Associations between traits of neurodevelopmental conditions and executive functions in preschool aged children with tuberous sclerosis complex

Tuberous sclerosis complex (TSC) is a rare genetic condition caused by mutations in TSC1 or TSC2 gene (Curatolo et al., 2015), which leads to the development of benign tumors in multiple organ systems. These mutations dysregulate the mammalian target of rapamycin (mTOR) pathway, thus playing a pivotal role in diverging brain development with more severe presentations associated with TSC2 mutations (Rosset et al., 2017). Among the variability of TSC manifestations, up to 90% of individuals with TSC will have epilepsy, particularly in the first year of life (Bolton et al., 2015). Early-onset epilepsy in TSC is associated with diverging neurocognitive profiles and increased likelihood of overlapping neurodevelopmental conditions (NDCs) or traits of autism, attention deficit hyperactivity disorder (ADHD) and intellectual disability (ID) in early to middle childhood (Berghoff et al., 2023; Gupta et al., 2020) defined as TSC-associated neuropsychiatric disorders (TAND) (de Vries et al., 2020). The neuropsychological cluster of TAND outlines potential challenges in executive functions (EFs) (de Vries et al., 2018) reported from early childhood into adulthood (McDonald et al., 2024; Tierney et al., 2011). EFs are domain general neurocognitive constructs that support goal-oriented behaviors (Spiegel et al., 2021) and are commonly characterized into three core domains: inhibition, working memory (WM) and attentional shifting (Diamond, 2013). Diamond (2013) further defines inhibition as the process of sustained self-control, restriction of impulsive behaviors and modulated attention. WM refers to updating and manipulating available information, and shifting is defined as quick adaptability to change by employing alternative strategies. Early childhood is a critical developmental period for EF. In typically developing (TD) children, EF abilities emerge in the first year of life (Hendry et al., 2016) and become more stable during the preschool ages (3-5 years) (Shaul & Schwartz, 2013). Inhibition and WM become apparent core domains at preschool, and shifting continues to develop into adolescence (Kofler et al., 2024). Considering the rapid development of EF in early years, core EF differences may be more detectable during preschool ages which may serve as behavioral markers for neurodevelopmental risk (Terroux et al., 2025). Lower EF abilities become more identifiable into preschool age in children with NDCs, including autism, ADHD, ID, and co-occurring conditions compared to TD children (Christoforou et al., 2023; Lee et al., 2025). Studies show children with elevated autistic traits display lower attentional shifting and global EF skills (Ko et al., 2024), and children with more ADHD traits exhibit lower WM and inhibitory abilities (Kofler et al., 2024; Sinzig et al., 2008). Additionally, children with co-occurring autism, ADHD and/or ID exhibit significantly lower EF abilities across all core EF domains compared to children with only one confirmed NDC (Sadozai et al., 2024). However, associations between EF, intellectual abilities and traits of autism and ADHD are inconsistently reported potentially reflecting the heterogeneity of these conditions and domain-specific EF measurement (Sankalaite et al., 2025). Given the EF profiles observed in children with elevated traits of autism and ADHD, similar EF profiles in preschool age children with TSC may be expected. To date, a range of EF domains in individuals with TSC have been explored using the Self-Report Quantified Tuberous Sclerosis Complex-Associated Neuropsychiatric Disorders Checklist (TAND-SQ; (Heunis et al., 2023), an indirect measure, based on parent or self-reporting. The TAND-SQ measures attention, visuospatial skills and processing speed, across a wide range of individuals with and without co-occurring conditions (Cardozo et al., 2024; Marcinkowska et al., 2025; McDonald et al., 2024), yet the core EF domains are poorly characterized. Early studies show 66% of children with TSC, age 6-18 years, have difficulties in attention and goal-directed activities, and challenges continue to emerge with chronological age (Prather & de Vries, 2004). Indirect parent-report measures report 32% of children with TSC, aged 1-19 years, show cognitive flexibility difficulties (Toldo et al., 2019). There is limited evidence examining specific EF domains in individuals with TSC using a combination of measures. Moreover, few studies examine how traits of autism and ADHD are associated with EF abilities in TSC. Direct measures of EF, typically assessed using observational, experimental or laboratory performance-based tasks, show variable outcomes in early childhood potentially due to task impurity (Wilkey, 2023). Direct measures often capture behaviors under structured conditions with specific tools and may only provide specific outcomes (Skogan et al., 2015). The ecological validity has been challenged on direct measures compared to indirect measures that draw on naturalistic and daily environments, such as the Behavior Rating Inventory of Executive Function-Preschool Version (BRIEF-P;(Gioia et al., 2003). Despite low to moderate correlations between direct and indirect measures reflecting task impurity (Miranda et al., 2015), use of both measures allows for a more comprehensive approach to understanding EF profiles in early childhood. Yet, existing TSC studies often assess wide age ranges or report on indirect parent-report measures alone. This preregistered secondary analysis examines domain-specific EF abilities in preschool-aged children with TSC and their associations with autistic and ADHD traits. Using an existing dataset which includes standardized parent-rated EF scores (BRIEF-P), direct EF tasks, and indirect parent-report measures of autism and ADHD, this study aims to understand how EF relates to neurodevelopmental traits in children with TSC. Identifying early EF profiles may inform future interventions to support learning and self-regulation from the preschool age.