Differential changes in frontolimbic functional connectivity following 12-week psychostimulant monotherapy in ADHD youth with and without familial risk for bipolar I disorder.

Background

Although attention-deficit/hyperactivity disorder (ADHD), psychostimulant medications, and BD family history are risk factors for developing bipolar I disorder (BD), their contribution to the aberrant ventrolateral prefrontal cortex (VLPFC) and amygdala (AMY) functional connectivity (FC) implicated in the pathophysiology of BD remain unclear.

Methods

We investigated the effects of 12-week daily oral psychostimulant monotherapy on AMY-VLPFC FC during emotional and task-related attentional processing in ADHD youth with ('high-risk', HR) and without ('low-risk', LR) a first-degree relative with BD. LR received mixed amphetamine salts-extended release (MAS) and HR were randomized to MAS or placebo (PLA). Functional magnetic resonance scans were acquired at baseline and week 12 during a continuous performance task with emotional distracters. Generalized psychophysiological interaction analysis assessed AMY-VLPFC FC during emotional and task-related attentional processing.

Results

The study included 116 youth [healthy controls n = 38, LR-MAS n = 42, HR-MAS n = 24, HR-PLA n = 12]. Following treatment, neither LR-MAS nor HR-MAS exhibited changes in bilateral AMY-VLPFC FC during emotional processing. During task-related attentional processing, HR-MAS youth showed greater longitudinal increase in right AMY-VLPFC negative FC compared with LR-MAS (P = 0.034) and HR-PLA groups (P = 0.007). Compared with HR-MAS, LR-MAS exhibited greater reductions in ADHD total and inattention symptoms.

Conclusions

These findings suggest that familial BD risk may be associated with a differential longitudinal neurofunctional response to a regimen of psychostimulant monotherapy during attentional, but not emotional, processing.