Artificial Intelligence Assistive Software Tool for Automated Detection and Quantification of Amyloid-Related Imaging Abnormalities.

Importance: Amyloid-related imaging abnormalities (ARIA) are brain magnetic resonance imaging (MRI) findings associated with the use of amyloid-ß-directed monoclonal antibody therapies in Alzheimer disease (AD). ARIA monitoring is important to inform treatment dosing decisions and might be improved through assistive software. Objective: To assess the clinical performance of an artificial intelligence (AI)-based software tool for assisting radiological interpretation of brain MRI scans in patients monitored for ARIA. Design, Setting, and Participants: This diagnostic study used a multiple-reader multiple-case design to evaluate the diagnostic performance of radiologists assisted by the software vs unassisted. The study enrolled 16 US Board of Radiology-certified radiologists to perform radiological reading with (assisted) and without the software (unassisted). The study encompassed 199 retrospective cases, where each case consisted of a predosing baseline and a postdosing follow-up MRI of patients from aducanumab clinical trials PRIME, EMERGE, and ENGAGE. Statistical analysis was performed from April to July 2023. Exposures: Use of icobrain aria, an AI-based assistive software for ARIA detection and quantification. Main Outcomes and Measures: Coprimary end points were the difference in diagnostic accuracy between assisted and unassisted detection of ARIA-E (edema and/or sulcal effusion) and ARIA-H (microhemorrhage and/or superficial siderosis) independently, assessed with the area under the receiver operating characteristic curve (AUC). Results: Among the 199 participants included in this study of radiological reading performance, mean (SD) age was 70.4 (7.2) years; 105 (52.8%) were female; 23 (11.6%) were Asian, 1 (0.5%) was Black, 157 (78.9%) were White, and 18 (9.0%) were other or unreported race and ethnicity. Among the 16 radiological readers included, 2 were specialized neuroradiologists (12.5%), 11 were male individuals (68.8%), 7 were individuals working in academic hospitals (43.8%), and they had a mean (SD) of 9.5 (5.1) years of experience. Radiologists assisted by the software were significantly superior in detecting ARIA than unassisted radiologists, with a mean assisted AUC of 0.87 (95% CI, 0.84-0.91) for ARIA-E detection (AUC improvement of 0.05 [95% CI, 0.02-0.08]; P = .001]) and 0.83 (95% CI, 0.78-0.87) for ARIA-H detection (AUC improvement of 0.04 [95% CI, 0.02-0.07]; P = .001). Sensitivity was significantly higher in assisted reading compared with unassisted reading (87% vs 71% for ARIA-E detection; 79% vs 69% for ARIA-H detection), while specificity remained above 80% for the detection of both ARIA types. Conclusions and Relevance: This diagnostic study found that radiological reading performance for ARIA detection and diagnosis was significantly better when using the AI-based assistive software. Hence, the software has the potential to be a clinically important tool to improve safety monitoring and management of patients with AD treated with amyloid-ß-directed monoclonal antibody therapies.

Task-Related Modulation of Sensorimotor GABA+ Levels in Association with Brain Activity and Motor Performance: A Multimodal MRS-fMRI Study in Young and Older Adults.

Recent studies suggest an important role of the principal inhibitory neurotransmitter GABA for motor performance in the context of aging. Nonetheless, as previous magnetic resonance spectroscopy (MRS) studies primarily reported resting-state GABA levels, much less is known about transient changes in GABA levels during motor task performance and how these relate to behavior and brain activity patterns. Therefore, we investigated GABA+ levels of left primary sensorimotor cortex (SM1) acquired before, during, and after execution of a unimanual/bimanual action selection task in 30 (human) young adults (YA; age 24.5 ± 4.1, 15 male) and 30 older adults (OA; age 67.8 ± 4.9, 14 male). In addition to task-related MRS data, task-related functional magnetic resonance imaging (fMRI) data were acquired. Behavioral results indicated lower motor performance in OA as opposed to YA, particularly in complex task conditions. MRS results demonstrated lower GABA+ levels in OA as compared with YA. Furthermore, a transient task-related decrease of GABA+ levels was observed, regardless of age. Notably, this task-induced modulation of GABA+ levels was linked to task-related brain activity patterns in SM1 such that a more profound task-induced instantaneous lowering of GABA+ was related to higher SM1 activity. Additionally, higher brain activity was related to better performance in the bimanual conditions, despite some age-related differences. Finally, the modulatory capacity of GABA+ was positively related to motor performance in OA but not YA. Together, these results underscore the importance of transient dynamical changes in neurochemical content for brain function and behavior, particularly in the context of aging.SIGNIFICANCE STATEMENT Emerging evidence designates an important role to regional GABA levels in motor control, especially in the context of aging. However, it remains unclear whether changes in GABA levels emerge when executing a motor task and how these changes relate to brain activity patterns and performance. Here, we identified a transient decrease of sensorimotor GABA+ levels during performance of an action selection task across young adults (YA) and older adults (OA). Interestingly, whereas a more profound GABA+ modulation related to higher brain activity across age groups, its association with motor performance differed across age groups. Within OA, our results highlighted a functional merit of a task-related release from inhibitory tone, i.e. lowering regional GABA+ levels was associated with task-relevant brain activity.

Neurophysiological modulations in the (pre)motor-motor network underlying age-related increases in reaction time and the role of GABA levels - a bimodal TMS-MRS study.

It has been argued that age-related changes in the neurochemical and neurophysiological properties of the GABAergic system may underlie increases in reaction time (RT) in older adults. However, the role of GABA levels within the sensorimotor cortices (SMC) in mediating interhemispheric interactions (IHi) during the processing stage of a fast motor response, as well as how both properties explain interindividual differences in RT, are not yet fully understood. In this study, edited magnetic resonance spectroscopy (MRS) was combined with dual-site transcranial magnetic stimulation (dsTMS) for probing GABA+ levels in bilateral SMC and task-related neurophysiological modulations in corticospinal excitability (CSE), and primary motor cortex (M1)-M1 and dorsal premotor cortex (PMd)-M1 IHi, respectively. Both CSE and IHi were assessed during the preparatory and premotor period of a delayed choice RT task. Data were collected from 25 young (aged 18-33 years) and 28 older (aged 60-74 years) healthy adults. Our results demonstrated that older as compared to younger adults exhibited a reduced bilateral CSE suppression, as well as a reduced magnitude of long latency M1-M1 and PMd-M1 disinhibition during the preparatory period, irrespective of the direction of the IHi. Importantly, in older adults, the GABA+ levels in bilateral SMC partially accounted for task-related neurophysiological modulations as well as individual differences in RT. In contrast, in young adults, neither task-related neurophysiological modulations, nor individual differences in RT were associated with SMC GABA+ levels. In conclusion, this study contributes to a comprehensive initial understanding of how age-related differences in neurochemical properties and neurophysiological processes are related to increases in RT.

GABA levels are differentially associated with bimanual motor performance in older as compared to young adults.

Although gamma aminobutyric acid (GABA) is of particular importance for efficient motor functioning, very little is known about the relationship between regional GABA levels and motor performance. Some studies suggest this relation to be subject to age-related differences even though literature is scarce. To clarify this matter, we employed a comprehensive approach and investigated GABA levels within young and older adults across multiple motor tasks as well as multiple brain regions. Specifically, 30 young and 30 older adults completed a task battery of three different bimanual tasks. Furthermore, GABA levels were obtained within bilateral primary sensorimotor cortex (SM1), bilateral dorsal premotor cortex, the supplementary motor area and bilateral dorsolateral prefrontal cortex (DLPFC) using magnetic resonance spectroscopy. Results indicated that older adults, as compared to their younger counterparts, performed worse on all bimanual tasks and exhibited lower GABA levels in bilateral SM1 only. Moreover, GABA levels across the motor network and DLPFC were differentially associated with performance in young as opposed to older adults on a manual dexterity and bimanual coordination task but not a finger tapping task. Specifically, whereas higher GABA levels related to better manual dexterity within older adults, higher GABA levels predicted poorer bimanual coordination performance in young adults. By determining a task-specific and age-dependent association between GABA levels across the cortical motor network and performance on distinct bimanual tasks, the current study advances insights in the role of GABA for motor performance in the context of aging.

The role of the PMd in task complexity: functional connectivity is modulated by motor learning and age.

The dorsal premotor cortex (PMd) plays a key role in the control and learning of motor tasks, especially when task complexity is high. This study sought to investigate the effect of task complexity on PMd-seeded functional connectivity in the context of aging using psychophysiological interaction analyses. Young and older participants were enrolled in a 3-day training protocol whereby task-related functional magnetic resonance imaging data were acquired. During training, movement was either internally generated or externally generated in the absence or presence of online visual feedback, respectively. Behavioral results indicated that older adults tended to have more difficulties with the complex task variants as compared with young adults. On a neural level, older adults demonstrated difficulties in flexibly adjusting their neural resources dependent on the feedback provided. Furthermore, PMd-seeded connectivity was related to a behavioral task complexity index in both age groups, albeit mediated by age. Together, these results highlight the importance of PMd in adaptability to task complexity and its age-related effects.

Comparison of Multivendor Single-Voxel MR Spectroscopy Data Acquired in Healthy Brain at 26 Sites.

Background The hardware and software differences between MR vendors and individual sites influence the quantification of MR spectroscopy data. An analysis of a large data set may help to better understand sources of the total variance in quantified metabolite levels. Purpose To compare multisite quantitative brain MR spectroscopy data acquired in healthy participants at 26 sites by using the vendor-supplied single-voxel point-resolved spectroscopy (PRESS) sequence. Materials and Methods An MR spectroscopy protocol to acquire short-echo-time PRESS data from the midparietal region of the brain was disseminated to 26 research sites operating 3.0-T MR scanners from three different vendors. In this prospective study, healthy participants were scanned between July 2016 and December 2017. Data were analyzed by using software with simulated basis sets customized for each vendor implementation. The proportion of total variance attributed to vendor-, site-, and participant-related effects was estimated by using a linear mixed-effects model. P values were derived through parametric bootstrapping of the linear mixed-effects models (denoted Pboot). Results In total, 296 participants (mean age, 26 years ± 4.6; 155 women and 141 men) were scanned. Good-quality data were recorded from all sites, as evidenced by a consistent linewidth of N-acetylaspartate (range, 4.4-5.0 Hz), signal-to-noise ratio (range, 174-289), and low Cramér-Rao lower bounds (≤5%) for all of the major metabolites. Among the major metabolites, no vendor effects were found for levels of myo-inositol (Pboot > .90), N-acetylaspartate and N-acetylaspartylglutamate (Pboot = .13), or glutamate and glutamine (Pboot = .11). Among the smaller resonances, no vendor effects were found for ascorbate (Pboot = .08), aspartate (Pboot > .90), glutathione (Pboot > .90), or lactate (Pboot = .28). Conclusion Multisite multivendor single-voxel MR spectroscopy studies performed at 3.0 T can yield results that are coherent across vendors, provided that vendor differences in pulse sequence implementation are accounted for in data analysis. However, the site-related effects on variability were more profound and suggest the need for further standardization of spectroscopic protocols. © RSNA, 2020 Online supplemental material is available for this article.

Sensorimotor cortex neurometabolite levels as correlate of motor performance in normal aging: evidence from a 1H-MRS study.

Aging is associated with gradual alterations in the neurochemical characteristics of the brain, which can be assessed in-vivo with proton-magnetic resonance spectroscopy (1H-MRS). However, the impact of these age-related neurochemical changes on functional motor behavior is still poorly understood. Here, we address this knowledge gap and specifically focus on the neurochemical integrity of the left sensorimotor cortex (SM1) and the occipital lobe (OCC), as both regions are main nodes of the visuomotor network underlying bimanual control. 1H-MRS data and performance on a set of bimanual tasks were collected from a lifespan (20-75 years) sample of 86 healthy adults. Results indicated that aging was accompanied by decreased levels of N-acetylaspartate (NAA), glutamate-glutamine (Glx), creatine â€‹+ â€‹phosphocreatine (Cr) and myo-inositol (mI) in both regions, and decreased Choline (Cho) in the OCC region. Lower NAA and Glx levels in the SM1 and lower NAA levels in the OCC were related to poorer performance on a visuomotor bimanual coordination task, suggesting that NAA could serve as a potential biomarker for the integrity of the motor system supporting bimanual control. In addition, lower NAA, Glx, and mI levels in the SM1 were found to be correlates of poorer dexterous performance on a bimanual dexterity task. These findings highlight the role for 1H-MRS to study neurochemical correlates of motor performance across the adult lifespan.

Big GABA II: Water-referenced edited MR spectroscopy at 25 research sites.

Accurate and reliable quantification of brain metabolites measured in vivo using 1H magnetic resonance spectroscopy (MRS) is a topic of continued interest. Aside from differences in the basic approach to quantification, the quantification of metabolite data acquired at different sites and on different platforms poses an additional methodological challenge. In this study, spectrally edited γ-aminobutyric acid (GABA) MRS data were analyzed and GABA levels were quantified relative to an internal tissue water reference. Data from 284 volunteers scanned across 25 research sites were collected using GABA+ (GABA + co-edited macromolecules (MM)) and MM-suppressed GABA editing. The unsuppressed water signal from the volume of interest was acquired for concentration referencing. Whole-brain T1-weighted structural images were acquired and segmented to determine gray matter, white matter and cerebrospinal fluid voxel tissue fractions. Water-referenced GABA measurements were fully corrected for tissue-dependent signal relaxation and water visibility effects. The cohort-wide coefficient of variation was 17% for the GABA + data and 29% for the MM-suppressed GABA data. The mean within-site coefficient of variation was 10% for the GABA + data and 19% for the MM-suppressed GABA data. Vendor differences contributed 53% to the total variance in the GABA + data, while the remaining variance was attributed to site- (11%) and participant-level (36%) effects. For the MM-suppressed data, 54% of the variance was attributed to site differences, while the remaining 46% was attributed to participant differences. Results from an exploratory analysis suggested that the vendor differences were related to the unsuppressed water signal acquisition. Discounting the observed vendor-specific effects, water-referenced GABA measurements exhibit similar levels of variance to creatine-referenced GABA measurements. It is concluded that quantification using internal tissue water referencing is a viable and reliable method for the quantification of in vivo GABA levels.

Motor inhibition efficiency in healthy aging: the role of γ-aminobutyric acid.

The ability to cancel a motor response is critical for optimal functioning in various facets of daily life. Hence, efficient inhibitory motor control is a key function throughout the lifespan. Considering the fact that inhibitory motor function gradually declines with advancing age, it is not surprising that the study of motor inhibition in this age group is gaining considerable interest. In general, we can distinguish between two prominent types of motor inhibition, namely proactive and reactive inhibition. Whereas the anticipation for upcoming stops (proactive inhibition) appears readily preserved at older age, the ability to stop an already planned or initiated action (reactive inhibition) generally declines with advancing age. The differential impact of aging on proactive and reactive inhibition at the behavioral level prompts questions about the neural architecture underlying both types of inhibitory motor control. Here we will not only highlight the underlying structural brain properties of proactive and reactive inhibitory control but we will also discuss recent developments in brain-behavioral approaches, namely the registration of neurochemical compounds using magnetic resonance spectroscopy. This technique allows for the direct detection of the primary inhibitory neurotransmitter in the brain, i.e., γ-aminobutyric acid, across the broader cortical/subcortical territory, thereby opening new perspectives for better understanding the neural mechanisms mediating efficient inhibitory control in the context of healthy aging. Ultimately, these insights may contribute to the development of interventions specifically designed to counteract age-related declines in motor inhibition.

Age-related alterations in the modulation of intracortical inhibition during stopping of actions.

We investigated the effect of age on the ability to modulate GABAA-ergic and GABAB-ergic inhibitory activity during stopping of action (reactive inhibition) and preparation to stop (proactive inhibition). Twenty-five young and twenty-nine older adults performed an anticipated response version of the stop-signal task with varying levels of stop-signal probability. Paired-pulse transcranial magnetic stimulation was applied to left primary motor cortex to assess the modulation of GABAA-mediated short-interval intracortical inhibition (SICI) during stopping and GABAB-mediated long-interval intracortical inhibition (LICI) during the anticipation of a stop-signal. At the behavioral level, reactive inhibition was affected by aging as indicated by longer stop-signal reaction times in older compared to young adults. In contrast, proactive inhibition was preserved at older age as both groups slowed down their go response to a similar degree with increasing stop-signal probability. At the neural level, the amount of SICI was higher in successful stop relative to go trials in young but not in older adults. LICI at the start of the trial was modulated as a function of stop-signal probability in both young and older adults. Our results suggest that specifically the recruitment of GABAA-mediated intracortical inhibition during stopping of action is affected by aging.

Age-related differences in GABA levels are driven by bulk tissue changes.

Levels of GABA, the main inhibitory neurotransmitter in the brain, can be regionally quantified using magnetic resonance spectroscopy (MRS). Although GABA is crucial for efficient neuronal functioning, little is known about age-related differences in GABA levels and their relationship with age-related changes in brain structure. Here, we investigated the effect of age on GABA levels within the left sensorimotor cortex and the occipital cortex in a sample of 85 young and 85 older adults using the MEGA-PRESS sequence. Because the distribution of GABA varies across different brain tissues, various correction methods are available to account for this variation. Considering that these correction methods are highly dependent on the tissue composition of the voxel of interest, we examined differences in voxel composition between age groups and the impact of these various correction methods on the identification of age-related differences in GABA levels. Results indicated that, within both voxels of interest, older (as compared to young adults) exhibited smaller gray matter fraction accompanied by larger fraction of cerebrospinal fluid. Whereas uncorrected GABA levels were significantly lower in older as compared to young adults, this age effect was absent when GABA levels were corrected for voxel composition. These results suggest that age-related differences in GABA levels are at least partly driven by the age-related gray matter loss. However, as alterations in GABA levels might be region-specific, further research should clarify to what extent gray matter changes may account for age-related differences in GABA levels within other brain regions.

GABA levels and measures of intracortical and interhemispheric excitability in healthy young and older adults: an MRS-TMS study.

Edited magnetic resonance spectroscopy (MRS) and transcranial magnetic stimulation (TMS) have often been used to study the integrity of the GABAergic neurotransmission system in healthy aging. To investigate whether the measurement outcomes obtained with these 2 techniques are associated with each other in older human adults, gamma-aminobutyric acid (GABA) levels in the left sensorimotor cortex were assessed with edited MRS in 28 older (63-74 years) and 28 young adults (19-34 years). TMS at rest was then used to measure intracortical inhibition (short-interval intracortical inhibition/long-interval intracortical inhibition), intracortical facilitation, interhemispheric inhibition from left to right primary motor cortex (M1) and recruitment curves of left and right M1. Our observations showed that short-interval intracortical inhibition and long-interval intracortical inhibition in the left M1 were reduced in older adults, while GABA levels did not significantly differ between age groups. Furthermore, MRS-assessed GABA within left sensorimotor cortex was not correlated with TMS-assessed cortical excitability or inhibition. These observations suggest that healthy aging gives rise to altered inhibition at the postsynaptic receptor level, which does not seem to be associated with MRS-assessed GABA+ levels.

The neurochemical basis of the contextual interference effect.

Efficient practice organization maximizes learning outcome. Although randomization of practice as compared to blocked practice damages training performance, it boosts retention performance, an effect called contextual interference. Motor learning modulates the GABAergic (gamma-aminobutyric acid) system within the sensorimotor cortex (SM); however, it is unclear whether different practice regimes differentially modulate this system and whether this is impacted by aging. Young and older participants were trained on 3 variations of a visuomotor task over 3 days, following either blocked or random practice schedule and retested 6 days later. Using magnetic resonance spectroscopy, SM and occipital cortex GABA+ levels were measured before and after training during the first and last training days. We found that (1) behavioral data confirmed the contextual interference effects, (2) within-day occipital cortex GABA+ levels decreased in random and increased in blocked group. This effect was more pronounced in older adults; and (3) baseline SM GABA+ levels predicted initial performance. These findings indicate a differential modulation of GABA levels across practice groups that is amplified by aging.

Challenge to Promote Change: The Neural Basis of the Contextual Interference Effect in Young and Older Adults.

Motor performance deteriorates with age. Hence, studying the effects of different training types on performance improvement is particularly important. Here, we investigated the neural correlates of the contextual interference (CI) effect in 32 young (YA; 16 female) and 28 older (OA; 12 female) human adults. Participants were randomly assigned to either a blocked or a random practice schedule, practiced three variations of a bimanual visuomotor task over 3 d, and were retested 6 d later. Functional magnetic resonance imaging data were acquired during the first and last training days and during retention. Although the overall performance level was lower in OA than YA, the typical CI effects were observed in both age groups, i.e., inferior performance during acquisition but superior performance during retention for random relative to blocked practice. At the neural level, blocked practice showed higher brain activity in motor-related brain regions compared with random practice across both age groups. However, although activity in these regions decreased with blocked practice in both age groups, it was either preserved (YA) or increased (OA) as a function of random practice. In contrast, random compared with blocked practice resulted in greater activations in visual processing regions across age groups. Interestingly, in OA, the more demanding random practice schedule triggered neuroplastic changes in areas of the default mode network, ultimately leading to better long-term retention. Our findings may have substantial implications for the optimization of practice schedules, and rehabilitation settings in particular.SIGNIFICANCE STATEMENT In aging societies, it is critically important to understand how motor skills can be maintained or enhanced in older adults, with the ultimate goal to prolong functional independence. Here, we demonstrated that a more challenging random as opposed to a blocked practice environment temporarily reduced performance during the acquisition phase but resulted in lasting benefits for skill retention. In older adults, learning success was critically dependent on reduction of activation in areas of the default mode network, pointing to plastic functional changes in brain regions that are vulnerable to aging effects. The random practice context led to increased economy of brain activity and better skill retention. This provides new perspectives for reversing the negative consequences of aging.

Anatomy of Subcortical Structures Predicts Age-Related Differences in Skill Acquisition.

Skill acquisition capabilities vary substantially from one individual to another. Volumetric brain studies have demonstrated that global volume of several subcortical structures predicts variations in learning outcome in young adults (YA) and older adults (OA). In this study, for the first time, we utilized shape analysis, which offers a more sensitive detection of subregional brain anatomical deformations, to investigate whether subregional anatomy of subcortical structures is associated with training-induced performance improvement on a bimanual task in YA and OA, and whether this association is age-dependent. Compared with YA, OA showed poorer performance, greater performance improvement, and smaller global volume and compressed subregional shape in subcortical structures. In OA, global volume of the right nucleus accumbens and subregional shape of the right thalamus, caudate, putamen and nucleus accumbens were positively correlated with acquisition of difficult (non-preferred) but not easy (preferred) task conditions. In YA, global volume and subregional shape of the right hippocampus were negatively correlated with performance improvement in both the easy and difficult conditions. We argue that pre-existing neuroanatomical measures of subcortical structures involved in motor learning differentially predict skill acquisition potential in YA and OA.

Big GABA: Edited MR spectroscopy at 24 research sites.

Magnetic resonance spectroscopy (MRS) is the only biomedical imaging method that can noninvasively detect endogenous signals from the neurotransmitter γ-aminobutyric acid (GABA) in the human brain. Its increasing popularity has been aided by improvements in scanner hardware and acquisition methodology, as well as by broader access to pulse sequences that can selectively detect GABA, in particular J-difference spectral editing sequences. Nevertheless, implementations of GABA-edited MRS remain diverse across research sites, making comparisons between studies challenging. This large-scale multi-vendor, multi-site study seeks to better understand the factors that impact measurement outcomes of GABA-edited MRS. An international consortium of 24 research sites was formed. Data from 272 healthy adults were acquired on scanners from the three major MRI vendors and analyzed using the Gannet processing pipeline. MRS data were acquired in the medial parietal lobe with standard GABA+ and macromolecule- (MM-) suppressed GABA editing. The coefficient of variation across the entire cohort was 12% for GABA+ measurements and 28% for MM-suppressed GABA measurements. A multilevel analysis revealed that most of the variance (72%) in the GABA+ data was accounted for by differences between participants within-site, while site-level differences accounted for comparatively more variance (20%) than vendor-level differences (8%). For MM-suppressed GABA data, the variance was distributed equally between site- (50%) and participant-level (50%) differences. The findings show that GABA+ measurements exhibit strong agreement when implemented with a standard protocol. There is, however, increased variability for MM-suppressed GABA measurements that is attributed in part to differences in site-to-site data acquisition. This study's protocol establishes a framework for future methodological standardization of GABA-edited MRS, while the results provide valuable benchmarks for the MRS community.

Two hands, one brain, and aging.

Many activities of daily living require moving both hands in an organized manner in space and time. Therefore, understanding the impact of aging on bimanual coordination is essential for prolonging functional independence and well-being in older adults. Here we investigated the behavioral and neural determinants of bimanual coordination in aging. The studies surveyed in this review reveal that aging is associated with cortical hyper-activity (but also subcortical hypo-activity) during performance of bimanual tasks. In addition to changes in activation in local areas, the interaction between distributed brain areas also exhibits age-related effects, i.e., functional connectivity is increased in the resting brain as well as during task performance. The mechanisms and triggers underlying these functional activation and connectivity changes remain to be investigated. This requires further research investment into the detailed study of interactions between brain structure, function and connectivity. This will also provide the foundation for interventional research programs towards preservation of brain health and behavioral performance by maximizing neuroplasticity potential in older adults.