title: Metabolic changes assessed by MRS accurately reflect brain function during drug-induced epilepsy in mice in contrast to fMRI-based hemodynamic readouts.
abstract: Functional proton magnetic resonance spectroscopy (1H-MRS) enables the non-invasive assessment of neural activity by measuring signals arising from endogenous metabolites in a time resolved manner. Proof-of-principle of this approach has been demonstrated in humans and rats; yet functional 1H-MRS has not been applied in mice so far, although it would be of considerable interest given the many genetically engineered models of neurological disorders established in this species only. Mouse 1H-MRS is challenging as the high demands on spatial resolution typically result in long data acquisition times not commensurable with functional studies. Here, we propose an approach based on spectroscopic imaging in combination with the acquisition of the free induction decay to maximize signal intensity. Highly resolved metabolite maps have been recorded from mouse brain with 12 min temporal resolution. This enabled monitoring of metabolic changes following the administration of bicuculline, a GABA-A receptor antagonist. Changes in levels of metabolites involved in energy metabolism (lactate and phosphocreatine) and neurotransmitters (glutamate) were investigated in a region-dependent manner and shown to scale with the bicuculline dose. GABAergic inhibition induced spectral changes characteristic for increased neurotransmitter turnover and oxidative stress. In contrast to metabolic readouts, BOLD and CBV fMRI responses did not scale with the bicuculline dose indicative of the failure of neurovascular coupling. Nevertheless fMRI measurements supported the notion of increased oxidative stress revealed by functional MRS. Hence, the combined analysis of metabolic and hemodynamic changes in response to stimulation provides complementary insight into processes associated with neural activity.
authors.affiliation: Institute for Biomedical Engineering, University and ETH Zurich, Wolfgang-Pauli-Strasse 27, 8093 Zurich, Switzerland.
authors.forename: Aline
authors.initials: A
authors.lastname: Seuwen
authors.affiliation: Institute for Biomedical Engineering, University and ETH Zurich, Wolfgang-Pauli-Strasse 27, 8093 Zurich, Switzerland.
authors.forename: Aileen
authors.initials: A
authors.lastname: Schroeter
authors.affiliation: Institute for Biomedical Engineering, University and ETH Zurich, Wolfgang-Pauli-Strasse 27, 8093 Zurich, Switzerland; Center for Neuroscience Research, University and ETH Zurich, Wolfgang-Pauli-Strasse 27, 8093 Zurich, Switzerland.
authors.forename: Joanes
authors.initials: J
authors.lastname: Grandjean
authors.affiliation: Institute for Biomedical Engineering, University and ETH Zurich, Wolfgang-Pauli-Strasse 27, 8093 Zurich, Switzerland; Institute of Pharmacology and Toxicology, University of Zurich, Winterthurer Str. 190, 8057 Zurich, Switzerland; Center for Neuroscience Research, University and ETH Zurich, Wolfgang-Pauli-Strasse 27, 8093 Zurich, Switzerland; Experimental and Clinical Imaging Technologies, EXCITE Zurich, Zurich, Switzerland. Electronic address: rudin@biomed.ee.ethz.ch.
authors.forename: Markus
authors.initials: M
authors.lastname: Rudin
mesh_terms: D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D004827:Epilepsy / Q000139:chemically induced / Q000378:metabolism*; D005260:Female; D058787:GABA-A Receptor Antagonists / Q000494:pharmacology*; D008279:Magnetic Resonance Imaging / Q000379:methods*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D051379:Mice; D008810:Mice, Inbred C57BL; D000069336:Neurovascular Coupling / Q000502:physiology*; D018384:Oxidative Stress / Q000502:physiology*; D066244:Proton Magnetic Resonance Spectroscopy / Q000379:methods*
chemical_list: D058787:GABA-A Receptor Antagonists; D001640:Bicuculline
keywords: Bicuculline; Metabolism; Mouse; Spectroscopic imaging; Stimulation; fMRI