Robert K. McNamara

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.