Association between glutamate/glutamine and blood oxygen level dependent signal in the left dorsolateral prefrontal region during verbal working memory

Abstract

Functional MRI (fMRI) has provided much insight into the changes in the neuronal activity on the basis of blood oxygen level dependent (BOLD) phenomenon. The dynamic changes in the metabolites can be detected using functional proton magnetic resonance spectroscopy (H-fMRS). The strategy of combining fMRI and H-fMRS would facilitate the understanding of the neurochemical interpretation of the BOLD signal. The dorsolateral prefrontal region is critically involved in the processing of working memory (WM), as demonstrated by the studies involving the neuroimaging, neuropsychological, and electrophysiological experiments. In this study, we tested the association between BOLD signal and changes in brain metabolites in the left dorsolateral prefrontal region using N-back verbal WM task. We used single-voxel task-based H-MRS acquired in the left dorsolateral prefrontal region and fMRI during the performance of N-back verbal WM task to investigate the association between changes in metabolites and BOLD response in 10 healthy participants. The correlation between changes in metabolites and percent signal change was examined by the Pearson correlation. The Pearson correlation analysis revealed a significant positive correlation between the BOLD signal and glutamate/glutamine in the left dorsolateral prefrontal region during the verbal WM. Our finding suggests that glutamate/glutamine cycle plays a critical role in the neuronal activation as reflected by the changes in the BOLD response.

Acute effects of ketamine on the pregenual anterior cingulate: linking spontaneous activation, functional connectivity, and glutamate metabolism

“…Several other studies have reported positive associations, BOLD responses and glutamatergic metabolite concentrations [ 83 , 84 ]; however, a recent systematic review reports no coherent relationship between glutamate and BOLD activation [ 83 ]. One possible reason for this could be that the majority of studies did not separate Glu and Gln due to methodological difficulties, but rather report the two compounds together as Glx.…”

Proof of mechanism and target engagement of glutamatergic drugs for the treatment of schizophrenia: RCTs of pomaglumetad and TS-134 on ketamine-induced psychotic symptoms and pharmacoBOLD in healthy volunteers

“…Glutamate reuptake in glia accounts for ~50% of energy expenditure in the brain [ 17 ], so that changes in glutamate/glutamine cycling and energy expenditure are highly correlated [ 18 – 21 ]. The increased energy expenditure, in turn, leads to an increase in local cerebral blood flow that can be detected using BOLD imaging [ 22 – 24 ].…”

Functional MRS studies of GABA and Glutamate/Glx – a systematic review and meta-analysis

“…Glu plays a major role during activity-dependent energy demands as the most abundant aminoacid and the main excitatory neurotransmitter in the brain (Ligneul et al, 2021). Increasing evidence demonstrates the close regulation between glucose consumption and glutamateglutamine cycling (Sibson et al, 1998;Rothman et al, 2003), which was theorised to lead to increasing Glu levels during the BOLD-activation period (Betina Ip et al, 2017;Vijayakumari et al, 2018;Martínez-Maestro et al, 2019). Additionally, Glu is also a major determinant for neuronal plasticity during periods of high neural activity as Glu influence the production of of brain-derived neurotrophic factor (BDNF) which regulates survival, differentiation and synaptogenesis in the CNS to change patterns of neuronal connectivity (Gonçalves-Ribeiro et al, 2019;Valtcheva and Venance, 2019).…”

“…The metabolic and neuronal processes are also tightly interlinked, with Glu existing in exchangeable pools. Increasing evidence demonstrates the close regulation between glucose consumption and glutamate-glutamine cycling (Sibson et al, 1998; Rothman et al, 2003), which leads to increasing Glu levels during the BOLD-activation period (Betina Ip et al, 2017; Vijayakumari et al, 2018; Martínez-Maestro et al, 2019; Ligneul et al, 2021). Additionally, Glu levels are also a major determinant for neuronal plasticity during periods of high neural activity (Gonçalves-Ribeiro et al, 2019; Valtcheva and Venance, 2019).…”