Changes in Cortical Microstructure of the Human Brain Resulting from Long-Term Motor Learning.

The mechanisms subserving motor skill acquisition and learning in the intact human brain are not fully understood. Previous studies in animals have demonstrated a causal relationship between motor learning and structural rearrangements of synaptic connections, raising the question of whether neurite-specific changes are also observable in humans. Here, we use advanced diffusion magnetic resonance imaging (MRI), sensitive to dendritic and axonal processes, to investigate neuroplasticity in response to long-term motor learning. We recruited healthy male and female human participants (age range 19-29) who learned a challenging dynamic balancing task (DBT) over four consecutive weeks. Diffusion MRI signals were fitted using Neurite Orientation Dispersion and Density Imaging (NODDI), a theory-driven biophysical model of diffusion, yielding measures of tissue volume, neurite density and the organizational complexity of neurites. While NODDI indices were unchanged and reliable during the control period, neurite orientation dispersion increased significantly during the learning period mainly in primary sensorimotor, prefrontal, premotor, supplementary, and cingulate motor areas. Importantly, reorganization of cortical microstructure during the learning phase predicted concurrent behavioral changes, whereas there was no relationship between microstructural changes during the control phase and learning. Changes in neurite complexity were independent of alterations in tissue density, cortical thickness, and intracortical myelin. Our results are in line with the notion that structural modulation of neurites is a key mechanism supporting complex motor learning in humans.SIGNIFICANCE STATEMENT The structural correlates of motor learning in the human brain are not fully understood. Results from animal studies suggest that synaptic remodeling (e.g., reorganization of dendritic spines) in sensorimotor-related brain areas is a crucial mechanism for the formation of motor memory. Using state-of-the-art diffusion magnetic resonance imaging (MRI), we found a behaviorally relevant increase in the organizational complexity of neocortical microstructure, mainly in primary sensorimotor, prefrontal, premotor, supplementary, and cingulate motor regions, following training of a challenging dynamic balancing task (DBT). Follow-up analyses suggested structural modulation of synapses as a plausible mechanism driving this increase, while colocalized changes in cortical thickness, tissue density, and intracortical myelin could not be detected. These results advance our knowledge about the neurobiological basis of motor learning in humans.

Age-related decline in GABAergic intracortical inhibition can be counteracted by long-term learning of balance skills.

Ageing induces a decline in GABAergic intracortical inhibition, which seems to be associated not only with decremental changes in well-being, sleep quality, cognition and pain management but also with impaired motor control. So far, little is known regarding whether targeted interventions can prevent the decline of intracortical inhibition in the primary motor cortex in the elderly. Therefore, the present study investigated whether age-related cortical dis-inhibition could be reversed after 6 months of balance learning and whether improvements in postural control correlated with the extent of reversed dis-inhibition. The results demonstrated that intracortical inhibition can be upregulated in elderly subjects after long-term balance learning and revealed a correlation between changes in balance performance and intracortical inhibition. This is the first study to show physical activity-related upregulation of GABAergic inhibition in a population with chronic dis-inhibition and may therefore be seminal for many pathologies in which the equilibrium between inhibitory and excitatory neurotransmitters is disturbed. KEY POINTS: Ageing induces a decline in GABAergic intracortical inhibition. So far, little is known regarding whether targeted interventions can prevent the decline of intracortical inhibition in the primary motor cortex in the elderly. After 6 months of balance learning, intracortical inhibition can be upregulated in elderly subjects. The results of this study also revealed a correlation between changes in balance performance and intracortical inhibition. This is the first study to show physical activity-related upregulation of GABAergic inhibition in a population with chronic dis-inhibition.

Test-retest reliability of multi-parametric maps (MPM) of brain microstructure.

Multiparameter mapping (MPM) is a quantitative MRI protocol that is promising for studying microstructural brain changes in vivo with high specificity. Reliability values are an important prior knowledge for efficient study design and facilitating replicable findings in development, aging and neuroplasticity research. To explore longitudinal reliability of MPM we acquired the protocol in 31 healthy young subjects twice over a rescan interval of 4 weeks. We assessed the within-subject coefficient of variation (WCV), the between-subject coefficient of variation (BCV), and the intraclass correlation coefficient (ICC). Using these metrics, we investigated the reliability of (semi-) quantitative magnetization transfer saturation (MTsat), proton density (PD), transversal relaxation (R2*) and longitudinal relaxation (R1). To increase relevance for explorative studies in development and training-induced plasticity, we assess reliability both on local voxel- as well as ROI-level. Finally, we disentangle contributions and interplay of within- and between-subject variability to ICC and assess the optimal degree of spatial smoothing applied to the data. We reveal evidence that voxelwise ICC reliability of MPMs is moderate to good with median values in cortex (subcortical GM): MT: 0.789 (0.447) PD: 0.553 (0.264) R1: 0.555 (0.369) R2*: 0.624 (0.477). The Gaussian smoothing kernel of 2 to 4 mm FWHM resulted in optimal reproducibility. We discuss these findings in the context of longitudinal intervention studies and the application to research designs in neuroimaging field.

Colocalized White Matter Plasticity and Increased Cerebral Blood Flow Mediate the Beneficial Effect of Cardiovascular Exercise on Long-Term Motor Learning.

Cardiovascular exercise (CE) is a promising intervention strategy to facilitate cognition and motor learning in healthy and diseased populations of all ages. CE elevates humoral parameters, such as growth factors, and stimulates brain changes potentially relevant for learning and behavioral adaptations. However, the causal relationship between CE-induced brain changes and human's ability to learn remains unclear. We tested the hypothesis that CE elicits a positive effect on learning via alterations in brain structure (morphological changes of gray and white matter) and function (functional connectivity and cerebral blood flow in resting state). We conducted a randomized controlled trial with healthy male and female human participants to compare the effects of a 2 week CE intervention against a non-CE control group on subsequent learning of a challenging new motor task (dynamic balancing; DBT) over 6 consecutive weeks. We used multimodal neuroimaging [T1-weighted magnetic resonance imaging (MRI), diffusion-weighted MRI, perfusion-weighted MRI, and resting state functional MRI] to investigate the neural mechanisms mediating between CE and learning. As expected, subjects receiving CE subsequently learned the DBT at a higher rate. Using a modified nonparametric combination approach along with multiple mediator analysis, we show that this learning boost was conveyed by CE-induced increases in cerebral blood flow in frontal brain regions and changes in white matter microstructure in frontotemporal fiber tracts. Our study revealed neural mechanisms for the CE-learning link within the brain, probably allowing for a higher flexibility to adapt to highly novel environmental stimuli, such as learning a complex task.SIGNIFICANCE STATEMENT It is established that cardiovascular exercise (CE) is an effective approach to promote learning and memory, yet little is known about the underlying neural transfer mechanisms through which CE acts on learning. We provide evidence that CE facilitates learning in human participants via plasticity in prefrontal white matter tracts and a colocalized increase in cerebral blood flow. Our findings are among the first to demonstrate a transfer potential of experience-induced brain plasticity. In addition to practical implications for health professionals and coaches, our work paves the way for future studies investigating effects of CE in patients suffering from prefrontal hypoperfusion or white matter diseases.

Making the rich richer: Frontoparietal tDCS enhances transfer effects of a single-session distractor inhibition training on working memory in high capacity individuals but reduces them in low capacity individuals.

Working memory (WM) performance depends on the ability to extract relevant while inhibiting irrelevant information from entering the WM storage. This distractor inhibition ability can be trained and is known to induce transfer effects on WM performance. Here we asked whether transfer on WM can be boosted by transcranial direct current stimulation (tDCS) during a single-session distractor inhibition training. As WM performance is ascribed to the frontoparietal network, in which prefrontal areas are associated with inhibiting distractors and posterior parietal areas with storing information, we placed the anode over the prefrontal and the cathode over the posterior parietal cortex during a single-session distractor inhibition training. This network-oriented stimulation protocol should enhance inhibition processes by shifting the neural activity from posterior to prefrontal regions. WM improved after a single-session distractor inhibition training under verum stimulation but only in subjects with a high WM capacity. In subjects with a low WM capacity, verum tDCS reduced the transfer effects on WM. We assume tDCS to strengthen the frontostriatal pathway in individuals with a high WM capacity leading to efficient inhibition of distractors. In contrast, the cathodal stimulation of the posterior parietal cortex might have hindered usual compensational mechanism in low capacity subjects, i.e. maintaining also irrelevant information in memory. Our results thus stress the need to adjust tDCS protocols to well-founded knowledge about neural networks and individual cognitive differences.

Interindividual differences in gray and white matter properties are associated with early complex motor skill acquisition.

Brain circuits mediate but also constrain experience-induced plasticity and corresponding behavioral changes. Here we tested whether interindividual behavioral differences in learning a challenging new motor skill correlate with variations in brain anatomy. Young, healthy participants were scanned using structural magnetic resonance imaging (T1-weighted MPRAGE, n = 75 and/or diffusion-weighted MRI, n = 59) and practiced a complex whole-body balancing task on a seesaw-like platform. Using conjunction tests based on the nonparametric combination (NPC) methodology, we found that gray matter volume (GMV) in the right orbitrofrontal cortex was positively related to the subjects' initial level of proficiency and their ability to improve performance during practice. Similarly, we obtained a strong trend toward a positive correlation between baseline fractional anisotropy (FA) in commissural prefrontal fiber pathways and later motor learning. FA results were influenced more strongly by radial than axial diffusivity. However, we did not find unique anatomical correlates of initial performance and learning to rate. Our findings reveal structural predispositions for successful motor skill performance and acquisition in frontal brain structures and underlying frontal white matter tracts. Together with previous results, these findings support the view that structural constraints imposed by the brain determine subsequent behavioral success and underline the importance of structural brain network constitution before learning starts.

Rapid and specific gray matter changes in M1 induced by balance training.

Training-induced changes in cortical structure can be observed non-invasively with magnetic resonance imaging (MRI). While macroscopic changes were found mainly after weeks to several months of training in humans, imaging of motor cortical networks in animals revealed rapid microstructural alterations after a few hours of training. We used MRI to test the hypothesis of immediate and specific training-induced alterations in motor cortical gray matter in humans. We found localized increases in motor cortical thickness after 1h of practice in a complex balancing task. These changes were specific to motor cortical effector representations primarily responsible for balance control in our task (lower limb and trunk) and these effects could be confirmed in a replication study. Cortical thickness changes (i) linearly increased across the training session, (ii) occurred independent of alterations in resting cerebral blood flow and (iii) were not triggered by repetitive use of the lower limbs. Our findings show that motor learning triggers rapid and specific gray matter changes in M1.

Higher surface folding of the human premotor cortex is associated with better long-term learning capability.

The capacity to learn enabled the human species to adapt to various challenging environmental conditions and pass important achievements on to the next generation. A growing body of research suggests links between neocortical folding properties and numerous aspects of human behavior, but their impact on enhanced human learning capacity remains unexplored. Here we leverage three training cohorts to demonstrate that higher levels of premotor cortical folding reliably predict individual long-term learning gains in a challenging new motor task, above and beyond initial performance differences. Individual folding-related predisposition to motor learning was found to be independent of cortical thickness and intracortical microstructure, but dependent on larger cortical surface area in premotor regions. We further show that learning-relevant features of cortical folding occurred in close spatial proximity to practice-induced structural brain plasticity. Our results suggest a link between neocortical surface folding and human behavioral adaptability.

Overlapping and parallel cerebello-cerebral networks contributing to sensorimotor control: an intrinsic functional connectivity study.

In concert with sensorimotor control areas of the cerebrum, the cerebellum shows differential activation patterns during a variety of sensorimotor-related tasks. However, the spatial details and extent of the complex and heterogeneous cerebello-cerebral systems involved in action control remain uncertain. In this study, we use intrinsic functional connectivity (iFC) to examine cerebello-cerebral networks of five cerebellar lobules (I-IV, V, VI, and VIIIa/b) that have been empirically identified to form the functional basis of sensorimotor processes. A refined cerebellar seed-region selection allowed us to identify a network of primary sensorimotor and supplementary motor areas (I-V), a network of prefrontal, premotor, occipito-temporal and inferior-parietal regions (VI), and two largely overlapping networks involving premotor and superior parietal regions, the temporo-parietal junction as well as occipito-temporal regions (VIIIa/b). All networks involved the medial prefrontal/cingulate cortex. These cerebral clusters were used in a partial correlation analysis to systematically map cerebral connectivity throughout the entire cerebellum. We discuss these findings in the framework of affective and cognitive control, sensorimotor, multisensory systems, and executive/language systems. Within the cerebellum we found that cerebro-cerebellar systems seem to run in parallel, as indicated by distinct sublobular functional topography of prefrontal, parietal, sensorimotor, cingulate, and occipito-temporal regions. However, all areas showed overlapping connectivity to various degrees in both hemispheres. The results of both analyses demonstrate that different sublobular parts of the cerebellar lobules may dominate in different aspects of primary or higher-order sensorimotor processing. This systems-level cerebellar organization provides a more detailed structure for cerebello-cerebral interaction which contributes to our understanding of complex motor behavior.

Reversed timing-dependent associative plasticity in the human brain through interhemispheric interactions.

Spike timing-dependent plasticity (STDP) has been proposed as one of the key mechanisms underlying learning and memory. Repetitive median nerve stimulation, followed by transcranial magnetic stimulation (TMS) of the contralateral primary motor cortex (M1), defined as paired-associative stimulation (PAS), has been used as an in vivo model of STDP in humans. PAS-induced excitability changes in M1 have been repeatedly shown to be time-dependent in a STDP-like fashion, since synchronous arrival of inputs within M1 induces long-term potentiation-like effects, whereas an asynchronous arrival induces long-term depression (LTD)-like effects. Here, we show that interhemispheric inhibition of the sensorimotor network during PAS, with the peripheral stimulation over the hand ipsilateral to the motor cortex receiving TMS, results in a LTD-like effect, as opposed to the standard STDP-like effect seen for contralateral PAS. Furthermore, we could show that this reversed-associative plasticity critically depends on the timing interval between afferent and cortical stimulation. These results indicate that the outcome of associative stimulation in the human brain depends on functional network interactions (inhibition or facilitation) at a systems level and can either follow standard or reversed STDP-like mechanisms.

Cortical thickness in primary sensorimotor cortex influences the effectiveness of paired associative stimulation.

Non-invasive brain stimulation protocols in general and paired associative stimulation (PAS) in particular seem to alter corticospinal excitability and thereby to influence behaviour with a high degree of inter-subject variability. The cause of this variability is multidimensional and to some extent still unknown. Here, we tested the hypothesis that individual variations in cortical thickness can explain some of the variability of PAS-induced excitability changes. Ten minutes of a facilitatory PAS protocol (PAS(LTP)) rapidly increased corticospinal excitability in the majority of the subjects (14/19 subjects) while others showed no such effect (5/19 subjects). A whole brain correlation analysis based on high resolution T1-weighted images revealed a significant positive relationship of PAS(LTP)-induced excitability changes with cortical thickness of the underlying left sensorimotor cortex (SM1) only. Cortical thickness alone, among other potential influencing factors, explained about half of the PAS(LTP) variance, indicating that subjects with a strong after-effect were those with thicker gray matter in this region. Based on these findings, we provide novel evidence that local brain structure influences the individual amount of functional plasticity induced by PAS(LTP). While the underlying neurophysiological and/or anatomical reasons for this effect still remain elusive at this point, we conclude that cortical thickness should be considered as an important and until now not recognized modulating factor in studies employing non-invasive brain stimulation techniques.

Dynamic modulation of intrinsic functional connectivity by transcranial direct current stimulation.

Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technique capable of modulating cortical excitability and thereby influencing behavior and learning. Recent evidence suggests that bilateral tDCS over both primary sensorimotor cortices (SM1) yields more prominent effects on motor performance in both healthy subjects and chronic stroke patients than unilateral tDCS over SM1. To better characterize the underlying neural mechanisms of this effect, we aimed to explore changes in resting-state functional connectivity during both stimulation types. In a randomized single-blind crossover design, 12 healthy subjects underwent functional magnetic resonance imaging at rest before, during, and after 20 min of unilateral, bilateral, and sham tDCS stimulation over SM1. Eigenvector centrality mapping (ECM) was used to investigate tDCS-induced changes in functional connectivity patterns across the whole brain. Uni- and bilateral tDCS over SM1 resulted in functional connectivity changes in widespread brain areas compared with sham stimulation both during and after stimulation. Whereas bilateral tDCS predominantly modulated changes in primary and secondary motor as well as prefrontal regions, unilateral tDCS affected prefrontal, parietal, and cerebellar areas. No direct effect was seen under the stimulating electrode in the unilateral condition. The time course of changes in functional connectivity in the respective brain areas was nonlinear and temporally dispersed. These findings provide evidence toward a network-based understanding regarding the underpinnings of specific tDCS interventions.

Priming cardiovascular exercise improves complex motor skill learning by affecting the trajectory of learning-related brain plasticity.

In recent years, mounting evidence from animal models and studies in humans has accumulated for the role of cardiovascular exercise (CE) in improving motor performance and learning. Both CE and motor learning may induce highly dynamic structural and functional brain changes, but how both processes interact to boost learning is presently unclear. Here, we hypothesized that subjects receiving CE would show a different pattern of learning-related brain plasticity compared to non-CE controls, which in turn associates with improved motor learning. To address this issue, we paired CE and motor learning sequentially in a randomized controlled trial with healthy human participants. Specifically, we compared the effects of a 2-week CE intervention against a non-CE control group on subsequent learning of a challenging dynamic balancing task (DBT) over 6 consecutive weeks. Structural and functional MRI measurements were conducted at regular 2-week time intervals to investigate dynamic brain changes during the experiment. The trajectory of learning-related changes in white matter microstructure beneath parieto-occipital and primary sensorimotor areas of the right hemisphere differed between the CE vs. non-CE groups, and these changes correlated with improved learning of the CE group. While group differences in sensorimotor white matter were already present immediately after CE and persisted during DBT learning, parieto-occipital effects gradually emerged during motor learning. Finally, we found that spontaneous neural activity at rest in gray matter spatially adjacent to white matter findings was also altered, therefore indicating a meaningful link between structural and functional plasticity. Collectively, these findings may lead to a better understanding of the neural mechanisms mediating the CE-learning link within the brain.

Differences in Decision-Making Behavior Between Elite and Amateur Team-Handball Players in a Near-Game Test Situation.

Athletic features distinguishing experts from non-experts in team sports are relevant for performance analyses, talent identification and successful training. In this respect, perceptual-cognitive factors like decision making have been proposed to be important predictor of talent but, however, assessing decision making in team sports remains a challenging endeavor. In particular, it is now known that decisions expressed by verbal reports or micro-movements in the laboratory differ from those actually made in on-field situations in play. To address this point, our study compared elite and amateur players' decision-making behavior in a near-game test environment including sport-specific sensorimotor responses. Team-handball players (N = 44) were asked to respond as quickly as possible to representative, temporally occluded attack sequences in a team-handball specific defense environment on a contact plate system. Specifically, participants had to choose and perform the most appropriate out of four prespecified, defense response actions. The frequency of responses and decision time were used as dependent variables representing decision-making behavior. We found that elite players responded significantly more often with offensive responses (p < 0.05, odds ratios: 2.76-3.00) in left-handed attack sequences. Decision time decreased with increasing visual information, but no expertise effect was found. We suppose that expertise-related knowledge and processing of kinematic information led to distinct decision-making behavior between elite and amateur players, evoked in a domain-specific and near-game test setting. Results also indicate that the quality of a decision might be of higher relevance than the required time to decide. Findings illustrate application opportunities in the context of performance analyses and talent identification processes.

Brain Activation During Active Balancing and Its Behavioral Relevance in Younger and Older Adults: A Functional Near-Infrared Spectroscopy (fNIRS) Study.

Age-related deterioration of balance control is widely regarded as an important phenomenon influencing quality of life and longevity, such that a more comprehensive understanding of the neural mechanisms underlying this process is warranted. Specifically, previous studies have reported that older adults typically show higher neural activity during balancing as compared to younger counterparts, but the implications of this finding on balance performance remain largely unclear. Using functional near-infrared spectroscopy (fNIRS), differences in the cortical control of balance between healthy younger (n = 27) and older (n = 35) adults were explored. More specifically, the association between cortical functional activity and balance performance across and within age groups was investigated. To this end, we measured hemodynamic responses (i.e., changes in oxygenated and deoxygenated hemoglobin) while participants balanced on an unstable device. As criterion variables for brain-behavior-correlations, we also assessed postural sway while standing on a free-swinging platform and while balancing on wobble boards with different levels of difficulty. We found that older compared to younger participants had higher activity in prefrontal and lower activity in postcentral regions. Subsequent robust regression analyses revealed that lower prefrontal brain activity was related to improved balance performance across age groups, indicating that higher activity of the prefrontal cortex during balancing reflects neural inefficiency. We also present evidence supporting that age serves as a moderator in the relationship between brain activity and balance, i.e., cortical hemodynamics generally appears to be a more important predictor of balance performance in the older than in the younger. Strikingly, we found that age differences in balance performance are mediated by balancing-induced activation of the superior frontal gyrus, thus suggesting that differential activation of this region reflects a mechanism involved in the aging process of the neural control of balance. Our study suggests that differences in functional brain activity between age groups are not a mere by-product of aging, but instead of direct behavioral relevance for balance performance. Potential implications of these findings in terms of early detection of fall-prone individuals and intervention strategies targeting balance and healthy aging are discussed.

Dynamic properties of human brain structure: learning-related changes in cortical areas and associated fiber connections.

Recent findings in neuroscience suggest that adult brain structure changes in response to environmental alterations and skill learning. Whereas much is known about structural changes after intensive practice for several months, little is known about the effects of single practice sessions on macroscopic brain structure and about progressive (dynamic) morphological alterations relative to improved task proficiency during learning for several weeks. Using T1-weighted and diffusion tensor imaging in humans, we demonstrate significant gray matter volume increases in frontal and parietal brain areas following only two sessions of practice in a complex whole-body balancing task. Gray matter volume increase in the prefrontal cortex correlated positively with subject's performance improvements during a 6 week learning period. Furthermore, we found that microstructural changes of fractional anisotropy in corresponding white matter regions followed the same temporal dynamic in relation to task performance. The results make clear how marginal alterations in our ever changing environment affect adult brain structure and elucidate the interrelated reorganization in cortical areas and associated fiber connections in correlation with improvements in task performance.

Long-term effects of motor training on resting-state networks and underlying brain structure.

Acquired motor skills are coded in fronto-parietal brain networks, but how these networks evolve through motor training is unclear. On the one hand, increased functional connectivity has been shown immediately after a training session; on the other hand, training-induced structural changes are visible only after several weeks. Based on known associations between functional and structural network development during human ontogeny, we hypothesised that learning a challenging motor task leads to long-lasting changes in functional resting-state networks and the corresponding cortical and sub-cortical brain structures. Using longitudinal functional and structural MRI at multiple time points, we demonstrate increased fronto-parietal network connectivity one week after two brief motor training sessions in a dynamic balancing task, although subjects were engaged in their regular daily activities during the week. Repeated training sessions over six consecutive weeks progressively modulate these changes in accordance with individual performance improvements. Multimodal correlation analyses showed an association between structural grey matter alterations and functional connectivity changes in prefrontal and supplementary-motor areas. These coincident changes were most prominent in the first three weeks of training. In contrast, changes in fronto-parietal functional connectivity and the underlying white matter fibre structure developed gradually during the six weeks. Our results demonstrate a tight correlation between training-induced functional and structural brain plasticity on the systems level and suggest a functional relevance of intrinsic brain activity for morphological adaptation in the human brain.

Enhancing the effect of repetitive I-wave paired-pulse TMS (iTMS) by adjusting for the individual I-wave periodicity.

BACKGROUND: Repeated application of paired-pulse TMS over the primary motor cortex (M1) in human subjects with an inter-pulse interval (IPI) of 1.5 ms (iTMS(1.5 ms)) has been shown to significantly increase paired-pulse MEP (ppMEP) amplitudes during the stimulation period and increased single-pulse MEP amplitudes for up to 10 minutes after termination of iTMS. RESULTS: Here we show in a cross-over design that a modified version of the iTMS(1.5 ms) protocol with an I-wave periodicity adjusted to the individual I1-peak wave latency (iTMS(adj)) resulted in a stronger effect on ppMEPs relative to iTMS(1.5 ms). CONCLUSIONS: Based on these findings, our results indicate that the efficiency of iTMS strongly depends on the individual choice of the IPI and that parameter optimization of the conventional iTMS(1.5 ms) protocol might improve the outcome of this novel non-invasive brain stimulation technique.

Longitudinal Reproducibility of Neurite Orientation Dispersion and Density Imaging (NODDI) Derived Metrics in the White Matter.

Diffusion-weighted magnetic resonance imaging (DWI) is undergoing constant evolution with the ambitious goal of developing in-vivo histology of the brain. A recent methodological advancement is Neurite Orientation Dispersion and Density Imaging (NODDI), a histologically validated multi-compartment model to yield microstructural features of brain tissue such as geometric complexity and neurite packing density, which are especially useful in imaging the white matter. Since NODDI is increasingly popular in clinical research and fields such as developmental neuroscience and neuroplasticity, it is of vast importance to characterize its reproducibility (or reliability). We acquired multi-shell DWI data in 29 healthy young subjects twice over a rescan interval of 4 weeks to assess the within-subject coefficient of variation (CVWS), between-subject coefficient of variation (CVBS) and the intraclass correlation coefficient (ICC), respectively. Using these metrics, we compared regional and voxel-by-voxel reproducibility of the most common image analysis approaches (tract-based spatial statistics [TBSS], voxel-based analysis with different extents of smoothing ["VBM-style"], ROI-based analysis). We observed high test-retest reproducibility for the orientation dispersion index (ODI) and slightly worse results for the neurite density index (NDI). Our findings also suggest that the choice of analysis approach might have significant consequences for the results of a study. Collectively, the voxel-based approach with Gaussian smoothing kernels of ≥4 mm FWHM and ROI-averaging yielded the highest reproducibility across NDI and ODI maps (CVWS mostly ≤3%, ICC mostly ≥0.8), respectively, whilst smaller kernels and TBSS performed consistently worse. Furthermore, we demonstrate that image quality (signal-to-noise ratio [SNR]) is an important determinant of NODDI metric reproducibility. We discuss the implications of these results for longitudinal and cross-sectional research designs commonly employed in the neuroimaging field.

Intrinsic Connectivity Changes Mediate the Beneficial Effect of Cardiovascular Exercise on Sustained Visual Attention.

Cardiovascular exercise (CE) is an evidence-based healthy lifestyle strategy. Yet, little is known about its effects on brain and cognition in young adults. Furthermore, evidence supporting a causal path linking CE to human cognitive performance via neuroplasticity is currently lacking. To understand the brain networks that mediate the CE-cognition relationship, we conducted a longitudinal, controlled trial with healthy human participants to compare the effects of a 2-week CE intervention against a non-CE control group on cognitive performance. Concomitantly, we used structural and functional magnetic resonance imaging to investigate the neural mechanisms mediating between CE and cognition. On the behavioral level, we found that CE improved sustained attention, but not processing speed or short-term memory. Using graph theoretical measures and statistical mediation analysis, we found that a localized increase in eigenvector centrality in the left middle frontal gyrus, probably reflecting changes within an attention-related network, conveyed the effect of CE on cognition. Finally, we found CE-induced changes in white matter microstructure that correlated with intrinsic connectivity changes (intermodal correlation). These results suggest that CE is a promising intervention strategy to improve sustained attention via brain plasticity in young, healthy adults.