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Bioenergetics and abnormal functional connectivity in psychotic disorders

Molecular Psychiatry volume 26, pages 2483–2492 (2021)Cite this article

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Abstract

Psychotic Disorders such as schizophrenia (SZ) and bipolar disorder (BD) are characterized by abnormal functional connectivity (FC) within neural networks such as the default mode network (DMN), as well as attenuated anticorrelation between DMN and task-positive networks (TPN). Bioenergetic processes are critical for synaptic connectivity and are also abnormal in psychotic disorders. We therefore examined the association between brain energy metabolism and FC in psychotic disorders. 31P magnetization transfer spectroscopy from medial prefrontal cortex (MPFC) and whole-brain fMRI data were collected from demographically matched groups of SZ, BD, and healthy control (HC) subjects. The creatine kinase (CK) reaction flux calculated from spectroscopy was used as an index of regional energy production rate. FC maps were generated with MPFC as the seed region. Compared to HC, SZ showed significantly lower CK flux, while both BD and SZ patients showed decreased anticorrelation between MPFC and TPN. CK flux was significantly correlated with FC between MPFC and other DMN nodes in HC. This positive correlation was reduced modestly in BD and strongly in SZ. CK flux was negatively correlated with the anticorrelation between MPFC and TPN in HC, but this relationship was not observed in BD or SZ. These results indicate that MPFC energy metabolism rates are associated with stronger FC within networks and stronger anticorrelation between networks in HC. However, this association is decreased in SZ and BD, where bioenergetic and FC abnormalities are evident. This pattern may suggest that impairment in energy production in psychotic disorders underlies the impaired neural connectivity.

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Fig. 1: Medical prefrontal cortex functional connectivity in healthy controls and patients.
Fig. 2: Brain areas with significant correlation between functional connectivity and creatine kinase reaction flux.
Fig. 3: Correlation between medial prefrontal cortex functional connectivity and creatine kinase reaction flux.

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Acknowledgements

The authors thank our volunteers and Mr Elliot Kuan, and Ms Margaret Gardner for their assistance in the experiments and subject recruitment. This research work was supported by National Institutes of Health (NIH) grants: R21MH114020, R01MH114982, P50MH115846, K24MH104449, R01AG066670.

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  1. These authors contributed equally: Xiaopeng Song, Xi Chen

Authors and Affiliations

  1. Psychotic Disorders Division, McLean Hospital, Belmont, MA, 02478, USA

    Xiaopeng Song, Xi Chen, Cagri Yuksel, Dost Öngür & Fei Du

  2. McLean Imaging Center, McLean Hospital, Belmont, MA, 02478, USA

    Xiaopeng Song, Xi Chen, Junliang Yuan, Diego A. Pizzagalli, Dost Öngür & Fei Du

  3. Harvard Medical School, Boston, MA, 02115, USA

    Xiaopeng Song, Xi Chen, Cagri Yuksel, Diego A. Pizzagalli, Brent Forester, Dost Öngür & Fei Du

  4. National Clinical Research Center for Mental Disorders, Peking University Sixth Hospital, 100191, Beijing, China

    Junliang Yuan

  5. Center for Depression, Anxiety and Stress Research, McLean Hospital, Belmont, MA, 02478, USA

    Diego A. Pizzagalli

  6. Division of Geriatric Psychiatry, McLean Hospital, Belmont, MA, 02478, USA

    Brent Forester

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Correspondence to Fei Du.

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Conflict of interest

Over the past 3 years, Dr. DAP has received consulting fees from Akili Interactive Labs, BlackThorn Therapeutics, Boehringer Ingelheim, Compass Pathway, Otsuka Pharmaceuticals, and Takeda Pharmaceuticals; one honorarium from Alkermes, and research funding from NIMH, Dana Foundation, Brain and Behavior Research Foundation, Millennium Pharmaceuticals. In addition, he has received stock options from BlackThorn Therapeutics. Dr. BF has received research funding from the NIA, Rogers Family Foundation, Spier Family Foundation, Eli Lilly and Biogen and consulting fees from Biogen. Dr. CY received research support from Diamentis Inc. No funding from these entities was used to support the current work, and all views expressed are solely those of the authors. None of the other authors have conflict of interest to declare.

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Song, X., Chen, X., Yuksel, C. et al. Bioenergetics and abnormal functional connectivity in psychotic disorders. Mol Psychiatry 26, 2483–2492 (2021). https://doi.org/10.1038/s41380-020-00993-z

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