2.1 LIMBIC MICROSTRUCTURE AND CONNECTIVITY MARKERS OF ATTENTIONAL DEFICITS IN YOUTH AT RISK FOR BIPOLAR DISORDER

Abstract

Although symptoms of ADHD and having a biological parent with bipolar disorder (BD) are risk factors for developing BD, neural biomarkers of risk are poorly understood. We used diffusion tensor imaging (DTI) and resting-state functional connectivity (RSFC) to compare limbic microstructure and connectivity among youth with ADHD with (high-risk [HR]) and without (low-risk [LR]) a family history of BD and a healthy comparison group. Three groups of psychostimulant-free youth (ages 10-18 years) were recruited: 1) HR youth with ADHD and a first-degree relative with BD (HR); 2) LR youth with ADHD and no first-degree relative with a mood disorder (LR); and 3) healthy comparison youth (HC). Diffusion-weighted and resting-state echo-planar images were collected using a Philips 3.0 T MR scanner. Fractional anisotropy (FA) and mean diffusivity (MD) maps were calculated. Bilateral amygdala were used as the seeds to estimate connectivity. Multiple-comparisons correction was determined using Monte Carlo simulations using AlphaSim (p < 0.05 and voxels ≥40). A total of 105 youth (61% male; mean [SD] age of 14.5 [2.5] years; HR, n = 31; LR, n = 38; HC, n = 36) were recruited. Group comparisons revealed significant FA differences in bilateral insular cortex and right cuneus and MD differences in the left inferior frontal gyrus. Post hoc analyses revealed that the LR group has increased FA in the bilateral insula, right anterior cingulum, bilateral putamen, right caudate, and right cuneus, and increased MD in the bilateral inferior frontal gyri, left amygdala, and right hippocampus. HR youth exhibit increased FA in the bilateral insula and the left superior and inferior temporal cortex, and increased MD in the right amygdala, bilateral inferior frontal gyri, and right medial frontal gyrus. RSFC analyses revealed that HR exhibited greater right amygdala to right ventrolateral prefrontal cortex (R-VLPFC) connectivity compared with both HC (p < 0.001) and LR (p = 0.017) youth. Altered microstructure in the dorsal striatum was present in youth with ADHD and not in youth with attention deficits who are at risk for developing BD. Right amygdala-VLPFC resting-state hyperconnectivity distinguish youth at risk for BD and may represent a prodromal risk biomarker for bipolar disorder.