Sophia Frangou

Offspring of parents with psychiatric illness (PH+) face elevated but heterogeneous risk for psychiatric disorders: while many exhibit emotional and cognitive difficulties, a substantial proportion remain free of diagnosable psychopathology. Adolescence—marked by rapid brain maturation—offers a critical period to study neurodevelopmental pathways of vulnerability and resilience in asymptomatic high-risk youth, yet prior work has largely focused on symptomatic samples. Using offspring of healthy parents (PH–) as a normative reference, we aimed to (1) identify neurodevelopmental subtypes within asymptomatic PH+ children via multimodal neuroimaging; (2) compare these subtypes on environmental exposures, cognitive and psychosocial factors, and subclinical symptoms; and (3) determine whether subtype membership predicts three-year changes in psychopathology. We analyzed data from the ABCD Study comprising 941 PH+ and 1,446 PH– children (ages 9–10) without baseline psychopathology. Imaging features included cortical thickness, surface area, subcortical volumes, gray–white matter contrast (GWC), and neurite density index (NDI). A semi-supervised HYDRA clustering approach derived subtypes among PH+ youth using PH– data as the reference. Subtypes were contrasted with PH– peers on imaging, environmental/psychosocial measures, and CBCL internalizing/externalizing scores at baseline and three-year follow-up. Models adjusted for age, sex, and site, with FDR correction. Three PH+ subtypes emerged. Subtype 1 (Delayed Maturation—Escalating Risk): Expanded cortical surface area and subcortical volumes, elevated GWC, reduced neurite density; it showed the highest baseline symptoms and the greatest escalation in internalizing symptoms over time. Subtype 2 (Atypical Maturation—Latent Vulnerability): Increased cortical thickness and NDI, reduced surface area/volume, greatest socioeconomic adversity; it had elevated baseline symptoms and a significant proportion of individuals showing reliable internalizing worsening, yet no overall group-level symptom trajectory difference. Subtype 3 (Accelerated Maturation—Resilient Profile): Pronounced cortical thinning, increased surface area, reduced GWC, elevated NDI in regulatory and associative cortices; it exhibited elevated baseline symptoms but no clinical deterioration, fewer environmental risks, and stronger peer relationships. Familial psychiatric risk is linked to distinct neurodevelopmental trajectories even among asymptomatic youth. Brain-based subtyping improves understanding of heterogeneous neurodevelopmental pathways in high-risk youth, supporting developmentally informed frameworks for stratified monitoring and future mechanistic research.

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