2026 ECNP Congress

PS02-2078

Multivariate brain morphological–immune patterns underlying internalizing and externalizing behaviour during development

Emma Tassi — C. Colli, F. Bottaro, G. Ratti, C. Cabasino, P. Enrico, E. Maggioni, C. Bonivento, M. Mauri, N. Agarwal, R. Girometti, M. Nobile, A.M. Finardi, R. Furlan, P. Brambilla · Fondazione IRCCS Ca Granda Ospedale Policlinico di Milano, Department of Neurosciences and Mental Health, Milano, Italy

2026 ECNP Congress

Background

Emotional and behavioral difficulties in childhood and adolescence are early vulnerability markers for psychopathological disorders [1,2]. Evidence supports a bidirectional link between peripheral immune dysregulation and brain structural alterations in emotion regulation regions [3,4], and inflammatory profiles may define transdiagnostic behavioral phenotypes in emerging mental disorders [5]. However, multivariate associations among these domains during development remain unexplored. This study characterized associations between cortical thickness (CT), immunological gene expression, demographic variables, and emotional-behavioral profiles in a developmental sample referred for emotional-behavioral problems.

Methods

Fifty-one subjects (20/31 males / females; mean age 15.51 years) were included. Regional CT was extracted from 68 Desikan-Killiany atlas regions using CAT12 [6]. Twenty-seven immunological gene expression markers (<5% missingness) and demographics (age, sex) were additional predictors. Clinical outcome comprised 11 Child Behavior Checklist (CBCL) scales [7], including Internalizing, Externalizing, and Total Problems with eight syndrome subscales. Multi-block Partial Least Squares (MB-PLS) extracted latent variables (LVs) maximizing shared covariance between predictor blocks and outcomes [8,9]. For each LV, block scores, loadings, and Block Importance in Projection (BIP) were computed per predictor block, alongside composite super scores summarizing information across blocks. Significance was assessed via Pearson correlation between predictor and response super scores, followed by permutation testing (n=1000).

Results

Three LVs were retained, selected on cumulative explained CBCL variance (30.4%) and confirmed by significant predictor–response correlations (p < 0.05) surviving permutation testing. LV1 was driven by CT (BIP = 96.9%), capturing widespread cortical thinning - particularly in frontal and temporal regions - associated with higher social and thought problems. LV2 was dominated by the immunological block (BIP = 61.8%) and selectively associated with the internalizing domain, particularly anxiety. The immune profile reflected T-cell activation and co-stimulation (CD27, IL2RA, CD38), T-cell differentiation and regulatory signaling (GATA3, TGFB1), and immune cell trafficking (CCR7, CCR6), converging on positive regulation of lymphocyte activation and T-cell differentiation. This heightened activation was associated with greater internalizing symptom intensity, alongside thinned limbic CT but preserved visual/medial cortex. LV3 showed balanced contributions from immunological (BIP = 73.4%) and CT (23.3%) blocks and was selectively associated with the externalizing domain, particularly somatic complaints and aggressive behavior. The immune profile reflected reduced expression of B-cell and immunoglobulin-mediated immunity markers (IGHD, CD19), helper T-cell markers (CD4), transcriptional regulators of immune cell maturation (NAB2), immune cell trafficking receptors (CCR7, CCR6), and a Th17-related cytokine (IL23A), converging on lymphocyte differentiation, immunoglobulin-mediated immune response, and immune cell trafficking. This reduced expression involved in immune cell differentiation and maturation was associated with greater externalizing symptom intensity. CT alterations included increased auditory and cingulate thickness but decreased parahippocampal CT. Across components, male sex was a consistent vulnerability factor and younger age strengthened immune–behavior associations.

Conclusions

MB-PLS revealed distinct brain-immune-behavior axes: heightened immune activation was associated with internalizing symptoms, while reduced expression of markers related to immune differentiation and maturation was linked to externalizing problems [3,10]. These findings suggest that different immune states may underlie distinct emotional-behavioral dimensions during development [4,11], highlighting cortical morphology and peripheral immune markers as complementary transdiagnostic vulnerability indices [5].

References

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