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Emotion dysregulation and right pars orbitalis constitute a neuropsychological pathway to attention deficit hyperactivity disorder

Nature Mental Health (2024)Cite this article

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Abstract

Emotion dysregulation is common in attention deficit hyperactivity disorder (ADHD), which is known to be clinically heterogeneous. However, it remains unclear whether emotion dysregulation represents a neuropsychological pathway to ADHD. Here, using a large population-based cohort (n = 6,053), we show that emotion dysregulation was associated with ADHD symptoms (partial eta2 = 0.21) and this persisted after controlling for the cognitive and motivational deficits. Emotion dysregulation mediated the association between smaller surface area of the right pars orbitalis and greater ADHD symptoms at 1-year follow-up, indicating an emotion pathway for ADHD. This pathway was associated with immune responses by both transcriptomic analyses and white blood cell markers. In an independent clinical sample for ADHD (n = 672), the emotion pathway improved the case/control classification accuracy. These findings suggest that emotion dysregulation is a core symptom and route to ADHD, which may not respond to the current pharmacological treatments for ADHD.

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Fig. 1: Significant contributions of emotion dysregulation to ADHD.
Fig. 2: Relationships among brain, three pathway assessments, immune pathway, and ADHD.
Fig. 3: Trajectory classification accuracy and clinical validations.

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Data availability

Data are publicly released on an annual basis through the NIMH Data Archive (NDA, https://nda.nih.gov/abcd). The ABCD Study data are openly available to qualified researchers for free. Access can be requested at https://nda.nih.gov/abcd/request-access. The ABCD data used in this report came from Data Release 5.0 (https://doi.org/10.15154/8873-zj65). An NDA study has been created for the data used in this report under the digital object identifier https://doi.org/10.15154/nfsk-9n15. ADHD-200 data are available from a dedicated database. Summary statistics of GWAS for ADHD is publicly available and can be downloaded from https://www.med.unc.edu/pgc/download-results/adhd/. The transcriptomic data were downloaded from the Allen Human Brain Atlas (AHBA, https://human.brain-map.org/). The multi-tissue cell-type markers data can be downloaded from the Cell Marker2.0 database (http://bio-bigdata.hrbmu.edu.cn/CellMarker/index.html). Source data are provided with this paper.

Code availability

Code for the replication of analyses conducted in the manuscript can be retrieved at https://github.com/DanTouHaHa/ER-in-ADHD.

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Acknowledgments

This study was partially supported by grants from the National Key Research and Development Program of China (no. 2023YFE0109700) (Q.L.), the National Natural Science Foundation of China (No. 82272079) (Q.L.), the Program of Shanghai Academic Research Leader (no. 23XD1423400) (Q.L.), and the Shanghai Municipal Science and Technology Major Project (nos. 2018SHZDZX01 and 2021SHZDZX0103) (Q.L.). Data used in the preparation of this article were obtained from the Adolescent Brain Cognitive Development (ABCD) Study (https://abcdstudy.org), held in the NIMH Data Archive (NDA). This is a multisite, longitudinal study designed to recruit more than 10,000 children aged 9–10 and follow them over 10 years into early adulthood. The ABCD Study is supported by the National Institutes of Health and additional federal partners under award numbers U01DA041048, U01DA050989, U01DA051016, U01DA041022, U01DA051018, U01DA051037, U01DA050987, U01DA041174, U01DA041106, U01DA041117, U01DA041028, U01DA041134, U01DA050988, U01DA051039, U01DA041156, U01DA041025, U01DA041120, U01DA051038, U01DA041148, U01DA041093, U01DA041089, U24DA041123, and U24DA041147. A full list of supporters is available at https://abcdstudy.org/federal-partners.html. A listing of participating sites and a complete listing of the study investigators can be found at https://abcdstudy.org/consortium_members/. ABCD consortium investigators designed and implemented the study and/or provided data but did not necessarily participate in the analysis or writing of this report. This manuscript reflects the views of the authors and may not reflect the opinions or views of the NIH or ABCD consortium investigators. The ABCD data repository grows and changes over time. The ABCD data used in this report came from Data Release 5.0 (https://doi.org/10.15154/8873-zj65).

Author information

Authors and Affiliations

  1. National Clinical Research Center for Aging and Medicine at Huashan Hospital, Institute of Science and Technology for Brain-Inspired Intelligence, Research Institute of Intelligent Complex Systems, Fudan University, Shanghai, China

    Wenjie Hou, Barbara J. Sahakian & Qiang Luo

  2. Departments of Psychiatry, University of Cambridge, Cambridge, UK

    Barbara J. Sahakian & Christelle Langley

  3. Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK

    Barbara J. Sahakian & Christelle Langley

  4. Liberal Arts and Sciences, New York University Shanghai, Shanghai, China

    Yuqing Yang

  5. Department of Psychology, University of Cambridge, Cambridge, UK

    R. A. I. Bethlehem

  6. State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, China

    Qiang Luo

  7. MOE Key Laboratory of Computational Neuroscience and Brain-Inspired Intelligence, Human Phenome Institute, Fudan University, Shanghai, China

    Qiang Luo

  8. Shanghai Research Center of Acupuncture and Meridian, Shanghai, China

    Qiang Luo

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  1. Wenjie Hou
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Contributions

Q.L. proposed and designed the study. W.H. and Q.L. analyzed the data. W.H. and Q.L. drafted the manuscript. B.J.S., C.L., Y.Y., and R.A.I.B. edited the manuscript. All authors contributed to the interpretation of results. All authors contributed to the visualization. All authors read and approved the manuscript.

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Correspondence to Qiang Luo.

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R.A.I.B. is a founder and director of Centile Biosciences Inc. This role did not influence his contribution to this project.

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Nature Mental Health thanks Sha Tao and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary Information

Supplementary Figs. 1–9, Tables 1–18, Methods and Results.

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Supplementary Data 1

Biological processes and cell types associated with three neuropsychological pathways.

Supplementary Data 2

Statistical data for Supplementary Figs. 1–9.

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Source Data Figs. 1–3

Statistical data.

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Hou, W., Sahakian, B.J., Langley, C. et al. Emotion dysregulation and right pars orbitalis constitute a neuropsychological pathway to attention deficit hyperactivity disorder. Nat. Mental Health (2024). https://doi.org/10.1038/s44220-024-00251-z

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