Glutamate concentration in the medial prefrontal cortex predicts resting-state cortical-subcortical functional connectivity in humans

Abstract

Communication between cortical and subcortical regions is integral to a wide range of psychological processes and has been implicated in a number of psychiatric conditions. Studies in animals have provided insight into the biochemical and connectivity processes underlying such communication. However, to date no experiments that link these factors in humans in vivo have been carried out. To investigate the role of glutamate in individual differences in communication between the cortex--specifically the medial prefrontal cortex (mPFC)--and subcortical regions in humans, a combination of resting-state fMRI, DTI and MRS was performed. The subcortical target regions were the nucleus accumbens (NAc), dorsomedial thalamus (DMT), and periaqueductal grey (PAG). It was found that functional connectivity between the mPFC and each of the NAc and DMT was positively correlated with mPFC glutamate concentrations, whilst functional connectivity between the mPFC and PAG was negatively correlated with glutamate concentration. The correlations involving mPFC glutamate and FC between the mPFC and each of the DMT and PAG were mirrored by correlations with structural connectivity, providing evidence that the glutamatergic relationship may, in part, be due to direct connectivity. These results are in agreement with existing results from animal studies and may have relevance for MDD and schizophrenia.

Figure 1. Region of interest locations.

ROI placement displayed on group mean anatomical image in MNI standard space. mPFC - blue, NAc - yellow, DMT - green, PAG - red.

Figure 2. Correlation results between FC, Glu and DTI.

Example tracts between the mPFC and each of the target regions are shown along with partial correlation graphs from the right hemisphere. Correlations between FC and Glu are shown, followed by correlations between FC and number of tracts. Note that values represent residuals after confounding variables have been regressed out of the data in the partial correlation (see Methods). Red diamonds = eyes open, blue triangles = eyes closed. * indicates p<0.05.

Figure 3. Result overview.

Overview of connectivity in EO, EC and EO>EC conditions. Shown are the mPFC, NAc, DMT, and PAG. Black lines denote that a relationship between FC and both Glu/NAA and structural measures are seen in the relevant condition. Dashed lines denote that a relationship between FC and Glu/NAA only is seen.+symbol beside arrow denotes a positive correlation with Glu/NAA, - symbol beside arrow denotes a negative correlation with Glu/NAA.