White matter alterations in Attention-Deficit/Hyperactivity Disorder (ADHD): a systematic review of 129 diffusion imaging studies with meta-analysis
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 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.
Additional information
supplementary information
prisma checklist
peak coordinates 1
peak coordinates 2
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