Association between attention-deficit/hyperactivity disorder symptom severity and white matter integrity moderated by in-scanner head motion

Abstract

Attention-deficit/hyperactivity disorder (ADHD) is a common and debilitating neurodevelopmental disorder associated with various negative life impacts. The manifestation of ADHD is very heterogeneous, and previous investigations on neuroanatomical alterations in ADHD have yielded inconsistent results. We investigated the mediating effect of in-scanner head motion and ADHD hyperactivity severity on motion-corrected fractional anisotropy (FA) using diffusion tensor imaging in the currently largest sample (n = 739) of medication-naïve children and adolescents (age range 5-22 years). We used automated tractography to examine whole-brain and mean FA of the tracts most frequently reported in ADHD; corpus callosum forceps major and forceps minor, left and right superior-longitudinal fasciculus, and left and right corticospinal tract (CST). Associations between FA and hyperactivity severity appeared when in-scanner head motion was not accounted for as mediator. However, causal mediation analysis revealed that these effects are fully mediated through in-scanner head motion for whole-brain FA, the corpus callosum forceps minor, and left superior-longitudinal fasciculus. Direct effect of hyperactivity severity on FA was only found for the left CST. This study illustrates the crucial role of in-scanner head motion in the identification of white matter integrity alterations in ADHD and shows how neglecting irremediable motion artifacts causes spurious findings. When the mediating effect of in-scanner head motion on FA is accounted for, an association between hyperactivity severity and FA is only present for the left CST; this may play a crucial role in the manifestation of hyperactivity and impulsivity symptoms in ADHD.

Fig. 1. Distribution of SWAN Hyperactivity score by study group.

Dashed line: group mean; x- axis: −3: very low; −2: low; −1: slightly lower; 0: average; 1: slightly higher; 2: high; 3: very high. ADHD, attention-deficit/hyperactivity disorder; ADHD-IN, ADHD predominantly inattentive presentation; ADHD-C, ADHD combined presentation; SWAN, Strengths and Weaknesses Assessment of Normal Behavior Rating Scale for ADHD.

Fig. 2. Illustration of anatomical location of regions of interest.

Corpus callosum forceps minor and major (blue), left and right corticospinal tract (green), left and right superior longitudinal fasciculus (red), and whole-brain white matter tracts (thin gray lines).

Fig. 3. Causal mediation analysis design.

Model Y (orange) captures the average direct effect (ADE) of SWAN-HY on FA. Model M (yellow) reflects the effect of SWAN-HY on motion regardless of FA. The indirect effect of SWAH-HY on FA through the mediation of motion is the average causal mediation effect (ACME) (blue). Model M0 (green) captures the relationship of SWAN-HY on FA disregarding any effect of motion. SWAN-HY, Strengths and Weaknesses Assessment of Normal Behavior Rating Scale for ADHD Hyperactivity Score; FA, fractional anisotropy.

Fig. 4. Results of causal mediation analysis with significant effects.

SWAN-HY, Strengths and Weaknesses Assessment of Normal Behavior Rating Scale for ADHD Hyperactivity Score; CST, corticospinal tract; SLF, superior longitudinal fasciculus; T1-weighted image: X = −1.

Fig. 5. Correlation of fractional anisotropy (FA) for each segment of the corticospinal tract (gray) with Strengths and Weaknesses Assessment of Normal Behavior Rating Scale for ADHD Hyperactivity Score (SWAN-HY) on clipped regions of interest (blue shaded tube).

FA values are regressed out for age, sex, IQ, acquisition site and in-scanner head motion. Strongest correlations were observed at caudal segments of the tract. Node, equidistant segment on tract between clipped regions of interest.