Abstract
Glutamate is involved in excitatory neurotransmission and metabolic processes related to brain function. Previous studies using proton functional magnetic resonance spectroscopy (1H fMRS) have demonstrated elevated cortical glutamate levels by 2–4% during visual and motor stimulation, relative to periods of no stimulation. Here, we extended this approach to working memory cognitive task performance, which has been consistently associated with dorsolateral prefrontal cortex (dlPFC) activation. Sixteen healthy adult volunteers completed a continuous visual fixation “rest” task followed by a letter 2-back working memory task during 1H fMRS acquisition of the left dlPFC, which encompassed Brodmann areas 45 and 46 over a 4.5-cm3 volume. Using a 100% automated fitting procedure integrated with LCModel, raw spectra were eddy current-, phase-, and shift-corrected prior to quantification resulting in a 32s temporal resolution or 8 averages per spectra. Task compliance was high (95 ± 11% correct) and the mean Cramer-Rao Lower Bound of glutamate was 6.9 ± 0.9%. Relative to continuous passive visual fixation, left dlPFC glutamate levels were significantly higher by 2.7% (0.32 mmol/kg wet weight) during letter 2-back performance. Elevated dlPFC glutamate levels reflect increased metabolic activity and excitatory neurotransmission driven by working memory-related cognitive demands. These results provide the first in vivo demonstration of elevated dlPFC glutamate levels during working memory.
Highlights
Glutamate is the most abundant neurotransmitter in the brain: ~10–12 mM [1]
For the first time in humans, that working memory processes increased in vivo glutamate levels in the dorsolateral prefrontal cortex (dlPFC) relative to the continuous passive visual fixation control condition
We suggest that working memory-related demands involving neural maintenance of letters during the delay periods drove an increase in excitatory neural activity in the dlPFC, which necessitated an increase in glucose utilization and oxidative metabolism
Summary
Glutamate is the most abundant neurotransmitter in the brain: ~10–12 mM [1]. In addition to its role as the primary excitatory neurotransmitter, glutamate is involved in the metabolic processes such as the tricarboxylic acid [TCA] cycle and is a neurochemical intermediate for other metabolites, such as GABA and glutamine (Figure 1) [2]. Seminal 1H fMRS research, conducted at 7 T, demonstrated visual stimulation increased glutamate levels by ~2–4% in the occipital lobe [4, 5]. Subsequent 1H fMRS studies observed significant glutamate modulation throughout the brain: [1] occipital lobe during visual stimulation [6,7,8,9,10]; [2] motor cortex during finger tapping [11]; [3] anterior cingulate cortex during Stroop task performance [12,13,14]; [4] hippocampus during associative memory [15]; and [5] elsewhere [16,17,18].
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