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.

Diffusion kurtosis imaging reveals abnormal gray matter and white matter development in some brain regions of children with attention‐deficit/hyperactivity disorder

“…In previous studies, the researchers found that ADHD patients had abnormal development of gray matter in the basal ganglia, abnormal development of white matter in the frontal and temporal lobes of the brain, and abnormal brain network connections (Cortese et al., 2021; De La Fuente et al., 2013; Gagnon et al., 2022; Klein et al., 2021; Parlatini et al., 2023; Schmithorst et al., 2016; Vilgis et al., 2016; Wu et al., 2020; Zhao et al., 2020, 2022). In this study, we found white matter abnormalities in frontal lobe, temporal lobe, and other brain areas in ADHD children, we also found gray matter abnormalities in caudate nucleus in ADHD children.…”

Shared genetic architecture and causal pathways between attention deficit hyperactivity disorder and restless legs syndrome

“…Byeong-Yeul Lee and his team identified a reduction in the body of the corpus callosum through thickness analysis 91 , while Deniz Sigirli and his team found significant changes in the posterior midbody of the corpus callosum through shape analysis 92 . A large meta-analysis encompassing 32 datasets (26 involving children and 6 involving adults) showed that one of the most significant and consistent white matter changes in ADHD patients is the reduced FA value in the body of the corpus callosum 93 . These studies suggest that changes in the corpus callosum body fibers are a common pathological feature of both diseases.…”

Cerebellar network alterations in adult attention-deficit/hyperactivity disorder

“…The most recent systematic review included 129 diffusion-weighted imaging studies of ADHD and reported alterations in diffuse brain connectivity, most consistently in the splenium and body of the corpus callosum. 6 The review highlighted that most studies have focused on frontostriatal networks, in line with a dominant pathophysiological hypothesis of ADHD. Further, only one-fifth of studies restricted recruitment to adults.…”

“… 4 , 5 The neurobiological characteristics underlying symptom severity, associated cognitive deficits, and treatment response in adults require further study. 3 , 6 Imaging studies have identified alterations in brain anatomy and function among people with ADHD compared with neurotypical controls, although these have mainly focused on children. Observed alterations include reduced volume of the basal ganglia and frontocingulate cortex, 7 , 8 and hypoactivation of frontostriatal regions during inhibition tasks.…”

“…These findings primarily focused on reduced fractional anisotropy (FA), a proxy measure of white-matter microstructural organization, among people with ADHD compared with neurotypical controls. 6 Other relevant brain connections, such as the cerebellar peduncles, have remained largely unexplored, especially in adults.…”