Younger, better performing adults typically show greater brain signal variability than older, poorer performers, but the mechanisms underlying this observation remain elusive. We attempt to restore deficient functional-MRI–based blood oxygen level-dependent (BOLD) signal variability (SD) levels in older adults by boosting dopamine via d-amphetamine (AMPH). Notably, older adults met or exceeded young adult SD levels under AMPH. AMPH-driven changes in SDSD also predicted AMPH-driven changes in reaction time speed and variability on a working memory task, but depended greatly on age and drug administration order. These findings (i) suggest that dopamine may account for adult age differences in brain signal variability and (ii) highlight the importance of considering practice effects and state dependencies when evaluating the neurochemical basis of age- and cognition-related brain dynamics.
Better-performing younger adults typically express greater brain signal variability relative to older, poorer performers. Mechanisms for age and performance-graded differences in brain dynamics have, however, not yet been uncovered. Given the age-related decline of the dopamine (DA) system in normal cognitive aging, DA neuromodulation is one plausible mechanism. Hence, agents that boost systemic DA [such as d-amphetamine (AMPH)] may help to restore deficient signal variability levels. Furthermore, despite the standard practice of counterbalancing drug session order (AMPH first vs. placebo first), it remains understudied how AMPH may interact with practice effects, possibly influencing whether DA up-regulation is functional. We examined the effects of AMPH on functional-MRI–based blood oxygen level-dependent (BOLD) signal variability (SD) in younger and older adults during a working memory task (letter n-back). Older adults expressed lower brain signal variability at placebo, but met or exceeded young adult SD levels in the presence of AMPH. Drug session order greatly moderated change–change relations between AMPH-driven SD and reaction time means (RT) and SDs (RTSD). Older adults who received AMPH in the first session tended to improve in RTmean and RTSD when SD was boosted on AMPH, whereas younger and older adults who received AMPH in the second session showed either a performance improvement when SD decreased (for RT) or no effect at all (for RTSD). The present findings support the hypothesis that age differences in brain signal variability reflect aging-induced changes in dopaminergic neuromodulation. The observed interactions among AMPH, age, and session order highlight the state- and practice-dependent neurochemical basis of human brain dynamics.
Figure. Increased BOLD variability and improved cognitive performance under AMPH. Multivariate partial least-squares model of relation between SD, Age Group, AMPH, and Task Condition. Higher brain scores reflect higher BOLD signal variability. Error bars represent bootstrapped 95% confidence intervals (1,000× with replacement). Brain images are plotted in neurological orientation (left is Left). AMPH, amphetamine; BSR, bootstrap ratio.