Methylphenidate, Guanfacine, and Combined Treatment Effects on Electroencephalography Correlates of Spatial Working Memory in Attention-Deficit/Hyperactivity Disorder

Abstract

Objective: The combination of d-methylphenidate and guanfacine (an α-2A adrenergic agonist) may be an effective alternative to either agent as monotherapy in children with attention-deficit/hyperactivity disorder (ADHD). This study investigated the neural mechanisms underlying medication effects using cortical source analysis of electroencephalography (EEG) data.

Method: A total of 172 children with ADHD (aged 7-14; 118 boys) completed an 8-week randomized, double-blind, comparative study with 3 treatment arms: d-methylphenidate, guanfacine, or their combination. EEG modulations of brain oscillations at baseline and end point were measured during a spatial working memory task from cortical sources localized within the anterior cingulate (midfrontal) and primary visual cortex (midoccipital), based on previously reported ADHD and control differences. Linear mixed models examined treatment effects on EEG and performance measures.

Results: Combined treatment decreased midoccipital EEG power across most frequency bands and task phases. Several midoccipital EEG measures also showed significantly greater changes with combined treatment than with monotherapies. D-methylphenidate significantly increased midoccipital theta during retrieval, while guanfacine produced only trend-level reductions in midoccipital alpha during maintenance and retrieval. Task accuracy improved with combined treatment, was unchanged with d-methylphenidate, and worsened with guanfacine. Treatment-related changes in midoccipital power correlated with improvement in ADHD severity.

Conclusion: These findings show that combined treatment ameliorates midoccipital neural activity associated with treatment-related behavioral improvements and previously implicated in visuo-attentional deficits in ADHD. Both monotherapies had limited effects on EEG measures, with guanfacine further showing detrimental effects on performance. The identified midoccipital EEG profile may aid future treatment monitoring for children with ADHD.

Clinical trial registration information: Single Versus Combination Medication Treatment for Children With Attention Deficit Hyperactivity Disorder (Project1); https://clinicaltrials.gov/; NCT00429273.

Diversity & inclusion statement: We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. We worked to ensure sex and gender balance in the recruitment of human participants. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science. While citing references scientifically relevant for this work, we also actively worked to promote sex and gender balance in our reference list. We actively worked to promote inclusion of historically underrepresented racial and/or ethnic groups in science in our author group. We actively worked to promote sex and gender balance in our author group.

Keywords: attention-deficit/hyperactivity disorder; electroencephalography; guanfacine; methylphenidate; treatment effect.

Figure 1.. Occipital power modulations by treatment group at baseline and end of treatment.

Notes: Event-related spectral power was measured from a cortical source localized in the primary visual cortex (V1, Broadmann Area 17) (panel A) with of midoccipital topography (panel B). Time-frequency modulations during the encoding (E), maintenance (M) and retrieval (R) task phases are shown at baseline (panel C) and end of treatment (panel D) by medication group. Rectangles with solid line depict measures that showed treatment-specific medication-by-time interactions, whereas boxes with dashed line depict measures that showed significant post-hoc treatment-specific effects following main time effects.

Figure 2.. Change in performance measures (A) and EEG measures from the midoccipital cluster (B) between baseline and end of treatment.

Notes: **p≤.01; *p≤.05. Bars represent change from baseline to end of treatment in performance measures (A) and event-related EEG power (B) in each treatment group. Asterisks over horizontal square brackets represent differences between groups for measures showing significant medication-by-time interactions. Asterisks over individual bars represent within-group effects for measures showing significant main time effects. Abbreviations: COMB, combined treatment; DMPH, d-methylphenidate; GUAN, guanfacine; RT, mean reaction time; RTV, reaction time variability.