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 BOLD ) 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 BOLD levels in the presence of AMPH. Drug session order greatly moderated change-change relations between AMPH-driven SD BOLD and reaction time means (RT mean ) and SDs (RT SD ). Older adults who received AMPH in the first session tended to improve in RT mean and RT SD when SD BOLD was boosted on AMPH, whereas younger and older adults who received AMPH in the second session showed either a performance improvement when SD BOLD decreased (for RT mean ) or no effect at all (for RT SD ). 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.brain signal variability | dopamine | aging | working memory | fMRI H uman brain signals are characteristically variable and dynamic, at a variety of timescales and levels of analysis (1, 2). For decades, age-related cognitive deficits have been conceptualized as due to various forms of "noisy," inefficient neural processing (3, 4). However, the preponderance of available neuroimaging work on brain signal variability and aging indicates that healthy, higher performing, younger adults typically express more signal variability across trials and time in a variety of cortical regions relative to older, poorer performers (2, 5-7). Theoretical and computational explanations of this finding include notions such as flexibility/adaptability, dynamic range, Bayesian optimality, and multistability (2), but empirically supported mechanisms for age and performance-graded differences in human brain signal dynamics are not yet available. Dopamine (DA) neuromodulation may provide one such mechanism.DA neuromodulation is a leading mechanistic candidate for age-related cognitive losses (8-10). Concurrent with substantia nigra and ventral tegmental DA neuron loss, D 1 and D 2 receptor densities reduce notably from early to late adulthood acro...

Reduced moment-to-moment blood oxygen level-dependent (BOLD) signal variability has been consistently linked to advanced age and poorer cognitive performance, showing potential as a functional marker of brain aging. To date, however, this promise has rested exclusively on cross-sectional comparisons. In a sample of 74 healthy adults, we provide the first longitudinal evidence linking individual differences in BOLD variability, age, and performance across multiple cognitive domains over an average period of 2.5 years. As expected, those expressing greater loss of BOLD variability also exhibited greater decline in cognition. The fronto-striato-thalamic system emerged as a core neural substrate for these change–change associations. Preservation of signal variability within regions of the fronto-striato-thalamic system also cohered with preservation of functional integration across regions of this system, suggesting that longitudinal maintenance of “local” dynamics may require across-region communication. We therefore propose this neural system as a primary target in future longitudinal studies on the neural substrates of cognitive aging. Given that longitudinal change–change associations between brain and cognition are notoriously difficult to detect, the presence of such an association within a relatively short follow-up period bolsters the promise of brain signal variability as a viable, experimentally sensitive probe for studying individual differences in human cognitive aging.

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