Neurochemical changes in GABA+, Glx, and the excitatory/inhibitory ratio in the calcarine cortex with healthy aging

Aging has been associated with widespread alterations in neural structure and function, but the underlying biochemical changes remain less understood despite recent neurophysiological work suggesting age-related alterations in the excitatory/inhibitory (E/I) balance. In the current study, we used ¹H-MRS to quantify levels of excitatory (Glx: glutamate + glutamine) and inhibitory (GABA+: GABA + macromolecules) neurotransmitters in the calcarine cortex in 187 healthy adults (19-79 years-old). These neurotransmitter estimates were used to compute the E/I ratio, and all three parameters were examined for aging effects. Given our large sample, we also conducted supplementary analyses to estimate the concentration of secondary metabolites commonly implicated in aging, including total creatine (tCr), total N-acetyl aspartate (tNAA), total choline (tCho), and myo-inositol (mI). Following best practices, metabolite concentrations were estimated relative to the unsuppressed water signal and corrected for voxel tissue composition (i.e., gray matter, white matter, CSF). Our results indicated significant age-related declines in both GABA+ and Glx, along with a reduction in the E/I ratio, suggesting diminished inhibitory and excitatory tone with advancing age. We also found a decline in tNAA and an increase in tCr with increasing age. In summary, we provide compelling evidence through one of the largest studies of its kind for age-related shifts in excitatory and inhibitory neurotransmitter levels in the visual cortex. These changes may be critical to well-known, age-related physiological changes, including reduced neural selectivity and processing efficiency. These findings provide novel evidence that neurochemical alterations may contribute to the functional declines in cortical processing seen in healthy aging.