Methylphenidate, Guanfacine, and Combined Treatment Effects on Electroencephalography Correlates of Spatial Working Memory in Attention-Deficit/Hyperactivity Disorder
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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.
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Out of six studies testing effects of mostly longer-term guanfacine effects on cognition, four reported sedative symptoms or fatigue while two other studies did not record or report them.
“Out of six studies testing effects of mostly longer-term guanfacine effects on cognition, four reported sedative symptoms (39, 40, 43) or fatigue (44) while two other studies did not record or report them (39, 42).”
From Differential effects of a single dose of Lisdexamfetamine and Guanfacine on cognitive function in children with ADHD (2025) · cites this paper as [43]
The Methods (Procedures) describe an eight-week guanfacine trial assessing cognition, and the Discussion mentions sedative effects commonly observed with guanfacine. This paper does not report sedative symptoms or fatigue among its own participants, nor does it establish the citing sentence’s counts across six studies. Its mention of sedation is background, not a reported study result. (LLM, conf=0.82)
Experimental — accuracy not yet measuredThe study's findings extend evidence for detrimental effects of longer-term guanfacine use on working memory in a much larger sample of 172 children with ADHD.
“The findings extend evidence for detrimental effects of longer-term guanfacine use on WM in a much larger sample of 172 children with ADHD (43).”
From Differential effects of a single dose of Lisdexamfetamine and Guanfacine on cognitive function in children with ADHD (2025) · cites this paper as [43]
The study adds to the majority of previous studies showing either no or negative effects of guanfacine on cognition in children with ADHD.
“Nevertheless, our study adds to the majority of previous studies showing either no (39–42) or negative effects (43) of guanfacine on cognition in children with ADHD, with only a single very small numbered study in 17 adults with ADHD showing cognitive improvement in interference inhibition (44).”
From Differential effects of a single dose of Lisdexamfetamine and Guanfacine on cognitive function in children with ADHD (2025) · cites this paper as [43]
Guanfacine, while improving ADHD symptoms relative to placebo, may not be an optimal drug to improve specific attention measures.
“Together, this suggests that guanfacine, while improving ADHD symptoms relative to placebo (39–41, 43, 44), may not be an optimal drug to improve specific attention measures.”
From Differential effects of a single dose of Lisdexamfetamine and Guanfacine on cognitive function in children with ADHD (2025) · cites this paper as [43]
Only one of these studies reported reduced cognitive performance in a working memory task.
“While only one of these studies reported reduced cognitive performance in a WM task (43), impaired attention (as well as memory, working memory, reaction time and psychomotor function) has been observed after clonidine in neurotypical adults (78, 79), which similarly to guanfacine, is also an α2-adrenergic receptor agonist and can cause sedation.”
From Differential effects of a single dose of Lisdexamfetamine and Guanfacine on cognitive function in children with ADHD (2025) · cites this paper as [43]
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- Authors
- Michelini, G., Lenartowicz, A., Diaz-Fong, J. P., Bilder, R. M., McGough, J. J., McCracken, J. T., & Loo, S. K.
- Affiliations
- University of California, Los Angeles (US)
- Corresponding author
- Michelini, Giorgia
- Loo, Sandra K.
- ORCID
- Venue
- Journal of the American Academy of Child & Adolescent Psychiatry
- Publisher
- Elsevier BV
- Published
- 2023-01
- Volume
- 62
- Issue
- 1
- Pages
- 37-47
- ISSN
- 0890-8567 (ISSN-L)
- PMC
- PMC10829974
- OpenAlex
- W4291397581
- Cited by
- 12
- References
- 49
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 1 · 2023: 1 · 2022: 2
- FWCI
- 1.30
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of the American Academy of Child & Adolescent Psychiatry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Queen Mary Research Online (Queen Mary University of London) (submittedVersion, cc-by)
- Funders
- National Institute of Mental Health (P50MH077248, R01MH116268)
- Klingenstein Third Generation Foundation (20212999)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Attention Deficit Hyperactivity Disorder
- Social Sciences › Psychology › Neuropsychology and Physiological Psychology › Developmental and Educational Neuropsychology
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- attention deficit hyperactivity disorder, methylphenidate, guanfacine, spatial working memory, primary visual cortex, alpha oscillations, theta oscillations, children, treatment monitoring, ADHD symptom severity, anterior cingulate cortex
- MeSH terms
- Central Nervous System Stimulants, Attention Deficit Disorder with Hyperactivity, Child, Electroencephalography, Female, Humans, Male, Memory, Short-Term, Methylphenidate, Guanfacine
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