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1. Psychiatric phenotype in neurodevelopmental myoclonus-dystonia is underpinned by abnormality of cerebellar modulation on the cerebral cortex

Author: Clément Tarrano, Cécile Galléa, Cécile Delorme, Eavan M. McGovern, Cyril Atkinson-Clement, Vanessa Brochard, Stéphane Thobois, Christine Tranchant, David Grabli, Bertrand Degos, Jean Christophe Corvol, Jean-Michel Pedespan, Pierre Krystkowiak, Jean-Luc Houeto, Adrian Degardin, Luc Defebvre, Benoit Beranger, Davide Martino, Emmanuelle Apartis, Marie Vidailhet, Emmanuel Roze, and Yulia Worbe
Subjects: Myoclonus, Dystonia, Cerebellum, MRI, Network, Medicine, Science
Abstract: Abstract Psychiatric symptoms are common in neurodevelopmental movement disorders, including some types of dystonia. However, research has mainly focused on motor manifestations and underlying circuits. Myoclonus-dystonia is a rare and homogeneous neurodevelopmental condition serving as an illustrative paradigm of childhood-onset dystonias, associated with psychiatric symptoms. Here, we assessed the prevalence of psychiatric disorders and the severity of depressive symptoms in patients with myoclonus-dystonia and healthy volunteers (HV). Using resting-state functional neuroimaging, we compared the effective connectivity within and among non-motor and motor brain networks between patients and HV. We further explored the hierarchical organization of these networks and examined the relationship between their connectivity and the depressive symptoms. Comparing 19 patients to 25 HV, we found a higher prevalence of anxiety disorders and more depressive symptoms in the patient group. Patients exhibited abnormal modulation of the cerebellum on the cerebral cortex in the sensorimotor, dorsal attention, salience, and default mode networks. Moreover, the salience network activity was directed by the cerebellum in patients and was related to depressive symptoms. Altogether, our findings highlight the role of the cerebellar drive on both motor and non-motor cortical areas in this disorder, suggesting cerebellar involvement in the complex phenotype of such neurodevelopmental movement disorders.
Published: 2024
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2. Imbalanced motivated behaviors according to motor sign asymmetry in drug-naïve Parkinson’s disease

Author: Matthieu Béreau, Anna Castrioto, Mathieu Servant, Eugénie Lhommée, Maxime Desmarets, Amélie Bichon, Pierre Pélissier, Emmanuelle Schmitt, Hélène Klinger, Nadine Longato, Clélie Phillipps, Thomas Wirth, Valérie Fraix, Isabelle Benatru, Franck Durif, Jean-Philippe Azulay, Elena Moro, Emmanuel Broussolle, Stéphane Thobois, Christine Tranchant, Paul Krack, and Mathieu Anheim
Subjects: Medicine, Science
Abstract: Abstract Few studies have considered the influence of motor sign asymmetry on motivated behaviors in de novo drug-naïve Parkinson’s disease (PD). We tested whether motor sign asymmetry could be associated with different motivated behavior patterns in de novo drug-naïve PD. We performed a cross-sectional study in 128 de novo drug-naïve PD patients and used the Ardouin Scale of Behavior in Parkinson’s disease (ASBPD) to assess a set of motivated behaviors. We assessed motor asymmetry based on (i) side of motor onset and (ii) MDS-UPDRS motor score, then we compared right hemibody Parkinson’s disease to left hemibody Parkinson’s disease. According to the MDS-UPDRS motor score, patients with de novo right hemibody PD had significantly lower frequency of approach behaviors (p = 0.031), including nocturnal hyperactivity (p = 0.040), eating behavior (p = 0.040), creativity (p = 0.040), and excess of motivation (p = 0.017) than patients with de novo left hemibody PD. Patients with de novo left hemibody PD did not significantly differ from those with de novo right hemibody PD regarding avoidance behaviors including apathy, anxiety and depression. Our findings suggest that motor sign asymmetry may be associated with an imbalance between motivated behaviors in de novo drug-naïve Parkinson’s disease.
Published: 2023
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3. Autosomal recessive pathogenic MSTO1 variants in hereditary optic atrophy

Author: Sylvie Gerber, Lola Lessard, Cécile Rouzier, Samira Ait‐el‐Mkadem Saadi, Roxana Ameli, Stéphane Thobois, Lucie Abouaf, Françoise Bouhour, Josseline Kaplan, Audrey Putoux, Antoine Pegat, and Jean‐Michel Rozet
Subjects: Medicine (General), R5-920, Genetics, QH426-470
Abstract: Graphical Abstract Gerber et al report 2 autosomal recessive pathogenic Misato homolog 1 (MSTO1) variants causing hereditary optic atrophy and raise concerns about a previously identified dominant variant of MSTO1 by Gal et al (2017).
Published: 2023
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4. Clinical and genetic keys to cerebellar ataxia due to FGF14 GAA expansionsResearch in context

Author: Jean-Loup Méreaux, Claire-Sophie Davoine, David Pellerin, Giulia Coarelli, Marie Coutelier, Claire Ewenczyk, Marie-Lorraine Monin, Mathieu Anheim, Isabelle Le Ber, Stéphane Thobois, Florent Gobert, Léna Guillot-Noël, Sylvie Forlani, Ludmila Jornea, Anna Heinzmann, Aude Sangare, Bertrand Gaymard, Lucie Guyant-Maréchal, Perrine Charles, Cecilia Marelli, Jérôme Honnorat, Bertrand Degos, François Tison, Sophie Sangla, Marion Simonetta-Moreau, François Salachas, Maya Tchikviladzé, Giovanni Castelnovo, Fanny Mochel, Stephan Klebe, Anna Castrioto, Silvia Fenu, Aurélie Méneret, Frédéric Bourdain, Marion Wandzel, Virginie Roth, Céline Bonnet, Florence Riant, Giovanni Stevanin, Sandrine Noël, Anne-Laure Fauret-Amsellem, Melanie Bahlo, Paul J. Lockhart, Bernard Brais, Mathilde Renaud, Alexis Brice, and Alexandra Durr
Subjects: SCA27B, Hereditary cerebellar ataxia, GAA expansion, Diagnosis, Medicine, Medicine (General), R5-920
Abstract: Summary: Background: SCA27B caused by FGF14 intronic heterozygous GAA expansions with at least 250 repeats accounts for 10–60% of cases with unresolved cerebellar ataxia. We aimed to assess the size and frequency of FGF14 expanded alleles in individuals with cerebellar ataxia as compared with controls and to characterize genetic and clinical variability. Methods: We sized this repeat in 1876 individuals from France sampled for research purposes in this cross-sectional study: 845 index cases with cerebellar ataxia and 324 affected relatives, 475 controls, as well as 119 cases with spastic paraplegia, and 113 with familial essential tremor. Findings: A higher frequency of expanded allele carriers in index cases with ataxia was significant only above 300 GAA repeats (10.1%, n = 85) compared with controls (1.1%, n = 5) (p
Published: 2024
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5. Intrasubject subcortical quantitative referencing to boost MRI sensitivity to Parkinson's disease

Author: Laila Khedher, Jean-Marie Bonny, Ana Marques, Elodie Durand, Bruno Pereira, Marie Chupin, Tiphaine Vidal, Carine Chassain, Luc Defebvre, Nicolas Carriere, Valerie Fraix, Elena Moro, Stéphane Thobois, Elise Metereau, Graziella Mangone, Marie Vidailhet, Jean-Christophe Corvol, Stéphane Lehéricy, Nicolas Menjot de Champfleur, Christian Geny, Umberto Spampinato, Wassilios Meissner, Solène Frismand, Emmanuelle Schmitt, Anne Doé de Maindreville, Christophe Portefaix, Philippe Remy, Gilles Fénelon, Jean Luc Houeto, Olivier Colin, Olivier Rascol, Patrice Peran, and Franck Durif
Subjects: Parkinson’s disease, Magnetic resonance imaging, Variability, Iron, Computer applications to medicine. Medical informatics, R858-859.7, Neurology. Diseases of the nervous system, RC346-429
Abstract: Several postmortem studies have shown iron accumulation in the substantia nigra of Parkinson’s disease patients. Iron concentration can be estimated via MRI-R2∗ mapping. To assess the changes in R2∗ occurring in Parkinson’s disease patients compared to controls, a multicentre transversal study was carried out on a large cohort of Parkinson’s disease patients (n = 163) with matched controls (n = 82). In this study, 44 patients and 11 controls were removed due to motion artefacts, 21 patient and 6 controls to preserve matching. Thus, 98 patients and 65 age and sex-matched healthy subjects were selected with enough image quality.The study was conducted on patients with early to late stage Parkinson's disease. The images were acquired at 3Tesla in 12 clinical centres. R2∗ values were measured in subcortical regions of interest (substantia nigra, red nucleus, striatum, globus pallidus externus and globus pallidus internus) contralateral (dominant side) and ipsilateral (non dominant side) to the most clinically affected hemibody.As the observed inter-subject R2∗ variability was significantly higher than the disease effect, an original strategy (intrasubject subcortical quantitative referencing, ISQR) was developed using the measurement of R2∗ in the red nucleus as an intra-subject reference.R2∗ values significantly increased in Parkinson’s disease patients when compared with controls; in the substantia nigra (SN) in the dominant side (D) and in the non dominant side (ND), respectively (PSN_D and PSN_ND
Published: 2022
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6. Noradrenaline and Movement Initiation Disorders in Parkinson’s Disease: A Pharmacological Functional MRI Study with Clonidine

Author: Marion Criaud, Chloé Laurencin, Alice Poisson, Elise Metereau, Jérôme Redouté, Stéphane Thobois, Philippe Boulinguez, and Bénédicte Ballanger
Subjects: Parkinson’s disease, movement initiation, akinesia, inhibitory control, noradrenaline, clonidine, Cytology, QH573-671
Abstract: Slowness of movement initiation is a cardinal motor feature of Parkinson’s disease (PD) and is not fully reverted by current dopaminergic treatments. This trouble could be due to the dysfunction of executive processes and, in particular, of inhibitory control of response initiation, a function possibly associated with the noradrenergic (NA) system. The implication of NA in the network supporting proactive inhibition remains to be elucidated using pharmacological protocols. For that purpose, we administered 150 μg of clonidine to 15 healthy subjects and 12 parkinsonian patients in a double-blind, randomized, placebo-controlled design. Proactive inhibition was assessed by means of a Go/noGo task, while pre-stimulus brain activity was measured by event-related functional MRI. Acute reduction in noradrenergic transmission induced by clonidine enhanced difficulties initiating movements reflected by an increase in omission errors and modulated the activity of the anterior node of the proactive inhibitory network (dorsomedial prefrontal and anterior cingulate cortices) in PD patients. We conclude that NA contributes to movement initiation by acting on proactive inhibitory control via the α2-adrenoceptor. We suggest that targeting noradrenergic dysfunction may represent a new treatment approach in some of the movement initiation disorders seen in Parkinson’s disease.
Published: 2022
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7. Genetic and Phenotypic Basis of Autosomal Dominant Parkinson's Disease in a Large Multi-Center Cohort

Author: Suzanne Lesage, Marion Houot, Graziella Mangone, Christelle Tesson, Hélène Bertrand, Sylvie Forlani, Mathieu Anheim, Christine Brefel-Courbon, Emmanuel Broussolle, Stéphane Thobois, Philippe Damier, Franck Durif, Emmanuel Roze, François Tison, David Grabli, Fabienne Ory-Magne, Bertrand Degos, François Viallet, Florence Cormier-Dequaire, Anne-Marie Ouvrard-Hernandez, Marie Vidailhet, Ebba Lohmann, Andrew Singleton, Jean-Christophe Corvol, Alexis Brice, and for the French Parkinson disease Genetics Study Group(PDG)
Subjects: Parkinson's disease, LRRK2, G2019S, SNCA, VPS35, autosomal dominant inheritance, Neurology. Diseases of the nervous system, RC346-429
Abstract: LRRK2, SNCA, and VPS35 are unequivocally associated with autosomal dominant Parkinson's disease (PD). We evaluated the prevalence of LRRK2, SNCA, and VPS35 mutations and associated clinical features in a large French multi-center cohort of PD patients. Demographic and clinical data were collected for 1,805 index cases (592 with autosomal dominant inheritance and 1,213 isolated cases) since 1990. All probands were screened with TaqMan assays for LRRK2 Gly2019Ser. In the absence of this mutation, the coding sequences of the three genes were analyzed by Sanger sequencing and/or next-generation sequencing. The data for the three genes were analyzed according to age at onset, family history, ethnic origin and clinical features. We identified 160 index cases (8.9%) with known pathogenic variants: 138 with pathogenic LRRK2 variants (7.6%), including 136 with the Gly2019Ser mutation, 19 with SNCA point mutations or genomic rearrangements (1.1%), and three with the VPS35 Asp620Asn mutation (0.16%). Mutation frequencies were higher in familial than isolated cases, consistent with autosomal dominant inheritance (12.0 vs. 7.3%; OR 1.7, 95% CI [1.2–2.4], p = 0.001). PD patients with LRRK2 variants were more likely to have higher rates of late-onset PD (>50 years; OR 1.5, 95% CI [1.0–2.1], p = 0.03), whereas those with SNCA mutations tended to have earlier age at onset disease (≤ 50 years, p = 0.06). The clinical features of LRRK2 carriers and those without any pathogenic variants in known PD-associated genes were similar. The likelihood of detecting disease-causing mutations was higher in cases compatible with autosomal dominant inheritance.
Published: 2020
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8. Deep brain stimulation does not enhance neuroinflammation in multiple system atrophy

Author: Miguel Lopez-Cuina, Pierre-Olivier Fernagut, Marie-Hélène Canron, Anne Vital, Béatrice Lannes, André Maues De Paula, Nathalie Streichenberger, Dominique Guehl, Philippe Damier, Alexandre Eusebio, Jean-Luc Houeto, François Tison, Christine Tranchant, François Viallet, Tatiana Witjas, Stéphane Thobois, and Wassilios G. Meissner
Subjects: Deep brain stimulation, Multiple system atrophy, Atypical parkinsonism, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract: Slowly progressive, levodopa-responsive multiple system atrophy (MSA) may be misdiagnosed as Parkinson's disease (PD). Deep brain stimulation (DBS) is mostly ineffective in these patients and may even worsen the clinical course. Here we assessed whether neuropathological differences between patients with MSA who were treated with DBS of the subthalamic nucleus because of a misleading clinical presentation and typical disease cases may explain the more benign disease course of the former, and also the rapid clinical decline after surgery. The post-mortem assessment included the subthalamic nucleus, the globus pallidus, the thalamus and the putamen in five patients with MSA who received DBS and nine typical disease cases. There was no evidence for distinct neuroinflammatory profiles between both groups that could be related to the surgical procedure or that could explain the rapid clinical progression during DBS. Patients who received deep brain stimulation displayed a higher proportion of α-synuclein bearing neuronal cytoplasmic inclusions in the putamen compared with typical cases, while the number of surviving neurons was not different between groups. Our findings suggest that DBS does not induce neuroinflammatory changes in patients with MSA, at least several years after the surgery. We further hypothesize that the peculiar pattern of α-synuclein pathology may contribute to differences in the clinical phenotype, with a greater proportion of neuronal inclusions in the putamen being associated to a milder, “PD-like” phenotype with sustained levodopa response and slower disease progression.
Published: 2018
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9. Effects of dopamine and serotonin antagonist injections into the striatopallidal complex of asymptomatic MPTP-treated monkeys

Author: Sara Neumane, Stéphanie Mounayar, Caroline Jan, Justine Epinat, Bénédicte Ballanger, Nicolas Costes, Jean Féger, Stéphane Thobois, Chantal François, Véronique Sgambato-Faure, and Léon Tremblay
Subjects: Parkinson's disease, Primate, MPTP, Dopamine, Serotonin, Compensatory mechanism, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract: The cardinal symptoms of Parkinson's disease (PD), akinesia, rigidity and tremor, are only observed when the striatal level of dopamine (DA) is decreased by 60–80%. It is likely that compensatory mechanisms during the early phase of DA depletion delay the appearance of motor symptoms. In a previous study, we proposed a new PD monkey model with progressive MPTP intoxication. Monkeys developed all of the motor symptoms and then fully recovered despite a large DA cell loss in the substantia nigra (SN). Compensatory mechanisms certainly help to offset the dysfunction induced by the DA lesion, facilitating motor recovery in this model. Neurotransmitter measurements in the striatal sensorimotor and associative/limbic territories of these monkeys subsequently revealed that DA and serotonin (5-HT) could play a role in recovery mechanisms. To try to determine the involvement of these neurotransmitters in compensatory mechanisms, we performed local injections of DA and 5-HT antagonists (cis-flupenthixol and mianserin, respectively) into these two striatal territories and into the external segment of the globus pallidus (GPe). Injections were performed on monkeys that were in an asymptomatic state after motor recovery. Most parkinsonian motor symptoms reappeared in animals with DA antagonist injections either in sensorimotor, associative/limbic striatal territories or in the GPe. In contrast to the effects with DA antagonist, there were mild parkinsonian effects with 5-HT antagonist, especially after injections in sensorimotor territories of the striatum and the GPe. These results support a possible, but slight, involvement of 5-HT in compensatory mechanisms and highlight the possible participation of 5-HT in some behavioural disorders. Furthermore, these results support the notion that the residual DA in the different striatal territories and the GPe could be involved in important mechanisms of compensation in PD.
Published: 2012
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10. Early Illustrations of Geste Antagoniste in Cervical and Generalized Dystonia

Author: Emmanuel Broussolle, Chloé Laurencin, Emilien Bernard, Stéphane Thobois, Teodor Danaila, and Paul Krack
Subjects: Diseases of the musculoskeletal system, RC925-935, Neurology. Diseases of the nervous system, RC346-429
Abstract: Background: Geste antagoniste, or sensory trick, is a voluntary maneuver that temporarily reduces the severity of dystonic postures or movements. We present a historical review of early reports and illustrations of geste antagoniste.Results: In 1894, Brissaud described this phenomenon in Paris in patients with torticollis. He noted that a violent muscular contraction could be reversed by a minor voluntary action. He considered the improvement obtained by what he called “simple mannerisms, childish behaviour or fake pathological movements” was proof of the psychogenic origin of what he named mental torticollis. This concept was supported by photographical illustrations of the patients. The term geste antagoniste was used by Brissaud’s pupils, Meige and Feindel, in their 1902 monograph on movement disorders. Other reports and illustrations of this sign were published in Europe between 1894 and 1906. Although not mentioned explicitly, geste antagoniste was also illustrated in a case report of generalized dystonia in Oppenheim’s 1911 seminal description of dystonia musculorum deformans in Berlin.Discussion: Brissaud-Meige’s misinterpretation of the geste antagoniste unfortunately anchored the psychogenic origin of dystonia for decades. In New York, Herz brought dystonia back into the realm of organic neurology in 1944. Thereafter, it was given prominence by other authors, notably Fahn and Marsden in the 1970–1980s. Nowadays, neurologists routinely investigate for geste antagoniste when a dystonic syndrome is suspected, because it provides a further argument in favor of dystonia. The term alleviating maneuver was proposed in 2014 to replace sensory trick or geste antagoniste. This major sign is now part of the motor phenomenology of the 2013 Movement Disorder Society’s classification of dystonia.
Published: 2015
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11. A functional magnetic resonance imaging study of pathophysiological changes responsible for mirror movements in Parkinson's disease.

Author: Alice Poisson, Bénédicte Ballanger, Elise Metereau, Jérome Redouté, Danielle Ibarolla, Jean-Christophe Comte, Hélène Gervais Bernard, Marie Vidailhet, Emmanuel Broussolle, and Stéphane Thobois
Subjects: Medicine, Science
Abstract: Mirror movements correspond to involuntary movements observed in the limb contralateral to the one performing voluntary movement. They can be observed in Parkinson's disease (PD) but their pathophysiology remains unclear. The present study aims at identifying their neural correlates in PD using functional magnetic resonance imaging. Ten control subjects and 14-off drug patients with asymmetrical right-sided PD were included (8 with left-sided mirror movements during right-hand movements, and 6 without mirror movements). Between-group comparisons of BOLD signal were performed during right-hand movements and at rest (p
Published: 2013
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12. Levodopa effects on hand and speech movements in patients with Parkinson's disease: a FMRI study.

Author: Audrey Maillet, Alexandre Krainik, Bettina Debû, Irène Troprès, Christelle Lagrange, Stéphane Thobois, Pierre Pollak, and Serge Pinto
Subjects: Medicine, Science
Abstract: Levodopa (L-dopa) effects on the cardinal and axial symptoms of Parkinson's disease (PD) differ greatly, leading to therapeutic challenges for managing the disabilities in this patient's population. In this context, we studied the cerebral networks associated with the production of a unilateral hand movement, speech production, and a task combining both tasks in 12 individuals with PD, both off and on levodopa (L-dopa). Unilateral hand movements in the off medication state elicited brain activations in motor regions (primary motor cortex, supplementary motor area, premotor cortex, cerebellum), as well as additional areas (anterior cingulate, putamen, associative parietal areas); following L-dopa administration, the brain activation profile was globally reduced, highlighting activations in the parietal and posterior cingulate cortices. For the speech production task, brain activation patterns were similar with and without medication, including the orofacial primary motor cortex (M1), the primary somatosensory cortex and the cerebellar hemispheres bilaterally, as well as the left- premotor, anterior cingulate and supramarginal cortices. For the combined task off L-dopa, the cerebral activation profile was restricted to the right cerebellum (hand movement), reflecting the difficulty in performing two movements simultaneously in PD. Under L-dopa, the brain activation profile of the combined task involved a larger pattern, including additional fronto-parietal activations, without reaching the sum of the areas activated during the simple hand and speech tasks separately. Our results question both the role of the basal ganglia system in speech production and the modulation of task-dependent cerebral networks by dopaminergic treatment.
Published: 2012
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13. Glutamate cycle changes in the putamen of patients with de novo Parkinson's disease using 1H MRS

Author: Carine Chassain, Aurélie Cladiere, Camille Tsoutsos, Bruno Pereira, Fawzi Boumezbeur, Bérangère Debilly, Ana-Raquel Marques, Stéphane Thobois, Franck Durif, Qualité des Produits Animaux (QuaPA), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), CHU Clermont-Ferrand, CHU Gabriel Montpied [Clermont-Ferrand], Building large instruments for neuroimaging: from population imaging to ultra-high magnetic fields (BAOBAB), Service NEUROSPIN (NEUROSPIN), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Hospices Civils de Lyon (HCL), Institut des sciences cognitives Marc Jeannerod - Centre de neuroscience cognitive - UMR5229 (ISC-MJ), and Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)
Subjects: Parkinson?s disease, Neurology, Glutamine, Putamen, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology (clinical), Geriatrics and Gerontology, H-1 magnetic Resonance spectroscopy, Glutamate
Abstract: International audience; Introduction: To investigate glutamatergic metabolism changes in the putamen of patients with de novo Parkin-son's Disease (PD) and test the hypothesis that glutamate (Glu) levels are abnormally elevated in the putamen contralateral to where the motor clinical signs predominate as expected from observations in animal models. Methods: H-1 NMR spectra from 17 healthy control volunteers were compared with spectra from 17 de novo PD patients of who 14 were evaluated again after 2-3 years of disease progression. Statistical analysis used random-effects models. Results: The only significant difference between PD patients and controls was a higher glutamine (Gln) con-centration in the putamen ipsilateral to the hemibody with predominant motor signs (Visit 1: 6.0 +/- 0.4 mM vs. 5.2 +/- 0.2 mM, p < 0.05; Visit 2: 6.2 +/- 0.3 mM vs. 5.2 +/- 0.2 mM, p < 0.05). At Visit 1, PD patients had higher Glu and Gln levels in the putamen ipsilateral versus contralateral to dominant clinical signs (Glu: 12.2 +/- 0.6 mM vs. 10.4 +/- 0.6 mM, p < 0.05; Gln: 6.0 +/- 0.4 mM vs. 4.8 +/- 0.4 mM, p < 0.05; Glu and Gln pool (Glx): 17.9 +/- 0.8 mM vs. 14.7 +/- 1.1 mM, p < 0.05). At Visit 2, the sum of the two metabolites remained significantly higher in the ipsilateral versus contralateral putamen (Glx: 18.3 +/- 0.6 mM vs. 16.1 +/- 0.9 mM, p < 0.05). Conclusion: In de novo PD patients, the putamen ipsilateral to the more affected hemibody showed elevated Gln versus controls and elevated Glu and Gln concentrations versus the contralateral side. Abnormalities in Glu metabolism therefore occur early in PD but unexpectedly in the putamen contralateral to the more damaged hemisphere, suggesting they are not dependent solely on dopamine loss.
Published: 2022
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14. THN 102 for excessive daytime sleepiness associated with Parkinson's disease: a phase 2a trial

Author: Jean-Christophe, Corvol, Jean-Philippe, Azulay, Björn, Bosse, Yves, Dauvilliers, Luc, Defebvre, Fabian, Klostermann, Norbert, Kovacs, David, Maltête, William G, Ondo, Rajesh, Pahwa, Werner, Rein, Stéphane, Thobois, Martin, Valis, Aleksandar, Videnovic, Olivier, Rascol, Katarina, Zárubová, Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), NS-Park/FCRIN Network, UMS 015, Institut de Neurosciences de la Timone (INT), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Hôpital Gui de Chauliac [CHU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), CHU Montpellier, Université de Montpellier (UM), Département de neurologie [Lille], Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], University of Pécs Medical School (UP MS), University of Pecs, Service de neurologie [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU), Center for neurogenetics [Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York], Weill Medical College of Cornell University [New York], University of Kansas Medical Center [Kansas City, KS, USA], Theranexus [Lyon], Institut des sciences cognitives Marc Jeannerod - Centre de neuroscience cognitive - UMR5229 (ISC-MJ), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Hospices Civils de Lyon (HCL), Charles University [Prague] (CU), Massachusetts General Hospital [Boston], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), THN102-202 Study Investigators: Jean-Christophe Corvol, Jean-Philippe Azulay, Marek Baláž, Ralf Bodenschatz, Magdolna Bokor, Hana Brožová, Yves Dauvilliers, Luc Defebvre, Ondraj Fiala, Andràs Folyovich, Heinz Peter Herbst, Fabian Klostermann, Norbert Kovacs, Julianna Lajtos, Paul Lingor, David Maltête, Christian Oehlwein, Rajesh Pahwa, Jan Peregrin, Olivier Rascol, Daniela Rau, Ali Safavi, Joachim Springub, Jindra Svátová, Stéphane Thobois, Univ Lyon, Martin Valis, Làszlo Vécsei, Aleksandar Videnovic, Olga Waln, Katarina Zárubová, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Hôpital Gui de Chauliac, Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Département de neurologie[Lille], Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), University of Kansas Medical Center [Lawrence], Institut des sciences cognitives Marc Jeannerod - Centre de neuroscience cognitive - UMR5229 (CNC), Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, CHU Toulouse [Toulouse], and Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)
Subjects: Parkinson's disease, Excessive daytime sleepiness, Disorders of Excessive Somnolence, Placebo, sleepiness, 03 medical and health sciences, 0302 clinical medicine, Double-Blind Method, medicine, Clinical endpoint, Humans, 030304 developmental biology, 0303 health sciences, business.industry, Epworth Sleepiness Scale, Modafinil, Parkinson Disease, clinical trial, medicine.disease, Crossover study, 3. Good health, flecainide, Clinical trial, Drug Combinations, Neurology, Anesthesia, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology (clinical), medicine.symptom, modafinil, business, 030217 neurology & neurosurgery, medicine.drug
Abstract: International audience; BackgroundExcessive daytime sleepiness (EDS) is a frequent and disabling symptom of Parkinson's disease (PD) without approved treatment. THN102 is a novel combination drug of modafinil and low-dose flecainide.ObjectiveThe aim of this study is to evaluate the safety and efficacy of THN102 in PD patients with EDS.MethodsThe method involved a randomized, double-blind, placebo-controlled, crossover trial testing two doses of THN102 (200 mg/d modafinil with 2 mg/d [200/2] or 18 mg/d flecainide [200/18]) versus placebo; 75 patients were exposed to treatment. The primary endpoint was safety. The primary efficacy outcome was the change in Epworth Sleepiness Scale (ESS) score.ResultsBoth doses of THN102 were well tolerated. ESS significantly improved with THN102 200/2 (least square means vs. placebo [95% confidence interval, CI]: −1.4 [−2.49; −0.31], P = 0.012) but did not change significantly with the 200/18 dosage.ConclusionsTHN102 was well tolerated and showed a signal of efficacy at the 200/2 dose, supporting further development for the treatment of EDS in PD. © 2021 International Parkinson and Movement Disorder Society
Published: 2021
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15. Safety and efficacy of riluzole in spinocerebellar ataxia type 2 in France (ATRIL): a multicentre, randomised, double-blind, placebo-controlled trial

Author: Giulia Coarelli, Anna Heinzmann, Claire Ewenczyk, Clara Fischer, Marie Chupin, Marie-Lorraine Monin, Hortense Hurmic, Fabienne Calvas, Patrick Calvas, Cyril Goizet, Stéphane Thobois, Mathieu Anheim, Karine Nguyen, David Devos, Christophe Verny, Vito A G Ricigliano, Jean-François Mangin, Alexis Brice, Sophie Tezenas du Montcel, Alexandra Durr, Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Building large instruments for neuroimaging: from population imaging to ultra-high magnetic fields (BAOBAB), Service NEUROSPIN (NEUROSPIN), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Pellegrin, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Hospices Civils de Lyon (HCL), Institut des sciences cognitives Marc Jeannerod - Centre de neuroscience cognitive - UMR5229 (ISC-MJ), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Hôpital de Hautepierre [Strasbourg], Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Marseille, Lille Neurosciences & Cognition - U 1172 (LilNCog), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Lille, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Algorithms, models and methods for images and signals of the human brain (ARAMIS), Sorbonne Université (SU)-Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut des sciences cognitives Marc Jeannerod - Centre de neuroscience cognitive - UMR5229 (CNC), and Coarelli, Giulia
Subjects: [SDV] Life Sciences [q-bio], [SDV]Life Sciences [q-bio], Neurology (clinical)
Abstract: International audience; BackgroundRiluzole has been reported to be beneficial in patients with cerebellar ataxia; however, effectiveness in individual subtypes of disease is unclear due to heterogeneity in participants' causes and stages of disease. Our aim was to test riluzole in a single genetic disease, spinocerebellar ataxia type 2.MethodsWe did a randomised, double-blind, placebo-controlled, multicentre trial (the ATRIL study) at eight national reference centres for rare diseases in France that were part of the Neurogene National Reference Centre for Rare Diseases. Participants were patients with spinocerebellar ataxia type 2 with an age at disease onset of up to 50 years and a scale for the assessment and rating of ataxia (SARA) score of at least 5 and up to 26. Patients were randomly assigned centrally (1:1) to receive either riluzole 50 mg orally or placebo twice per day for 12 months. Two visits, at baseline and at 12 months, included clinical measures and 3T brain MRI. The primary endpoint was the proportion of patients whose SARA score improved by at least 1 point. Analyses were done in the intention-to-treat population (all participants who were randomly assigned) and were done with only the observed data (complete case analysis). This trial is registered at ClinicalTrials.gov (NCT03347344) and has been completed.FindingsBetween Jan 18, 2018, and June 14, 2019, we enrolled 45 patients. 22 patients were randomly assigned to receive riluzole and 23 to receive placebo. Median age was 42 years (IQR 36–57) in the riluzole group and 49 years (40–56) in the placebo group and 23 (51%) participants were women. All participants presented with moderate-stage disease, characterised by a median SARA score of 13·5 (IQR 9·5–16·5). The primary endpoint, SARA score improvement of at least 1 point after 12 months, was observed in seven patients (32%) in the treated group versus nine patients (39%) in the placebo group, with a mean difference of −10·3% (95% CI −37·4% to 19·2%; p=0·75). SARA score showed a median increase (ie, worsening) of 0·5 points (IQR −1·5 to 1·5) in the riluzole group versus 0·3 points (−1·0 to 2·5) in the placebo group (p=0·70). No serious adverse event was reported in the riluzole-treated group whereas four patients in placebo group had a serious adverse event (hepatic enzyme increase, fracture of external malleolus, rectorrhagia, and depression). The number of patients with adverse events was similar in both groups (riluzole 16 [73%] patients vs placebo 19 [83%] patients; p=0·49).InterpretationWe were able to recruit 45 patients moderately affected by spinocerebellar ataxia type 2 for this trial. Riluzole did not improve clinical or radiological outcomes in these patients. However, our findings provide data on progression of spinocerebellar ataxia type 2 that might prove to be valuable for the design of other clinical trials.
Published: 2022
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16. Amyotrophic lateral sclerosis associated with a pathological expansion in the ATXN7 gene

Author: Florent Cluse, Emilien Bernard, Isabelle Strubi-Vuillaume, David Devos, Kevin Mouzat, Serge Lumbroso, Caroline Froment Tilikete, StÉphane Thobois, Antoine Pegat, Hospices Civils de Lyon (HCL), Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Département de neurologie [Lille], Lille Neurosciences & Cognition - U 1172 (LilNCog), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut des Neurosciences de Montpellier (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut des sciences cognitives Marc Jeannerod - Centre de neuroscience cognitive - UMR5229 (ISC-MJ), and Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)
Subjects: Spinocerebellar ataxia type 7, congenital, hereditary, and neonatal diseases and abnormalities, Neurology, Polyglutamine expansion, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology (clinical), Motor neuron disease, Amyotrophic lateral sclerosis, Ataxin-7 gene
Abstract: International audience; Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant hereditary neurodegenerative disease caused by the expansion of a CAG-repeat in the ataxin-7 (ATXN7) gene, usually characterized by progressive cerebellar ataxia and retinal dystrophy. We report the case of a 45-year-old woman presenting with a rapid-onset amyotrophic lateral sclerosis (ALS) phenotype associated with a 39-CAG-repeat expansion in ATXN7. This patient had neither ataxia nor retinal dystrophy, but she had an oculomotor cerebellar syndrome and a family history suggestive of SCA7. In SCA7, shorter expansions may be associated with less severe and incomplete clinical phenotypes, which could explain the patient's phenotype. Unknown genetic and environmental factors may also influence the patient's phenotype. We suggest that a pathological expansion in ATXN7 should be considered in cases of ALS-like phenotype, particularly when associated with oculomotor abnormalities or a family history of ataxia or blindness.
Published: 2021
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17. Nucleus Basalis of Meynert Stimulation for Lewy Body Dementia: A Phase I Randomized Clinical Trial

Author: Julie Bourilhon, Olivier Godefroy, Luc Defebvre, Didier Hannequin, Romain Lefaucheur, Stéphane Derrey, Stéphane Thobois, Pierre Vera, Jean-Luc Houeto, Kathy Dujardin, André Gillibert, David Wallon, Teodor Danaila, Olivier Martinaud, Pierre Krystkowiak, Marie-Laure Welter, Mathieu Chastan, David Maltête, Equipe Quantification en Imagerie Fonctionnelle (QuantIF-LITIS), Laboratoire d'Informatique, de Traitement de l'Information et des Systèmes (LITIS), Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Université Le Havre Normandie (ULH), Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), and Normandie Université (NU)
Subjects: Male, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Deep Brain Stimulation, MESH: Mental Recall, Stimulation, Neuropsychological Tests, Nucleus basalis, law.invention, Lingual gyrus, 0302 clinical medicine, Postoperative Complications, Randomized controlled trial, MESH: Fluorodeoxyglucose F18, law, MESH: Postoperative Complications, MESH: Double-Blind Method, 030212 general & internal medicine, MESH: Treatment Outcome, MESH: Aged, MESH: Middle Aged, Cross-Over Studies, Brain, MESH: Neuropsychological Tests, Middle Aged, MESH: Positron-Emission Tomography, surgical procedures, operative, Implantable Neurostimulators, Treatment Outcome, Anesthesia, Basal Nucleus of Meynert, MESH: Basal Nucleus of Meynert, therapeutics, MESH: Radiopharmaceuticals, Lewy Body Disease, Deep brain stimulation, MESH: Sleep, MESH: Prosthesis Implantation, behavioral disciplines and activities, MESH: Cross-Over Studies, Article, Prosthesis Implantation, MESH: Brain, 03 medical and health sciences, Double-Blind Method, Fluorodeoxyglucose F18, medicine, Dementia, Humans, MESH: Lewy Body Disease, Aged, MESH: Humans, Lewy body, business.industry, medicine.disease, MESH: Male, MESH: Implantable Neurostimulators, nervous system diseases, nervous system, Positron-Emission Tomography, Mental Recall, Neurology (clinical), MESH: Deep Brain Stimulation, Radiopharmaceuticals, business, Sleep, 030217 neurology & neurosurgery, Stroop effect
Abstract: ObjectivesNucleus basalis of Meynert deep brain stimulation (NBM-DBS) has been proposed for patients with dementia. Here, we aim to assess the safety and effects of NBM-DBS in patients with Lewy body dementia (LBD), in a randomized, double-blind, crossover clinical trial.MethodsSix patients with mild to moderate LBD (mean [SD] age, 62.2 [7.8] years) were included, operated on for bilateral NBM-DBS, and assigned to receive either active or sham NBM-DBS followed by the opposite condition for 3 months. The primary outcome was the difference in the total free recalls of the Free and Cued Selective Reminding Test (FCSRT) between active and sham NBM-DBS. Secondary outcomes were assessments of the safety and effects of NBM-DBS on cognition, motor disability, sleep, and PET imaging.ResultsThere was no significant difference in the FCSRT score with active vs sham NBM-DBS. The surgical procedures were well tolerated in all patients, but we observed significant decreases in Stroop and Benton scores after electrode implantation. We observed no significant difference in other scales between active and sham NBM-DBS. With active NBM-DBS relative to baseline, phonemic fluency and motor disability significantly decreased. Lastly, the superior lingual gyrus metabolic activity significantly increased with active NBM-DBS.ConclusionsNBM-DBS does not appear to be totally safe for patients with LBD with no evidence of cognitive benefit.ClinicalTrials.gov IdentifierNCT01340001.Classification of EvidenceThis study provides Class II evidence that, for patients with LBD operated on for bilateral NBM-DBS, active NBM-DBS stimulation compared to sham stimulation did not significantly change selective recall scores.
Published: 2021
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18. Preoperative REM sleep behavior disorder and subthalamic nucleus deep brain stimulation outcome in Parkinson disease 1 year after surgery

Author: Isabelle Benatru, Dominique Guehl, Philippe Derost, Stéphane Thobois, David Devos, Franck Durif, Elodie Durand, Mélissa Tir, Ouhaid Lagha-Boukbiza, Elodie Hainque, Elsa Besse-Pinot, Caroline Giordana, Jean-Christophe Corvol, B. Debilly, David Maltête, Tiphaine Rouaud, Sophie Drapier, Lucie Hopes, Bruno Pereira, Ana Marques, Cécile Hubsch, Maria Livia Fantini, Olivier Rascol, Alexandre Eusebio, Caroline Moreau, Anne-Sophie Rolland, Béchir Jarraya, Neuro-Psycho Pharmacologie des Systèmes Dopimanégiques sous-corticaux (NPsy-Sydo), CHU Clermont-Ferrand-Université Clermont Auvergne (UCA), Unité de Biostatistiques [CHU Clermont-Ferrand], Direction de la recherche clinique et de l’innovation [CHU Clermont-Ferrand] (DRCI), CHU Clermont-Ferrand-CHU Clermont-Ferrand, CHU Lille, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service de neurologie [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Hôpital Guillaume-et-René-Laennec [Saint-Herblain], Institut de Neurosciences de la Timone (INT), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Service de neurologie [Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Service de Neurologie [CHU Rennes], CHU Pontchaillou [Rennes], Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Centre d'investigation clinique de Toulouse (CIC 1436), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d’Excellence en Maladies Neurodégénératives (NeuroToul), CHU Toulouse [Toulouse], Service de neurologie [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Service de Neurologie [Strasbourg], CHU Strasbourg-Hopital Civil, Service de Neurologie [CHU Nice], Hôpital Pasteur [Nice] (CHU)-Centre Hospitalier Universitaire de Nice (CHU Nice), Laboratoire de Neurosciences Fonctionnelles et Pathologies - UR UPJV 4559 (LNFP), Université de Picardie Jules Verne (UPJV), Institut des sciences cognitives Marc Jeannerod - Centre de neuroscience cognitive - UMR5229 (CNC), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Service de neurologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Fondation Ophtalmologique Adolphe de Rothschild [Paris], Hôpital Foch [Suresnes], Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Lille Neurosciences & Cognition - U 1172 (LilNCog (ex-JPARC)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Ministère des Affaires Sociales et de la Santé, The study was funded by the France Parkinson charity and French Ministry of Health (PHRC National 2012) and promoted by CHU Lille (coordinated by Pr Devos and Pr Corvol) with the support of the French network NS-PARK and supported by NS-PARK/F-CRIN and the Fédération de la Recherche Clinique du CHU de Lille., Marques, Ana, CHU Clermont-Ferrand-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), CHU Clermont-Ferrand, École d’Orthoptie - Clermont-Ferrand (EO - UdA), CHU Clermont-Ferrand-Université d'Auvergne - Clermont-Ferrand I (UdA), Service de Neurologie [CHU Clermont-Ferrand], CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand-CHU Estaing [Clermont-Ferrand], Service de neurologie et pathologie du mouvement, Hôpital Roger Salengro [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital Guillaume-et-René-Laennec [Saint-Herblain], Hôpital de la Timone [CHU - APHM] (TIMONE), CIC - Poitiers, Université de Poitiers-Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Direction Générale de l'Organisation des Soins (DGOS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Bordeaux [Bordeaux], Toulouse Neuro Imaging Center (ToNIC), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Toulouse Mind & Brain Institut (TMBI), Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées, Différenciation et communication neuronale et neuroendocrine (DC2N), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Strasbourg, Centre Hospitalier Universitaire de Nice (CHU Nice), Centre Hospitalier Universitaire de Nancy (CHU Nancy), Hôpital de la Fondation Ophtalmologique Adolphe de Rothschild [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service NEUROSPIN (NEUROSPIN), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Lille Neurosciences & Cognition - U 1172 (LilNCog), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Toulouse Mind & Brain Institut (TMBI), Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), Institut des sciences cognitives Marc Jeannerod - Centre de neuroscience cognitive - UMR5229 (ISC-MJ), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Hôpital Guillaume-et-René-Laennec [Saint-Herblain]-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes (UN)
Subjects: medicine.medical_specialty, Activities of daily living, Deep Brain Stimulation, REM Sleep Behavior Disorder, Disease, Risk Assessment, REM sleep behavior disorder, 03 medical and health sciences, 0302 clinical medicine, Quality of life, Subthalamic Nucleus, Rating scale, medicine, Humans, Prospective Studies, 030212 general & internal medicine, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Prospective cohort study, business.industry, Subthalamic nucleus deep brain stimulation, Parkinson Disease, medicine.disease, 3. Good health, Surgery, Treatment Outcome, Preoperative Period, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology (clinical), Neurosurgery, business, 030217 neurology & neurosurgery, Research Article
Abstract: Background and ObjectivesTo determine whether patients with Parkinson disease (PD) eligible for subthalamic nucleus deep brain stimulation (STN-DBS) with probable REM sleep behavior disorder (RBD) preoperatively could be more at risk of poorer motor, nonmotor, and quality of life outcomes 12 months after surgery compared to those without RBD.MethodsWe analyzed the preoperative clinical profile of 448 patients with PD from a French multicentric prospective study (PREDISTIM) according to the presence or absence of probable RBD based on the RBD Single Question and RBD Screening Questionnaire. Among the 215 patients with PD with 12 months of follow-up after STN-DBS, we compared motor, cognitive, psycho-behavioral profile, and quality of life outcomes in patients with (pre-opRBD+) or without (pre-opRBD–) probable RBD preoperatively.ResultsAt preoperative evaluation, pre-opRBD+ patients were older (61 ± 7.2 vs 59.5 ± 7.7 years; p = 0.02), had less motor impairment (Movement Disorder Society–sponsored version of the Unified Parkinson’s Disease Rating Scale [MDS-UPDRS] III “off”: 38.7 ± 16.2 vs 43.4 ± 7.1; p = 0.03) but more nonmotor symptoms on daily living activities (MDS-UPDRS I: 12.6 ± 5.5 vs 10.7 ± 5.3; p < 0.001), had more psychobehavioral manifestations (Ardouin Scale of Behavior in Parkinson's Disease total: 7.7 ± 5.1 vs 5.1 ± 0.4; p = 0.003), and had worse quality of life (Parkinson's Disease Questionnaire–39: 33 ± 12 vs 29 ± 12; p = 0.03), as compared to pre-opRBD– patients. Both pre-opRBD+ and pre-opRBD– patients had significant MDS-UPDRS IV score decrease (−37% and −33%, respectively), MDS-UPDRS III “med ‘off’/stim ‘on’” score decrease (−52% and −54%), and dopaminergic treatment decrease (−52% and −49%) after surgery, with no between-group difference. There was no between-group difference for cognitive and global quality of life outcomes.ConclusionsIn patients with PD eligible for STN-DBS, the presence of probable RBD preoperatively is not associated with a different clinical outcome 1 year after neurosurgery.Trial Registration InformationNCT02360683.Classification of EvidenceThis study provides Class II evidence that in patients with PD eligible for STN-DBS, the presence of probable RBD preoperatively is not associated with poorer outcomes 1 year post surgery.
Published: 2021
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19. Dissociation in reactive and proactive inhibitory control in Myoclonus dystonia

Author: Vanessa Brochard, Cyril Atkinson-Clement, Yulia Worbe, David Grabli, Stéphane Thobois, Jean‐Michel Pedespan, Nicolas Wattiez, Christine Tranchant, Romain Valabregue, Pierre Krystkoviak, Emmanuel Roze, Bertrand Degos, Clément Tarrano, Emmanuelle Apartis, Charlotte Rosso, Cécile Delorme, Camille-Albane Porte, Luc Defebvre, Jean-Luc Houeto, Marie Vidailhet, Eavan McGovern, Jean-Christophe Corvol, Pierre Pouget, Adrian Degardin, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Hôpital Côte de Nacre [CHU Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Université de Caen Normandie (UNICAEN), Normandie Université (NU), Centre d'investigation clinique Neurosciences [CHU Pitié Salpêtrière] (CIC Neurosciences), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Neurophysiologie Respiratoire Expérimentale et Clinique (UMRS 1158), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), St Vincent's University Hospital, Institut des sciences cognitives Marc Jeannerod - Centre de neuroscience cognitive - UMR5229 (CNC), Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Hospices Civils de Lyon (HCL), Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA), Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpitaux Paris Seine-Saint-Denis [Bobigny], CHU de Bordeaux Pellegrin [Bordeaux], CHU Amiens-Picardie, CIC - Poitiers, Université de Poitiers-Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Direction Générale de l'Organisation des Soins (DGOS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier de Tourcoing, Troubles cognitifs dégénératifs et vasculaires - U 1171 (TCDV), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Saint-Antoine [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Neurophysiologie Respiratoire Expérimentale et Clinique, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université de Caen Normandie - UFR Santé (UNICAEN Santé), Normandie Université (NU)-Normandie Université (NU), Centre d'investigation clinique pluridisciplinaire [CHU Pitié Salpêtrière] (CIC-P 1421), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Service de neurologie [Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), CHU Lille, Service de Neurologie [CHU Saint-Antoine], Atkinson-Clement, Cyril, Service de pédiatrie, CHU Pellegrin, Département de neurologie[Lille], Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de neurologie et pathologie du mouvement, Hôpital Roger Salengro [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Equipe NEMESIS - Centre de Recherches de l'Institut du Cerveau et de la Moelle épinière (NEMESIS-CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Institut des sciences cognitives Marc Jeannerod - Centre de neuroscience cognitive - UMR5229 (ISC-MJ), and ANR-18-CE37-0008,CADETS,Cognition et développement cérébral chez adolescents avec Syndrome de Gilles de la Tourette(2018)
Subjects: Male, Myoclonus, 0301 basic medicine, Deep Brain Stimulation, medicine.medical_treatment, lcsh:Medicine, Stop signal, Synaptic Transmission, Comorbidities, [SCCO]Cognitive science, 0302 clinical medicine, lcsh:Science, ComputingMilieux_MISCELLANEOUS, Dystonia, Multidisciplinary, Inhibition, Psychological, Dystonic Disorders, Proactive Inhibition, Neurological manifestations, Facilitation, Female, medicine.symptom, Adult, medicine.medical_specialty, Deep brain stimulation, Dissociative Disorders, Globus Pallidus, Inhibitory postsynaptic potential, Article, Young Adult, 03 medical and health sciences, Internal medicine, Reaction Time, medicine, Humans, Movement disorders, Reactive inhibition, business.industry, [SCCO.NEUR]Cognitive science/Neuroscience, lcsh:R, Reactive Inhibition, [SCCO] Cognitive science, medicine.disease, nervous system diseases, 030104 developmental biology, Endocrinology, nervous system, lcsh:Q, business, Neurological disorders, 030217 neurology & neurosurgery
Abstract: Myoclonus-dystonia (MD) is a syndrome characterized by myoclonus of subcortical origin and dystonia, frequently associated with psychiatric comorbidities. The motor and psychiatric phenotypes of this syndrome likely result from cortico-striato-thamalo-cerebellar-cortical pathway dysfunction. We hypothesized that reactive and proactive inhibitory control may be altered in these patients. Using the Stop Signal Task, we assessed reactive and proactive inhibitory control in MD patients with (n = 12) and without (n = 21) deep brain stimulation of the globus pallidus interna and compared their performance to matched healthy controls (n = 24). Reactive inhibition was considered as the ability to stop an already initiated action and measured using the stop signal reaction time. Proactive inhibition was assessed through the influence of several consecutive GO or STOP trials on decreased response time or inhibitory process facilitation. The proactive inhibition was solely impaired in unoperated MD patients. Patients with deep brain stimulation showed impairment in reactive inhibition, independent of presence of obsessive–compulsive disorders. This impairment in reactive inhibitory control correlated with intrinsic severity of myoclonus (i.e. pre-operative score). The results point to a dissociation in reactive and proactive inhibitory control in MD patients with and without deep brain stimulation of the globus pallidus interna.
Published: 2020
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20. Isolated parkinsonism is an atypical presentation of GRN and C9orf72 gene mutations Authors

Author: Florence Cormier, Timothée Lenglet, Alexis Brice, Jean-Christophe Corvol, Fabienne Clot, Vincent Deramecourt, Karl Mondon, Dario Saracino, Stéphane Thobois, Vincent Huin, Aurélie Méneret, Emilie Beaufils, Cécile Delorme, Audrey Gabelle, Fábio Carneiro, Marie Vidailhet, Isabelle Le Ber, Mélissa Tir, Marie-Odile Habert, Daniela Andriuta, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Algorithms, models and methods for images and signals of the human brain (ARAMIS), Sorbonne Université (SU)-Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Lille Neurosciences & Cognition - U 1172 (LilNCog (ex-JPARC)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), UF Neurométabolique Bioclinique et Génétique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut des sciences cognitives Marc Jeannerod - Centre de neuroscience cognitive - UMR5229 (CNC), Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Laboratoire d'Imagerie Biomédicale (LIB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Département de neurologie [Montpellier], Hôpital Gui de Chauliac [Montpellier]-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université de Tours (UT), Service de neurologie [Amiens], CHU Amiens-Picardie, Excellence Laboratory LabEx DISTALZ, The research leading to these results received funding from the 'Investissements d'avenir' ANR-11-INBS-0011. This work was funded by the Programme Hospitalier de Recherche Clinique (PHRC) FTLD-exome (to ILB, promotion by Assistance Publique – Hôpitaux de Paris) and by PHRC Predict-PGRN (to ILB, promotion by Assistance Publique – Hôpitaux de Paris)., Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Lille Neurosciences & Cognition - U 1172 (LilNCog), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut des sciences cognitives Marc Jeannerod - Centre de neuroscience cognitive - UMR5229 (ISC-MJ), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Imagerie Biomédicale [Paris] (LIB), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [CHU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université de Montpellier (UM), Laboratoire de Neurosciences Fonctionnelles et Pathologies - UR UPJV 4559 (LNFP), Université de Picardie Jules Verne (UPJV), ANR-16-IDEX-0006,MUSE,MUSE(2016), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [Montpellier]-Université de Montpellier (UM), Gestionnaire, HAL Sorbonne Université 5, Service de neurologie 1 [CHU Pitié-Salpétrière], Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université de Tours
Subjects: Male, 0301 basic medicine, Parkinson's disease, TDP-43, Disease, Bioinformatics, Progranulins, 0302 clinical medicine, C9orf72, Age of Onset, Family history, PSP, Parkinsonism, Parkinson Disease, FTD, Middle Aged, Pedigree, 3. Good health, Neurology, Frontotemporal Dementia, Neurons and Cognition (q-bio.NC), [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], FTLD, GRN, Frontotemporal dementia, CBS, 03 medical and health sciences, Parkinsonian Disorders, medicine, Humans, Dementia, Cognitive Dysfunction, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Aged, C9orf72 Protein, business.industry, medicine.disease, nervous system diseases, 030104 developmental biology, Quantitative Biology - Neurons and Cognition, FOS: Biological sciences, Mutation, Etiology, Neurology (clinical), Geriatrics and Gerontology, business, 030217 neurology & neurosurgery
Abstract: Introduction A phenotype of isolated parkinsonism mimicking Idiopathic Parkinson's Disease (IPD) is a rare clinical presentation of GRN and C9orf72 mutations, the major genetic causes of frontotemporal dementia (FTD). It still remains controversial if this association is fortuitous or not, and which clinical clues could reliably suggest a genetic FTD etiology in IPD patients. This study aims to describe the clinical characteristics of FTD mutation carriers presenting with IPD phenotype, provide neuropathological evidence of the mutation's causality, and specifically address their “red flags” according to current IPD criteria. Methods Seven GRN and C9orf72 carriers with isolated parkinsonism at onset, and three patients from the literature were included in this study. To allow better delineation of their phenotype, the presence of supportive, exclusion and “red flag” features from MDS criteria were analyzed for each case. Results Amongst the ten patients (5 GRN, 5 C9orf72), seven fulfilled probable IPD criteria during all the disease course, while behavioral/language or motoneuron dysfunctions occurred later in three. Disease duration was longer and dopa-responsiveness was more sustained in C9orf72 than in GRN carriers. Subtle motor features, cognitive/behavioral changes, family history of dementia/ALS were suggestive clues for a genetic diagnosis. Importantly, neuropathological examination in one patient revealed typical TDP-43-inclusions without alpha-synucleinopathy, thus demonstrating the causal link between FTD mutations, TDP-43-pathology and PD phenotype. Conclusion We showed that, altogether, family history of early-onset dementia/ALS, the presence of cognitive/behavioral dysfunction and subtle motor characteristics are atypical features frequently present in the parkinsonian presentations of GRN and C9orf72 mutations.
Published: 2020
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21. Analyse génétique et phénotypique des formes autosomiques dominantes dans une large cohorte multi-centrique

Author: Suzanne, Lesage, Marion, Houot, Graziella, Mangone, Christelle, Tesson, Hélène, Bertrand, Sylvie, Forlani, Mathieu, Anheim, Christine, Brefel-Courbon, Emmanuel, Broussolle, Stéphane, Thobois, Philippe, Damier, Franck, Durif, Emmanuel, Roze, François, Tison, David, Grabli, Fabienne, Ory-Magne, Bertrand, Degos, François, Viallet, Florence, Cormier-Dequaire, Anne-Marie, Ouvrard-Hernandez, Marie, Vidailhet, Ebba, Lohmann, Andrew, Singleton, Jean-Christophe, Corvol, Alexis, Brice, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut de la Mémoire et de la Maladie d'Alzheimer [Paris] (IM2A), Sorbonne Université (SU), Service de neurologie 1 [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Centre d'investigation clinique Neurosciences [CHU Pitié Salpêtrière] (CIC Neurosciences), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Les Hôpitaux Universitaires de Strasbourg (HUS), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA), CHU Toulouse [Toulouse], Hôpital Pierre-Paul Riquet [Toulouse], Institut des sciences cognitives Marc Jeannerod - Centre de neuroscience cognitive - UMR5229 (CNC), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Hospices Civils de Lyon (HCL), Centre hospitalier universitaire de Nantes (CHU Nantes), Centre d’Investigation Clinique de Nantes (CIC Nantes), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes), CHU Clermont-Ferrand, Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Dynamique et physiopathologie des réseaux neuronaux, Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre interdisciplinaire de recherche en biologie (CIRB), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Parole et Langage (LPL), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire [Grenoble] (CHU), Hertie Institute for Clinical Brain Research [Tubingen], University of Tübingen, National Institutes of Health [Bethesda] (NIH), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut de la Mémoire et de la Maladie d'Alzheimer [CHU Pitié-Salpétriêre] (IM2A), Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Centre d'investigation clinique pluridisciplinaire [CHU Pitié Salpêtrière] (CIC-P 1421), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), and Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: genotype-phenotype correlations, [SCCO.NEUR]Cognitive science/Neuroscience, [SDV]Life Sciences [q-bio], Parkinson's disease, LRRK2, Brief Research Report, autosomal dominant inheritance, [SCCO]Cognitive science, Neurology, Parkinson’s disease, G2019S, SNCA, MESH: Parkinson’s disease, SNCA, VPS35, VPS35
Abstract: International audience; LRRK2, SNCA, and VPS35 are unequivocally associated with autosomal dominant Parkinson's disease (PD). We evaluated the prevalence of LRRK2, SNCA, and VPS35 mutations and associated clinical features in a large French multi-center cohort of PD patients. Demographic and clinical data were collected for 1,805 index cases (592 with autosomal dominant inheritance and 1,213 isolated cases) since 1990. All probands were screened with TaqMan assays for LRRK2 Gly2019Ser. In the absence of this mutation, the coding sequences of the three genes were analyzed by Sanger sequencing and/or next-generation sequencing. The data for the three genes were analyzed according to age at onset, family history, ethnic origin and clinical features. We identified 160 index cases (8.9%) with known pathogenic variants: 138 with pathogenic LRRK2 variants (7.6%), including 136 with the Gly2019Ser mutation, 19 with SNCA point mutations or genomic rearrangements (1.1%), and three with the VPS35 Asp620Asn mutation (0.16%). Mutation frequencies were higher in familial than isolated cases, consistent with autosomal dominant inheritance (12.0 vs. 7.3%; OR 1.7, 95% CI [1.2-2.4], p = 0.001). PD patients with LRRK2 variants were more likely to have higher rates of late-onset PD (>50 years; OR 1.5, 95% CI [1.0-2.1], p = 0.03), whereas those with SNCA mutations tended to have earlier age at onset disease (≤ 50 years, p = 0.06). The clinical features of LRRK2 carriers and those without any pathogenic variants in known PD-associated genes were similar. The likelihood of detecting disease-causing mutations was higher in cases compatible with autosomal dominant inheritance.
Published: 2020
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22. Utilisation de l’imagerie cérébrale dans notre pratique face à un syndrome parkinsonien

Author: Stéphane Thobois, S. Prange, Institut des sciences cognitives Marc Jeannerod - Centre de neuroscience cognitive - UMR5229 (CNC), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Hospices Civils de Lyon (HCL), and Université de Lyon
Subjects: 03 medical and health sciences, 0302 clinical medicine, [SDV]Life Sciences [q-bio], Neurology (clinical), 030217 neurology & neurosurgery, 030218 nuclear medicine & medical imaging, 3. Good health
Abstract: Resume Le diagnostic positif et differentiel d’un syndrome parkinsonien est parfois difficile pour le neurologue. L’imagerie cerebrale, dans ses differentes modalites, represente une aide importante au diagnostic. L’IRM cerebrale permet de mettre en evidence des anomalies evocatrices de syndromes parkinsoniens « plus » ou de pathologies pouvant comporter un syndrome parkinsonien (lesions vasculaires, hydrocephalie, maladie de Wilson…). L’utilisation de nouvelles sequences permet par ailleurs de visualiser les anomalies morphologiques de la substance noire dans la maladie de Parkinson mais cela n’a pas d’interet pratique aujourd’hui. Le DATscan* ou la TEP [18F]-Dopa affirment ou infirment la presence d’une degenerescence dopaminergique de la voie nigro-striee, permettant de preciser si l’on se situe dans le cadre d’un syndrome parkinsonien degeneratif ou non (quel que soit son type) ou d’une autre pathologie. La TEP FDG et la scintigraphie au MIBG aident au diagnostic differentiel entre maladie de Parkinson et syndromes parkinsoniens « plus ».
Published: 2020
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23. Quality of life predicts outcome of deep brain stimulation in early Parkinson disease

Author: Stéphane Thobois, Marie Vidailhet, Stéphane Derrey, Andrea Kistner, Philippe Damier, Daniel Weiss, W.M. Michael Schuepbach, Günther Deuschl, Thomas D. Hälbig, Tobias Wächter, Andreas Kupsch, Michael T. Barbe, Jan Vesper, Carmen Schade-Brittinger, Christine Brefel-Courbon, G.R. Fink, Jean-Luc Houeto, Friederike Sixel-Döring, Alireza Gharabaghi, Jens Volkmann, Karina Knudsen, David Maltête, Andrea A. Kühn, Andrea Falk, Patrick Mertens, Gerd-H. Schneider, Lars Timmermann, Alfons Schnitzler, Eric Seigneuret, Fabienne Ory-Magne, Pascal Derkinderen, Patrick Chaynes, Tatiana Witjas, Joern Rau, Valérie Fraix, S. Paschen, J. Regis, Lisa Tonder, Lars Wojtecki, Marcus O. Pinsker, Paul Krack, Haidar S. Dafsari, Andreas Hartmann, Fanny Pineau, Laura Paschen, Claudia Trenkwalder, Yves Agid, Universität Bern [Bern] (UNIBE), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), CIC AP-HP (pitie-Salpetriere)/inserm, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Medtronic [Minneapolis, MI, USA], Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], University of Geneva [Switzerland], Centre de coordination des essais cliniques, Philipps-University, Marburg, Allemagne., Centre d'investigation clinique Neurosciences [CHU Pitié Salpêtrière] (CIC Neurosciences), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), NeuroCure Clinical Research Center (NCRC), Charité University Medical Center, Charité (Campus Mitte), Berlin, Germany., Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Department of Neuroscience, Karolinska institutet, Stockholm, Sweden, Department of Neuroscience, Karolinska institutet, Department of Neurology, University Medical Center Schleswig-Holstein, Arnold-Heller-Street 3, Kiel 24105, Germany., Department of Neurology, Christian-Albrechts-University, Kiel, Germany., Christian-Albrechts-Universität zu Kiel (CAU), University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Neurology, Cologne, Germany., National Parkinson Foundation Centre of Excellence, King's College Hospital, London, UK., Department of Neurology, University of Cologne, Cologne, Germany., Department of Neurology, Movement Disorder and Neuromodulation Unit, Charité-Universitätsmedizin, Berlin, Germany., NeuroCure Clinical Research Center, Charité-Universitätsmedizin, Berlin, Germany., Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Department of Neurology & Neurosurgery, Charite University Medicine Berlin, Campus Virchow Klinikum & Benjamin Franklin, Berlin, Germany., Centre Hospitalier Universitaire [Grenoble] (CHU), Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), UM des troubles du mouvement, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, Service d'Anatomie et Cytopathologie [Toulouse], Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'investigation clinique de Toulouse (CIC 1436), Department of Functional Neurosurgery and Stereotaxy, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany., Service de neurochirurgie [CHU Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Nutrition, inflammation et dysfonctionnement de l'axe intestin-cerveau (ADEN), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de neurologie [Rouen], Normandie Université (NU)-Normandie Université (NU), Clinique neurologique, Hôpital Laennec, Neuropathies du système nerveux entérique et pathologies digestives, implication des cellules gliales entériques, Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM), Paracelsus-Elena-Klinik, Kassel, Germany., Department of Neurology, Philipps University Marburg, Germany., Paracelsus Elena Klinik, Centre for Parkinson's Disease & Movement Disorders, Department of Neurosurgery, University of Tuebingen, Center of Neurology, Hertie Institute for Clinical Brain Research, University of Tuebingen, University of Vermont [Burlington], Stereotactic and Functional Neurosurgery Service and Gamma Knife Unit CHU Timone Marseille, France., AP-HM, CHU Timone, Pole de Neurosciences Cliniques, Department of Neurology, Marseille, France., Service de Neurologie, Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Service Public de Wallonie, Department of Nuclear Medicine and PET Centre Aarhus University Hospital, Institute of Clinical Medicine Aarhus University, Norrebrogade 44, Building 10, 8000, Aarhus C, Denmark., Somnomar, Sleep Research Institute, Service de neurologie [Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), CIC - Poitiers, Université de Poitiers-Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Direction Générale de l'Organisation des Soins (DGOS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neurologie et thérapeutique expérimentale, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR70-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Heinrich-Heine-Universität Düsseldorf [Düsseldorf], Département de Neurologie [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-IFR70-CHU Pitié-Salpêtrière [APHP], Charité - Universitätsmedizin Berlin / Charite - University Medicine Berlin, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-Institut National de la Santé et de la Recherche Médicale (INSERM), CIC Toulouse, Service de Pharmacologie Médicale et Clinique, CHU Toulouse [Toulouse], University of Vermont College of Medicine [Burlington, VT, USA], Laboratoire de Neurosciences Cognitives [Marseille] (LNC), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR70-Université Pierre et Marie Curie - Paris 6 (UPMC), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Universität Bern [Bern], Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Charité Hospital, Humboldt Universität zu Berlin, and Service de neurochirurgie [Rouen]
Subjects: 0301 basic medicine, medicine.medical_specialty, Parkinson's disease, Deep brain stimulation, medicine.medical_treatment, 610 Medicine & health, Disease, law.invention, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, Quality of life, Rating scale, law, Internal medicine, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Clinical endpoint, Medicine, ddc:610, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], 10. No inequality, ComputingMilieux_MISCELLANEOUS, business.industry, medicine.disease, humanities, 3. Good health, nervous system diseases, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], Subthalamic nucleus, 030104 developmental biology, Neurology (clinical), business, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, 030217 neurology & neurosurgery
Abstract: ObjectiveTo investigate predictors for improvement of disease-specific quality of life (QOL) after deep brain stimulation (DBS) of the subthalamic nucleus (STN) for Parkinson disease (PD) with early motor complications.MethodsWe performed a secondary analysis of data from the previously published EARLYSTIM study, a prospective randomized trial comparing STN-DBS (n = 124) to best medical treatment (n = 127) after 2 years follow-up with disease-specific QOL (39-item Parkinson's Disease Questionnaire summary index [PDQ-39-SI]) as the primary endpoint. Linear regression analyses of the baseline characteristics age, disease duration, duration of motor complications, and disease severity measured at baseline with the Unified Parkinson’s Disease Rating Scale (UPDRS) (UPDRS-III “off” and “on” medications, UPDRS-IV) were conducted to determine predictors of change in PDQ-39-SI.ResultsPDQ-39-SI at baseline was correlated to the change in PDQ-39-SI after 24 months in both treatment groups (p < 0.05). The higher the baseline score (worse QOL) the larger the improvement in QOL after 24 months. No correlation was found for any of the other baseline characteristics analyzed in either treatment group.ConclusionImpaired QOL as subjectively evaluated by the patient is the most important predictor of benefit in patients with PD and early motor complications, fulfilling objective gold standard inclusion criteria for STN-DBS. Our results prompt systematically including evaluation of disease-specific QOL when selecting patients with PD for STN-DBS.Clinicaltrials.gov identifierNCT00354133.
Published: 2019
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24. Wait and you shall see: sexual delay discounting in hypersexual Parkinson’s disease

Author: Stéphane Thobois, Franck Durif, Romuald Girard, Emmanuel Broussolle, Paul Krack, Ignacio Obeso, Emilie Favre, Miguel Ulla, Seongmin Park, Tiphaine Vidal, Jean-Claude Dreher, Institut des sciences cognitives Marc Jeannerod - Centre de neuroscience cognitive - UMR5229 (ISC-MJ), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Neurologie C, Hospices Civils de Lyon (HCL)-Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Hospices Civils de Lyon (HCL)-Université de Lyon, Service de Neurologie [CHU Clermont-Ferrand], CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand-CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand, Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Hospices Civils de Lyon (HCL), Département de neurologie, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, Neuro-Psycho Pharmacologie des Systèmes Dopimanégiques sous-corticaux (NPsy-Sydo), CHU Clermont-Ferrand-Université d'Auvergne - Clermont-Ferrand I (UdA), and Institut des sciences cognitives Marc Jeannerod - Centre de neuroscience cognitive - UMR5229 (CNC)
Subjects: Male, 0301 basic medicine, medicine.medical_specialty, Parkinson's disease, Sexual Behavior, Prefrontal Cortex, Neuroimaging, Audiology, Gyrus Cinguli, 03 medical and health sciences, 0302 clinical medicine, Humans, Medicine, Prefrontal cortex, Anterior cingulate cortex, medicine.diagnostic_test, business.industry, [SCCO.NEUR]Cognitive science/Neuroscience, Ventral striatum, Parkinson Disease, Middle Aged, medicine.disease, Magnetic Resonance Imaging, Disruptive, Impulse Control, and Conduct Disorders, 030104 developmental biology, medicine.anatomical_structure, Delay Discounting, Case-Control Studies, Posterior cingulate, Incentive salience, Dopamine Agonists, Ventral Striatum, Hypersexuality, Neurology (clinical), medicine.symptom, business, Functional magnetic resonance imaging, 030217 neurology & neurosurgery
Abstract: Patients with Parkinson's disease may develop impulse control disorders under dopaminergic treatments. Impulse control disorders include a wide spectrum of behaviours, such as hypersexuality, pathological gambling or compulsive shopping. Yet, the neural systems engaged in specific impulse control disorders remain poorly characterized. Here, using model-based functional MRI, we aimed to determine the brain systems involved during delay-discounting of erotic rewards in hypersexual patients with Parkinson's disease (PD+HS), patients with Parkinson's disease without hypersexuality (PD - HS) and controls. Patients with Parkinson's disease were evaluated ON and OFF levodopa (counterbalanced). Participants had to decide between two options: (i) wait for 1.5 s to briefly view an erotic image; or (ii) wait longer to see the erotic image for a longer period of time. At the time of decision-making, we investigated which brain regions were engaged with the subjective valuation of the delayed erotic reward. At the time of the rewarded outcome, we searched for the brain regions responding more robustly after waiting longer to view the erotic image. PD+HS patients showed reduced discounting of erotic delayed rewards, compared to both patients with Parkinson's disease and controls, suggesting that they accepted waiting longer to view erotic images for a longer period of time. Thus, when using erotic stimuli that motivate PD+HS, these patients were less impulsive for the immediate reward. At the brain system level, this effect was paralleled by the fact that PD+HS, as compared to controls and PD - HS, showed a negative correlation between subjective value of the delayed reward and activity of medial prefrontal cortex and ventral striatum. Consistent with the incentive salience hypothesis combining learned cue-reward associations with current relevant physiological state, dopaminergic treatment in PD+HS boosted excessive 'wanting' of rewards and heightened activity in the anterior medial prefrontal cortex and the posterior cingulate cortex, as reflected by higher correlation with subjective value of the option associated to the delayed reward when ON medication as compared to the OFF medication state. At the time of outcome, the anterior medial prefrontal/rostral anterior cingulate cortex showed an interaction between group (PD+HS versus PD - HS) and medication (ON versus OFF), suggesting that dopaminergic treatment boosted activity of this brain region in PD+HS when viewing erotic images after waiting for longer periods of time. Our findings point to reduced delay discounting of erotic rewards in PD+HS, both at the behavioural and brain system levels, and abnormal reinforcing effect of levodopa when PD+HS patients are confronted with erotic stimuli.10.1093/brain/awy298_video1awy298media15983845074001.
Published: 2019
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25. Long-term effects of anterior pallidal deep brain stimulation for Tourette's syndrome

Author: Marie-Laure, Welter, Jean-Luc, Houeto, Yulia, Worbe, Mamadou Hassimiou, Diallo, Andreas, Hartmann, Sophie, Tezenas du Montcel, Solène, Ansquer, Stéphane, Thobois, Denys, Fontaine, Tiphaine, Rouaud, Emmanuel, Cuny, Carine, Karachi, Luc, Mallet, and Mallet, Luc
Subjects: Adult, Male, Deep Brain Stimulation, Tourette's syndrome, Middle Aged, Globus Pallidus, Internal globus pallidus, Young Adult, ddc:616.89, Treatment Outcome, Deep brain stimulation, Tics, Humans, Female, Tourette Syndrome
Published: 2019

26. Neurological manifestations in adults with phenylketonuria: new cases and review of the literature

Author: Stéphane Thobois, Alain Fouilhoux, Claire Douillard, François Feillet, Paul Jaulent, Sybil Charriere, Service de Neurologie [Lyon], CHU Lyon, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service d'urgence et de réanimation pédiatriques [Hôpital Edouard Herriot - HCL], Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Service d'Electroneuromyographie et Service de Neurologie C [Hôpital Pierre Wertheimer - HCL], Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Université de Lyon, Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Claude Bernard Lyon 1 (UCBL), Hôpital Claude Huriez [Lille], and CHU Lille
Subjects: Adult, medicine.medical_specialty, Pediatrics, congenital, hereditary, and neonatal diseases and abnormalities, Neurology, Phenylketonurias, Phenylalanine, [SDV]Life Sciences [q-bio], Neurological symptoms, Disease, 03 medical and health sciences, 0302 clinical medicine, medicine, Brain mri, Humans, 030212 general & internal medicine, Neuroradiology, Cerebellar ataxia, business.industry, Leucopathy, White Matter, 3. Good health, Discontinuation, Adult phenylketonuria, Brain MRI, Neurology (clinical), Nervous System Diseases, medicine.symptom, Headaches, business, 030217 neurology & neurosurgery
Abstract: Early Access: NOV 2019; International audience; OBJECTIVE: Phenylketonuria (PKU) is a rare autosomal recessive disease characterised by high plasma phenylalanine levels inducing, if untreated, serious neurological manifestations in children but also, rarely, in adults who stopped their diet. The objective of the study was to describe the neurological manifestations observed in adults with PKU. METHODS: We analysed cases reported in French reference centres for inborn errors of metabolism and cases already reported in the literature. RESULTS: We report 8 new cases of neurological manifestations and 22 cases in the literature, which occurred in adult PKU patients, associated with chronic or rapid increase of phenylalanine levels, mostly when strict low-phenylalanine diet was stopped early in life. Neurological symptoms consisted in cerebellar ataxia, tremor, brisk reflexes, visual loss, sensory manifestations, and/or headaches. Visual loss was more frequent in the new cases (4/8) of the present series than in the literature (4/22). These neurological complications were associated with leucopathy on brain magnetic resonance imaging (27/29). The start of a low-phenylalanine diet improved or fully reversed neurological manifestations, even in patients with late diagnosis during adulthood. CONCLUSION: Neurological manifestations can complicate PKU in adult patients with elevated phenylalanine levels, after long or short period of diet discontinuation. Neurologists should be aware of this diagnosis, and measure phenylalaninemia in case of neurological symptoms associated with non-specific leucopathy on brain MRI. PKU patients should be systematically encouraged to continue their diet and their medical follow-up to avoid neurological complications.
Published: 2019
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27. Deep brain stimulation does not enhance neuroinflammation in multiple system atrophy

Author: Béatrice Lannes, Stéphane Thobois, Wassilios G. Meissner, Anne Vital, Alexandre Eusebio, Jean-Luc Houeto, Tatiana Witjas, François Viallet, Christine Tranchant, Dominique Guehl, Pierre-Olivier Fernagut, François Tison, Miguel Lopez-Cuina, André Maues De Paula, Nathalie Streichenberger, Philippe Damier, Marie-Hélène Canron, Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de neurosciences expérimentales et cliniques (LNEC), Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Bordeaux [Bordeaux], Service de pathologie [CHU Strasbourg], CHU Strasbourg, Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Services de Neurochimie et de Pathologie, Hôpital Neurologique de Bron, Service de neurologie [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Hôpital Guillaume-et-René-Laennec [Saint-Herblain], Hôpital de la Timone [CHU - APHM] (TIMONE), Service de neurologie [Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Département de Neurologie, CHU Strasbourg-Hopital Civil, Laboratoire Parole et Langage (LPL), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Assistance Publique - Hôpitaux de Marseille (APHM), Institut des sciences cognitives Marc Jeannerod - Centre de neuroscience cognitive - UMR5229 (ISC-MJ), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Physiologie et physiopathologie de la signalisation cellulaire (PPSC), Université Bordeaux Segalen - Bordeaux 2-Université Sciences et Technologies - Bordeaux 1 (UB)-CHU Bordeaux [Bordeaux]-Centre National de la Recherche Scientifique (CNRS), Institut des sciences cognitives Marc Jeannerod - Centre de neuroscience cognitive - UMR5229 (CNC), Université Bordeaux Segalen - Bordeaux 2-Université Sciences et Technologies - Bordeaux 1-CHU Bordeaux [Bordeaux]-Centre National de la Recherche Scientifique (CNRS), and Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)
Subjects: Adult, Male, 0301 basic medicine, Pathology, medicine.medical_specialty, Levodopa, Deep brain stimulation, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Thalamus, lcsh:RC321-571, 03 medical and health sciences, 0302 clinical medicine, Atrophy, medicine, Humans, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Neuroinflammation, ComputingMilieux_MISCELLANEOUS, Aged, Inflammation, business.industry, Putamen, Multiple system atrophy, Middle Aged, medicine.disease, nervous system diseases, Subthalamic nucleus, 030104 developmental biology, Globus pallidus, Neurology, nervous system, Atypical parkinsonism, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Caudate Nucleus, business, 030217 neurology & neurosurgery, medicine.drug
Abstract: Slowly progressive, levodopa-responsive multiple system atrophy (MSA) may be misdiagnosed as Parkinson's disease (PD). Deep brain stimulation (DBS) is mostly ineffective in these patients and may even worsen the clinical course. Here we assessed whether neuropathological differences between patients with MSA who were treated with DBS of the subthalamic nucleus because of a misleading clinical presentation and typical disease cases may explain the more benign disease course of the former, and also the rapid clinical decline after surgery. The post-mortem assessment included the subthalamic nucleus, the globus pallidus, the thalamus and the putamen in five patients with MSA who received DBS and nine typical disease cases. There was no evidence for distinct neuroinflammatory profiles between both groups that could be related to the surgical procedure or that could explain the rapid clinical progression during DBS. Patients who received deep brain stimulation displayed a higher proportion of α-synuclein bearing neuronal cytoplasmic inclusions in the putamen compared with typical cases, while the number of surviving neurons was not different between groups. Our findings suggest that DBS does not induce neuroinflammatory changes in patients with MSA, at least several years after the surgery. We further hypothesize that the peculiar pattern of α-synuclein pathology may contribute to differences in the clinical phenotype, with a greater proportion of neuronal inclusions in the putamen being associated to a milder, "PD-like" phenotype with sustained levodopa response and slower disease progression.
Published: 2018
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28. Clonidine modulates the activity of the subthalamic-supplementary motor loop: evidence from a pharmacological study combining deep brain stimulation and electroencephalography recordings in Parkinsonian patients

Author: Charlotte Spay, Stéphane Thobois, Guillaume Lio, Brian Lau, Emmanuel Broussolle, Philippe Boulinguez, Bénédicte Ballanger, Marion Albares, Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut des sciences cognitives Marc Jeannerod - Centre de neuroscience cognitive - UMR5229 (CNC), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Institut des Sciences cognitives Marc Jeannerod - Laboratoire sur le langage, le cerveau et la cognition (L2C2), École normale supérieure - Lyon (ENS Lyon)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Hospices Civils de Lyon (HCL), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut des sciences cognitives Marc Jeannerod - Centre de neuroscience cognitive - UMR5229 (ISC-MJ), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and ANR-16-CE37-0007,LOCOMOTIV,Les troubles de l'initiation de l'action et les dysfonctionnements des interactions cortico-subthalamiques dans la maladie de parkinson(2016)
Subjects: Male, 0301 basic medicine, STN, Parkinson's disease, medicine.medical_treatment, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Electroencephalography, Biochemistry, Tourette syndrome, 0302 clinical medicine, supplementary motor area, Neural Pathways, Adrenergic alpha-2 Receptor Agonists, SMA, reaction time, subthalamic nucleus, Supplementary motor area, medicine.diagnostic_test, electroence- phalography, Motor Cortex, Parkinson Disease, Middle Aged, 3. Good health, Clonidine, deep brain stimulation, Treatment Outcome, medicine.anatomical_structure, PD, Female, Cues, medicine.drug, Deep brain stimulation, RT, 03 medical and health sciences, Cellular and Molecular Neuroscience, medicine, Humans, clonidine, Aged, business.industry, medicine.disease, Brain Waves, 030104 developmental biology, response inhibition Abbreviations used: DBS, Brain stimulation, noradrenaline, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, NA, business, Neuroscience, Photic Stimulation, 030217 neurology & neurosurgery
Abstract: International audience; Clonidine is an anti-hypertensive medication which acts as an alpha-adrenergic receptor agonist. As the noradrenergic system is likely to support cognitive functions including attention and executive control, other clinical uses of clonidine have recently gained popularity for the treatment of neuropsychiatric disorders like attention-deficit hyperactivity disorder or Tourette syndrome, but the mechanism of action is still unclear. Here, we test the hypothesis that the noradrenergic system regulates the activity of subthalamo-motor cortical loops, and that this influence can be modulated by clonidine. We used pharmacological manipulation of clonidine in a placebo-controlled study in combination with subthalamic nucleus-deep brain stimulation (STN-DBS) in 16 Parkinson's disease patients performing a reaction time task requiring to refrain from reacting (proactive inhibition). We recorded electroencephalographical activity of the whole cortex, and applied spectral analyses directly at the source level after advanced blind source separation. We found only one cortical source localized to the supplementary motor area (SMA) that supported an interaction of pharmacological and subthalamic stimulation. Under placebo, STN-DBS reduced proactive alpha power in the SMA, a marker of local inhibitory activity. This effect was associated with the speeding-up of movement initiation. Clonidine substantially increased proactive alpha power from the SMA source, and canceled out the benefits of STN-DBS on movement initiation. These results provide the first direct neural evidence in humans that the tonic inhibitory activity of the subthalamocortical loops underlying the control of movement initiation is coupled to the noradrenergic system, and that this activity can be targeted by pharmacological agents acting on alpha-adrenergic receptors.
Published: 2018
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29. Amyotrophic lateral sclerosis in Huntington disease gene carrier

Author: Emilien Bernard, P. Leblanc, Stéphane Thobois, M. Bost, Emmanuel Broussolle, K. Mouzat, Serge Lumbroso, Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut NeuroMyoGène (INMG), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Risques Rocheux et Ouvrages géotechniques (IFSTTAR/GERS/RRO), Université de Lyon-Institut Français des Sciences et Technologies des Transports, de l'Aménagement et des Réseaux (IFSTTAR), Service d'Electroneuromyographie et Service de Neurologie C [Hôpital Pierre Wertheimer - HCL], Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Neurosciences précliniques, Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lyon, Laboratoire de Biochimie [CHRU Nîmes], Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Laboratoire de biologie et modélisation de la cellule (LBMC UMR 5239), Université de Lyon-Université de Lyon-École normale supérieure - Lyon (ENS Lyon)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hospices Civils de Lyon (HCL), Institut des Neurosciences de Montpellier (INM), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL)
Subjects: 0301 basic medicine, Genetics, Disease gene, business.industry, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Heterozygote advantage, medicine.disease, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Neurology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Mutation (genetic algorithm), Medicine, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology (clinical), Amyotrophic lateral sclerosis, Trinucleotide repeat expansion, business, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, ComputingMilieux_MISCELLANEOUS
Abstract: International audience
Published: 2017
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30. On-line motor control in patients with Parkinson's disease

Author: Philippe Vindras, Stéphane Thobois, Robert Turner, V. Gaveau, Michel Desmurget, and Emmanuel Broussolle
Subjects: Adult, Male, Parkinson's disease, Eye Movements, Movement, Neuropsychological Tests, Basal Ganglia, Feedback, Central nervous system disease, Huntington's disease, Basal ganglia, medicine, Reaction Time, Humans, Latency (engineering), Aged, Motor control, Parkinson Disease, Signal Processing, Computer-Assisted, Middle Aged, medicine.disease, Saccadic masking, Visual field, Huntington Disease, Female, Neurology (clinical), Psychology, Neuroscience, Psychomotor Performance
Abstract: Summary Recent models based, in part on a study of Huntington’s disease, suggest that the basal ganglia are involved in on-line movement guidance. Two experiments were conducted to investigate this idea. First, we studied advanced Parkinson’s disease patients performing a reaching task known to depend on on-line guidance. The task was to ‘look and point’ in the dark at visual targets displayed in the peripheral visual field. In some trials, the target location was slightly modified during saccadic gaze displacement (when vision is suppressed). In both patient and control groups, the target jump induced a gradual modification of the movement which diverged smoothly from its original path to reach the new target location. No deficit was found in the patients, except for an increased latency to respond to the target jump (Parkinson’s disease: 243 ms; controls: 166 ms). A computational simulation indicated that this response slowing was likely to be a by-product of bradykinesia. The unexpected inconsistency between this result and previous reports was investigated in a second experiment. We hypothesized that the relevant factor was the characteristics of the corrections to be performed. To test this prediction, we investigated a task requiring corrections of the same type as investigated in Huntington’s disease, namely large, consciously detected errors induced by large target jumps at hand movement onset. In contrast with the smooth adjustments observed in the first experiment, the subjects responded to the target jump by generating a discrete corrective sub-movement. While this iterative response was relatively rapid in the control subjects (220 ms), Parkinson’s disease patients exhibited either dramatically late (>730 ms) or totally absent on-line corrections. When on-line corrections were absent, the initial motor response was completed before a second corrective response was initiated (the latency of the corrective response was the same as the latency of the initial response). Considered together, these results suggest that basal ganglia dependent circuits are not critical for feedback loops involving a smooth modulation of the ongoing command. These circuits may rather contribute to the generation of discrete corrective sub-movements. This deficit is in line with the general impairment of sequential and simultaneous actions in patients with basal ganglia disorders.
Published: 2017

31. Subthalamic nucleus stimulation effects on single and combined task performance in Parkinson’s disease patients: a PET study

Author: Didier Lebars, Cyril Atkinson-Clement, Franck Lavenne, Audrey Maillet, Stéphane Thobois, Pierre Pollak, Alexandre Krainik, Jérôme Redouté, Serge Pinto, Laboratoire Parole et Langage (LPL), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Institut des sciences cognitives Marc Jeannerod - Centre de neuroscience cognitive - UMR5229 (CNC), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Centre d'Etude et de Recherche Multimodal Et Pluridisciplinaire en imagerie du vivant (CERMEP - imagerie du vivant), Université de Lyon-Université de Lyon-CHU Grenoble-Hospices Civils de Lyon (HCL)-CHU Saint-Etienne-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Centre Hospitalier Universitaire [Grenoble] (CHU), Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpitaux Universitaires de Genève (HUG), Hôpital Neurologique Lyon, Institut des sciences cognitives Marc Jeannerod - Centre de neuroscience cognitive - UMR5229 (ISC-MJ), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-CHU Grenoble-Hospices Civils de Lyon (HCL)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)
Subjects: Male, Speech production, Parkinson's disease, medicine.medical_treatment, Audiology, Hand movement, computer.software_genre, Subthalamic nucleus, Task (project management), Behavioral Neuroscience, [SCCO]Cognitive science, 0302 clinical medicine, Voxel, Deep brain stimulation, [SHS.LANGUE]Humanities and Social Sciences/Linguistics, 05 social sciences, Neuropsychology, Parkinson Disease, Middle Aged, Magnetic Resonance Imaging, Psychiatry and Mental health, surgical procedures, operative, Neurology, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Psychology, therapeutics, medicine.medical_specialty, Cognitive Neuroscience, Neuroimaging, Motor Activity, behavioral disciplines and activities, 050105 experimental psychology, 03 medical and health sciences, Cellular and Molecular Neuroscience, medicine, Reaction Time, Humans, Speech, 0501 psychology and cognitive sciences, Radiology, Nuclear Medicine and imaging, Aged, medicine.disease, Hand, nervous system diseases, nervous system, Positron-Emission Tomography, Parkinson’s disease, Neurology (clinical), Neuroscience, computer, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Subthalamic nucleus deep brain stimulation (STNDBS) represents one of the most efficacious treatments for Parkinson’s disease, along with L-dopa therapy. The objective of the present work was to identify the cerebral networks associated with hand movement and speech production tasks performed alone and simultaneously, as well as the effects of STN-DBS on these profiles. Clinical, behavioral, and neuroimaging (oxygen 15-labeled water and Positron Emission Tomography) investigations were used to study single and combined performances of unilateral hand movements and speech production in 11 unmedicated individuals with PD, both off and on STN-DBS. Specifically, a flexible factorial design with the tasks (hand movement, speech production, combined task) and the STN-DBS conditions (off, on) as main factors was chosen for brain activation statistical analysis, using a Family-Wise Error corrected p-value at the cluster level of at least 10 contiguous voxels. Increased activation of fronto-parietal and cingulate areas was observed under STN-DBS for hand movement in single and combined tasks, respectively, reflecting a partial restoration of cortico-subcortical connections. The lack of results for speech production for both off and on STN-DBS could illustrate its relatively poor response to the treatment. STN-DBS tended to restore the additive function capacity that can be achieved when performing the combined task. We confirmed with original neuroimaging data that speech is much less responsive to STN-DBS than any other motor function and we concluded that speech outcomes following STN-DBS can be different from those observed pre-operatively following L-dopa administration.
Published: 2017
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32. Semi-quantitative analysis of visually normal 123I-FP-CIT across three large databases revealed no difference between control and patients

Author: Anthime Flaus, Remi Philippe, Stephane Thobois, Marc Janier, and Christian Scheiber
Subjects: 123I-FP-CIT SPECT, Normal reference values, Age effect, Parkinsonism, Medical physics. Medical radiology. Nuclear medicine, R895-920
Abstract: Abstract Background To show the equivalence between the specific binding ratios (SBR) of visually normal 123I-FP-CIT SPECT scans from patients to those from healthy volunteers (Hv) or patients without dopaminergic degeneration to allow their use as a reference database. Methods The SBR values of visually normal SPECT scans from 3 groups were studied: (1) suspected Parkinsonism and no diagnostic follow-up (ScanOnlyDB: n = 764, NM/CT 670 CZT, GE Healthcare), (2) no degenerative dopaminergic pathology after a 5-year follow-up (NoDG5YearsDB: n = 237, Symbia T2, Siemens Medical Solutions), and 3) Hv (HvDB: n = 118, commercial GE database). A general linear model (GLM) was constructed with caudate, putamen, and striatum SBR as the dependent variables, and age and gender as the independent variables. Following post-reconstruction harmonization of the data, DB were combined in pairs, ScanOnlyDB&NoDG5yearsDG and ScanOnlyDB&HvDB before performing GLM analysis. Additionally, ScanOnlyDB GLM estimates were compared to those published from Siemens commercial DB (SiemensDB) and ENC-DAT. Results The dispersion parameters, R 2 and the SBR coefficients of variation, did not differ between databases. For all volumes of interest and all databases, SBR decreased significantly with age (e.g., decrease per decade for the striatum: − 4.94% for ScanOnlyDB, − 4.65% for NoDG5YearsDB, − 5.69% for HvDB). There was a significant covariance between SBR and gender for ScanOnlyDB (P
Published: 2023
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33. Patterns of bidirectional communication between cortex and basal ganglia during movement in patients with Parkinson disease

Author: Alek Pogosyan, Patrick Mertens, Peter Brown, Elodie Lalo, Gustavo Polo, Stéphane Thobois, and Andrew Sharott
Subjects: Male, Deep brain stimulation, medicine.medical_treatment, Deep Brain Stimulation, Movement, Local field potential, Brain mapping, Levodopa, Subthalamic Nucleus, Cortex (anatomy), Basal ganglia, medicine, Humans, Aged, Physics, Cerebral Cortex, Analysis of Variance, Brain Mapping, General Neuroscience, Dopaminergic, Electroencephalography, Parkinson Disease, Articles, Middle Aged, nervous system diseases, Coupling (electronics), Subthalamic nucleus, medicine.anatomical_structure, nervous system, Dopamine Agonists, Female, Neuroscience
Abstract: Cortico-basal ganglia networks are considered to comprise several parallel and mostly segregated loops, where segregation is achieved in space through topographic connectivity. Recently, it has been suggested that functional segregation may also be achieved in the frequency domain, by selective coupling of related activities at different frequencies. So far, however, any coupling across frequency in the human has only been modeled in terms of unidirectional influences, a misplaced assumption given the looped architecture of the basal ganglia, and has been considered in static terms. Here, we investigate the pattern of bidirectional coupling between mesial and lateral cortical areas and the subthalamic nucleus (STN) at rest and during movement, with and without pharmacological dopaminergic input, in patients with Parkinson's disease. We simultaneously recorded scalp electroencephalographic activity and local field potentials from depth electrodes and deduced patterns of directed coherence between cortical and STN levels across three frequency bands [sub-β (3–13 Hz), β (14–35 Hz), γ (65–90 Hz)] in the different states. Our results show (1) asymmetric bidirectional coupling between STN and both mesial and lateral cortical areas with greater drives from cortex to STN at frequencies
Published: 2016
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34. A randomized, controlled, double-blind, crossover trial of zonisamide in myoclonus-dystonia

Author: Noël Zahr, Stéphane Thobois, Fanny Charbonnier-Beaupel, Elodie Hainque, Sophie Dupont, Eugénie Mutez, Anne Doé De Maindreville, Nathalie Cozic, Cécile Hubsch, Alain Mallet, Aurélie Méneret, Christine Tranchant, Sophie Drapier, Fabienne Clot, Cecilia Bonnet, Vanessa Brochard, Emmanuel Roze, David Grabli, André-Pierre Legrand, Emmanuelle Apartis, Thibaud Lebouvier, Marie Vidailhet, Jean-Philippe Azulay, Bertrand Degos, Anne Bissery, Jean-Christophe Corvol, Gérald Glibert, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut des sciences cognitives Marc Jeannerod - Centre de neuroscience cognitive - UMR5229 (CNC), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Pôle Tête-Cou-CETD, Les Hôpitaux Universitaires de Strasbourg (HUS), Comportement et noyaux gris centraux = Behavior and Basal Ganglia [Rennes], CHU Pontchaillou [Rennes]-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université européenne de Bretagne - European University of Brittany (UEB)-Institut des Neurosciences Cliniques de Rennes (INCR), Service de Neurologie [Rennes] = Neurology [Rennes], CHU Pontchaillou [Rennes], Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Hôpital de la Timone [CHU - APHM] (TIMONE), Neurologie et thérapeutique expérimentale, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR70-Université Pierre et Marie Curie - Paris 6 (UPMC), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Equipe NEMESIS - Centre de Recherches de l'Institut du Cerveau et de la Moelle épinière (NEMESIS-CRICM), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Saint-Antoine [AP-HP], Centre d'investigation clinique Neurosciences [CHU Pitié Salpêtrière] (CIC Neurosciences), Service de neurologie 1 [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Institut des sciences cognitives Marc Jeannerod - Centre de neuroscience cognitive - UMR5229 (ISC-MJ), Université de Rennes (UR)-Université européenne de Bretagne - European University of Brittany (UEB)-CHU Pontchaillou [Rennes]-Institut des Neurosciences Cliniques de Rennes = Institute of Clinical Neurosciences of Rennes (INCR), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR70-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université européenne de Bretagne - European University of Brittany (UEB)-CHU Pontchaillou [Rennes]-Institut des Neurosciences Cliniques de Rennes (INCR), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Service de Neurologie [CHU Pitié-Salpêtrière], and IFR70-CHU Pitié-Salpêtrière [AP-HP]
Subjects: Adult, Male, 0301 basic medicine, congenital, hereditary, and neonatal diseases and abnormalities, Adolescent, [SDV]Life Sciences [q-bio], Zonisamide, Placebo, Severity of Illness Index, law.invention, Disability Evaluation, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Double-Blind Method, Randomized controlled trial, law, Sarcoglycans, Severity of illness, mental disorders, medicine, Humans, Dystonia, Cross-Over Studies, Isoxazoles, medicine.disease, Crossover study, Confidence interval, 3. Good health, nervous system diseases, Treatment Outcome, 030104 developmental biology, Dystonic Disorders, Anesthesia, Female, Neurology (clinical), medicine.symptom, Psychology, Myoclonus, 030217 neurology & neurosurgery, Central Nervous System Agents, medicine.drug
Abstract: International audience; Objective: To evaluate the efficacy and safety of zonisamide in patients with myoclonus-dystonia. Methods: We conducted a randomized, double-blind, placebo-controlled crossover trial of zonisamide (300 mg/d) in 24 patients with myoclonus-dystonia. Each treatment period consisted of a 6-week titration phase followed by a 3-week fixed-dose phase. The periods were separated by a 5-week washout period. The co–primary outcomes were action myoclonus severity (section 4 of the Unified Myoclonus Rating Scale [UMRS 4]) and myoclonus-related functional disability (UMRS 5). Secondary outcomes included dystonia severity, assessed with the movement and disability subscales of the Burke-Fahn-Marsden-Dystonia Rating Scale (BFM), the Clinical Global Impression–Improvement scale (CGI), and safety measures. Wilcoxon signed-rank tests for paired data were used to analyze treatment effects. Results: Twenty-three patients (11 men, 12 women) were analyzed in the intention-to-treat analysis. Zonisamide significantly improved both action myoclonus (median improvement [95% confidence limits] −5 [−9.25 to −1.44], p = 0.003) and myoclonus-related functional disability (median improvement [95% confidence limits] −2 [−2.58 to −2.46], p = 0.007) compared to placebo. Zonisamide also significantly improved dystonia (BFM movement) compared to placebo (median improvement [95% confidence limits] −3 [−8.46 to 0.03], p = 0.009). No difference was found between zonisamide and placebo with respect to the CGI (median improvement [95% confidence limits] −1 [−1.31 to 0.09], p = 0.1). Zonisamide was well-tolerated. Conclusions: Zonisamide is well-tolerated and effective on the motor symptoms of myoclonus-dystonia. Classification of evidence: This study provides Class I evidence that zonisamide improves myoclonus and related disability in patients with myoclonus-dystonia
Published: 2016
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35. Slowness in Movement Initiation is Associated with Proactive Inhibitory Network Dysfunction in Parkinson’s Disease

Author: Danièle Ibarrola, Alice Poisson, Philippe Boulinguez, Bénédicte Ballanger, Elise Metereau, Jérôme Redouté, Pierre Baraduc, Stéphane Thobois, Antonio P. Strafella, Emmanuel Broussolle, Marion Criaud, Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre d'Etude et de Recherche Multimodal Et Pluridisciplinaire en imagerie du vivant (CERMEP - imagerie du vivant), Université de Lyon-Université de Lyon-CHU Grenoble-Hospices Civils de Lyon (HCL)-CHU Saint-Etienne-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Institut des sciences cognitives Marc Jeannerod - Centre de neuroscience cognitive - UMR5229 (CNC), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Hospices Civils de Lyon (HCL), Montreal Neurological Institute and Hospital, McGill University = Université McGill [Montréal, Canada], Centre de Recherches sur la Cognition et l'Apprentissage (CeRCA), Centre National de la Recherche Scientifique (CNRS)-Université de Tours-Université de Poitiers, Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, and Université de Poitiers-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, Parkinson's disease, Brain activity and meditation, Precuneus, Caudate nucleus, Brain mapping, 050105 experimental psychology, Developmental psychology, Antiparkinson Agents, Executive Function, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Neurochemical, medicine, proactive control, Humans, 0501 psychology and cognitive sciences, reaction time, Brain Mapping, business.industry, 05 social sciences, fMRI, Motor Cortex, Brain, Parkinson Disease, Middle Aged, medicine.disease, Magnetic Resonance Imaging, Inhibition, Psychological, medicine.anatomical_structure, Proactive Inhibition, Response inhibition, Parkinson’s disease, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology (clinical), business, Neuroscience, Psychomotor Performance, 030217 neurology & neurosurgery, Executive dysfunction
Abstract: International audience; Background: Impairment in initiating movements in PD might be related to executive dysfunction associated with abnormal proactive inhibitory control, a pivotal mechanism consisting in gating movement initiation in uncertain contexts.Objective: Testing this hypothesis on the basis of direct neural-based evidence. Methods: Twelve PD patients on antiparkinsonian medication and fifteen matched healthy controls performed a simple reaction time task during event-related functional MRI scanning.Results: For all subjects, the level of activation of SMA was found to predict RT on a trial-by-trial basis. The increase in movement initiation latency observed in PD patients with regard to controls was associated with pre-stimulus BOLD increases within several nodes of the proactive inhibitory network (caudate nucleus, precuneus, thalamus).Conclusions: These results provide physiological data consistent with impaired control of proactive inhibition over motor initiation in PD. Patients would be locked into a mode of control maintaining anticipated inhibition over willed movements even when the situation does not require action restraint. The functional and neurochemical bases of brain activity associated with executive settings need to be addressed thoroughly in future studies to better understand disabling symptoms that have few therapeutic options like akinesia
Published: 2016
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36. Imaging Dopamine and Serotonin Systems on MPTP Monkeys: A Longitudinal PET Investigation of Compensatory Mechanisms

Author: Sara Neumane, Frédéric Bonnefoi, Didier Lebars, Nicolas Costes, Franck Lavenne, Bénédicte Ballanger, Christian Tourvielle, Stéphane Thobois, Emmanuel Broussolle, Sandra Duperrier, Maude Beaudoin-Gobert, Léon Tremblay, Elise Météreau, Véronique Sgambato-Faure, Justine Epinat, Luc Zimmer, Institut des sciences cognitives Marc Jeannerod - Centre de neuroscience cognitive - UMR5229 (CNC), Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Hospices Civils de Lyon (HCL), Centre d'Etude et de Recherche Multimodal Et Pluridisciplinaire en imagerie du vivant (CERMEP - imagerie du vivant), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-CHU Grenoble-Hospices Civils de Lyon (HCL)-CHU Saint-Etienne-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Université de Lyon-CHU Grenoble-Hospices Civils de Lyon (HCL)-CHU Saint-Etienne-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), and Ballanger, Benedicte
Subjects: 0301 basic medicine, Male, medicine.medical_specialty, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Parkinson's disease, PET imaging, Serotonergic, DASB, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Neurochemical, Parkinsonian Disorders, Dopamine, Internal medicine, medicine, Animals, Longitudinal Studies, MPTP, Raclopride, General Neuroscience, Putamen, Dopaminergic Neurons, Dopaminergic, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Articles, Corpus Striatum, 3. Good health, serotonin, Macaca fascicularis, 030104 developmental biology, Endocrinology, chemistry, compensatory mechanisms, Positron-Emission Tomography, MPPF, dopamine, Psychology, Neuroscience, 030217 neurology & neurosurgery, medicine.drug, Serotonergic Neurons, serotonin Significance Statement
Abstract: It is now widely accepted that compensatory mechanisms are involved during the early phase of Parkinson's disease (PD) to delay the expression of motor symptoms. However, the neurochemical mechanisms underlying this presymptomatic period are still unclear. Here, we measuredin vivolongitudinal changes of both the dopaminergic and serotonergic systems in seven asymptomatic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-intoxicated monkeys (when motor symptoms are less apparent) using PET. We used the progressively MPTP-intoxicated monkey model that expresses recovery from motor symptoms to study the changes in dopamine synthesis ([18F]DOPA), dopamine D2/D3receptors ([11C]raclopride), and serotonin transporter11C-N,N-dimethyl-2-(-2-amino-4-cyanophenylthio) benzylamine ([11C]DASB) and serotonin 1A receptor ([18F]MPPF) levels between four different states (baseline, early symptomatic, full symptomatic and recovered). During the early symptomatic state, we observed increases of [18F]DOPA uptake in the anterior putamen, [11C]raclopride binding in the posterior striatum, and 2′-methoxyphenyl-(N-2′-pyridinyl)-p-[18F]fluoro-benzamidoethylpiperazine [18F]MPPF uptake in the orbitofrontal cortex and dorsal ACC. After recovery from motor symptoms, the results mainly showed decreased [11C]raclopride binding in the anterior striatum and limbic ACC. In addition, our findings supported the importance of pallidal dopaminergic neurotransmission in both the early compensatory mechanisms and the functional recovery mechanisms, with reduced aromatic L-amino acid decarboxylase (AAAD) activity closely related to the appearance or perseveration of motor symptoms. In parallel, this study provides preliminary evidence of the role of the serotonergic system in compensatory mechanisms. Nonetheless, future studies are needed to determine whether there are changes in SERT availability in the early symptomatic state and if [18F]MPPF PET imaging might be a promising biomarker of early degenerative changes in PD.SIGNIFICANCE STATEMENTThe present research provides evidence of the potential of combining a multitracer PET imaging technique and a longitudinal protocol applied on a progressively 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-intoxicated monkey model to further elucidate the nature of the compensatory mechanisms involved in the preclinical period of Parkinson's disease (PD). In particular, by investigating the dopaminergic and serotonergic changes both presynaptically and postsynaptically at four different motor states (baseline, early symptomatic, full symptomatic, and recovered), this study has allowed us to identify putative biomarkers for future therapeutic interventions to prevent and/or delay disease expression. For example, our findings suggest that the external pallidum could be a new target for cell-based therapies to reduce PD symptoms.
Published: 2016
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37. Parkinson's Disease Revealed by a Resting Tongue Tremor

Author: Paul Jaulent, Chloé Laurencin, Henri Robert, and Stéphane Thobois
Subjects: medicine.medical_specialty, medicine.anatomical_structure, Physical medicine and rehabilitation, Parkinson's disease, Neurology, Tongue, business.industry, Ocular tremor, medicine, Neurology (clinical), Case Reports, business, medicine.disease
Published: 2015

38. Behavioural impact of a double dopaminergic and serotonergic lesion in the non-human primate

Author: Sandra Duperrier, Léon Tremblay, Bénédicte Ballanger, Justine Epinat, Nicolas Costes, Didier Le Bars, Elise Météreau, Véronique Sgambato-Faure, Maude Beaudoin-Gobert, Frédéric Bonnefoi, Franck Lavenne, Sara Neumane, François Liger, Stéphane Thobois, Christian Tourvielle, Emmanuel Broussolle, Institut des sciences cognitives Marc Jeannerod - Centre de neuroscience cognitive - UMR5229 (CNC), Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Centre d'Etude et de Recherche Multimodal Et Pluridisciplinaire en imagerie du vivant (CERMEP - imagerie du vivant), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-CHU Grenoble-Hospices Civils de Lyon (HCL)-CHU Saint-Etienne-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Institut de Chimie et Biochimie Moléculaires et Supramoléculaires (ICBMS), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut de Chimie du CNRS (INC)-École Supérieure Chimie Physique Électronique de Lyon-Centre National de la Recherche Scientifique (CNRS), Université de Lyon, Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], and Hospices Civils de Lyon (HCL)
Subjects: Male, Parkinson's disease, Nortropanes, Dopamine, N-Methyl-3,4-methylenedioxyamphetamine, Dopamine Agents, Sulfides, Serotonergic, Antiparkinson Agents, Levodopa, Lesion, 03 medical and health sciences, chemistry.chemical_compound, monkey Abbreviations: 5, Serotonin Agents, 0302 clinical medicine, Chlorocebus aethiops, Basal ganglia, medicine, Animals, Radionuclide Imaging, 030304 developmental biology, Brain Mapping, 0303 health sciences, Aniline Compounds, Mental Disorders, MPTP, Dopaminergic, Brain, MPTP Poisoning, MDMA, medicine.disease, nervous system diseases, serotonin, Disease Models, Animal, Macaca fascicularis, dyskinesia, chemistry, Dyskinesia, Female, neuropsychiatric symptoms, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology (clinical), medicine.symptom, Psychology, Neuroscience, 030217 neurology & neurosurgery, medicine.drug
Abstract: International audience; Serotonergic (5-HT) neurons degenerate in Parkinson's disease. To determine the role of this 5-HT injury-besides the dopaminergic one in the parkinsonian symptomatology-we developed a new monkey model exhibiting a double dopaminergic/ serotonergic lesion by sequentially using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 3,4-methylenedioxy-N-methamphetamine (MDMA, better known as ecstasy). By positron emission tomography imaging and immunohistochemistry, we demonstrated that MDMA injured 5-HT nerve terminals in the brain of MPTP monkeys. Unexpectedly, this injury had no impact on tremor or on bradykinesia, but altered rigidity. It abolished the L-DOPA-induced dyskinesia and neuropsychiatric-like behaviours, without altering the anti-parkinsonian response. These data demonstrate that 5-HT fibres play a critical role in the expression of both motor and non-motor symptoms in Parkinson's disease, and highlight that an imbalance between the 5-HT and dopaminergic innervating systems is involved in specific basal ganglia territories for different symptoms.
Published: 2015
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39. Interaction of Noradrenergic Pharmacological Manipulation and Subthalamic Stimulation on Movement Initiation Control in Parkinson's Disease

Author: Marion Albares, Philippe Domenech, Gustavo Polo, Bénédicte Ballanger, Philippe Boulinguez, Stéphane Thobois, Emmanuel Broussolle, Emilie Favre, Institut des sciences cognitives Marc Jeannerod - Centre de neuroscience cognitive - UMR5229 (CNC), Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Espace et action, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Hospices Civils de Lyon (HCL), Service de neurochirurgie fonctionnelle, Institut des Sciences Cognitives (ISC), Centre de Recherches sur la Cognition et l'Apprentissage (CeRCA), Université de Poitiers-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), and Centre National de la Recherche Scientifique (CNRS)-Université de Tours-Université de Poitiers
Subjects: Male, Agonist, Parkinson's disease, STN-DBS, medicine.drug_class, Deep Brain Stimulation, Movement, Biophysics, Stimulation, Placebo, Clonidine, Executive control, lcsh:RC321-571, 03 medical and health sciences, 0302 clinical medicine, Subthalamic Nucleus, Adrenergic alpha-2 Receptor Agonists, medicine, Humans, Receptor, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Aged, 030304 developmental biology, Reaction time, 0303 health sciences, General Neuroscience, Dopaminergic, Parkinson Disease, Middle Aged, medicine.disease, Combined Modality Therapy, Pathophysiology, 3. Good health, nervous system diseases, surgical procedures, operative, nervous system, Noradrenaline, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology (clinical), Psychology, Akinesia, Neuroscience, therapeutics, Psychomotor Performance, 030217 neurology & neurosurgery, medicine.drug
Abstract: International audience; Background: Slowness in movement initiation (akinesia) is a cardinal feature of Parkinson's disease (PD), which is still poorly understood. Notably, akinesia is restored by subthalamic nucleus deep brain stimulation (STN-DBS) but not fully reversed by current dopaminergic treatments. It was recently suggested that this disorder is of executive nature (related to inhibitory control of response) and of non-dopaminergic origin (possibly noradrenergic). Objective: To test the double hypothesis that: 1) the ability to control movement initiation is modified by noradrenergic neurotransmission modulation, and 2) this effect is mediated by the regulation of STN activity. Methods: Sixteen STN-DBS PD patients were enrolled in a placebo-controlled study investigating the effects of noradrenergic attenuation by clonidine (f2-adrenergic receptor agonist). Movement initiation latency was assessed by means of a cue-target reaction time task. Patients, who remained on their chronic dopaminergic medication, were tested on four sessions: two with placebo (ON-or OFF-DBS), and two with a 150 mg oral dose of clonidine (ON-or OFF-DBS). Results: In the OFF stimulation condition, patients were locked into a mode of control maintaining inappropriate response inhibition. This dysfunctional executive setting was overcome by STN-DBS. Clonidine, however, was found to impair specifically the ability to release inhibitory control in the ON-DBS state. Conclusions: Overall our results suggest an important implication of the noradrenergic system in the pathophysiology of akinesia in PD. Reducing the noradrenergic "tonus" may even block the positive action of STN-DBS on akinesia, suggesting, at least by part, a noradrenergic-dependent STN-DBS efficiency.
Published: 2015
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40. Motor cortex stimulation does not improve dystonia secondary to a focal basal ganglia lesion

Author: Emmanuel Broussolle, Pierre Burbaud, Isabelle Rieu, Patrick Mertens, Pierre Pollak, Philippe Derost, Stephan Chabardes, Jean-Jacques Lemaire, Magaly Aya Kombo, Stéphane Thobois, Jean Pascal Lefaucheur, Franck Durif, Marie Vidailhet, Jing Xie, Bruno Pereira, Neuro-Psycho Pharmacologie des Systèmes Dopimanégiques sous-corticaux (NPsy-Sydo), CHU Clermont-Ferrand-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), UM des troubles du mouvement, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, Service de Neurologie, Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Neurosciences précliniques, Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), University Institute for Intelligent Systems and Numerical Applications in Engineering, University of Las Palmas de Gran Canaria (ULPGC), Service de neurologie [Saint-Antoine], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Sorbonne Université, Dept Neurol, Syngenta, CHU Clermont-Ferrand, Neurologie et thérapeutique expérimentale, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR70-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Neurochirurgie [CHU Clermont-Ferrand], CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Institut Pascal (IP), SIGMA Clermont (SIGMA Clermont)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR70-Université Pierre et Marie Curie - Paris 6 (UPMC), Service de Neurochirurgie [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Gabriel Montpied [Clermont-Ferrand], and SIGMA Clermont (SIGMA Clermont)-Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])
Subjects: Male, Patch-Clamp Techniques, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Neurological disorder, Neuropsychological Tests, Basal ganglia, Age of Onset, 10. No inequality, ComputingMilieux_MISCELLANEOUS, Pain Measurement, Dystonia, Cross-Over Studies, [SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, Motor Cortex, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, Middle Aged, Central sulcus, Magnetic Resonance Imaging, medicine.anatomical_structure, Muscle Spasticity, Anesthesia, Female, medicine.symptom, [SPI.SIGNAL]Engineering Sciences [physics]/Signal and Image processing, Motor cortex, Adult, congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, Visual analogue scale, Pain, Electric Stimulation Therapy, [SDV.MHEP.CHI]Life Sciences [q-bio]/Human health and pathology/Surgery, Lesion, Young Adult, Basal Ganglia Diseases, Double-Blind Method, otorhinolaryngologic diseases, [INFO.INFO-IM]Computer Science [cs]/Medical Imaging, medicine, Humans, Pain Management, Spasticity, Aged, business.industry, [SCCO.NEUR]Cognitive science/Neuroscience, medicine.disease, ddc:616.8, nervous system diseases, Surgery, Neurology (clinical), business, Tomography, X-Ray Computed
Abstract: Objective: To assess the efficacy of epidural motor cortex stimulation (MCS) on dystonia, spasticity, pain, and quality of life in patients with dystonia secondary to a focal basal ganglia (BG) lesion. Methods: In this double-blind, crossover, multicenter study, 5 patients with dystonia secondary to a focal BG lesion were included. Two quadripolar leads were implanted epidurally over the primary motor (M1) and premotor cortices, contralateral to the most dystonic side. The leads were placed parallel to the central sulcus. Only the posterior lead over M1 was activated in this study. The most lateral or medial contact of the lead (depending on whether the dystonia predominated in the upper or lower limb) was selected as the anode, and the other 3 as cathodes. One month postoperatively, patients were randomly assigned to on- or off-stimulation for 3 months each, with a 1-month washout between the 2 conditions. Voltage, frequency, and pulse width were fixed at 3.8 V, 40 Hz, and 60 μs, respectively. Evaluations of dystonia (Burke-Fahn-Marsden Scale), spasticity (Ashworth score), pain intensity (visual analog scale), and quality of life (36-Item Short Form Health Survey) were performed before surgery and after each period of stimulation. Results: Burke-Fahn-Marsden Scale, Ashworth score, pain intensity, and quality of life were not statistically significantly modified by MCS. Conclusions: Bipolar epidural MCS failed to improve any clinical feature in dystonia secondary to a focal BG lesion. Classification of evidence: This study provides Class I evidence that bipolar epidural MCS with the anode placed over the motor representation of the most affected limb failed to improve any clinical feature in dystonia secondary to a focal BG lesion.
Published: 2014
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41. A Common Optimization Principle for Motor Execution in Healthy Subjects and Parkinsonian Patients

Author: Stéphane Thobois, Pierre Baraduc, Jing Gan, Michel Desmurget, and Emmanuel Broussolle
Subjects: Healthy behavior, Male, medicine.medical_specialty, Deep Brain Stimulation, Acceleration, Models, Neurological, Individuality, Stimulation, Hypokinesia, Developmental psychology, Antiparkinson Agents, Levodopa, Executive Function, Physical medicine and rehabilitation, Parkinsonian Disorders, medicine, Reaction Time, Humans, Isotonic Contraction, Aged, Movement (music), General Neuroscience, Healthy subjects, Motor control, Articles, Middle Aged, Biomechanical Phenomena, Subthalamic nucleus, Motor Skills, Data Interpretation, Statistical, Female, Psychology, Movement planning, Motor execution, Algorithms
Abstract: Recent research on Parkinson's disease (PD) has emphasized that parkinsonian movement, although bradykinetic, shares many attributes with healthy behavior. This observation led to the suggestion that bradykinesia in PD could be due to a reduction in motor motivation. This hypothesis can be tested in the framework of optimal control theory, which accounts for many characteristics of healthy human movement while providing a link between the motor behavior and a cost/benefit trade-off. This approach offers the opportunity to interpret movement deficits of PD patients in the light of a computational theory of normal motor control. We studied 14 PD patients with bilateral subthalamic nucleus (STN) stimulation and 16 age-matched healthy controls, and tested whether reaching movements were governed by similar rules in these two groups. A single optimal control model accounted for the reaching movements of healthy subjects and PD patients, whatever the condition of STN stimulation (on or off). The choice of movement speed was explained in all subjects by the existence of a preset dynamic range for the motor signals. This range was idiosyncratic and applied to all movements regardless of their amplitude. In PD patients this dynamic range was abnormally narrow and correlated with bradykinesia. STN stimulation reduced bradykinesia and widened this range in all patients, but did not restore it to a normal value. These results, consistent with the motor motivation hypothesis, suggest that constrained optimization of motor effort is the main determinant of movement planning (choice of speed) and movement production, in both healthy and PD subjects.
Published: 2013

42. Deep Brain Stimulation of the Subthalamic Nucleus, but not Dopaminergic Medication, Improves Proactive Inhibitory Control of Movement Initiation in Parkinson's Disease

Author: Philippe Boulinguez, Emmanuel Broussolle, Stéphane Thobois, Emilie Favre, Bénédicte Ballanger, Institut des sciences cognitives Marc Jeannerod - Centre de neuroscience cognitive - UMR5229 (CNC), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], and Hospices Civils de Lyon (HCL)
Subjects: Male, medicine.medical_specialty, Deep brain stimulation, Neurology, Parkinson's disease, STN-DBS, medicine.medical_treatment, Deep Brain Stimulation, Dopamine, Dopamine Agents, Executive control, Antiparkinson Agents, 03 medical and health sciences, 0302 clinical medicine, Subthalamic Nucleus, Motor system, medicine, Humans, Pharmacology (medical), 030304 developmental biology, Pharmacology, Reaction time, 0303 health sciences, Dopaminergic, Parkinson Disease, Middle Aged, medicine.disease, Subthalamic nucleus, Proactive Inhibition, Response inhibition, Female, Original Article, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology (clinical), Cues, Psychology, Akinesia, Neuroscience, 030217 neurology & neurosurgery, medicine.drug
Abstract: International audience; Slowness in movement initiation is a cardinal feature of Parkinson’s disease (PD) that is still poorly understood and unsuccessfully alleviated by standard therapies. Here, we raise this major clinical issue within the framework of a novel theoretical model that allows a better understanding of the basic mechanisms involved in movement initiation. This model assumes that movement triggering is inhibited by default to prevent automatic responses to unpredictable events. We investigated to which extent the top-down control necessary to release this locking state before initiating actions is impaired in PD and restored by standard therapies. We used a cue–target reaction time task to test both the ability to initiate fast responses to targets and the ability to refrain from reacting to cues. Fourteen patients with dopaminergic (DA) medication and 11 with subthalamic nucleus (STN) stimulation were tested on and off treatment, and compared with 14 healthy controls. We found evidence that patients withdrawn from treatment have trouble voluntarily releasing proactive inhibitory control; while DA medication broadly reduces movement initiation latency, it does not reinstate a normal pattern of movement initiation; and stimulation of the STN specifically re-establishes the efficiency of the top-down control of proactive inhibition. These results suggest that movement initiation disorders that resist DA medication are due to executive, not motor, dysfunctions. This conclusion is discussed with regard to the role the STN may play as an interface between non-DA executive and DA motor systems in cortico-basal ganglia loops.
Published: 2013
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43. Parkinsonian apathy responds to dopaminergic stimulation of D2/D3 receptors with piribedil

Author: Jean-Louis Quesada, Hélène Klinger, Jing Xie, Anna Castrioto, Andrea Kistner, Emmanuelle Schmitt, Jean-Luc Bosson, Pierre Pelissier, Claire Ardouin, Eugénie Lhommée, Stéphane Thobois, Pierre Pollak, Stephan Chabardes, Valérie Fraix, Paul Krack, Amélie Bichon, Emmanuel Broussolle, and Patrick Mertens
Subjects: Male, medicine.medical_specialty, Beck Anxiety Inventory, Apathy/drug effects/physiology, Apathy, Placebo, Antiparkinson Agents, Piribedil/pharmacology/therapeutic use, Piribedil, Parkinson Disease/drug therapy/psychology, Double-Blind Method, Receptors, Dopamine D3/agonists/physiology, medicine, Humans, Prospective Studies, Psychiatry, Depression (differential diagnoses), Aged, Dopamine Agonists/pharmacology, Receptors, Dopamine D2, Receptors, Dopamine D3, Beck Depression Inventory, Anhedonia, Parkinson Disease, Receptors, Dopamine D2/agonists/physiology, Middle Aged, ddc:616.8, Treatment Outcome, Anesthesia, Dopamine Agonists, Anxiety, Antiparkinson Agents/pharmacology/therapeutic use, Female, Neurology (clinical), medicine.symptom, Psychology, medicine.drug
Abstract: Apathy is one of the most common symptoms encountered in Parkinson's disease, and is defined as a lack of motivation accompanied by reduced goal-directed cognition, behaviour and emotional involvement. In a previous study we have described a delayed withdrawal syndrome after successful motor improvement related to subthalamic stimulation allowing for a major decrease in dopaminergic treatment. This withdrawal syndrome correlated with a diffuse mesolimbic dopaminergic denervation. To confirm our hypothesis of parkinsonian apathy being related to mesolimbic dopaminergic denervation, we performed a randomized controlled study using piribedil, a relatively selective D2/D3 dopamine agonist to treat parkinsonian apathy, using the model of postoperative apathy. A 12-week prospective, placebo-controlled, randomized, double-blinded trial was conducted in 37 patients with Parkinson's disease presenting with apathy (Starkstein Apathy Scale score > 14) following subthalamic nucleus stimulation. Patients received either piribedil up to 300 mg per day (n = 19) or placebo (n = 18) for 12 weeks. The primary end point was the improvement of apathy under treatment, as assessed by the reduction of the Starkstein Apathy Scale score in both treatment groups. Secondary end points included alleviation in depression (Beck Depression Inventory), anxiety (Beck Anxiety Inventory), improvement of quality of life (PDQ39) and anhedonia (Snaith-Hamilton Pleasure Scale). Exploratory endpoints consisted in changes of the Robert Inventory score and Hamilton depression scales. An intention to treat analysis of covariance analysis was performed to compare treatment effects (P < 0.05). The number of premature study dropouts was seven in the placebo and five in the piribedil groups, mostly related to intolerance to hypodopaminergic symptoms. At follow-up evaluation, the apathy score was reduced by 34.6% on piribedil versus 3.2% on placebo (P = 0.015). With piribedil, modifications in the Beck depression and anxiety scores were -19.8% and -22.8%, respectively versus +1.4% and -8.3% with placebo, without reaching significance level. Piribedil led to a trend towards improvement in quality of life (-16.2% versus +6.7% on placebo; P = 0.08) and anhedonia (-49% versus -5.6% on the placebo; P = 0.08). Apathy, assessed by the Robert Inventory score, improved by 46.6% on piribedil and worsened by 2.3% on placebo (P = 0.005). Depression, measured by the Hamilton score, improved in the piribedil group (P = 0.05). No significant side effects were observed. The present study provides a class II evidence of the efficacy of the dopamine agonist piribedil in the treatment of apathy in Parkinson's disease.
Published: 2013

44. History of the 'geste antagoniste' sign in cervical dystonia

Author: Emmanuel Broussolle, Alice Poisson, Christophe Vial, Chloé Loiraud, Giulia Serra, Stéphane Thobois, and Paul Krack
Subjects: medicine.medical_specialty, History, 18th Century, History, 21st Century, Sign (linguistics), German, History, 17th Century, Terminology as Topic, medicine, International literature, Psychogenic disease, Humans, Cervical dystonia, Sensory trick, Psychiatry, Torticollis, Literature, Dystonia, Neurologic Examination, Neurologic Examination/*history, Gestures, business.industry, History, 19th Century, History, 20th Century, medicine.disease, language.human_language, Neurology, language, Neurology (clinical), business, Psychology, Torticollis/*history/physiopathology, Gesture
Abstract: The geste antagoniste is a voluntary maneuver that temporarily reduces the severity of dystonic posture or movements. It is a classical feature of focal and particularly cervical dystonia. However, the precise historical aspects of geste antagoniste still remain obscure. The goals of this review were (1) to clarify the origin of the geste antagoniste sign; (2) to identify the factors that led to its diffusion in the international literature; (3) to follow the evolution of that term across the twentieth century. We used medical and neurological French, German and English literature of the late nineteenth and early twentieth centuries, and the PubMed database by entering the terms geste antagoniste, antagonistic gesture and sensory trick. The geste antagoniste sign is a legacy of the Paris Neurological School of the end of the nineteenth century. The term was introduced by Meige and Feindel in their 1902 book on tics, written in the vein of their master, Brissaud, who first described this sign in 1893. The almost immediate translations of this book by Giese into German and Kinnier Wilson into English contributed to the rapid spreading of the term geste antagoniste, which is still in use worldwide today. The term antagonistic gesture is the translation proposed by Kinnier Wilson, which also led to the use of the term geste antagonistique. The geste antagoniste sign has long been considered a solid argument for the psychogenic origins of dystonia until the 1980s when Marsden made strong arguments for its organic nature.
Published: 2012

45. Role of serotonergic 1A receptor dysfunction in depression associated with Parkinson's disease

Author: Jérôme Lerond, Anne-Evelyne Vallet, Emmanuel Broussolle, Didier Le Bars, Véronique Sgambato-Faure, Stéphane Thobois, Léon Tremblay, Julien Eche, Bénédicte Ballanger, Hélène Klinger, Institut des sciences cognitives Marc Jeannerod - Centre de neuroscience cognitive - UMR5229 (CNC), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Université de Lyon, Hospices Civils de Lyon (HCL), Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Service de neurologie C [Hôpital Pierre Wertheimer - HCL], and Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL)
Subjects: Adult, Male, Fluorine Radioisotopes, medicine.medical_specialty, Parkinson's disease, Aminopyridines, Serotonergic, Piperazines, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Limbic system, Internal medicine, medicine, Humans, Parkinson, Aged, 030304 developmental biology, Temporal cortex, 0303 health sciences, Ventral striatum, Brain, Parkinson Disease, Middle Aged, medicine.disease, Magnetic Resonance Imaging, serotonin, medicine.anatomical_structure, Endocrinology, PET, Neurology, chemistry, nervous system, Positron-Emission Tomography, Receptor, Serotonin, 5-HT1A, depression, Female, Orbitofrontal cortex, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Serotonin Antagonists, Neurology (clinical), [18F]MPPF, MPPF, Psychology, Insula, Neuroscience, 030217 neurology & neurosurgery
Abstract: International audience; Depression is frequent in Parkinson's disease, but its pathophysiology remains unclear. Two recent studies have investigated the role of serotonergic system at the presynaptic level. The objective of the present study was to use positron emission tomography and [18F]MPPF to investigate the role of postsynaptic serotonergic system dysfunction in the pathophysiology of depression in Parkinson's disease. Four parkinsonian patients with depression and 8 parkinsonian patients without depression were enrolled. Each patient underwent a scan using [18F]MPPF, a selective serotonin 1A receptor antagonist. Voxel‐by‐voxel statistical comparison of [18F]MPPF uptake of the 2 groups of parkinsonian patients and with 7 matched normal subjects was made using statistical parametric mapping (P uncorrected < .001). Compared with nondepressed parkinsonian patients, depressed patients exhibited reduced tracer uptake in the left hippocampus, the right insula, the left superior temporal cortex, and the orbitofrontal cortex. Compared with controls, nondepressed parkinsonian patients presented reduced [18F]MPPF uptake bilaterally in the inferior frontal cortex as well as in the right ventral striatum and insula. Compared with controls, [18F]MPPF uptake was decreased in depressed parkinsonian patients in the left dorsal anterior cingulate and orbitofrontal cortices, in the right hippocampic region, and in the temporal cortex. The present imaging study suggests that abnormalities in serotonin 1A receptor neurotransmission in the limbic system may be involved in the neural mechanisms underlying depression in patients with Parkinson's disease.
Published: 2012
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46. Subthalamic stimulation in Parkinson's disease: restoring the balance of motivated behaviours

Author: Magaly Aya Kombo, Valérie Fraix, Eugénie Lhommée, Eric Seigneuret, Stephan Chabardes, Sebastien Carnicella, Jean-Louis Quesada, Stéphane Thobois, Paul Krack, Jean-Luc Bosson, Patrick Mertens, Alim-Louis Benabid, Emmanuelle Schmitt, Hélène Klinger, Jing Xie, Andrea Kistner, Amélie Bichon, Claire Ardouin, Emmanuel Broussolle, Gustavo Polo, and Pierre Pollak
Subjects: Male, medicine.medical_specialty, Levodopa, Dyskinesia, Drug-Induced, Parkinson's disease, Deep Brain Stimulation, Impulse Control Disorders/etiology/therapy, Neuropsychological Tests, Severity of Illness Index, Statistics, Nonparametric, Antiparkinson Agents, Cohort Studies, Physical medicine and rehabilitation, Dopamine, Subthalamic Nucleus, Punding, Deep Brain Stimulation/methods, medicine, Humans, Apathy, Psychiatry, Dopamine dysregulation syndrome, Aged, Psychiatric Status Rating Scales, Motivation, Dopaminergic, Parkinson Disease, Parkinson Disease/complications/therapy, Middle Aged, medicine.disease, ddc:616.8, Disruptive, Impulse Control, and Conduct Disorders, Motivation/drug effects/physiology, Subthalamic Nucleus/physiology, Dyskinesia, Dyskinesia, Drug-Induced/etiology/therapy, Levodopa/adverse effects/therapeutic use, Female, Neurology (clinical), Antiparkinson Agents/adverse effects, medicine.symptom, Psychology, medicine.drug
Abstract: Addictions to dopaminergic drugs or to pleasant behaviours are frequent and potentially devastating neuropsychiatric disorders observed in Parkinson's disease. They encompass impulse control disorders, punding and dopamine dysregulation syndrome. A relationship with dopaminergic treatment is strongly suggested. Subthalamic stimulation improves motor complications and allows for drastic reductions in medication. This treatment might, therefore, be considered for patients with behavioural addictions, when attempts to reduce dopaminergic medication have failed. However, conflicting data have reported suppression, alleviation, worsening or new onset of behavioural addictions after subthalamic stimulation. Non-motor fluctuations are also a disabling feature of the disease. We prospectively investigated behaviour in a cohort of 63 patients with Parkinson's disease, before and 1 year after subthalamic stimulation using the Ardouin scale, with systematic evaluation of functioning in overall appetitive or apathetic modes, non-motor fluctuations, dopaminergic dysregulation syndrome, as well as behavioural addictions (including impulse control disorders and punding) and compulsive use of dopaminergic medication. Defined drug management included immediate postoperative discontinuation of dopamine agonists and reduction in levodopa. Motor and cognitive statuses were controlled (Unified Parkinson's Disease Rating Scale, Mattis Dementia Rating Scale, frontal score). After surgery, the OFF medication motor score improved (-45.2%), allowing for a 73% reduction in dopaminergic treatment, while overall cognitive evaluation was unchanged. Preoperative dopamine dysregulation syndrome had disappeared in 4/4, behavioural addictions in 17/17 and compulsive dopaminergic medication use in 9/9 patients. New onset of levodopa abuse occurred in one patient with surgical failure. Non-motor fluctuations were significantly reduced with improvements in off-dysphoria (P ≤ 0.001) and reduction in on-euphoria (P ≤ 0.001). There was an inversion in the number of patients functioning in an overall appetitive mode (29 before versus 2 after surgery, P ≤ 0.0001) to an overall apathetic mode (3 before versus 13 after surgery, P
Published: 2012

47. Singular DYT6 phenotypes in association with new THAP1 frameshift mutations

Author: Stéphane Thobois, Gael Gallouedec, Vuthy Ea, Sylvie Tuffery-Giraud, Monika Rudzińska, Gwenaëlle Collod-Béroud, Pierre Burbaud, Christine Tranchant, Alain Destée, Jean-Paul Adenis, Arnaud Blanchard, Laura Cif, Patrick Calvas, Anna Potulska-Chromik, Mireille Claustres, Michel Borg, Isabelle Benatru, Piotr Janik, Alexandre Kreisler, Philippe Damier, Isabelle Vuillaume, Sylvie Odent, Bernard Sablonnière, Anna Lusakowska, Mélissa Yana Frédéric, Agathe Roubertie, Samer Janoura, Coline Coquart, Philippe Coubes, Lucie Guyant-Maréchal, Marion Simonetta-Moreau, Laurence Faivre, COLLOD-BEROUD, Gwenaëlle, Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut des Neurosciences de Montpellier (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Imagerie cérébrale et handicaps neurologiques (ICHN), Institut des sciences du cerveau de Toulouse. (ISCT), Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Arnaud de Villeneuve [CHRU Montpellier], Service de Neurologie [CHU Limoges], CHU Limoges, Service d'Ophtalmologie [CHU Limoges], Service de Neurologie générale, vasculaire et dégénérative (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service de Neurologie [CHU Nice], Hôpital Pasteur [Nice] (CHU)-Centre Hospitalier Universitaire de Nice (CHU Nice), Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Hôpital Pellegrin, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Physiologie et physiopathologie de la signalisation cellulaire (PPSC), Université Bordeaux Segalen - Bordeaux 2-Université Sciences et Technologies - Bordeaux 1 (UB)-CHU Bordeaux [Bordeaux]-Centre National de la Recherche Scientifique (CNRS), Service Génétique Médicale [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Service de Neurochirurgie [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-CHU Gui de Chauliac [Montpellier], CIC Plurithématique de Nantes, Institut National de la Santé et de la Recherche Médicale (INSERM)-Ministère des Affaires sociales et de la Santé-Direction générale de l'offre de soins (DGOS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Service de neurologie [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Hôpital Guillaume-et-René-Laennec [Saint-Herblain], Département de neurologie [Lille], Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Service de neurologie [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU), Medical University of Warsaw - Poland, Centre Hospitalier de Roanne, Service de génétique clinique [Rennes], Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, Department of neurology, Uniwersytet Jagielloński w Krakowie = Jagiellonian University (UJ), Service de neurologie C [Hôpital Pierre Wertheimer - HCL], Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Laboratoire de Biochimie et Biologie Moléculaire (LILLE - Biochimie et Biol Moléculaire), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de Neurologie [Strasbourg], CHU Strasbourg-Hopital Civil, Institut de Génomique Fonctionnelle (IGF), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, IFR3, Université Montpellier 1 (UM1)-Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Bordeaux Segalen - Bordeaux 2-Université Sciences et Technologies - Bordeaux 1-CHU Bordeaux [Bordeaux]-Centre National de la Recherche Scientifique (CNRS), Service de génétique médicale, CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Département de neurologie[Lille], Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-hôpital Sud, Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Service de Neuropédiatrie, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Guy de Chauliac, Imagerie cérébrale et handicaps neurologiques, Service de Neurologie, Clinique neurologique, Hôpital Laennec, Department of Experimental Cardiology, Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA)-University of Amsterdam [Amsterdam] (UvA)-Heart Failure Research Center (HFRC), Génétique médicale et fonctionnelle du cancer et des maladies neuropsychiatriques, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Embryology, University of Warsaw (UW)-Institute of Zoology, Département de Pharmacologie, PRES Université Lille Nord de France, Service de Génétique Clinique, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Sud, Jagiellonian University [Krakow] (UJ), Institut des sciences cognitives Marc Jeannerod - Centre de neuroscience cognitive - UMR5229 (CNC), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Centre de Biologie-Pathologie, UF de Neurobiologie-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Département de neurologie, Hôpital universitaire de Strasbourg, Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Neurochirurgie [CHRU Montpellier], and Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [CHU Montpellier]
Subjects: Biology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, MESH: Phenotype, Frameshift mutation, 03 medical and health sciences, 0302 clinical medicine, MESH: Dystonia Musculorum Deformans, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Genetics, 0303 health sciences, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Middle Aged, MESH: Humans, MESH: Apoptosis Regulatory Proteins, [SCCO.NEUR]Cognitive science/Neuroscience, [SCCO.NEUR] Cognitive science/Neuroscience, MESH: Frameshift Mutation, MESH: Adult, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Phenotype, MESH: Male, Neurology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology (clinical), MESH: Nuclear Proteins, MESH: Female, 030217 neurology & neurosurgery, MESH: DNA-Binding Proteins
Abstract: International audience
Published: 2011
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48. Non-motor dopamine withdrawal syndrome after surgery for Parkinson's disease: predictors and underlying mesolimbic denervation

Author: Jean-Louis Quesada, Pierre Pollak, Alim-Louis Benabid, Emmanuel Broussolle, Jean-Luc Bosson, Hélène Klinger, Rachid Hassani, Paul Krack, Anthonin Reilhac, Gustavo Polo, Jing Xie, Andrea Kistner, Marc Savasta, Maria Clara Coelho Braga, Didier Lebars, Eric Seigneuret, Claire Ardouin, Nicolas Costes, Stéphane Thobois, Patrick Mertens, Alexandra Juphard, Léon Tremblay, Stephan Chabardes, Valérie Fraix, Christelle Lagrange, Eugénie Lhommée, Savasta, Marc, Service de neurologie C [Hôpital Pierre Wertheimer - HCL], Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Institut des sciences cognitives Marc Jeannerod - Centre de neuroscience cognitive - UMR5229 (CNC), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), INSERM U836, équipe 10, Dynamique des réseaux neuronaux du mouvement, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Unité de Désordres du Mouvement, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-CHU Grenoble, Unité de Désordres du Mouvement, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, Service de Neurologie A, Hôpital des Spécialités, INSERM U836, équipe 7, Nanomédecine et cerveau, Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de neurochirurgie, ANTE-INSERM U836, équipe 11, Fonctions cérébrales et neuromodulation, Université de Lyon, Service de Neurochirurgie [Hopital Pierre Wertheimer - HCL], Centre d'Etude et de Recherche Multimodal Et Pluridisciplinaire en imagerie du vivant (CERMEP - imagerie du vivant), Université de Lyon-Université de Lyon-CHU Grenoble-Hospices Civils de Lyon (HCL)-CHU Saint-Etienne-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), CIC - Grenoble, Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de neurochirurgie, Commissariat à l'énergie atomique et aux énergies alternatives - Laboratoire d'Electronique et de Technologie de l'Information (CEA-LETI), Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Programme Hospitalier de Recherche Clinique Interregional and Eutherapie Pharmaceutical Company, Université de Lyon-Université de Lyon-CHU Grenoble-Hospices Civils de Lyon (HCL)-CHU Saint-Etienne-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Institut des sciences cognitives Marc Jeannerod - Centre de neuroscience cognitive - UMR5229 (ISC-MJ), Université Joseph Fourier - Grenoble 1 (UJF)-Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-CHU Grenoble-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, Parkinson's disease, Deep Brain Stimulation, Postoperative Complications, 0302 clinical medicine, Depression/etiology/psychology, MESH: Postoperative Complications, Limbic System, Apathy, MESH: Double-Blind Method, Prospective Studies, MESH: Dopamine Agonists, MESH: Aged, 0303 health sciences, MESH: Middle Aged, Depression, Methylphenidate, Dopamine Agonists/adverse effects, Dopaminergic, Parkinson Disease, Denervation/psychology, MESH: Follow-Up Studies, Middle Aged, Denervation, MESH: Predictive Value of Tests, Substance Withdrawal Syndrome, 3. Good health, MESH: Limbic System, Substance Withdrawal Syndrome/etiology/psychology, Dopamine Agonists, Postoperative Complications/chemically induced/etiology/psychology, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], medicine.symptom, Psychology, medicine.drug, Adult, medicine.medical_specialty, Levodopa, MESH: Depression, MESH: Substance Withdrawal Syndrome, Deep Brain Stimulation/adverse effects, Dopamine agonist, Parkinson Disease/drug therapy/psychology/surgery, 03 medical and health sciences, Double-Blind Method, Predictive Value of Tests, Dopamine receptor D3, Dopamine, medicine, Humans, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Denervation, Aged, 030304 developmental biology, MESH: Humans, MESH: Adult, medicine.disease, MESH: Male, MESH: Prospective Studies, ddc:616.8, Surgery, Limbic System/surgery, Neurology (clinical), MESH: Deep Brain Stimulation, MESH: Female, 030217 neurology & neurosurgery, MESH: Parkinson Disease, Follow-Up Studies
Abstract: International audience; Apathy has been reported to occur after subthalamic nucleus stimulation, a treatment of motor complications in advanced Parkinson's disease. We carried out a prospective study of the occurrence of apathy and associated symptoms, predictors and mechanisms in the year following subthalamic stimulation. Dopamine agonist drugs were discontinued immediately after surgery and levodopa was markedly reduced within 2 weeks. Apathy and depression were assessed monthly, using the Starkstein apathy scale and the Beck Depression Inventory. Dopamine agonists were re-introduced if patients developed apathy or depression. Preoperative non-motor fluctuations were evaluated using the Ardouin Scale. Depression, apathy and anxiety were evaluated both on and off levodopa. Analysis of predictors of apathy was performed using a Cox proportional hazard model. Twelve patients who developed apathy and a control group of 13 patients who did not underwent [11C]-raclopride positron emission tomography scanning before and after oral intake of methylphenidate. In 63 patients with Parkinson's disease treated with subthalamic stimulation, dopaminergic treatment was decreased by 82% after surgery. Apathy occurred after a mean of 4.7 (3.3-8.2) months in 34 patients and was reversible in half of these by the 12-month follow-up. Seventeen patients developed transient depression after 5.7 (4.7-9.3) months and these fell into the apathy group with one single exception. At baseline, fluctuations in depression, apathy and anxiety scores were greater in the group with apathy. Fluctuations in apathy, depression and anxiety ratings during a baseline levodopa challenge were also significant predictors of postoperative apathy in univariate analysis, but not motor and cognitive states or the level of reduction of dopaminergic medication. The multivariate model identified non-motor fluctuations in everyday life and anxiety score during the baseline levodopa challenge as two independent significant predictors of postoperative apathy. Without methylphenidate, [11C]-raclopride binding potential values were greater in apathetic patients bilaterally in the orbitofrontal, dorsolateral prefrontal, posterior cingulate and temporal cortices, left striatum and right amygdala, reflecting greater dopamine D2/D3 receptor density and/or reduced synaptic dopamine level in these areas. The variations of [11C]-raclopride binding potential values induced by methylphenidate were greater in non-apathetic patients in the left orbitofrontal cortex, dorsolateral prefrontal cortex, thalamus and internal globus pallidus and bilaterally in the anterior and posterior cingulate cortices, consistent with a more important capacity to release dopamine. Non-motor fluctuations are related to mesolimbic dopaminergic denervation. Apathy, depression and anxiety can occur after surgery as a delayed dopamine withdrawal syndrome. A varying extent of mesolimbic dopaminergic denervation and differences in dopaminergic treatment largely determine mood, anxiety and motivation in patients with Parkinson's disease, contributing to different non-motor phenotypes.
Published: 2010
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49. Exhaustive analysis of BH4 and dopamine biosynthesis genes in patients with Dopa-responsive dystonia

Author: Stéphane Thobois, Alexandra Durr, Agnès Camuzat, Diane Doummar, Cécile Cazeneuve, Emmanuel Roze, Chankannira Sân, Alexis Brice, Delphine Bouteiller, Brigitte Chabrol, Myriem Abada, Pierre Castelnau, David Grabli, Fabienne Clot, Estelle Fedirko, Karine Nguyen, G. Ponsot, Alana Ward, Michael Hutchinson, Marie Vidailhet, Roger Gil, Pierre Landrieu, Fabienne Picard, Annick Toutain, Philippe Damier, and Eric LeGuern
Subjects: Adult, Male, medicine.medical_specialty, Heterozygote, Tyrosine 3-Monooxygenase, Adolescent, Dopamine, Ubiquitin-Protein Ligases, Dopamine Agents, Dystonic Disorders/drug therapy/*genetics/metabolism, Biology, medicine.disease_cause, Parkin, Levodopa, Alcohol Oxidoreductases/genetics, Young Adult, Internal medicine, medicine, Tyrosine 3-Monooxygenase/genetics, Humans, Point Mutation, Ubiquitin-Protein Ligases/genetics, Age of Onset, Sepiapterin reductase, GTP Cyclohydrolase, Child, Genetics, Dystonia, Mutation, Parkinsonism, Point mutation, Biopterin/*analogs & derivatives/biosynthesis, Middle Aged, medicine.disease, Biopterin, nervous system diseases, ddc:616.8, Levodopa/*therapeutic use, Alcohol Oxidoreductases, Endocrinology, Sepiapterin reductase deficiency, Dystonic Disorders, Child, Preschool, Female, Neurology (clinical), Dopamine/*biosynthesis, GTP Cyclohydrolase/genetics, Dystonic disorder, Dopamine Agents/*therapeutic use
Abstract: Dopa-responsive dystonia is a childhood-onset dystonic disorder, characterized by a dramatic response to low dose of L-Dopa. Dopa-responsive dystonia is mostly caused by autosomal dominant mutations in the GCH1 gene (GTP cyclohydrolase1) and more rarely by autosomal recessive mutations in the TH (tyrosine hydroxylase) or SPR (sepiapterin reductase) genes. In addition, mutations in the PARK2 gene (parkin) which causes autosomal recessive juvenile parkinsonism may present as Dopa-responsive dystonia. In order to evaluate the relative frequency of the mutations in these genes, but also in the genes involved in the biosynthesis and recycling of BH4, and to evaluate the associated clinical spectrum, we have studied a large series of index patients (n = 64) with Dopa-responsive dystonia, in whom dystonia improved by at least 50% after L-Dopa treatment. Fifty seven of these patients were classified as pure Dopa-responsive dystonia and seven as Dopa-responsive dystonia-plus syndromes. All patients were screened for point mutations and large rearrangements in the GCH1 gene, followed by sequencing of the TH and SPR genes, then PTS (pyruvoyl tetrahydropterin synthase), PCBD (pterin-4a-carbinolamine dehydratase), QDPR (dihydropteridin reductase) and PARK2 (parkin) genes. We identified 34 different heterozygous point mutations in 40 patients, and six different large deletions in seven patients in the GCH1 gene. Except for one patient with mental retardation and a large deletion of 2.3 Mb encompassing 10 genes, all patients had stereotyped clinical features, characterized by pure Dopa-responsive dystonia with onset in the lower limbs and an excellent response to low doses of L-Dopa. Dystonia started in the first decade of life in 40 patients (85%) and before the age of 1 year in one patient (2.2%). Three of the 17 negative GCH1 patients had mutations in the TH gene, two in the SPR gene and one in the PARK2 gene. No mutations in the three genes involved in the biosynthesis and recycling of BH4 were identified. The clinical presentations of patients with mutations in TH and SPR genes were strikingly more complex, characterized by mental retardation, oculogyric crises and parkinsonism and they were all classified as Dopa-responsive dystonia-plus syndromes. Patient with mutation in the PARK2 gene had Dopa-responsive dystonia with a good improvement with L-Dopa, similar to Dopa-responsive dystonia secondary to GCH1 mutations. Although the yield of mutations exceeds 80% in pure Dopa-responsive dystonia and Dopa-responsive dystonia-plus syndromes groups, the genes involved are clearly different: GCH1 in the former and TH and SPR in the later.
Published: 2009

50. A multitracer dopaminergic PET study of young-onset parkinsonian patients with and without parkin gene mutations

Author: Sophie Tezenas du Montcel, Alexis Brice, Yves Agid, Stéphane Thobois, Maria-Joao Ribeiro, Emmanuel Broussolle, Luc Mallet, Bruno Dubois, Pierre Pollak, Philippe Remy, Ebba Lohmann, Suzanne Lesage, Antoine Pelissolo, Savasta, Marc, Service Hospitalier Frédéric Joliot (SHFJ), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Hôpital Neurologique, Hospices Civils de Lyon (HCL)-Université de Lyon, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Département de Biostatistique, Santé Publique et Information Médicale [CHU Pitié-Salpêtrière] (BIOSPIM ), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Modelisation in Clinical Research, Université Pierre et Marie Curie - Paris 6 (UPMC), Neurologie et thérapeutique expérimentale, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR70-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de psychiatrie adulte [CHU Pitié-Salpêtière], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Centre de référence sur les démences rares et maladie de Pick, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Behavior, Emotion and Basal Ganglia, Institut National de la Santé et de la Recherche Médicale (INSERM)-Center of Clinical Investigation, Département de neurologie, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, CIC AP-HP (pitie-Salpetriere)/inserm, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Service de néphrologie et transplantation, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Hôpital Henri Mondor, INSERM/AP-HP PCR02006-P011104, Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, and Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR70-Université Pierre et Marie Curie - Paris 6 (UPMC)
Subjects: Male, Ubiquitin-Protein Ligases/*genetics, Striatum, Gene mutation, Parkin, Receptors, Dopamine, 0302 clinical medicine, MESH: Receptors, Dopamine, Tissue Distribution, MESH: Heterozygote, Parkinsonian Disorders/*genetics/*metabolism/radionuclide imaging, 0303 health sciences, MESH: Middle Aged, Putamen, Dopaminergic, Brain, Middle Aged, 3. Good health, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Radiopharmaceuticals, medicine.medical_specialty, Heterozygote, MESH: Mutation, Mutation/genetics, Ubiquitin-Protein Ligases, Receptors, Dopamine/*metabolism, Substantia nigra, Statistical parametric mapping, 03 medical and health sciences, Brain/*metabolism/radionuclide imaging, MESH: Brain, Parkinsonian Disorders, Internal medicine, medicine, Humans, Radiology, Nuclear Medicine and imaging, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Tissue Distribution, Radionuclide Imaging, Psychiatry, 030304 developmental biology, Radioisotopes, MESH: Humans, business.industry, MESH: Parkinsonian Disorders, Radioisotopes/diagnostic use/*pharmacokinetics, MESH: Ubiquitin-Protein Ligases, MESH: Male, ddc:616.8, nervous system diseases, Radiopharmaceuticals/diagnostic use/pharmacokinetics, Endocrinology, Mutation, Cardiovascular agent, MESH: Radioisotopes, Radiopharmaceuticals, business, MESH: Female, 030217 neurology & neurosurgery
Abstract: International audience; The impact of parkin gene mutations on nigrostriatal dopaminergic degeneration is not well established. The purpose of this study was to characterize by PET using (18)F-fluoro-l-3,4-dihydroxyphenylalanine ((18)F-fluoro-l-DOPA), (11)C-PE2I, and (11)C-raclopride the pattern of dopaminergic lesions in young-onset Parkinson disease (YOPD) patients with or without mutations of the parkin gene and to correlate the clinical and neuropsychologic characteristics of these patients with PET results. METHODS: A total of 35 YOPD patients were enrolled (16 with parkin mutation, 19 without). The uptake constant (K(i)) of (18)F-fluoro-l-DOPA and the binding potential (BP) of (11)C-PE2I (BP(DAT)) and of (11)C-raclopride (BP(D2)) were calculated in the striatum. Comparisons were made between the 2 groups of YOPD and between controls and patients. For each radiotracer, parametric images were obtained, and statistical parametric mapping (SPM) analysis using a voxel-by-voxel statistical t test was performed. Correlations between the cognitive and motor status and PET results were analyzed. RESULTS: In YOPD patients, (18)F-fluoro-l-DOPA K(i) values were reduced to 68% (caudate) and 40% (putamen) of normal values (P < 0.0001). This decrease was symmetric and comparable for nonparkin and parkin patients. No correlation was found between the K(i) values and cognitive or motor status. (11)C-PE2I BP(DAT) values in YOPD patients were decreased to 56% (caudate) and 41% (putamen) of normal values (P < 0.0001) and did not differ between the 2 YOPD populations. The mean (11)C-raclopride BP(D2) values were reduced to 72% (caudate) and 84% (putamen) of the normal values (P < 0.02) and did not differ between nonparkin and parkin patients. SPM analyses showed in patients an additional decrease of (11)C-raclopride in the frontal cortex and a decrease of (18)F-fluoro-l-DOPA and (11)C-PE2I uptake in the substantia nigra bilaterally (P < 0.05, false-discovery rate-corrected). CONCLUSION: Carriers of parkin mutations are indistinguishable on PET markers of dopaminergic dysfunction from other YOPD patients with long disease duration.
Published: 2009
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