Bridge-building between communities: Imagining the future of biomedical autism research.

A paradigm shift in research culture is required to ease perceived tensions between autistic people and the biomedical research community. As a group of autistic and non-autistic scientists and stakeholders, we contend that through participatory research, we can reject a deficit-based conceptualization of autism while building a shared vision for a neurodiversity-affirmative biomedical research paradigm.

Examining the Boundary Sharpness Coefficient as an Index of Cortical Microstructure in Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is associated with atypical brain development. However, the phenotype of regionally specific increased cortical thickness observed in ASD may be driven by several independent biological processes that influence the gray/white matter boundary, such as synaptic pruning, myelination, or atypical migration. Here, we propose to use the boundary sharpness coefficient (BSC), a proxy for alterations in microstructure at the cortical gray/white matter boundary, to investigate brain differences in individuals with ASD, including factors that may influence ASD-related heterogeneity (age, sex, and intelligence quotient). Using a vertex-based meta-analysis and a large multicenter structural magnetic resonance imaging (MRI) dataset, with a total of 1136 individuals, 415 with ASD (112 female; 303 male), and 721 controls (283 female; 438 male), we observed that individuals with ASD had significantly greater BSC in the bilateral superior temporal gyrus and left inferior frontal gyrus indicating an abrupt transition (high contrast) between white matter and cortical intensities. Individuals with ASD under 18 had significantly greater BSC in the bilateral superior temporal gyrus and right postcentral gyrus; individuals with ASD over 18 had significantly increased BSC in the bilateral precuneus and superior temporal gyrus. Increases were observed in different brain regions in males and females, with larger effect sizes in females. BSC correlated with ADOS-2 Calibrated Severity Score in individuals with ASD in the right medial temporal pole. Importantly, there was a significant spatial overlap between maps of the effect of diagnosis on BSC when compared with cortical thickness. These results invite studies to use BSC as a possible new measure of cortical development in ASD and to further examine the microstructural underpinnings of BSC-related differences and their impact on measures of cortical morphology.

Atypical measures of diffusion at the gray-white matter boundary in autism spectrum disorder in adulthood.

Autism spectrum disorder (ASD) is a highly complex neurodevelopmental condition that is accompanied by neuroanatomical differences on the macroscopic and microscopic level. Findings from histological, genetic, and more recently in vivo neuroimaging studies converge in suggesting that neuroanatomical abnormalities, specifically around the gray-white matter (GWM) boundary, represent a crucial feature of ASD. However, no research has yet characterized the GWM boundary in ASD based on measures of diffusion. Here, we registered diffusion tensor imaging data to the structural T1-weighted images of 92 adults with ASD and 92 matched neurotypical controls in order to examine between-group differences and group-by-sex interactions in fractional anisotropy and mean diffusivity sampled at the GWM boundary, and at different sampling depths within the superficial white and into the gray matter. As hypothesized, we observed atypical diffusion at and around the GWM boundary in ASD, with between-group differences and group-by-sex interactions depending on tissue class and sampling depth. Furthermore, we identified that altered diffusion at the GWM boundary partially (i.e., ~50%) overlapped with atypical gray-white matter tissue contrast in ASD. Our study thus replicates and extends previous work highlighting the GWM boundary as a crucial target of neuropathology in ASD, and guides future work elucidating etiological mechanisms.

Sex-specific impact of prenatal androgens on social brain default mode subsystems.

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.

Large-scale analyses of the relationship between sex, age and intelligence quotient heterogeneity and cortical morphometry in autism spectrum disorder.

Significant heterogeneity across aetiologies, neurobiology and clinical phenotypes have been observed in individuals with autism spectrum disorder (ASD). Neuroimaging-based neuroanatomical studies of ASD have often reported inconsistent findings which may, in part, be attributable to an insufficient understanding of the relationship between factors influencing clinical heterogeneity and their relationship to brain anatomy. To this end, we performed a large-scale examination of cortical morphometry in ASD, with a specific focus on the impact of three potential sources of heterogeneity: sex, age and full-scale intelligence (FIQ). To examine these potentially subtle relationships, we amassed a large multi-site dataset that was carefully quality controlled (yielding a final sample of 1327 from the initial dataset of 3145 magnetic resonance images; 491 individuals with ASD). Using a meta-analytic technique to account for inter-site differences, we identified greater cortical thickness in individuals with ASD relative to controls, in regions previously implicated in ASD, including the superior temporal gyrus and inferior frontal sulcus. Greater cortical thickness was observed in sex specific regions; further, cortical thickness differences were observed to be greater in younger individuals and in those with lower FIQ, and to be related to overall clinical severity. This work serves as an important step towards parsing factors that influence neuroanatomical heterogeneity in ASD and is a potential step towards establishing individual-specific biomarkers.

Enhancement of indirect functional connections with shortest path length in the adult autistic brain.

Autism is a neurodevelopmental condition characterized by atypical brain functional organization. Here we investigated the intrinsic indirect (semi-metric) connectivity of the functional connectome associated with autism. Resting-state functional magnetic resonance imaging scans were acquired from 65 neurotypical adults (33 males/32 females) and 61 autistic adults (30 males/31 females). From functional connectivity networks, semi-metric percentages (SMPs) were calculated to assess the proportion of indirect shortest functional pathways at global, hemisphere, network, and node levels. Group comparisons were then conducted to ascertain differences between autism and neurotypical control groups. Finally, the strength and length of edges were examined to explore the patterns of semi-metric connections associated with autism. Compared with neurotypical controls, autistic adults displayed significantly higher SMP at all spatial scales, similar to prior observations in adolescents. Differences were primarily in weaker, longer-distance edges in the majority between networks. However, no significant diagnosis-by-sex interaction effects were observed on global SMP. These findings suggest increased indirect functional connectivity in the autistic brain is persistent from adolescence to adulthood and is indicative of reduced functional network integration.

In Vivo Evidence of Reduced Integrity of the Gray-White Matter Boundary in Autism Spectrum Disorder.

Atypical cortical organization and reduced integrity of the gray-white matter boundary have been reported by postmortem studies in individuals with autism spectrum disorder (ASD). However, there are no in vivo studies that examine these particular features of cortical organization in ASD. Hence, we used structural magnetic resonance imaging to examine differences in tissue contrast between gray and white matter in 98 adults with ASD and 98 typically developing controls, to test the hypothesis that individuals with ASD have significantly reduced tissue contrast. More specifically, we examined contrast as a percentage between gray and white matter tissue signal intensities (GWPC) sampled at the gray-white matter boundary, and across different cortical layers. We found that individuals with ASD had significantly reduced GWPC in several clusters throughout the cortex (cluster, P < 0.05). As expected, these reductions were greatest when tissue intensities were sampled close to gray-white matter interface, which indicates a less distinct gray-white matter boundary in ASD. Our in vivo findings of reduced GWPC in ASD are therefore consistent with prior postmortem findings of a less well-defined gray-white matter boundary in ASD. Taken together, these results indicate that GWPC might be utilized as an in vivo proxy measure of atypical cortical microstructural organization in future studies.

Imaging sex/gender and autism in the brain: Etiological implications.

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. © 2016 Wiley Periodicals, Inc.

Frontal networks in adults with autism spectrum disorder.

It has been postulated that autism spectrum disorder is underpinned by an 'atypical connectivity' involving higher-order association brain regions. To test this hypothesis in a large cohort of adults with autism spectrum disorder we compared the white matter networks of 61 adult males with autism spectrum disorder and 61 neurotypical controls, using two complementary approaches to diffusion tensor magnetic resonance imaging. First, we applied tract-based spatial statistics, a 'whole brain' non-hypothesis driven method, to identify differences in white matter networks in adults with autism spectrum disorder. Following this we used a tract-specific analysis, based on tractography, to carry out a more detailed analysis of individual tracts identified by tract-based spatial statistics. Finally, within the autism spectrum disorder group, we studied the relationship between diffusion measures and autistic symptom severity. Tract-based spatial statistics revealed that autism spectrum disorder was associated with significantly reduced fractional anisotropy in regions that included frontal lobe pathways. Tractography analysis of these specific pathways showed increased mean and perpendicular diffusivity, and reduced number of streamlines in the anterior and long segments of the arcuate fasciculus, cingulum and uncinate--predominantly in the left hemisphere. Abnormalities were also evident in the anterior portions of the corpus callosum connecting left and right frontal lobes. The degree of microstructural alteration of the arcuate and uncinate fasciculi was associated with severity of symptoms in language and social reciprocity in childhood. Our results indicated that autism spectrum disorder is a developmental condition associated with abnormal connectivity of the frontal lobes. Furthermore our findings showed that male adults with autism spectrum disorder have regional differences in brain anatomy, which correlate with specific aspects of autistic symptoms. Overall these results suggest that autism spectrum disorder is a condition linked to aberrant developmental trajectories of the frontal networks that persist in adult life.

Improving effect size estimation and statistical power with multi-echo fMRI and its impact on understanding the neural systems supporting mentalizing.

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 between-subject variance at the group-level. Smoothing can attenuate ME-ICA-related effect size improvements in certain circumstances. Power simulations demonstrate that ME-ICA-related 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.

Biological sex affects the neurobiology of autism.

In autism, heterogeneity is the rule rather than the exception. One obvious source of heterogeneity is biological sex. Since autism was first recognized, males with autism have disproportionately skewed research. Females with autism have thus been relatively overlooked, and have generally been assumed to have the same underlying neurobiology as males with autism. Growing evidence, however, suggests that this is an oversimplification that risks obscuring the biological base of autism. This study seeks to answer two questions about how autism is modulated by biological sex at the level of the brain: (i) is the neuroanatomy of autism different in males and females? and (ii) does the neuroanatomy of autism fit predictions from the 'extreme male brain' theory of autism, in males and/or in females? Neuroanatomical features derived from voxel-based morphometry were compared in a sample of equal-sized high-functioning male and female adults with and without autism (n = 120, n = 30/group). The first question was investigated using a 2 × 2 factorial design, and by spatial overlap analyses of the neuroanatomy of autism in males and females. The second question was tested through spatial overlap analyses of specific patterns predicted by the extreme male brain theory. We found that the neuroanatomy of autism differed between adult males and females, evidenced by minimal spatial overlap (not different from that occurred under random condition) in both grey and white matter, and substantially large white matter regions showing significant sex × diagnosis interactions in the 2 × 2 factorial design. These suggest that autism manifests differently by biological sex. Furthermore, atypical brain areas in females with autism substantially and non-randomly (P < 0.001) overlapped with areas that were sexually dimorphic in neurotypical controls, in both grey and white matter, suggesting neural 'masculinization'. This was not seen in males with autism. How differences in neuroanatomy relate to the similarities in cognition between males and females with autism remains to be understood. Future research should stratify by biological sex to reduce heterogeneity and to provide greater insight into the neurobiology of autism.

Recommendations for a Better Understanding of Sex and Gender in the Neuroscience of Mental Health.

There are prominent sex/gender differences in the prevalence, expression, and life span course of mental health and neurodiverse conditions. However, the underlying sex- and gender-related mechanisms and their interactions are still not fully understood. This lack of knowledge has harmful consequences for those with mental health problems. Therefore, we set up a cocreation session in a 1-week workshop with a multidisciplinary team of 25 researchers, clinicians, and policy makers to identify the main barriers in sex and gender research in the neuroscience of mental health. Based on this work, here we provide recommendations for methodologies, translational research, and stakeholder involvement. These include guidelines for recording, reporting, analysis beyond binary groups, and open science. Improved understanding of sex- and gender-related mechanisms in neuroscience may benefit public health because this is an important step toward precision medicine and may function as an archetype for studying diversity.

Brain-charting autism and attention deficit hyperactivity disorder reveals distinct and overlapping neurobiology.

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.

Characterizing Subcortical Structural Heterogeneity in Autism.

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.

Medical symptoms and conditions in autistic women.

LAY ABSTRACT: 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.

Is there an association between prenatal testosterone and autistic traits in adolescents?

Prenatal testosterone (pT) is a crucial component in physiological masculinization in humans. In line with the Prenatal Sex Steroid Theory of autism, some studies have found a positive correlation between pT and autistic traits in childhood. However, effects in adolescence have not been explored. Hormonal and environmental changes occurring during puberty may alter the strength or the nature of prenatal effects on autistic traits. The current study examines if pT relates to autistic traits in a non-clinical sample of adolescents and young adults (N = 97, 170 observations; age 13-21 years old). It also explores pT interactions with pubertal stage and timing. PT concentrations were measured from amniotic fluid extracted in the 2nd trimester of gestation via amniocentesis conducted for clinical purposes. Autistic traits were measured by self- and parent-reports on the Autism Spectrum Quotient (AQ) which provides a total score and 5 sub-scores (social skills, communication, imagination, attention switching and attention to detail). Self-reported pubertal stage was regressed on age to provide a measure of relative timing. We found no statistical evidence for a direct association between pT and autistic traits in this adolescent sample (males, females or full sample). Exploratory analyses suggested that pT correlated positively with autistic traits in adolescents with earlier puberty-onset, but statistical robustness of this finding was limited. Further exploratory post-hoc tests suggested the pT-by-pubertal timing interaction was stronger in males relative to females, in self-reported compared to parent-reported AQ and specifically for social traits. These findings require replication in larger samples. Findings have implications for understanding the effects of pT on human behavior, specifically existence of effects in adolescence.

Maternal age, autistic-like traits and mentalizing as predictors of child autistic-like traits in a population-based cohort.

BACKGROUND: Many empirical studies suggest that higher maternal age increases the likelihood of having an autistic child. However, little is known about factors that may explain this relationship or if higher maternal age is related to the number of autistic-like traits in offspring. One possibility is that mothers who have a higher number of autistic-like traits, including greater challenges performing mentalizing skills, are delayed in finding a partner. The goal of our study is to assess the relationship between maternal age, mentalizing skills and autistic-like traits as independent predictors of the number of autistic-like traits in offspring. METHODS: In a population-based study in the Netherlands, information on maternal age was collected during pre- and perinatal enrolment. Maternal mentalizing skills and autistic-like traits were assessed using the Reading the Mind in the Eyes Test and the Autism Spectrum Quotient, respectively. Autistic-like traits in children were assessed with the Social Responsiveness Scale. A total of 5718 mother/child dyads had complete data (Magechild = 13.5 years; 50.2% girls). RESULTS: The relationship between maternal age and autistic-like traits in offspring best fits a U-shaped curve. Furthermore, higher levels of autistic features in mothers are linked to higher levels of autistic-like traits in their children. Lower mentalizing performance in mothers is linked to higher levels of autistic-like traits in their children. LIMITATIONS: We were able to collect data on both autistic-like traits and the mentalizing skills test in a large population of mothers, but we did not collect these data in a large number of the fathers. CONCLUSIONS: The relationships between older and younger mothers may have comparable underlying mechanisms, but it is also possible that the tails of the U-shaped curve are influenced by disparate mechanisms.

COVID-19 health and social care access for autistic people: European policy review.

BACKGROUND: The global COVID-19 pandemic has had an unprecedented impact on European health and social care systems, with demands on testing, hospital and intensive care capacity exceeding available resources in many regions. This has led to concerns that some vulnerable groups, including autistic people, may be excluded from services. METHODS: We reviewed policies from 15 European member states, published in March-July 2020, pertaining to (1) access to COVID-19 tests; (2) provisions for treatment, hospitalisation and intensive care units (ICUs); and (3) changes to standard health and social care. In parallel, we analysed survey data on the lived experiences of 1301 autistic people and caregivers. RESULTS: Autistic people experienced significant barriers when accessing COVID-19 services. First, despite being at elevated risk of severe illness due to co-occurring health conditions, there was a lack of accessibility of COVID-19 testing. Second, many COVID-19 outpatient and inpatient treatment services were reported to be inaccessible, predominantly resulting from individual differences in communication needs. Third, ICU triage protocols in many European countries (directly or indirectly) resulted in discriminatory exclusion from lifesaving treatments. Finally, interruptions to standard health and social care left over 70% of autistic people without everyday support. CONCLUSIONS: The COVID-19 pandemic has further exacerbated existing healthcare inequalities for autistic people, probably contributing to disproportionate increases in morbidity and mortality, mental health and behavioural difficulties, and reduced quality of life. An urgent need exists for policies and guidelines on accessibility of COVID-19 services to be updated to prevent the widespread exclusion of autistic people from services, which represents a violation of international human rights law.

Sex/gender differences in neurology and psychiatry: Autism.

Autism is a heterogenous set of early-onset neurodevelopmental conditions that are more prevalent in males than in females. Due to the high phenotypic, neurobiological, developmental, and etiological heterogeneity in the autism spectrum, recent research programs are increasingly exploring whether sex- and gender-related factors could be helpful markers to clarify the heterogeneity in autism and work toward a personalized approach to intervention and support. In this chapter, we summarize recent clinical and neuroscientific research addressing sex/gender influences in autism and explore how sex/gender-based investigations shed light on similar or different underlying neurodevelopmental mechanisms of autism by sex/gender. We review evidence that may help to explain some of the underlying sex-related biological mechanisms associated with autism, including genetics and the effects of sex steroid hormones in the prenatal environment. We conclude that current research points toward coexisting quantitative and, perhaps more evidently, qualitative sex/gender-modulation effects in autism across multiple neurobiological aspects. However, converging findings of specific neurobiological presentations and sex/gender-informed mechanisms cutting across the many subgroups within the autism spectrum are still lacking. Future research should use big data approaches and new stratification methods to decompose sex/gender-related heterogeneity in autism and work toward personalized, sex/gender-informed intervention and support for autistic people.

Intrinsic excitation-inhibition imbalance affects medial prefrontal cortex differently in autistic men versus women.

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.

Autism is a condition that is usually diagnosed early in life that affects how a person communicates and socializes, and is often characterized by repetitive behaviors. One key theory of autism is that it reflects an imbalance in levels of excitation and inhibition in the brain. Excitatory signals are those that make other brain cells more likely to become active; inhibitory signals have the opposite effect. In non-autistic individuals, inhibitory activity outweighs excitatory activity. In people with autism, by contrast, an increase in excitatory activity is believed to produce an imbalance in excitation and inhibition. Most of the evidence to support this excitation-inhibition imbalance theory has come from studies of rare mutations that cause autism. Many of these mutations occur on the sex chromosomes or are influenced by androgen hormones (hormones that usually play a role on typically male traits). However, most people with autism do not possess these particular mutations. It was thus unclear whether the theory could apply to everyone with autism or, for example, whether it may better apply to specific groups of individuals based on their sex or gender. This is especially important given that about four times as many men and boys compared to women and girls are diagnosed with autism. Trakoshis, Martínez-Cañada et al. have now found a way to ask whether any imbalance in excitation and inhibition in the brain occurs differently in men and women. Using computer modeling, they identified a signal in brain scans that corresponds to an imbalance of excitation and inhibition. After showing that the technique works to identify real increases in excitation in the brain scans of mice, Trakoshis, Martínez-Cañada et al. looked for this signal, or biomarker, in brain scans of people with and without autism. All the people in the study identified with the gender that matched the sex they were assigned at birth. The results revealed differences between the men and women with autism. Men with autism showed an imbalance in excitation and inhibition in specific 'social brain' regions including the medial prefrontal cortex, but women with autism did not. Notably, many of these brain regions are strongly affected by androgen hormones. Previous studies have found that women with autism are sometimes better at hiding or 'camouflaging' their difficulties when socializing or communicating than men with autism. Trakoshis, Martínez-Cañada et al. showed that the better a woman was at camouflaging her autism, the more her brain activity in this region resembled that of non-autistic women. Excitation-inhibition imbalance may thus affect specific brain regions involved in socializing and communication more in men who have autism than in women with the condition. Balanced excitation and inhibition in these brain areas may enable some women with autism to camouflage their difficulties socializing or communicating. Being able to detect imbalances in activity using standard brain imaging could be useful for clinical trials. Future studies could use this biomarker to monitor responses to drug treatments that aim to adjust the balance between excitation and inhibition.