Dynamic Recovery: GABA Agonism Restores Neural Variability in Older, Poorer Performing Adults

Abstract

Aging is associated with cognitive impairment, but there are large individual differences in these declines. One neural measure that is lower in older adults and predicts these individual differences is moment-to-moment brain signal variability. Testing the assumption that GABA should heighten neural variability, we examined whether reduced brain signal variability in older, poorer performing adults could be boosted by increasing GABA pharmacologically. Brain signal variability was estimated using fMRI in 20 young and 24 older healthy human adults during placebo and GABA agonist sessions. As expected, older adults exhibited lower signal variability at placebo, and, crucially, GABA agonism boosted older adults' variability to the levels of young adults. Furthermore, poorer performing older adults experienced a greater increase in variability on drug, suggesting that those with more to gain benefit the most from GABA system potentiation. GABA may thus serve as a core neurochemical target in future work on aging- and cognition-related human brain dynamics.

SIGNIFICANCE STATEMENT Prior research indicates that moment-to-moment brain signal variability is lower in older, poorer performing adults. We found that this reduced brain signal variability could be boosted through GABA agonism in older adults to the levels of young adults and that this boost was largest in the poorer performing older adults. These results provide the first evidence that brain signal variability can be restored by increasing GABAergic activity and suggest the promise of developing interventions targeting inhibitory systems to help slow cognitive declines in healthy aging.