There was no evidence that psychostimulants were associated with ‘slowing’ of overall growth of the cortical mantle- a notable finding given the reports of possible psychostimulant related slowing of height and weight gain in children and adolescents (3
). Adolescents with ADHD untreated with psychostimulants showed regional decreases in cortical thickness relative both to their peers with the disorder who took psychostimulants and typically developing adolescents. However, the functional significance of the finding is unclear, partly as we did not collect cognitive data at both time points in most subjects. Additionally, it is important to note that the increased cortical thinning in the ADHD group stopping psychostimulants was not associated with any difference in clinical outcome. With these caveats in mind, it is still worthwhile to consider some possible interpretations. Psychostimulants tend to normalize goal-directed activity (19
) and cognitive processes, including planning, cognitive flexibility, vigilance and response inhibition (23
). In healthy adults, methylphenidate induced improvement in working memory is associated with alterations of cerebral blood flow in the left dorsolateral prefrontal, supplementary motor and posterior parietal cortex-overlapping in part with the regions we find to be differentially sensitive to psychostimulants (24
). In children with ADHD, psychostimulant induced improvement in the ability to inhibit prepotent responses is associated with increased frontal (and striatal) activity as assayed by functional MRI (25
). In adults with ADHD, correction of executive deficits by psychostimulants is associated with altered prefrontal cortical activity- with increased activation of the premotor and decreased activation of the middle and medial prefrontal cortex (26
). Thus, psychostimulant induced increase in age appropriate levels of cognition and action, and perhaps underlying localized fronto-parietal neural activity, might foster cortical development within the normative range. In this regard psychostimulant effects on the developing brain in ADHD can be conceptualized as an example of activity-dependent neuroplasticity. Additionally, it is possible that psychostimulants have a direct trophic effect on the cortex, particularly in view of the growing evidence for the role of catecholaminergic neurotransmitters in cortical development (27
), although this explanation does not account for the highly regional effects detected.
The current study extends our previous demonstration of more normative white matter volumes in those with a history of psychostimulant use by demonstrating effects on gray matter morphology
). Our longitudinal approach enabled detection of correlates of psychostimulant treatment on the rate of cortical development; this was not possible in our earlier cross sectional analysis that compared cortical thickness at study entry in groups with differing psychostimulant histories (13
). Additionally, by using the metric of cortical thickness, determined at over 40,000 cortical points, we were able to detect more localized changes missed by lobar volumetric studies. The ‘on’ and ‘off’ medication groups were age-matched to ensure that any differences in cortical trajectories are not confounded by age effects.
In a recent study we demonstrated delay in cortical maturation in most of the frontal (excluding the sensorimotor region) and temporal cortex (8
) using the age of attaining peak cortical thickness as a developmental marker. An assessment of whether psychostimulant treatment contributes to this phenomenon is limited as in the current study we focused on the adolescent phase of cortical thinning and did not examine the childhood phase of increase in cortical thickness. However some considerations argue against psychostimulants being a major factor in the altered timing of maturation. The regions that were sensitive to medication were highly focal, (unlike the disturbance in timing of maturation which involved most of the cortex) and encompassed areas with both late -the dorsolateral prefrontal regions-and early maturation -the motor regions.
At the time of the first scan (~12years) the ADHD medication groups did not differ significantly from each other in cortical thickness in the regions shown in , perhaps reflecting their similar history of medication exposure prior to the first scan. In prefrontal regions, the typically developing group attains peak cortical thickness earlier and thus enters the phase of cortical thinning earlier than those with ADHD (see (8
). However, the typically developing group also reaches a higher peak (i.e. a thicker cortex) and thus starts thinning from a higher baseline. By age 12, the ADHD and typically developing cohorts reported upon in (8
) do not differ significantly in estimated cortical thickness in the prefrontal regions shown in .
In this observational study, it is important to consider the possibility that the group differences in cortical trajectories are attributable to other dimensions on which the groups differ. The groups did not differ in initial clinical characteristics or clinical outcome, removing the possibility that differences in the severity of the disorder or clinical course underpinned the findings. The groups also did not differ significantly on other variables known to affect cortical trajectories such as gender and intelligence. Of course the ideal design is a randomized trial comparing cortical growth in children on psychostimulants against an un-medicated comparison group- but this is both logistically and ethically challenging. Other limitations of the current study include the lack of external validation of treatment histories which were based purely on patient and parent report. It is impossible to exclude neuroanatomic effects of the non-psychostimulant medication received by the ADHD groups, although the prevalence of such non-psychostimulant medication was low and did not differ between groups at the time of final assessment.
Within the inherent limitations of an observational study, we find highly regional differential associations between cortical development and psychostimulant treatment in ADHD which may reflect activity dependent cortical plasticity.