Non-invasive measurement of neurotransmitter-specific glucose metabolism in the human brain using proton-observed proton-edited 13C-MRS (POPE13C-MRS)

Non-invasive measurement of neurotransmitter-specific glucose metabolism in the human brain remains a major challenge, limiting mechanistic insight into excitatory-inhibitory imbalance across neurological and psychiatric disorders. Current methods lack the ability to selectively and precisely resolve neurotransmitter-specific metabolic pathways, particularly GABA, while remaining compatible with clinically feasible acquisitions. Here, we introduce a clinically compatible approach which enables targeted and non-invasive detection of glutamate, GABA, and lactate metabolism in the human brain. Called proton-observed proton-edited {superscript 1}3C-magnetic resonance spectroscopy (POPE-{superscript 1}3C-MRS), the method uses an exogenous {superscript 1}3C-glucose probe combined with standard proton radiofrequency hardware and widely available MR pulse sequences. We use a cross-species validation framework to first calibrate POPE-{superscript 1}3C-MRS in mice and then demonstrate its feasibility in humans at ultra-high field. While in vivo GABA labelling has been previously reported, POPE-{superscript 1}3C-MRS provides, for the first time, robust access to GABAergic metabolism using standard MRI hardware, feasible within clinical constraints, including applicability to deep brain regions. By refining existing indirect {superscript 1}H-{superscript 1}3C-MRS strategies and enabling targeted probing of excitatory and inhibitory metabolic pathways, POPE-{superscript 1}3C-MRS opens new opportunities for studying neurometabolic coupling and excitatory-inhibitory balance in vivo, with broad implications for translational and clinical neuroscience.