White matter alterations in Attention-Deficit/Hyperactivity Disorder (ADHD): a systematic review of 129 diffusion imaging studies with meta-analysis

Abstract

Aberrant anatomical brain connections in attention-deficit/hyperactivity disorder (ADHD) are reported inconsistently across diffusion weighted imaging (DWI) studies. Based on a pre-registered protocol (Prospero: CRD42021259192), we searched PubMed, Ovid, and Web of Knowledge until 26/03/2022 to conduct a systematic review of DWI studies. We performed a quality assessment based on imaging acquisition, preprocessing, and analysis. Using signed differential mapping, we meta-analyzed a subset of the retrieved studies amenable to quantitative evidence synthesis, i.e., tract-based spatial statistics (TBSS) studies, in individuals of any age and, separately, in children, adults, and high-quality datasets. Finally, we conducted meta-regressions to test the effect of age, sex, and medication-naïvety. We included 129 studies (6739 ADHD participants and 6476 controls), of which 25 TBSS studies provided peak coordinates for case-control differences in fractional anisotropy (FA)(32 datasets) and 18 in mean diffusivity (MD)(23 datasets). The systematic review highlighted white matter alterations (especially reduced FA) in projection, commissural and association pathways of individuals with ADHD, which were associated with symptom severity and cognitive deficits. The meta-analysis showed a consistent reduced FA in the splenium and body of the corpus callosum, extending to the cingulum. Lower FA was related to older age, and case-control differences did not survive in the pediatric meta-analysis. About 68% of studies were of low quality, mainly due to acquisitions with non-isotropic voxels or lack of motion correction; and the sensitivity analysis in high-quality datasets yielded no significant results. Findings suggest prominent alterations in posterior interhemispheric connections subserving cognitive and motor functions affected in ADHD, although these might be influenced by non-optimal acquisition parameters/preprocessing. Absence of findings in children may be related to the late development of callosal fibers, which may enhance case-control differences in adulthood. Clinicodemographic and methodological differences were major barriers to consistency and comparability among studies, and should be addressed in future investigations.

Fig. 1

PRISMA 2020 flow diagram.

Fig. 2. Projection pathways and associated impairment.

This figure displays the distinct components of the frontostriatal and thalamo-frontal connections (panel a); cerebellar pathways (panel b); and the corticospinal tract (panel c). Significant associations between tract metrics and cognitive deficits or symptoms are reported. Additional abbreviations: ATR anterior thalamic radiation, FS frontostriatal tract.

Fig. 3. Association and commissural pathways and associated impairment.

This figure shows the three branches of the superior longitudinal fasciculus (SLF) (Panel a); the cingulum (CING), uncinate (UNC), inferior longitudinal fasciculus (ILF) and inferior fronto-occipital fasciculus (IFOF) (Panel b); and the main subdivisions of the corpus callosum (CC) (Panel c). Significant associations between tract metrics and cognitive deficits or symptoms are reported.

Fig. 4. Results of the meta-analysis of TBSS studies.

The meta-analysis of TBSS studies comparing fractional anisotropy (FA) between individuals with ADHD (any age) and typically developing (TD) controls showed that individuals with ADHD had lower FA in the splenium of the corpus callosum (CC), extending to the posterior cingulum, and in the body of the CC. Peak coordinates are reported in Supplementary Table S6.