The neural and genetic underpinnings of different developmental trajectories of Attention-Deficit/Hyperactivity Symptoms in children and adolescents

Abstract

Background: The trajectory of attention-deficit hyperactivity disorder (ADHD) symptoms in children and adolescents, encompassing descending, stable, and ascending patterns, delineates their ADHD status as remission, persistence or late onset. However, the neural and genetic underpinnings governing the trajectory of ADHD remain inadequately elucidated.

Methods: In this study, we employed neuroimaging techniques, behavioral assessments, and genetic analyses on a cohort of 487 children aged 6-15 from the Children School Functions and Brain Development project at baseline and two follow-up tests for 1 year each (interval 1: 1.14 ± 0.32 years; interval 2: 1.14 ± 0.30 years). We applied a Latent class mixed model (LCMM) to identify the developmental trajectory of ADHD symptoms in children and adolescents, while investigating the neural correlates through gray matter volume (GMV) analysis and exploring the genetic underpinnings using polygenic risk scores (PRS).

Results: This study identified three distinct trajectories (ascending-high, stable-low, and descending-medium) of ADHD symptoms from childhood through adolescence. Utilizing the linear mixed-effects (LME) model, we discovered that attention hub regions served as the neural basis for these three developmental trajectories. These regions encompassed the left anterior cingulate cortex/medial prefrontal cortex (ACC/mPFC), responsible for inhibitory control; the right inferior parietal lobule (IPL), which facilitated conscious focus on exogenous stimuli; and the bilateral middle frontal gyrus/precentral gyrus (MFG/PCG), accountable for regulating both dorsal and ventral attention networks while playing a crucial role in flexible modulation of endogenous and extrinsic attention. Furthermore, our findings revealed that individuals in the ascending-high group exhibited the highest PRS for ADHD, followed by those in the descending-medium group, with individuals in the stable-low group displaying the lowest PRS. Notably, both ascending-high and descending-medium groups had significantly higher PRS compared to the stable-low group.

Conclusions: The developmental trajectory of ADHD symptoms in the general population throughout childhood and adolescence can be reliably classified into ascending-high, stable-low, and descending-medium groups. The bilateral MFG/PCG, left ACC/mPFC, and right IPL may serve as crucial brain regions involved in attention processing, potentially determining these trajectories. Furthermore, the ascending-high pattern of ADHD symptoms exhibited the highest PRS for ADHD.

Keywords: ADHD; Children and adolescents; Genetic; Neurodevelopmental; Symptom trajectory.

Fig. 1

The different developmental trajectories of ADHD symptoms. The shaded areas represent the 95% confidence intervals. Individual participants are represented by individual lines, and participants measured once are represented by dots

Fig. 2

The different developmental changes of GMV among descending-medium, stable-low, and ascending-high groups. A The age effects on GMV. B The group (descending-medium, stable-low, and ascending-high) effect on GMV. C The interaction of age and group on GMV. GMV, gray matter volume. The color bar represents z value. L, left; R, right

Fig. 3

The different developmental trajectories of GMV in four clusters across descending-medium, stable-low, and ascending-high groups. A The developmental trajectory of GMV in left ACC/mPFC. B The developmental trajectory of GMV in the right IPL. C The developmental trajectory of GMV in left MFG/PCG. D The developmental trajectory of GMV in right MFG/PCG. GMV, gray matter volume; ACC/mPFC, anterior cingulate/medial frontal cortex; IPL, inferior parietal lobule; MFG/PCG, middle frontal gyrus/precentral gyrus. The shaded areas represent the 95% confidence intervals. Individual participants are represented by individual lines, and participants measured once are represented by dots

Fig. 4

Mean PRS for ADHD by descending-medium, stable-low, and ascending-high group. Significant group comparisons are indicated with asterisks ✝0.05 < p < 0.10 (marginally significant); *p < 0.05; **p < 0.01; ***p < 0.001, PRS, polygenic risk score