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Brain metabolite alterations related to alcohol use: a meta-analysis of proton magnetic resonance spectroscopy studies

Molecular Psychiatry volume 27, pages 3223–3236 (2022)Cite this article

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Abstract

Alcohol misuse and alcohol use disorder (AlUD) have neurobiological consequences. This meta-analysis of proton magnetic resonance spectroscopy (MRS) studies aimed to assess the differences in brain metabolite levels in alcohol misuse and AUD relative to controls (PROSPERO registration: CRD42020209890). Hedge’s g with random-effects modeling was used. Sub-group and meta-regression techniques explored potential sources of demographic and MRS parameter heterogeneity. A comprehensive literature review identified 43 studies, resulting in 69 models across gray and white matter (GM, WM). Lower N-acetylaspartate levels were found in frontal, anterior cingulate cortex (ACC), hippocampal, and cerebellar GM, and frontal and parietal WM, suggesting decreased neuronal and axonal viability. Lower choline-containing metabolite levels (all metabolites contributing to choline peak) were found in frontal, temporal, thalamic, and cerebellar GM, and frontal and parietal WM, suggesting membrane alterations related to alcohol misuse. Lower creatine-containing metabolite levels (Cr; all metabolites contributing to Cr peak) were found in temporal and occipital cortical GM, while higher levels were noted in midbrain/brainstem GM; this finding may have implications for using Cr as an internal reference. The lack of significant group differences in glutamate-related levels is possibly related to biological and methodological complexities. The few studies reporting on GABA found lower levels restricted to the ACC. Confounding variables were age, abstinence duration, treatment status, and MRS parameters (echo time, quantification type, data quality). This first meta-analysis of proton MRS studies consolidates the numerous individual studies to identify neurometabolite alterations within alcohol misuse and AUD. Future studies can leverage this new formalized information to investigate treatments that might effectively target the observed disturbances.

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Fig. 1: Overall significant results across all brain regions and metabolites.
Fig. 2: Forest plots for three of the major neurometabolites measured with proton MRS.
Fig. 3: Forest plot of GABA results across all VOIs.

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Acknowledgements

We would like to acknowledge Teri Lynn Herbert (MUSC) for her invaluable help with setting up the literature searches for this meta-analysis. Dr Anna Kirkland is currently funded through the NIDA T32 at MUSC (DA007288-30), Brittney Browning is funded through the NIAAA T32 (AA007474-34), and Dr Lindsay Squeglia is funded through an NIAAA K23 (AA025399) and R01 (AA027399).

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  1. Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, SC, USA

    Anna E. Kirkland, ReJoyce Green & Lindsay M. Squeglia

  2. Department of Neuroscience, Medical University of South Carolina, Charleston, SC, USA

    Brittney D. Browning

  3. National Institutes of Health, NIDA and NIAAA, Baltimore, MD, USA

    Lorenzo Leggio

  4. Department of Radiology and Biomedical Imaging, University of California San Francisco and VA Medical Center, San Francisco, CA, USA

    Dieter J. Meyerhoff

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Contributions

Conceptualization: AEK, BDB, LMS. Methodology: AEK, BDB, LL, DJM, LMS. Software: AEK, BDB. Formal Analysis: AEK. Data Curation: AEK, BDB. Writing—Original Draft: AEK, BDB, LMS. Writing—Review & Editing: All authors. Visualization: AEK, BDB, RG. Supervision: LMS.

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Correspondence to Anna E. Kirkland.

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LL is a U.S. federal employee at the National Institutes of Health, and his work is funded by the NIDA and NIAAA intramural research program. Outside his federal employment, he receives an honorarium from the UK Medical Council on Alcoholism (Editor-in-Chief for Alcohol and Alcoholism) and royalties from Routledge for a textbook. All other authors report no biomedical financial interests or potential competing interests.

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Kirkland, A.E., Browning, B.D., Green, R. et al. Brain metabolite alterations related to alcohol use: a meta-analysis of proton magnetic resonance spectroscopy studies. Mol Psychiatry 27, 3223–3236 (2022). https://doi.org/10.1038/s41380-022-01594-8

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