Abstract
BACKGROUND: Bipolar I disorder (BD) is associated with reduced white matter microstructural integrity in the uncinate fasciculus (UF), a primary fiber tract connecting frontolimbic systems. Although familial history for BD, attention-deficit/hyperactivity disorder (ADHD), and psychostimulants are important risk factors implicated in BD pathoetiology, their impact on UF microstructure remains poorly understood. METHODS: This diffusion tensor imaging study investigated UF microstructural integrity prior to and following 12 weeks of psychostimulant treatment in ADHD youth with ('high-risk', HR) and without ('low-risk', LR) a first-degree relative with BD. Healthy controls were included for comparative purposes. LR youth received 12-week open-label mixed amphetamine salts-extended release (MAS-XR), and HR youth were randomized to either MAS-XR or placebo (PLA). Bilateral UF fractional anisotropy (FA) and axial diffusivity (AD) were assessed using automated fiber quantification. RESULTS: A total of 137 participants were included in the analyses. At baseline, there were no significant group differences in bilateral UF microstructural metrics. Following 12-week MAS-XR treatment, significant group-by-time interactions were found for left UF FA and AD between HR-MAS and LR-MAS, as well as for left UF FA between HR-MAS and HR-PLA. Specifically, left UF FA and UF AD decreased significantly in HR-MAS but remained unchanged in LR-MAS and HR-PLA groups. At week 12, left UF FA was lower in HR-MAS relative to HC but not in LR-MAS or HR-PLA. Segment-wise analyses further revealed that UF microstructural changes in the HR-MAS group were localized to the anterior segments. CONCLUSIONS: These results suggest that HR-ADHD youth are uniquely vulnerable to reductions in left UF microstructural integrity following psychostimulant treatment, suggesting potential relevance to BD pathoprogression.