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...

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...

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...

Social communication depends on our ability to understand others’ emotions, motives, and intentions. In order to understand others’ experiences accurately, we often rely on our own experiences. But, complete reliance on own experiences leads to inaccurate and biased interpretation of others’ behaviors. Therefore, a mechanism which allows to differe...

Introduction Understanding the emotional responsivity style and neurocognitive profiles of depression‐related processes in at‐risk youth may be helpful in revealing those most likely to develop affective disorders. However, the multiplicity of biopsychosocial risk factors makes it difficult to disentangle unique and combined effects at a neurobiolo...

Background. While genetics is clearly implicated in the etiology of autism, other biological factors may also increase the likelihood of an autism diagnosis. Many of these pertain to obstetric history and maternal medical conditions, but as they tend to co-occur it is difficult to ascertain which ones are most predictive of child's autism. Methods....

Determining the best partition for a dataset can be a challenging task because of the lack of a priori information within an unsupervised learning framework and the absence of a unique clustering validation approach to evaluate clustering solutions. Here we present reval: a Python package that leverages stability-based relative clustering validatio...

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 propo...

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 p...

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 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 predict tr...

Aims: Studies have suggested that exposure to prenatal infections may be a risk factor in the aetiology of neurodevelopmental disorders such as schizophrenia and autism, but that its effects may differ by timing of exposure. Evidence on other psychiatric outcomes, however, is scarce and mixed. The aims of this study were to examine whether exposure...

Fombonne’s (2020) editorial is a thought-provoking appraisal of the literature on ‘camouflaging’, whereby some autistic people mask or compensate for their autistic characteristics as an attempt to fit in and to cope with disabilities under neurotypical social norms. Fombonne (2020) highlights three issues of contention: (a) construct validity and...

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...

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder that is accompanied by neurodevelopmental differences in regional cortical volume (CV), and a potential layer-specific pathology. Conventional measures of CV, however, do not indicate how volume is distributed across cortical layers. In a sample of 92 typi- cally developing (TD...

Motherese is an experience-expectant, human-specific and innate form of parent speech that enhances social and language learning, and affect and emotion development in infants. An early sign of ASD is the child’s lack of responding to motherese and reduced social mother-child interactions. To learn why, we devised a novel experiment quantifying (a)...

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

Understanding heterogeneity is an important goal on the path to precision medicine for autism spectrum disorders (ASD). We examined how cortical thickness (CT) in ASD can be parameterized as an individualized metric of atypicality relative to typically-developing (TD) age-related norms. Across a large sample (n = 870 per group) and wide age range (...

Intranasal oxytocin administration has been shown to influence a variety of outcomes related to social behavior and cognition in clinical and typical samples. One possibility for these diverse effects is that oxytocin alters functional connectivity of social brain regions. However, this hypothesis has not been tested in autistic women. Using a cros...

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 i...

Determining the number of clusters that best partitions a dataset can be a challenging task because of 1) the lack of a priori information within an unsupervised learning framework; and 2) the absence of a unique clustering validation approach to evaluate clustering solutions. Here we present reval: a Python package that leverages stability-based r...

Cortical regional identities develop through anterior-posterior (A-P) and dorsal-ventral (D-V) prenatal genomic patterning gradients. Here we find that A-P and D-V genomic patterning of cortical surface area (SA) and thickness (CT) is intact in typically developing and autistic toddlers with good language outcome, but is absent in autistic toddlers...

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 co...

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 co...

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 co...

Introduction: Previous studies have suggested that there is an association between maternal infections during pregnancy and children’s neurodevelopmental and psychiatric outcomes. There have been some indications that theses links may depend on the timing of exposure in pregnancy, though no firm conclusions have been drawn. Further, relatively few...

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 propo...