New Research
White Matter Microstructure in Subjects With Attention-Deficit/Hyperactivity Disorder and Their Siblings

https://doi.org/10.1016/j.jaac.2013.01.010Get rights and content

Objective

Previous voxel-based and regions-of-interest (ROI)–based diffusion tensor imaging (DTI) studies have found above-normal mean diffusivity (MD) and below-normal fractional anisotropy (FA) in subjects with attention-deficit/hyperactivity disorder (ADHD). However, findings remain mixed, and few studies have examined the contribution of ADHD familial liability to white matter microstructure.

Method

We used refined DTI tractography methods to examine MD, FA, axial diffusivity (AD), and radial diffusivity (RD) of the anterior thalamic radiation, cingulum, corticospinal tract, inferior fronto-occipital fasciculus, inferior longitudinal fasciculus, forceps major, forceps minor, superior longitudinal fasciculus, and uncinate fasciculus in children and adolescents with ADHD (n = 56), unaffected siblings of ADHD probands (n = 31), and healthy controls (n = 17).

Results

Subjects with ADHD showed significantly higher MD than controls in the anterior thalamic radiation, forceps minor, and superior longitudinal fasciculus. Unaffected siblings of subjects with ADHD displayed similar differences in MD as subjects with ADHD. Although none of the tested tracts showed a significant effect of FA, the tracts with elevated MD likewise displayed elevated AD both in subjects with ADHD and in unaffected siblings. Differences in RD between subjects with ADHD, unaffected siblings, and controls were not as widespread as differences in MD and AD.

Conclusion

Our findings suggest that disruptions in white matter microstructure occur in several large white matter pathways in association with ADHD and indicate a familial liability for the disorder. Furthermore, MD may reflect these abnormalities more sensitively than FA.

Section snippets

Participants

Subjects with ADHD, unaffected siblings, and control subjects (all between the ages of 6 and 18 years) were recruited from the community or referred to the study by their physicians or through other ongoing studies of ADHD at the University of California, Los Angeles (UCLA). All children were evaluated for ADHD and other psychiatric diagnoses based on an interview with the primary caretaker, usually the mother, using a semi-structured diagnostic interview, the Kiddie-Schedule for Affective

Results

The control, unaffected sibling, and ADHD groups did not differ in terms of age or full-scale IQ, but they did significantly differ with regard to gender (Table 1). Gender was thus included as a factor in the linear mixed model. Although the groups did not significantly differ with regard to age, age was included as a factor to further reduce any age-related variance.

For analyses of FA, significant main effects of hemisphere were observed for the cingulum and CST (both leftward) and the IFO and

Discussion

Despite some previous reports of significant FA differences in subjects with ADHD with respect to controls,8 we did not detect significant diagnosis effects for FA in any of the nine tracts examined, in line with at least one prior study that reported no differences in whole-brain FA between subjects with ADHD and controls.58 One possible explanation of the lack of significant FA effects in our study rests on the observation that FA varies with the ratio of RD to AD.59 Hence, concomitant

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      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.)(

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      Other white matter tracts have not been as extensively studied, and for many tracts there has been mixed findings relating to white matter microstructure with some studies finding between-group differences but others failing to find a difference. Reduced organisation of white matter microstructure has been reported in the arcuate fasciculus (Chiang et al., 2016; Tung et al., 2021), inferior longitudinal fasciculus (Pavuluri et al., 2009); uncinate fasciculus (Tung et al., 2021; Tamm et al., 2012; Fuelscher et al., 2021; Nagel et al., 2011), inferior fronto-occipital fasciculus (Tung et al., 2021; Pastura et al., 2016; Adisetiyo et al., 2014; Tamm et al., 2012; Fuelscher et al., 2021); corticospinal tract (Hamilton et al., 2008; Fuelscher et al., 2021), external capsule (Pastura et al., 2016; Wu et al., 2017; Adisetiyo et al., 2014); fronto-pontine tract (Fuelscher et al., 2021); parieto-occipital pontine tract (Fuelscher et al., 2021), frontal aslant tract (Tung et al., 2021), perpendicular fasciculus (Tung et al., 2021); stria terminalis (Tung et al., 2021); forceps major (Lin et al., 2020) and forceps minor (Qiu et al., 2011; King et al., 2015; Lawrence et al., 2013; Svatkova et al., 2016) as well as in white matter tracts in the parahippocampal gyrus (Peterson et al., 2011), lingual gyrus (Peterson et al., 2011); striatum (Wu et al., 2017; Ashtari et al., 2005); premotor region (Ashtari et al., 2005), motor cortex (Jacobson et al., 2015), basal ganglia (Qiu et al., 2011; Li, 2010), fornix (Davenport et al., 2010); fronto-parietal tracts (Nagel et al., 2011) and white matter in the medial orbitofrontal cortex (Jacobson et al., 2015), parieto-occipital region (Ashtari et al., 2005); cerebellar peduncle (Ashtari et al., 2005; Bechtel et al., 2009) and cerebellum (Nagel et al., 2011). Increased white matter microstructural organisation has been reported in the corticospinal tract (Silk et al., 2009); uncinate fasciculus (Tamm et al., 2012; Silk et al., 2009), inferior fronto-occipital fasciculus (Tamm et al., 2012), inferior longitudinal fasciculus (Silk et al., 2009; Svatkova et al., 2016), corticospinal tract (Svatkova et al., 2016), striatum (Peterson et al., 2011), anterior forceps (Tamm et al., 2012) and forceps minor (Tamm et al., 2012; Lawrence et al., 2013), as well as in white matter in the frontal region (Davenport et al., 2010; Li, 2010), and temporo-occipital white matter (Kobel, 2010).

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    This work was supported by grants from the National Institutes of Health and the National Institute of Mental Health (RC1MH088507, R01MH092301 and P41RR013642).

    The UCLA Statistical Consulting Center provided statistical support for this research.

    Disclosure: Drs. Levitt, Loo, O’Neill, Alger, and Narr, Ms. Lawrence, Mr. Ly, and Mr. Yee report no biomedical financial interests or potential conflicts of interest.

    Supplemental material cited in this article is available online.

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