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ZusammenfassungDie überwiegende Anzahl bisheriger Studien zu Apraxien fokussiert die Rolle der linken Hemisphäre (LH), obwohl im klinischen Alltag apraktische Defizite auch bei Patienten mit rechtshemisphärischen Schlaganfällen (RH) beobachtet werden. Daher wurden in der aktuellen Untersuchung die Prävalenz und Ausprägung apraktischer Defizite bei Patienten mit linkshemisphärischen (n = 66) und rechtshemisphärischen (n = 73) Schlaganfällen verglichen, nachdem für Alter und sprachliche Leistung kontrolliert worden war.Unter Anwendung dieser Kontrollvariablen ergab sich kein signifikanter Unterschied zwischen den linkshemisphärisch und rechtshemisphärisch betroffenen Patienten bei der Imitation von Handpositionen. Übereinstimmend mit früheren Berichten schnitten die Patienten mit rechtshemisphärischen Schlaganfällen aber bei der Imitation der Fingerkonstellationen schlechter ab. Interessanterweise zeigten die rechtshemisphärisch betroffenen Patienten auch geringere Leistungen bei den bukkofazialen Items des Kölner Apraxie Screenings (KAS), vornehmlich bei Gesten der oberen Gesichtshälfte. Für beide Patientengruppen wirkten sich sprachliche Auffälligkeiten mehr auf die Pantomime- als auf die Imitationsleistungen beeinträchtigend aus.Die Ergebnisse legen nahe, dass nach der Kontrolle für Alter und sprachliche Leistungen die Prävalenz und Ausprägung apraktischer Defizite bei Patienten mit rechts- und linkshemisphärischen Schlaganfällen nicht signifikant unterschiedlich sind und in den jeweiligen Rehabilitationsprogrammen entsprechend berücksichtigt werden sollten.

Introduction. Transcranial direct current stimulation (tDCS) non-invasively modulates cortical function. We and others reported that tDCS could promote recovery after stroke (Braun et al., Exp. Neurol., 2016; Hummel et al., Brain, 2005). As a stroke affects entire networks, an aspect long neglected in translational research, we recently established a resting-state functional magnetic resonance imaging (rs-fMRI) protocol to detect similar network alterations in both rodent and human stroke (Blaschke et al., under review). We here investigated whether rs-fMRI can validate the efficacy of tDCS in altering functional connectivity after experimental stroke. Methods. Focal cortical stroke was induced via photothrombosis in male C57Bl/6J mice. Three days thereafter, cathodal tDCS over the lesioned sensory-motor cortex was applied for 15 minutes each day for ten days (charge density of 39600 C/m2). Longitudinal assessment of functional connectivity as measured by rs-fMRI was performed for up to 28 days post-stroke using a 9.4 T Bruker small animal scanner. Images were registered to the Allen Mouse Brain Atlas to derive seed regions for graph-based analysis and global graph parameters of network integration (characteristic path length, CPL) and segregation (clustering coefficient, CC) were computed over a sparse density range (10 – 30 % density), mimicking the brains“ functional structure. Additionally, a multiple linear regression was fitted to predict motor recovery based on initial network alteration, initial motor deficit, and tDCS treatment on motor recovery. Results. Ischemia induced an increase in connectivity. Already detectable three days after stroke, effects peaked at day 14, and spontaneously declined by day 28. Moreover, there was a significant reduction in characteristic path length (CPL) 14 days after stroke (p Conclusion. Stroke induces characteristic network changes that can be detected by rs-fMRI. Importantly, these network changes can, at least in part, be reversed by tDCS. Besides, the data suggest that early markers of network impairment improve the prediction of motor recovery. Overall, the data suggest that the characterization of functional connectivity by rs-fMRI is a powerful tool to analyze global changes after experimental stroke and to assess the therapeutic effects of non-invasive brain stimulation in preclinical studies.

Das Kolner Apraxie-Screening (KAS) erfasst apraktische Defizite nach linkshemispharischen Schlaganfallen. Ziel dieser Studie ist es, durch Anpassungen des Testmaterials des KAS und psychometrische Analysen ein diagnostisches Verfahren fur Patienten mit rechtshemispharischem Schlaganfall zu entwickeln. Mittels Itemanalysen von Daten 77 gesunder Probanden und 100 rechtshemispharischer Schlaganfallpatienten wurden 8 KAS-Items ausgeschlossen. Das somit noch aus 12 Items bestehende KAS-R weist eine gute interne Konsistenz (α = 0,795) sowie eine hohe Sensitivitat (79,4 %) und Spezifitat (84,4 %) auf. Bei einem Cut-off-Wert von ≤ 46 (von 48) Punkten zeigen 39 der 100 Schlaganfallpatienten eine Apraxie. Dabei korreliert das KAS-R – im Sinne einer guten Konstruktvaliditat – signifikant mit den externen Validierungsverfahren. Die Ergebnisse zeigen, dass das KAS-R ein reliables und valides diagnostisches Verfahren fur apraktische Defizite nach rechtshemispharischem Schlaganfall ist.

While visuo-spatial deficits are well characterized cognitive sequelae of right hemisphere (RH) stroke, apraxic deficits in RH stroke remain poorly understood. Likewise, very little is known about the association between apraxic and visuo-spatial deficits in RH stroke or about the putative common or differential pathophysiology underlying these deficits. Therefore, we examined the behavioral and lesion patterns of apraxic deficits (pantomime of object use and bucco-facial imitation) and visuo-spatial deficits (line bisection and letter cancellation tasks) in 50 sub-acute RH stroke patients. Using principal component analysis (PCA), we characterized the relationship between the two deficits. We hypothesized that any interaction of these neuropsychological measures may be influenced by the demands of ego-centric/space-based and/or allo-centric/object-based processing. Contra-lesional visuo-spatial deficits were common in our clinically representative patient sample, affecting more than half of RH stroke patients. Furthermore, about one third of all patients demonstrated apraxic deficits. PCA revealed that pantomiming and the imitation of bucco-facial gestures loaded clearly on a first component (PCA1), while letter cancellation loaded heavily on a second component (PCA2). For line bisection, overall mean deviation loaded on PCA1, while the difference between the mean deviations in contra- versus ipsi-lesional space loaded on PCA2. These results propose that PCA1 represents allo-centric/object-based processing and PCA2 2 ego-centric/space-based processing. This interpretation was corroborated by the statistical lesion analyses with the component scores. Data suggest that apraxic pantomime and imitation deficits in RH stroke result, at least in part, from disturbed allo-centric/object-based processing.

Background: The phosphoglycoprotein osteopontin (OPN) is upregulated in the brain following cerebral ischemia, where is exerts neuroprotective properties. We previously demonstrated OPN to increase survival and proliferation of neural stem cells (NSC) in vitro and in vivo. In culture, OPN additionally promotes NSC migration as well as a neuronal differentiation fate. Based on these data, we hypothesized OPN to induce NSC migration as well as neurogenesis in vivo as well. We here aimed to establish and visualize these effects using non-invasive in vivo imaging. Methods: Transgenic mice expressing luciferase (luc) under the doublecortin (DCX) promoter were used for brain-specific bioluminescence imaging (BLI) of DCX + neuroblasts. Focal cerebral ischemia was induced via photothrombosis (PT) in n = 27 mice, while n = 16 mice served as healthy control (CNT). Mice were randomized to receive either OPN (n = 14 PT, n = 8 CNT), or saline (n = 13 PT, n = 8 CNT) via a single injection into the lateral ventricle of the brain. Magnetic resonance imaging (MRI) was performed to verify and localize infarcts. BLI data was repetitively obtained for a period of 28 days in each individual animal. Ex vivo, immunohistochemistry for DCX + neuroblasts served to validate imaging data at high resolution. Results: In both healthy as well as stroke mice treated with OPN intracerebroventricularly, we observed enhanced migration of DCX + neuroblasts towards the site of OPN injection over a period of 28 days, as assessed by BLI ( p 0.01 each). Moreover, the total flux of photons was increased in healthy mice 2 days after OPN injection, consistent with an expansion of neuroblasts numbers ( p 0.01 ). Under ischemic conditions, OPN increased neuroblast numbers as surrogate for neurogenesis throughout the observation period of 28 days, as assessed by BLI ( p 0.05 ). Conclusions: Data suggest positive effects of OPN on both the migration of neuroblasts as well as on neurogenesis in vivo. BLI visualizes and quantifies these effects non-invasively in the experimental animal in a longitudinal fashion, allowing to monitor the temporo-spatial dynamics of NSC mobilization under physiological conditions as well as in cerebral ischemia. The results confirm OPN as a promising drug to promote regeneration after stroke via its effects on neural stem cells.

Introduction Neuroimaging studies in stroke patients with hemiparesis have shown altered brain activation in the contralesional hemisphere including the primary motor cortex (M1), dorsal premotor cortex (dPMC) and anterior intraparietal sulcus (aIPS) already in the first week after stroke ( Rehme et al., 2011 ). The role of these regions for motor recovery is still under debate, with some studies suggesting a supportive influence ( Lotze et al., 2006 ) while other point to a maladaptive role ( Nowak et al., 2008 ). Especially functional reorganization in the early phase after stroke is not well understood, although this phase might be critical for non-invasive interventions aiming at supporting recovery of function ( Grefkes and Fink, 2016 ). We here used fMRI-guided online TMS applied over the contralesional M1, dPMC and aIPS of first-ever stroke patients with hand motor deficits in order to probe their role for movements of the paretic hand. Methods FMRI data were recorded from 13 patients 1–8 days after first-ever ischemic stroke and 14 age-matched healthy volunteers during index finger tapping in order to localize task-related activation in the contralesional hemisphere. Each subjects’ individual maxima in the contralesional M1, dPMC and aIPS were then used as targets to apply short trains of rTMS (10 Hz trains, 90% of rMT) time locked to task execution (online-TMS). Sham stimulation served as a control condition and was conducted at 90% of rMT, tilted over the parieto-occipital vertex in order to minimize interference with the motor system. Task performance was measured using a 3D motion analysis system. Imaging data were preprocessed and analyzed using SPM8 and the MarsBar toolbox. Results The severity of stroke as assessed by the NIHSS showed a positive correlation with the partients’ activation peaks in contralesional M1, indicating higher levels of activity in more affected patients. TMS application over the individual fMRI maxima led to differential effects on motor performance. In contralesional M1 and dPMC, TMS interference with local activity led to a normalization of kinematics in patients showing higher activation during paretic hand movements. This finding implies that early increases of neural activity in these regions after stroke rather represent a maladaptive process interfering with motor performance of the stroke-affected hand. In contrast, TMS-Effects with aIPS led to an increase of tapping amplitude and peak velocity across the patient group, thus normalizing performance. Conclusion The present study examined the role of contralesional M1, dPMC and aIPS activity for motor performance in early subacute stroke patients. While higher activation of M1 and dPMC in the first week after stroke were related to an improvement of motor fluency during online TMS interference, stimulation also of lower activation in contralesional aIPS led to a normalization of spatial aspects of motor performance. These findings suggest a disturbing influence of all examined regions on different features of movement kinematics already during the first days after stroke in mildly to moderately affected patients.

Background Event-related transcranial magnetic stimulation (TMS) allows to interfere with neural processing of cortical areas. While we have a rather good knowledge of the role of frontoparietal areas for motor performance of the contralateral hand, the contribution of ipsilateral areas is far less understood (Davare et al., 2007) . Neuroimaging studies found an increasing recruitment of ipsilateral motor regions in healthy elderly, implying a supportive influence during normative aging Hutchinson et al., 2002 , Riecker et al., 2006 . To test this hypothesis, we used online-TMS to investigate the role of ipsilateral primary motor cortex (M1), premotor cortex (dPMC), and the anterior intraparietal sulcus (aIPS) in motor tasks of different complexity in young and elderly subjects. Methods 30 healthy, right-handed subjects (15 young (27.8 y); 15 elderly (61.3 y)) conducted four motor tasks of different complexity: (i) simple reaction time task, (ii) maximum finger and (iii) hand tapping frequencies, and (iv) rapid pointing between two defined targets. Tapping and pointing tasks were recorded with kinematic motion analyzer system (Zebris). TMS pulses were applied as 10 Hz-trains, time-locked to task execution. Stimulation was applied at 90% intensity of the resting motor threshold (rMT) to ipsilateral M1, dPMC, and aIPS. Sham-stimulation at 90% of rMT to parieto-occipital vertex served as control condition. Results In the finger tapping task (ii) we found both a main effect of online-TMS and an interaction effect between group and stimulation site. While in elderly stimulation over dPMC led to a decrease in tapping intervall, performance in the young group was mainly affected by M1-stimulation. Furthermore, for the target pointing task (iv) we found a decrease of aiming accuracy in the elderly group upon TMS interference with aIPS and dPMC but the young stayed unaffected by stimulation over all sites. Finally, age correlated with a frequency reduction of hand tapping (iii) induced by aIPS-stimulation. Conclusion Our findings suggest that there are differential roles of investigated areas in motor performance in aging. The data further displays relevance of dPMC and aIPS in repetitive tapping and target pointing tasks in elderly. Both regions seem to be causally engaged in maintaining performance in elderly. This might indicate that an increasing recruitment of ipsilateral motor regions Hutchinson et al., 2002 , Riecker et al., 2006 seems to have a supportive influence on motor performance in elderly.

The performance of motor actions is a highly complex task where the movement of different body parts has to be coordinated by the activity of various brain regions. In particular, the interplay of brain regions of the motor cortex is crucial. In the study presented here, the interaction of different motor related brain regions during simple internally and externally initiated finger movements was investigated during preparation and execution of those movements. To this end, EEG data (64 channel system) were recorded from 18 right-handed healthy participants (22–35 years, 10 female). The participants performed a finger tapping paradigm that contained left and right index finger movements which were triggered either by a visual cue or by voluntary choice. We carried out inter-regional phase-locking analysis of Morlet wavelet phases in delta-theta (2–7 Hz), alpha (8–12 Hz) and beta (13–30 Hz) frequency bands of the Laplacian referenced EEG data in order to identify coupling between brain regions during the motor task. We analyzed connectivity in a network involving electrodes lying above the premotor areas (PM: FC3, FC4), the supplementary motor areas (SMA: Cz, FCz) and the primary motor cortex (M1: C3, C4) as nodes. We found significant changes of synchronization in the delta-theta frequency band during both movement preparation and execution. The construction of lateralization networks revealed that the phase-locking effect in these frequency bands was stronger for connections from motor regions to supplementary motor areas contralaterally to the moving hand than on the ipsilateral side. The interregional synchronizations appeared only when both regions showed strong intraregional phase locking. Thus, intraregional phase locking in the delta-theta frequencies seems to be a prerequisite for interregional phase locking. We hypothesize that both intra- and interregional phase locking form a functional network of synchronous activity. This activity enhances the excitability of the motor system so that transient cue signals are able to induce different kinds of movements during movement preparation. Additionally we found strong synchronization in the beta-frequency band that appeared after the movement has been executed for connections from the supplementary motor areas to the primary motor cortex and the pre-motor cortex contralaterally to the moving hand. Since this synchronization effect is expressed significantly stronger during the self-initiated than during visually-triggered finger movements, we suggest that it might be related to the suppression of the internal “go” cue after the movement was executed.

Background Event-related (“online”) transcranial magnetic stimulation (TMS) allows to interfere with neural processing of distinct cortical areas. While we have a rather good knowledge on the role of frontoparietal areas for motor performance of the contralateral hand, the contribution of areas in the hemisphere ipsilateral to the moving hand is far less understood ( [Davare et al., 2007] , [Vollmer et al., 2015] ). For example, neuroimaging studies found an increasing ipsilateral recruitment of motor regions in healthy eldery subjects, implying a supportive influence during normative ageing ( [Hutchinson et al., 2002] , [Riecker et al., 2006] ). To test this hypothesis, we used online-TMS to investigate the role of ipsilateral primary motor cortex (M1), premotor cortex (dPMC) and anterior intraparietal sulcus (aIPS) in motor tasks of different complexity in young and elderly subjects. Methods Young (range: 20–30 years) and elderly (range: 50–70 years) healthy, right-handed subjects conducted four motor tasks of different complexity with their right hand: (i) simple reaction time, (ii) maximum finger and (iii) hand tapping frequencies and (iv) rapid pointing between two defined targets. Tapping and pointing tasks were measured with kinematic, three-dimensional recordings using an ultrasound motion analyzer system (Zebris). TMS pulses were applied as 10 Hz-trains time-locked to task execution. Stimulation was applied at 90% of resting motor threshold (rMT) to ipsilateral M1, dPMC and aIPS. Sham-stimulation at 90% of rMT to parieto-occipital vertex served as control condition. Results Online-TMS applied to ipsilateral M1 led to a significant response slowing and to a significantly increased coeffcient of variation in the simple reaction time task in elderly subjects. In contrast, performance of more complex motor tasks was not affected by ipsilateral M1-stimulation. TMS applied to the ipsilateral dPMC or aIPS affected the more complex motor tasks. DPMC-stimulation caused a reduction of tapping amplitude and a significant reduction of overall performance in the finger tapping task. TMS applied to the aIPS led to a significant reduction of tapping amplitude and tended to reduce overall performance in the hand tapping task. Furthermore, subjects showed a significant decrease of aiming accuracy in the pointing task, upon TMS interference with ipsilateral dPMC as well as aIPS in elderly subjects. Finally, within the group of elderly subjects, age strongly correlated with a frequency reduction of hand tapping induced by both M1- and aIPS-stimulation. Conclusion Consistent with previous work ( Vollmer et al., 2015 ), our findings underline the impact of ipsilateral M1 on simple motor task. We also show that in eldery subjects ipsilateral dPMC as well as ipsilateral aIPS seem to be causally engaged in maintaining performance in more complex motor tasks. These findings agree with neuroimaging studies indicating the IPS’ particular involvement in visuomotor tasks ( Grefkes et al., 2006 ). Of note, our results support the notion of age-dependent recruitment of ipsilateral M1 in motor tasks ( [Hutchinson et al., 2002] , [Riecker et al., 2006] ) and suggest a similar relevance of aIPS for motor performance in healthy ageing individuals.

Background/Objective Previous research on the neural basis of cognitive control processes has mainly focused on cortical areas, while the role of subcortical structures in cognitive control is less clear. Models of basal ganglia function as well as clinical studies in neurodegenerative diseases suggest that the striatum (putamen and nucleus caudatus) modulates the inhibition of response impulses and thereby contributes to an important aspect of cognitive control. The present study aimed at further investigating the putative role of the striatum within the fronto-striatal network in cognitive control processes. Methods Twenty-three patients with unilateral lesions (caused by stroke) involving the striatum and 32 age-matched neurologically healthy controls performed a unimanual version of the Simon task. In the Simon task, the correspondence between stimulus location and response location is manipulated, so that the efficacy of cognitive control processes can be inferred by the (prolonged) reaction times in situations when a response conflict has to be resolved. Results Stroke patients responded overall slower and more erroneous than controls. The difference in response times to incongruent versus congruent trials (known as the Simon effect) was reduced in the ipsilesional/-lateral hemifield, but did not differ significantly between groups in the current unimanual version of the Simon task. Discussion Thus, in stroke patients unilateral lesions of the striatum did not significantly impair cognitive control processes (here: control of response interference). Possible compensatory mechanisms and implications of these findings for theoretical accounts of the Simon effect are discussed.

Objective Whether processing of function knowledge about tools (i.e., knowing what a tool is used for) draws upon action or semantic knowledge remains controversial. Methods We investigated this issue using fMRI. 17 subjects performed three experimental tasks tapping into different aspects of tool knowledge. Data were analyzed using SPM and dynamic causal modeling (DCM). Results The behavioral data and fMRI activation pattern suggested that function knowledge about tools was processed similarly as non-motor-related semantic tool knowledge (here: the monetary value of a tool) and could therefore be classified as “motor-related semantic knowledge”, whereas action knowledge (i.e., how a tool is used) was processed differently. Processing of action knowledge activated areas of the ventro-dorsal stream (i.e., the lateral occipito-temporal cortex (LOTC) bilaterally, the left intraparietal sulcus (IPS), the left supramarginal gyrus (SMG), and the left inferior frontal gyrus (IFG)). In contrast, ventral stream areas were activated by the processing of semantic tool knowledge: the fusiform gyrus (FFG) bilaterally, the angular gyrus (ANG) bilaterally, and the medial prefrontal cortex (mPFC). Analyzing the effective connectivity between these areas with DCM revealed interactions between the processing streams (between LOTC and FFG as well as between SMG and ANG) and reciprocal modulatory effects. Conclusions This fMRI-study substantiates that action and semantic knowledge about tools are processed along two separate routes and that function knowledge (i.e., knowing what a tool is used for) draws upon the semantic system. In addition, connectivity analysis with DCM revealed relevant interactions between the processing streams at lower and higher levels.

Transcranial direct current stimulation (tDCS) has been suggested as an adjuvant tool to promote recovery of function after stroke, but the mechanisms of its action to date remain poorly understood. Moreover, studies aimed at unraveling those mechanisms have essentially been limited to the rat, where tDCS activates resident microglia as well as endogenous neural stem cells. Here we studied the effects of tDCS on microglia activation and neurogenesis in the mouse brain. Male wild-type mice were subjected to repetitive tDCS of either anodal or cathodal polarity; sham-stimulated mice served as control. Activated microglia in the cerebral cortex, and neuroblasts generated in the subventricular zone as the major neural stem cell niche, were assessed immunohistochemically. Repetitive tDCS at a sub-lesional charge density led to a polarity-dependent downregulation of the constitutive expression of Iba1 by microglia in the mouse cortex. In contrast, both anodal and – to an even greater extent – cathodal tDCS induced neurogenesis from the subventricular zone. Data suggest that tDCS elicits its action through multi-facetted mechanisms, including immunomodulation and neurogenesis, and thus support the idea of using tDCS to induce regeneration and to promote recovery of function. Furthermore, data suggest that the effects of tDCS may be animal- and polarity-specific.

Introduction Coordinated hand movements derive from fine-tuned interactions of various motor regions. Transcranial magnetic stimulation (TMS) allows to test the role of cortical motor areas. Disturbing the activity of the primary motor cortex (M1) ipsilateral to the moving hand via ‘online’ TMS, i.e., applied during task execution, has been shown to alter the recruitment of hand muscles in grip-lift-tasks ( Davare et al., 2007 ). Then again, similar stimulation had no effect on the performance of simple reaction-time tasks ( Nardone et al., 2013 ). Conflicting data might result from differences in stimulation parameters (e.g., stimulation intensity) or from motor task specific effect of online-TMS interference. We, here, applied online TMS to M1 while subjects performed motor-tasks of different complexities with the ipsilateral hand to further our insights into the exact role of the ipsilateral M1 in hand movement. Material and methods 16 healthy, right-handed subjects performed three different motor tasks with the right index finger (simple reaction-time and maximum finger-tapping task) or the right hand (maximum grip strength over one second). TMS Pulses were applied as 10 Hz-trains time-locked to motor task execution. Performance was measured for four different conditions. Real-stimulation was applied at three different intensities: (i) 70%, (ii) 80%, or (iii) 90% of the resting motor threshold (RMT) to the right M1. Sham-stimulation was applied at 90% RMT over parieto-occipital vertex. The order of stimulation blocks was pseudo-randomized across subjects. Results Online TMS applied to the right M1 differentially affected motor task performance with the right (ipsilateral) hand. Maximum finger-tapping frequency and the integrated grip strength time course were significantly reduced by real compared to sham stimulation. Of note, we found a stimulation intensity dependent effect with higher stimulation intensities leading to stronger reduction in motor performance. In contrast, performance in the simple reaction-time task was not affected by online TMS. Discussion We found online TMS applied to M1 to impact on the motor function of the ipsilateral hand. Importantly, the ‘virtual lesion’ effect induced by online TMS strongly depended on the intensity at which pulses were applied and the given motor task. Our results suggest M1 to functionally contribute to the repetitive and timely precise recruitment of ipsilateral hand muscles. Finally, our experimental approach also offers the opportunity to study the altered role of the ipsilateral M1 in disease, e.g., during motor network reorganization following stroke.

Introduction One of the key symptoms of Parkinson’s disease (PD) is the impairment of spontaneous movement also known as akinesia ( Berardelli et al., 2001 ). Correspondingly, patients performing motor tasks feature abnormal activation in regions such as posterior medial frontal cortex (pMFC) and putamen ( Herz et al., 2013 ). These areas play crucial roles in the internal timing of volitional movements in healthy individuals ( Hoffstaedter et al., 2013 ). Yet, little is known about these regions’ functional connectivity (FC) in PD and its relationship with akinesia. The present study investigated FC alterations of the ’motor initiation network’ in PD, using a seed-based resting-state (RS) analysis. Methods RS fMRI data of 60 patients diagnosed with idiopathic PD (mean age 61.6 ± 10.2; mean disease duration 6.5 ± 5.5 years) and 72 healthy volunteers (mean age 60.1 ± 8.8, matched for age, gender and within-scanner movement) was acquired at two sites. After spatial preprocessing (realignment, normalization, smoothing), temporal filtering was conducted including motion confound removal and band-pass filtering. Seeds in bilateral putamen and pMFC were derived from a meta-analysis on volitional movements ( Hoffstaedter et al., 2014 ). Two more seeds were selected in bilateral primary motor cortex (M1). For each seed, (i) whole-brain FC and (ii) its interaction with akinesia (UPDRS item 3.14) were assessed. RS networks for the aforementioned regions were first mapped in healthy controls only: Contrasting each region’s FC to the FC of all respective other seeds yielded maps of specific connectivity with either seed. These networks were then used to map whole-brain corrected changes of FC in PD. Results were cluster-level corrected for multiple comparisons ( p Results In healthy participants, RS analysis differentiated three networks, specifically (more than all other seeds) connected to bilateral putamen, bilateral M1, and pMFC. In PD, all seeds consistently featured decreased FC with regions in their most related network. That is, M1 mainly showed FC decrease within the M1-related network, pMFC lost FC with anterior insulae and left dorsolateral prefrontal cortex (DLPFC; pMFC-related network), and putamen lost FC with caudate nucleus, pallidum and thalamus (Putamen-related network). Additionally, putamen FC decreased extensively also in those regions more related to M1 and pMFC, including visual, superior parietal, primary somatosensory, M1, pMFC and DLPFC. Testing for each seed’s interaction with akinesia, pMFC showed a decreased FC with inferior parietal lobe (IPL) in the pMFC-related network. In turn, FC of the other seeds did not significantly relate to akinesia. Conclusions The present study examined RS FC changes of bilateral putamen, M1 and pMFC in PD. In patients, putamen FC suggests a marked cortico-striatal decoupling, in line with pathophysiological models of the disease ( Braak et al., 2004 ). In contrast, pMFC featured more selective FC decreases, predominantly in regions involved in motor control ( Hoffstaedter et al., 2013 , Hoffstaedter et al., 2014 ). Notably, akinesia was exclusively related to pMFC-connectivity. With increasing impairment, pMFC decoupled from the right IPL. In sum, the present study demonstrates a disruption of cortico-striatal FC and specifies the role of pMFC - IPL connectivity for movement initiation in PD.

Motor actions are generated by complex interactions of various brain regions. The same brain regions can build various functional networks depending on the action. Identifying the neural signals that encode an action’s component (selection, preparation, execution) remains a difficult task. In the current study, EEG data were recorded continuously from 18 young (22–35 years) and 16 elderly (60–71 years) right-handed healthy subjects as they performed a simple motor task. The task required participants to execute a left or right index finger tapping triggered by a visual cue or by an uncued voluntary choice. We found that voluntary and visually triggered movements exhibit significant phase locking in the delta-theta frequency band (2–7 Hz) around movement onset both in young and old subjects. However, significant differences in movement and processing time between the two groups of subjects were observed as well. Moreover, there was a negative correlation between the movement time and the maximal value of the phase-locking index (PLI) in young subjects. This indicates that the aforementioned changes in behavioral performance result from a decrease of PLI in the respective motor regions. In summary, we suggest that this enhanced intra-regional synchrony, which seems to be impaired in the elderly, helps the simultaneously active pathways of distinct cortical networks that initiate voluntary and stimulus-triggered movements, converge to a common motor output and activate the appropriate muscles to perform the movement. This mechanism may thus be regarded as a prototype for organizing more complex motor activities.

Background TMS studies examining the role of the unaffected hemisphere in motor function after stroke have mainly focused on the contralesional primary motor cortex (M1), revealing both supporting ( Lotze et al., 2006 , Rehme et al., 2011 ) as well as disturbing ( Vollmer et al., 2015 , Nowak et al., 2008 ) influence for recovery of function. However, the relevance of other contralesional motor areas for paretic hand function has rarely been examined, especially with respect to motor recovery in the first days and weeks after stroke. Therefore, we tested the effects of online-TMS applied to contralesional primary motor cortex, anterior intraparietal sulcus (aIPS) and dorsal premotor cortex (dPMC) while stroke patients performed different motor tasks with their paretic hand. Methods Patients with first-ever ischemic left hemispheric stroke performed motor tasks of different complexities with their paretic right hand while being stimulated with ‘online TMS’: (i) index finger tapping, (ii) hand tapping, (iii) visuomotor pointing task (pointing back and forth between two defined targets) and (iv) simple reaction time task. Performance was measured using a three-dimensional motion analyzer system (Zebris). Patients were measured in the acute stage after stroke. Results Compared to healthy controls, acute stroke patients showed reduced finger tapping amplitudes during TMS interference with ipsilateral (=contralesional) aIPS. Likewise, reaction times deteriorated upon contralesional aIPS stimulation in stroke patients but not in controls. Finally, accuracy in the 3D pointing task not only deteriorated upon aIPS stimulation (like in controls) but in addition also during interference with contralesional M1, which was exclusively found in the stroke patients group. Conclusion We here found evidence that especially anterior intraparietal cortex –an area critically engaged in hand motor function by means of parieto-frontal loops– has a relevant influence on motor performance of the paretic hand early after stroke. Therefore, aIPS might constitute an interesting stimulation target for excitability enhancing brain stimulation protocols in order to support recovery of function after stroke.

The interpretation of interpersonal gaze behavior requires the use of complex cognitive processes and guides social interactions. Among a variety of different gaze characteristics, gaze direction and gaze duration modulate crucially the meaning of the “social gaze”. Nevertheless, prior neuroimaging studies disregarded the relevance of gaze duration by focusing on gaze direction only. The present functional magnetic resonance imaging (fMRI) study focused on the differentiation of these two gaze parameters. Therefore direct gaze displayed by virtual characters was contrasted with averted gaze and, additionally, systematically varied with respect to gaze duration (i.e., 1, 2.5 or 4 s). Consistent with prior findings, behavioral data showed that likeability was higher for direct than for averted gaze and increased linearly with increasing direct gaze duration. On the neural level, distinct brain regions were associated with the processing of gaze direction and gaze duration: (i) the comparison between direct and averted gaze revealed activations in bilateral occipito-temporal regions including the posterior superior temporal sulcus (pSTS); (ii) whereas increasing duration of direct gaze evoked differential neural responses in the medial prefrontal cortex (MPFC) including orbitofrontal and paracingulate regions. The results suggest two complementary cognitive processes related to different gaze parameters. On the one hand, the recruitment of multimodal sensory regions in the pSTS indicates detection of gaze direction via complex visual analysis. On the other hand, the involvement of the MPFC associated with outcome monitoring and mentalizing indicates higher-order social cognitive processes related to evaluation of the ongoing communicational input conveyed by direct gaze duration .

Introduction Healthy elderly adults typically show greater regional activity in frontoparietal brain regions relative to young adults when performing motor control tasks ( Ward and Frackowiak, 2003 , Vallesi et al., 2011 ). However, the functional role of enhanced activity within the motor network is still a matter of debate. One hypothesis is that higher levels of neural activity reflect a compensatory mechanism to account for age-related decline in neural networks. We, therefore, used a systems-level approach to investigate networks dynamics underlying motor control in young and elderly subjects. We hypothesized that advanced aging is associated with reduced connectivity in the basic motor network, which is compensated by stronger influence of non-primary motor areas like prefrontal cortex. Methods We scanned 12 young (age 22–33) and 12 elderly subjects (age 52–74) employing a computerized task involving both basic (finger tapping) and higher motor control processing (internally and externally cued movement selection and initiation). Dynamic Causal Modelling (DCM) for fMRI was used to assess effective connectivity in a bilateral frontoparietal network comprising dorsolateral prefrontal cortex, dorsal premotor cortex, intraparietal cortex and primary motor cortex. Results Elderly subjects showed a significant slowing in movement selection and initiation. This slowing was accompanied by increases in both regional brain activity and effective connectivity between frontoparietal brain regions in elderly compared to young subjects. However, within the group of elderly subjects, coupling strengths of premotor cortex with primary motor cortex and intraparietal cortex decreased with advancing age, whereas connectivity between prefrontal and premotor cortex increased as a function of age. Discussion Network interactions underlying visuomotor transformation (parietal-premotor) and motor execution (premotor-primary motor cortex) follow an U-curve relationship: Connectivity is generally elevated in old relative to young subjects, yet decreases with advanced aging. In contrast, prefrontal influences on premotor cortex increase with advanced aging. These findings are in line with the ”posterior to anterior shift theory” described for regional brain activity, thereby extending it to network interactions related to higher motor control ( Davis et al., 2008 ).

Introduction Intermittent theta-burst stimulation (iTBS) effectively increases cortical excitability within the human brain (Huang et al., 2005). However, individual after-effects of iTBS vary between subjects, with a large proportion not responding at all in terms of changes in excitability (Ridding and Ziemann, 2010; Hamada et al., 2013). We here investigated whether subjects responding to iTBS show differential changes in resting-state functional connectivity (rsFC) within the cortical motor system compared to subjects with no response and whether the application of multiple iTBS-blocks can alter responsiveness. Methods We used a sham-stimulation controlled, single-blinded within-subject design to test for iTBS after-effects on (i) motor evoked potentials (MEPs) and (ii) resting-state functional connectivity (rsFC) in 16 healthy, right-handed subjects ( m =7, 27±3years). iTBS was applied over the left primary motor cortex (M1-iTBS) and over the parieto-occipital vertex (sham-iTBS) in separate sessions. In each stimulation session three iTBS blocks were applied, separated by 15min. Seed-based whole-brain rsFC was computed for the stimulated M1. Results Subjects were divided into groups of responders ( n =7) and non-responders ( n =9) according to iTBS-induced changes in MEPs (criterion: increase of at least 10% compared to baseline; Hinder et al., 2014). Increases in MEP-amplitudes following all three M1-iTBS blocks compared to sham-iTBS could exclusively be found for responders. Likewise, rsFC between M1 and premotor areas was significantly higher in responders after all three iTBS blocks ( p ⩽0.05, cluster-level FWE-corrected), whereas no significant increases could be found for the non-responder group. Dose-dependent increases in MEP-amplitudes and rsFC could also only be found for responders. Importantly, non-responders featured higher levels of pre-interventional rsFC compared to responders ( p ⩽0.01, cluster-level FWE-corrected). Individual changes in MEPs and rsFC did not correlate. Discussion Significant iTBS-induced modulations of rsFC and MEP-amplitudes were exclusively found for the responder group, suggesting that responsiveness to iTBS is paralleled by differential changes in motor network connectivity. However, there was no linear correlation between changes in MEP-amplitudes and rsFC. Additional iTBS blocks did not cause a conversion from non-responders to responders, but rather enhanced cortical excitability and rsFC in responders. Furthermore, lower levels of pre-interventional rsFC might contribute to better effectiveness of iTBS.

Background Affected hand movements are associated with a successive increase of neural activity in both hemispheres in the first weeks after stroke, which then return to levels observed in healthy controls, particularly in patients making full motor recovery. Little is known about the changes of the interplay of brain regions that enable the modulation of motor performance after stroke. In healthy subjects, an important feature of faster hand movements is mediated by a more effective coupling between distinct cortical and subcortical motor areas. But the mechanisms underlying the dynamic modulation of motor behavior in stroke patients related to motor impairment and recovery thereof are still unclear. Methods We, therefore, investigated 10 chronic stroke patients with mild to moderate unilateral hand motor deficits and 10 healthy, age-matched controls by using functional magnetic resonance imaging (fMRI). Motor system activity was assessed by fist closures at different movement frequencies (0.5 Hz, 1.0 Hz, and 2.0 Hz) performed with the affected/right or unaffected/left hand. Results When chronic stroke patients moved their affected, right hand, the fMRI data revealed a stronger frequency-dependent increase of neural activity within both the dorsolateral premotor cortex (PMd) and the superior parietal lobe (SPL), contralateral to the lesioned hemisphere as compared to healthy controls. Conclusion Our findings suggest a critical contribution of contralateral PMd and SPL in the flexible adaption of the brain to varying motor demands in chronic stroke patients controlling temporal and spatial preciseness of recovered complex hand movements in the contralesional hemisphere.

Neuropsychological studies of patients suffering from apraxia strongly imply a left hemisphere basis for skilful object use, the neural mechanisms of which, however, remain to be elucidated. We therefore carried out a PET study in 14 healthy human volunteers with the aim to isolate the neural mechanisms underlying the sensorimotor transformation of object-triggers into skilled actions. We employed a factorial design with two factors (RESPONSE: naming, pantomiming; and TRIGGER: actions, objects) and four conditions (IA: imitating the observed pantomime; IO: pantomiming the use of the object shown; NA: naming the observed pantomime; NO: naming the object shown). The design thus mainly aims at investigating the interaction [i.e. (IO – IA) – (NO – NA)] which allows the assessment of increased neural activity specific to the sensorimotor transformation of object-triggers into skilled actions. The results ( P < 0.05, corrected) showed that producing a wide range of skilled actions triggered by objects (controlled for perceptual, motor, semantic, and lexical effects) activated left inferior parietal cortex. The data provide an explanation for why patients with lesions including left parietal cortex suffer from ideational apraxia as assessed by impaired object use and pantomining to visually presented objects (Brain 111 (1988) 1173; Cogn. Neuropsychol. 18 (2001) 671).