Objective Psychostimulant medications are the gold standard of treatment for attention-deficit/hyperactivity disorder (ADHD); however, a significant minority (~30%) of individuals with ADHD fail to respond favorably. Noradrenergic agents are increasingly used as ADHD monotherapies or adjuncts for suboptimal stimulant response, yet knowledge of their cortical effects is limited. This study is the first to examine comparative effects of guanfacine (an alpha adrenergic 2A agonist), psychostimulant, and their combination on resting state cortical activity in ADHD. Method The sample comprised 179 participants aged 7 to 14 years old with ADHD (113 boys, 55 girls). Participants were randomized to one of three blinded conditions: guanfacine (GUAN), d-methylphenidate (DMPH), or a combination (COMB). Electroencephalography (EEG) was performed pre-, mid-, and post-medication titration, with concomitant assessment of behavioral and cognitive functioning. Results Analyses of spectral power measures during resting EEG suggested that each medication condition displayed a distinct profile of effects on cortical activity. Significant time effects suggested that GUAN decreased global alpha-band (8–12 hertz [Hz]) power, DMPH and COMB increased centro-parietal beta-band (13–21 Hz) power, and COMB resulted in decreased theta-band (4–7 Hz) power. Relative to other medication groups, COMB was associated with significantly lower theta power and DMPH with higher beta-band power compared to the GUAN group. Medication-related changes in theta power were correlated with improvements in behavioral and cognitive functioning. Conclusion These data revealed distinct underlying medication-related effects on neural mechanisms. The COMB condition uniquely exhibited an EEG profile that was associated with improved behavioral and cognitive functioning. Clinical trial registration information Single Versus Combination Medication Treatment for Children With Attention Deficit Hyperactivity Disorder; http://clinicaltrials.gov/; NCT00429273.

Objective The Child Behavior Checklist–Dysregulation Profile (CBCL/DP) identifies youth at increased risk for significant psychopathology. Although the genetic architecture and several biological correlates of the CBCL/DP have been described, little work has elucidated its underlying neurobiology. We examined the potential utility of electroencephalography (EEG), along with behavioral and cognitive assessments, in differentiating individuals based on the CBCL/DP. Method Participants aged 7–14 years were categorized into three age- and sex-matched groups based on clinical assessment and CBCL/DP: typically developing non-attention-deficit/hyperactivity disorder (ADHD) controls (n=38), ADHD without the CBCL/DP (ADHD/DP−)(n=38), and individuals with the CBCL/DP (CBCL/DP+) (n=38). Groups were compared with EEG and measures of clinical phenomenology and cognition. Results ADHD/DP− and CBCL/DP+ groups had increased inattention, but the CBCL/DP+ group had increased hyperactive/impulsive symptoms, disruptive behavior, mood, and anxiety comorbidities compared with ADHD alone. Cognitive profiles suggested that ADHD/DP− participants had fast impulsive responses, while CBCL/DP+ participants were slow and inattentive. On EEG, CBCL/DP+ had a distinct profile of attenuated delta and elevated alpha band spectral power in central and parietal regions compared to ADHD/DP− and controls. The low delta/high alpha profile was correlated with measures of emotion and behavior problems and not with inattentive symptomatology or cognitive measures. There were no EEG differences between ADHD/DP− and control groups. Conclusions An EEG/cognitive profile suggests a distinct pattern of underlying neural dysfunction with the CBCL/DP that might ultimately serve as a biosignature. Further work is required to identify potential relationships with clinically defined psychiatric disorders, particularly those of dysregulated mood.