Nada Kojovic

The brain’s ability to regulate blood flow is fundamental to both its function and development. In the context of neurodevelopmental disorders such as schizophrenia, understanding the complex interactions between cerebrovascular health and brain function is crucial for unraveling the pathophysiology of psychosis. This study investigates the developmental trajectory of cerebrovascular reactivity (CVR) in 22q11 deletion syndrome (22q11.2DS) compared to healthy controls, and its association with psychosis susceptibility. Using one of the largest longitudinal data-set of resting-state fMRI, we mapped for the first time voxel-level CVR across development. We found an early reduction in CVR in 22q11.2DS, and in particular in those who later developed positive psychotic symptoms (PPS + ). These reductions were evident within the anterior cingulate cortex, frontal lobes, and globi pallidi (GP). We propose that the pattern of CVR alterations presenting early during childhood is possibly linked to altered blood-brain barrier integrity or permeability, potentially involving endothelial or tight-junction dysfunction; however, BBB integrity was not directly measured in this study. A decrease in CVR during childhood and within the frontal regions and GP was predictive of subsequent development of positive psychotic symptoms), which often occurs during adolescence in 22q11.2DS patients. These findings suggest that cerebrovascular health is critical for normal brain development, particularly in regions like the striatum, which are vulnerable to vascular damage due to their anatomical features. These results underline the potential of CVR as an early biomarker for psychosis vulnerability, emphasizing the need for targeted interventions to mitigate neurodevelopmental disruptions of cerebrovascular health in 22q11.2DS.

Autism is a highly heterogenous neurodevelopmental condition that can significantly compromise the quality of life. For children showing atypical trajectories of development in their early years, early and intensive intervention has shown promise in enhancing the development of language, cognition, and social skills. Yet, marked variability in intervention response remains insufficiently understood. Characterizing this heterogeneity is essential for informing intervention strategies tailored to each child's developmental profile. The aim of the present work was to identify subgroups based on intervention response trajectories and investigate subgroup‐specific predictors of intervention outcomes. We analyzed longitudinal data from 125 children (15.2–42.0 months) receiving the Early Start Denver Model (ESDM) intervention over an average follow‐up period of 2 years (mean = 1.93 ± 0.25). Children gained an average of 17 points in Developmental Quotient (DQ), showed significant improvement in their adaptive skills and exhibited diminution of autism features. Using K‐means clustering, we identified 3 subgroups: Progressive Group A (PrGA; 36%), which had the highest baseline cognitive scores (82.3) and gained 17 DQ points in average throughout the intervention; Progressive Group B (PrGB; 41.6%), which showed significant developmental delay at baseline (mean DQ = 56.3) and gained 30 DQ points; and the Persistent Support Needs Group (PSNG; 22.4%), which also started in the range of delay (mean DQ = 47.7) and remained in this range throughout intervention (mean DQ = 41.1). Subgroup‐specific analysis revealed distinct patterns of baseline factors, including stronger adaptive skills and fewer autism features, associated with a higher cognitive outcome for PrGA and PrGB. Comparison of PrGB and PSNG further identified factors distinguishing children with similar levels of cognitive delay at baseline who nevertheless followed markedly different developmental trajectories. Lower levels of repetitive and restricted behaviors, stronger adaptive functioning, and greater cumulative intervention exposure characterized the PrGB group, suggesting that both child‐related and intervention‐related factors may contribute to variability in developmental outcomes.

Early intensive intervention for autistic children aims to support developmental progress in social and communication domains. Although outcomes are typically assessed using standardized measures of child development, parental perspectives during early intervention remain largely understudied. Here, we examined parental perceptions after 6 months of intensive Early Start Denver Model (ESDM) intervention. Participants were parents of 104 autistic children aged 1.3–3.5 years enrolled in an individualized therapist‐delivered ESDM intervention following diagnosis confirmation. Child development was assessed at entry (baseline) and 6 months later (follow‐up). At follow‐up, parents completed an 18‐item questionnaire capturing their perceptions of child progress across twelve domains as well as changes in parenting skills, personal well‐being, and family life. Descriptive analyses, item‐level correlations, and principal component analysis (PCA) were conducted to identify underlying components. Parents generally indicated improvements across all domains, with aggravation rarely reported. PCA revealed three intercorrelated components (Social Communication, Nonverbal Social Engagement, and Positive Parental Experience), each showing distinct associations with child or parent measures. Parental perceptions of child development were strongly correlated with standardized developmental assessments, particularly in social communication. While parents also reported enhanced parenting skills and positive personal and familial impacts, these experiences were not associated with child developmental gains but with parental education and the number of siblings in the household. These findings underscore the importance of integrating parental perspectives alongside clinical assessments when evaluating early intervention outcomes. Future research should investigate how parental perceptions evolve over longer periods and how they may inform family‐centered care and post‐intervention support.

PACS1 neurodevelopmental disorder (PACS1‐NDD), also known as Schuurs–Hoeijmakers syndrome, is a rare genetic condition caused by a recurrent de novo mutation in the PACS1 gene. Autistic traits have been reported in PACS1‐NDD, but systematic longitudinal assessments are lacking. We followed five children (3 females) with genetically confirmed PACS1‐NDD, aged 1.4–6.2 years at entry, over 2–3.5 years (29 assessments). Measures included standardized behavioral and cognitive assessments, eye‐tracking, and structural MRI. Data were compared to 357 autistic and 123 typically developing children from a longitudinal cohort. Children with PACS1‐NDD showed global developmental delays with heterogeneous trajectories. Adaptive and communication profiles overlapped with autistic children, while motor impairments were more pronounced. Vocabulary and grammar were delayed, but pragmatic skills were relatively preserved. All children with PACS1‐NDD exhibited autistic traits with elevated restricted and repetitive behaviors and milder social‐communication difficulties. ADHD symptoms were subthreshold and predominantly inattentive. Eye‐tracking revealed preserved social interest but reduced gaze typicality in naturalistic contexts. MRI showed globally reduced gray and white matter volumes. These findings provide the first longitudinal, multimodal characterization of PACS1‐NDD, informing clinical care and targeted outcome measures for therapeutic trials, and highlighting the need for larger studies to validate and extend these findings.

Early intensive intervention for autistic children aims to support developmental progress in social and communication domains. Although outcomes are typically assessed using standardized measures of child development, parental perspectives during early intervention remain largely understudied. Here, we examined parental perceptions after six months of participation in an intensive Early Start Denver Model (ESDM) program. Participants were parents of 104 autistic children aged 1.3 to 3.5 years enrolled in an individualized therapist-delivered ESDM intervention program following diagnosis confirmation. Child development was assessed at entry (baseline) and six months later (follow-up). At follow-up, parents completed an 18-item questionnaire capturing their perceptions of child progress across twelve domains as well as changes in parenting skills, personal well-being and family life. Descriptive analyses, item-level correlations, and principal component analysis (PCA) were conducted to identify underlying components. Parents generally indicated perceptions of improvements across all domains, with aggravation rarely reported. They also indicated enhanced parenting skills and positive personal and familial impacts. PCA revealed three intercorrelated components (Social Communication, Nonverbal Social Engagement, and Positive Parental Experience) each showing distinct associations with child or parent measures. These findings underscore the importance of integrating parental perspectives alongside clinical assessments when evaluating early intervention outcomes. Future research should investigate how parental perceptions evolve over longer periods and how they may inform family-centered care and post-intervention support.

Background & Aims: Language development in autism is heterogeneous and strongly predicts later functioning. The balance between receptive and expressive abilities and their developmental trajectories, however, remains poorly understood. While some autistic children exhibit a relative expressive advantage (ExpAdv), others show receptive advantage (RecAdv) or a balanced profile. Prior studies report inconsistent findings and are often limited by cross-sectional designs and small samples. The present study aimed to (1) describe longitudinal trajectories of receptive and expressive language in autistic and typically developing (TD) children; (2) classify children into ExpAdv, Balanced, and RecAdv profiles across early childhood; and (3) examine the stability and transitions of these profiles over time, including associated clinical features. Methods: We analyzed 1,174 longitudinal time points from 318 autistic children and 294 time points from 108 TD children (1.2–5.8 years) from the Geneva Autism Cohort. Receptive and expressive language were assessed with the Mullen Scales of Early Learning. Receptive-expressive balance was quantified as the ratio of receptive to expressive age equivalent scores, classifying children into ExpAdv, Balanced, and RecAdv profiles using adapted cut-offs. Mixed-effects models examined developmental trajectories, and Sankey diagrams visualized profile transitions. Autism features and adaptive behavior were compared across profiles. Results: Autistic children displayed lower expressive and receptive language than TD peers, with receptive abilities exceeding expressive skills in both groups. Overall, 30–35% of autistic children were classified as ExpAdv at 18–36 months, declining to ∼12% by 48–54 months, while Balanced and RecAdv profiles became more prevalent with age. ExpAdv was associated with slower verbal and non­verbal developmental gains. Balanced and RecAdv profiles showed moderate stability (50–60%), whereas ExpAdv was less stable and frequently transitioned toward Balanced profiles. Autistic children with stable ExpAdv profiles were more often female and showed weaker adaptive communication. Conclusions: Receptive-expressive language profiles in autistic children are dynamic. ExpAdv profile is more frequent in younger autistic children, less stable, and linked to slower verbal and non-verbal development and greater autism severity. Implications: ExpAdv may represent an early marker of autism associated with slower expressive and receptive language growth. Longitudinal monitoring of receptive and expressive skills is essential, as transitions toward Balanced or RecAdv profiles are associated with improved developmental outcomes. We discuss clinical considerations regarding language assessment, longitudinal monitoring, and interpretation of receptive-expressive profiles.

Obesity and behavioral impulsivity are highly heritable traits that share overlapping genetic risk and often co-occur in childhood. This study investigates whether maturation of the nucleus accumbens shell (NAC-shell) inhibitory-control circuit mediates shared vulnerability to both traits. Using state-of-the-art dynamic fMRI, we mapped NAC-shell development across 460 longitudinal assessments from childhood to adulthood, in 136 healthy controls and 126 individuals with 22q11.2 deletion syndrome (22q11DS), a genetic model conferring high risk for obesity and impulsivity. Blunted NAC-shell maturation predicted steeper BMI increases and persistent neurocognitive impulsivity, consistently mediating their association in both HC and 22q11DS populations. NAC-shell development explained both impulsivity/obesity genetic vulnerability linked to 22q11DS and familial correlations between affected/unaffected siblings. These findings propose NAC-shell maturation as a transdiagnostic endophenotype underlying obesity and self-regulation, bridging neurodevelopment, genetics, and behavior. They could inform future early-screening and precision preventive strategies for youth at risk of obesity and other impulsivity-related phenotypes.

Autism is a highly heterogenous neurodevelopmental condition that can significantly compromise the quality of life. For children showing atypical trajectories of development in their early years, early and intensive intervention has shown promise in enhancing the development of language, cognition, and social skills. Yet, marked variability in intervention response remains insufficiently understood. Characterizing this heterogeneity is essential for informing intervention strategies tailored to each child’s developmental profile. The aim of the present work was to identify subgroups based on intervention response trajectories and investigate subgroup-specific predictors of intervention outcomes. We analyzed longitudinal data from 125 children (15.2 - 42.0 months) receiving the Early Start Denver Model (ESDM) intervention over an average follow-up period of 2 years (mean = 1.93, ± 0.25). Children gained an average of 17 points in Developmental Quotient (DQ), showed significant improvement in their adaptive skills and exhibited diminution of autism features. Using K-means clustering, we identified 3 subgroups: Progressive Group A (PrGA; 36%), which had the highest baseline cognitive scores (82.3) and gained 17 DQ points in average throughout the intervention; Progressive Group B (PrGB; 41.6%), which showed significant developmental delay at baseline (mean DQ = 56.3) and gained 30 DQ points; and the Persistent Support Needs Group (PSNG; 22.4%), which also started in the range of delay (mean DQ = 47.7) and remained in this range throughout intervention (mean DQ = 41.1). Subgroup-specific analysis revealed distinct patterns of baseline factors, including stronger adaptive skills and fewer autism features, associated with a higher cognitive outcome for PrGA and PrGB. Comparison of PrGB and PSNG further identified factors distinguishing children with similar levels of cognitive delay at baseline who nevertheless followed markedly different developmental trajectories. Lower levels of repetitive and restricted behaviors, stronger adaptive functioning, and greater cumulative intervention exposure characterized the PrGB group, suggesting that both child-related and intervention-related factors may contribute to variability in developmental outcomes. Lay Summary: In a group of 125 autistic children receiving Early Start Denver Model intervention, we observed significant gain in cognitive and adaptive skills as well as reduced levels of autism features. We identified 3 subgroups of responses with different developmental trajectories. Distinct baseline factors were associated with the intervention outcome in different subgroups indicating that predictors of response are not the same for all children. These findings highlight the importance of personalized approaches to early intervention to enhance the developmental outcomes of autistic children.

PACS1 neurodevelopmental disorder (PACS1-NDD), also known as Schuurs-Hoeijmakers syndrome, is a rare genetic condition caused by a recurrent de novo mutation in the PACS1 gene. In addition to somatic and clinical features, autistic traits have been reported, although systematic and longitudinal assessments are lacking. We followed five children (3 females) with genetically confirmed PACS1-NDD, aged 1.4–6.2 years at study entry, over a 2–3.5-year period, yielding 29 repeated assessments. Assessments encompassed standardized measures of behavior and cognition, alongside eye-tracking and structural MRI. Data were compared to 357 autistic and 123 typically developing children from our large longitudinal cohort following autistic and typically developing children. Children with PACS1-NDD showed global developmental delays with heterogeneous individual trajectories. Adaptive and communication profiles overlapped with those of autistic children, while motor functioning was more severely affected. Vocabulary and grammar were delayed, but pragmatic skills were relatively preserved. All children exhibited some autistic traits with consistently elevated restricted and repetitive behaviors and milder social-communication difficulties. ADHD symptoms were subthreshold and predominantly inattentive. Eye-tracking revealed preserved social interest but reduced gaze typicality in more naturalistic contexts. Finally, MRI showed globally reduced gray and white matter volumes. In PACS1-NDD, the apparent dissociation between elevated restricted and repetitive behaviors and relatively preserved social communication may suggest opportunities to build on social strengths while addressing motor, adaptive, and executive functioning challenges. Together, these findings provide the first longitudinal, multimodal characterization of PACS1-NDD, inform clinical care and the development of targeted outcome measures for therapeutic trials, and highlight the need for future studies in larger samples to validate and extend these results.

The brain’s ability to regulate blood flow is fundamental to both its function and development. In the context of neurodevelopmental disorders such as schizophrenia, understanding the complex interactions between cerebrovascular health and brain function is crucial for unraveling the pathophysiology of psychosis. This study investigates the developmental trajectory of cerebrovascular reactivity (CVR) in 22q11 deletion syndrome (22q11.2DS) compared to healthy controls, and its association with psychosis susceptibility. Using a longitudinal data-set of resting-state fMRI, we mapped voxel-level CVR across development. We found significant and early CVR impairments in 22q11.2DS, and in particular in those who later developed positive psychotic symptoms (PPS+). These impairments were evident within the anterior cingulate cortex, frontal lobes, and globi pallidi (GB). We propose that the pattern of CVR reduction presenting early during childhood is possibly linked to blood brain barrier impairment. A decrease in CVR during childhood and within the frontal regions and GB was predictive of subsequent development of positive psychotic symptoms (PPS), which often occurs during adolescence in 22q11.2DS patients. These findings suggest that cerebrovascular health is critical for normal brain development, particularly in regions like the striatum, which are vulnerable to vascular damage due to their anatomical features. These results underline the potential of CVR as an early biomarker for psychosis vulnerability, emphasizing the need for targeted interventions to mitigate neurodevelopmental disruptions of cerebrovascular health in 22q11.2DS.