Abnormal functional connectivity in children with attention-deficit/hyperactivity disorder

Abstract

Background: Attention-deficit/hyperactivity disorder (ADHD) is typically characterized by symptoms of inattention and hyperactivity/impulsivity, but there is increased recognition of a motivation deficit too. This neuropathology may reflect dysfunction of both attention and reward-motivation networks.

Methods: To test this hypothesis, we compared the functional connectivity density between 247 ADHD and 304 typically developing control children from a public magnetic resonance imaging database. We quantified short- and long-range functional connectivity density in the brain using an ultrafast data-driven approach.

Results: Children with ADHD had lower connectivity (short- and long-range) in regions of the dorsal attention (superior parietal cortex) and default-mode (precuneus) networks and in cerebellum and higher connectivity (short-range) in reward-motivation regions (ventral striatum and orbitofrontal cortex) than control subjects. In ADHD children, the orbitofrontal cortex (region involved in salience attribution) had higher connectivity with reward-motivation regions (striatum and anterior cingulate) and lower connectivity with superior parietal cortex (region involved in attention processing).

Conclusions: The enhanced connectivity within reward-motivation regions and their decreased connectivity with regions from the default-mode and dorsal attention networks suggest impaired interactions between control and reward pathways in ADHD that might underlie attention and motivation deficits in ADHD.

Figure 1

Distribution of short-range (top panel) and long-range (bottom panel) functional connectivity density (FCD) in the human brain for 247 attention-deficit/hyperactivity disorder children and 304 typically developing children and the statistical differences (t score) between the groups. Functional connectivity density mapping threshold used to compute short- and long-range FCD: r > .6. One-way analysis of variance with three covariates (age, gender, and mean motion) was used to contrast short- and long-range FCD maps across groups. ADHD, attention-deficit/hyperactivity disorder; TDC, typically developing children.

Figure 2

Bar plot showing the average values for short-range (left) and long-range (right) functional connectivity density (FCD) across subjects and regions of interest (ROIs) for attention-deficit/hyperactivity disorder (ADHD) children (n = 247) and typically developing children (TDC) (n = 304). Error bars are standard errors of the mean. Statistical significance between ADHD and TDC for all ROIs: p < .01. Cubic ROI volume: .73 cc (27 imaging voxels); ROI center coordinates in Table 3. Numbers in region labels are Brodmann areas. CER, cerebellum; L, left hemisphere; OFC, orbitofrontal cortex; Precun, precuneus; R, right hemisphere; SFC, superior frontal cortex; SPC, superior parietal cortex; VS, ventral striatum.

Figure 3

Scatter plots showing correlations between rating scores and average values of short- and long-range functional connectivity density (FCD) in parietal (top panels) and reward-motivational (bottom panels) regions of interest (ROIs). Sample: 67 attention-deficit/hyperactivity disorder (ADHD) boys (full circles) and 63 typically developing children (TDC) boys (open circles) from Peking University. Cubic ROI volume: .73 cc (27 imaging voxels); ROI center coordinates in Table 3. OFC, orbitofrontal cortex.

Figure 4

Statistical significance (color-coded t score) of resting-state functional connectivity patterns for the superior parietal cortex (SPC) seed (cubic region of interest [ROI] centered at x, y, z = (−24, −66, 63) mm; ROI volume = 125 imaging voxels) for 304 typically developing children (TDC) and 247 attention-deficit/hyperactivity disorder (ADHD) children and their differences. One-way analysis of variance with three covariates (age, gender, and mean motion). RSFC, resting-state functional connectivity.

Figure 5

Effect of medications on short-range functional connectivity density (FCD) in reward-motivational regions of interest (ROIs) (right orbitofrontal cortex [OFC]/insula and ventral striatum [VS]) and of long-range FCD in cerebellum and superior parietal cortex (SPC) ROIs. Statistical significance: *p < .05. Sample: 119 unmedicated and 68 medicated attention-deficit/hyperactivity disorder (ADHD) children and 304 unmedicated typically developing children (TDC). Cubic ROI volume: .73 cc (27 imaging voxels); ROI center coordinates in Table 3. Cereb, cerebellum; med, medication.