Non-invasive measurement of neurotransmitter-specific glucose metabolism in the human brain using proton-observed proton-edited ¹³ C-MRS (POPE ¹³ C-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. Existing approaches either lack neurotransmitter specificity or require specialised hardware that constrains clinical applicability. Here, we introduce proton-observed proton-edited ¹³ C magnetic resonance spectroscopy (POPE ¹³ C-MRS), an approach that enables non-invasive detection of glutamate, GABA, and lactate metabolism using standard proton MRI hardware. The method combines administration of ¹³ C-labelled glucose with targeted proton editing to detect ¹ H- ¹³ C satellite resonances. Using a cross-species proof-of-concept approach, we demonstrate consistent detection of neurotransmitter-specific ¹³ C labelling in mice and feasibility in the human brain at ultra-high field. POPE ¹³ C-MRS provides a readout of glutamatergic and GABAergic metabolism, enabling in vivo assessment of excitatory-inhibitory metabolic balance. This establishes a means for probing neurometabolic coupling with potential applications in translational and clinical neuroscience.