Association of γ-aminobutyric acid and glutamate/glutamine in the lateral prefrontal cortex with patterns of intrinsic functional connectivity in adults

Abstract

This study examined how levels of neurotransmitters in the lateral prefrontal cortex (LPFC), a region underlying higherorder cognition, are related to the brain's intrinsic functional organization. Using magnetic resonance spectroscopy (MRS), GABA+ and Glx (glutamate + glutamine) levels in the left dorsal (DLPFC) and left ventral (VLPFC) lateral prefrontal cortex were obtained in a sample of 64 female adults (mean age = 48.5). We measured intrinsic connectivity via resting-state fMRI in three ways: (a) via seed-based connectivity for each of the two spectroscopy voxels; (b) via the spatial configurations of 17 intrinsic networks defined by a well-known template; and (c) via examination of the temporal interrelationships between these intrinsic networks. The results showed that different neurotransmitter indexes (Glx-specific, GABA+-specific, Glx-GABA+ average and Glx-GABA+ ratio) were associated with distinct patterns of intrinsic connectivity. Neurotransmitter levels in the left LPFC are mainly associated with connectivity of right hemisphere prefrontal (e.g., DLPFC) or striatal (e.g., putamen) regions, two areas of the brain connected to LPFC via large white matter tracts. While the directions of these associations were mixed, in most cases, higher Glx levels are related to reduced connectivity. Prefrontal neurotransmitter levels are also associated with the degree of connectivity between non-prefrontal regions. These results suggest robust relationships between the brain's intrinsic functional organization and local neurotransmitters in the LPFC which may be constrained by white matter neuroanatomy.

Perceived Stress, Cortical GABA, and Functional Connectivity Correlates: A Hypothesis-Generating Preliminary Study

“…Although we found perceived stress to be related to GABA levels in the left DLPFC but not to RSFC with the left DLPFC voxel seed, we did observe a significant negative relationship between GABA levels in the left DLPFC and RSFC between the left DLPFC voxel and the left LPFC node of the CEN. The LPFC includes the DLPFC, the ventrolateral prefrontal cortex (VLPFC) and frontal eye fields ( 59 ) and GABA+ levels in the DLPFC and VLPFC have been shown to be positively correlated ( 60 ); thus, it would be expected to find an association of left DLPFC GABA with connectivity between the left DLPFC and the left LPFC node. Previous research has shown that GABA concentrations in the mPFC are associated with between-network anticorrelations of the DMN and CEN but that DLPFC GABA concentrations did not play a significant role in between-network interactions ( 61 ).…”

Neurochemical and functional interactions for improved perceptual decisions through training

“…Further, the neurochemical balance between excitation and inhibition has been suggested to play a key role in brainwide network interactions ( 40 ). Human MRS studies have linked Glu and GABA concentrations at rest with functional connectivity as measured by resting-state functional magnetic resonance imaging (rs-fMRI) ( 41 – 44 ), consistent with the role of glutamatergic excitation and GABAergic inhibition in neural dynamics.…”

The differential association between local neurotransmitter levels and whole‐brain resting‐state functional connectivity in two distinct cingulate cortex subregions

“…Here, the mean rsFC was controlled since it can reduce positive biases when the global signal regression is not performed for the rsFC calculation (Glasser et al, 2018; Smith et al, 2011). Glu served as the control metabolite for GABA, and vice versa, in the primary analysis (Wang et al, 2020). Additional tests were done with tCr and NAA as control metabolites or without control metabolites (reported in Table S1).…”

“…Duncan and colleagues concluded that the rsFC between regions, especially within the default mode network (DMN), is positively correlated with the Glu level and negatively correlated with the GABA level in the investigated DMN MRS voxel (Duncan, Wiebking, & Northoff, 2014). However, the generalized hypothesis of a region-independent relationship between local neurotransmitter levels and rsFC was challenged by rsfMRI-MRS studies focusing on regions outside the DMN, such as the left dorsal and left ventral lateral prefrontal cortex (Wang et al, 2020).…”