The intermuscular 3–7 Hz drive is not affected by distal proprioceptive input in myoclonus-dystonia

In dystonia, both sensory malfunctioning and an abnormal intermuscular low-frequency drive of 3–7 Hz have been found, although cause and effect are unknown. It is hypothesized that sensory processing is primarily disturbed and induces this drive. Accordingly, experimenter-controlled sensory input should be able to influence the frequency of the drive. In six genetically confirmed myoclonus-dystonia (MD) patients and six matched controls, the low-frequency drive was studied with intermuscular coherence analysis. External perturbations were applied mechanically to the wrist joint in small frequency bands (0–4, 4–8 and 8–12 Hz; ‘angle protocol) and at single frequencies (1, 5, 7 and 9 Hz; ‘torque’ protocol). The low-frequency drive was found in the neck muscles of 4 MD patients. In these patients, its frequency did not shift due to the perturbation. In the torque protocol, the externally applied frequencies could be detected in all controls and in the two patients without the common drive. The common low-frequency drive was not be affected by external perturbations in MD patients. Furthermore, the torque protocol did not induce intermuscular coherences at the applied frequencies in these patients, as was the case in healthy controls and in patients without the drive. This suggests that the dystonic 3–7 Hz drive is caused by a sensory-independent motor drive and sensory malfunctioning in MD might rather be a consequence than a cause of dystonia

Adenosine A2A receptors in Parkinson’s disease treatment

Latest results on the action of adenosine A2A receptor antagonists indicate their potential therapeutic usefulness in the treatment of Parkinson’s disease. Basal ganglia possess high levels of adenosine A2A receptors, mainly on the external surfaces of neurons located at the indirect tracts between the striatum, globus pallidus, and substantia nigra. Experiments with animal models of Parkinson’s disease indicate that adenosine A2A receptors are strongly involved in the regulation of the central nervous system. Co-localization of adenosine A2A and dopaminergic D2 receptors in striatum creates a milieu for antagonistic interaction between adenosine and dopamine. The experimental data prove that the best improvement of mobility in patients with Parkinson’s disease could be achieved with simultaneous activation of dopaminergic D2 receptors and inhibition of adenosine A2A receptors. In animal models of Parkinson’s disease, the use of selective antagonists of adenosine A2A receptors, such as istradefylline, led to the reversibility of movement dysfunction. These compounds might improve mobility during both monotherapy and co-administration with L-DOPA and dopamine receptor agonists. The use of adenosine A2A receptor antagonists in combination therapy enables the reduction of the L-DOPA doses, as well as a reduction of side effects. In combination therapy, the adenosine A2A receptor antagonists might be used in both moderate and advanced stages of Parkinson’s disease. The long-lasting administration of adenosine A2A receptor antagonists does not decrease the patient response and does not cause side effects typical of L-DOPA therapy. It was demonstrated in various animal models that inhibition of adenosine A2A receptors not only decreases the movement disturbance, but also reveals a neuroprotective activity, which might impede or stop the progression of the disease. Recently, clinical trials were completed on the use of istradefylline (KW-6002), an inhibitor of adenosine A2A receptors, as an anti-Parkinson drug

Neuroanatomical Study of the A11 Diencephalospinal Pathway in the Non-Human Primate

BACKGROUND: The A11 diencephalospinal pathway is crucial for sensorimotor integration and pain control at the spinal cord level. When disrupted, it is thought to be involved in numerous painful conditions such as restless legs syndrome and migraine. Its anatomical organization, however, remains largely unknown in the non-human primate (NHP). We therefore characterized the anatomy of this pathway in the NHP. METHODS AND FINDINGS: In situ hybridization of spinal dopamine receptors showed that D1 receptor mRNA is absent while D2 and D5 receptor mRNAs are mainly expressed in the dorsal horn and D3 receptor mRNA in both the dorsal and ventral horns. Unilateral injections of the retrograde tracer Fluoro-Gold (FG) into the cervical spinal enlargement labeled A11 hypothalamic neurons quasi-exclusively among dopamine areas. Detailed immunohistochemical analysis suggested that these FG-labeled A11 neurons are tyrosine hydroxylase-positive but dopa-decarboxylase and dopamine transporter-negative, suggestive of a L-DOPAergic nucleus. Stereological cell count of A11 neurons revealed that this group is composed by 4002±501 neurons per side. A 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) intoxication with subsequent development of a parkinsonian syndrome produced a 50% neuronal cell loss in the A11 group. CONCLUSION: The diencephalic A11 area could be the major source of L-DOPA in the NHP spinal cord, where it may play a role in the modulation of sensorimotor integration through D2 and D3 receptors either directly or indirectly via dopamine formation in spinal dopa-decarboxylase-positives cells

Riluzole Attenuates L-DOPA-Induced Abnormal Involuntary Movements Through Decreasing CREB1 Activity

Chronic administration of L-DOPA, the first-line treatment of dystonic symptoms in childhood or in Parkinson's disease, often leads to the development of abnormal involuntary movements (AIMs), which represent an important clinical problem. Although it is known that Riluzole attenuates L-DOPA-induced AIMs, the molecular mechanisms underlying this effect are not understood. Therefore, we studied the behavior and performed RNA sequencing of the striatum in three groups of rats that all received a unilateral lesion with 6-hydroxydopamine in their medial forebrain bundle, followed by the administration of saline, L-DOPA, or L-DOPA combined with Riluzole. First, we provide evidence that Riluzole attenuates AIMs in this rat model. Subsequently, analysis of the transcriptomics data revealed that Riluzole is predicted to reduce the activity of CREB1, a transcription factor that regulates the expression of multiple proteins that interact in a molecular landscape involved in apoptosis. Although this mechanism underlying the beneficial effect of Riluzole on AIMs needs to be confirmed, it provides clues towards novel or existing compounds for the treatment of AIMs that modulate the activity of CREB1 and, hence, its downstream targets

Searches for transverse momentum dependent flow vector fluctuations in Pb-Pb and p-Pb collisions at the LHC

CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQFINANCIADORA DE ESTUDOS E PROJETOS - FINEPFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESPThe measurement of azimuthal correlations of charged particles is presented for Pb-Pb collisions at root S-NN 2.76 TeV and p-Pb collisions at root S-NN 5.02 TeV with the ALICE detector at the CERN Large Hadron Collider. These correlations are measured for the second, third and fourth order flow vector in the pseudorapidity region vertical bar eta vertical bar 0.8 as a function of centrality and transverse momentum pT using two observables, to search for evidence of PT-dependent flow vector fluctuations. For Ph-Ph collisions at 2.76 TeV, the measurements indicate that PT-dependent fluctuations are only present for the second order flow vector. Similar results have been found for p-Pb collisions at 5.02 TeV. These measurements are compared to hydrodynamic model calculations with event-by-event geometry fluctuations in the initial state to constrain the initial conditions and transport properties of the matter created in Ph-Ph and p-Pb collisions.9133CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQFINANCIADORA DE ESTUDOS E PROJETOS - FINEPFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESPCONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQFINANCIADORA DE ESTUDOS E PROJETOS - FINEPFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESPSem informaçãoSem informaçãoSem informaçãoThe ALICE collaboration would like to thank all its engineers and technicians for their invaluable contributions to the construction of the experiment and the CERN accelerator teams for the outstanding performance of the LHC complex. The ALICE collaboration gratefully acknowledges the resources and support provided by all Grid centres and the Worldwide LHC Computing Grid (WLCG) collaboration. The ALICE collaboration acknowledges the following funding agencies for their support in building and running the ALICE detector: A.I. Alikhanyan National Science Laboratory (Yerevan Physics Institute) Foundation (ANSL), State Committee of Science and World Federation of Scientists (WFS), Armenia; Austrian Academy of Sciences and Nationalstiftung fur Forschung, Technologie und Entwicklung, Austria; Ministry of Communications and High Technologies, National Nuclear Research Center, Azerbaijan; Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq), Universidade Federal do Rio Grande do Sul (UFRGS), Financiadora de Estudos e Projetos (Finep) and Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP), Brazil; Ministry of Science & Technology of China (MSTC), National Natural Science Foundation of China (NSFC) and Ministry of Education of China (MOEC), China; Ministry of Science, Education and Sport and Croatian Science Foundation, Croatia; Ministry of Education, Youth and Sports of the Czech Republic, Czech Republic; The Danish Council for Independent Research Natural Sciences, the Carlsberg Foundation and Danish National Research Foundation (DNRF), Denmark; Helsinki Institute of Physics (HIP), Finland; Commissariat a l'Energie Atomique (CEA) and Institut National de Physique Nucleaire et de Physique des Particules (IN2P3) and Centre National de la Recherche Scientifique (CNRS), France; Bundesministerium fur Bildung, Wissenschaft, Forschung und Technologie (BMBF) and GSI Helmholtzzentrum fur Schwerionenforschung GmbH, Germany; General Secretariat for Research and Technology, Ministry of Education, Research and Religions, Greece; National Research, Development and Innovation Office, Hungary; Department of Atomic Energy Government of India (DAE) and Council of Scientific and Industrial Research (CSIR), New Delhi, India; Indonesian Institute of Science, Indonesia; Centro Fermi Museo Storico della Fisica e Centro Studi e Ricerche Enrico Fermi and Istituto Nazionale di Fisica Nucleare (INFN), Italy; Institute for Innovative Science and Technology, Nagasaki Institute of Applied Science (IIST), Japan Society for the Promotion of Science (JSPS) KAKENHI and Japanese Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan; Consejo Nacional de Ciencia (CONACYT) y Tecnologia, through Fondo de Cooperacion Internacional en Ciencia y Tecnologia (FONCICYT) and Direccion General de Asuntos del Personal Academico (DGAPA), Mexico; Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO), Netherlands; The Research Council of Norway, Norway; Commission on Science and Technology for Sustainable Development in the South (COMSATS), Pakistan; Pontificia Universidad Catolica del Peril, Peru; Ministry of Science and Higher Education and National Science Centre, Poland; Korea Institute of Science and Technology Information and National Research Foundation of Korea (NRF), Republic of Korea; Ministry of Education and Scientific Research, Institute of Atomic Physics and Romanian National Agency for Science, Technology and Innovation, Romania; Joint Institute for Nuclear Research (JINR), Ministry of Education and Science of the Russian Federation and National Research Centre Kurchatov Institute, Russia; Ministry of Education, Science, Research and Sport of the Slovak Republic, Slovakia; National Research Foundation of South Africa, South Africa; Centro de Aplicaciones Tecnologicas y Desarrollo Nuclear (CEADEN), Cubaenergia, Cuba, Ministerio de Ciencia e Innovacion and Centro de Investigaciones Energeticas, Medioambientales y Tecnologicas (CIEMAT), Spain; Swedish Research Council (VR) and Knut & Alice Wallenberg Foundation (KAW), Sweden; European Organization for Nuclear Research, Switzerland; National Science and Technology Development Agency (NSDTA), Suranaree University of Technology (SUT) and Office of the Higher Education Commission under NRU project of Thailand, Thailand; Turkish Atomic Energy Agency (TAEK), Turkey; National Academy of Sciences of Ukraine, Ukraine; Science and Technology Facilities Council (STFC), United Kingdom; National Science Foundation of the United States of America (NSF) and United States Department of Energy, Office of Nuclear Physics (DOE NP), United States of America

Searches for transverse momentum dependent flow vector fluctuations in Pb-Pb and p-Pb collisions at the LHC

The measurement of azimuthal correlations of charged particles is presented for Pb-Pb collisions at sNN=2.76 TeV and p-Pb collisions at sNN=5.02 TeV with the ALICE detector at the CERN Large Hadron Collider. These correlations are measured for the second, third and fourth order flow vector in the pseudorapidity region |η| < 0.8 as a function of centrality and transverse momentum pT using two observables, to search for evidence of pT-dependent flow vector fluctuations. For Pb-Pb collisions at 2.76 TeV, the measurements indicate that pT-dependent fluctuations are only present for the second order flow vector. Similar results have been found for p-Pb collisions at 5.02 TeV. These measurements are compared to hydrodynamic model calculations with event-by-event geometry fluctuations in the initial state to constrain the initial conditions and transport properties of the matter created in Pb–Pb and p–Pb collisions