Prior Movement of One Arm Facilitates Motor Adaptation in the Other.

Many movements in daily life are embedded in motion sequences that involve more than one limb, demanding the motor system to monitor and control different body parts in quick succession. During such movements, systematic changes in the environment or the body might require motor adaptation of specific segments. However, previous motor adaptation research has focused primarily on motion sequences produced by a single limb, or on simultaneous movements of several limbs. For example, adaptation to opposing force fields is possible in unimanual reaching tasks when the direction of a prior or subsequent movement is predictive of force field direction. It is unclear, however, whether multilimb sequences can support motor adaptation processes in a similar way. In the present study (38 females, 38 males), we investigated whether reaches can be adapted to different force fields in a bimanual motor sequence when the information about the perturbation is associated with the prior movement direction of the other arm. In addition, we examined whether prior perceptual (visual or proprioceptive) feedback of the opposite arm contributes to force field-specific motor adaptation. Our key finding is that only active participation in the bimanual sequential task supports pronounced adaptation. This result suggests that active segments in bimanual motion sequences are linked across limbs. If there is a consistent association between movement kinematics of the linked and goal movement, the learning process of the goal movement can be facilitated. More generally, if motion sequences are repeated often, prior segments can evoke specific adjustments of subsequent movements.SIGNIFICANCE STATEMENT Movements in a limb's motion sequence can be adjusted based on linked movements. A prerequisite is that kinematics of the linked movements correctly predict which adjustments are needed. We show that use of kinematic information to improve performance is even possible when a prior linked movement is performed with a different limb. For example, a skilled juggler might have learned how to correctly adjust his catching movement of the left hand when the right hand performed a throwing action in a specific way. Linkage is possibly a key mechanism of the human motor system for learning complex bimanual skills. Our study emphasizes that learning of specific movements should not be studied in isolation but within their motor sequence context.

Posterior reversible encephalopathy syndrome associated with antibiotic therapy: a case report and systematic review.

Posterior reversible encephalopathy syndrome (PRES) is an acute neurological condition associated with different etiologies, including antibiotic therapy. To date, most data regarding antibiotic-related PRES are limited to case reports and small case series. Here, we report a novel case description and provide a systematic review of the clinico-radiological characteristics and prognosis of available cases of PRES associated with antibiotic therapy. We performed a systematic literature search in PubMed and Scopus from inception to 10 January 2024, following PRISMA guidelines and a predefined protocol. The database search yielded 12 subjects (including our case). We described the case of a 55-year-old female patient with PRES occurring one day after administration of metronidazole and showing elevated serum neurofilament light chain protein levels and favorable outcome. In our systematic review, antibiotic-associated PRES was more frequent in female patients (83.3%). Metronidazole and fluoroquinolones were the most reported antibiotics (33.3% each). Clinical and radiological features were comparable to those of PRES due to other causes. Regarding the prognosis, about one third of the cases were admitted to the intensive care unit, but almost all subjects (90.0%) had a complete or almost complete clinical and radiological recovery after prompt cessation of the causative drug. Antibiotic-associated PRES appears to share most of the characteristics of classic PRES. Given the overall good prognosis of the disease, it is important to promptly diagnose antibiotic-associated PRES and discontinue the causative drug.

Influence of noninvasive brain stimulation on connectivity and local activation: a combined tDCS and fMRI study.

The effect of transcranial direct current stimulation (tDCS) on neurobiological mechanisms underlying executive function in the human brain remains elusive. This study aims at examining the effect of anodal and cathodal tDCS over the left dorsolateral prefrontal cortex (DLPFC) in comparison with sham stimulation on resting-state connectivity as well as functional activation and working memory performance. We hypothesized perturbed fronto-parietal resting-state connectivity during stimulation and altered working memory performance combined with modified functional working memory-related activation. We applied tDCS with 1 mA for 21 min over the DLPFC inside an fMRI scanner. During stimulation, resting-state fMRI was acquired and task-dependent fMRI during working memory task performance was acquired directly after stimulation. N = 36 healthy subjects were studied in a within-subject design with three different experimental conditions (anodal, cathodal and sham) in a double-blind design. Seed-based functional connectivity analyses and dynamic causal modeling were conducted for the resting-state fMRI data. We found a significant stimulation by region interaction in the seed-based ROI-to-ROI resting-state connectivity, but no effect on effective connectivity. We also did not find an effect of stimulation on task-dependent signal alterations in working memory activation in our regions of interest and no effect on working memory performance parameters. We found effects on measures of seed-based resting-state connectivity, while measures of effective connectivity and task-based connectivity did not show any stimulation effect. We could not replicate previous findings of tDCS stimulation effects on behavioral outcomes. We critically discuss possible methodological limitations and implications for future studies.

The impact of lesion side on bilateral upper limb coordination after stroke.

BACKGROUND: A stroke frequently results in impaired performance of activities of daily life. Many of these are highly dependent on effective coordination between the two arms. In the context of bimanual movements, cyclic rhythmical bilateral arm coordination patterns can be classified into two fundamental modes: in-phase (bilateral homologous muscles contract simultaneously) and anti-phase (bilateral muscles contract alternately) movements. We aimed to investigate how patients with left (LHS) and right (RHS) hemispheric stroke are differentially affected in both individual-limb control and inter-limb coordination during bilateral movements. METHODS: We used kinematic measurements to assess bilateral coordination abilities of 18 chronic hemiparetic stroke patients (9 LHS; 9 RHS) and 18 age- and sex-matched controls. Using KINARM upper-limb exoskeleton system, we examined individual-limb control by quantifying trajectory variability in each hand and inter-limb coordination by computing the phase synchronization between hands during anti- and in-phase movements. RESULTS: RHS patients exhibited greater impairment in individual- and inter-limb control during anti-phase movements, whilst LHS patients showed greater impairment in individual-limb control during in-phase movements alone. However, LHS patients further showed a swap in hand dominance during in-phase movements. CONCLUSIONS: The current study used individual-limb and inter-limb kinematic profiles and showed that bilateral movements are differently impaired in patients with left vs. right hemispheric strokes. Our results demonstrate that both fundamental bilateral coordination modes are differently controlled in both hemispheres using a lesion model approach. From a clinical perspective, we suggest that lesion side should be taken into account for more individually targeted bilateral coordination training strategies. TRIAL REGISTRATION: the current experiment is not a health care intervention study.

Distributed networks for auditory memory differentially contribute to recall precision.

Re-directing attention to objects in working memory can enhance their representational fidelity. However, how this attentional enhancement of memory representations is implemented across distinct, sensory and cognitive-control brain network is unspecified. The present fMRI experiment leverages psychophysical modelling and multivariate auditory-pattern decoding as behavioral and neural proxies of mnemonic fidelity. Listeners performed an auditory syllable pitch-discrimination task and received retro-active cues to selectively attend to a to-be-probed syllable in memory. Accompanied by increased neural activation in fronto-parietal and cingulo-opercular networks, valid retro-cues yielded faster and more perceptually sensitive responses in recalling acoustic detail of memorized syllables. Information about the cued auditory object was decodable from hemodynamic response patterns in superior temporal sulcus (STS), fronto-parietal, and sensorimotor regions. However, among these regions retaining auditory memory objects, neural fidelity in the left STS and its enhancement through attention-to-memory best predicted individuals' gain in auditory memory recall precision. Our results demonstrate how functionally discrete brain regions differentially contribute to the attentional enhancement of memory representations.

Multimodal Assessment of the Motor System in Patients With Chronic Ischemic Stroke.

BACKGROUND AND PURPOSE: Despite continuing efforts in the multimodal assessment of the motor system after stroke, conclusive findings on the complementarity of functional and structural metrics of the ipsilesional corticospinal tract integrity and the role of the contralesional hemisphere are still lacking. This research aimed to find the best combination of motor system metrics, allowing the classification of patients into 3 predefined groups of upper limb motor recovery. METHODS: We enrolled 35 chronic ischemic stroke patients (mean 47 [26-66] years old, 29 [6-58] months poststroke) with a single supratentorial lesion and unilateral upper extremity weakness. Patients were divided into 3 groups, depending on upper limb motor recovery: good, moderate, and bad. Nonparametric statistical tests and regression analysis were used to investigate the relationships among microstructural (fractional anisotropy (FA) ratio of the corticospinal tracts at the internal capsule (IC) level (classic method) and along the length of the tracts (Fréchet distance), and of the corpus callosum) and functional (motor evoked potentials [MEPs] for 2 hand muscles) motor system metrics. Stratification rules were also tested using a decision tree classifier. RESULTS: IC FA ratio in the IC and MEP absence were both equally discriminative of the bad motor outcome (96% accuracy). For the 3 recovery groups' classification, the best parameter combination was IC FA ratio and the Fréchet distance between the contralesional and ipsilesional corticospinal tract FA profiles (91% accuracy). No other metrics had any additional value for patients' classification. MEP presence differed for 2 investigated muscles. CONCLUSIONS: This study demonstrates that better separation between 3 motor recovery groups may be achieved when considering the similarity between corticospinal tract FA profiles along its length in addition to region of interest-based assessment and lesion load calculation. Additionally, IC FA ratio and MEP absence are equally important markers for poor recovery, while for MEP probing it may be important to investigate more than one hand muscle.

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.

Semi-automated generation of individual computational models of the human head and torso from MR images.

PURPOSE: Simulating the interaction of the human body with electromagnetic fields is an active field of research. Individualized models are increasingly being used, as anatomical differences affect the simulation results. We introduce a processing pipeline for creating individual surface-based models of the human head and torso for application in simulation software based on unstructured grids. The pipeline is designed for easy applicability and is publicly released on figshare. METHODS: The pipeline covers image acquisition, segmentation, generation of segmentation masks, and surface mesh generation of the single, external boundary of each structure of interest. Two gradient-echo sequences are used for image acquisition. Structures of the head and body are segmented using several atlas-based approaches. They consist of bone/skull, subarachnoid cerebrospinal fluid, gray matter, white matter, spinal cord, lungs, the sinuses of the skull, and a combined class of all other structures including skin. After minor manual preparation, segmentation images are processed to segmentation masks, which are binarized images per segmented structure free of misclassified voxels and without an internal boundary. The proposed workflow is applied to 2 healthy subjects. RESULTS: Individual differences of the subjects are well represented. The models are proven to be suitable for simulation of the RF electromagnetic field distribution. CONCLUSION: Image segmentation, creation of segmentation masks, and surface mesh generation are highly automated. Manual interventions remain for preparing the segmentation images prior to segmentation mask generation. The generated surfaces exhibit a single boundary per structure and are suitable inputs for simulation software.

Dopaminergic modulation of hemodynamic signal variability and the functional connectome during cognitive performance.

Dopamine underlies important aspects of cognition, and has been suggested to boost cognitive performance. However, how dopamine modulates the large-scale cortical dynamics during cognitive performance has remained elusive. Using functional MRI during a working memory task in healthy young human listeners, we investigated the effect of levodopa (l-dopa) on two aspects of cortical dynamics, blood oxygen-level-dependent (BOLD) signal variability and the functional connectome of large-scale cortical networks. We here show that enhanced dopaminergic signaling modulates the two potentially interrelated aspects of large-scale cortical dynamics during cognitive performance, and the degree of these modulations is able to explain inter-individual differences in l-dopa-induced behavioral benefits. Relative to placebo, l-dopa increased BOLD signal variability in task-relevant temporal, inferior frontal, parietal and cingulate regions. On the connectome level, however, l-dopa diminished functional integration across temporal and cingulo-opercular regions. This hypo-integration was expressed as a reduction in network efficiency and modularity in more than two thirds of the participants and to different degrees. Hypo-integration co-occurred with relative hyper-connectivity in paracentral lobule and precuneus, as well as posterior putamen. Both, l-dopa-induced BOLD signal variability modulation and functional connectome modulations proved predictive of an individual's l-dopa-induced benefits in behavioral performance, namely response speed and perceptual sensitivity. Lastly, l-dopa-induced modulations of BOLD signal variability were correlated with l-dopa-induced modulation of nodal connectivity and network efficiency. Our findings underline the role of dopamine in maintaining the dynamic range of, and communication between, cortical systems, and their explanatory power for inter-individual differences in benefits from dopamine during cognitive performance.

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.

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.

Using carbogen for calibrated fMRI at 7Tesla: comparison of direct and modelled estimation of the M parameter.

Task-evoked changes in cerebral oxygen metabolism can be measured using calibrated functional Magnetic Resonance Imaging (fMRI). This technique requires the use of breathing manipulations such as hypercapnia, hyperoxia or a combination of both to determine a calibration factor M. The M-value is usually obtained by extrapolating the BOLD signal measured during the gas manipulation to its upper theoretical physiological limit using a biophysical model. However, a recently introduced technique uses a combination of increased inspired concentrations of O2 and CO2 to saturate the BOLD signal completely. In this study, we used this BOLD saturation technique to measure M directly at 7Tesla (T). Simultaneous carbogen-7 (7% CO2 in 93% O2) inhalation and visuo-motor task performance were used to elevate venous oxygen saturation in visual and motor areas close to their maximum, and the BOLD signal measured during this manipulation was used as an estimate of M. As accurate estimation of M is crucial for estimation of valid oxidative metabolism values, these directly estimated M-values were assessed and compared with M-values obtained via extrapolation modelling using the generalized calibration model (GCM) on the same dataset. Average M-values measured using both methods were 10.4±3.9% (modelled) and 7.5±2.2% (direct) for a visual-related ROI, and 11.3±5.2% (modelled) and 8.1±2.6% (direct) for a motor-related ROI. Results from this study suggest that, for the CO2 concentration used here, modelling is necessary for the accurate estimation of the M parameter. Neither gas inhalation alone, nor gas inhalation combined with a visuo-motor task, was sufficient to completely saturate venous blood in most subjects. Calibrated fMRI studies should therefore rely on existing models for gas inhalation-based calibration of the BOLD signal.

Regional reproducibility of calibrated BOLD functional MRI: implications for the study of cognition and plasticity.

Calibrated BOLD fMRI is a promising alternative to the classic BOLD contrast due to its reduced venous sensitivity and greater physiological specificity. The delayed adoption of this technique for cognitive studies may stem partly from a lack of information on the reproducibility of these measures in the context of cognitive tasks. In this study we have explored the applicability and reproducibility of a state-of-the-art calibrated BOLD technique using a complex functional task at 7 tesla. Reproducibility measures of BOLD, CBF, CMRO2 flow-metabolism coupling n and the calibration parameter M were compared and interpreted for three ROIs. We found an averaged intra-subject variation of CMRO2 of 8% across runs and 33% across days. BOLD (46% across runs, 36% across days), CBF (33% across runs, 46% across days) and M (41% across days) showed significantly higher intra-subject variability. Inter-subject variability was found to be high for all quantities, though CMRO2 was the most consistent across brain regions. The results of this study provide evidence that calibrated BOLD may be a viable alternative for longitudinal and cognitive MRI studies.

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.

The role of left temporo-parietal and inferior frontal cortex in comprehending syntactically complex sentences: A brain stimulation study.

BACKGROUND AND OBJECTIVES: Syntactic competence relies on a left-lateralized network converging on hubs in inferior-frontal and posterior-temporal cortices. We address the question whether anodal transcranial direct current stimulation (a-tDCS) over these hubs can modulate comprehension of sentences, whose syntactic complexity systematically varied along the factors embedding depths and canonicity. Semantic content and length of the sentences were kept identical and forced choice picture matching was required after the full sentence had been presented. METHODS: We used a single-blind, within-subject, sham-controlled design, applying a-tDCS targeting left posterior tempo-parietal (TP) and left inferior frontal cortex (FC). Stimulation sites were determined by individual neuro-navigation. 20 participants were included of whom 19 entered the analysis. Results were analysed using (generalized) mixed models. In a pilot-experiment in another group of 20 participants we validated the manipulation of syntactic complexity by the two factors embedding depth and argument-order. RESULTS: Reaction times increased and accuracy decreased with higher embedding depth and non-canonical argument order in both experiments. Notably a-tDCS over TP enhanced sentence-to-picture matching, while FC-stimulation showed no consistent effect. Moreover, the analysis disclosed a session effect, indicating improvements of task performance especially regarding speed. CONCLUSIONS: We conclude that the posterior 'hub' of the neuronal network affording syntactic analysis represents a 'bottleneck', likely due to working-memory capacity and the challenges of mapping semantic to syntactic information allowing for role assignment. While this does not challenge the role of left inferior-frontal cortex for syntax processing and novel-grammar learning, the application of highly established syntactic rules during sentence comprehension may be considered optimized, thus not augmentable by a-tDCS in the uncompromised network. SIGNIFICANCE STATEMENT: Anodal transcranial direct current stimulation (a-tDCS) over left temporo-parietal cortex enhances comprehension of complex sentences in uncompromised young speakers. Since a-tDCS over left frontal cortex did not elicit any change, the 'bottleneck' for the understanding of complex sentences seems to be the posterior, temporo-parietal rather than the anterior inferior-frontal 'hub' of language processing. Regarding the attested role of inferior-frontal cortex in syntax processing, we suggest that its function is optimized in competent young speakers, preventing further enhancement by (facilitatory) tDCS. Results shed light on the functional anatomy of syntax processing during sentence comprehension; moreover, they open perspectives for research in the lesioned language network of people with syntactic deficits due to aphasia.

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

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

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

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