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The ability to recognize and respond to actions performed by others is fundamental for a wide range of activities involving social interactions. However, despite an enormous number of functional imaging studies, a precise delineation of the brain regions crucial for distinct aspects of action recognition has remained elusive. Moreover, the degree of overlap between regions involved in active action performance is controversial. To elucidate these issues, 98 acute stroke patients (68 male, age mean ± SD, 65 ± 13 years) were examined in the acute period after stroke (mean ± SD 4.4 ± 2 days after symptom onset). First, action recognition was assessed with a newly designed test which required patients to distinguish between correctly and incorrectly performed tool-associated actions depicted in short videos. Errors categories comprised conceptual (e.g., spreading jam on toast with a paint brush), and spatio-temporal errors (orientation of the tool, hand configuration, and movement kinematics). Second, actual use of tools was probed using an established test which, in analogy to the error categories for action recognition, included separate measures for the ability to match tools and recipients (e.g., hammer – nail; conceptual score), and for the quality of the executed action (e.g., hammering; spatio-temporal score). Lesions were delineated on diffusion-weighted scans for voxel-based lesion-symptom mapping. Impaired recognition of conceptual errors was associated mainly with lesions to the anterior middle temporal gyrus as well as to the caudal middle frontal gyrus. Conversely, the detection of spatio-temporal errors depended on the posterior superior temporal gyrus and sulcus, inferior parietal lobule (IPL) and ventral premotor cortex (vPMC). Analyses for distinct spatio-temporal error subcategories revealed that superior temporal lesions specifically affected the recognition of kinematic and tool orientation errors, while inferior parietal and premotor damage selectively impaired the discrimination of hand configurations. Lastly, compared to the recognition of conceptual and spatio-temporal errors, both active tool-recipient matching and action execution, respectively, were more dependent on the IPL and vPMC; conversely, action recognition deficits were more strongly associated with occipito-temporal and superior temporal lesions. The results demonstrate that action recognition is enabled by a network of dissociable regions that are specialized for the processing of distinct action features. While the decoding of conceptual action aspects relies mainly on anterior temporal regions, IPL and vPMC mediate the recognition of hand configurations, and the posterior superior temporal lobe is crucial for the processing of movement kinematics and tool orientation. Our findings show that, with the exception of the hand configuration, action recognition does not rely on the fronto-parietal regions that subserve the performance of actual tool use.

Objective We examined 8 patients with hemihypesthesia due to an ischemic thalamic lesion to explore the effects of a central sensory dysfunction on motor cortex excitability. Methods Motor excitability was assessed using transcranial magnetic stimulation techniques and electrical peripheral nerve stimulation. Motor function was evaluated by the Nine-Hole-Peg Test and measurement of hand grip strength. The affected side was compared with the non-lesioned side and with an age-matched control group. Results Patients had a loss of inhibition and an increase of facilitation in the motor cortex of the affected side. The silent period was prolonged and motor function was impaired on the affected side. Conclusions A thalamic lesion can modulate motor cortical excitability. Significance This study suggests that, under normal conditions, somatosensory afferents influence inhibitory and excitatory properties in the motor cortex.

Objective : To explore whether patients with myopathy present changes in motoneuronal excitability. Methods : Patients with well-defined myopathies were studied with single and paired pulse transcranial magnetic stimulations and electrical nerve stimulations to explore neuronal motor excitability. Motor-evoked potentials were recorded from the clinically unaffected first dorsal interosseous muscle ( n =10) and the paretic deltoid muscle ( n =8). Results : Compared to an age-matched healthy control group, myopathic patients showed a reduction of intracortical inhibition, enhancements of α-motoneuron excitability and increased amplitudes of motor-evoked potentials during target muscle contraction. These alterations were present in clinically affected and clinically unaffected muscles. Conclusion : In myopathy, nervous system excitability may be altered, presenting as a motor disinhibition on cortical and subcortical levels.

Objectives : To explore subclinical disturbances in the motor cortex of patients with Alzheimer's disease (AD). Methods : We used transcranial magnetic stimulation in a paired pulse technique to test intracortical inhibition (ICI) and intracortical facilitation in mildly to moderately demented AD patients with a normal neurological examination. Patients were studied before and during treatment with the cholinesterase inhibitor donepezil. Results : AD patients had a reduced ICI compared to an age-matched control group. The amount of disinhibition correlated with the severity of dementia. Treatment with 10 mg donepezil daily was associated with an increase of ICI. Conclusions : The subclinical motor cortex disinhibition in AD patients indicates a functional disturbance, and is probably associated with a cholinergic deficit.

Objective : To study the effect of different types of unilateral pinch grips on excitability of the ipsilateral motor cortex. Methods : In 9 healthy volunteers, transcranial magnetic stimuli (TMS) were applied over one motor cortex while the subjects performed either phasic or tonic ipsilateral pinch grips with different force levels (range 1–40% maximum voluntary contraction, MVC). Motor evoked potentials (MEP) were recorded from the relaxed contralateral first dorsal interosseous muscle (FDI) and were compared to MEPs obtained during muscle relaxation of both hands. In additional experiments, transcranial electrical stimuli (TES) were administered and F waves were recorded after electrical stimulation of the ulnar nerve. Results : Phasic pinch grips with low force (1 and 2% MVC) induced a significant decrease of TMS-induced MEP amplitudes. The effect lasted for about 100 ms after reaching the force level and was similar for both right and left-handed pinch grips. TES-induced MEPs and F waves remained unchanged. In contrast, tonic contractions (20 and 40% MVC) enhanced MEPs in the homologous FDI. Conclusions : Phasic pinch grips with low force inhibit the motor cortex responsible for the contralateral homologous hand muscle. This effect, which is probably mediated transcallosally, might act at the level of the motor cortex.

Objectives : To test whether a disinhibition occurs in the human motor cortex after stroke. Methods : Patients with a mild to moderate hemiparesis after an acute unilateral ischemic stroke were compared with age-matched healthy controls. We used paired transcranial magnetic stimuli (TMS) to investigate intracortical inhibition and facilitation. Single TMS were applied to obtain a cortical silent period. Results : Intracortical inhibition was significantly reduced in the affected hemisphere at interstimulus intervals of 2, 3 and 4 ms. The cortical silent period was significantly prolonged when compared to the unaffected hemisphere of the patients and to the control group. Motor cortex disinhibition observed in stroke patients was associated either with minimal impairment at the onset of symptoms or with rapidly improving motor functions. Conclusions : Motor cortex disinhibition occurs in humans after stroke. We suggest that this disinhibition is indicative of compensatory mechanisms, which are involved in recovery-related reorganization.

Early diagnosis of different modalities in neglect after right hemisphere ischemic lesion and subsequent adequate therapy is crucial in regard to the clinical outcome (e.g. Buxbaum et al., 2004). Bed-side tests in the acute phase after stroke usually include only clinical examination and paper based cancellation tests (e.g. Ota search task, Bell‘s Cancellation). Additional testing such as recording of deficit in visual exploration by tracking of eye movements and standardized test for diagnosis of representational neglect have so far been only conducted in as non-bed-side tests in sub-acute or chronic stages (Isihai et al., 1989). The present study thus investigates the visual exploration during two different tasks in the acute phase of neglect, using a mobile eye-tracking device. Altogether, 31 acute stroke patients with right hemisphere lesion were included. Out of these, 28 could tolerate the eye-tracking device. The first task was a modified baking tray task in which the patients had to collect (first trial) and redistribute (second trial) 16 "cookies" equally on a tray (modified baking tray Task, Fig. 1a and b; Tham, 1996). For diagnosis of representational deficits a second task consisted of enlisting objects presented on a picture board (third trial, Fig. 2a) and to reproduce the named objects while focussing the white back of the board (fourth trial). The eye movements were tracked during all trials (Fig. 2b and c). Additionally, well-established clinical and paper-based evaluation was carried out. Behavioural results of the modified baking tray task confirm a neglect to the left during collection and redistribution of the cookies ( F =14.710, p F =10.458; p =.004). Enlisting of the objects on the picture board also confirmed a neglect to the left ( F =24.238; p F =48.438; p F =30.221; p Both bedside tests for diagnosis of neglect were proved to be applicable in the very acute phase after ischemic stroke: during collection of the cookies as well as naming and recalling of objects on the picture board, the left space was disregarded. We further demonstrate additional representational deficits in these patients that exceed the deficits in visual neglect. For redistribution of the cookies as well as naming the objects from memory – even though all cookies had been collected before and all objects named before - a stronger deficit to the left was found. Representation of the spatial setup thus seems to be even more biased during intrinsically motivated tasks. Tracking of the visual exploration additionally helped to objectify these results and showed to be, at least partly, applicably in acute bed-side tests. Since the diagnosis of the modality of representational deficits has so far not been investigated in the very acute stage of stroke, only little is known about its development and impact on rehabilitation. Further studies will be necessary on this topic.

Background Meaningful gestures are one of the key features of social interaction and comprise both object-associated transitive movements (e.g. hammering) as well as intransitive movements referring to a communicative content (e.g. waving goodbye). The ability to imitate meaningful gestures is frequently impaired in apraxia due to left-hemispheric stroke. However, the pathophysiology behind these deficits so far remained unresolved. A dual stream-model for a dichotomized organisation of higher cognitive functions such as language or praxis has been proposed, with a dorsal stream involved in sensorimotor processing and a ventral stream for content and imagery. Aim of the study was to elucidate the role of the dual stream-model in imitation of meaningful movements using voxel-based lesion-symptom mapping (VLSM). Methods We performed VLSM in a sample of 136 left-hemispheric stroke patients (mean age ± SD 65 years ± 15, 83 male). Neuropsychological testing and MR-imaging were carried out in the acute phase after ischemic stroke (5.1 ± 1.9 days after symptom onset) to avoid interference with brain reorganization. Imitation deficits were assessed with a block of ten object-related movements and a block of ten communicative gestures presented by the examiner, patients were instructed to imitate the movement. Lesions were mapped on the diffusion-weighted image (if not available on Flair- image), statistical analysis with Brunner–Munzel Test was performed using non-parametric statistics implemented in MRIcron. Results Deficits in both, imitation of transitive and intransitive movements were associated with lesions in areas of the dorsal stream involved in motor control and action representations, such as the inferior parietal lobule, and the supramarginal gyrus. In addition to these common areas, deficits in imitation of intransitive movements showed a specific association with the superior and middle temporal lobe, whereas deficient transitive movements were also related to lesions within the ventral premotor cortex without involvement of temporal structures. Conclusion Deficits affecting imitation of transitive and intransitive gestures result from different and characteristic neuroanatomical lesion patterns. Our data suggest that imitation of transitive gestures depicting common tool-associated actions mainly involves stored motor programs and, thus, is mainly based on the dorsal stream. Conversely, imitation of intransitive communicative gestures additionally relies on the ventral stream, probably due to the higher semantic content, given the often symbolic character of intransitive gestures.

Background Apraxia, a disorder of higher motor control, frequently leads to impaired tool use or imitation capacities due to left hemispheric lesions. However, despite similar lesion size or location, patients present with different apraxic deficits thus different early reorganization mechanism may be assumed. To understand the impaired praxis network after stroke on a functional level, we correlated behavioral performance in imitation and tool use tasks with activation patterns in fMRI of 47 acute left-hemispheric stroke patients. Methods A cohort of 47 acute stroke patients (mean age 63.5 years ± SD 13.6; 13 female) with first ever embolic stroke in the left arteria cerebri media territory were tested for deficits in imitation of meaningless hand and finger postures and tool associated actions (pantomime of tool use, imitation of tool use, actual tool use). Testing was performed mean 4.8 days ± SD 2.9 post stroke. FMRI was acquired during presentation of video sequences of tool-associated actions viewed from a first-person perspective. Voxel wise linear regression analyses for task scores only and with lesion volume as covariate as well as group differences for categorized behavioral performance (deficit vs. no deficit) were calculated to analyze activity associated with behavioral performance in tool use and meaningless imitation. Analyses were performed using GLMflex. Results are presented on a p Results Intact imitation of meaningless postures was associated with activation in the left middle occipital gyrus as well as in the left superior temporal lobe in linear regression analyses and categorical group differences (deficit vs. no deficit). Tool associated tasks correlated with activation in the left supramarginal gyrus and superior temporal lobe without occipital activation. For group differences in pantomime of tool use (deficit vs. no deficit) an additional activation for patients with low behavioral performance could be found in the posterior middle temporal gyrus. Conclusion For intact imitation of meaningless postures and tool associated actions, specific left hemispheric activation patterns in the acute phase after stroke could be determined. These areas are commonly associated to the left hemispheric praxis network. While intact imitation of meaningless gestures seems to rely on intact left middle occipital gyrus for visual analysis of the presented movement tool associated actions rather seem to rely on integrity of the supramarginal gyrus, known to store movement engrams. Patients with deficits in pantomime of tool use additionally show activation of posterior middle temporal gyrus for semantic movement information. These mechanisms possibly can be interpreted as early compensatory effort.

Introduction Anodal transcranial direct-current stimulation (tDCS) has been shown to modulate cortical excitability and to improve motor learning (Nitsche and Paulus, 2000; Reis et al., 2009). The human studies on tDCS generally use low stimulation intensities-approximately 0.4–0.8A/m 2 -to ensure safe levels. However, the dose–response relationship of tDCS on functional measures of cortical excitability and possible adverse effects of tDCS have not yet been investigated. Objective In this in vivo animal model of tDCS dose-dependent effects of anodal tDCS on cortical excitability were investigated and safety limits for safe application were determined. Methods Adult male Sprague–Dawley rats were equipped with electrodes for tDCS stimulation at the left primary motor cortex and the chest region. Furthermore, EEG electrodes were surgically placed above the somatosensory cortices and the cerebellum (grounding electrode). In separate sessions, the rats were then exposed to anodal tDCS of different intensities (between 2 and 31.8A/m 2 ) for 20min. EEG and sensory evoked potentials were continuously recorded prior to, during and after tDCS, in freely moving (EEG) or anaesthetised (SEP) animals. Results EEG data clearly showed that low stimulation intensities did not affect EEG patterns. Mild EEG alterations-showing more spiky waves and increased amplitudes-were present at the lowest stimulation intensity of 2A/m 2 , while at an intensity of 31.8A/m 2 EEG seizure patterns were observed, also associated with clinical seizures (facial twitch, head nodding, i.e. stage 1–2 on the Racine seizure scale). The calculated threshold (ED1, effective dose 1%) for first occurrence of EEG alterations was 1.35A/m 2 , the ED50 was estimated at 9.2A/m 2 . SEP data are currently under investigation. Conclusions Since only a high stimulation intensity, approximately 40 times higher than that applied to humans, was found to cause seizures, the stimulation intensities applied in human studies are unlikely to be harmful. This suggests that higher stimulation intensities could be applied in human studies, thereby possibly further improving plasticity, i.e. learning, without putting the brain at risk.

Introduction Transcranial electrical stimulation (TES) has been shown to enhance motor learning. Several stimulation protocols are known to be effective, but have not yet been directly compared for practical motor learning. Question Electrode placement and stimulation parameters were varied on a realistic motor task to allow a direct comparison of their efficacy to enhance complex motor skill learning. Methods A novel, complex, continuous motor task was developed for the study: the tracing task. Participants traced over a series of template words and shapes on a graphics tablet with their nondominant (left) hand in a manner similar to handwriting while performance was evaluated by calculating how close the trace was to the template. The experiment took place over three days in order to measure both online and offline learning effects. Electrode montages and stimulation parameters varied as follows: transcranial direct current stimulation (tDCS) with anodal stimulation over the contralateral motor cortex and cathodal stimulation over either the ipsilateral motor cortex or ipsilateral supraorbital area; high frequency (100–640 Hz) transcranial random noise stimulation (tRNS) over the supraorbital area and the contralateral motor cortex. These were compared with sham stimulation and tRNS of the supraorbital area and posterior temporal lobe (T6 of 10–20 system) as a reference active stimulation region. TES was applied for 20 min with a current density of 60 μ A/cm2 for tDCS and tRNS. Results TES of all types applied over the motor cortex improved motor skill acquisition over 2 days of training and a follow up compared to sham stimulation. In all groups, this effect was driven by large online effects within sessions, which developed faster in the tDCS groups compared to the tRNS group. In the active control experiment for region specificity (posterior temporal tRNS) tRNS was less effective and altered subcomponents of learning differently (offline stabilization). Conclusions TES is effective at improving motor learning with motor cortex stimulation. tRNS is as effective as tDCS, and may be preferable as nonpolarised currents appear safer (demonstrated in deep brain stimulation) and do not have cathodal inhibition effects.

Introduction Transcranial direct current stimulation (tDCS) has been shown to modulate cortical excitability and to improve motor learning (Nitsche and Paulus, 2000; Reis et al., 2009; Fritsch et al., 2010). To date there is no data available on the safety aspects of tDCS covering a broad range of stimulation intensities, thus limitations for dosages applied to humans are still based empirically on other types of electrical brain stimulation (Agnew and McCreery, 1987). Objectives The aim of this study was to investigate lesion threshold, accompanying neurodegeneration and possible microstructural changes in glial cells in an animal model of tDCS. Methods The tDCS electrode was placed in a screw tube surgically fixed on the skull above the left primary motor cortex of 47 Male Sprague Dawley rats. Anodal tDCS was applied in different intensities (254.8, 127.4, 63.7, 31.8, 15.9 and 8A/sqm) or as sham stimulation for 20min under slight isoflurane anesthesia. For each intensity animals were sacrificed either 24h (acute effects) or 7days (chronic effects) after intervention. Histological analyses of neurodegeneration (HE-staining, Fluoro-Jade C), astrocyte (anti-GFAP) and microglial (anti-CD11b [OX-42]) cell counts/density and/or morphological changes were evaluated. Results Macroscopical lesions could be observed at tDCS intensity of 127A/sqm and above whereas the lesion dose 50 (LD 50) for microscopical neurodegeneration was determined at 60A/sqm. Threshold for damage in neuronal and glial cells and change in morphology (activation) was identical. These changes could be detected both in the acute and chronic group. Notably, signs of still ongoing neurodegeneration, though to a slighter extent, were seen 7days after stimulation. Brain swelling, which was seen underneath the stimulation electrode 24h following the highest intensity used, was not present one week after stimulation. Conclusions Our results demonstrate that the LD 50 intensity of anodal tDCS for unwanted structural effects is 75 times higher than the intensities applied to humans to date. Additional safety derives from the fact that structures between brain and stimulation electrode, which lead to energy absorbtion, are thicker in humans compared to rats. Cell death, as a trigger for glial reaction, continues even 7days after the intervention. Based on our results we conclude that higher tDCS intensities in human studies can be applied without risking structural damage.