Abstract
BACKGROUND: Although attention-deficit/hyperactivity disorder (ADHD) with familial risk for bipolar I disorder (BD) may represent a more severe illness conferring greater risk for developing BD, associated neurostructural substrates remain poorly understood. This study examined cerebellum structural alterations, which prior studies suggested may be associated with BD risk. METHODS: We enrolled 151 youth (ages 10-18 years) in three groups: psychostimulant-free ADHD youth with a biological parent or sibling with BD (high-risk, n = 52, mean age 13.8 ± 2.6 years), psychostimulant-free ADHD youth without any first- or second-degree relative with mood or psychotic disorders (low-risk, n = 50, mean age 14.1 ± 2.5 years), and healthy controls (HC, n = 49, mean age 14.6 ± 2.4 years). ADHD youth were stimulant-naïve or had no psychostimulant exposure within 3 months prior to enrollment. Region-of-interest (ROI) analyses were conducted on the whole cerebellum and 28 lobules to quantify cerebellar volumes using the SUIT toolbox, and voxel-based morphometry (VBM) analyses were also performed. Exploratory analyses evaluated associations between regional cerebellar volumes and symptom measures. RESULTS: Significant group differences in volume were observed for the whole cerebellum, bilateral lobules VIIIa, right VIIb, and left X. Post hoc comparisons showed that the high-risk group exhibited volume deficits in the whole cerebellum, bilateral lobules VIIIa, and right VIIb, compared with HC and low-risk groups, whereas both high-risk and low-risk groups exhibited left X volume deficits compared to HC. Similar results were obtained using VBM. Among all ADHD youth, significant inverse correlations were observed between significant ROI volumes and Child Behavior Checklist (CBCL) total score and several subscales, including the dysregulation profile. CONCLUSIONS: Psychostimulant-free ADHD youth with BD familial risk exhibit whole and regional cerebellar volume deficits compared with those without such risk and healthy youth. Inverse associations between regional cerebellar volumes and CBCL total and subscale scores among ADHD youth suggest clinical relevance and may represent a potential BD risk biomarker.