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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.

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.

The ability to regulate emotions is essential for adaptive behavior. This ability is suggested to be mediated by the connectivity between prefrontal brain regions and the amygdala. Yet, it is still unknown whether the ability to regulate emotions can be trained by using a non-emotional procedure, such as the recruitment of executive control (EC). Participants who were trained using a high-frequent executive control (EC) task (80% incongruent trials) showed reduced amygdala reactivity and behavioral interference of aversive pictures. These effects were observed only following multiple-session training and not following one training session. In addition, they were not observed for participants exposed to low-frequent EC training (20% incongruent trials). Resting-state functional connectivity analysis revealed a marginally significant interaction between training group and change in the connectivity between the amygdala and the right inferior frontal gyrus (IFG). Amygdala-IFG connectivity was significantly increased following the training only in the high-frequent EC training group. These findings are the first to show that non-emotional training can induce changes in amygdala reactivity to aversive information and alter amygdala-prefrontal connectivity.

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.

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.

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.

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.

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.

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.