China Academy of Medical science

Beijing, China

China Academy of Medical science

Beijing, China
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Tass P.A.,Jülich Research Center | Tass P.A.,University of Cologne | Qin L.,China Academy of Medical science | Hauptmann C.,Jülich Research Center | And 12 more authors.
Annals of Neurology | Year: 2012

Coordinated reset neuromodulation consists of the application of consecutive brief high-frequency pulse trains through the different contacts of the stimulation electrode. In theoretical studies, by achieving unlearning of abnormal connectivity between neurons, coordinated reset neuromodulation reduces pathological synchronization, a hallmark feature of Parkinson's disease pathophysiology. Here we show that coordinated reset neuromodulation of the subthalamic nucleus has both acute and sustained long-lasting aftereffects on motor function in parkinsonian nonhuman primates. Long-lasting aftereffects were not observed with classical deep brain stimulation. These observations encourage further development of coordinated reset neuromodulation for treating motor symptoms in Parkinson disease patients. Copyright © 2012 American Neurological Association.


Ko W.K.D.,Motac Neuroscience Ltd | Ko W.K.D.,Institut Universitaire de France | Ko W.K.D.,French National Center for Scientific Research | Pioli E.,Motac Neuroscience Ltd | And 8 more authors.
Movement Disorders | Year: 2014

Amantadine, an N-methyl-D-aspartate glutamate receptor antagonist, is currently the only pharmacological treatment for levodopa-induced dyskinesia (LID) in Parkinson's disease (PD), but causes adverse effects on the central nervous system at therapeutic doses. Fenobam, a negative modulator of metabotropic glutamate receptor subtype 5, has recently been reported to attenuate LID in MPTP-treated macaques. The aim of the current study was to investigate the treatment interactions of fenobam and amantadine on LID in the MPTP-treated macaque model of PD. The antidyskinetic and -parkinsonian effects were measured after administration of fenobam (10-30 mg/kg) and amantadine (10-30 mg/kg) alone and in combination. Fenobam (30 mg/kg) and amantadine (30 mg/kg) alone reduced LID, whereas lower doses of either drug did not cause any significant effects. A combined treatment of fenobam and amantadine at subthreshold doses (10 and 20 mg/kg) significantly reduced LID without worsening PD disability. These data suggest that a low-dose combination of fenobam and amantadine can be used for alleviating dyskinesia without causing adverse motor effects. Such combined therapies may offer a new therapeutic strategy for treatment of LID in PD patients. © 2014 International Parkinson and Movement Disorder Society.


Fox S.H.,University of Western Ontario | Fox S.H.,University of Toronto | Fox S.H.,Toronto Western Hospital | Johnston T.H.,University of Western Ontario | And 5 more authors.
Movement Disorders | Year: 2012

Levodopa-induced dyskinesia (LID) is a major limitation of long-term management of Parkinson's disease. The roadblocks that have hindered the development of new treatments for levodopa-induced dyskinesia were discussed at a meeting organized by the Michael J. Fox Foundation for Parkinson's research (New York, NY, March 2011). Among these, the lack of consensus methodology and clinical applicability for eliciting and rating LID in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys was highlighted as a particular concern. Here we present an update on the practical use of rating scales for evaluating LID in MPTP-lesioned primate models of PD, with a focus on macaques, and present specifics on the Non-Human Primate Dyskinesia Rating Scale. © 2012 Movement Disorder Society.


Camus S.M.J.,Institut Universitaire de France | Blois-Heulin C.,French National Center for Scientific Research | Li Q.,China Academy of Medical science | Li Q.,Motac Neuroscience Ltd | And 4 more authors.
PLoS ONE | Year: 2013

Background:To date, experimental and preclinical studies on neuropsychiatric conditions have almost exclusively been performed in experimentally-induced animal models and have only rarely relied upon an ethological approach where animals have been observed in more naturalistic settings. The laboratory species of choice has been the rodent while the potential of more closely-related non-human primates have remained largely underexplored.Methods:The present study, therefore, aimed at investigating the possible existence of spontaneous atypical/abnormal behaviours displayed by 40 cynomolgus macaques in captive conditions using an unbiased ethological scan-sampling analysis followed by multifactorial correspondence analysis and a hierarchical clustering.Results:The study identified five distinct profiles (groups A to E) that significantly differed on several behaviours, body postures, body orientations, gaze directions and locations in the cage environment. We suggest that animals from the low n groups (D and E) present depressive-like and anxious-like symptoms, reminiscent of depressive and generalized anxiety disorders. Inter-individual differences were highlighted through unbiased ethological observations of spontaneous behaviours and associated parameters, although these were not associated with differences in plasma or cerebrospinal fluid levels of either stress-related hormones or monoamines, i.e. in accordance with the human situation.Conclusions:No interventional behavioural testing was required to discriminate between 3 typical and 2 atypical ethologically-defined behavioural profiles, reminiscent of certain depressive-like and anxiety-like symptoms. The use of unbiased behavioural observations might, thus, allow the identification of animal models of human mental/behavioural disorders and their most appropriate control groups. © 2013 Camus et al.


Porras G.,Institut Universitaire de France | Porras G.,French National Center for Scientific Research | Li Q.,China Academy of Medical science | Bezard E.,Institut Universitaire de France | And 2 more authors.
Cold Spring Harbor Perspectives in Medicine | Year: 2012

The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) primate models of Parkinson's disease (PD) reproduce most, although not all, of the clinical and pathological hallmarks of PD. The present contribution presents the possibilities offered by the MPTP monkey models of PD to readers with minimal knowledge of PD, emphasizing the diversity of species, route and regimen of administration, symptoms and pathological features. Readers would eventually find out that there is not a single MPTP monkey model of PD but instead MPTP monkey models of PD, each addressing a specific experimental need. © 2012 Cold Spring Harbor Laboratory Press; all rights reserved.


Yin M.,Brown University | Borton D.A.,Brown University | Borton D.A.,Ecole Polytechnique Federale de Lausanne | Komar J.,Brown University | And 15 more authors.
Neuron | Year: 2014

Brain recordings in large animal models and humans typically rely on a tethered connection, which has restricted the spectrum of accessible experimental and clinical applications. To overcome this limitation, we have engineered a compact, lightweight, high data rate wireless neurosensor capable of recording the full spectrum of electrophysiological signals fromthe cortex of mobile subjects. The wireless communication system exploits a spatially distributed network of synchronized receivers that is scalable to hundreds of channels and vast environments. To demonstrate the versatility of our wireless neurosensor, we monitored cortical neuron populations in freely behaving nonhuman primates during natural locomotion and sleep-wake transitions in ecologically equivalent settings. The interface is electrically safe and compatible with the majority of existing neural probes, which may support previously inaccessible experimental and clinical research. © 2014 Elsevier Inc.


Santini E.,Karolinska Institutet | Sgambato-Faure V.,French Institute of Health and Medical Research | Sgambato-Faure V.,University of Lyon | Li Q.,University of Bordeaux Segalen | And 6 more authors.
PLoS ONE | Year: 2010

Background: In rodents, the development of dyskinesia produced by L-DOPA in the dopamine-depleted striatum occurs in response to increased dopamine D1 receptor-mediated activation of the cAMP - protein kinase A and of the Rasextracellular signal-regulated kinase (ERK) signalling pathways. However, very little is known, in non-human primates, about the regulation of these signalling cascades and their association with the induction, manifestation and/or maintenance of dyskinesia. Methodology/Results: We here studied, in the gold-standard non-human primate model of Parkinson's disease, the changes in PKA-dependent phosphorylation of DARPP-32 and GluR1 AMPA receptor, as well as in ERK and ribosomal protein S6 (S6) phosphorylation, associated to acute and chronic administration of L-DOPA. Increased phosphorylation of DARPP-32 and GluR1 was observed in both L-DOPA first-ever exposed and chronically-treated dyskinetic parkinsonian monkeys. In contrast, phosphorylation of ERK and S6 was enhanced preferentially after acute L-DOPA administration and decreased during the course of chronic treatment. Conclusion: Dysregulation of cAMP signalling is maintained during the course of chronic L-DOPA administration, while abnormal ERK signalling peaks during the initial phase of L-DOPA treatment and decreases following prolonged exposure. While cAMP signalling enhancement is associated with dyskinesia, abnormal ERK signalling is associated with priming. © 2010 Santini et al.


Liu Z.,China Academy of Medical science
Zhonghua nei ke za zhi [Chinese journal of internal medicine] | Year: 2012

To investigate the clinical and pathological characteristics of dermatomyositis with muscular perifascicular atrophy (PFA). A series of 104 consecutive patients clinically and pathologically diagnosed as dermatomyositis by muscle biopsy in our laboratory from December, 2003 to August, 2011, were enrolled in this study. Muscle biopsy of all the enrolled patients had shown PFA of muscle fibers. Among the 104 patients, 34 were males and 70 were females with a mean age of 45 years old. Among them, 8 cases had normal electromyogram; 42 had normal serum creatine kinase level; 11 were diagnosed as carcinoma; 75 were found to be combined with interstitial lung disease (ILD). Based on morphologic changes of muscle biopsy, they were divided into pure PFA group with 54 cases and PFA plus focal damage group with 50 cases. Compared with the pure PFA group, there was prominent mononuclear cell infiltration into perimysial intermediate sized vessels and membrane attack complement (MAC) deposition in the intramuscular capillaries in the PFA plus group. Skin biopsy had been taken in 12 cases together with muscle biopsy and had shown the "border effect" of both PFA and interface dermatitis in muscle and skin. Our study suggests that chronic immune vascular damage and insufficiency in dermatomyositis may cause ischemia and focal myofiber damage in "watershed" regions. The incidence of ILD in our dermatomyositis patients with PFA is high.


To investigate the relationship between end-tidal carbon dioxide with its related indicators and ventilation/perfusion of the acute respiratory distress syndrome (ARDS) lung, and to explore a feasible way to titrate positive end-expiratory pressure (PEEP) in clinical practice. Five mixed-breed dogs with oleic acid lung injury model were mechanically ventilated at a serial PEEP trial including a recruitment maneuver (RM) before each PEEP level changed. The value of blood dynamics, end-tidal carbon dioxide partial pressure (PetCO2) and arterial carbon dioxide pressure under different PEEP levels were recorded. Arterial end-tidal carbon dioxide gradient (Pa-etCO2) and dead space fraction (Vd/Vt%) were calculated. All dogs received CT scan. Lung volume under different pressure levels, and ratio and volume of alveolar closing pressure, collapsed alveoli, sufficiently and insufficiently ventilated alveoli were obtained. Alveolar opening and closing analysis were performed by non-liner regression equation. The mean pressure when Vd/Vt% obtained lowest level were (11.2 ± 4.4) cm H2O (1 cm H2O = 0.098 kPa), which had no significant difference when compared to alveolar closing pressure [(11.5 ± 3.2) cm H2O](P > 0.05). The fraction of insufficiently ventilated and collapsed alveoli showed a significant linear correlation with the Vd/Vt% when PEEP was lower than P(min) (r = 0.632, P = 0.004). There was a linear correlation between the Vd/Vt% and the fraction of over-distended alveoli when PEEP was higher than P(min) (r = 0.770, P = 0.001). Closing pressure is in accordance with PEEP level after RM having reached the best ventilation/circulation ratio. The characteristics of lung collapse can be revealed by Vd/Vt% changes after RM. To titrate PEEP for the lowest Vd/Vt% after RM may be a feasible way to match the best ventilation and circulation effects of PEEP.


Bezard E.,Institut Universitaire de France | Bezard E.,Institute for Neurodegenerative Diseases | Bezard E.,China Academy of Medical science | Tronci E.,University of Cagliari | And 8 more authors.
Movement Disorders | Year: 2013

The serotonin (5-hydroxytryptamine [5HT]) system has recently emerged as an important player in the appearance of l-3,4-dihydroxyphenylalanine (levodopa [l-dopa])-induced dyskinesia in animal models of Parkinson's disease. In fact, dopamine released as a false transmitter from serotonin neurons appears to contribute to the pulsatile stimulation of dopamine receptors, leading to the appearance of the abnormal involuntary movements. Thus, drugs able to dampen the activity of serotonin neurons hold promise for the treatment of dyskinesia. The authors investigated the ability of the mixed 5-HT 1A/1B receptor agonist eltoprazine to counteract l-dopa-induced dyskinesia in 6-hydroxydopamine-lesioned rats and in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated macaques. The data demonstrated that eltoprazine is extremely effective in suppressing dyskinesia in experimental models, although this effect was accompanied by a partial worsening of the therapeutic effect of l-dopa. Interestingly, eltoprazine was found to (synergistically) potentiate the antidyskinetic effect of amantadine. The current data indicated that eltoprazine is highly effective in counteracting dyskinesia in preclinical models. However, the partial worsening of the l-dopa effect observed after eltoprazine administration represents a concern; whether this side effect is due to a limitation of the animal models or to an intrinsic property of eltoprazine needs to be addressed in ongoing clinical trials. The data also suggest that the combination of low doses of eltoprazine with amantadine may represent a valid strategy to increase the antidyskinetic effect and reduce the eltoprazine-induced worsening of l-dopa therapeutic effects. © 2012 Movement Disorder Society.

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