Neuroimaging of Supraventricular Frontal White Matter in Children with Familial Attention-Deficit Hyperactivity Disorder and Attention-Deficit Hyperactivity Disorder Due to Prenatal Alcohol Exposure

Abstract

Attention-deficit hyperactivity disorder (ADHD) is common in patients with (ADHD+PAE) and without (ADHD-PAE) prenatal alcohol exposure (PAE). Many patients diagnosed with idiopathic ADHD actually have covert PAE, a treatment-relevant distinction. To improve differential diagnosis, we sought to identify brain differences between ADHD+PAE and ADHD-PAE using neurobehavioral, magnetic resonance spectroscopy, and diffusion tensor imaging metrics that had shown promise in past research. Children 8-13 were recruited in three groups: 23 ADHD+PAE, 19 familial ADHD-PAE, and 28 typically developing controls (TD). Neurobehavioral instruments included the Conners 3 Parent Behavior Rating Scale and the Delis-Kaplan Executive Function System (D-KEFS). Two dimensional magnetic resonance spectroscopic imaging was acquired from supraventricular white matter to measure N-acetylaspartate compounds, glutamate, creatine + phosphocreatine (creatine), and choline-compounds (choline). Whole brain diffusion tensor imaging was acquired and used to to calculate fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity from the same superventricular white matter regions that produced magnetic resonance spectroscopy data. The Conners 3 Parent Hyperactivity/Impulsivity Score, glutamate, mean diffusivity, axial diffusivity, and radial diffusivity were all higher in ADHD+PAE than ADHD-PAE. Glutamate was lower in ADHD-PAE than TD. Within ADHD+PAE, inferior performance on the D-KEFS Tower Test correlated with higher neurometabolite levels. These findings suggest white matter differences between the PAE and familial etiologies of ADHD. Abnormalities detected by magnetic resonance spectroscopy and diffusion tensor imaging co-localize in supraventricular white matter and are relevant to executive function symptoms of ADHD.

Keywords: Attention-deficit hyperactivity disorder; Diffusion tensor imaging; Fetal alcohol spectrum disorder; Magnetic resonance spectroscopy; Tower test; White matter.

Fig. 1

STimulated Excitation Acquisition Mode (TR/TE/TM = 2000/20/10 ms) magnetic resonance spectroscopic imaging for a representative participant in register with T1-weighted MRI in sagittal (upper frame) section. In the lower frame, the T1-weighted MRI has been resliced to match the orientation of the magnetic resonance spectroscopic imaging slab. The yellow lines in the lower frame demarcate the 16 × 16 two-dimensional array of 10 × 10 × 10 mm³ spectroscopic imaging voxels. The white box in the lower frame indicates the 8 × 8 subarray from which usable spectra are acquired. The upper frame illustrates three sagittal T1w MRI sections that intersect with the excitation box and include the left frontal white matter, right frontal white matter, and midline frontal gray matter. Together the upper and lower frames illustrate that the magnetic resonance spectroscopic imaging sampling volume includes a substantial amount of frontal supraventricular white matter

Fig. 2

STimulated Excitation Acquisition Mode (TR/TE/TM = 2000/20/10 ms) magnetic resonance spectroscopic imaging data for a sample voxel in supraventricular white matter. (Upper frame) The yellow box identifies a voxel on slices of T1w MRI and (resampled to magnetic resonance spectroscopic imaging resolution) gray matter (GM), white matter (WM), mean diffusivity (MD), and fractional anisotropy (FA) volumes, as well as the non-water-suppressed (NWS) magnetic resonance spectroscopic image. (Lower frame) Measured (red) and best fit (green) water-supressed magnetic resonance spectrum from the voxel identified in the images. The abscissa marks chemical shift in parts per million (ppm). Labelled are principal resonances for N-acetyaspartate compounds (NAA), glutamate (Glu), total creatine (= creatine + phosphocreatine), and choline-compounds (Cho). Note that relatively tight fit of these signals achieved with the SVFit2016 software package (Alger et al. 2016)

Fig. 3

Neurobehavioral (upper panels) and neuroimaging (lower panels) metrics differ in children with attention deficit-hyperactivity disorder with prenatal alcohol exposure (ADHD+PAE; red circles) from those with familial attention deficit-hyperactivity disorder without prenatal alcohol exposure (ADHD-PAE; blue triangles), and typically developing controls (TD; green diamonds). Means and standard deviations are depicted by horizontal and vertical lines, respectively. In ADHD+PAE, the Conners Hyperactivity/Impulsivity Score was 12.2% higher than in ADHD-PAE (p < 0.05; post hoc protected Mann-Whitney U-test following omnibus Kruskal-Wallis test) and 74.8% higher than in TD (p < 0.005). The Conners Hyperactivity/Impulsivity Sore was also 55.8% higher in ADHD-PAE than in TD (p < 0.005). The Verbal Fluency Category Switching Score from the Delis-Kaplan Executive Function System significantly distinguished ADHD+PAE from TD (− 31,6%, p < 0,.0005), but only distinguished ADHD+PAE from ADHD-PAE (− 17.8%, p < 0.10 trend) and ADHD-PAE from TD (− 16.7%, p < 0.10) at trend level. Glutamate in supraventricular white matter was 9.6% higher (p = 0.05) in ADHD+PAE than in ADHD-PAE and 10.3% lower (p < 0.05) in ADHD-PAE than in TD. Mean diffusivity (MD) of supraventricular white matter was 5.4% higher (p < 0.005) in ADHD+PAE than in ADHD-PAE. Similar results (not shown) were observed for axial diffusivity (2.8%, p < 0.05) and radial diffusivity (6.1%, p < 0.05). Also, mean diffusivity was 2.9% lower in ADHD-PAE than in TD (p < 0.05). Although there is overlap between groups for all metrics, these findings suggest brain differences between the PAE and familial etiologies of ADHD. All metrics are adjusted for participant age. IU (Institutional Units)

Fig. 4

Selected correlation analysis (including linear regression and Pearson and Spearman correlation coefficients with p-values) between neurobehavioral and neuroimaging metrics in children with ADHD+PAE (red circles, upper) and in TD (green diamonds, lower). In ADHD+PAE, the Tower Test Total Achievement Score decreased with increasing creatine in supraventricular white matter (r = − 0.60, p < 0.005). Similar results (not shown) were observed for glutamate (r = − 0.41, p = 0.05) and choline (r = − 0.42, p < 0.05). Higher Tower Test Mean First Move Time (indicating inferior performance) accompanied higher levels of N-acetylaspartate (r = 0.59, p < 0.05). A similar result (not shown) was observed for glutamate (r = 0.49, p < 0.05). In TD, Trail Making Test Visual Scanning Score decreased (i.e., worse performance) for increasing creatine (r = 0.59, p < 0.05) and for increasing radial diffusivity (r = − 0.62, p = 0.001). A complementary opposite result (not shown) was observed for fractional anisotropy (r = 0.53, p = 0.005). All metrics are adjusted for participant age

Fig. 5

Selected correlations (including linear regression and Pearson and Spearman correlation coefficients and p-values between diffusion tensor imaging and magnetic resonance spectroscopy metrics in children with ADHD-PAE (blue triangles, upper panel) and in TD (green diamonds, lower panel). In ADHD-PAE, fractional anisotropy in supraventricular white matter increased with increasing glutamate (r = 0.49, p < 0.05). A similar relationship (not shown) was observed for fractional anisotropy and choline (r = 0.75, p = 0.001). In TD, in contrast, fractional anisotropy decreased with increasing glutamate (r = − 0.42, p < 0.05) and (not shown) with increasing creatine (r = − 0.49, p < 0.05). Radial diffusivity in ADHD+PAE decreased with increasing choline (r = − 0.71, p = 0.001). A similar relationship was observed for mean diffusivity and choline (r = − 0.57, p < 0.05). In TD, in contrast, radial diffusivity increased with increasing glutamate (r = 0.39, p < 0.05)