Molecular Autism最新文献

Background: Autism spectrum disorder (ASD) is a neurodevelopmental disorder defined by social communication deficits, repetitive behaviors and restricted interests. Studies have reported aberrant sensory responses, including altered experiences of social touch, in individuals with ASD. However, the relationship between atypical social touch and social networks in ASD remains poorly understood. Social touch is used to strengthen and manage social networks in many species. Studies in general populations across diverse cultures show that the extent of permissible touch is consistently linked to the strength of emotional bonds between the toucher and the touched individual. This study examined relationship-specific patterns of social touch and their association with emotional bonding in individuals with ASD.

Methods: Seventy adults with ASD and 70 typically developed (TD) adults rated their emotional bonds with different social network members (e.g., partners, fathers, strangers) and the pleasantness of being touched by each. Participants also identified body regions where they allowed touch. We hypothesized that patterns of interpersonal touch allowance and emotional bonding, and their relationship, would differ between ASD and TD adults.

Result: In all social network members except children and female friends, ASD adults allowed significantly less social touching than TD adults. Compared to TD adults, ASD adults also reported having significantly weaker emotional bonds with one social network member and experiencing significantly less pleasantness when touched by multiple members of their social network. In both groups, strength of emotional bond was significantly correlated with permissible touch area. Linear regression analyses showed that our ASD participants were more reliant on bodily touch allowance for emotional bonding than the TD controls.

Limitations: More participants are necessary to secure sufficient number of social network members in ASD.

Conclusions: Our results suggest that adults with ASD generally prefer less social touch from most social network members and show reduced emotional bonding with only a specific connection. In addition, touch allowance was more strongly associated with emotional bonding in ASD than TD adults. These findings highlight the influence of autistic traits on the relationship between social touch and emotional bonding within social networks.

Background: Accurately determining the sample size ("N") of a dataset is a key consideration for experimental design. Misidentification of sample size can lead to pseudoreplication, a process of artificially inflating the number of experimental replicates which systematically underestimates variability, overestimates effect sizes and invalidates statistical tests performed on the data. While many journals have adopted stringent requirements with regard to statistical reporting over the last decade, it remains unknown whether such efforts have had a meaningful impact on statistical rigour.

Methods: Here, we evaluated the prevalence of this type of statistical error among neuroscience studies involving animal models of Fragile-X Syndrome (FXS) and those using animal models of neurological disorders at large published between 2001 and 2024.

Results: We found that pseudoreplication was present in the majority of publication, increasing over time despite marked improvements in statistical reporting over the last decade. This trend generalised beyond the FXS literature to rodent studies of neurological disorders at large between 2012 and 2024, suggesting that pseudoreplication remains a widespread issue in the literature.

Limitations: The scope of this study was limited to rodent-model studies of neurological disorders which had the potential for being pseudoreplicated, by allowing repeat observations from individual animals. We did not consider reviews or articles whose experimental design could not allow for pseudoreplication, for example studies which reported only behavioural results, or studies which did not use inferential statistics.

Conclusions: These observations identify an urgent need for better standards in experimental design and increased vigilance for this type of error during peer review. While reporting standards have significantly improved over the past two decades, this alone has not been enough to curb the prevalence of pseudoreplication. We offer suggestions for how this can be remedied as well as quantifying the severity of this particular type of statistical error. Although the examined literature concerns a specific neuroscience-related area of research, the implications of pseudoreplication apply to all fields of empirical research.

Background: So-called 'mismatch accounts' propose that, rather than arising from a socio-cognitive deficit present in autistic people, mentalising difficulties are the product of a mismatch in neurotype between interaction partners. Although this idea has grown in popularity over recent years, there is currently only limited empirical evidence to support mismatch theories. Moreover, the social model of disability such theories are grounded in demands a culturally situated view of social interaction, yet research on mentalising and/or autism is largely biased towards Western countries, with little knowledge on how successful mentalising is defined differently, and how tools to assess socio-cognitive ability compare, across cultures.

Methods: Using a widely employed mentalising task-the animations task-, the current study investigated and compared the bi-directional mentalising performance of British and Japanese autistic and non-autistic adults and assessed observer-agent kinematic similarity as a potential dimension along which mismatches may occur between neurotypes. Participants were asked to depict various mental state- and action-based interactions by moving two triangles across a touch-screen device before viewing and interpreting stimuli generated by other participants.

Results: In the UK sample, our results replicate a seminal prior study in showing poorer mentalising abilities in non-autistic adults for animations generated by the autistic group. Crucially, the same pattern did not emerge in the Japanese sample, where there were no mentalising differences between the two groups.

Limitations: Limitations of the current study include that efforts to match all samples within and across cultures in terms of IQ, gender, and age were not successful in all comparisons, but control analyses suggest this did not affect our results. Furthermore, any performance differences were found for both the mental state- and action-based conditions, mirroring prior work and raising questions about the domain-specificity of the employed task.

Conclusions: Our results add support for a paradigm shift in the autism literature, moving beyond deficit-based models and towards acknowledging the inherently relational nature of social interaction. We further discuss how our findings suggest limited cultural transferability of common socio-cognitive measures rather than superior mentalising abilities in Japanese autistic adults, underscoring the need for more cross-cultural research and the development of culturally sensitive scientific and diagnostic tools.

Background: Behavioral endocrinology examines associations between hormone expression, such as testosterone and cortisol, and behavior; both of which have been implicated in autism spectrum disorder (ASD). The overarching aim of the study was to examine the intersection of sex-based (Male, Female), hormonal (testosterone, cortisol), diagnostic (ASD, typically developing, (TD)) and developmental (age, puberty) patterns over four years of a longitudinal study in a well-characterized sample of youth (spanning 10 to 17 years).

Methods: In year 1 (Y1), participants included 140 autistic youth (36 females, 104 males) and 105 TD youth (46 females, 59 males.). For Y4, participants included 83 ASD and 77 TD youth. Immediate waking morning salivary samples were collected for hormone assay. Mixed effects and ordinary linear regression models were used, as well as mediation effects of hormones on behavior.

Results: For cortisol, there was a significant diagnosis by sex by age interaction (X² = 15.62, df = 3, p = 0.0014, S = 0.2446) showing that autistic females evidence higher morning cortisol that increased over developmental progression compared to TD females. Moreover, ASD males had stunted testosterone growth compared to TD males (Est = 0.1530, p = 0.0130). Regarding biobehavioral associations in year 1, diagnosis (X² = 80.72, df = 1, p < 0.0001, S = 0.5704) and cortisol (X² = 14.42, df = 3, p = 0.0024, S = 0.2159) were associated with social problems; however, there were no effects for testosterone on diagnosis or a mediation effect on social problems. There was a significant effect of diagnosis on CBCL Aggression score (X² = 34.39, df = 1, p < 0.0001, S = 0.3692) independent of hormonal measurements.

Limitations: Despite the large sample, it was not fully representative based on race, ethnicity or intellectual profile. Attrition of the sample is also acknowledged especially between portions of Y2 and Y3 due to the COVID-19 pandemic. Finally, only the immediate morning salivary samples were used due to lower and undetectable concentration levels of testosterone in younger and female children.

Conclusions: Collectively, these findings underscore the need to elucidate the biobehavioral patterns that emerge during the complex adolescent transition for autistic youth to determine how they impact clinical and long-term outcomes. The unique hormonal trajectories may be related to differences in advanced pubertal progression and affective states found in autistic females.

Background: The key pathological mechanisms underlying autism spectrum disorder (ASD) remain relatively undetermined, potentially due to the heterogenous nature of the condition. Targeted studies of a series of monogenic ASDs have revealed postsynaptic dysfunction as a central conserved mechanism. Presynaptic dysfunction is emerging as an additional disease locus in neurodevelopmental disorders; however, it is unclear whether this dysfunction drives ASD or is an adaptation to the altered brain microenvironment.

Methods: To differentiate between these two competing scenarios, we performed a high content analysis of key stages of the synaptic vesicle lifecycle in primary neuronal cultures derived from a series of preclinical rat models of monogenic ASD. These five independent models (Nrxn1^+/-, Nlgn3^-/y, Syngap^+/-, Syngap^+/Δ-GAP, Pten^+/-) were specifically selected to have perturbations in a diverse palette of genes that were expressed either at the pre- or post-synapse. Synaptic vesicle exocytosis and cargo trafficking were triggered via two discrete trains of activity and monitored using the genetically-encoded reporter synaptophysin-pHluorin. Activity-dependent bulk endocytosis was assessed during intense neuronal activity using the fluid phase marker tetramethylrhodamine-dextran.

Results: Both synaptic vesicle fusion events and cargo trafficking were unaffected in all models investigated under all stimulation protocols. However, a key convergent phenotype across neurons derived from all five models was revealed, a depression in activity-dependent bulk endocytosis.

Limitations: The study is exclusively conducted in primary cultures of hippocampal neurons; therefore, the impact on neurons from other brain regions or altered brain microcircuitry was not assessed. No molecular mechanism has been identified for this depression.

Conclusion: This suggests that depression of activity-dependent bulk endocytosis is a presynaptic homeostatic mechanism to correct for intrinsic dysfunction in ASD neurons.

Background: Divergent age-related functional brain connectivity in autism spectrum disorder (ASD) has been observed using resting-state fMRI, although the specific findings are inconsistent across studies. Common statistical regression approaches that fit identical models across functional brain networks may contribute to these inconsistencies. Relationships among functional networks have been reported to follow unique nonlinear developmental trajectories, suggesting the need for flexible modeling. Here we apply generalized additive models (GAMs) to flexibly adapt to distinct network trajectories and simultaneously describe divergent age-related changes from childhood into mid-adulthood in ASD.

Methods: 1107 males, aged 5-40, from the ABIDE I & II cross-sectional datasets were analyzed. Functional connectivity was extracted using a network-based template. Connectivity values were harmonized using COMBAT-GAM. Connectivity-age relationships were assessed with thin-plate spline GAMs. Post-hoc analyses defined the age-ranges of divergent aging in ASD.

Results: Typically developing (TD) and ASD groups shared 15 brain connections that significantly changed with age (FDR-corrected p < 0.05). Network connectivity exhibited diverse nonlinear age-related trajectories across the functional connectome. Comparing ASD and TD groups, default mode to central executive between-network connectivity followed similar nonlinear paths with no group differences. Contrarily, the ASD group had chronic hypoconnectivity throughout default mode-ventral attentional (salience) and default mode-somatomotor aging trajectories. Within-network somatomotor connectivity was similar between groups in childhood but diverged in adolescence with the ASD group showing decreased within-network connectivity. Network connectivity between the somatomotor network and various other functional networks had fully disrupted age-related pathways in ASD compared to TD, displaying significantly different model curvatures and fits.

Limitations: The present analysis includes only male participants and has a restricted age range, limiting analysis of early development and later life aging, years 40 and beyond. Additionally, our analysis is limited to large-scale network cortical functional parcellation. To parse more specificity of brain region connectivity, a fine-grained functional parcellation including subcortical areas may be warranted.

Conclusion: Flexible non-linear modeling minimizes statistical assumptions and allows diagnosis-related brain connections to follow independent data-driven age-related pathways. Using GAMs, we describe complex age-related pathways throughout the human connectome and observe distinct periods of divergence in autism.

Imitation is foundational to early social learning, yet autistic children often exhibit significant impairments in imitation, potentially impacting their social communication skills. This study examined the relationship between imitation abilities and social communication in autistic children and evaluated the effectiveness of the Early Start Denver Model (ESDM) intervention. The study included 52 autistic children aged 2-5, divided into an experimental group receiving ESDM intervention and a control group undergoing standard rehabilitation. We assessed the children's imitation and social communication skills before and after the intervention. Results indicated a significant positive correlation between imitation and social communication skills both before and after the intervention. Specifically, various forms of imitation (e.g., vocal, gestural, object-related) were closely linked to different domains of social communication (e.g., expressive communication, joint attention, social skills). Baseline imitation levels and improvements in imitation were significant predictors of enhanced social communication, jointly accounting for over half of the observed improvements in social communication, with imitation improvement being the strongest predictor. Age positively moderated the relationship between imitation and social communication, with older children showing a stronger impact of imitation on social communication. Although these effects were evident across groups, the ESDM group showed greater gains in imitation skills compared to the control group. However, we did not find evidence of an intervention effect on social communication skills. This study underscores the critical role of imitation in the social communication development of autistic children. These findings support the enhancement of imitation skills in early interventions for autistic children, highlighting the effectiveness of ESDM in fostering imitation abilities.

Background: Autism spectrum disorder (ASD) is marked by disruptions in low-level sensory processing and higher-order sociocognitive functions, suggesting a complex interplay between different brain regions across the cortical hierarchy. However, the developmental trajectory of this hierarchical organization in ASD remains underexplored. Herein, we investigated the maturational abnormalities in the cortical hierarchy among individuals with ASD.

Methods: Resting-state functional magnetic resonance imaging data from three large-scale datasets were analyzed: Autism Brain Imaging Data Exchange I and II and Lifespan Human Connectome Project Development (aged 5-22 years). The principal functional connectivity gradient representing cortical hierarchy was estimated using diffusion map embedding. By applying normative modeling with the generalized additive model for location, scale, and shape (GAMLSS), we captured the nonlinear trajectories of the developing functional gradient, as well as the individual-level deviations in ASD from typical development based on centile scores measured as deviations from the normative curves. A whole-brain summary metric, the functional hierarchy score, was derived to measure the extent of abnormal maturation in individuals with ASD. Finally, through a series of mediation analyses, we examined the potential role of network-level connectomic disruptions between the diagnoses and deviations in the cortical hierarchy.

Results: The maturation of cortical hierarchy in individuals with ASD followed a non-linear trajectory, showing delayed maturation during childhood compared to that of typically developing individuals, followed by an accelerated "catch-up" phase during adolescence and a subsequent decline in young adulthood. The nature of these deviations varied across networks, with sensory and attention networks displaying the most pronounced abnormalities in childhood, while higher-order networks, particularly the default mode network (DMN), remaining impaired from childhood to adolescence. Mediation analyses revealed that the persistent reduction in DMN segregation throughout development was a key contributor to the atypical development of cortical hierarchy in ASD.

Limitations: The uneven distribution of samples across age groups, particularly in the later stages of development, limited our ability to fully capture developmental trajectories among older individuals.

Conclusions: These findings highlight the importance of understanding the developmental trajectories of cortical organization in ASD, collectively suggesting that early interventions aimed at promoting the normative development of higher-order networks may be critical for improving outcomes in individuals with ASD.