Regional Excitatory-Inhibitory Balance Relates to Self-Reference Effect on Recollection via the Precuneus/Posterior Cingulate Cortex-Medial Prefrontal Cortex Connectivity.

Self-related representation can enhance perception and memory -a phenomenon known as the self-referential effect (SRE). While SRE has been linked to the activation of the default mode network (DMN), including the precuneus/posterior cingulate cortex (Pcu/PCC) and the medial prefrontal cortex (mPFC), the underlying neurochemical processes of DMN activations remain unclear. The balance of excitation and inhibition (E/I balance) within brain circuits is crucial for cognition and may play a role in the SRE. We examine whether the ratio of glutamate/glutamine (Glx) to γ-aminobutyric acid (GABA) concentrations, measured by 1H-Magnetic Resonance Spectroscopy (1H-MRS) as a proxy measure for E/I balance, is associated with DMN neural processes involved in self-referential encoding. Fifty-four healthy participants aged 7-35 (25 female) underwent MRS to measure levels of Glx and GABA in Pcu/PCC, and completed a functional Magnetic Resonance Imaging (fMRI) scan during an encoding task that involved self-referential and semantic judgments. We found that the self-related condition led to better subsequent memory and greater activation in the Pcu/PCC compared to the semantic condition. Activations in the Pcu/PCC was positively correlated with the Glx/GABA+ ratio. Task-dependent functional connectivity analysis revealed that connectivity between the Pcu/PCC and medial prefrontal cortex (mPFC) was positively associated with both the Glx/GABA+ ratio and the SRE effect on recollection accuracy. Furthermore, mediation analysis showed that a higher Glx/GABA+ ratio correlated with better SRE on memory recollection through increased Pcu/PCC-mPFC connectivity. Our study provides valuable insights into how neurochemical activity is associated with self-related cognition via functional connectivity of large-scale brain networks.Significance Statement Self-related representation can enhance perception and memory - a phenomenon known as the self-referential effect (SRE). While SRE has been linked to the activation of the default mode network (DMN), the underlying neurochemical processes remain unclear. Our study found that SRE was associated with the ratio of glutamate/glutamine (Glx) and γ-aminobutyric acid (GABA) concentrations, a proxy measure of excitatory/inhibitory balance, through functional connectivity between key nodes of the DMN. These findings indicate the critical role of excitatory/inhibitory balance in self-related processes, which may provide new insights into psychiatric disorders characterized by impaired self-awareness.