tDCS over the motor cortex improves lexical retrieval of action words in poststroke aphasia.

One-third of stroke survivors worldwide suffer from aphasia. Speech and language therapy (SLT) is considered effective in treating aphasia, but because of time constraints, improvements are often limited. Noninvasive brain stimulation is a promising adjuvant strategy to facilitate SLT. However, stroke might render "classical" language regions ineffective as stimulation sites. Recent work showed the effectiveness of motor cortex stimulation together with intensive naming therapy to improve outcomes in aphasia (Meinzer et al. 2016). Although that study highlights the involvement of the motor cortex, the functional aspects by which it influences language remain unclear. In the present study, we focus on the role of motor cortex in language, investigating its functional involvement in access to specific lexico-semantic (object vs. action relatedness) information in poststroke aphasia. To this end, we tested effects of anodal transcranial direct current stimulation (tDCS) to the left motor cortex on lexical retrieval in 16 patients with poststroke aphasia in a sham-controlled, double-blind study design. Critical stimuli were action and object words, and pseudowords. Participants performed a lexical decision task, deciding whether stimuli were words or pseudowords. Anodal tDCS improved accuracy in lexical decision, especially for words with action-related content and for pseudowords with an "action-like" ending ( t15 = 2.65, P = 0.036), but not for words with object-related content and pseudowords with "object-like" characteristics. We show as a proof-of-principle that the motor cortex may play a specific role in access to lexico-semantic content. Thus motor-cortex stimulation may strengthen content-specific word-to-semantic concept associations during language treatment in poststroke aphasia. NEW & NOTEWORTHY The role of motor cortex (MC) in language processing has been debated in both health and disease. Recent work has suggested that MC stimulation together with speech and language therapy enhances outcomes in aphasia. We show that MC stimulation has a differential effect on object- and action-word processing in poststroke aphasia. We propose that MC stimulation may specifically strengthen word-to-semantic concept association in aphasia. Our results potentially provide a way to tailor therapies for language rehabilitation.

tDCS Over the Motor Cortex Shows Differential Effects on Action and Object Words in Associative Word Learning in Healthy Aging.

Healthy aging is accompanied by a continuous decline in cognitive functions. For example, the ability to learn languages decreases with age, while the neurobiological underpinnings for the decline in learning abilities are not known exactly. Transcranial direct current stimulation (tDCS), in combination with appropriate experimental paradigms, is a well-established technique to investigate the mechanisms of learning. Based on previous results in young adults, we tested the suitability of an associative learning paradigm for the acquisition of action- and object-related words in a cohort of older participants. We applied tDCS to the motor cortex (MC) and hypothesized an involvement of the MC in learning action-related words. To test this, a cohort of 18 healthy, older participants (mean age 71) engaged in a computer-assisted associative word-learning paradigm, while tDCS stimulation (anodal, cathodal, sham) was applied to the left MC. Participants' task performance was quantified in a randomized, cross-over experimental design. Participants successfully learned novel words, correctly translating 39.22% of the words after 1 h of training under sham stimulation. Task performance correlated with scores for declarative verbal learning and logical reasoning. Overall, tDCS did not influence associative word learning, but a specific influence was observed of cathodal tDCS on learning of action-related words during the NMDA-dependent stimulation period. Successful learning of a novel lexicon with associative learning in older participants can only be achieved when the learning procedure is changed in several aspects, relative to young subjects. Learning success showed large inter-individual variance which was dependent on non-linguistic as well as linguistic cognitive functions. Intriguingly, cathodal tDCS influenced the acquisition of action-related words in the NMDA-dependent stimulation period. However, the effect was not specific for the associative learning principle, suggesting more neurobiological fragility of learning in healthy aging compared with young persons.

White matter integrity of premotor-motor connections is associated with motor output in chronic stroke patients.

Corticocortical functional interactions between the primary motor cortex (M1) and secondary motor areas, such as the dorsal (PMd) and ventral (PMv) premotor cortices and the supplementary motor area (SMA) are relevant for residual motor output after subcortical stroke. We hypothesized that the microstructural integrity of the underlying white matter tracts also plays a role in preserved motor output. Using diffusion-tensor imaging we aimed at (i) reconstructing individual probable intrahemispheric connections between M1 and the three secondary areas (PMd, PMv, SMA) and (ii) examining the extent to which the tract-related microstructural integrity correlates with residual motor output. The microstructural integrity of the tract connecting ipsilesional M1 and PMd was significantly associated with motor output (R = 0.78, P = 0.02). The present results support the view that ipsilesional secondary motor areas such as the PMd might support M1 via corticocortical connections to generate motor output after stroke.

EEG oscillatory phase-dependent markers of corticospinal excitability in the resting brain.

Functional meaning of oscillatory brain activity in various frequency bands in the human electroencephalogram (EEG) is increasingly researched. While most research focuses on event-related changes of brain activity in response to external events there is also increasing interest in internal brain states influencing information processing. Several studies suggest amplitude changes of EEG oscillatory activity selectively influencing cortical excitability, and more recently it was shown that phase of EEG activity (instantaneous phase) conveys additional meaning. Here we review this field with many conflicting findings and further investigate whether corticospinal excitability in the resting brain is dependent on a specific spontaneously occurring brain state reflected by amplitude and instantaneous phase of EEG oscillations. We applied single pulse transcranial magnetic stimulation (TMS) over the left sensorimotor cortex, while simultaneously recording ongoing oscillatory activity with EEG. Results indicate that brain oscillations reflect rapid, spontaneous fluctuations of cortical excitability. Instantaneous phase but not amplitude of oscillations at various frequency bands at stimulation site at the time of TMS-pulse is indicative for brain states associated with different levels of excitability (defined by size of the elicited motor evoked potential). These results are further evidence that ongoing brain oscillations directly influence neural excitability which puts further emphasis on their role in orchestrating neuronal firing in the brain.

Differential behavioral and physiological effects of anodal transcranial direct current stimulation in healthy adults of younger and older age.

Changes in γ-aminobutyric acid (GABA) mediated synaptic transmission have been associated with age-related motor and cognitive functional decline. Since anodal transcranial direct current stimulation (atDCS) has been suggested to target cortical GABAergic inhibitory interneurons, its potential for the treatment of deficient inhibitory activity and functional decline is being increasingly discussed. Therefore, after-effects of a single session of atDCS on resting-state and event-related short-interval intracortical inhibition (SICI) as evaluated with double-pulse TMS and dexterous manual performance were examined using a sham-controlled cross-over design in a sample of older and younger participants. The atDCS effect on resting-state inhibition differed in direction, magnitude, and timing, i.e., late relative release of inhibition in the younger and early relative increase in inhibition in the older. More pronounced release of event-related inhibition after atDCS was exclusively seen in the older. Event-related modulation of inhibition prior to stimulation predicted the magnitude of atDCS-induced effects on resting-state inhibition. Specifically, older participants with high modulatory capacity showed a disinhibitory effect comparable to the younger. Beneficial effects on behavior were mainly seen in the older and in tasks requiring higher dexterity, no clear association with physiological changes was found. Differential effects of atDCS on SICI, discussed to reflect GABAergic inhibition at the level of the primary motor cortex, might be distinct in older and younger participants depending on the functional integrity of the underlying neural network. Older participants with preserved modulatory capacity, i.e., a physiologically "young" motor network, were more likely to show a disinhibitory effect of atDCS. These results favor individually tailored application of tDCS with respect to specific target groups.

Development of movement-related intracortical inhibition in acute to chronic subcortical stroke.

OBJECTIVE: A prospective longitudinal cohort study in stroke patients was performed to better understand the role of γ-aminobutyric acid-dependent intracortical inhibition (ICI) for recovery after stroke. METHODS: Patients with acute first-ever subcortical stroke and hand paresis were recruited, and motor function as well as ICI were measured up to 1 year after stroke. Motor recovery was defined as the change in hand motor function from the acute to the chronic stage (Δ = recovery over 1 year). Primary outcome measures for hand motor function were the recovery of grip strength (ΔGS) and finger-tapping speed (ΔFT). Using double-pulse transcranial magnetic stimulation, we studied ICI in the ipsilesional primary motor cortex during the preparation of a movement with the paretic hand at different time points during recovery (first week, 7 weeks, 3 months, and 1 year after stroke). RESULTS: Eleven patients were enrolled (mean age 62.9 ± 3.8 years). The results of a multiple regression analysis showed a significant association of movement-related ICI in the acute stage only (first week) with motor recovery over 1 year (ΔGS: R(2) = 0.75, F = 17.6, p = 0.006; ΔFT: R(2) = 0.55, F = 7.3, p = 0.035). More disinhibition of ICI in the acute phase of stroke predicted more improvement in ΔGS (ß = -0.86, p = 0.006) and ΔFT (ß = -0.74, p = 0.035), independent of the initial motor deficit. CONCLUSIONS: Movement-related ICI one week after a subcortical stroke is associated with better outcome of hand motor function. Disinhibition in the ipsilesional primary motor cortex could be a mechanism of how the brain attempts to promote motor recovery after stroke.

A clinical and neurobiological case of IgM NMDA receptor antibody associated encephalitis mimicking bipolar disorder.

Autoimmune encephalitis associated with IgG antibodies to the N-methyl-d-aspartic acid receptor subunit NR1 (NMDAR) presents with neurological symptoms, such as seizures, and especially psychiatric symptoms, such as hallucinations, psychosis, agitation and anxiety. To date, however, the pathological relevance of IgM NMDAR antibodies remains elusive. Here, we describe clinical, neuroradiological and neurobiological findings of a 28-year-old male presenting with IgM NMDAR antibodies coincident with autoimmune encephalitis characterized by symptoms of bipolar disorder. After repeated steroid treatment, cognitive and psychiatric abnormalities improved and no NMDAR antibody was detectable. Using primary neuronal cultures, we demonstrate that patient's serum containing IgM NMDAR antibodies reduced the detection of NMDAR on neuronal cells and decreased cell survival. Although NMDAR encephalitis with IgG antibodies is increasingly recognized and diagnosed, atypical presentations with NMDAR antibodies with immunoglobulin subclasses other than IgG pose a diagnostic and therapeutic challenge. Further clinical and neurobiological studies are needed to study the pathophysiological relevance of IgM NMDAR antibodies.

Associative vocabulary learning: development and testing of two paradigms for the (re-) acquisition of action- and object-related words.

Despite a growing number of studies, the neurophysiology of adult vocabulary acquisition is still poorly understood. One reason is that paradigms that can easily be combined with neuroscientfic methods are rare. Here, we tested the efficiency of two paradigms for vocabulary (re-) acquisition, and compared the learning of novel words for actions and objects. Cortical networks involved in adult native-language word processing are widespread, with differences postulated between words for objects and actions. Words and what they stand for are supposed to be grounded in perceptual and sensorimotor brain circuits depending on their meaning. If there are specific brain representations for different word categories, we hypothesized behavioural differences in the learning of action-related and object-related words. Paradigm A, with the learning of novel words for body-related actions spread out over a number of days, revealed fast learning of these new action words, and stable retention up to 4 weeks after training. The single-session Paradigm B employed objects and actions. Performance during acquisition did not differ between action-related and object-related words (time*word category: p = 0.01), but the translation rate was clearly better for object-related (79%) than for action-related words (53%, p = 0.002). Both paradigms yielded robust associative learning of novel action-related words, as previously demonstrated for object-related words. Translation success differed for action- and object-related words, which may indicate different neural mechanisms. The paradigms tested here are well suited to investigate such differences with neuroscientific means. Given the stable retention and minimal requirements for conscious effort, these learning paradigms are promising for vocabulary re-learning in brain-lesioned people. In combination with neuroimaging, neuro-stimulation or pharmacological intervention, they may well advance the understanding of language learning to optimize therapeutic strategies.

Convergence of human brain mapping tools: neuronavigated TMS parameters and fMRI activity in the hand motor area.

Functional magnetic resonance imaging (fMRI) and transcranial magnetic stimulation (TMS) are well-established tools for investigating the human motor system in-vivo. We here studied the relationship between movement-related fMRI signal changes in the primary motor cortex (M1) and electrophysiological properties of the hand motor area assessed with neuronavigated TMS in 17 healthy subjects. The voxel showing the highest task-related BOLD response in the left hand motor area during right hand movements was identified for each individual subject. This fMRI peak voxel in M1 served as spatial target for coil positioning during neuronavigated TMS. We performed correlation analyses between TMS parameters, BOLD signal estimates and effective connectivity parameters of M1 assessed with dynamic causal modeling (DCM). The results showed a negative correlation between the movement-related BOLD signal in left M1 and resting as well as active motor threshold (MT) obtained for left M1. The DCM analysis revealed that higher excitability of left M1 was associated with a stronger coupling between left supplementary motor area (SMA) and M1. Furthermore, BOLD activity in left M1 correlated with ipsilateral silent period (ISP), i.e. the stronger the task-related BOLD response in left M1, the higher interhemispheric inhibition effects targeting right M1. DCM analyses revealed a positive correlation between the coupling of left SMA with left M1 and the duration of ISP. The data show that TMS parameters assessed for the hand area of M1 do not only reflect the intrinsic properties at the stimulation site but also interactions with remote areas in the human motor system.

Coordination of uncoupled bimanual movements by strictly timed interhemispheric connectivity.

Independent use of both hands is characteristic of human action in daily life. By nature, however, in-phase bimanual movements, for example clapping, are easier to accomplish than anti-phase movements, for example playing the piano. It is commonly agreed that interhemispheric interactions play a central role in the coordination of bimanual movements. However, the spatial, temporal, and physiological properties of the interhemispheric signals that coordinate different modes of bimanual movements are still not completely understood. More precisely, do individual interhemispheric connectivity parameters have behavioral relevance for bimanual rapid anti-phase coordination? To address this question, we measured movement-related interhemispheric interactions, i.e., inhibition and facilitation, and correlated them with the performance during bimanual coordination. We found that movement-related facilitation from right premotor to left primary motor cortex (rPMd-lM1) predicted performance in anti-phase bimanual movements. It is of note that only fast facilitation during the preparatory period of a movement was associated with success in anti-phase movements. Modulation of right to left primary motor interaction (rM1-lM1) was not related to anti-phase but predicted bimanual in-phase and unimanual behavior. These data suggest that strictly timed modulation of interhemispheric rPMd-lM1 connectivity is essential for independent high-frequency use of both hands. The rM1-lM1 results indicate that adjustment of connectivity between homologous M1 may be important for the regulation of homologous muscle synergies.

The involvement of the left motor cortex in learning of a novel action word lexicon.

Current theoretical positions assume that action-related word meanings are established by functional connections between perisylvian language areas and the motor cortex (MC) according to Hebb's associative learning principle. To test this assumption, we probed the functional relevance of the left MC for learning of a novel action word vocabulary by disturbing neural plasticity in the MC with transcranial direct current stimulation (tDCS). In combination with tDCS, subjects learned a novel vocabulary of 76 concrete, body-related actions by means of an associative learning paradigm. Compared with a control condition with "sham" stimulation, cathodal tDCS reduced success rates in vocabulary acquisition, as shown by tests of novel action word translation into the native language. The analysis of learning behavior revealed a specific effect of cathodal tDCS on the ability to associatively couple actions with novel words. In contrast, we did not find these effects in control experiments, when tDCS was applied to the prefrontal cortex or when subjects learned object-related words. The present study lends direct evidence to the proposition that the left MC is causally involved in the acquisition of novel action-related words.

Distinct temporospatial interhemispheric interactions in the human primary and premotor cortex during movement preparation.

The preparation of a voluntary unimanual action requires sequential processing in bihemispheric motor areas. In both animals and humans, activity in the dorsal premotor cortex (PMd) ipsilateral to the moving hand has been demonstrated to precede ipsilateral primary motor cortex (M1) activity. We investigated with double-pulse transcranial magnetic stimulation how right-hemispheric motor areas (rM1, rPMd) modulate left M1 (lM1) during the preparatory period of a finger movement with the dominant right hand. We tested the hypothesis that the influence of higher order motor areas such as rPMd on lM1 (rPMd-lM1) precedes interhemispheric interactions between homologue primary motor areas (rM1-lM1). rPMd-lM1 showed modulation in the early and late phase of movement preparation, whereas the intrinsic state of inhibition between rM1-lM1 was only modulated in the late phase. The present results complement existing hierarchical models of cortical movement control by demonstrating temporospatially distinct involvement of interhemispheric interactions from PMd and M1 during movement preparation.

Structural correlates of functional language dominance: a voxel-based morphometry study.

BACKGROUND AND PURPOSE: The goal of this study was to explore the structural correlates of functional language dominance by directly comparing the brain morphology of healthy subjects with left- and right-hemisphere language dominance. METHODS: Twenty participants were selected based on their language dominance from a cohort of subjects with known language lateralization. Structural differences between both groups were assessed by voxel-based morphometry, a technique that automatically identifies differences in the local gray matter volume between groups using high-resolution T1-weighted magnetic resonance images. RESULTS: The main findings can be summarized as follows: (1) Subjects with right-hemisphere language dominance had significantly larger gray matter volume in the right hippocampus than subjects with left-hemisphere language dominance. (2) Leftward structural asymmetries in the posterior superior temporal cortex, including the planum temporale (PT), were observed in both groups. CONCLUSIONS: Our study does not support the still prevalent view that asymmetries of the PT are related in a direct way to functional language lateralization. The structural differences found in the hippocampus underline the importance of the medial temporal lobe in the neural language network. They are discussed in the context of recent findings attributing a critical role of the hippocampus in the development of language lateralization.

Walking the talk--speech activates the leg motor cortex.

Speech may have evolved from earlier modes of communication based on gestures. Consistent with such a motor theory of speech, cortical orofacial and hand motor areas are activated by both speech production and speech perception. However, the extent of speech-related activation of the motor cortex remains unclear. Therefore, we examined if reading and listening to continuous prose also activates non-brachiofacial motor representations like the leg motor cortex. We found corticospinal excitability of bilateral leg muscle representations to be enhanced by speech production and silent reading. Control experiments showed that speech production yielded stronger facilitation of the leg motor system than non-verbal tongue-mouth mobilization and silent reading more than a visuo-attentional task thus indicating speech-specificity of the effect. In the frame of the motor theory of speech this finding suggests that the system of gestural communication, from which speech may have evolved, is not confined to the hand but includes gestural movements of other body parts as well.

Plastic changes in the human H-reflex pathway at rest following skillful cycling training.

OBJECTIVE: The spinal cord is capable of activity-dependent plasticity, but the extent of its participation in human motor learning is not known. Here, we tested the hypothesis that acquisition of a locomotor-related skill modulates the pathway of the H-reflex, a measure of spinal cord excitability that is susceptible to plastic changes. METHODS: Subjects were tested on their ability to establish a constant cycling speed on a recumbent bike despite frequent changes in pedal resistance. The coefficient of variation of speed (CV(speed)) measured their ability to acquire this skill (decreasing CV(speed) with training reflects performance improvements). Soleus H-reflexes were taken at rest before and after cycling. RESULTS: Ability to establish a target speed increased and H-reflex size decreased more after cycling training involving frequent changes in pedal resistance that required calibrated locomotor compensatory action than with training involving constant pedal resistances and lesser compensation. The degree of performance improvement correlated with the reduction in the amplitude of the H-reflex. CONCLUSIONS: Skillful establishment of a constant cycling speed despite changing pedal resistances is associated with persistent modulation of activity in spinal pathways. SIGNIFICANCE: Recalibration of activity in the H-reflex pathway may be part of the control strategy required for locomotor-related skill acquisition.

Modulation of H-reflex excitability by tetanic stimulation.

OBJECTIVE: This study investigated a strategy to elicit reversible facilitation of the soleus monosynaptic H-reflex in humans using a modified tetanic stimulation technique. METHODS: Interventional tetanic stimulation (ITS) was applied to the tibial nerve in the popliteal fossa, and soleus H-reflexes were recorded before and after stimulation in 15 healthy volunteers. RESULTS: ITS resulted in significantly increased soleus H-reflex amplitudes that outlasted the stimulation period by approximately 16 min. The effect of ITS on soleus motor evoked potentials to transcranial magnetic stimulation and on somatosensory evoked potentials to tibial nerve stimulation was also investigated; no significant changes were found. CONCLUSIONS: ITS produced a reversible increase in H-reflexes in the absence of changes in motor evoked potential or somatosensory evoked potential that outlasted the intervention period for up to 16 min. SIGNIFICANCE: This technique may be used in future studies to investigate whether the induced increased H-reflex excitability influences locomotion.