Cerebellar direct current stimulation enhances on-line motor skill acquisition through an effect on accuracy

The cerebellum is involved in the update of motor commands during error-dependent learning. Transcranial direct current stimulation (tDCS), a form of noninvasive brain stimulation, has been shown to increase cerebellar excitability and improve learning in motor adaptation tasks. Although cerebellar involvement has been clearly demonstrated in adaptation paradigms, a type of task that heavily relies on error-dependent motor learning mechanisms, its role during motor skill learning, a behavior that likely involves errordependent as well as reinforcement and strategic mechanisms, is not completely understood. Here, in humans, we delivered cerebellar tDCS to modulate its activity during novel motor skill training over the course of 3 d and assessed gains during training (on-line effects), between days (off-line effects), and overall improvement. We found that excitatory anodal tDCS applied over the cerebellum increased skill learning relative to sham and cathodal tDCS specifically by increasing on-line rather than off-line learning. Moreover, the larger skill improvement in the anodal group was predominantly mediated by reductions in error rate rather than changes in movement time. These results have important implications for using cerebellar tDCS as an intervention to speed up motor skill acquisition and to improve motor skill accuracy, as well as to further our understanding of cerebellar function

Two forms of short-interval intracortical inhibition in human motor cortex

Background: Pulses of transcranial magnetic stimulation (TMS) with a predominantly anterior-posterior (AP) or posterior-anterior (PA) current direction over the primary motor cortex appear to activate distinct excitatory inputs to corticospinal neurons. In contrast, very few reports have examined whether the inhibitory neurons responsible for short-interval intracortical inhibition (SICI) are sensitive to TMS current direction. Objectives: To investigate whether SICI evaluated with AP and PA conditioning stimuli (CSPA and CSAP) activate different inhibitory pathways. SICI was always assessed using a PA-oriented test stimulus (TSPA). Methods: Using two superimposed TMS coils, CSPA and CSAP were applied at interstimulus intervals (ISI) of 1–5 ms before a TSPA, and at a range of different intensities. Using a triple stimulation design, we then tested whether SICI at ISI of 3 ms using opposite directions of CS (SICICSPA3 and SICICSAP3) interacted differently with three other forms of inhibition, including SICI at ISI of 2 ms (SICICSPA2), cerebellum-motor cortex inhibition (CBI 5 ms) and short-latency afferent inhibition (SAI 22 ms). Finally, we compared the effect of tonic and phasic voluntary contraction on SICICSPA3 and SICICSAP3. Results: CSAP produced little SICI at ISIs = 1 and 2 ms. However, at ISI = 3 ms, both CSAP and CSPA were equally effective at the same percent of maximum stimulator output. Despite this apparent similarity, combining SICICSPA3 or SICICSAP3 with other forms of inhibition led to quite different results: SICICSPA3 interacted in complex ways with CBI, SAI and SICICSPA2, whereas the effect of SICICSAP3 appeared to be quite independent of them. Although SICICSPA and SICICSAP were both reduced by the same amount during voluntary tonic contraction compared with rest, in a simple reaction time task SICICSAP was disinhibited much earlier following the imperative signal than SICICSPA. Conclusions: SICICSPA appears to activate a different inhibitory pathway to that activated by SICICSAP. The difference is behaviourally relevant since the pathways are controlled differently during volitional contraction. The results may explain some previous pathological data and open the possibility of testing whether these pathways are differentially recruited in a range of tasks

The Merit(nTOF-11) High Intensity Liquid Mercury Target Experiment at the CERN PS

The MERIT(nTOF-11) experiment is a proof-ofprinciple test of a target system for a high power proton beam to be used as front-end for a neutrino factory or a muon collider. The experiment took data in autumn 2007 with the fast-extracted beam from the CERN Proton Synchrotron (PS) to a maximum intensity of $30 × 10^{12}$ per pulse. The target system, based on a free mercury jet, is capable of intercepting a 4-MW proton beam inside a 15-T magnetic field required to capture the low energy secondary pions as the source for intense muon beams. Partice detectors installed around the target setup measure the secondary particle flux out of the target and can probe cavitation effects in the mercury jet when excited by an intense proton beam.Preliminary results of the data analysis will be presented here

Time Structure of Particle Production in the Merit High-Power Target Experiment

The MERIT experiment is a proof-of-principle test of a target system for high power proton beam to be used as front-end for a neutrino factory complex or amuon collider. The experiment took data in autumn 2007 with the fast extracted beam from the CERN Proton Synchrotron (PS) to a maximum intensity of about 30 × 1012 protons per pulse. We report results from the portion of the MERIT experiment in which separated beam pulses were delivered to a free mercury jet target with time intervals between pulses varying from 2 to 700 μs. The analysis is based on the responses of particle detectors placed along side and downstream of the target

Machine learning assisted DSC-MRI radiomics as a tool for glioma classification by grade and mutation status

Background: Combining MRI techniques with machine learning methodology is rapidly gaining attention as a promising method for staging of brain gliomas. This study assesses the diagnostic value of such a framework applied to dynamic susceptibility contrast (DSC)-MRI in classifying treatment-naïve gliomas from a multi-center patients into WHO grades II-IV and across their isocitrate dehydrogenase (IDH) mutation status. Methods: Three hundred thirty-three patients from 6 tertiary centres, diagnosed histologically and molecularly with primary gliomas (IDH-mutant = 151 or IDH-wildtype = 182) were retrospectively identified. Raw DSC-MRI data was post-processed for normalised leakage-corrected relative cerebral blood volume (rCBV) maps. Shape, intensity distribution (histogram) and rotational invariant Haralick texture features over the tumour mask were extracted. Differences in extracted features across glioma grades and mutation status were tested using the Wilcoxon two-sample test. A random-forest algorithm was employed (2-fold cross-validation, 250 repeats) to predict grades or mutation status using the extracted features. Results: Shape, distribution and texture features showed significant differences across mutation status. WHO grade II-III differentiation was mostly driven by shape features while texture and intensity feature were more relevant for the III-IV separation. Increased number of features became significant when differentiating grades further apart from one another. Gliomas were correctly stratified by mutation status in 71% and by grade in 53% of the cases (87% of the gliomas grades predicted with distance less than 1). Conclusions: Despite large heterogeneity in the multi-center dataset, machine learning assisted DSC-MRI radiomics hold potential to address the inherent variability and presents a promising approach for non-invasive glioma molecular subtyping and grading

Genetic Deletion of the Nociceptin/Orphanin FQ Receptor in the Rat Confers Resilience to the Development of Drug Addiction

The nociceptin (NOP) receptor is a G-protein-coupled receptor whose natural ligand is the nociceptin/orphanin FQ (N/OFQ) peptide. Evidence from pharmacological studies suggests that the N/OFQ system is implicated in the regulation of several addiction-related phenomena, such as drug intake, withdrawal and relapse. Here, to further explore the role of NOP system in addiction, we used NOP (-/-) rats to study the motivation for cocaine, heroin and alcohol self-administration in the absence of N/OFQ function. Conditioned place preference (CPP) and saccharin (0.2% w/v) self-administration were also investigated. Results showed that NOP (-/-) rats self-administer less cocaine (0.25, 0.125 or 0.5 mg/infusion) both under a Fixed Ratio 1 and a Progressive Ratio schedule of reinforcement compared to wild type (Wt) controls. Consistently, cocaine (10 mg/kg, i.p.) was able to induce CPP in Wt but not in NOP (-/-). When NOP (-/-) rats were tested for heroin (20 μg/infusion) and ethanol (10% v/v) self-administration, they showeda significantly lower drug intake compared to Wt. Conversely, saccharin self-administration was not affected by NOP deletion, excluding the possibility of nonspecific learning deficits or generalized disruption of reward mechanisms in NOP (-/-) rats. These findings were confirmed with pharmacological experiments using two selective NOP antagonists, SB-612111 and LY2817412. Both drugs attenuated alcohol self-administration in Wt rats but not in NOP (-/-) rats. In conclusion, our results demonstrate that genetic deletion of NOP receptors confers resilience to drug abuse and support a role for NOP receptor antagonism as a potential treatment option for drug addiction.Neuropsychopharmacology accepted article preview online, 26 August 2016. doi:10.1038/npp.2016.171

An immunohistochemical study of the antinociceptive effect of calcitonin in ovariectomized rats

<p>Abstract</p> <p>Background</p> <p>Calcitonin is used as a treatment to reduce the blood calcium concentration in hypercalcemia and to improve bone mass in osteoporosis. An analgesic effect of calcitonin has been observed and reported in clinical situations. Ovariectomaized (OVX) rats exhibit the same hormonal changes as observed in humans with osteoporosis and are an animal model of postmenopousal osteoporosis. The aim of this study to investigate antinociceptive effect of calcitonin in OVX rats using the immunohistochemical study.</p> <p>Methods</p> <p>We assessed the antinociceptive effects of calcitonin in an ovariectomized (OVX) rat model, which exhibit osteoporosis and hyperalgesia, using the immunohistochemical method. Fifteen rats were ovariectomized bilaterally, and ten rats were received the same surgery expected for ovariectomy as a sham model. We used five groups: the OVX-CT (n = 5), the sham-CT (n = 5), and the OVX-CT-pcpa (n = 5) groups recieved calcitonin (CT: 4 U/kg/day), while OVX-vehi (n = 5) and the sham-vehi (n = 5) groups received vehicle subcutaneously 5 times a week for 4 weeks. The OVX-CT-pcpa-group was given traperitoneal injection of p-chlorophenylalanine (pcpa; an inhibitor of serotonin biosynthesis) (100 mg/kg/day) in the last 3 days of calcitonon injection. Two hours after 5% formalin (0.05 ml) subcutaneously into the hind paw, the L5 spinal cord were removed and the number of Fos-immunoreactive (ir) neurons were evaluated using the Mann-Whitney-U test.</p> <p>Results</p> <p>The numbers of Fos-ir neurons in the OVX-CT and sham-CT groups were significantly less than in the OVX-vehi and sham-vehi groups, respectively (p = 0.0090, p = 0.0090). The number of Fos-ir neurons in the OVX-CT-pcpa-group was significantly more than that of the OVX-CT-group (p = 0.0283), which means pcpa inhibits calcitonin induced reduction of c-Fos production.</p> <p>Conclusion</p> <p>The results in this study demonstrated that 1) the increase of c-Fos might be related to hyperalgesia in OVX-rats. 2) Calcitonin has an antinociceptive effect in both OVX and sham rats. 3) The central serotonergic system is involved in the antinociceptive properties of calcitonin.</p

Adenosine Triphosphate Stimulates Aquifex aeolicus MutL Endonuclease Activity

BACKGROUND:Human PMS2 (hPMS2) homologues act to nick 5' and 3' to misincorporated nucleotides during mismatch repair in organisms that lack MutH. Mn(++) was previously found to stimulate the endonuclease activity of these homologues. ATP was required for the nicking activity of hPMS2 and yPMS1, but was reported to inhibit bacterial MutL proteins from Thermus thermophilus and Aquifex aeolicus that displayed homology to hPMS2. Mutational analysis has identified the DQHA(X)(2)E(X)(4)E motif present in the C-terminus of PMS2 homologues as important for endonuclease activity. METHODOLOGIES/PRINCIPAL FINDINGS:We examined the effect ATP had on the Mn(++) induced nicking of supercoiled pBR322 by full-length and mutant A. aeolicus MutL (Aae MutL) proteins. Assays were single time point, enzyme titration experiments or reaction time courses. The maximum velocity for MutL nicking was determined to be 1.6+/-0.08x10(-5) s(-1) and 4.2+/-0.3x10(-5) s(-1) in the absence and presence of ATP, respectively. AMPPNP stimulated the nicking activity to a similar extent as ATP. A truncated Aae MutL protein composed of only the C-terminal 123 amino acid residues was found to nick supercoiled DNA. Furthermore, mutations in the conserved C-terminal DQHA(X)(2)E(X)(4)E and CPHGRP motifs were shown to abolish Aae MutL endonuclease activity. CONCLUSIONS:ATP stimulated the Mn(++) induced endonuclease activity of Aae MutL. Experiments utilizing AMPPNP implied that the stimulation did not require ATP hydrolysis. A mutation in the DQHA(X)(2)E(X)(4)E motif of Aae MutL further supported the role of this region in endonclease activity. For the first time, to our knowledge, we demonstrate that changing the histidine residue in the conserved CPHGRP motif abolishes endonucleolytic activity of a hPMS2 homologue. Finally, the C-terminal 123 amino acid residues of Aae MutL were sufficient to display Mn(++) induced nicking activity

Efficient long-range conduction in cable bacteria through nickel protein wires

Filamentous cable bacteria display long-range electron transport, generating electrical currents over centimeter distances through a highly ordered network of fibers embedded in their cell envelope. The conductivity of these periplasmic wires is exceptionally high for a biological material, but their chemical structure and underlying electron transport mechanism remain unresolved. Here, we combine high-resolution microscopy, spectroscopy, and chemical imaging on individual cable bacterium filaments to demonstrate that the periplasmic wires consist of a conductive protein core surrounded by an insulating protein shell layer. The core proteins contain a sulfur-ligated nickel cofactor, and conductivity decreases when nickel is oxidized or selectively removed. The involvement of nickel as the active metal in biological conduction is remarkable, and suggests a hitherto unknown form of electron transport that enables efficient conduction in centimeter-long protein structures