A positive influence of basal ganglia iron concentration on implicit sequence learning

Abstract

Iron homeostasis is important for maintaining normal physiological brain functioning. In two independent samples, we investigate the link between iron concentration in the basal ganglia (BG) and implicit sequence learning (ISL). In Study 1, we used quantitative susceptibility mapping and task-related fMRI to examine associations among regional iron concentration measurements, brain activation, and ISL in younger and older adults. In Study 2, we examined the link between brain iron and ISL using a metric derived from fMRI in an age-homogenous sample of older adults. Three main findings were obtained. First, BG iron concentration was positively related to ISL in both studies. Second, ISL was robust for both younger and older adults, and performance-related activation was found in fronto-striatal regions across both age groups. Third, BG iron was positively linked to task-related BOLD signal in fronto-striatal regions. This is the first study investigating the relationship among brain iron accumulation, functional brain activation, and ISL, and the results suggest that higher brain iron concentration may be linked to better neurocognitive functioning in this particular task.

Implicit associative learning relates to basal ganglia gray matter microstructure in young and older adults

“…These results coincide with a growing body of functional [9,11,44,[50][51][52][53], structural [10], and genotypic [28] evidence showing that basal ganglia (particularly caudate) relates to both early and late stages of learning. Moreover, our finding that globus pallidus, not just caudate, microstructure contributes to IAL performance is consistent with emerging work [11,53], potentially signifying that later learning is affected by differences in the presence of iron or other microstructural alterations like dendritic arborization that may have a larger impact on extracellular sources of diffusion captured by the hindered diffusion metric. In contrast, early learning may be impacted by differences in neurite density or other intracellular neurobiological substrates captured by the restricted diffusion metric in caudate.…”

“…The present study examined age group differences in IAL as a function of learning stage, age group differences in basal ganglia and hippocampal gray matter microstructure, relationships between IAL and gray matter microstructure across age groups, and whether these IALmicrostructure relationships were moderated by age. We extended earlier work by assessing microstructure of subcortical gray matter and by controlling for iron content, which is known to increase with age [24,[39][40][41][42], affect diffusion [23,25], and relate to learning [11]. In line with our predictions, older adults exhibited deficits in IAL and differences in diffusion across all three metrics for the basal ganglia (caudate, putamen) and hippocampus compared to young adults.…”

“…One neurobiological factor of particular interest here is iron, given that it accumulates in basal ganglia regions with age [23,25,[40][41][42], attenuates the diffusion signal at acquisition [25], and relates to various cognitive functions [24,41,48], including IAL [11]. Interestingly, hindered diffusion, which showed the most variability in age effects across regions, appeared to track with the presence of iron.…”

“…Studies reporting no age group differences in the neural substrates of IAL often do not disaggregate results by learning stage. For example, one study using quantitative susceptibility mapping (QSM) found that iron concentration in caudate and globus pallidus positively correlated with overall IAL in both young and older adults [11]. As such, although there is converging evidence of basal ganglia (caudate, globus pallidus) and hippocampal involvement throughout learning, a more comprehensive examination of relationships between learning and these neural substrates as a function of learning stage and aging is warranted, which is the focus of our current study.…”

Age group differences in learning-related activity reflect task stage, not learning stage

“…This pattern of results is consistent with our recent diffusion imaging work, in which we found that microstructural integrity of globus pallidum (and caudate) gray matter related to better late IAL performance in younger and older participants from the current study (Franco et al, 2020), thereby providing converging evidence between structural and functional markers of IAL. We previously argued, like others (Persson et al, 2020), that the neural substrates of IAL may be influenced by the presence of iron, which can attenuate the MR signal at acquisition (Haacke et al, 2005) and across basal ganglia regions that differentially accumulate iron across the lifespan (Hallgren and Sourander, 1958). For example, we may be more sensitive to age group differences in neural markers of IAL in basal ganglia regions that gradually accumulate moderate amounts of iron throughout the lifespan (caudate, putamen) compared to regions that accumulate large amounts of iron by early adulthood (globus pallidum).…”