Reliability of quantitative multiparameter maps is high for magnetization transfer and proton density but attenuated for R1 and R2 * in healthy young adults.

We investigate the reliability of individual differences of four quantities measured by magnetic resonance imaging-based multiparameter mapping (MPM): magnetization transfer saturation (MT), proton density (PD), longitudinal relaxation rate (R1 ), and effective transverse relaxation rate (R2 *). Four MPM datasets, two on each of two consecutive days, were acquired in healthy young adults. On Day 1, no repositioning occurred and on Day 2, participants were repositioned between MPM datasets. Using intraclass correlation effect decomposition (ICED), we assessed the contributions of session-specific, day-specific, and residual sources of measurement error. For whole-brain gray and white matter, all four MPM parameters showed high reproducibility and high reliability, as indexed by the coefficient of variation (CoV) and the intraclass correlation (ICC). However, MT, PD, R1 , and R2 * differed markedly in the extent to which reliability varied across brain regions. MT and PD showed high reliability in almost all regions. In contrast, R1 and R2 * showed low reliability in some regions outside the basal ganglia, such that the sum of the measurement error estimates in our structural equation model was higher than estimates of between-person differences. In addition, in this sample of healthy young adults, the four MPM parameters showed very little variability over four measurements but differed in how well they could assess between-person differences. We conclude that R1 and R2 * might carry only limited person-specific information in some regions of the brain in healthy young adults, and, by implication, might be of restricted utility for studying associations to between-person differences in behavior in those regions.

Hippocampal maturity promotes memory distinctiveness in childhood and adolescence.

Adaptive learning systems need to meet two complementary and partially conflicting goals: detecting regularities in the world versus remembering specific events. The hippocampus (HC) keeps a fine balance between computations that extract commonalities of incoming information (i.e., pattern completion) and computations that enable encoding of highly similar events into unique representations (i.e., pattern separation). Histological evidence from young rhesus monkeys suggests that HC development is characterized by the differential development of intrahippocampal subfields and associated networks. However, due to challenges in the in vivo investigation of such developmental organization, the ontogenetic timing of HC subfield maturation remains controversial. Delineating its course is important, as it directly influences the fine balance between pattern separation and pattern completion operations and, thus, developmental changes in learning and memory. Here, we relate in vivo, high-resolution structural magnetic resonance imaging data of HC subfields to behavioral memory performance in children aged 6-14 y and in young adults. We identify a multivariate profile of age-related differences in intrahippocampal structures and show that HC maturity as captured by this pattern is associated with age differences in the differential encoding of unique memory representations.

Optimization and validation of automated hippocampal subfield segmentation across the lifespan.

Automated segmentation of hippocampal (HC) subfields from magnetic resonance imaging (MRI) is gaining popularity, but automated procedures that afford high speed and reproducibility have yet to be extensively validated against the standard, manual morphometry. We evaluated the concurrent validity of an automated method for hippocampal subfields segmentation (automated segmentation of hippocampal subfields, ASHS; Yushkevich et al., ) using a customized atlas of the HC body, with manual morphometry as a standard. We built a series of customized atlases comprising the entorhinal cortex (ERC) and subfields of the HC body from manually segmented images, and evaluated the correspondence of automated segmentations with manual morphometry. In samples with age ranges of 6-24 and 62-79 years, 20 participants each, we obtained validity coefficients (intraclass correlations, ICC) and spatial overlap measures (dice similarity coefficient) that varied substantially across subfields. Anterior and posterior HC body evidenced the greatest discrepancies between automated and manual segmentations. Adding anterior and posterior slices for atlas creation and truncating automated output to the ranges manually defined by multiple neuroanatomical landmarks substantially improved the validity of automated segmentation, yielding ICC above 0.90 for all subfields and alleviating systematic bias. We cross-validated the developed atlas on an independent sample of 30 healthy adults (age 31-84) and obtained good to excellent agreement: ICC (2) = 0.70-0.92. Thus, with described customization steps implemented by experts trained in MRI neuroanatomy, ASHS shows excellent concurrent validity, and can become a promising method for studying age-related changes in HC subfield volumes.

Behavioral correlates of changes in hippocampal gray matter structure during acquisition of foreign vocabulary.

Experience can affect human gray matter volume. The behavioral correlates of individual differences in such brain changes are not well understood. In a group of Swedish individuals studying Italian as a foreign language, we investigated associations among time spent studying, acquired vocabulary, baseline performance on memory tasks, and gray matter changes. As a way of studying episodic memory training, the language learning focused on acquiring foreign vocabulary and lasted for 10weeks. T1-weighted structural magnetic resonance imaging and cognitive testing were performed before and after the studies. Learning behavior was monitored via participants' use of a smartphone application dedicated to the study of vocabulary. A whole-brain analysis showed larger changes in gray matter structure of the right hippocampus in the experimental group (N=33) compared to an active control group (N=23). A first path analyses revealed that time spent studying rather than acquired knowledge significantly predicted change in gray matter structure. However, this association was not significant when adding performance on baseline memory measures into the model, instead only the participants' performance on a short-term memory task with highly similar distractors predicted the change. This measure may tap similar individual difference factors as those involved in gray matter plasticity of the hippocampus.

Fiber density between rhinal cortex and activated ventrolateral prefrontal regions predicts episodic memory performance in humans.

The prefrontal cortex (PFC) is assumed to contribute to goal-directed episodic encoding by exerting cognitive control on medial temporal lobe (MTL) memory processes. However, it is thus far unclear to what extent the contribution of PFC-MTL interactions to memory manifests at a structural anatomical level. We combined functional magnetic resonance imaging and fiber tracking based on diffusion tensor imaging in 28 young, healthy adults to quantify the density of white matter tracts between PFC regions that were activated during the encoding period of a verbal free-recall task and MTL subregions. Across the cohort, the strength of fiber bundles linking activated ventrolateral PFC regions and the rhinal cortex (comprising the peri- and entorhinal cortices) of the MTL correlated positively with free-recall performance. These direct white matter connections provide a basis through which activated regions in the PFC can interact with the MTL and contribute to interindividual differences in human episodic memory.

The dynamics of change in striatal activity following updating training.

Increases in striatal activity have been suggested to mediate training-related improvements in working-memory ability. We investigated the temporal dynamics of changes in task-related brain activity following training of working memory. Participants in an experimental group and an active control group, trained on easier tasks of a constant difficulty in shorter sessions than the experimental group, were measured before, after about 1 week, and after more than 50 days of training. In the experimental group an initial increase of working-memory related activity in the functionally defined right striatum and anatomically defined right and left putamen was followed by decreases, resulting in an inverted u-shape function that relates activity to training over time. Activity increases in the striatum developed slower in the active control group, observed at the second posttest after more than 50 days of training. In the functionally defined left striatum, initial activity increases were maintained after more extensive training and the pattern was similar for the two groups. These results shed new light on the relation between activity in the striatum (especially the putamen) and the effects of working memory training, and illustrate the importance of multiple measurements for interpreting effects of training on regional brain activity.

The integrity of dopaminergic and noradrenergic brain regions is associated with different aspects of late-life memory performance.

Changes in dopaminergic neuromodulation play a key role in adult memory decline. Recent research has also implicated noradrenaline in shaping late-life memory. However, it is unclear whether these two neuromodulators have distinct roles in age-related cognitive changes. Here, combining longitudinal MRI of the dopaminergic substantia nigra-ventral tegmental area (SN-VTA) and noradrenergic locus coeruleus (LC) in younger (n = 69) and older (n = 251) adults, we found that dopaminergic and noradrenergic integrity are differentially associated with memory performance. While LC integrity was related to better episodic memory across several tasks, SN-VTA integrity was linked to working memory. Longitudinally, we found that older age was associated with more negative change in SN-VTA and LC integrity. Notably, changes in LC integrity reliably predicted future episodic memory. These differential associations of dopaminergic and noradrenergic nuclei with late-life cognitive decline have potential clinical utility, given their degeneration in several age-associated diseases.

Change in Latent Gray-Matter Structural Integrity Is Associated With Change in Cardiovascular Fitness in Older Adults Who Engage in At-Home Aerobic Exercise.

In aging humans, aerobic exercise interventions have been found to be associated with more positive or less negative changes in frontal and temporal brain areas, such as the anterior cingulate cortex (ACC) and hippocampus, relative to no-exercise control conditions. However, individual measures such as gray-matter (GM) probability may afford less reliable and valid conclusions about maintenance or losses in structural brain integrity than a latent construct based on multiple indicators. Here, we established a latent factor of GM structural integrity based on GM probability assessed by voxel-based morphometry, magnetization transfer saturation, and mean diffusivity. Based on this latent factor, we investigated changes in structural brain integrity during a six-month exercise intervention in brain regions previously reported in studies using volumetric approaches. Seventy-five healthy, previously sedentary older adults aged 63-76 years completed an at-home intervention study in either an exercise group (EG; n = 40) or in an active control group (ACG; n = 35). Measures of peak oxygen uptake (VO2peak) taken before and after the intervention revealed a time-by-group interaction, with positive average change in the EG and no reliable mean change in the ACG. Significant group differences in structural brain integrity changes were observed in the right and left ACC, right posterior cingulate cortex (PCC), and left juxtapositional lobule cortex (JLC). In all instances, average changes in the EG did not differ reliably from zero, whereas average changes in the ACG were negative, pointing to maintenance of structural brain integrity in the EG, and to losses in the ACG. Significant individual differences in change were observed for right ACC and left JLC. Following up on these differences, we found that exercising participants with greater fitness gains also showed more positive changes in structural integrity. We discuss the benefits and limitations of a latent-factor approach to changes in structural brain integrity, and conclude that aerobic fitness interventions are likely to contribute to brain maintenance in old age.

Rostral locus coeruleus integrity is associated with better memory performance in older adults.

For decades, research into memory decline in human cognitive ageing has focused on neocortical regions, the hippocampus and dopaminergic neuromodulation. Recent findings indicate that the locus coeruleus (LC) and noradrenergic neuromodulation may also play an important role in shaping memory development in later life. However, technical challenges in quantification of LC integrity have hindered the study of LC-cognition associations in humans. Using high-resolution, neuromelanin-sensitive magnetic resonance imaging, we found that individual differences in learning and memory were positively associated with LC integrity across a variety of memory tasks in both younger (n = 66) and older adults (n = 228). Moreover, we observed functionally relevant age differences confined to rostral LC. Older adults with a more 'youth-like' rostral LC also showed higher memory performance. These findings link non-invasive, in vivo indices of LC integrity to memory in ageing and highlight the role of the LC norepinephrine system in the decline of cognition.

Assessing reliability in neuroimaging research through intra-class effect decomposition (ICED).

Magnetic resonance imaging has become an indispensable tool for studying associations of structural and functional properties of the brain with behavior in humans. However, generally recognized standards for assessing and reporting the reliability of these techniques are still lacking. Here, we introduce a new approach for assessing and reporting reliability, termed intra-class effect decomposition (ICED). ICED uses structural equation modeling of data from a repeated-measures design to decompose reliability into orthogonal sources of measurement error that are associated with different characteristics of the measurements, for example, session, day, or scanning site. This allows researchers to describe the magnitude of different error components, make inferences about error sources, and inform them in planning future studies. We apply ICED to published measurements of myelin content and resting state functional connectivity. These examples illustrate how longitudinal data can be leveraged separately or conjointly with cross-sectional data to obtain more precise estimates of reliability.

Exercise-Induced Fitness Changes Correlate with Changes in Neural Specificity in Older Adults.

Neural specificity refers to the degree to which neural representations of different stimuli can be distinguished. Evidence suggests that neural specificity, operationally defined as stimulus-related differences in functional magnetic resonance imaging (fMRI) activation patterns, declines with advancing adult age, and that individual differences in neural specificity are associated with individual differences in fluid intelligence. A growing body of literature also suggests that regular physical activity may help preserve cognitive abilities in old age. Based on this literature, we hypothesized that exercise-induced improvements in fitness would be associated with greater neural specificity among older adults. A total of 52 adults aged 59-74 years were randomly assigned to one of two aerobic-fitness training regimens, which differed in intensity. Participants in both groups trained three times a week on stationary bicycles. In the low-intensity (LI) group, the resistance was kept constant at a low level (10 Watts). In the high-intensity (HI) group, the resistance depended on participants' heart rate and therefore typically increased with increasing fitness. Before and after the 6-month training phase, participants took part in a functional MRI experiment in which they viewed pictures of faces and buildings. We used multivariate pattern analysis (MVPA) to estimate the distinctiveness of neural activation patterns in ventral visual cortex (VVC) evoked by face or building stimuli. Fitness was also assessed before and after training. In line with our hypothesis, training-induced changes in fitness were positively associated with changes in neural specificity. We conclude that physical activity may protect against age-related declines in neural specificity.