Differential Brain Development with Low and High IQ in Attention-Deficit/Hyperactivity Disorder

Attention-Deficit/Hyperactivity Disorder (ADHD) and intelligence (IQ) are both heritable phenotypes. Overlapping genetic effects have been suggested to influence both, with neuroimaging work suggesting similar overlap in terms of morphometric properties of the brain. Together, this evidence suggests that the brain changes characteristic of ADHD may vary as a function of IQ. This study investigated this hypothesis in a sample of 108 children with ADHD and 106 typically developing controls, who participated in a cross-sectional anatomical MRI study. A subgroup of 64 children also participated in a diffusion tensor imaging scan. Brain volumes, local cortical thickness and average cerebral white matter microstructure were analyzed in relation to diagnostic group and IQ. Dimensional analyses investigated possible group differences in the relationship between anatomical measures and IQ. Second, the groups were split into above and below median IQ subgroups to investigate possible differences in the trajectories of cortical development. Dimensionally, cerebral gray matter volume and cerebral white matter microstructure were positively associated with IQ for controls, but not for ADHD. In the analyses of the below and above median IQ subgroups, we found no differences from controls in cerebral gray matter volume in ADHD with below-median IQ, but a delay of cortical development in a number of regions, including prefrontal areas. Conversely, in ADHD with above-median IQ, there were significant reductions from controls in cerebral gray matter volume, but no local differences in the trajectories of cortical development

Differences in the development of cortical thickness or children with ADHD and below median IQ ADHD versus matched controls.

<p>The figure shows t-maps from the comparison of the developmental trajectories of cortical thickness between subgroups of children with ADHD and below median IQ and matched controls. Critical t-values were t = 3.69 for the right hemisphere and t = 4.27 for the left hemisphere. For the two significant prefrontal regions, scatterplots with the best fit are shown for the below median IQ data. Fits for the entire group are also shown as a reference. Abbreviations: ADHD, Attention- Deficit/Hyperactivity Disorder; PFC, prefrontal cortex.</p

Data for brain volumes and global white matter microstructure and results of the tests for main effects of group, group by age interactions and dimensional IQ effects.

<p>Abbreviations: ADHD, Attention-Deficit/Hyperactivity Disorder; FA, Fractional Anisotropy.</p><p>Note: covariates for gender, age and slice thickness on T1 were included in all analyses (except the analysis of cerebral FA where there were no differences in slice thickness); a. n_Control = 98, n_ADHD = 90; b. raw ventricular volumes are tabulated. For analyses, these measures were log-transformed due to a deviation from normality; c. n_Control = 96, n_ADHD = 90; d. n_Control = 34, n_ADHD = 30, not split in IQ groups due to small group size; e. This column reports analyses of age effects on the whole diagnostic groups (not split by IQ). Analyses on the group with age<14 years (n_control = 93, n_ADHD = 85) showed the same pattern of results except for Mean Cortical Thickness (p = .028). Both groups showed decreasing thickness with age, but the regression line was steeper in the control group; f. This column reports analyses of IQ effects where IQ is treated as a dimensional measure, with its effects tested on the whole diagnostic groups. As these analyses were performed on continuous measures, three above median IQ outliers were excluded from structural MRI dataset for the IQ analyses (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0035770#s2" target="_blank">Methods</a>).</p

Demographic data.

<p>Abbreviations: ADHD, Attention-Deficit/Hyperactivity Disorder (I = inattentive type, HI = hyperactive/impulsive type, C = combined type); AM, Above Median; BM, Below Median; ODD, Oppositional Defiant Disorder; DISC-IV, Diagnostic Interview Schedule for Children-Fourth Edition; CBCL, Child Behavior Checklist; TRF, Teacher Report Form; SES, Socio-Economic Status.</p>a<p>Four children that met DISC-IV criteria for ODD also met criteria for CD;</p>b<p>CBCL unavailable for 2 Control_{Below-median IQ}, 2 Control_{Above-median IQ}, 11 ADHD_{Below-median IQ}, 2 ADHD_{Above-median IQ} in structural MRI sample, for 1 Control and 3 ADHD in DTI sample; TRF unavailable for 5 Control_{Below-median IQ}, 8 Control_{Above-median IQ}, 12 ADHD_{Below-median IQ}, 5 ADHD_{Above-median IQ} in structural MRI sample, for 1 control and 9 ADHD in DTI sample.</p>c<p>Medication histories were available for 87% of ADHD_{Below-median IQ} and 79% of the ADHD_{Above-median IQ} children in the structural MRI sample and 87% of ADHD children in the DTI sample. Reported is the percentage of established use in the entire (sub)sample. Corrected duration is calculated as: duration of use in months/((age in months) – 60).</p

Hypothetical model of differences in cortical thickness and cerebral gray matter volume in children with ADHD and low or high IQ.

<p>3A. In children with ADHD and low IQ, cortical peak thickness is shifted towards the right, to peak at a later age. 3B. Our results suggest a reduction in cortical surface area associated with ADHD and low IQ that is stable across age. 3C. A rightward shift in the developmental trajectory of cortical thickness combines with reduced cortical surface area (3B) to give only a minimal reduction in cerebral gray matter volume for much of the age range past the peak (using the approximation that mean cortical thickness x total cortical surface area = cortical gray matter volume, which comprises over 80% of cerebral gray matter in our data). 3D. In children with ADHD and high IQ, cortical peak volume is more similar to that of controls, resulting in more parallel trajectories with a slight difference in offset. 3E. The reduction in cortical surface area may be less pronounced in children with ADHD and high IQ than in children with ADHD and low IQ. 3F. More parallel trajectories of cortical development combined with reduced surface area (3E) will give a stable reduction in cerebral gray matter across the age range. Abbreviations: ADHD, Attention- Deficit/Hyperactivity Disorder.</p