Altered White Matter Microstructure in Children With Attention-Deficit/Hyperactivity Disorder

doi:10.1016/j.jaac.2010.12.003

Journal of the American Academy of Child & Adolescent Psychiatry

Volume 50, Issue 3, March 2011, Pages 283-292

https://doi.org/10.1016/j.jaac.2010.12.003 Get rights and content

Objective

Identification of biomarkers is a priority for attention-deficit/hyperactivity disorder (ADHD). Studies have documented macrostructural brain alterations in ADHD, but few have examined white matter microstructure, particularly in preadolescent children. Given dramatic white matter maturation across childhood, microstructural differences seen in adolescents and adults with ADHD may reflect compensatory restructuring, rather than early neurophenotypic markers of the disorder.

Method

Using tract-based spatial statistics, mean fractional anisotropy (FA) maps were created using diffusion tensor imaging. FA, mean diffusivity (MD), and associated axial and radial diffusivities were compared between 16 children with ADHD and 20 healthy children (age 7-9 years).

Results

Youth with ADHD showed decreased FA in frontoparietal, frontolimbic, cerebellar, corona radiata, and temporo-occipital white matter compared with controls. In addition, ADHD was associated with lower MD in the posterior limb of the internal capsule and frontoparietal white matter and greater MD in frontolimbic white matter. Lower axial diffusion and/or higher radial diffusion were differentially observed for youth with ADHD in earlier versus later maturing areas of group FA/MD difference.

Conclusions

This study suggests that, even prior to adolescence, ADHD represents a disorder of altered structural connectivity of the brain, characterized by distributed atypical white matter microstructure. In addition, later maturing frontolimbic pathways were abnormal in children with ADHD, likely due to delayed or decreased myelination, a finding not previously demonstrated in the adolescent or adult stages of the disorder. These results suggest that disruptions in white matter microstructure may play a key role in the early pathophysiology of ADHD.

Section snippets

Participants

Recruited participants included 40 right-handed children 7 to 9 years of age, 22 of whom met DSM-IV criteria for ADHD and 18 non-ADHD comparison youth; four children (two per group) were excluded due to excessive motion during imaging, resulting in 20 youth with ADHD and 16 control youth used for analyses. Families of the two groups were recruited from an ongoing study of children with ADHD by countywide mailings and public advertisements. Written informed consent/assent was obtained from all

Demographics

Table 1 presents sample demographics and a clinical summary. Groups did not differ with regard to age, IQ, ethnicity, or annual household income. Gender differed and was statistically covaried in all analyses reported. Aside from the elevated rates of oppositional-defiant disorder (ODD) in the ADHD group, which is nearly universal in such samples, active comorbid disorders were generally absent from the sample, with exception of two children with ADHD having generalized anxiety disorder (Table 1

Discussion

Evaluation of white matter microstructure in childhood ADHD is crucial for examining the stability and replicability of white matter microstructural abnormalities in ADHD across development to promote the identification of early biomarkers of the disease. To that end, the present results confirm that microstructure in long-range white matter pathways shows abnormality, even before adolescence, in a sample that is largely medication naive and free of major comorbidity (except ODD, which did not

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Attention Deficit/Hyperactivity Disorder (ADHD) is a neurodevelopmental disorder with many functional impairments thought to be underpinned by difficulties in executive function domains such as working memory. The superior longitudinal fasciculus (SLF) plays an integral role in the development of working memory in neurotypical children. Neuroimaging research suggests reduced white matter organization of the SLF may contribute to working memory difficulties commonly seen in ADHD. This study aimed to examine the relationship between white matter organization of the SLF and working memory in children with ADHD.
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Regression analyses revealed children with ADHD exhibited poorer working memory, and lower volume and AFD of the left SLF-II compared to healthy controls. There was also an association between reaction time and variability (RT and RT-V) and the left SLF-II. Further analyses revealed volume of the left SLF-II mediated the relationship between ADHD and working memory performance (RT and RT-V).
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Increased IIV in both short and long RTs was positively associated with the specific attention problems factor (Cohen’s d = 0.13 and d = 0.15, respectively). Increased IIV in long RTs was also positively associated with radial diffusivity in the left and right corticospinal tract (both tracts, d = 0.12).
Using a large sample and a data-driven dimensional approach to psychopathology, the results provide novel evidence for a small but specific association between IIV and attention problems in children and support previous findings on the relevance of white matter microstructure for IIV.
A Mega-analytic Study of White Matter Microstructural Differences Across 5 Cohorts of Youths With Attention-Deficit/Hyperactivity Disorder
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While attention-deficit/hyperactivity disorder (ADHD) has been associated with differences in the structural connections formed by the brain’s white matter tracts, studies of such differences have yielded inconsistent findings, likely reflecting small sample sizes. Thus, we conducted a mega-analysis on in vivo measures of white matter microstructure obtained through diffusion tensor imaging of more than 6000 participants from 5 cohorts.
In a mega-analysis, linear mixed models were used to test for associations between the fractional anisotropy of 42 white matter tracts and ADHD traits and diagnosis. Contrasts were made against measures of mood, anxiety, and other externalizing problems.
Overall, 6993 participants (ages 6–18 years, mean age 10.62 years [SD 1.99]; 3368 girls, 3625 boys; 764 African American, 4146 non-Hispanic White, and 2083 other race/ethnicities) had measures of ADHD and other emotional/behavioral symptoms (N = 6933) and/or enough clinical data to allow a diagnosis of ADHD (n = 951) or its absence (n = 4884). Both the diagnosis and symptoms of ADHD were associated with lower fractional anisotropy of the inferior longitudinal and left uncinate fasciculi (at a false discovery rate–adjusted p < .05). Associated effect sizes were small (the strongest association with ADHD traits had an effect size of partial r = −0.14, while the largest case-control difference was associated with an effect size of d = −0.3). Similar microstructural anomalies were not present for anxiety, mood, or externalizing problems. Findings held when ADHD cases and control subjects were matched on in-scanner motion.
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Citation Excerpt :
On the other hand, multiple smaller WM bundles mostly comprising the corona radiata, thalamic radiation, cingulum, forceps minor and major, cerebellum and internal capsule have also been associated with ADHD symptom severity scores (Table 3.)( Ameis et al., 2016; Ashtari et al., 2005; Lawrence et al., 2013; Lin et al., 2020; Nagel et al., 2011; Qiu et al., 2012; Sudre et al., 2020; Wu et al., 2017; Zhan et al., 2017). While some authors did not report significant associations in their studies (Cha et al., 2015; Hamilton et al., 2008), others reported significant associations between ADHD symptom severity and WM diffusion measures in the dorsolateral, orbitofrontal, medial prefrontal and ventrolateral WM bundles (Table 3.)(
The apparent increase in the prevalence of the attention deficit hyperactivity disorder (ADHD) diagnosis raises many questions regarding the variability of the subjective diagnostic method. This comprehensive review reports findings in studies assessing white matter (WM) bundles in diffusion MRI and symptom severity in children with ADHD. These studies suggested the involvement of the connections between the frontal, parietal, and basal ganglia regions. This review discusses the limitations surrounding diffusion tensor imaging (DTI) and suggests novel imaging techniques allowing for a more reliable representation of the underlying biology. We propose a more inclusive approach to studying ADHD that includes known endophenotypes within the ADHD diagnosis. Aligned with the Research Domain Criteria Initiative, we also propose to investigate attentional capabilities and impulsive behaviours outside of the borders of the diagnosis. We support the existing hypothesis that ADHD originates from a developmental error and propose that it could lead to an accumulation in time of abnormalities in WM microstructure and pathways. Finally, state-of-the-art diffusion processing and novel artificial intelligence approaches would be beneficial to fully understand the pathophysiology of ADHD.
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To investigate WM alterations, particularly the changes in long-range fibers, in drug-naive children with attention deficit hyperactivity disorder (ADHD), we conducted tract-based spatial statistics (TBSS) analysis on diffusion tensor imaging (DTI) data.
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: This research was supported by the United Negro College Fund/Merck Fellowship Program (D.F.), the Ford Foundation (D.F.), K08 NS52147 (B.N.), Dana Foundation Brain and Immuno-Imaging Grant (B.N.), R01 MH59105 (J.N.), and the Oregon Health and Science University Neuropsychiatric Institute (J.N.).

: Disclosure: Drs. Nagel, Bathula, Kroenke, Fair, and Nigg, and Ms. Schmitt, and Ms. Herting report no biomedical financial interests or potential conflicts of interest.

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New researchAltered White Matter Microstructure in Children With Attention-Deficit/Hyperactivity Disorder

Objective

Method

Results

Conclusions

Section snippets

Participants

Demographics

Discussion

Psychiatry Res

Biol Psychiatry

Neurosc Lett

Biol Psychiatry

Neuropharmacology

Biol Psychiatry

J Am Acad Child Adolesc Psychiatry

Neuroimage

Neuroimage

Biol Psychiatry

Brain Res

Biol Psychiatry

J Am Acad Child Adolesc Psychiatry

Med Image Anal

Comput Biomed Res

Neuroimage

Neuron

Brain Res Cogn Brain Res

Neuroimage

Brain Res

Biol Psychiatry

Epilepsy Behav

J Am Acad Child Adolesc Psychiatry

Brain Res Bull

Mol Genet Metab

Neuron

Biol Psychiatry

The economic impact of attention-deficit/hyperactivity disorder in children and adolescents

J Pediatr Psychol

Developmental trajectories of brain volume abnormalities in children and adolescents with attention-deficit/hyperactivity disorder

JAMA

Distributed grey and white matter deficits in hyperkinetic disorder: MRI evidence for anatomical abnormality in an attentional network

Psychol Med

New insights into attention-deficit/hyperactivity disorder using structural neuroimaging

Curr Psychiatry Rep

New research
Altered White Matter Microstructure in Children With Attention-Deficit/Hyperactivity Disorder