Childhood psychiatric disorders as anomalies in neurodevelopmental trajectories

Abstract

Childhood psychiatric disorders are rarely static; rather they change over time and longitudinal studies are ideally suited to capture such dynamic processes. Using longitudinal data, insights can be gained into the nature of the perturbation away from the trajectory of typical development in childhood disorders. Thus, some disorders may reflect a delay in neurodevelopmental trajectories. Our studies in children with attention-deficit/hyperactivity disorder (ADHD) suggest that cortical development is delayed with a rightward shift along the age axis in cortical trajectories, most prominent in prefrontal cortical regions. Other disorders may be characterized by differences in the velocity of trajectories: the basic shape of neurodevelopmental curves remains intact, but with disrupted tempo. Thus, childhood onset schizophrenia is associated with a marked increase during adolescence in the velocity of loss of cerebral gray matter. By contrast, in childhood autism there is an early acceleration of brain growth, which overshoots typical dimensions leading to transient cerebral enlargement. Finally, there may be more profound deviations from typical neurodevelopment, with a complete "derailing" of brain growth and a loss of the features which characterize typical brain development. An example is the almost complete silencing of white matter growth during adolescence of patients with childhood onset schizophrenia. Adopting a longitudinal perspective also readily lends itself to the understanding of the neural bases of differential clinical outcomes. Again taking ADHD as an example, we found that remission is associated with convergence to the template of typical development, whereas persistence is accompanied by progressive divergence away from typical trajectories.

Figure 1

How developmental trajectories can go awry. In all examples hypothetical data representing the change in cortical thickness of a cerebral point is given. (A) The pathological trajectory has the same form as the typical trajectory but is displaced rightward along the age axis and so key characteristics such as the age of peak thickness, shown in the bold arrows, is attained later. (B) The pathological trajectory has the same form, but changes at a higher velocity. (C) The pathological trajectory loses the form or shape of a typical trajectory.

Figure 2

(A) Dorsal view of the cortical regions where peak thickness was attained at each age. The darker color indicates regions where a peak age could not be calculated or the peak age was estimated to lie outside the age range covered. Both groups showed a similar sequence of the regions which attained peak thickness, but the ADHD group showed considerable delay in reaching this developmental marker. (B) Kaplan Meier curves illustrating the proportion of cortical points which had attained peak thickness at each age for (a) all cerebral cortical points and (b) the prefrontal cortex. The median age by which 50% of cortical points had attained their peak differed significantly between the groups (all P<1.0 × 10⁻²⁰).

Figure 3

Tissue growth rates mapped in healthy controls and COS patients. (A, B) These maps show the average rates of tissue growth (red) and tissue loss (blue) throughout the brain in percentage per year, for healthy controls (A) and COS patients (B). (C, D) These corresponding maps show the significance of the tissue growth in (A, B), respectively. There is almost no significant growth in the COS patients compared to the healthy controls.

Figure 4

Cortical normalization in ADHD with a good clinical outcome. The brain template shows regions where good outcome ADHD converges with the trajectory of typically developing children. Regions in blue and green show where this occurs at a trend level, and regions in yellow and red show where the convergence is significant, namely the right superior parietal lobule. The graphs show the cortical change in the right superior parietal lobule for the groups showing partial remission (top) and full remission (bottom).