Functional MRS studies of GABA and glutamate/Glx - A systematic review and meta-analysis

Abstract

Functional magnetic resonance spectroscopy (fMRS) can be used to investigate neurometabolic responses to external stimuli in-vivo, but findings are inconsistent. We performed a systematic review and meta-analysis on fMRS studies of the primary neurotransmitters Glutamate (Glu), Glx (Glutamate + Glutamine), and GABA. Data were extracted, grouped by metabolite, stimulus domain, and brain region, and analysed by determining standardized effect sizes. The quality of individual studies was rated. When results were analysed by metabolite type small to moderate effect sizes of 0.29-0.47 (p < 0.05) were observed for changes in Glu and Glx regardless of stimulus domain and brain region, but no significant effects were observed for GABA. Further analysis suggests that Glu, Glx and GABA responses differ by stimulus domain or task and vary depending on the time course of stimulation and data acquisition. Here, we establish effect sizes and directionality of GABA, Glu and Glx response in fMRS. This work highlights the importance of standardised reporting and minimal best practice for fMRS research.

Keywords: FMRS; Functional magnetic resonance spectroscopy; GABA; Glutamate; Glx; Meta-analysis; Review; Systematic.

Figure 1:

PRISMA flow diagram (Page et al., 2021; Haddaway et al., 2022)

Figure 2:

(A) Brain ROIs and stimulus domains of included fMRS studies of Glu/Glx. (B) Brain ROIs and stimulus domains of included fMRS studies of GABA. Note that brain ROIs were generalized by the authors to optimize inclusion.

Figure 3:

(A) MRS-Q assessment of MRS studies (B) Risk of Bias Assessment Tool for Nonrandomized Studies (RoBANS) quality.

Figure 4:

(A) Overall effect sizes by type of data and metabolite irrespective of stimulus domains. (B) Overall effect sizes by type of paradigm and metabolite. N: number of studies included; Glu/Glx: Glu or Glx studies; I²: I² index for heterogeneity. A high I² suggests there are external factors and biases driving the dispersion of effect sizes. *Statistically significant at p < 0.05, and at p < 0.01 when the degrees of freedom < 4 for RVE t-tests.

Figure 5:

Overall effect sizes by type of stimulus and metabolite. N: number of studies included; Glu/Glx: Glu or Glx studies; I²: I² index for heterogeneity. A high I² suggests there are external factors and biases driving the dispersions of effect sizes. * Statistically significant at p <0.05, and at p <0.01 when the degrees of freedom < 4 for RVE t-tests.

Figure 6:

Overall effect sizes by ROIs. Glu/Glx: Glu or Glx studies; N: number of studies included; I²: I² index for heterogeneity. A high I² suggests there are external factors and biases driving the dispersions of effect sizes. * Statistically significant at p < 0.05, and at p < 0.01 when the degrees of freedom < 4 for RVE t-tests.

Figure 7:

Effect size of each study in relation to time of data acquisition during fMRS. Only metabolite levels during stimulus periods were included. Time 0 s is considered the start of the MRS acquisition. The size of dots represents the weight of the effect size.

Figure 8:

Meta-analysis of only ‘high quality’ studies as assessed by MRS-Q pooled based on stimulus domains. N: number of studies included; I²: I² index for heterogeneity. A high I² suggests there are external factors and biases driving the dispersions of effect sizes. *Statistically significant at p <0.05, and at p <0.01 when the degrees of freedom < 4 for RVE t-tests.

Figure 9:

Relationship between effect size and number of transients used in included studies. The size of each dot represents the weight of effect size. met: metabolites; GABA: γ-Aminobutyric acid; Glu: Glutamate; Glx: Glutamine + Glutamate.

Figure 10:

Influence of range of transient width on metabolite levels. N: number of studies included; I²: I² index for heterogeneity. A high I² suggests there are external factors and biases driving the dispersions of effect sizes. *Statistically significant at p <0.05, and at p <0.01 when the degrees of freedom < 4 for RVE t-tests.

Figure 11.

Effect size of each study in relation to voxel size in milliliters. The line represents a linear regression line for visual purposes only. ρ: Spearman’s rho; met: metabolites; GABA: γ-Aminobutyric acid; Glu: Glutamate; Glx: Glutamine+Glutamate.