Temporally resolved glutamate and GABA responses measured in human medial frontal cortex during working memory encoding and recall

Abstract Resolving rapid neurochemical changes during cognition is key to linking neurophysiology with behaviour. We developed a mixed block/event-related design of a working memory (WM) task for functional magnetic resonance spectroscopy (fMRS) at 7T to resolve glutamate and GABA fluctuations during encoding and recall phases of WM. Participants performed the WM task interleaved with rest and control conditions while semi-LASER spectra were acquired from the medial frontal cortex. Group-level phase-specific analyses revealed significant glutamate, but not GABA, increases during encoding and recall relative to control. However, larger individual increases in GABA during encoding predicted higher WM accuracy. Glutamate exhibited distinct, temporally resolved peaks for encoding (∼1.1s) and recall (∼1.4s). These time courses extend beyond previously reported post-stimulus windows and align closely with behavioural response latencies. Our findings provide temporally high-resolved characterisations of glutamate responses during distinct phases of WM and highlight differential roles of glutamate and GABA in WM processes.