Highlights • Glutamate and GABA are essential in plasticity and processing efficiency. • Cognitive impairments are linked with altered prefrontal glutamate (glu) and GABA. • We assessed glu/GABA using magnetic resonance spectroscopy in a calculation prodigy. • Prefrontal glu/GABA ratios are reduced in a calculation prodigy vs. non-prodigies. • Exceptional cognitive abilities may be reflected in non-invasive measures of glu/GABA. Abstract Alterations in excitatory and inhibitory neurotransmitters (glutamate and GABA, respectively) have been found in various neuropsychiatric disorders, but have not been examined in individuals with prodigious cognitive abilities. Understanding exceptional brain processing is critical for developing biomedical interventions for cognitive and neurodevelopmental atypicalities. We tested the 11-fold world champion in mental calculation, G.M., and compared his right middle frontal gyrus, which has been associated with mathematical prodigy, to four healthy control expert calculators, who were not prodigies. We found substantially lower frontal glutamate/GABA compared to non-prodigy controls, but not glutamate or GABA individually, measured with magnetic resonance spectroscopy. We suggest that prefrontal glutamate/GABA is a potential marker of extraordinary cognitive skills. [ABSTRACT FROM AUTHOR]