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Early-onset neurodevelopmental conditions (e.g., autism) affect males more frequently than females. Androgens may play a role in this male-bias by sex-differentially impacting early prenatal brain development, particularly neural circuits that later develop specialized roles in social cognition. Here, we find that increasing prenatal testosterone in humans is associated with later reduction of functional connectivity between social brain default mode (DMN) subsystems in adolescent males, but has no effect in females. Since testosterone can work directly via the androgen receptor (AR) or indirectly via the estrogen receptor through aromatase conversion to estradiol, we further examined how a potent non-aromatizable androgen, dihydrotestosterone (DHT), acts via the AR to influence gene expression in human neural stem cells (hNSC)—particularly for genes of high-relevance for DMN circuitry. DHT dysregulates a number of genes enriched for syndromic causes of autism and intellectual disability and for genes that in later development are expressed in anatomical patterns that highly correspond to the cortical midline DMN subsystem. DMN-related and DHT-affected genes (e.g., MEF2C) are involved in a number of synaptic processes, many of which impact excitation-inhibition balance. Androgens have male-specific prenatal influence over social brain circuitry in humans and may be relevant towards explaining some component of male-bias in early-onset neurodevelopmental conditions.

Funder: National Institute for Psychobiology in Israel, Hebrew University of Jerusalem; FundRef: https://doi.org/10.13039/501100001739, Funder: Templeton World Charitable Foundation, Funder: NIHR Biomedical Research Centre in Cambridge, Funder: Autism Research Trust, Sex-steroids, such as testosterone, are thought to be one of the biological factors implicated in autism. This relies on the sex bias in the diagnosis of autism (boys are approximately four times more likely to be diagnosed than girls) and findings of associations with fetal testosterone levels in traits and abilities related to autism. The current study aimed to examine the association between medical conditions and physical symptoms, which tend to manifest in adulthood, and autism in females. Moreover, we examined their association with autistic traits throughout the spectrum. We focused on autistic women because there is little research focusing on the healthcare needs of autistic women, but those that exist suggest heightened vulnerability, and lower access to medical care. We find that conditions related to steroid hormones function are more frequent in autistic women and that they correlate with autistic traits. Specifically, we found that body mass index, reproductive system diagnoses, prediabetes symptoms, irregular puberty onset, and menstrual irregularities were significantly more frequent in autistic women and were significantly correlated with autistic traits in neurotypical women. The findings have important implications for raising awareness in autistic women of the possibility of medical conditions which might need medical attention. In addition, healthcare providers should consider these associations when performing healthcare maintenance checks and/or screening for autism.

Early-onset neurodevelopmental conditions (e.g., autism) affect males more frequently than females. Androgens may play a role in this male-bias by sex-differentially impacting early prenatal brain development, particularly neural circuits that later develop specialized roles in social cognition. Here, we find that increasing prenatal testosterone in humans is associated with later reduction of functional connectivity between social brain default mode (DMN) subsystems in adolescent males, but has no effect in females. Since testosterone can work directly via the androgen receptor (AR) or indirectly via the estrogen receptor through aromatase conversion to estradiol, we further examined how a potent non-aromatizable androgen, dihydrotestosterone (DHT), acts via the AR to influence gene expression in human neural stem cells (hNSC)-particularly for genes of high-relevance for DMN circuitry. DHT dysregulates a number of genes enriched for syndromic causes of autism and intellectual disability and for genes that in later development are expressed in anatomical patterns that highly correspond to the cortical midline DMN subsystem. DMN-related and DHT-affected genes (e.g., MEF2C) are involved in a number of synaptic processes, many of which impact excitation-inhibition balance. Androgens have male-specific prenatal influence over social brain circuitry in humans and may be relevant towards explaining some component of male-bias in early-onset neurodevelopmental conditions.

The results leading to this publication have received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 777394 for the project AIMS-2-TRIALS. This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation programme and EFPIA and AUTISM SPEAKS, Autistica, SFARI. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results. Any views expressed are those of the author(s) and not necessarily those of the funders.

Supplemental material, sj-docx-1-aut-10.1177_13623613211022091 for Medical symptoms and conditions in autistic women by Tslil Simantov, Alexa Pohl, Alexandros Tsompanidis, Elizabeth Weir, Michael V Lombardo, Amber Ruigrok, Paula Smith, Carrie Allison, Simon Baron-Cohen and Florina Uzefovsky in Autism

The prevalence, age of onset, and symptomatology of many neuropsychiatric conditions differ between males and females. To understand the causes and consequences of sex differences it is important to establish where they occur in the human brain. We report the first meta-analysis of typical sex differences on global brain volume, a descriptive account of the breakdown of studies of each compartmental volume by six age categories, and whole-brain voxel-wise meta-analyses on brain volume and density. Gaussian-process regression coordinate-based meta-analysis was used to examine sex differences in voxel-based regional volume and density. On average, males have larger total brain volumes than females. Examination of the breakdown of studies providing total volumes by age categories indicated a bias towards the 18-59 year-old category. Regional sex differences in volume and tissue density include the amygdala, hippocampus and insula, areas known to be implicated in sex-biased neuropsychiatric conditions. Together, these results suggest candidate regions for investigating the asymmetric effect that sex has on the developing brain, and for understanding sex-biased neurological and psychiatric conditions.

We organized 10Kin1day, a pop-up scientific event with the goal to bring together neuroimaging groups from around the world to jointly analyze 10,000+ existing MRI connectivity datasets during a 3-day workshop. In this report, we describe the motivation and principles of 10Kin1day, together with a public release of 8,000+ MRI connectome maps of the human brain.

Prior work has revealed sex/gender-dependent autistic characteristics across behavioural and neural/biological domains. It remains unclear whether and how neural sex/gender differences are related to behavioural sex/gender differences in autism. Here, we examined whether atypical neural responses during mentalizing and self-representation are sex/gender-dependent in autistic adults and explored whether 'camouflaging' (acting as if behaviourally neurotypical) is associated with sex/gender-dependent neural responses. In total, N = 119 adults (33 typically developing males, 29 autistic males, 29 typically developing females and 28 autistic females) participated in a task-related functional magnetic resonance imaging paradigm to assess neural activation within right temporo-parietal junction and ventromedial prefrontal cortex during mentalizing and self-representation. Camouflaging in autism was quantified as the discrepancy between extrinsic behaviour in social-interpersonal contexts and intrinsic status. While autistic men showed hypoactive right temporo-parietal junction mentalizing and ventromedial prefrontal cortex self-representation responses compared to typically developing men, such neural responses in autistic women were not different from typically developing women. In autistic women only, increasing camouflaging was associated with heightened ventromedial prefrontal cortex self-representation response. There is a lack of impaired neural self-representation and mentalizing in autistic women compared to typically developing women. Camouflaging is heightened in autistic women and may relate to neural self-representation response. These results reveal brain-behaviour relations that help explain sex/gender-heterogeneity in social brain function in autism.

Excitation-inhibition (E:I) imbalance is theorized as an important pathophysiological mechanism in autism. Autism affects males more frequently than females and sex-related mechanisms (e.g., X-linked genes, androgen hormones) can influence E:I balance. This suggests that E:I imbalance may affect autism differently in males versus females. With a combination of in-silico modeling and in-vivo chemogenetic manipulations in mice, we first show that a time-series metric estimated from fMRI BOLD signal, the Hurst exponent (H), can be an index for underlying change in the synaptic E:I ratio. In autism we find that H is reduced, indicating increased excitation, in the medial prefrontal cortex (MPFC) of autistic males but not females. Increasingly intact MPFC H is also associated with heightened ability to behaviorally camouflage social-communicative difficulties, but only in autistic females. This work suggests that H in BOLD can index synaptic E:I ratio and that E:I imbalance affects autistic males and females differently., eLife, 9, ISSN:2050-084X

BACKGROUND: The tremendous clinical and aetiological diversity among individuals with autism spectrum disorder (ASD) has been a major obstacle to the development of new treatments, as many may only be effective in particular subgroups. Precision medicine approaches aim to overcome this challenge by combining pathophysiologically based treatments with stratification biomarkers that predict which treatment may be most beneficial for particular individuals. However, so far, we have no single validated stratification biomarker for ASD. This may be due to the fact that most research studies primarily have focused on the identification of mean case-control differences, rather than within-group variability, and included small samples that were underpowered for stratification approaches. The EU-AIMS Longitudinal European Autism Project (LEAP) is to date the largest multi-centre, multi-disciplinary observational study worldwide that aims to identify and validate stratification biomarkers for ASD. METHODS: LEAP includes 437 children and adults with ASD and 300 individuals with typical development or mild intellectual disability. Using an accelerated longitudinal design, each participant is comprehensively characterised in terms of clinical symptoms, comorbidities, functional outcomes, neurocognitive profile, brain structure and function, biochemical markers and genomics. In addition, 51 twin-pairs (of which 36 had one sibling with ASD) are included to identify genetic and environmental factors in phenotypic variability. RESULTS: Here, we describe the demographic characteristics of the cohort, planned analytic stratification approaches, criteria and steps to validate candidate stratification markers, pre-registration procedures to increase transparency, standardisation and data robustness across all analyses, and share some 'lessons learnt'. A clinical characterisation of the cohort is given in the companion paper (Charman et al., accepted). CONCLUSION: We expect that LEAP will enable us to confirm, reject and refine current hypotheses of neurocognitive/neurobiological abnormalities, identify biologically and clinically meaningful ASD subgroups, and help us map phenotypic heterogeneity to different aetiologies.

Excitation-inhibition (E:I) imbalance is theorized as an important pathophysiological mechanism in autism. Autism affects males more frequently than females and sex-related mechanisms (e.g., X-linked genes, androgen hormones) can influence E:I balance. This suggests that E:I imbalance may affect autism differently in males versus females. With a combination of in-silico modeling and in-vivo chemogenetic manipulations in mice, we first show that a time-series metric estimated from fMRI BOLD signal, the Hurst exponent (H), can be an index for underlying change in the synaptic E:I ratio. In autism we find that H is reduced, indicating increased excitation, in the medial prefrontal cortex (MPFC) of autistic males but not females. Increasingly intact MPFC H is also associated with heightened ability to behaviorally camouflage social-communicative difficulties, but only in autistic females. This work suggests that H in BOLD can index synaptic E:I ratio and that E:I imbalance affects autistic males and females differently.

Additional file 2. An overview of the countries under study with regards to demographics, autism prevalence, and SEN policy. Description: BA = Bavaria; NRW = North Rhein Westphalia; S = Saxony; LS = Lower Saxony; FL = Flanders; WA = Wallonia; GC = The German Speaking Community in Belgium. * Dutch population size was found using data from Eurostat [32], the size of the Länder was reported by the German Statistics Office [34], and the Belgian population size was reported by the Belgian Federal Government [33]. ** Autism prevalence rates in the Netherlands were reported by Roelfsema and colleagues [20], in Germany by Bachmann and colleagues [35], and in Belgium by Dereu and colleagues [36].

Additional file 1. An overview of the demographics of the countries under study. Description: BA = Bavaria; NRW = North Rhein Westphalia; S = Saxony; LS = Lower Saxony; FL = Flanders; WA = Wallonia; GC = The German Speaking Community in Belgium. * Dutch population size was found using data from Eurostat [32], the size of the Länder was reported by the German Statistics Office [34], and the Belgian population size was reported by the Belgian Federal Government [33]. ** Autism prevalence rates in the Netherlands were reported by Roelfsema and colleagues [20], in Germany by Bachmann and colleagues [35], and in Belgium by Dereu and colleagues [36].

The results leading to this publication have received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 777394 for the project AIMS-2-TRIALS. This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation programme and EFPIA and AUTISM SPEAKS, Autistica, SFARI. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results. Any views expressed are those of the author(s) and not necessarily those of the funders.

Introduction: The universal right to education for people with disabilities has been highlighted by the Universal Declaration on Human Rights and the Convention on the Rights of Persons with Disabilities. In this paper, we mapped policies addressing the right to education and special education needs of autistic children in Denmark, Sweden, and Finland. Methods: A policy path analysis was carried out using a scoping review as an underlying framework for data gathering. Policy mapping was performed independently by both lead authors to increase reliability. Results and discussion: The values of the Universal Declaration of Human Rights and the Convention on the Rights of Persons with Disabilities have been closely translated into the respective education systems of the countries under study, offering special education needs services and support in mainstream education with the aim of including as many children into mainstream education as possible. Even though the education systems are comparable, the approaches between the countries under study are slightly different. Denmark and Sweden have passed several policies specifically geared towards special education needs, while Finland incorporates this more in general education policy. Conclusion: All countries under study have incorporated the values of the Universal Declaration of Human Rights and the Convention on the Rights of Persons with Disabilities in their respective education systems while emphasising the need to include as many children in the mainstream system as possible.

Additional file 1. An overview of the demographics of the countries under study. Description: BA = Bavaria; NRW = North Rhein Westphalia; S = Saxony; LS = Lower Saxony; FL = Flanders; WA = Wallonia; GC = The German Speaking Community in Belgium. * Dutch population size was found using data from Eurostat [32], the size of the Länder was reported by the German Statistics Office [34], and the Belgian population size was reported by the Belgian Federal Government [33]. ** Autism prevalence rates in the Netherlands were reported by Roelfsema and colleagues [20], in Germany by Bachmann and colleagues [35], and in Belgium by Dereu and colleagues [36].

Supplemental material, sj-docx-1-aut-10.1177_13623613211022091 for Medical symptoms and conditions in autistic women by Tslil Simantov, Alexa Pohl, Alexandros Tsompanidis, Elizabeth Weir, Michael V Lombardo, Amber Ruigrok, Paula Smith, Carrie Allison, Simon Baron-Cohen and Florina Uzefovsky in Autism

Additional file 2. An overview of the countries under study with regards to demographics, autism prevalence, and SEN policy. Description: BA = Bavaria; NRW = North Rhein Westphalia; S = Saxony; LS = Lower Saxony; FL = Flanders; WA = Wallonia; GC = The German Speaking Community in Belgium. * Dutch population size was found using data from Eurostat [32], the size of the Länder was reported by the German Statistics Office [34], and the Belgian population size was reported by the Belgian Federal Government [33]. ** Autism prevalence rates in the Netherlands were reported by Roelfsema and colleagues [20], in Germany by Bachmann and colleagues [35], and in Belgium by Dereu and colleagues [36].

We organized 10Kin1day, a pop-up scientific event with the goal to bring together neuroimaging groups from around the world to jointly analyze 10,000+ existing MRI connectivity datasets during a 3-day workshop. In this report, we describe the motivation and principles of 10Kin1day, together with a public release of 8,000+ MRI connectome maps of the human brain. Ongoing grand-scale projects like the European Human Brain Project (1), the US Brain Initiative (2), the Human Connectome Project (3), the Chinese Brainnetome (4) and exciting world-wide neuroimaging collaborations such as ENIGMA (5) herald the new era of big neuroscience. In conjunction with these major undertakings, there is an emerging trend for bottom-up initiatives, starting with small-scale projects built upon existing collaborations and infrastructures. As described by Mainen et al. (6), these initiatives are centralized around self-organized groups of researchers working on the same challenges and sharing interests and specialized expertise. These projects could scale and open up to a larger audience and other disciplines over time, eventually lining up and merging their findings with other programs to make the bigger picture., The 10Kin1day workshop was generously sponsored by the Neuroscience and Cognition program Utrecht (NCU) of the Utrecht University (https://www.uu.nl/en/research/ neuroscience-and-cognition-utrecht), the ENIGMA consortium (http://enigma.ini.usc.edu), and personal grants: MvdH: NWOVIDI (452-16-015), MQ Fellowship; SB-C: the Wellcome Trust; Medical Research Council UK; NIHR CLAHRC for Cambridgeshire and Peterborough Foundation National Health Services Trust; Autism Research Trust; LB: New Investigator Award, Canadian Institutes of Health Research; Dara Cannon: Health Research Board (HRB), Ireland (grant code HRA-POR2013-324); SC: Research Grant Council (Hong Kong)-GRF 14101714; Eveline Crone: ERC-2010-StG-263234; UD: DFG, grant FOR2107 DA1151/5-1, DA1151/5-2, SFB-TRR58, Project C09, IZKF, grant Dan3/012/17; SD: MRC-RFA-UFSP-012013 (Shared Roots MRC Flagship grant); TF: Marie Curie Programme, International Training Programme, r’Birth; DG: National Science Centre (UMO-2011/02/A/NZ5/00329); BG: National Science Centre (UMO-2011/02/A/NZ5/00329); JH: Western Sydney University Postgraduate Research Award; LH: Science Foundation Ireland, ERC; HH: Research Grant Council (Hong Kong)-GRF 14101714; LJ: Velux Stiftung, grant 369 & UZH University Research Priority Program Dynamics of Healthy Aging; AJ: DFG, grant FOR2107 JA 1890/7-1; KJ: National Science Centre (UMO-2013/09/N/HS6/02634); VK: The Russian Foundation for Basic Research (grant code 15-06-05758A); TK: DFG, grant FOR2107 KI 588/14-1, DFG, grant FOR2107 KI 588/15-1; AK: DFG, grant FOR2107 KO 4291/4-1, DFG, grant FOR2107 KO 4291/3-1; IL: The Russian Foundation for Basic Research (grant code 15-06-05758A); EL: Health and Medical Research Fund - 11121271; SiL: NHMRC-ARC Dementia Fellowship 1110414, NHMRC Dementia Research Team Grant 1095127, NHMRC Project Grant 1062319; CL-J: 537-2011, 2014849; AM: Wellcome Trust Strategic Award (104036/Z/14/Z), MRC Grant MC_PC_17209; CM: Heisenberg-Grant, German Research Foundation, DFG MO 2363/3-2; PM: Foundation for Science and Technology, Portugal - PDE/BDE/113601/2015; KN: National Science Centre (UMO-2011/02/A/NZ5/00329); PN: National Science Centre (UMO-2013/09/N/HS6/02634); JiP: NWO-Veni 451-10-007; PaR: PER and US would like to thank the Schizophrenia Research Institute and the Chief-Investigators of the Australian Schizophrenia Research Bank V. Carr, U. Schall, R. Scott, A. Jablensky, B. Mowry, P. Michie, S. Catts, F. Henskens, and C. Pantelis; AS: National Science Centre (UMO-2011/02/A/NZ5/00329); SS: European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 707730; CS-M: Carlos III Health Institute (PI13/01958), Carlos III Health Institute (PI16/00889), Carlos III Health Institute (CPII16/00048); ES: National Science Centre (UMO-2011/02/A/NZ5/00329); AT: The Russian Foundation for Basic Research (grant code 1506-05758A); DT-G: PI14/00918, PI14/00639; Leonardo Tozzi: Marie Curie Programme, International Training Programme, r’Birth; SV: IMPRS Neurocom stipend; TvE: National Center for Research Resources at the National Institutes of Health (grant numbers: NIH 1 U24 RR021992 (Function Biomedical Informatics Research Network), NIH 1 U24 RR025736-01 (Biomedical Informatics Research Network Coordinating Center; http://www.birncommunity.org) and the NIH Big Data to Knowledge (BD2K) award (U54 EB020403 to Paul Thompson). NvH: NWO-VIDI (452-11-014); MW: National Science Centre (UMO-2011/02/A/NZ5/00329); Veronica O’Keane: Meath Foundation; AV and AW: CRC Obesity Mechanism (SFB 1052) Project A1 funded by DFG. The funding sources had no role in the study design, data collection, analysis, and interpretation of the data.

Autobiographical descriptions and clinician observations suggest that some individuals with autism, particularly females, 'camouflage' their social communication difficulties, which may require considerable cognitive effort and lead to increased stress, anxiety and depression. Using data from 60 age- and IQ-matched men and women with autism (without intellectual disability), we operationalized camouflaging in adults with autism for the first time as the quantitative discrepancy between the person's 'external' behavioural presentation in social-interpersonal contexts (measured by the Autism Diagnostic Observation Schedule) and the person's 'internal' status (dispositional traits measured by the Autism Spectrum Quotient and social cognitive capability measured by the 'Reading the Mind in the Eyes' Test). We found that the operationalized camouflaging measure was not significantly correlated with age or IQ. On average, women with autism had higher camouflaging scores than men with autism (Cohen's d = 0.98), with substantial variability in both groups. Greater camouflaging was associated with more depressive symptoms in men and better signal-detection sensitivity in women with autism. The neuroanatomical association with camouflaging score was largely sex/gender-dependent and significant only in women: from reverse inference, the most correlated cognitive terms were about emotion and memory. The underlying constructs, measurement, mechanisms, consequences and heterogeneity of camouflaging in autism warrant further investigation.

Background The tremendous clinical and aetiological diversity among individuals with autism spectrum disorder (ASD) has been a major obstacle to the development of new treatments, as many may only be effective in particular subgroups. Precision medicine approaches aim to overcome this challenge by combining pathophysiologically based treatments with stratification biomarkers that predict which treatment may be most beneficial for particular individuals. However, so far, we have no single validated stratification biomarker for ASD. This may be due to the fact that most research studies primarily have focused on the identification of mean case-control differences, rather than within-group variability, and included small samples that were underpowered for stratification approaches. The EU-AIMS Longitudinal European Autism Project (LEAP) is to date the largest multi-centre, multi-disciplinary observational study worldwide that aims to identify and validate stratification biomarkers for ASD. Methods LEAP includes 437 children and adults with ASD and 300 individuals with typical development or mild intellectual disability. Using an accelerated longitudinal design, each participant is comprehensively characterised in terms of clinical symptoms, comorbidities, functional outcomes, neurocognitive profile, brain structure and function, biochemical markers and genomics. In addition, 51 twin-pairs (of which 36 had one sibling with ASD) are included to identify genetic and environmental factors in phenotypic variability. Results Here, we describe the demographic characteristics of the cohort, planned analytic stratification approaches, criteria and steps to validate candidate stratification markers, pre-registration procedures to increase transparency, standardisation and data robustness across all analyses, and share some ‘lessons learnt’. A clinical characterisation of the cohort is given in the companion paper (Charman et al., accepted). Conclusion We expect that LEAP will enable us to confirm, reject and refine current hypotheses of neurocognitive/neurobiological abnormalities, identify biologically and clinically meaningful ASD subgroups, and help us map phenotypic heterogeneity to different aetiologies. Electronic supplementary material The online version of this article (doi:10.1186/s13229-017-0146-8) contains supplementary material, which is available to authorized users.

The male preponderance in autism prevalence has brought together the disparate topics of sex/gender and autism research. Two directions of neuroimaging studies on the relationships between sex/gender and autism may inform male-specific risk mechanisms and female-specific protective mechanisms of autism. First, we review how sex/gender moderates autism-related brain changes and how this informs general models of autism etiology. Better-powered human neuroimaging studies suggest that the brain characteristics of autism are qualitatively, rather than simply quantitatively, different between males and females. However, age and comorbidities might substantially moderate the pattern of differences. Second, we review how the relationship between autism-related brain changes (separately in males and females) and normative brain sex/gender differences informs specific etiological-developmental mechanisms. Both human and animal studies converge to indicate that the brain characteristics of autism are partly associated with normative brain sex/gender differences, suggesting convergence or overlap between the mechanisms leading to and modifying the development of autism and the mechanisms underlying sex differentiation and/or gender socialization. Future animal work needs to investigate sex differences in rodent mutants modeling autism-relevant genes and environmental exposures. Future human work needs to address the substantial phenotypic and etiological heterogeneity of autism and to focus on longitudinal neuroimaging studies (from early development) on the developmental trajectories of sex/gender-differential neural characteristics of autism. Combining animal and human work links up the causal chain from etiological factors, brain and physical development, to phenotypes. These together help delineate the different roles of sex and gender in relation to risk vs. protective mechanisms.

Functional magnetic resonance imaging (fMRI) research is routinely criticized for being statistically underpowered due to characteristically small sample sizes and much larger sample sizes are being increasingly recommended. Additionally, various sources of artifact inherent in fMRI data can have detrimental impact on effect size estimates and statistical power. Here we show how specific removal of non-BOLD artifacts can improve effect size estimation and statistical power in task-fMRI contexts, with particular application to the social-cognitive domain of mentalizing/theory of mind. Non-BOLD variability identification and removal is achieved in a biophysical and statistically principled manner by combining multi-echo fMRI acquisition and independent components analysis (ME-ICA). Without smoothing, group-level effect size estimates on two different mentalizing tasks were enhanced by ME-ICA at a median rate of 24% in regions canonically associated with mentalizing, while much more substantial boosts (40- 149%) were observed in non-canonical cerebellar areas. Effect size boosting occurs via reduction of non-BOLD noise at the subject-level and consequent reductions in betweensubject variance at the group-level. Smoothing can attenuate ME-ICA-related effect size improvements in certain circumstances. Power simulations demonstrate that ME-ICArelated effect size enhancements enable much higher-powered studies at traditional sample sizes. Cerebellar effects observed after applying ME-ICA may be unobservable with conventional imaging at traditional sample sizes. Thus, ME-ICA allows for principled design-agnostic non-BOLD artifact removal that can substantially improve effect size estimates and statistical power in task-fMRI contexts. ME-ICA could mitigate some issues regarding statistical power in fMRI studies and enable novel discovery of aspects of brain organization that are currently under-appreciated and not well understood., This work was supported by a Wellcome Trust project grant to SB-C and ETB. MVL was supported by the Wellcome Trust and fellowships from Jesus College, Cambridge and the British Academy. PK was supported by the National Institutes of Health–Cambridge Scholars Program. ETB is employed half-time by the University of Cambridge and halftime by GlaxoSmithKline (GSK)., This is the author accepted manuscript. It first appeared from Elseiver at http://dx.doi.org/10.1016/j.neuroimage.2016.07.022.

Background: Autism and attention deficit hyperactivity disorder (ADHD) are heterogeneous neurodevelopmental conditions with complex underlying neurobiology. Despite overlapping presentation and sex-biased prevalence, autism and ADHD are rarely studied together, and sex differences are often overlooked. Normative modelling provides a unified framework for studying age-specific and sex-specific divergences in neurodivergent brain development., Methods: Here we use normative modelling and a large, multi-site neuroimaging dataset to characterise cortical anatomy associated with autism and ADHD, benchmarked against models of typical brain development based on a sample of over 75,000 individuals. We also examined sex and age differences, relationship with autistic traits, and explored the co-occurrence of autism and ADHD (autism+ADHD)., Results: We observed robust neuroanatomical signatures of both autism and ADHD. Overall, autistic individuals showed greater cortical thickness and volume localised to the superior temporal cortex, whereas individuals with ADHD showed more global effects of cortical thickness increases but lower cortical volume and surface area across much of the cortex. The autism+ADHD group displayed a unique pattern of widespread increases in cortical thickness, and certain decreases in surface area. We also found evidence that sex modulates the neuroanatomy of autism but not ADHD, and an age-by-diagnosis interaction for ADHD only., Conclusions: These results indicate distinct cortical differences in autism and ADHD that are differentially impacted by age, sex, and potentially unique patterns related to their co-occurrence., Competing Interests: Disclosures EB reports consultancy work for Boehringer Ingelheim, Sosei Heptares, SR One, GlaxoSmithKline. EB, RAIB, JS, AFA-B are co-founders of Centile Bioscience. PAD receives research support from Biohaven Pharmaceuticals. M-C Lai has received editorial honorarium from SAGE Publications. RN reported receiving grants from Brain Canada, Hoffman La Roche, Otsuka Pharmaceuticals, and Maplight Therapeutics outside the submitted work. EA reported receiving grants from Roche and Anavex; receiving nonfinancial support from AMO Pharma and CRA-Simons Foundation; and receiving personal fees from Roche, Impel, Ono, and Quadrant outside the submitted work; in addition, EA had a patent for Anxiety Meter issued 14/755/084 (United States) and a patent for Anxiety Meter pending 2,895,954 (Canada) as well as receiving royalties from APPI and Springer. All other authors report no biomedical financial interests or potential conflicts of interest.

Autism presents with significant phenotypic and neuroanatomical heterogeneity, and neuroimaging studies of the thalamus, globus pallidus and striatum in autism have produced inconsistent and contradictory results. These structures are critical mediators of functions known to be atypical in autism, including sensory gating and motor function. We examined both volumetric and fine-grained localized shape differences in autism using a large ( n =3145, 1045-1318 after strict quality control), cross-sectional dataset of T1-weighted structural MRI scans from 32 sites, including both males and females (assigned-at-birth). We investigated three potentially important sources of neuroanatomical heterogeneity: sex, age, and intelligence quotient (IQ), using a meta-analytic technique after strict quality control to minimize non-biological sources of variation. We observed no volumetric differences in the thalamus, globus pallidus, or striatum in autism. Rather, we identified a variety of localized shape differences in all three structures. Including age, but not sex or IQ, in the statistical model improved the fit for both the pallidum and striatum, but not for the thalamus. Age-centered shape analysis indicated a variety of age-dependent regional differences. Overall, our findings help confirm that the neurodevelopment of the striatum, globus pallidus and thalamus are atypical in autism, in a subtle location-dependent manner that is not reflected in overall structure volumes, and that is highly non-uniform across the lifespan., Competing Interests: Conflict of Interest EO is an employee of Genentech, Inc. DGMM has served on advisory Boards to Roche and Servier. He also receives a stipend for editorial work from Springer. M-CL serves as an editor of the journal Autism and has received editorial honorarium from SAGE Publications.