Mapping Inter-Metabolite Relationships in the Human Brain: A Multi-Site, Multi-Modal MRS Study
Abstract
Abstract Technological advances in magnetic resonance spectroscopy (MRS), particularly at ultra-high field strengths (e.g., 7T), now allow for the reliable quantification of an increasing number of brain metabolites across multiple brain regions. How-ever, most studies remain constrained to analyses of isolated metabolite levels, overlooking the complex interdependencies that govern neurometabolic regula-tion. Here, we present a multivariate framework that applies network analysis and systematic evaluation of pairwise metabolite ratios to a reference dataset of 53 individuals, revealing coordinated patterns of metabolite covariation as well as a hierarchical inter-metabolite architecture. We validate the generaliz-ability and robustness of these findings across four independent MRS datasets, encompassing both longitudinal and cross-sectional samples from 78 humans and 7 rats across five brain regions and three field strengths. Our results show that inter-metabolite relationships are broadly conserved across methodological contexts, while selective axes exhibit graded, network-informed modulation in response to physiological challenges such as caloric restriction or transcranial magnetic stimulation. By moving beyond univariate measures, our multivariate framework accommodates the innate complexity in human brain metabolism and carries translational relevance for biomarker discovery and the development of metabolically targeted therapeutic strategies.
Authors 22
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Ramona Leenings corresponding
Charité - Universitätsmedizin Berlin
Affiliation as printed
Department of Psychiatry and Neuroscience, Charite Universitaetsmedizin Berlin, Berlin, Germany;
Department of Psychiatry and Neuroscience, Charite Universitaetsmedizin Berlin, Berlin, Germany
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Affiliation as printed
Department of Psychiatry, Psychotherapy and Psychosomatics, RWTH Aachen University, Aachen, Germany;
Department of Psychiatry, Psychotherapy and Psychosomatics, RWTH Aachen University, Aachen, Germany
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Affiliation as printed
Department of Psychiatry, Psychotherapy and Psychosomatics, RWTH Aachen University, Aachen, Germany;
Department of Psychiatry, Psychotherapy and Psychosomatics, RWTH Aachen University, Aachen, Germany
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Affiliation as printed
Institute of Neuroscience and Medicine 4, Forschungszentrum Juelich, Germany;
Institute of Neuroscience and Medicine 4, Forschungszentrum Juelich, Germany
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Affiliation as printed
Institute of Neuroscience and Medicine 4, Forschungszentrum Juelich, Germany;
Institute of Neuroscience and Medicine 4, Forschungszentrum Juelich, Germany
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Affiliation as printed
Medical Physics Group , Institute for Diagnostic and Interventional Radiology , Jena University Hospital , Jena , Germany
Werner-Kaiser-Research Center , Jena University Hospital , Jena , Germany
Medical Physics Group, Institute for Diagnostic and Interventional Radiology, Jena University Hospital, Jena, Germa
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Center for Stroke Research Berlin · Charité - Universitätsmedizin Berlin
Affiliation as printed
Center for Stroke Research Berlin, Charite - Universitaetsmedizin Berlin, Berlin, Germany;
Center for Stroke Research Berlin, Charite - Universitaetsmedizin Berlin, Berlin, Germany
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Center for Stroke Research Berlin · Charité - Universitätsmedizin Berlin
Affiliation as printed
Center for Stroke Research Berlin, Charite - Universitaetsmedizin Berlin, Berlin, Germany;
Center for Stroke Research Berlin, Charite - Universitaetsmedizin Berlin, Berlin, Germany
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Affiliation as printed
High-field MR Center, Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Vienna, Austria.;
High-field MR Center, Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Vienna, Austria
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Affiliation as printed
High-field MR Center, Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Vienna, Austria.;
High-field MR Center, Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Vienna, Austria
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Affiliation as printed
High-field MR Center, Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Vienna, Austria.;
High-field MR Center, Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Vienna, Austria
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Affiliation as printed
Department of Psychiatry and Psychotherapy, Jena University Hospital, Jena, Germany;
Department of Psychiatry and Psychotherapy, Jena University Hospital, Jena, Germany
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Charité - Universitätsmedizin Berlin
Affiliation as printed
Department of Psychiatry and Neuroscience , Charité - Universitätsmedizin Berlin , Berlin , Germany
Department of Psychiatry and Neuroscience, Charite Universitaetsmedizin Berlin, Berlin, Germany
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Affiliation as printed
University Bonn, Medical Faculty, Department of Psychiatry and Psychotherapy, Bonn, Germany;
University Bonn, Medical Faculty, Department of Psychiatry and Psychotherapy, Bonn, Germany
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Goethe University Frankfurt · University Hospital Frankfurt
Affiliation as printed
Goethe University Frankfurt, University Hospital, Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, Frankfurt, Germany;
Goethe University Frankfurt, University Hospital, Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, Frankfurt, Germany
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Goethe University Frankfurt · University Hospital Frankfurt
Affiliation as printed
Goethe University Frankfurt, University Hospital, Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, Frankfurt, Germany;
Goethe University Frankfurt, University Hospital, Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, Frankfurt, Germany
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Affiliation as printed
Department of Radiology, University of Muenster, Germany;
Department of Radiology, University of Muenster, Germany
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Goethe University Frankfurt · University Hospital Frankfurt
Affiliation as printed
Goethe University Frankfurt, University Hospital, Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, Frankfurt, Germany;
Goethe University Frankfurt, University Hospital, Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, Frankfurt, Germany
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Affiliation as printed
University Bonn, Medical Faculty, Department of Psychiatry and Psychotherapy, Bonn, Germany;
University Bonn, Medical Faculty, Department of Psychiatry and Psychotherapy, Bonn, Germany
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Goethe University Frankfurt · University Hospital Frankfurt
Affiliation as printed
Goethe University Frankfurt, University Hospital, Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, Frankfurt, Germany;
Goethe University Frankfurt, University Hospital, Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, Frankfurt, Germany
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Affiliation as printed
University Clinic and Outpatient Clinic for Radiology, University Hospital Halle, Germany
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Charité - Universitätsmedizin Berlin
Affiliation as printed
Department of Psychiatry and Neuroscience, Charite Universitaetsmedizin Berlin, Berlin, Germany;
Department of Psychiatry and Neuroscience, Charite Universitaetsmedizin Berlin, Berlin, Germany
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