Complex sequential learning is not facilitated by transcranial direct current stimulation over DLPFC or M1.

Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique which was found to have a positive modulatory effect on online sequence acquisition or offline motor consolidation, depending on the relative role of the associated brain region. Primary motor regions (M1) and dorsolateral prefrontal cortices (DLPFC) have both been related to sequential learning. However, research so far did not systematically disentangle their differential roles in online and offline learning especially in more complex sequential paradigms. In this study, the influence of anodal M1 leg area-tDCS and anodal DLPFC-tDCS applied during complex sequential learning (online and offline) was investigated using a complex whole body serial reaction time task (CWB-SRTT) in 42 healthy volunteers. TDCS groups did not differ from sham tDCS group regarding their response and reaction time (online) and also not in terms of overnight consolidation (offline). Sequence specific learning and the number of recalled items also did not differ between groups. Results may be related to unspecific parameters such as timing of the stimulation or current intensity but can also be attributed to the relative role of M1 and DLPFC during early complex learning. Taken together, the current study provides preliminary evidence that M1 leg area or DLPFC modulation by means of tDCS does not improve complex sequential skill learning. SIGNIFICANCE STATEMENT: Understanding motor learning is helpful to deepen our knowledge about the human ability to acquire new skills. Complex sequential learning tasks have only been studied, sparsely, but are particularly mimicking challenges of daily living. The present study studied early motor learning in a complex serial reaction time task while transcranial direct current stimulation (tDCS) was either applied to leg primary motor cortex or bilateral dorsolateral prefrontal cortex. TDCS did not affect sequential learning, neither directly during performance nor in terms of sequence consolidation. Results provide preliminary information that M1 or bilateral DLPFC modulation does not improve early complex motor learning.

The impact of acute blood-flow-restriction resistance exercise on somatosensory-evoked potentials in healthy adults.

Blood-flow-restriction exercise (BFREX) is an emerging method to stimulate hypertrophy and strength without the need for high training loads. However, the impact of BFREX concerning somatosensory processing remains elusive. Here, we aimed to investigate the acute effects of BFREX on somatosensory processing in healthy adults using somatosensory-evoked potentials (SEPs). Twelve healthy adults (23.0 ± 3.2 years of age) participated in a randomized crossover experiment, consisting of three experimental conditions: application of blood-flow restriction without resistance exercise (BFR), resistance exercise for multiple sets with blood-flow restriction (BFREX) and traditional resistance exercise (unilateral biceps curls) for multiple sets without BFR (EX). SEP measurements were recorded bilaterally before, during and after each condition. SEP amplitudes were largely unaffected during various occlusive conditions. Nonetheless, our findings demonstrate a significant decrease in N9 latencies for condition EX compared with BFR, specifically in the exercised limb (mean difference = -0.26 ms, SE = 0.06 ms, P = 0.002, d = -0.335). This study provides evidence on the lack of impact of BFREX within the somatosensory domain, according to current guidelines. As an alternative method to traditional high-load resistance exercise, BFREX might offer a considerable upside for rehabilitative settings by reducing strain on the musculoskeletal system.

Increased Cortical Activity in Novices Compared to Experts During Table Tennis: A Whole-Brain fNIRS Study Using Threshold-Free Cluster Enhancement Analysis.

There is a growing interest to understand the neural underpinnings of high-level sports performance including expertise-related differences in sport-specific skills. Here, we aimed to investigate whether expertise level and task complexity modulate the cortical hemodynamics of table tennis players. 35 right-handed table tennis players (17 experts/18 novices) were recruited and performed two table tennis strokes (forehand and backhand) and a randomized combination of them. Cortical hemodynamics, as a proxy for cortical activity, were recorded using functional near-infrared spectroscopy, and the behavioral performance (i.e., target accuracy) was assessed via video recordings. Expertise- and task-related differences in cortical hemodynamics were analyzed using nonparametric threshold-free cluster enhancement. In all conditions, table tennis experts showed a higher target accuracy than novices. Furthermore, we observed expertise-related differences in widespread clusters compromising brain areas being associated with sensorimotor and multisensory integration. Novices exhibited, in general, higher activation in those areas as compared to experts. We also identified task-related differences in cortical activity including frontal, sensorimotor, and multisensory brain areas. The present findings provide empirical support for the neural efficiency hypothesis since table tennis experts as compared to novices utilized a lower amount of cortical resources to achieve superior behavioral performance. Furthermore, our findings suggest that the task complexity of different table tennis strokes is mirrored in distinct cortical activation patterns. Whether the latter findings can be useful to monitor or tailor sport-specific training interventions necessitates further investigations.

Reduction of somatosensory functional connectivity by transcranial alternating current stimulation at endogenous mu-frequency.

Alpha, the most prominent human brain rhythm, might reflect a mechanism of functional inhibition for gating neural processing. This concept has been derived predominantly from local measures of inhibition, while large-scale network mechanisms to guide information flow are largely unknown. Here, we investigated functional connectivity changes on a whole-brain level by concurrent transcranial alternating current stimulation (tACS) and resting-state functional MRI in humans. We specifically focused on somatosensory alpha-band oscillations by adjusting the tACS frequency to each individual´s somatosensory (mu-) alpha peak frequency (mu-tACS). Potential differences of Eigenvector Centrality of primary somatosensory cortex (S1) as well as on a whole brain level between mu-tACS and sham were analyzed. Our results demonstrate that mu-tACS induces a locally-specific decrease in whole-brain functional connectivity of left S1. An additional exploratory analysis revealed that this effect primarily depends on a decrease in functional connectivity between S1 and a network of regions that are crucially involved in somatosensory processing. Furthermore, the decrease in functional centrality was specific to mu-tACS and was not observed when tACS was applied in the gamma-range in an independent study. Our findings provide evidence that modulated somatosensory (mu-) alpha-activity may affect whole-brain network level activity by decoupling primary sensory areas from other hubs involved in sensory processing.

Intermuscular coherence between homologous muscles during dynamic and static movement periods of bipedal squatting.

Coordination of functionally coupled muscles is a key aspect of movement execution. Demands on coordinative control increase with the number of involved muscles and joints, as well as with differing movement periods within a given motor sequence. While previous research has provided evidence concerning inter- and intramuscular synchrony in isolated movements, compound movements remain largely unexplored. With this study, we aimed to uncover neural mechanisms of bilateral coordination through intermuscular coherence (IMC) analyses between principal homologous muscles during bipedal squatting (BpS) at multiple frequency bands (alpha, beta, and gamma). For this purpose, participants performed bipedal squats without additional load, which were divided into three distinct movement periods (eccentric, isometric, and concentric). Surface electromyography (EMG) was recorded from four homologous muscle pairs representing prime movers during bipedal squatting. We provide novel evidence that IMC magnitudes differ between movement periods in beta and gamma bands, as well as between homologous muscle pairs across all frequency bands. IMC was greater in the muscle pairs involved in postural and bipedal stability compared with those involved in muscular force during BpS. Furthermore, beta and gamma IMC magnitudes were highest during eccentric movement periods, whereas we did not find movement-related modulations for alpha IMC magnitudes. This finding thus indicates increased integration of afferent information during eccentric movement periods. Collectively, our results shed light on intermuscular synchronization during bipedal squatting, as we provide evidence that central nervous processing of bilateral intermuscular functioning is achieved through task-dependent modulations of common neural input to homologous muscles.NEW & NOTEWORTHY It is largely unexplored how the central nervous system achieves coordination of homologous muscles of the upper and lower body within a compound whole body movement, and to what extent this neural drive is modulated between different movement periods and muscles. Using intermuscular coherence analysis, we show that homologous muscle functions are mediated through common oscillatory input that extends over alpha, beta, and gamma frequencies with different synchronization patterns at different movement periods.

Anodal transcranial direct current stimulation reduces motor slowing in athletes and non-athletes.

BACKGROUND: Motor fatigability describes a phenomenon that occurs when exhaustive exercise or physically demanding tasks are executed over an extended period of time. Concerning fast repetitive movements, it is noticeable by a reduction in movement speed (motor slowing, MoSlo) and occurs due to both central and peripheral factors. The aim of the present study was to examine the presence of MoSlo during hand- (HTT) and foot-tapping tasks (FTT) comparing trained football (FB) and handball players (HB) and non-athletes (NA). Furthermore, we were interested in how far anodal transcranial direct current stimulation (tDCS) might be capable of modulating MoSlo as compared to sham. METHODS: A total number of 46 participants were enrolled in a sham-controlled, double-blinded, cross-over study. HTT and FTT were performed before, during, after as well as 30 min after 20 min of tDCS over the leg area of the primary motor cortex (M1). RESULTS: We could demonstrate that MoSlo during HTT and FTT is a general phenomenon that is observed independent of the type of sports and/or training status. Furthermore, we were able to show a tDCS-induced reduction in MoSlo specifically during FTT in both trained athletes and NA. No such effects could be observed for HTT, indicating local specificity of tDCS-induced effects on a behavioral level. CONCLUSION: We could demonstrate that tDCS is capable of reducing motor fatigability during fast repetitive movements. These findings are of pivotal interest for many sports where fatigability resistance is a limiting factor in maintaining repetitive movement patterns.

Structural connectivity prior to whole-body sensorimotor skill learning associates with changes in resting state functional connectivity.

Changes in resting state functional connectivity are induced by sensorimotor training and assumed to be concomitant of motor learning, although a potential relationship between functional and structural connectivity associated with sensorimotor sequence learning remains elusive. To investigate whether initial structural connectivity relates to changes in functional connectivity, we evaluated resting state functional connectivity (rs-FC), white matter fibre density (FD), fibre-bundle cross-section (FC), and gray matter volume (GMV) in healthy human participants before and after two days of performing a complex whole-body serial reaction time task (CWB-SRTT). As CWB-SRTT was implicit, participants were not told about the presence of any sequence. Since the lateral prefrontal cortex (PFC) plays an important role in sequence learning, we hypothesized that structural connectivity within the PFC prior to learning is associated with changes in rs-FC involving the lateral PFC. Sequence specific improvements, as assessed by the time difference between the last random and the last sequence blocks, were observed for reaction times, suggesting that sensorimotor sequence memory was acquired. Rs-FC between the right lateral PFC and bilateral striatum increased significantly in the learning group, when compared to a control group who performed only random blocks. This indicated that rs-FC changes are related to sequence memory but not to exercise itself. In addition, changes in rs-FC between the right lateral PFC and the left striatum were correlated with sequence specific improvements in individual reaction times. Furthermore, changes in rs-FC between right lateral PFC and left striatum were positively correlated with FC in the right anterior corona radiata measured before the task. We did not find any structural changes or significant correlations in FD or GMV. These findings suggest that an early phase of sensorimotor sequence learning in complex whole-body movements is associated with an increase in rs-FC between prefrontal and subcortical regions. Furthermore, we provide novel evidence that CWB-SRTT-induced changes in rs-FC were correlated with FC within the PFC.

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.

Changes in neurovascular coupling during cycling exercise measured by multi-distance fNIRS: a comparison between endurance athletes and physically active controls.

It is well known that endurance exercise modulates the cardiovascular, pulmonary, and musculoskeletal system. However, knowledge about its effects on brain function and structure is rather sparse. Hence, the present study aimed to investigate exercise-dependent adaptations in neurovascular coupling to different intensity levels in motor-related brain regions. Moreover, expertise effects between trained endurance athletes (EA) and active control participants (ACP) during a cycling test were investigated using multi-distance functional near-infrared spectroscopy (fNIRS). Initially, participants performed an incremental cycling test (ICT) to assess peak values of power output (PPO) and cardiorespiratory parameters such as oxygen consumption volume (VO2max) and heart rate (HRmax). In a second session, participants cycled individual intensity levels of 20, 40, and 60% of PPO while measuring cardiorespiratory responses and neurovascular coupling. Our results revealed exercise-induced decreases of deoxygenated hemoglobin (HHb), indicating an increased activation in motor-related brain areas such as primary motor cortex (M1) and premotor cortex (PMC). However, we could not find any differential effects in brain activation between EA and ACP. Future studies should extend this approach using whole-brain configurations and systemic physiological augmented fNIRS measurements, which seems to be of pivotal interest in studies aiming to assess neural activation in a sports-related context.

Motor learning in a complex balance task and associated neuroplasticity: a comparison between endurance athletes and nonathletes.

Studies suggested that motor expertise is associated with functional and structural brain alterations, which positively affect sensorimotor performance and learning capabilities. The purpose of the present study was to unravel differences in motor skill learning and associated functional neuroplasticity between endurance athletes (EA) and nonathletes (NA). For this purpose, participants had to perform a multimodal balance task (MBT) training on 2 sessions, which were separated by 1 wk. Before and after MBT training, a static balance task (SBT) had to be performed. MBT-induced functional neuroplasticity and neuromuscular alterations were assessed by means of functional near-infrared spectroscopy (fNIRS) and electromyography (EMG) during SBT performance. We hypothesized that EA would showed superior initial SBT performance and stronger MBT-induced improvements in SBT learning rates compared with NA. On a cortical level, we hypothesized that MBT training would lead to differential learning-dependent functional changes in motor-related brain regions [such as primary motor cortex (M1)] during SBT performance. In fact, EA showed superior initial SBT performance, whereas learning rates did not differ between groups. On a cortical level, fNIRS recordings (time × group interaction) revealed a stronger MBT-induced decrease in left M1 and inferior parietal lobe (IPL) for deoxygenated hemoglobin in EA. Even more interesting, learning rates were correlated with fNIRS changes in right M1/IPL. On the basis of these findings, we provide novel evidence for superior MBT training-induced functional neuroplasticity in highly trained athletes. Future studies should investigate these effects in different sports disciplines to strengthen previous work on experience-dependent neuroplasticity.NEW & NOTEWORTHY Motor expertise is associated with functional/structural brain plasticity. How such neuroplastic reorganization translates into altered motor learning processes remains elusive. We investigated endurance athletes (EA) and nonathletes (NA) in a multimodal balance task (MBT). EA showed superior static balance performance (SBT), whereas MBT-induced SBT improvements did not differ between groups. Functional near-infrared spectroscopy recordings revealed a differential MBT training-induced decrease of deoxygenated hemoglobin in left primary motor cortex and inferior parietal lobe between groups.

Mirror Motor Activity During Right-Hand Contractions and Its Relation to White Matter in the Posterior Midbody of the Corpus Callosum.

Cortical activity during simple unimanual actions is typically lateralized to contralateral sensorimotor areas, while a more bilateral pattern is observed with an increase in task demands. In parallel, increasing task demands are associated with subtle mirror muscle activity in the resting hand, implying a relative loss in motor selectivity. The corpus callosum (CC) is crucially involved in unimanual tasks by mediating both facilitatory and inhibitory interactions between bilateral motor cortical systems, but its association with mirror motor activity is yet unknown. Here, we used diffusion-weighted imaging and bilateral electromyographic (EMG) measurements during a unimanual task to investigate potential relationships between white matter microstructure of the CC and mirror EMG activity. Participants performed an unimanual pinch force task with both hands alternatively. Four parametrically increasing force levels were exerted while EMG activity was recorded bilaterally from first dorsal interosseus muscles. Consistent with previous findings, mirror EMG activity increased as a function of force. Additionally, there was a significant relationship between the slope of increasing mirror EMG during right-hand contractions and fractional anisotropy in transcallosal fibers connecting both M1. No significant relationships were found for fibers connecting dorsal premotor cortices or supplementary motor area, indicating the local specificity of the observed brain-physiology relationship.

Improving motor performance without training: the effect of combining mirror visual feedback with transcranial direct current stimulation.

Mirror visual feedback (MVF) during motor training has been shown to improve motor performance of the untrained hand. Here we thought to determine if MVF-induced performance improvements of the left hand can be augmented by upregulating plasticity in right primary motor cortex (M1) by means of anodal transcranial direct current stimulation (a-tDCS) while subjects trained with the right hand. Participants performed a ball-rotation task with either their left (untrained) or right (trained) hand on two consecutive days (days 1 and 2). During training with the right hand, MVF was provided concurrent with two tDCS conditions: group 1 received a-tDCS over right M1 (n = 10), whereas group 2 received sham tDCS (s-tDCS, n = 10). On day 2, performance was reevaluated under the same experimental conditions compared with day 1 but without tDCS. While baseline performance of the left hand (day 1) was not different between groups, a-tDCS exhibited stronger MVF-induced performance improvements compared with s-tDCS. Similar results were observed for day 2 (without tDCS application). A control experiment (n = 8) with a-tDCS over right M1 as outlined above but without MVF revealed that left hand improvement was significantly less pronounced than that induced by combined a-tDCS and MVF. Based on these results, we provide novel evidence that upregulating activity in the untrained M1 by means of a-tDCS is capable of augmenting MVF-induced performance improvements in young normal volunteers. Our findings suggest that concurrent MVF and tDCS might have synergistic and additive effects on motor performance of the untrained hand, a result of relevance for clinical approaches in neurorehabilitation and/or exercise science.

Augmenting mirror visual feedback-induced performance improvements in older adults.

Previous studies have indicated that age-related behavioral alterations are not irreversible but are subject to amelioration through specific training interventions. Both training paradigms and non-invasive brain stimulation (NIBS) can be used to modulate age-related brain alterations and thereby influence behavior. It has been shown that mirror visual feedback (MVF) during motor skill training improves performance of the trained and untrained hands in young adults. The question remains of whether MVF also improves motor performance in older adults and how performance improvements can be optimised via NIBS. Here, we sought to determine whether anodal transcranial direct current stimulation (a-tDCS) can be used to augment MVF-induced performance improvements in manual dexterity. We found that older adults receiving a-tDCS over the right primary motor cortex (M1) during MVF showed superior performance improvements of the (left) untrained hand relative to sham stimulation. An additional control experiment in participants receiving a-tDCS over the right M1 only (without MVF/motor training of the right hand) revealed no significant behavioral gains in the left (untrained) hand. On the basis of these findings, we propose that combining a-tDCS with MVF might be relevant for future clinical studies that aim to optimise the outcome of neurorehabilitation.

Cortical topography of intracortical inhibition influences the speed of decision making.

The neocortex contains orderly topographic maps; however, their functional role remains controversial. Theoretical studies have suggested a role in minimizing computational costs, whereas empirical studies have focused on spatial localization. Using a tactile multiple-choice reaction time (RT) task before and after the induction of perceptual learning through repetitive sensory stimulation, we extend the framework of cortical topographies by demonstrating that the topographic arrangement of intracortical inhibition contributes to the speed of human perceptual decision-making processes. RTs differ among fingers, displaying an inverted U-shaped function. Simulations using neural fields show the inverted U-shaped RT distribution as an emergent consequence of lateral inhibition. Weakening inhibition through learning shortens RTs, which is modeled through topographically reorganized inhibition. Whereas changes in decision making are often regarded as an outcome of higher cortical areas, our data show that the spatial layout of interaction processes within representational maps contributes to selection and decision-making processes.

Facilitation of inferior frontal cortex by transcranial direct current stimulation induces perceptual learning of severely degraded speech.

Perceptual learning requires the generalization of categorical perceptual sensitivity from trained to untrained items. For degraded speech, perceptual learning modulates activation in a left-lateralized network, including inferior frontal gyrus (IFG) and inferior parietal cortex (IPC). Here we demonstrate that facilitatory anodal transcranial direct current stimulation (tDCS(anodal)) can induce perceptual learning in healthy humans. In a sham-controlled, parallel design study, 36 volunteers were allocated to the three following intervention groups: tDCS(anodal) over left IFG, IPC, or sham. Participants decided on the match between an acoustically degraded and an undegraded written word by forced same-different choice. Acoustic degradation varied in four noise-vocoding levels (2, 3, 4, and 6 bands). Participants were trained to discriminate between minimal (/Tisch/-FISCH) and identical word pairs (/Tisch/-TISCH) over a period of 3 d, and tDCS(anodal) was applied during the first 20 min of training. Perceptual sensitivity (d') for trained word pairs, and an equal number of untrained word pairs, was tested before and after training. Increases in d' indicate perceptual learning for untrained word pairs, and a combination of item-specific and perceptual learning for trained word pairs. Most notably for the lowest intelligibility level, perceptual learning occurred only when tDCS(anodal) was applied over left IFG. For trained pairs, improved d' was seen on all intelligibility levels regardless of tDCS intervention. Over left IPC, tDCS(anodal) did not modulate learning but instead introduced a response bias during training. Volunteers were more likely to respond "same," potentially indicating enhanced perceptual fusion of degraded auditory with undegraded written input. Our results supply first evidence that neural facilitation of higher-order language areas can induce perceptual learning of severely degraded speech.

Quantifying motor adaptation in a sport-specific table tennis setting.

Studies on motor adaptation aim to better understand the remarkable, largely implicit capacity of humans to adjust to changing environmental conditions. So far, this phenomenon has mainly been investigated in highly controlled laboratory setting, allowing only limited conclusions and consequences for everyday life scenarios. Natural movement tasks performed under externally valid conditions would provide important support on the transferability of recent laboratory findings. Therefore, one major goal of the current study was to create and assess a new table tennis paradigm mapping motor adaptation in a more natural and sport-specific setting. High-speed cinematographic measurements were used to determine target accuracy in a motor adaptation table tennis paradigm in 30 right-handed participants. In addition, we investigated if motor adaptation was affected by temporal order of perturbations (serial vs. random practice). In summary, we were able to confirm and reproduce typical motor adaptation effects in a sport-specific setting. We found, according to previous findings, an increase in target errors with perturbation onset that decreased during motor adaptation. Furthermore, we observed an increase in target errors with perturbation offset (after-effect) that decrease subsequently during washout phase. More importantly, this motor adaptation phenomenon did not differ when comparing serial vs. random perturbation conditions.

The impact of cerebellar transcranial direct current stimulation on isometric bench press performance in trained athletes.

Athletic development centers on optimizing performance, including technical skills and fundamental motor abilities such as strength and speed. Parameters such as maximum contraction force and rate of force development, influence athletic success, although performance gains become harder to achieve as athletic abilities increase. Non-invasive transcranial direct current stimulation of the cerebellum (CB-tDCS) has been used successfully to increase force production in novices, although the potential effects in athletes remain unexplored. The present study examined the effects of CB-tDCS on maximum isometric voluntary contraction force (MVCiso) and isometric rate of force development (RFDiso) during a bench press task in well-trained athletes. 21 healthy, male, strength-trained athletes participated in a randomized, sham-controlled, double-blinded crossover design. Each participant completed the isometric bench press (iBP) task on two separate days, with at least 5 days between sessions, while receiving either CB-tDCS or sham stimulation. Electromyography (EMG) recordings of three muscles involved in iBP were acquired bilaterally to uncover differences in neuromuscular activation and agonist-antagonist co-contraction between conditions. Contrary to our hypothesis, no significant differences in MVCiso and RFDiso were observed between CB-tDCS and sham conditions. Furthermore, no tDCS-induced differences in neuromuscular activation or agonist-antagonist co-contraction were revealed. Here, we argue that the effects of CB-tDCS on force production appear to depend on the individual's training status. Future research should study individual differences in tDCS responses between athletes and novices, as well as the potential of high-definition tDCS for precise brain region targeting to potentially enhance motor performance in athletic populations.

Language learning without control: the role of the PFC.

Learning takes place throughout lifetime but differs in infants and adults because of the development of the PFC, a brain region responsible for cognitive control. To test this hypothesis, adults were investigated in a language learning paradigm under inhibitory, cathodal transcranial direct current stimulation over PFC. The experiment included a learning session interspersed with test phases and a test-only session. The stimulus material required the learning of grammatical dependencies between two elements in a novel language. In a parallel design, cathodal transcranial direct current stimulation over the left PFC, right PFC, or sham stimulation was applied during the learning session but not during the test-only session. Event-related brain potentials (ERPs) were recorded during both sessions. Whereas no ERP learning effects were observed during the learning session, different ERP learning effects as a function of prior stimulation type were found during the test-only session, although behavioral learning success was equal across conditions. With sham stimulation, the ERP learning effect was reflected in a centro-parietal N400-like negativity indicating lexical processes. Inhibitory stimulation over the left PFC, but not over the right PFC, led to a late positivity similar to that previously observed in prelinguistic infants indicating associative learning. The present data demonstrate that adults can learn with and without cognitive control using different learning mechanisms. In the presence of cognitive control, adult language learning is lexically guided, whereas it appears to be associative in nature when PFC control is downregulated.

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.