Michael Lombardo

Istituto Italiano di Tecnologia | IIT · Center for Neuroscience and Cognitive Systems CNCS

Oxytocin may influence various human behaviors and the connectivity across subcortical and cortical networks. Previous oxytocin studies are male biased and often constrained by task-based inferences. Here, we investigate the impact of oxytocin on resting-state connectivity between subcortical and cortical networks in women. We collected resting-sta...

Maternal immune activation (MIA) via infection during pregnancy is known to increase risk for autism spectrum disorder (ASD). However, it is unclear how MIA disrupts fetal brain gene expression in ways that may explain this increased risk. Here we examine how MIA dysregulates rat fetal brain gene expression (at a time point analogous to the end of...

Individuals affected by autism spectrum conditions (ASC) are considerably heterogeneous. Novel approaches are needed to parse this heterogeneity to enhance precision in clinical and translational research. Applying a clustering approach taken from genomics and systems biology on two large independent cognitive datasets of adults with and without AS...

Autism (ASD) is vastly heterogeneous, particularly in early language development. While ASD language trajectories in the first years of life are highly unstable, by early childhood these trajectories stabilize and are predictive of longer-term outcome. Early neural substrates that predict/precede such outcomes are largely unknown, but could have co...

Background Autism spectrum disorders (ASD) are etiologically heterogeneous and complex. Functional genomics work has begun to identify a diverse array of dysregulated transcriptomic programs (e.g., synaptic, immune, cell cycle, DNA damage, WNT signaling, cortical patterning and differentiation) potentially involved in ASD brain abnormalities during...

Importance In the neurotypical brain, regions develop in coordinated patterns, providing a fundamental scaffold for brain function and behavior. Whether altered patterns contribute to clinical profiles in neurodevelopmental conditions, including autism, remains unclear. Objectives To examine if, in autism, brain regions develop differently in rela...

Background Phenotypic heterogeneity in early language, intellectual, motor, and adaptive functioning (LIMA) features are amongst the most striking features that distinguish different types of autistic individuals. Yet the current diagnostic criteria uses a single label of autism and implicitly emphasizes what individuals have in common as core soci...

Background Motor difficulties are common in many, but not all, autistic individuals. These difficulties can co-occur with other problems, such as delays in language, intellectual, and adaptive functioning. Biological mechanisms underpinning such difficulties are less well understood. Poor motor skills tend to be more common in individuals carrying...

Genomic mechanisms enhancing risk in males may contribute to sex bias in autism. The ubiquitin protein ligase E3A gene ( Ube3a ) affects cellular homeostasis via control of protein turnover and by acting as transcriptional coactivator with steroid hormone receptors. Overdosage of Ube3a via duplication or triplication of chromosomal region 15q11-13...

Language and social symptoms improve with age in some autistic toddlers, but not in others, and such outcome differences are not clearly predictable from clinical scores alone. Here we aim to identify early-age brain alterations in autism that are prognostic of future language ability. Leveraging 372 longitudinal structural MRI scans from 166 autis...

Background Prenatal infections are associated with childhood developmental outcomes such as reduced cognitive abilities, emotional problems and other developmental vulnerabilities. However, there is currently a lack of research examining whether this arises due to potential intermediary variables like low birth weight or preterm birth, or due to so...

Background Social affective and communication symptoms are central to autism spectrum disorder (ASD), yet their severity differs across toddlers: Some toddlers with ASD display improving abilities across early ages and develop good social and language skills, while others with “profound” autism have persistently low social, language and cognitive s...

Phenotypic heterogeneity in early language, intellectual, motor, and adaptive functioning (LIMA) features are amongst the most striking features that distinguish different types of autistic individuals. Yet the current diagnostic criteria uses a single label of autism and implicitly emphasizes what individuals have in common as core social-communic...

Chromosome 22q11.2 deletion is among the strongest known genetic risk factors for neuropsychiatric disorders, including autism and schizophrenia. Brain imaging studies have reported disrupted large-scale functional connectivity in people with 22q11 deletion syndrome (22q11DS). However, the significance and biological determinants of these functiona...

Background: Prenatal infections are associated with childhood developmental outcomes such as reduced cognitive abilities, emotional problems and other developmental vulnerabilities. However, there is currently a lack of research examining whether this arises due to potential intermediary variables like low birthweight or preterm birth, or due to so...

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 framewor...

Excitation-inhibition (E:I) imbalance has long been considered one of the primary neurobiological theories explaining autism. However, the theory has been bolstered heavily by research on high-penetrance genetic mechanisms which are only found in a small proportion of the autism population. Thus, how well does E:I imbalance explain idiopathic autis...

Human brain size changes dynamically through early development, peaks in adolescence, and varies up to 2-fold among adults. However, the molecular genetic underpinnings of interindividual variation in brain size remain unknown. Here, we leveraged postmortem brain RNA sequencing and measurements of brain weight (BW) in 2,531 individuals across three...

Structural magnetic resonance imaging (MRI) quality is known to impact and bias neuroanatomical estimates and downstream analysis, including case-control comparisons, and a growing body of work has demonstrated the importance of careful quality control (QC) and evaluated the impact of image and image-processing quality. However, the growing size of...

Variation in human gaze can be explained by a variety of factors. Within an individual, gaze patterns can be quite reliable and can be explained in part by heritable common genetic mechanisms. If individual gaze patterns are strongly idiosyncratic, could they enable highly accurate detection of individuals via a ‘gaze fingerprint’? And are gaze fin...

Objectives Previous research suggests that prenatal maternal infections may be linked to later childhood neurodevelopmental outcomes and socioemotional difficulties. We exploited a large linked administrative health dataset to examine relationships between prenatal infections and early childhood development outcomes in Greater Glasgow & Clyde (GGC)...

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 exa...

A major goal of precision medicine is to predict prognosis based on individualized information at the earliest possible points in development. Using early snapshots of adaptive functioning and unsupervised data-driven discovery methods, we uncover highly stable early autism subtypes that yield information relevant to later prognosis. Data from the...

Individuals with autism spectrum disorder (henceforth referred to as autism) display significant variation in clinical outcome. For instance, across age, some individuals’ adaptive skills naturally improve or remain stable, while others’ decrease. To pave the way for ‘precision-medicine’ approaches, it is crucial to identify the cross-sectional and...

Early motor difficulties are a common in many, but not all, autistic individuals. These difficulties tend to be highly present in individuals carrying rare genetic mutations with high penetrance for autism. Many of these rare genetic mechanisms also cause neurophysiological dysregulation of excitation-inhibition balance (E:I). A predicted downstrea...

Background Social and language abilities are closely intertwined during early typical development. In autism spectrum disorder (ASD), however, deficits in social and language development are early-age core symptoms. We previously reported that superior temporal cortex, a well-established social and language region, shows reduced activation to socia...

Background Attenuated social attention is a key marker of autism spectrum disorder (ASD). Recent neuroimaging findings also emphasize an altered processing of sensory salience in ASD. The locus coeruleus–norepinephrine system (LC-NE) has been established as a modulator of this sensory salience processing (SSP). We tested the hypothesis that altered...

Background: Reward processing has been proposed to underpin the atypical social feature of autism spectrum disorder (ASD). However, previous neuroimaging studies have yielded inconsistent results regarding the specificity of atypicalities for social reward processing in ASD. Aims: Utilising a large sample, we aimed to assess reward processing in...

Identifying prognostic early brain alterations is crucial for autism spectrum disorder (ASD). Leveraging structural MRI data from 166 ASD and 109 typical developing (TD) toddlers and controlling for brain size, we found that, compared to TD, ASD toddlers showed larger or thicker lateral temporal regions; smaller or thinner frontal lobe and midline...

Background: Autism spectrum disorder (autism) is a complex neurodevelopmental condition with pronounced behavioral, cognitive, and neural heterogeneities across individuals. Here, our goal was to characterize heterogeneity in autism by identifying patterns of neural diversity as reflected in BOLD fMRI in the way individuals with autism engage with...

Structural magnetic resonance imaging (MRI) quality is known to impact and bias neuroanatomical estimates and downstream analysis, including case-control comparisons. However, despite this, limited work has systematically evaluated the impact of image and image-processing quality on these measures, or compared different quality control (QC) methods...

Objective: The male preponderance in prevalence of autism is among the most pronounced sex ratios across neurodevelopmental conditions. The authors sought to elucidate the relationship between autism and typical sex-differential neuroanatomy, cognition, and related gene expression. Methods: Using a novel deep learning framework trained to predic...

Background Maternal prenatal infections have been linked to children’s neurodevelopment and cognitive outcomes. It remains unclear, however, whether infections occurring during specific vulnerable gestational periods can affect children’s cognitive outcomes. The study aimed to examine maternal infections in each trimester of pregnancy and associati...

Human brain size increases dynamically through early development, peaks in adolescence, and varies up to two-fold among adults. Although previous studies have elucidated changes in brain size across evolution, development, traits, and diseases, the molecular underpinnings of interindividual variation in brain size remain unknown. Here, we leverage...

Autism spectrum disorder is a heterogeneous neurodevelopmental disorder. Early brain overgrowth yet reduced cerebellar size is well recognized for autism, but cortical regions involved show inconsistent patterns of alteration. No complete and replicable map of early regional brain size alterations has been charted. It is also not clear whether indi...

Many neurodevelopmental conditions, including autism, affect males more than females. Genomic mechanisms enhancing risk in males may contribute to this sex-bias. The ubiquitin protein ligase E3A gene (Ube3a) exerts pleiotropic effects on cellular homeostasis via control of protein turnover and by acting as transcriptional coactivator with steroid h...

A major goal of precision medicine is to predict prognosis based on individualized information at the earliest possible points in development. Using early snapshots of adaptive functioning and unsupervised data-driven discovery methods, we uncover highly stable early autism subtypes that yield information relevant to later prognosis. Data from the...

Gender dysphoria (GD) is characterized by distress due to an incongruence between experienced gender and sex assigned at birth. Brain functional connectivity in adolescents who experience GD may be associated with experienced gender (vs. assigned sex) and/or brain networks implicated in own-body perception. Furthermore, sexual orientation may be re...

Autism is a clinical consensus diagnosis made based on behavioral symptoms of early developmental difficulties in domains of social-communication (SC) and restricted repetitive behaviors (RRB). Many readily assume that alongside being optimal for separating individuals based on SC and RRB behavioral domains, that the label should also be highly use...

Background: Understanding the development of the neuronal circuitry underlying autism spectrum disorder (ASD) is critical to shed light into its etiology and for the development of treatment options. Resting state EEG provides a window into spontaneous local and long-range neuronal synchronization and has been investigated in many ASD studies, but...

Over the past few decades, neuroimaging has become a ubiquitous tool in basic research and clinical studies of the human brain. However, no reference standards currently exist to quantify individual differences in neuroimaging metrics over time, in contrast to growth charts for anthropometric traits such as height and weight ¹ . Here we assemble an...

Objective: Autism spectrum disorder (ASD) is a lifelong neurodevelopmental condition that is associated with significant difficulties in adaptive behavior and variation in clinical outcomes across the life span. Some individuals with ASD improve, whereas others may not change significantly, or regress. Hence, the development of "personalized medic...

Objectives The male preponderance in autism spectrum conditions (ASC) prevalence is among the most pronounced sex ratios across different neurodevelopmental conditions. Here, we aimed to elucidate the relationship between autism and typical sex-differential neuroanatomy, cognition, and related gene expression. Methods Using a novel deep learning f...

Maternal prenatal infections have been linked to children's neurodevelopment and cognitive outcomes. It remains unclear, however, whether infections occurring during specific vulnerable gestational periods can affect children's cognitive outcomes. The study aimed to examine maternal infections in each trimester of pregnancy and associations with ch...

Oxytocin is hypothesized to promote social interactions by enhancing the salience of social stimuli. While previous neuroimaging studies have reported that oxytocin enhances amygdala activation to face stimuli in autistic men, effects in autistic women remain unclear. In this study, the influence of intranasal oxytocin on activation and functional...

Affective speech, including motherese, captures an infant’s attention and enhances social, language and emotional development. Decreased behavioural response to affective speech and reduced caregiver–child interactions are early signs of autism in infants. To understand this, we measured neural responses to mild affect speech, moderate affect speec...

Background The neurocognitive mechanisms underlying autism spectrum disorder (ASD) remain unclear. Progress has been largely hampered by small sample sizes, variable age ranges and resulting inconsistent findings. There is a pressing need for large definitive studies to delineate the nature and extent of key case/control differences to direct resea...

Background Joint developmental trajectories of internalizing and externalizing problems show considerable heterogeneity; however, this can be parsed into a small number of meaningful subgroups. Doing so offered insights into risk factors that lead to different patterns of internalizing/externalizing trajectories. However, despite both domains of pr...

Early detection and intervention are believed to be key to facilitating better outcomes in children with autism, yet the impact of age at treatment start on the outcome is poorly understood. While clinical traits such as language ability have been shown to predict treatment outcome, whether or not and how information at the genomic level can predic...

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...

Postmortem studies have revealed increased density of excitatory synapses in the brains of individuals with autism spectrum disorder (ASD), with a putative link to aberrant mTOR-dependent synaptic pruning. ASD is also characterized by atypical macroscale functional connectivity as measured with resting-state fMRI (rsfMRI). These observations raise...

Social and language abilities are closely intertwined during early development. Yet, it is still unknown how neural features underlying early social and language deficits are linked in toddlers with autism spectrum disorders (ASD). We examined functional connectivity of left and right temporal language regions and its correlations with language and...

Objective: Autism spectrum disorder (ASD) is accompanied by highly individualized neuroanatomical deviations that potentially map onto distinct genotypes and clinical phenotypes. This study aimed to link differences in brain anatomy to specific biological pathways to pave the way toward targeted therapeutic interventions. Methods: The authors ex...

Cortical regionalization develops via genomic patterning along anterior-posterior (A-P) and dorsal-ventral (D-V) gradients. Here, we find that normative A-P and D-V genomic patterning of cortical surface area (SA) and thickness (CT), present in typically developing and autistic toddlers with good early language outcome, is absent in autistic toddle...

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 auti...

Background: Oxytocin is hypothesized to promote positive social interactions by enhancing the salience of social stimuli, which may be reflected by altered amygdala activation. While previous neuroimaging studies have reported that oxytocin enhances amygdala activation to emotional face stimuli in autistic men, effects in autistic women remain uncl...

Over the past 25 years, neuroimaging has become a ubiquitous tool in basic research and clinical studies of the human brain. However, there are no reference standards against which to anchor measures of individual differences in brain morphology, in contrast to growth charts for traits such as height and weight. Here, we built an interactive online...

Social-communication (SC) and restricted repetitive behaviors (RRB) are autism diagnostic symptom domains. SC and RRB severity can markedly differ within and between individuals and may be underpinned by different neural circuitry and genetic mechanisms. Modeling SC-RRB balance could help identify how neural circuitry and genetic mechanisms map ont...