overlapping contributions of evolutionary psychiatry and the neurodiversity movement.

Perspectives on autism and psychiatric conditions are affected by a mix of scientific and social influences. Evolutionary psychiatry (EP) and the neurodiversity movement are emerging paradigms that reflect these distinct influences, with the former grounded in scientific theory and the latter driven by political and social principles. Despite their separate foundations, there is a significant overlap between EP and neurodiversity that has not been explored. Specifically, both paradigms reframe disorders as natural cognitive differences rather than disease; expand the concept of "normal" beyond that implied in modern psychiatry; focus on relative strengths; recognize that modern environments disadvantage certain individuals to cause functional impairment; emphasize cognitive variation being socially accommodated and integrated rather than treated or cured; and can help reduce stigmatization. However, in other ways, they are distinct and sometimes in conflict. EP emphasizes scientific explanation, defines "dysfunction" in objective terms, and differentiates heterogenous cases based on underlying causes (e.g. autism due to de novo genetic mutations). The neurodiversity movement emphasizes social action, removes barriers to inclusion, promotes inclusive language, and allows unrestricted identification as neurodivergent. By comparing and contrasting these two approaches, we find that EP can, to some extent, support the goals of neurodiversity. In particular, EP perspectives could be convincing to groups more responsive to scientific evidence and help achieve a middle ground between neurodiversity advocates and critics of the movement.

CD38 genetic variation is associated with increased personal distress to an emotional stimulus.

Genetic variation in CD38-a putative oxytocin pathway gene-has been linked to higher oxytocin levels, empathy, and sensitive parenting, but also to more negative interpersonal outcomes (e.g., alienation from friends and family, poorer romantic relationship quality). To reconcile these seemingly contradictory findings, we drew upon the idea that CD38 variation may heighten social-emotional sensitivity and, consequently, make individuals prone to negative emotions in distressing interpersonal situations. To test this hypothesis, we performed a secondary analysis of a dataset including participants' (n = 171; 94 females) empathic concern ("sympathetic") and distress-related ("anxious") responses to an emotional video. Distress responses were higher for the CD38 rs3796863 AA/AC group vs. the CC group (p = 0.03, η2 = 0.027); however, there was no significant effect of genotype for empathic concern responses to the video or for indices of trait empathy. These findings provide preliminary evidence that, in the face of an interpersonal stressor, CD38 genetic variation may predict more self-focused, aversive emotional reactions. More broadly, this finding highlights the need to adopt a more nuanced perspective in which the influence of oxytocin system variation (assessed by oxytocin-related genetic variation) should be considered in light of the social context.

Oxytocin enhances basolateral amygdala activation and functional connectivity while processing emotional faces: preliminary findings in autistic vs non-autistic women.

Oxytocin is hypothesized to promote social interactions by enhancing the salience of social stimuli. While previous neuroimaging studies have reported that oxytocin enhances amygdala activation to face stimuli in autistic men, effects in autistic women remain unclear. In this study, the influence of intranasal oxytocin on activation and functional connectivity of the basolateral amygdala-the brain's 'salience detector'-while processing emotional faces vs shapes was tested in 16 autistic and 21 non-autistic women by functional magnetic resonance imaging in a placebo-controlled, within-subject, cross-over design. In the placebo condition, minimal activation differences were observed between autistic and non-autistic women. However, significant drug × group interactions were observed for both basolateral amygdala activation and functional connectivity. Oxytocin increased left basolateral amygdala activation among autistic women (35-voxel cluster, Montreal Neurological Institute (MNI) coordinates of peak voxel = -22 -10 -28; mean change = +0.079%, t = 3.159, PTukey = 0.0166) but not among non-autistic women (mean change = +0.003%, t = 0.153, PTukey = 0.999). Furthermore, oxytocin increased functional connectivity of the right basolateral amygdala with brain regions associated with socio-emotional information processing in autistic women, but not in non-autistic women, attenuating group differences in the placebo condition. Taken together, these findings extend evidence of oxytocin's effects on the amygdala to specifically include autistic women and specify the subregion of the effect.

Effects of oxytocin administration on salivary sex hormone levels in autistic and neurotypical women.

BACKGROUND: Oxytocin administration, which may be of therapeutic value for individuals with social difficulties, is likely to affect endogenous levels of other socially relevant hormones. However, to date, the effects of oxytocin administration on endogenous hormones have only been examined in neurotypical individuals. The need to consider multi-hormone interactions is particularly warranted in oxytocin trials for autism due to evidence of irregularities in both oxytocin and sex steroid systems. METHODS: In this double-blind cross-over study, saliva samples were collected from 16 autistic and 29 neurotypical women before and after intranasal administration of 24 IU oxytocin or placebo. Oestradiol, testosterone, and oxytocin levels were quantified in saliva samples. Participants also completed the Autism-Spectrum Quotient (AQ) and Empathy Quotient (EQ) questionnaires. RESULTS: Distinct patterns of change in testosterone and oestradiol levels pre- to-post-administration were observed in autistic relative to neurotypical women (ANCOVA, p < 0.05 main effect of Group), controlling for sample collection time. The mean percent change oestradiol was + 8.8% for the autism group and - 13.0% for the neurotypical group (t = 1.81, p = 0.08), while the mean percent change testosterone was + 1.1% in the autism group and - 12.6% in the neurotypical group (t = 1.26, p = 0.22). In the oxytocin condition, the mean percent change oestradiol was + 12.6% in the autism group and - 6.9% in the neurotypical group (t = 1.78, p = 0.08), while the mean percent change testosterone was + 14.4% in the autism group and - 15.2% in the neurotypical group (t = 3.00, p = 0.006). Robust regression confirmed that group differences in percent change hormone levels were not driven by a small number of influential individuals. Baseline hormone levels did not differ between groups when considered individually. However, baseline testosterone relative to oestradiol (T:E2 ratio) was higher in autistic women (p = 0.023, Cohen's d = 0.63), and this ratio correlated positively and negatively with AQ and EQ scores, respectively, in the combined sample. LIMITATIONS: Further studies with larger and more diverse autistic sample are warranted to confirm these effects. CONCLUSIONS: This study provides the first evidence that oxytocin influences endogenous testosterone levels in autistic individuals, with autistic women showing increases similar to previous reports of neurotypical men. These findings highlight the need to consider sex steroid hormones as a variable in future oxytocin trials.

Experimental empathy induction promotes oxytocin increases and testosterone decreases.

Oxytocin and testosterone coordinate adaptive social behaviors with stimuli in the environment. Administration of oxytocin and testosterone is associated with increased and reduced indicators of empathy, respectively, but how levels of these hormones are jointly affected by naturalistic empathy-inducing stimuli remains unclear. In this study, salivary oxytocin and testosterone levels were measured in 173 healthy adults before and after watching a video involving a gravely ill child. Participants also completed questionnaires to assess psychological variables predicted to affect oxytocin reactivity (Autism-Spectrum Quotient, Interpersonal Reactivity Index, Empathy and Systemizing Quotients). On average, there was a 14% increase in oxytocin (p = 0.003) and 4% decrease in testosterone (p = 0.001) pre- to post-video. Opposite directional changes in hormone levels occurred together, as supported by a chi-square test (p < 0.001) and a circular statistics test (p < 0.05). Considered separately, psychological traits did not predict hormone levels or changes to any appreciable degree. However, oxytocin and testosterone changes were linked with empathy relative to systemizing such that: (1) 'Empathy Bias' was associated with a large oxytocin increase but little change in testosterone, while (2) 'Systemizing Bias' and 'Balance' between empathy and systemizing were associated with a decrease in testosterone but little change in oxytocin. These findings suggest that participants were divisible into 'high oxytocin responders' (relatively empathetic) and 'high testosterone responders' (balanced or systemizing-biased). These findings support a model of joint, opposite changes in oxytocin and testosterone under experimental empathy induction, with high, somewhat predictable, diversity in individual responses.

Using a Psychopharmacogenetic Approach To Identify the Pathways Through Which-and the People for Whom-Testosterone Promotes Aggression.

Little is known about the neurobiological pathways through which testosterone promotes aggression or about the people in whom this effect is observed. Using a psychopharmacogenetic approach, we found that testosterone increases aggression in men ( N = 308) with select personality profiles and that these effects are further enhanced among those with fewer cytosine-adenine-guanine (CAG) repeats in exon 1 of the androgen receptor (AR) gene, a polymorphism associated with increased AR efficiency. Testosterone's effects were rapid (~30 min after administration) and mediated, in part, by subjective reward associated with aggression. Testosterone thus appears to promote human aggression through an AR-related mechanism and to have stronger effects in men with the select personality profiles because it more strongly upregulates the subjective pleasure they derive from aggression. Given other evidence that testosterone regulates reward through dopaminergic pathways, and that the sensitivity of such pathways is enhanced among individuals with the personality profiles we identified, our findings may also implicate dopaminergic processes in testosterone's heterogeneous effects on aggression.

Effect of exogenous testosterone on cooperation depends on personality and time pressure.

The social heuristic hypothesis posits that human cooperation is an intuitive response that is expressed especially under conditions of time-constraint. Conversely, it proposes that for individuals given an opportunity for reflection, cooperation is more likely to be curtailed by an optimizing process calibrated to maximize individual benefit in a given situation. Notably, the steroid hormone testosterone has also been implicated in intuitive decision-making, including both prosocial and anti-social behaviors, with effects strongest in men with particular dispositional characteristics. This raises the possibility that increased testosterone may augment the effects predicted by the social heuristic hypothesis, particularly among men higher in specific dispositional characteristics (dominance, impulsivity, independent self-construal: high risk for testosterone-induced antisocial behavior). Here, in a testosterone administration study with a relatively large sample of men (N = 400), we test this possibility in a double-blind, placebo-controlled paradigm, with men randomly assigned to play a one-shot public goods game either under time-pressure (forced intuition) or with a time delay (forced reflection). Results revealed that within the placebo group, time-pressure (versus forced delay) increased cooperation among low risk men, but decreased cooperation among high risk men. Testosterone further moderated this pattern by abolishing the time-pressure effect in low risk men and-in high risk men-reversing the effect by selectively reducing offers (compared to placebo) under forced delay. This is the first evidence that testosterone and personality can interact with time-pressure and delay to predict human cooperation.

Williams syndrome deletions and duplications: Genetic windows to understanding anxiety, sociality, autism, and schizophrenia.

We describe and evaluate an integrative hypothesis for helping to explain the major neurocognitive features of individuals with Williams syndrome region deletions and duplications. First, we demonstrate how the cognitive differences between Williams syndrome individuals, individuals with duplications of this region, and healthy individuals parallel the differences between individuals subject to effects of increased or decreased oxytocin. Second, we synthesize evidence showing that variation in expression of the gene GTF2I (General Transcription Factor II-I) underlies the primary social phenotypes of Williams syndrome and that common genetic variation in GTF2I mediates oxytocin reactivity, and its correlates, in healthy populations. Third, we describe findings relevant to the hypothesis that the GTF2I gene is subject to parent of origin effects whose behavioral expression fits with predictions from the kinship theory of genomic imprinting. Fourth, we describe how Williams syndrome can be considered, in part, as an autistic syndrome of Lorna Wing's 'active-but-odd' autism subtype, in contrast to associations of duplications with both schizophrenia and autism.

The Williams syndrome prosociality gene GTF2I mediates oxytocin reactivity and social anxiety in a healthy population.

The neurohormone oxytocin plays a central role in human social behaviour and cognition, and oxytocin dysregulation may contribute to psychiatric disorders. However, genetic factors influencing individual variation in the oxytocinergic system remain poorly understood. We genotyped 169 healthy adults for a functional polymorphism in GTF2I (general transcription factor II-I), a gene associated with high prosociality and reduced social anxiety in Williams syndrome, a condition reported to involve high oxytocin levels and reactivity. Participants' salivary oxytocin levels were measured before and after watching a validated empathy-inducing video. Oxytocin reactivity, defined as pre- to post-video percentage change in salivary oxytocin, varied substantially and significantly between individuals with different GTF2I genotypes, with, additionally, a trend towards an interaction between genotype and sex. Individuals with more oxytocin-reactive genotypes also reported significantly lower social anxiety. These findings suggest a model whereby GTF2I has a continuum of effects on human sociality, from the extreme social phenotypes and oxytocin dysregulation associated with gene deletion in Williams syndrome, to individual differences in oxytocin reactivity and sociality associated with common polymorphisms in healthy populations.

Association testing of vasopressin receptor 1a microsatellite polymorphisms in non-clinical autism spectrum phenotypes.

Variation in the AVPR1a gene, which codes for a receptor for the neurohormone vasopressin, has been found to relate to autism risk. Interestingly, variation in this gene also relates to differences in social behaviour in non-clinical populations. Variation in this gene may affect expression of AVPR1a receptors in brain areas involved in social behaviour. Here, we tested whether AVPR1a variation was associated with Autism Quotient (AQ) scores, a questionnaire that measures non-clinical manifestations of autism, in a population of 873 healthy university students. The AVPR1a RS1 and RS3 microsatellites were examined, and variants were categorized as "long" or "short". The RS3 long/long genotype was significantly associated with a higher AQ score (i.e., a more autistic-like phenotype) for the combined population and for females only. Further examination showed that this relationship was due to a specific RS3 variant, termed the "target allele", which previous research has linked to reduced altruism and increased marital problems in healthy individuals. We also observed that the relationship between RS3 genotype and AQ score was mainly due to the "attention switching" (the ability to shift attention from one task to another) component of the questionnaire; this ability is commonly impaired in autism spectrum disorders. Overall, our study establishes continuity between the existing AVPR1a research in clinical and non-clinical populations. Our results suggest that vasopressin may exert its effects on social behaviour in part by modulating attentional focus between social and non-social cues. Autism Res 2017, 10: 750-756. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.