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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 < 0.01). Intriguingly, ten days of cathodal tDCS treatment reversed the ischemia-induced hyperconnectivity, with reversal of ischemia-induced reduction in CPL (p < 0.05). Networks effect correlated to tDCS accelerated motor recovery within the observation period. On the individual level, multiple linear regression model (F (3,22) = 11.1, p < 0.001, adjusted R2 =.54) revealed, that - besides the initial motor deficit (p < 0.01) - functional network alteration (p < 0.01) and the treatment with tDCS (p < 0.01) significantly improved prediction of motor recovery after stroke. 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. [ABSTRACT FROM AUTHOR]

Abstract: Investigations of local field potentials of the subthalamic nucleus of patients with Parkinson’s disease have provided evidence for pathologically exaggerated oscillatory beta-band activity (13–30Hz) which is amenable to physiological modulation by, e.g., voluntary movement. Previous functional magnetic resonance imaging studies in healthy controls have provided evidence for an increase of subthalamic nucleus blood-oxygenation-level-dependant signal in incremental force generation tasks. However, the modulation of neuronal activity by force generation and its relationship to peripheral feedback remain to be elucidated. We hypothesised that beta-band activity in the subthalamic nucleus is modulated by incremental force generation. Subthalamic nucleus local field potentials were recorded intraoperatively in 13 patients with Parkinson’s disease (37 recording sites) during rest and five incremental isometric force generation conditions of the arm with applied loads of 0–400g (in 100-g increments). Repeated measures analysis of variance (ANOVA) revealed a modulation of local field potential (LFP) power in the upper beta-band (in 24–30Hz; F (3.042) =4.693, p =0.036) and the gamma-band (in 70–76Hz; F (4) =4.116, p =0.036). Granger-causality was computed with the squared partial directed coherence and showed no significant modulation during incremental isometric force generation. Our findings indicate that the upper beta- and gamma-band power of subthalamic nucleus local field potentials are modulated by the physiological task of force generation in patients with Parkinson’s disease. This modulation seems to be not an effect of a modulation of peripheral feedback. [Copyright &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 < 0.05). 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. [ABSTRACT FROM AUTHOR]