Attention-deficit hyperactivity disorder symptoms and brain morphology: Examining confounding bias

Abstract

Background: Associations between attention-deficit/hyperactivity disorder (ADHD) and brain morphology have been reported, although with several inconsistencies. These may partly stem from confounding bias, which could distort associations and limit generalizability. We examined how associations between brain morphology and ADHD symptoms change with adjustments for potential confounders typically overlooked in the literature (aim 1), and for IQ and head motion, which are typically corrected for but play ambiguous roles (aim 2).Methods: Participants were 10-year-old children from the Adolescent Brain Cognitive Development (N=7,722) and Generation R (N=2,531) studies. Cortical area, volume, and thickness were measured with MRI and ADHD symptoms with the Child Behavior Checklist. Surface-based cross-sectional analyses were run.Results: ADHD symptoms related to widespread cortical regions when solely adjusting for demographic factors. Additional adjustments for socioeconomic and maternal behavioral confounders (aim 1) generally attenuated associations, as cluster sizes halved and effect sizes substantially reduced. Cluster sizes further changed when including IQ and head motion (aim 2), however, we argue that adjustments might have introduced bias.Conclusions: Careful confounder selection and control can help identify more robust and specific regions of associations for ADHD symptoms, across two cohorts. We provided guidance to minimizing confounding bias in psychiatric neuroimaging.Funding: Authors are supported by an NWO-VICI grant (NWO-ZonMW: 016.VICI.170.200 to HT) for HT, LDA, SL, and the Sophia Foundation S18-20, and Erasmus University and Erasmus MC Fellowship for RLM.

Brain-charting autism and attention deficit hyperactivity disorder reveals distinct and overlapping neurobiology

“…We confirm previous reports of global reductions in grey and white matter volume and total surface area in ADHD, as well as widespread regional decreases in CV and SA 59–63,65 . We also confirm recent reports of greater, but not lower, CT, which contradict some earlier studies of ADHD 60–64,72,73 . Of note, head motion poses a critical challenge in neuroimaging studies of ADHD 72 (as well as autism 113,147 ).…”

“…We also confirm recent reports of greater, but not lower, CT, which contradict some earlier studies of ADHD 60–64,72,73 . Of note, head motion poses a critical challenge in neuroimaging studies of ADHD 72 (as well as autism 113,147 ). Thus, it is possible that earlier reports of cortical thinning in ADHD were confounded by motion and other aspects of MRI quality 148 , along with small sample sizes, as has been observed in autism 112,113 .…”

“…Reduced total brain volume, grey matter volume and cortical surface area in individuals with ADHD have been rather consistently reported [59][60][61][62][63][64][65] . However, while earlier studies reported decreases in cortical thickness [66][67][68][69][70] , more recent studies with bigger sample sizes have found no or only very minimal differences [60][61][62][63][64][71][72][73] . Cortical alterations have most commonly been reported in frontal (primarily dorsolateral and ventrolateral prefrontal, and orbitofrontal), parietal, anterior cingulate and occipital cortices 59,71 .…”

Attention‐deficit hyperactivity disorder symptoms and brain morphology: Addressing potential selection bias with inverse probability weighting

“…Specifically, we found that the association between ADHD symptoms and the surface area of the middle temporal gyrus, as well as the thickness of the fusiform gyrus, were stronger after weighting. Previous attempts in population studies did not found significant associations of thickness measures with ADHD symptoms (Dall'Aglio et al, 2022), while other studies do find these associations with ADHD (Shaw et al, 2007). Selection bias could potentially be a part of the explanation for this discrepancy.…”

“…Numerous neuroimaging studies have been conducted to examine possible structural brain alterations associated with ADHD; however, many of their findings have been inconsistent or even contradictory (Samea et al, 2019). While several explanations exist for these inconsistencies, various forms of bias have been proposed as a possible explanation for these inconsistent results, indeed adjusting for a more comprehensive set of confounding factors altered some associations between brain structure and ADHD symptoms (Dall'Aglio et al, 2022). Next to confounding bias, selection bias (e.g., self‐selection into a study or loss to follow‐up) is another possible source of bias that could alter the interpretation of results.…”