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Roles of the medial and lateral orbitofrontal cortex in major depression and its treatment

Molecular Psychiatry (2024)Cite this article

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Abstract

We describe evidence for dissociable roles of the medial and lateral orbitofrontal cortex (OFC) in major depressive disorder (MDD) from structure, functional activation, functional connectivity, metabolism, and neurochemical systems. The reward-related medial orbitofrontal cortex has lower connectivity and less reward sensitivity in MDD associated with anhedonia symptoms; and the non-reward related lateral OFC has higher functional connectivity and more sensitivity to non-reward/aversive stimuli in MDD associated with negative bias symptoms. Importantly, we propose that conventional antidepressants act to normalize the hyperactive lateral (but not medial) OFC to reduce negative bias in MDD; while other treatments are needed to operate on the medial OFC to reduce anhedonia, with emerging evidence suggesting that ketamine may act in this way. The orbitofrontal cortex is the key cortical region in emotion and reward, and the current review presents much new evidence about the different ways that the medial and lateral OFC are involved in MDD.

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Fig. 1: Anatomy and functional specialization of the human medial and lateral OFC.
Fig. 2: Structure abnormalities of the medial and lateral OFC related to depression.
Fig. 3: Disrupted medial and lateral OFC activation in distinct subcomponents of reward-related processing.
Fig. 4: Abnormal resting-state voxel-level functional connectivity of the medial and lateral OFC in patients with major depression.
Fig. 5: Summary of the abnormalities of the medial and lateral orbitofrontal cortex in major depressive disorder.
Fig. 6: Summary of pathological abnormalities in the medial and lateral OFC in response to ketamine and to conventional antidepressant medications such as SSRIs.

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Data availability

The data that were used to support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

This work was partly supported by the grant from the National Key R&D Program of China (No. 2019YFA0709502 to JF), the grant from Shanghai Municipal Science and Technology Major Project (No. 2018SHZDZX01 to JF), ZJ Lab, and Shanghai Center for Brain Science and Brain-Inspired Technology, the grant from the 111 Project (No. B18015 to JF). This work was partly supported by the grants from the National Natural Sciences Foundation of China (No. 82071997 to WC) and the Shanghai Rising-Star Program (No. 21QA1408700 to WC). This work was supported by the project from China Postdoctoral Science Foundation (No. 2022M710804 to BZ).

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Author notes

  1. These authors contributed equally: Bei Zhang, Edmund T. Rolls.

Authors and Affiliations

  1. Institute of Science and Technology for Brain-Inspired Intelligence, Fudan University, Shanghai, PR China

    Bei Zhang, Edmund T. Rolls, Chao Xie, Wei Cheng & Jianfeng Feng

  2. Key Laboratory of Computational Neuroscience and Brain-Inspired Intelligence (Fudan University), Ministry of Education, Shanghai, PR China

    Bei Zhang, Chao Xie, Wei Cheng & Jianfeng Feng

  3. Oxford Centre for Computational Neuroscience, Oxford, UK

    Edmund T. Rolls

  4. Department of Computer Science, University of Warwick, Coventry, UK

    Edmund T. Rolls & Jianfeng Feng

  5. Medical Psychological Center, The Second Xiangya Hospital, Central South University, Changsha, PR China

    Xiang Wang

  6. Medical Psychological Institute, Central South University, Changsha, PR China

    Xiang Wang

  7. China National Clinical Research Center on Mental Disorders (Xiangya), Changsha, PR China

    Xiang Wang

  8. MOE Frontiers Center for Brain Science, Fudan University, Shanghai, PR China

    Wei Cheng & Jianfeng Feng

  9. Department of Neurology, Huashan Hospital, Fudan University, Shanghai, PR China

    Wei Cheng

  10. Zhangjiang Fudan International Innovation Center, Shanghai, PR China

    Jianfeng Feng

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BZ, WC, and JF conceived and designed the experiment. BZ drafted the manuscript with contributions from ETR, and comments from XW and CX. All authors read and approved the final manuscript.

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Correspondence to Edmund T. Rolls, Wei Cheng or Jianfeng Feng.

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Zhang, B., Rolls, E.T., Wang, X. et al. Roles of the medial and lateral orbitofrontal cortex in major depression and its treatment. Mol Psychiatry (2024). https://doi.org/10.1038/s41380-023-02380-w

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