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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.

Physical exercise has been suggested to improve cognitive performance through various neurobiological mechanisms, mediated by growth factors such as BDNF, IGF-I, and VEGF. Moreover, animal research has demonstrated that combined physical and cognitive stimulation leads to increased adult neurogenesis as compared to either experimental condition alone. In the present study, we therefore investigated whether a sequential combination of physical and spatial training in young, healthy adults elicits an additive effect on training and transfer gains. To this end, we compared the effects of (i) eight 20-minute sessions of cycling, (ii) sixteen 30-minute sessions of spatial training, (iii) a combination of both, and included (iv) a passive control cohort. We assessed longitudinal changes in cognitive performance, growth factor levels, and T1 relaxation of hippocampal subfields (acquired with 7 T MRI). While substantial physical and spatial training gains were elicited in all trained groups, longitudinal transfer changes did not differ between these groups. Notably, we found no evidence for an additive effect of sequential physical and spatial training. These results challenge the extrapolation from the findings reported in animals to young, healthy adults.

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 STATEMENTIt 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.

Given the worldwide increasing socioeconomic burden of aging-associated brain diseases, there is pressing need to gain in-depth knowledge about the neurobiology of brain anatomy changes across the life span. Advances in quantitative magnetic resonance imaging sensitive to brain's myelin, iron, and free water content allow for a detailed in vivo investigation of aging-related changes while reducing spurious morphometry differences. Main aim of our study is to link previous morphometry findings in aging to microstructural tissue properties in a large-scale cohort (n = 966, age range 46-86 y). Addressing previous controversies in the field, we present results obtained with different approaches to adjust local findings for global effects. Beyond the confirmation of age-related atrophy, myelin, and free water decreases, we report proportionally steeper volume, iron, and myelin decline in sensorimotor and subcortical areas paralleled by free water increase. We demonstrate aging-related white matter volume, myelin, and iron loss in frontostriatal projections. Our findings provide robust evidence for spatial overlap between volume and tissue property differences in aging that affect predominantly motor and executive networks.

Background While concurrent transcranial direct current stimulation (tDCS) affects motor memory acquisition and long-term retention, it is unclear how behavioral interference modulates long-term tDCS effects. Behavioral interference can be introduced through a secondary task learned in-between motor memory acquisition and later recall of the original task. Objective/hypothesis The cerebellum is important for the processing of errors if movements should be adapted to external perturbations (motor memory acquisition). We hypothesized that concurrent cerebellar tDCS during adaptation influences both memory acquisition and re-acquisition if motor errors are enlarged due to behavioral interference. Methods In a sham-controlled and double-blinded study, we applied anodal and cathodal tDCS to the ipsilateral cerebellum while subjects adapted reaching movements to an external, clockwise force field perturbation (acquisition task A) with their dominant right arm. Behavioral interference by an oppositely oriented, counter-clockwise perturbation (secondary task B) was introduced in between the acquisition and re-acquisition (24 h later) sessions. Results Learning task B disrupted memory retention of A and re-increased motor errors in the re-acquisition session. Anodal but not sham or cathodal tDCS impaired motor memory acquisition and, additionally, increased motor errors during re-acquisition of the original motor memory. Conclusion(s) Behavioral interference disrupted motor memory retention but tDCS delivered online during memory acquisition induced lasting and robust effects on re-acquisition performance one day later. Our data also suggest different error-processing mechanisms at work during motor memory acquisition and re-acquisition.

To better understand the process of neuroplasticity, this study assesses brain changes observed by voxel-based morphometry (VBM) in response to two different learning conditions. Twenty-two young, healthy subjects learned slacklining, a complex balancing task, with either their eyes open (EO, n = 11) or their eyes closed (EC, n = 11). The learning took place three times per week for four weeks, with learning periods of 1 hour, providing a total of 12 hours of learning. The scanning and testing protocols were applied at three time-points: (1) immediately before learning (baseline), (2) immediately afterwards (post-test), and (3) two months afterwards (follow-up). The EO group performed better on the task-specific test. Significant group*time interaction effects were found in sensory-motor areas at the post-test, with increases in the EO group only. The results suggest that VBM-observed brain changes in response to learning a complex balancing task vary depending on the learning success and the availability of visual input, and not solely on the amount of time spent on learning. These findings should be taken into account by future studies using similar methodologies.

Beyond its benefits for cardiovascular and musculoskeletal function, endurance exercise may also increase the information-processing capacities and plasticity of the brain. Here we summarize animal and human studies from the past decade demonstrating widespread exercise effects on brain structure and function at the systems, cellular, and molecular level of brain organization. These neurobiological mechanisms may explain the well-established positive exercise effects on performance in various behavioral domains but also its contribution to improved skill learning and neuroplasticity. With respect to the latter, only few empirical and theoretical studies are available to date. Therefore, the further aim of this chapter is to develop hypotheses about the mechanistic link between exercise and improved learning. We identify major knowledge gaps that need to be addressed to advance our understanding of how exercise should be organized to optimize motor learning.

We investigated morphometric brain changes in patients with Parkinson's disease (PD) that are associated with balance training. A total of 20 patients and 16 healthy matched controls learned a balance task over a period of 6 weeks. Balance testing and structural magnetic resonance imaging were performed before and after 2, 4, and 6 training weeks. Balance performance was re-evaluated after ∼20 months. Balance training resulted in performance improvements in both groups. Voxel-based morphometry revealed learning-dependent gray matter changes in the left hippocampus in healthy controls. In PD patients, performance improvements were correlated with gray matter changes in the right anterior precuneus, left inferior parietal cortex, left ventral premotor cortex, bilateral anterior cingulate cortex, and left middle temporal gyrus. Furthermore, a TIME × GROUP interaction analysis revealed time-dependent gray matter changes in the right cerebellum. Our results highlight training-induced balance improvements in PD patients that may be associated with specific patterns of structural brain plasticity. In summary, we provide novel evidence for the capacity of the human brain to undergo learning-related structural plasticity even in a pathophysiological disease state such as in PD.

The aim of the study was to investigate tDCS effects on motor skill learning in a complex whole body dynamic balance task (DBT). We hypothesized that tDCS over the supplementary motor area (SMA), a region that is known to be involved in the control of multi-joint whole body movements, will result in polarity specific changes in DBT learning. In a randomized sham-controlled, double-blinded parallel design, we applied 20 min of tDCS over the supplementary motor area (SMA) and prefrontal cortex (PFC) while subjects performed a DBT. Anodal tDCS over SMA with the cathode placed over contralateral PFC impaired motor skill learning of the DBT compared to sham. This effect was still present on the second day of training. Reversing the polarity (cathode over SMA, anode over PFC) did not affect motor skill learning neither on the first nor on the second day of training. To better disentangle whether the impaired motor skill learning was due to a modulation of SMA or PFC, we performed an additional control experiment. Here, we applied anodal tDCS over SMA together with a larger and presumably more ineffective electrode (cathode) over PFC. Interestingly this alternative tDCS electrode setup did not affect the outcome of DBT learning. Our results provide novel evidence that a modulation of the (right) PFC seems to impair complex multi-joint motor skill learning. Hence, future studies should take the positioning of both tDCS electrodes into account when investigating complex motor skill learning.

Background Non-invasive brain stimulation such as transcranial direct current stimulation (tDCS) has been shown to modulate cortical excitability and thereby influencing motor behaviour and learning. Hypothesis While there is increasing knowledge about the importance of the primary motor cortex (M1) in short- and long-term motor skill learning, little is known about the role of secondary motor areas such as the supplementary and pre-supplementary motor area (SMA/pre-SMA) especially in short-term motor performance. Since SMA but not pre-SMA is directly connected to M1, we hypothesize that anodal tDCS over SMA but not pre-SMA will facilitate visuomotor learning. Methods We applied anodal tDCS (tDCS anodal ) over left SMA, pre-SMA or M1 ( n =12 in each group) while subjects performed a visuomotor pinch force task (VPFT) with their right hand and compared VPFT performance relative to sham (tDCS sham ). Results For the first time, we could show that apart from tDCS anodal over left M1 also SMA but not pre-SMA stimulation promotes short-term improvements in visuomotor learning relative to tDCS sham . Conclusions Our findings provide novel evidence about the role of SMA in short-term visuomotor performance. This knowledge might be beneficial in developing hypothesis-driven clinical studies in neurorehabilitation.

Physical exercise is known to improve memory functions in both animals and humans by inducing various plastic changes in the hippocampus. The present study assumed that physical exercise thus could help to increase the effects of a subsequent hippocampus-dependent cognitive training on directly assessed training outcomes as well as on cognitive transfer measures covering spatial and verbal memory, spatial intelligence as well as attention measures. To identify possible mechanisms that support training-induced changes, we additionally examined brain-derived neurotrophic factor (BDNF), insulin-like growth factor I (IGF-I) as well as vascular endothelial growth factor (VEGF). We collected data from N = 99 young, healthy participants (60 females; age: 25.24 ± 3.55) who performed either eight twenty-minute sessions of a cycling exercise ( n = 26), 16 thirty-minute sessions of a computerized maze training ( n = 23), both training programs ( n = 24) or rested as passive controls ( n = 26). To examine both immediate and delayed training effects, we implemented four separate measurement occasions. Data analyses revealed that both the cycling exercise and maze training were highly effective as participants significantly improved their training outcomes from pre- to post-intervention, respectively. Moreover, participants in the combined condition demonstrated greater learning success in the first eight sessions of the maze training as compared to maze-training-only participants. This group difference, however, did not reach significance when considering all 16 maze training sessions simultaneously. At the level of cognitive transfer, we observed a significantly positive effect of our maze training on verbal memory retention as compared to passive controls. In contrast, neither the cycling exercise nor the combined condition led to significant changes in cognitive transfer. The assessed neurotrophic levels widely remained unaffected by our trainings. Post-maze IGF-I, however, was significantly reduced in the combined condition as compared to maze-training-only participants. Correlation analyses further revealed a significantly positive association between pre- to post-cycling changes in VEGF on the one hand and pre- to post-cycling changes in one of the attention measures on the other hand. The present study yields preliminary evidence for a direct catalytic effect of physical exercise on subsequent hippocampus-dependent learning in a young, healthy sample. This effect, however, did not transfer to non-trained cognitive abilities. Negative findings on both cognitive transfer and neurotrophic changes are discussed in light of methodological limitations of the study and are linked to the current literature.

Transcranial direct current stimulation (tDCS) modulates cortical excitability thereby influencing behavior and learning. While previous studies focused on tDCS after-effects, limited information about "online" tDCS effects is available. This in turn is an important prerequisite to better characterize and/or optimize tDCS effects. Here, we aimed to explore the feasibility of recording low-artifact somatosensory evoked potentials (SEPs) during tDCS using a novel ring electrode setup. We recorded SEP before, during and after 10 min of anodal or sham tDCS using a full-band direct current (DC) EEG system in a total number of 3 subjects. SEPs were recorded in the bore of the tDCS ring electrode. Using this approach, no tDCS-induced artifacts could be observed after the application of a standard EEG filter. This new setup might help to better characterize how tDCS alters evoked brain responses thus providing novel insight into underlying physiological effects during stimulation.

In sport events like Olympic Games or World Championships competitive athletes keep pushing the boundaries of human performance. Compared to team sports, high achievements in many athletic disciplines depend solely on the individual's performance. Contrasting previous research looking for expertise-related differences in brain anatomy at the group level, we aim to demonstrate changes in individual top athlete's brain, which would be averaged out in a group analysis. We compared structural magnetic resonance images (MRI) of three professional track-and-field athletes to age-, gender- and education-matched control subjects. To determine brain features specific to these top athletes, we tested for significant deviations in structural grey matter density between each of the three top athletes and a carefully matched control sample. While total brain volumes were comparable between athletes and controls, we show regional grey matter differences in striatum and thalamus. The demonstrated brain anatomy patterns remained stable and were detected after 2 years with Olympic Games in between. We also found differences in the fusiform gyrus in two top long jumpers. We interpret our findings in reward-related areas as correlates of top athletes' persistency to reach top-level skill performance over years.

oftheRomanpoetJuvenal(∼60–127AD).Juvenal’s intention with this phrase wasrather to teach his fellow Roman citizensthe right virtues worth praying for, thanmaking any scientific statement about theimpact of physical activity on the humanmind. But Juvenal’s phrase interpreted inthe latter context has turned true in lightof growing evidence from neurocognitiveresearch suggesting that physical fitnessindeed enhances cognitive function (for areview see Hillman et al., 2008).A more recent but even more impor-tant question is how physical activity andtraining may influence the developingbrain during periods in which the brainmatures, learns and forms connections(Amso and Casey, 2006). In adult animalsand humans, physical exercise was in factshown to influence the brains cellular andmolecular layout by stimulating neuroge-nesis (e.g., transiently elevating levels ofbrain-derived neurotrophic factor impor-tant for brain plasticity and behavior)in brain regions like the hippocampus,known to underpin memory formation(for a review see Voss et al., 2013).Research like this in children is funda-mentalforthedevelopmentofappropriateeducational concepts optimally embed-ding sport activities into children’s schoolday. Reality however speaks a differentlanguage, since even in light of previ-ous research indeed suggesting improvedcognitive function with enhanced physi-cal fitness (see e.g., Hillman et al., 2009;Pontifex et al., 2011; Voss et al., 2011;Chaddock et al., 2012), opportunities forphysical activities for children are progres-sively reduced, not only in school but alsoaround their home environment (Troianoet al., 2008). At the same time, societyis seeking for young sport talents in soc-cer, football, basketball, hockey, and otherfamous sports, progressively establishing aselection process segregating children intoan inactive group, receiving more schoolclass and less sport education, from thosetalents being intensively trained for a pos-sible professional sport career.That this development in sport edu-cation might be misleading was alreadysuggested by a number of recent cross-sectional studies showing improvedcognitive function with enhanced phys-ical fitness (see e.g., Hillman et al.,2009; Pontifex et al., 2011; Voss et al.,2011; Chaddock et al., 2012). The study“The effect of physical activity on func-tional MRI activation associated withcognitive control in children: a random-ized controlled intervention” by LauraChaddock-Heyman and colleagues hasgained a large community-wide inter-est after publication, since it is the firstlong-term interventional functional MRIstudy addressing the open question howphysical activity influences cognitivecapacity together with the function ofspecific prefrontal regions in children. Thestudy published in Frontiers in HumanNeuroscience in March 2013 is the conse-quent next step in this research field, sincethe cross-sectional studies conducted sofar bear the risk that instead of the physi-cal training itself, other hidden systematicbetween-group factors, such as genesandnutrition,mayexplainwhyphysi-cally active children outperformed theirlower fit peers on tasks of cognitive con-trol (Hillman et al., 2009; Pontifex et al.,2011; Voss et al., 2011; Chaddock et al.,2012). Furthermore, only a few studieson children have combined cognitive test-ing with brain imaging to examine howphysical activity and aerobic fitness relateto brain processes of enhanced cognitivefunction (Hillman et al., 2011). Recentevidencefromthefewbrainimagingstud-iespublishedsofarsuggestreducedneuralactivity in the prefrontal cortex togetherwith improved cognitive function in chil-dren with higher aerobic fitness levels(Chaddock et al., 2011; Voss et al., 2011).These findings are in agreement withstudies comparing adult’s with children’scognitivecontrolcapacitiesdemonstratingreduced activity in the frontal cortex ofadults coupled with enhanced cognitiveperformance (see e.g., Diamond, 2006;Bunge and Crone, 2009).The study design used by Chaddock-Heyman and colleagues acknowledgesthese previous studies also when account-ing for the two main problems that occurwhen investigating the developing brain:First, an interventional study involvingchildren over a longer time period needsto control for the “normal” progress in

In athletics, motor performance is determined by different abilities such as technique, endurance, strength and speed. Based on animal studies, motor speed is thought to be encoded in the basal ganglia, sensorimotor cortex and the cerebellum. The question arises whether there is a unique structural feature in the human brain, which allows “power athletes” to perform a simple foot movement significantly faster than “endurance athletes”. We acquired structural and functional brain imaging data from 32 track-and-field athletes. The study comprised of 16 “power athletes” requiring high speed foot movements (sprinters, jumpers, throwers) and 16 endurance athletes (distance runners) which in contrast do not require as high speed foot movements. Functional magnetic resonance imaging (fMRI) was used to identify speed specific regions of interest in the brain during fast and slow foot movements. Anatomical MRI scans were performed to assess structural grey matter volume differences between athletes groups (voxel based morphometry). We tested maximum movement velocity of plantarflexion (PF-Vmax) and acquired electromyographical activity of the lateral and medial gastrocnemius muscle. Behaviourally, a significant difference between the two groups of athletes was noted in PF-Vmax and fMRI indicates that fast plantarflexions are accompanied by increased activity in the cerebellar anterior lobe. The same region indicates increased grey matter volume for the power athletes compared to the endurance counterparts. Our results suggest that speed-specific neuro-functional and -structural differences exist between power and endurance athletes in the peripheral and central nervous system.

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.

The importance of the central nervous system in endurance exercise has not yet been exhaustively investigated because of difficulties in measuring cortical parameters in sport science. During exercise there are a lot of artifacts and perturbations which can affect signal quality of cortical brain activity. The technical developments of surface electroencephalography (EEG) minimize such influences during standardized test conditions on a bicycle ergometer. The aim of this study was to investigate how movement frequency affects cortical brain activity and established physiological parameters during exercise. In cycling peak performance is affected by cadence. The analysis of brain cortical activity might lead to new insights in the relation of power and cadence. In a laboratory study sixteen male, endurance-trained cyclists completed a 60 min endurance exercise on a high-performance bicycle ergometer. Cadence was changed every 10 min (90-120-60-120-60-90 rpm). EEG was used to analyze changes in cortical brain activity. Furthermore, heart rate, blood lactate and rate of perceived exertion (RPE) were measured after each cadence change. The results indicate that heart rate, blood lactate and RPE were higher at 120 rpm compared to 60 rpm. The spectral EEG power increased statistically significantly in the alpha-2 and beta-2 frequency range by changing cadence from 60 to 120 rpm. By lowering the cadence from 120 to 60 rpm the spectral power dropped statistically significantly in all analyzed EEG frequency bands. The data also showed a statistically significant decrease of spectral EEG power in all frequency ranges over time. In conclusion, the analyzed EEG data indicate that cadence should be considered as an independent exercise normative in the training process, because it directly influences metabolic, cardiac and cortical parameters.

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.

In contrast to a long-held view that structural brain plasticity is restricted to critical periods during ontogenesis, it is now well established that the adult human brain preserves its capacity for functional and structural changes throughout life. Although early experimental studies were mainly performed in animals, technical developments especially in the field of MRI enabled the non-invasive observation of functional and structural reorganization in the human brain. This article reports recent insights in human brain plasticity with particular emphasis on (dynamic) learning-related structural gray and white matter changes and its behavioral correlates.

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.

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 (iTMS1.5 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 iTMS1.5 ms protocol with an I-wave periodicity adjusted to the individual I1-peak wave latency (iTMSadj) resulted in a stronger effect on ppMEPs relative to iTMS1.5 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 iTMS1.5 ms protocol might improve the outcome of this novel non-invasive brain stimulation technique.

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.

Objective The contribution of the human anterior intraparietal area and the dorsal premotor cortex to arbitrary visuo-motor mapping during grasping were tested. Methods Trained right-handed subjects reached for and pincer-grasped a cube with the right hand in the absence of visual feedback after the cube location had been displayed for 200 ms. During the reaching movements, the colour of the cube changed and visual feedback about the change of colour was provided for 100 ms at 500 ms after movement onset (at the time of peak grasp aperture). Depending on colour, subjects were instructed to either pincer-grasp the cube in a horizontal or vertical grasp position with the latter necessitating wrist rotation (experiment 1) or to pincer-grasp and transport the cube to either a left or right target position (experiment 2). Within two consecutive 200 ms time windows (TMS 1 and 2) starting 500 ms and 700 ms after movement onset, respectively, double pulses of supra-threshold transcranial magnetic stimulation (inter-stimulus interval: 100 ms) were delivered over (i) the left primary motor cortex (90° vertically angulated coil position, control stimulation), (ii) the left dorsal premotor cortex or (ii) the left anterior intraparietal area. Results Compared to control stimulation, stimulation of the anterior intraparietal area, but not of the dorsal premotor cortex, at TMS 1 delayed the times to wrist rotation (experiment 1) and hand transport (experiment 2). Compared to control stimulation, stimulation of the dorsal premotor cortex, but not of the anterior intraparietal area, at TMS 2 delayed both wrist rotation (experiment 1) and hand transport (experiment 2). Conclusions We contend that the anterior intraparietal area and the dorsal premotor cortex are both involved albeit at different phases during the mapping of arbitrary visual cues with goal directed grasp and transport movements. Significance These data add to the current understanding of how human cortical areas work in concert during manual activities.

Introduction Transcranial direct current stimulation (tDCS) applied over primary motor cortex (M1) has been shown to influence motor skill learning in a polarity-dependent manner. Most of the studies used simplified models of motor skill learning with particular emphasis on hand movements with sequential character. However, the effect of tDCS on complex multi-joint learning paradigms has so far not been investigated. Objective The aim of the study was to investigate polarity-specific tDCS effects on motor skill learning and consolidation in a complex whole-body dynamic balance task (DBT). We hypothesized that tDCS over the supplementary motor area (SMA), a region that is known to be involved in the control of multi-joint whole-body movements, will result in polarity specific changes in DBT learning. Materials and methods In a parallel double-blinded design we applied 20 min of either anodal or cathodal tDCS over the supplementary motor area (SMA), while subjects performed a complex whole-body dynamic balancing task (DBT). A reference electrode was attached over the right forehead. For the DBT we used a discovery learning approach in which no information about the performance strategy was provided. Therefore, during the time course of DBT learning, subjects had to discover their optimal strategy to improve task performance. Results 20 min of anodal tDCS over SMA with a reference electrode (cathode) placed over the right forehead impaired motor skill learning of the DBT compared to sham. This effect was still present on the second day of training. Reversing the polarity (cathode over SMA, anode over right forehead) did not affect motor skill learning neither on the first nor on the second day of training. To better disentangle whether the impaired motor skill learning was due to a modulation of SMA or prefrontal regions, we performed an additional control experiment. Hence, we applied anodal tDCS over SMA together with a larger presumably more ineffective reference electrode (cathode) over the right forehead. Interestingly, this alternative tDCS electrode setup did not affect the outcome of DBT learning. Conclusions Our results provide novel evidence, that a modulation of the prefrontal cortex by the cathodal (reference) tDCS electrode impairs complex multi-joint motor skill learning. We suggest that inhibition of higher cognitive processes (e.g. strategy finding, feedback processing) rather than excitation of SMA might explain our finding. Hence, future studies should take the positioning of the tDCS reference electrode into account when investigating complex motor skill learning.