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Neurobiology of attention-deficit hyperactivity disorder: historical challenges and emerging frontiers

Nature Reviews Neuroscience volume 25, pages 759–775 (2024)Cite this article

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Abstract

Extensive investigations spanning multiple levels of inquiry, from genetic to behavioural studies, have sought to unravel the mechanistic foundations of attention-deficit hyperactivity disorder (ADHD), with the aspiration of developing efficacious treatments for this condition. Despite these efforts, the pathogenesis of ADHD remains elusive. In this Review, we reflect on what has been learned about ADHD while also providing a framework that may serve as a roadmap for future investigations. We emphasize that ADHD is a highly heterogeneous disorder with multiple aetiologies that necessitates a multifactorial dimensional phenotype, rather than a fixed dichotomous conceptualization. We highlight new findings that suggest a more brain-wide, ‘global’ view of the disorder, rather than the traditional localizationist framework, which asserts that a limited set of brain regions or networks underlie ADHD. Last, we underscore how underpowered studies that have aimed to associate neurobiology with ADHD phenotypes have long precluded the field from making progress. However, a new age of ADHD research with refined phenotypes, advanced methods, creative study designs and adequately powered investigations is beginning to put the field on a good footing. Indeed, the field is at a promising juncture to advance the neurobiological understanding of ADHD and fulfil the promise of clinical utility.

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Fig. 1: Timeline of key events and milestones in ADHD neurobiology research.
Fig. 2: Spatial scales of the nervous system for ADHD neurobiology investigation.
Fig. 3: New directions to improve power in neuroimaging studies of ADHD.

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Acknowledgements

The authors thank A. Moore for assistance with figure preparation. This work was supported by National Institute of Health grants R37MH059105 (D.A.F.), DA041148 (D.A.F.), DA04112 (D.A.F.), MH115357 (D.A.F.), MH096773 (D.A.F.), MH122066 (D.A.F.), MH121276 (D.A.F.), MH124567 (D.A.F.) and DA057486 (B.T.-C.), as well as funding from the Lynne and Andrew Redleaf Foundation (D.A.F.).

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Authors and Affiliations

  1. Institute of Child Development, University of Minnesota, Minneapolis, MN, USA

    Sanju Koirala, Jed T. Elison & Damien A. Fair

  2. Masonic Institute for the Developing Brain, University of Minnesota, Minneapolis, MN, USA

    Sanju Koirala, Gracie Grimsrud, Bart Larsen, Eric Feczko, Jed T. Elison, Steven M. Nelson, Brenden Tervo-Clemmens & Damien A. Fair

  3. Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA

    Gracie Grimsrud, Bart Larsen, Eric Feczko, Jed T. Elison, Steven M. Nelson & Damien A. Fair

  4. Division of Bioinformatics and Computational Biology, Department of Medical Informatics and Clinical Epidemiology, Oregon Health & Science University, Portland, OR, USA

    Michael A. Mooney

  5. Departments of Psychiatry, Oregon Health & Science University, Portland, OR, USA

    Michael A. Mooney & Joel T. Nigg

  6. Center for Mental Health Innovation, Oregon Health & Science University, Portland, OR, USA

    Michael A. Mooney & Joel T. Nigg

  7. Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA

    Michael A. Mooney

  8. Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, USA

    Joel T. Nigg

  9. Department of Psychiatry and Behavioral Sciences, University of Minnesota, Minneapolis, MN, USA

    Brenden Tervo-Clemmens

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Contributions

S.K. and G.G. researched data for the article. S.K., G.G., E.F., B.L., J.T.N., B.T.-C. and D.A.F. provided substantial contributions to discussion of the article’s content. S.K., G.G. and D.A.F. wrote the article. S.K., G.G., M.A.M., E.F., J.T.E., S.M.N., J.T.N., B.T.-C. and D.A.F. reviewed and edited the manuscript before submission.

Corresponding author

Correspondence to Damien A. Fair.

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Competing interests

D.A.F. is a patent holder on the Framewise Integrated Real-Time Motion Monitoring (FIRMM) software. He is also a co-founder of Turing Medical Inc., which licenses this software. S.M.N. is a consultant for Turing Medical Inc., which commercializes FIRMM technology. These interests have been reviewed and managed by the University of Minnesota in accordance with its conflict-of-interest policies. The other authors declare no competing interests.

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Nature Reviews Neuroscience thanks Francisco Castellanos, who co-reviewed with Luis Martinez Agulleiro; Katya Rubia; and James Swanson for their contribution to the peer review of this work.

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Glossary

Brain networks

Interconnected regions of the brain that communicate with each other.

Brain-wide association studies

Approach used to identify associations between brain-wide imaging measures and various behaviours.

Effect sizes

Magnitudes of the relationships observed between variables in a study.

Functional connectivity

Measures the degree to which the activity in one brain region is related to activity in another region.

Heterogeneity

Variability in symptoms, aetiologies, mechanisms and responses to treatment among individuals with the disorder.

Localizationist framework

The concept that specific brain functions can be attributed to specific regions of the brain.

Phenotypes

Observable characteristics or traits of an organism.

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Koirala, S., Grimsrud, G., Mooney, M.A. et al. Neurobiology of attention-deficit hyperactivity disorder: historical challenges and emerging frontiers. Nat. Rev. Neurosci. 25, 759–775 (2024). https://doi.org/10.1038/s41583-024-00869-z

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