Publications by authors named "Stéphane Thobois"

144 Publications

Comparison of clinical outcomes and accuracy of electrode placement between robot-assisted and conventional deep brain stimulation of the subthalamic nucleus: a single-center study.

Acta Neurochir (Wien) 2021 Mar 2. Epub 2021 Mar 2.

Service de Neurologie C, Centre Expert Parkinson, Hôpital Neurologique et Neurochirurgical Pierre Wertheimer, Hospices Civils de Lyon, 69003, Lyon, France.

Background: Several surgical methods are used for deep brain stimulation (DBS) of the subthalamic nucleus (STN) in Parkinson's disease (PD). This study aimed to compare clinical outcomes and electrode placement accuracy after robot-assisted (RAS) versus frame-based stereotactic (FSS) STN DBS in Parkinson's disease.

Methods: In this single-center open-label study, we prospectively collected data from 48 consecutive PD patients who underwent RAS (Neuromate®; n = 20) or FSS (n = 28) STN DBS with the same MRI-based STN targeting between October 2016 and December 2018 in the university neurological hospital of Lyon, France. Clinical variables were assessed before and 1 year after surgery. The number of electrode contacts within the STN was determined by merging post-operative CT and pre-operative MRI using Brainlab® GUIDE™XT software.

Results: One year after surgery, the improvement of motor manifestations (p = 0.18), motor complications (p = 0.80), and quality of life (p= 0.30) and the reduction of dopaminergic treatment (p = 0.94) and the rate of complications (p = 0.99) were similar in the two groups. Surgery duration was longer in the RAS group (p = 0.0001). There was no difference in the number of electrode contacts within the STN.

Conclusion: This study demonstrates that RAS and FSS STN DBS for PD provide similar clinical outcomes and accuracy of electrode placement.
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http://dx.doi.org/10.1007/s00701-021-04790-7DOI Listing
March 2021

Personality dimensions of patients can change during the course of parkinson's disease.

PLoS One 2021 7;16(1):e0245142. Epub 2021 Jan 7.

Toulouse NeuroImaging Center, University of Toulouse, Inserm, UPS, Toulouse, France.

Background: Studies assessing personality dimensions by the "Temperament and Character Inventory" (TCI) have previously found an association between Parkinson's disease (PD) and lower Novelty Seeking and higher Harm Avoidance scores. Here, we aimed to describe personality dimensions of PD patients with motor fluctuations and compare them to a normative population and other PD populations.

Methods: All PD patients awaiting Deep Brain Stimulation (DBS) answered the TCI before neurosurgery. Their results were compared to those of historical cohorts (a French normative population, a de novo PD population, and a PD population with motor fluctuations).

Results: Most personality dimensions of our 333 included PD patients with motor fluctuations who are candidates for DBS were different from those of the normative population and some were also different from those of the De Novo PD population, whereas they were similar to those of another population of PD patients with motor fluctuations.

Conclusions: During the course of PD, personality dimensions can change in parallel with the development of motor fluctuations, either due to the evolution of the disease and/or dopaminergic treatments.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0245142PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790271PMC
January 2021

Nucleus Basalis of Meynert Stimulation for Lewy Body Dementia: A Phase I Randomized Clinical Trial.

Neurology 2021 02 16;96(5):e684-e697. Epub 2020 Nov 16.

From the Departments of Neurology (D.M., D.W., R.L., D.H.), Neurophysiology (J.B., M.-L.W.), and Neurosurgery (S.D.), Rouen University Hospital and University of Rouen; INSERM U1239 (D.M.), Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, Mont-Saint-Aignan; Department of Neurology C (T.D., S.T.), Hopital Neurologique Pierre Wertheimer, University of Lyon, Université Claude Bernard Lyon 1, Faculté de Médecine Lyon Sud Charles Mérieux; Department of Neurology (L.D., K.D.), Lille University Hospital, INSERM 1171; Department of Neurology (J.-L.H.), CIC-INSERM 1402, CHU de Poitiers; Université de Poitiers (J.-L.H.); Department of Neurology (O.G., P.K.), Amiens University Hospital; Department of Neurology (O.M.), Caen University Hospital; Department of Biostatistics (A.G.), Rouen University Hospital; Department of Nuclear Medicine (M.C., P.V.), Henri Becquerel Cancer Center and Rouen University Hospital; and QuantIF-LITIS [EA (Equipe d'Accueil) 4108-FR CNRS 3638] (M.C., P.V.), Faculty of Medicine, University of Rouen, France.

Objectives: Nucleus 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.

Methods: Six 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.

Results: There 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.

Conclusions: NBM-DBS does not appear to be totally safe for patients with LBD with no evidence of cognitive benefit.

Clinicaltrialsgov Identifier: NCT01340001.

Classification Of Evidence: This 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.
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http://dx.doi.org/10.1212/WNL.0000000000011227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884989PMC
February 2021

Isolated parkinsonism is an atypical presentation of GRN and C9orf72 gene mutations.

Parkinsonism Relat Disord 2020 11 15;80:73-81. Epub 2020 Sep 15.

Sorbonne Université, Paris Brain Institute - Institut du Cerveau - ICM, Inserm U1127, CNRS UMR 7225, AP-HP - Hôpital Pitié-Salpêtrière, Paris, France; Centre de Référence des Démences Rares ou Précoces, IM2A, Département de Neurologie, AP-HP - Hôpital Pitié-Salpêtrière, Paris, France; Département de Neurologie, AP-HP - Hôpital Pitié-Salpêtrière, Paris, France; Paris Brain Institute - Institut du Cerveau - ICM, FrontLab, Paris, France. Electronic address:

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.
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http://dx.doi.org/10.1016/j.parkreldis.2020.09.019DOI Listing
November 2020

Clinical and Molecular Landscape of ALS Patients with Mutations: Novel Pathogenic Variants and Novel Phenotypes. A Single ALS Center Study.

Int J Mol Sci 2020 Sep 16;21(18). Epub 2020 Sep 16.

Laboratoire de Biochimie et Biologie Moleculaire, CHU Nimes, Nimes, Motoneuron Disease: Pathophysiology and Therapy, INM, University Montpellier, 30029 Nîmes CEDEX 9, France.

Mutations in the copper zinc superoxide dismutase 1 () gene are the second most frequent cause of familial amyotrophic lateral sclerosis (ALS). Nearly 200 mutations of this gene have been described so far. We report all pathogenic variants identified in patients followed in the single ALS center of Lyon, France, between 2010 and 2020. Twelve patients from 11 unrelated families are described, including two families with the not yet described and mutations. Splice site mutations were detected in two families. We discuss implications concerning genetic screening of gene in familial and sporadic ALS.
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http://dx.doi.org/10.3390/ijms21186807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554847PMC
September 2020

Early cognitive decline after bilateral subthalamic deep brain stimulation in Parkinson's disease patients with GBA mutations.

Parkinsonism Relat Disord 2020 07 9;76:56-62. Epub 2020 Jun 9.

Sorbonne Université, Inserm U1127, CNRS UMR 7225, Institut du Cerveau et de la Moelle épinière, Paris, France; Assistance Publique Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Département de Neurologie, Clinical Research Center Neurosciences, Paris, France. Electronic address:

Background: Subthalamic nucleus deep brain stimulation (STN-DBS) has demonstrated its efficacy on motor complications in advanced Parkinson's disease (PD) but does not modify disease progression. Genetic forms of PD have been associated with different cognitive progression profiles.

Objective: To assess the effect of PD-related genetic mutations on cognitive outcome after STN-DBS.

Methods: Patients with STN-DBS were screened for LRRK2, GBA, and PRKN mutations at the Pitié-Salpêtrière Hospital between 1997 and 2009. Patients with known monogenetic forms of PD from six other centers were also included. The Mattis Dementia Rating Scale (MDRS) was used to evaluate cognition at baseline and one-year post-surgery. The standardized Unified PD Rating Scale (UPDRS) evaluation On and Off medication/DBS was also administered. A generalized linear model adjusted for sex, ethnicity, age at onset, and disease duration was used to evaluate the effect of genetic factors on MDRS changes.

Results: We analyzed 208 patients (131 males, 77 females, 54.3 ± 8.8 years) including 25 GBA, 18 LRRK2, 22 PRKN, and 143 PD patients without mutations. PRKN patients were younger and had a longer disease duration at baseline. A GBA mutation was the only significant genetic factor associated with MDRS change (β = -2.51, p = 0.009). GBA mutation carriers had a more pronounced post-operative MDRS decline (3.2 ± 5.1) than patients with LRRK2 (0.9 ± 4.8), PRKN (0.5 ± 2.7) or controls (1.4 ± 4.4). The motor response to DBS was similar between groups.

Conclusion: GBA mutations are associated with early cognitive decline following STN-DBS. Neuropsychological assessment and discussions on the benefit/risk ratio of DBS are particularly important for this population.
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http://dx.doi.org/10.1016/j.parkreldis.2020.04.002DOI Listing
July 2020

Genetic and Phenotypic Basis of Autosomal Dominant Parkinson's Disease in a Large Multi-Center Cohort.

Front Neurol 2020 28;11:682. Epub 2020 Jul 28.

Sorbonne Université, Unité Mixte de Recherche (UMR) 1127, Paris, France.

, and are unequivocally associated with autosomal dominant Parkinson's disease (PD). We evaluated the prevalence of , and 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 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 variants (7.6%), including 136 with the Gly2019Ser mutation, 19 with point mutations or genomic rearrangements (1.1%), and three with the 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], = 0.001). PD patients with variants were more likely to have higher rates of late-onset PD (>50 years; OR 1.5, 95% CI [1.0-2.1], = 0.03), whereas those with mutations tended to have earlier age at onset disease (≤ 50 years, = 0.06). The clinical features of 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.
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http://dx.doi.org/10.3389/fneur.2020.00682DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7399219PMC
July 2020

Dissociation in reactive and proactive inhibitory control in Myoclonus dystonia.

Sci Rep 2020 08 18;10(1):13933. Epub 2020 Aug 18.

Sorbonne University, 75005, Paris, France.

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.
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http://dx.doi.org/10.1038/s41598-020-70926-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7434767PMC
August 2020

Deep Brain Stimulation for Freezing of Gait in Parkinson's Disease With Early Motor Complications.

Mov Disord 2020 01 22;35(1):82-90. Epub 2019 Nov 22.

Department of Neurology, UKSH, Kiel Campus Christian-Albrechts-University, Kiel, Germany.

Background: Effects of DBS on freezing of gait and other axial signs in PD patients are unclear.

Objective: Secondary analysis to assess whether DBS affects these symptoms within a large randomized controlled trial comparing DBS of the STN combined with best medical treatment and best medical treatment alone in patients with early motor complications (EARLYSTIM-trial).

Methods: One hundred twenty-four patients were randomized in the stimulation group and 127 patients in the best medical treatment group. Presence of freezing of gait was assessed in the worst condition based on item-14 of the UPDRS-II at baseline and follow-up. The posture, instability, and gait-difficulty subscore of the UPDRS-III, and a gait test including quantification of freezing of gait and number of steps, were performed in both medication-off and medication-on conditions.

Results: Fifty-two percent in both groups had freezing of gait at baseline based on UPDRS-II. This proportion decreased in the stimulation group to 34%, but did not change in the best medical treatment group at 24 months (P = 0.018). The steps needed to complete the gait test decreased in the stimulation group and was superior to the best medical treatment group (P = 0.016). The axial signs improved in the stimulation group compared to the best medical treatment group (P < 0.01) in both medication-off and medication-on conditions.

Conclusions: Within the first 2 years of DBS, freezing of gait and other axial signs improved in the medication-off condition compared to best medical treatment in these patients. © 2019 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.27892DOI Listing
January 2020

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

J Neurol 2020 Feb 7;267(2):531-542. Epub 2019 Nov 7.

Hospices Civils de Lyon, Hôpital Neurologique Pierre Wertheimer, Neurologie C, 69677, Bron Cedex, France.

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.
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http://dx.doi.org/10.1007/s00415-019-09608-2DOI Listing
February 2020

Visual sensory processing is altered in myoclonus dystonia.

Mov Disord 2020 01 30;35(1):151-160. Epub 2019 Sep 30.

Sorbonne Université, Paris, France; Inserm U1127, CNRS UMR 7225, UM 75, ICM, Paris, France.

Background: Abnormal sensory processing, including temporal discrimination threshold, has been described in various dystonic syndromes.

Objective: To investigate visual sensory processing in DYT-SGCE and identify its structural correlates.

Methods: DYT-SGCE patients without DBS (DYT-SGCE-non-DBS) and with DBS (DYT-SGCE-DBS) were compared to healthy volunteers in three tasks: a temporal discrimination threshold, a movement orientation discrimination, and movement speed discrimination. Response times attributed to accumulation of sensory visual information were computationally modelized, with μ parameter indicating sensory mean growth rate. We also identified the structural correlates of behavioral performance for temporal discrimination threshold.

Results: Twenty-four DYT-SGCE-non-DBS, 13 DYT-SGCE-DBS, and 25 healthy volunteers were included in the study. In DYT-SGCE-DBS, the discrimination threshold was higher in the temporal discrimination threshold (P = 0.024), with no difference among the groups in other tasks. The sensory mean growth rate (μ) was lower in DYT-SGCE in all three tasks (P < 0.01), reflecting a slower rate of sensory accumulation for the visual information in these patients independent of DBS. Structural imaging analysis showed a thicker left primary visual cortex (P = 0.001) in DYT-SGCE-non-DBS compared to healthy volunteers, which also correlated with lower μ in temporal discrimination threshold (P = 0.029). In DYT-SGCE-non-DBS, myoclonus severity also correlated with a lower μ in the temporal discrimination threshold task (P = 0.048) and with thicker V1 on the left (P = 0.022).

Conclusion: In DYT-SGCE, we showed an alteration of the visual sensory processing in the temporal discrimination threshold that correlated with myoclonus severity and structural changes in the primary visual cortex. © 2019 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.27857DOI Listing
January 2020

Early limbic microstructural alterations in apathy and depression in de novo Parkinson's disease.

Mov Disord 2019 11 15;34(11):1644-1654. Epub 2019 Jul 15.

Univ Lyon, Institut des Sciences Cognitives Marc Jeannerod, CNRS, UMR, 5229, Bron, France.

Background: Whether structural alterations underpin apathy and depression in de novo parkinsonian patients is unknown. The objectives of this study were to investigate whether apathy and depression in de novo parkinsonian patients are related to structural alterations and how structural abnormalities relate to serotonergic or dopaminergic dysfunction.

Methods: We compared the morphological and microstructural architecture in gray matter using voxel-based morphometry and diffusion tensor imaging coupled with white matter tract-based spatial statistics in a multimodal imaging case-control study enrolling 14 apathetic and 13 nonapathetic patients with de novo Parkinson's disease and 15 age-matched healthy controls, paired with PET imaging of the presynaptic dopaminergic and serotonergic systems.

Results: De novo parkinsonian patients with apathy had bilateral microstructural alterations in the medial corticostriatal limbic system, exhibiting decreased fractional anisotropy and increased mean diffusivity in the anterior striatum and pregenual anterior cingulate cortex in conjunction with serotonergic dysfunction. Furthermore, microstructural alterations extended to the medial frontal cortex, the subgenual anterior cingulate cortex and subcallosal gyrus, the medial thalamus, and the caudal midbrain, suggesting disruption of long-range nondopaminergic projections originating in the brainstem, in addition to microstructural alterations in callosal interhemispheric connections and frontostriatal association tracts early in the disease course. In addition, microstructural abnormalities related to depressive symptoms in apathetic and nonapathetic patients revealed a distinct, mainly right-sided limbic subnetwork involving limbic and frontal association tracts.

Conclusions: Early limbic microstructural alterations specifically related to apathy and depression emphasize the role of early disruption of ascending nondopaminergic projections and related corticocortical and corticosubcortical networks which underpin the variable expression of nonmotor and neuropsychiatric symptoms in Parkinson's disease. © 2019 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.27793DOI Listing
November 2019

Programming parameters of subthalamic deep brain stimulators in Parkinson's disease from a controlled trial.

Parkinsonism Relat Disord 2019 08 18;65:217-223. Epub 2019 Jun 18.

Department of Neurology, Christian-Albrechts-University, Kiel, Germany. Electronic address:

Background: Programming algorithms have never been tested for outcome. The EARLYSTIM study showed superior outcomes of deep brain stimulation of the subthalamic nucleus (STN-DBS) over best medical treatment in early Parkinson's disease (PD). Patients were programmed according to common guidelines but customized for each patient.

Methods: Stimulation parameters were systematically documented at 1, 5, 12, and 24 month in the cohort of 114 patients who had bilateral STN-DBS at 24 month. We investigated the influence of atypical programming, changes of stimulated electrode contacts and stimulation energy delivered. Outcomes were the Unified Parkinson's Disease Rating Scale (UPDRS) motor and ADL-subscores, health-related quality of life (PDQ-39) summary index and mobility- and ADL-subscores.

Results: At 1/5/12/24 months follow up, mean amplitude (1.8/2.5/2.6/2.8 V), impedance (1107/1286/1229/1189 Ω) and TEED (33.7/69.0/84.4/93.0 V2*μs*Hz/Ω) mainly increased in the first 5 months, while mean pulse width (60.0/62.5/65.1/65.8 μs), frequency (130/137.7/139.1/142.7 Hz) remained relatively stable. Typical programming (single monopolar electrode contact) was used in 80.7% of electrodes. Double monopolar (11/114) and bipolar (2/114) stimulation was only rarely required. There was no significant difference in clinical outcomes between the patient groups requiring contact changes (n = 32/28.1%) nor between typical (n = 83/72.8%) versus non-typical programming. Energy used for STN-DBS was higher for the dominant side of PD.

Conclusion: In the first 5 months an increase in amplitude is required to compensate for various factors. Monopolar stimulation is sufficient in 80% of patients at 24 months. Homogeneous stimulation strategies can account for the favorable outcomes reported in the Earlystim study.
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http://dx.doi.org/10.1016/j.parkreldis.2019.05.023DOI Listing
August 2019

A novel heterozygous ANO3 mutation responsible for myoclonic dystonia.

J Neurol Sci 2019 Aug 13;403:65-66. Epub 2019 Jun 13.

Hospices Civils de Lyon, Hôpital Neurologique Pierre Wertheimer, Service de Neurologie C, 69000 Lyon, France; Université de Lyon, Lyon 1 University, Lyon, F-69373; Centre de Neurosciences Cognitives de Lyon, CNRS UMR 5229, Bron F-69500, France.

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http://dx.doi.org/10.1016/j.jns.2019.06.014DOI Listing
August 2019

Structural Imaging in Parkinson's Disease: New Developments.

Curr Neurol Neurosci Rep 2019 06 18;19(8):50. Epub 2019 Jun 18.

Institut des Sciences Cognitives Marc Jeannerod, Université de Lyon, CNRS, UMR 5229, F-69675, Bron, France.

Purpose Of Review: To review the advances in structural imaging for the diagnosis, prognosis, and treatment of Parkinson's disease (PD) during the last 5 years.

Recent Findings: Structural imaging using high-field MRI (≥ 3 T) and new MR sequences sensitive to iron and nigral pigments have achieved to assess in vivo pathological surrogates useful for PD diagnosis (notably decreased nigral neuromelanin and loss of dorsal nigral hyperintensity, increased nigral iron content, diffusivity, and free-water), prodromal diagnosis (decreased neuromelanin signal in the locus coeruleus), and PD progression (with increasing nigral iron content (increasing R2* rate) and nigral damage (increasing free-water)). Additionally, evaluation of atrophy in small monoaminergic nuclei is useful for prognosis, including cholinergic basal forebrain nuclei atrophy for cognitive impairment. New advances in multimodal structural imaging improve diagnosis, prognosis, and prediction of invasive treatment outcome in PD, and may further benefit from machine learning and large scale longitudinal studies to better identify prognostic subtypes.
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http://dx.doi.org/10.1007/s11910-019-0964-5DOI Listing
June 2019

Descriptive analysis of the French NS-Park registry: Towards a nation-wide Parkinson's disease cohort?

Parkinsonism Relat Disord 2019 07 25;64:226-234. Epub 2019 Apr 25.

Sorbonne Université, Assistance Publique Hôpitaux de Paris, Institut du Cerveau et de la Moelle épinière, ICM, Inserm U 1127, CNRS UMR 7225, Department of Neurology, Hôpital Pitié-Salpêtrière, F-75013, Paris, France; Center for Interdisciplinary Research in Biology, Collège de France, INSERM U1050, CNRS UMR7241, Labex Memolife, Paris Sciences et Lettres, Paris, France; AP-HP, Department of Neurology, Hôpital Avicenne, Hôpitaux Universitaires de Paris - Seine Saint Denis, Bobigny, France. Electronic address:

Introduction: Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's. The French clinical research network for PD (NS-Park) has created a national patient registry to i)report medical activity of Parkinson Expert Centers (PECs) to the Ministry of Health, ii)facilitate PD patients pre-screening for clinical trials, iii) provide a source for pharmaco-epidemiology studies.

Objective: Assess the French Parkinsonian population at a nation-wide level and discover new clinical characteristics.

Methods: In this feasibility study, PECs prospectively collected clinical data in a standardized manner. The population main clinical characteristics are described, focusing on motor and non-motor symptoms and treatments, assessing its representativeness. By using an unbiased clustering with multiple correspondence analysis (MCA), we also investigate potential relationships between multiple variables like symptoms and treatments, as clues for future studies.

Results: Between 2012 and 2016, among 11,157 included parkinsonian syndromes, 9454 (85%) had PD. MCA identified various profiles depending on disease duration. Occurrences of motor complications, axial signs, cognitive disorders and Levodopa use increase over time. Neurovegetative symptoms, psychiatric disorders, sleep disturbances and impulse control disorders (ICDs) seem stable over time. As expected, ICDs were associated to dopaminergic agonist use but other associations, such as ICDs and sleep disturbances for instance, or anxiety and depression, were found.

Conclusions: Our results report one of the biggest PD registries ever reported and demonstrate the feasibility of implementing a nation-wide registry of PD patients in France, a potent tool for future longitudinal studies and clinical trials' population selection, and for pharmaco-epidemiology and cost-effectiveness studies.
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http://dx.doi.org/10.1016/j.parkreldis.2019.04.012DOI Listing
July 2019

Neuroimaging biomarkers for clinical trials in atypical parkinsonian disorders: Proposal for a Neuroimaging Biomarker Utility System.

Alzheimers Dement (Amst) 2019 Dec 2;11:301-309. Epub 2019 Apr 2.

Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom.

Introduction: Therapeutic strategies targeting protein aggregations are ready for clinical trials in atypical parkinsonian disorders. Therefore, there is an urgent need for neuroimaging biomarkers to help with the early detection of neurodegenerative processes, the early differentiation of the underlying pathology, and the objective assessment of disease progression. However, there currently is not yet a consensus in the field on how to describe utility of biomarkers for clinical trials in atypical parkinsonian disorders.

Methods: To promote standardized use of neuroimaging biomarkers for clinical trials, we aimed to develop a conceptual framework to characterize in more detail the kind of neuroimaging biomarkers needed in atypical parkinsonian disorders, identify the current challenges in ascribing utility of these biomarkers, and propose criteria for a system that may guide future studies.

Results: As a consensus outcome, we describe the main challenges in ascribing utility of neuroimaging biomarkers in atypical parkinsonian disorders, and we propose a conceptual framework that includes a graded system for the description of utility of a specific neuroimaging measure. We included separate categories for the ability to accurately identify an intention-to-treat patient population early in the disease (Early), to accurately detect a specific underlying pathology (Specific), and the ability to monitor disease progression (Progression).

Discussion: We suggest that the advancement of standardized neuroimaging in the field of atypical parkinsonian disorders will be furthered by a well-defined reference frame for the utility of biomarkers. The proposed utility system allows a detailed and graded description of the respective strengths of neuroimaging biomarkers in the currently most relevant areas of application in clinical trials.
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http://dx.doi.org/10.1016/j.dadm.2019.01.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6446052PMC
December 2019

[Parkinson's disease: from the description of the disease to its surgical treatment].

Rev Prat 2018 May;68(5):574-578

Université de Lyon, institut des sciences cognitives Marc-Jeannerod, CNRS, UMR 5229, Bron, France.

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May 2018

[Parkinson's disease treatment: from honey moon to motor fluctuations].

Rev Prat 2018 May;68(5):502-507

Faculté de médecine Lyon-Sud-Charles- Mérieux, université Lyon-1, université de Lyon, Lyon, France.

Parkinson's disease treatment: from honey moon to motor fluctuations. The treatment of Parkinson's disease remains symptomatic but allows, for many years, a good control of motor and non-motor signs. This treatment is complex and has to deal with very heterogeneous motor and non-motor presentation. Initial treatment is started once disability occurs and is mainly based either on levodopa or dopamine agonists. When motor fluctuations start, the principle of treatment is to optimize levodopa intake and combine various drugs depending on the clinical presentation. Third line strategies of treatment such as pumps or deep brain stimulation may be proposed at this stage. Later on, when doparesistant signs appear, treatment has often to be simplified, cognitive decline to be taken in charge and physiotherapy is crucial even if physical exercise is of great importance whatever the stage of the disease. Finally, non-motor manifestations have to be carefully addressed throughout the course of the disease because their impact on quality of life is sometimes greater than the one of motor signs.
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May 2018

Long-term effects of anterior pallidal deep brain stimulation for tourette's syndrome.

Mov Disord 2019 04 20;34(4):586-588. Epub 2019 Feb 20.

STIC: Traitement de la maladie de Gilles de la Tourette par stimulation bilatérale à haute fréquence de la partie antérieure du globus pallidus interne.

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http://dx.doi.org/10.1002/mds.27645DOI Listing
April 2019

Quality of life predicts outcome of deep brain stimulation in early Parkinson disease.

Neurology 2019 03 8;92(10):e1109-e1120. Epub 2019 Feb 8.

From the Département de Neurologie (W.M.M.S., A.H., T.D.H., F.P., Y.A., M.V.), Hôpital Pitié-Salpêtrière, Centre d'Investigation Clinique 1422, Institut du Cerveau et de la Moelle Epinière, Institut National de Santé et en Recherche Médicale, Assistance Publique Hôpitaux de Paris, France; Institute of Neurology (W.M.M.S.), Konolfingen; Department of Neurology (W.M.M.S.), University Hospital Bern and University of Bern, Switzerland; Medtronic (L.T.), Minneapolis, MN; Institute of Clinical Neuroscience & Medical Psychology and Department of Neurology (A.D., L.W.), Medical Faculty, Heinrich-Heine-University Düsseldorf, Germany; Movement Disorder Unit, Neurology (P.K.), CHU Grenoble Alpes; Grenoble Institut des Neurosciences (P.K., V.F., A. Kistner), University Grenoble Alpes; Inserm U1216 (P.K., V.F., A. Kistner), Grenoble, France; Department of Clinical Neurosciences (Neurology) (P.K.), Faculty of Medicine, University of Geneva, Switzerland; Coordinating Center for clinical trials of the Philipps University of Marburg (J.R., C.S.-B.); Neurochirurgische Klinik im Neurozentrum (A.F., L.P., S.P., J. Volkmann, K.K., G.D.),Christian-Albrechts-Universität Kiel; Neurologische Klinik und Poliklinik (J. Volkmann), Universitätsklinikum Würzburg; Department of Neurology (H.S.D., M.T.B., G.R.F., L.T.), University Hospital Cologne; Research Centre Jülich (G.R.F.); Klinik für Neurologie (T.D.H., A. Kühn, A. Kupsch) and Klinik für Neurochirurgie (G.-H.S.), Campus Virchow, Charité-Universitätsmedizin Berlin; Praxis Kupsch (A. Kupsch), Berlin, Germany; Service de Neurochirurgie (E.S.) and Service de Neurologie (V.F.), Hôpital Michallon, Centre Hospitalo-Universitaire, Grenoble; Departments of Neurosurgery (P.P.C.), Neurology (F.O.-M., C.B.-C.), and Clinical Pharmacology (C.B.-C.), University Hospital of Toulouse; ToNIC (F.O.-M., C.B.-C.), Toulouse Neuroimaging Center, University of Toulouse, Inserm, UPS, France; Department of Neurosurgery (J. Vesper), Universitätsklinikum Düsseldorf, Germany; Departments of Neurosurgery (S.D.) and Neurology (D.M.), Rouen University Hospital and University of Rouen; INSERM U1239 (D.M.), Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, Mont-Saint-Aignan; Service de Neurologie (P. Damier, P. Derkinderen), CHU Nantes, Hôpital Laënnec, France; Paracelsus-Elena-Klinik Kassel (F.S.-D., C.T.); Department of Neurosurgery (C.T.), University Medical Center Göttingen; Division of Functional and Restorative Neurosurgery and Centre for Integrative Neuroscience (A.G.), Tübingen; Abteilung für Neurologie (T.W.), Reha-Zentrum Bad Gögging, Passauer Wolf; Department for Neurodegenerative Diseases and Hertie Institute for Clinical Brain Research (D.W.), University of Tübingen; Division of Stereotactic and Functional Neurosurgery (M.O.P.), University Medical Center Freiburg, Germany; Departments of Functional and Stereotactic Neurosurgery and Radiosurgery (J.-.M.R.) and Neurology (T.W.), Timone University Hospital, INSERM, Marseille; Institut des Sciences Cognitives Marc Jeannerod (S.T.), CNRS, UMR 5229, Université de Lyon; Centre Expert Parkinson (S.T.), Service de Neurologie C, Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, Bron; Department of Neurosurgery (P.M.), University Hospital of Neurology and Neurosurgery, Hospices Civils de Lyon, Université de Lyon; Department of Neurology (J.-L.H.), INSERM-1402, Centre Hospitalier Universitaire de Poitiers, University of Poitiers, France; and Universitätsklinikum Giessen und Marburg (L.T.), Marburg Campus, Germany.

Objective: To 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.

Methods: We 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.

Results: PDQ-39-SI at baseline was correlated to the change in PDQ-39-SI after 24 months in both treatment groups ( < 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.

Conclusion: Impaired 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.

Clinicaltrialsgov Identifier: NCT00354133.
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http://dx.doi.org/10.1212/WNL.0000000000007037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6442017PMC
March 2019

A new MRI marker of ataxia with oculomotor apraxia.

Eur J Radiol 2019 Jan 29;110:187-192. Epub 2018 Nov 29.

Hospices Civils de Lyon, Neurology D and Neuro-Ophthalmology Unit, Hôpital Neurologique Pierre Wertheimer, Bron, F-69677, France; Université de Lyon, Lyon 1 University, Lyon, F-69373, France; Lyon Neuroscience Research Center, INSERM U1028 CNRS UMR5292, Team ImpAct, Bron, F-69676, France. Electronic address:

Purpose: Evaluate the specificity and sensitivity of disappearance of susceptibility weighted imaging (SWI) dentate nuclei (DN) hypointensity in oculomotor apraxia patients (AOA).

Method: In this prospective study, 27 patients with autosomal genetic ataxia (AOA (n = 11), Friedreich ataxia and ataxia with vitamin E deficit (n = 4), and dominant genetic ataxia (n = 12)) were included along with fifteen healthy controls. MRIs were qualitatively classified for the presence or absence of DN hypointensity on FLAIR and SWI sequences. The MRIs were then quantitatively studied, with measurement of a ratio of DN over brainstem white matter signal intensity through manual delineation. The institutional review board approved this study, and written informed consent was obtained. In the cross-sectional analysis, the Mann-Whitney test was applied.

Results: Qualitatively, the eleven AOA patients presented absence of both DN SWI and FLAIR hyposignals; three dominant genetic ataxia patients had moderate SWI DN hyposignal and absent FLAIR hyposignal; the thirteen remaining subjects presented normal SWI and FLAIR DN hyposignal. Absence of DN SWI hypointensity was 100% sensitive and specific to AOA. Quantitative signal intensity ratio (mean ± standard deviation) of the AOA group (98·96 ± 5·37%) was significantly higher than in control subjects group (76.40 ± 8.34%; p < 0.001), dominant genetic ataxia group (81·15 ± 9·94%; p < 0·001), and Friedreich ataxia and ataxia with vitamin E deficit group (87·56 ± 2·78%; p < 0·02).

Conclusion: This small study shows that loss of the normal hypointensity in the dentate nucleus on both SWI and FLAIR imaging at 3 T is a highly sensitive and specific biomarker for AOA.
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http://dx.doi.org/10.1016/j.ejrad.2018.11.035DOI Listing
January 2019

Wait and you shall see: sexual delay discounting in hypersexual Parkinson's disease.

Brain 2019 01;142(1):146-162

Neuroeconomics, Reward and Decision-making Team, Institut des Sciences Cognitives Marc Jeannerod, Centre National de la Recherche Scientifique, UMR 5229, Bron, France.

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.
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http://dx.doi.org/10.1093/brain/awy298DOI Listing
January 2019

Age and time course of long-term motor and nonmotor complications in Parkinson disease.

Neurology 2019 01 12;92(2):e148-e160. Epub 2018 Dec 12.

From Université Lyon (S.P., T.D., C.L., E.M., E.B., S.T.), Institut des Sciences Cognitives-Marc Jeannerod, CNRS, UMR 5229, Bron; Hospices Civils de Lyon (S.P., T.D., C.C., C.L., E.M., H.M., E.B., S.T.), Hôpital Neurologique Pierre Wertheimer, Service de Neurologie C, Centre Expert Parkinson, Bron; Université Lyon (C.L., E.B., D.M.-B., S.T.), Faculté de Médecine Lyon Sud Charles Mérieux, Oullins; Hospices Civils de Lyon (D.M.-B.), Service de Biostatistique, Lyon; and Université Lyon (D.M.-B.), Laboratoire de Biométrie et Biologie Évolutive, CNRS, UMR 5558, Pierre Benite, France.

Objective: To determine the time course of hazard for motor and nonmotor milestones of Parkinson disease (PD) in the long term and to investigate whether risk scales nonlinearly with time is instrumental in identifying changes in pathological processes and evaluating disease-modifying therapies in PD.

Methods: Outpatients with PD at the Lyon University Movement Disorders Center were evaluated for 7 clinical milestones in this retrospective cohort study, encompassing 4 domains of PD progression: (1) motor (motor fluctuations, dyskinesias); (2) axial (postural instability and falls, freezing of gait); (3) neuropsychiatric (impulse control disorders, hallucinations); and (4) cognitive (dementia) complications. For each complication, we estimated the outcome-specific hazard using parsimonious smooth parametric Poisson regression models allowing for nonlinear scaling over disease duration, age at diagnosis, current age, and their interaction.

Results: A total of 1,232 patients with PD experienced 1,527 disease-related complications in up to 12 years of follow-up. Specific to each complication, hazard rates increased dramatically starting from diagnosis and were highest for motor fluctuations and lowest for dementia up to 6 years after diagnosis in patients aged 65 years at diagnosis. Nonlinear patterns indicated dramatic changes in the course of PD after 5 years and predicted more severe axial prognosis after 70 years and for motor fluctuations, dyskinesias, and impulse control disorders before 60 years at diagnosis.

Conclusion: Time course of motor and nonmotor milestones in PD is determined by disease duration and age at diagnosis in nonlinear patterns and their interaction. This indicates disease- and age-specific thresholds across the multiple neurodegenerative processes accumulating in PD at different paces.
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http://dx.doi.org/10.1212/WNL.0000000000006737DOI Listing
January 2019

The Neuropsychiatric Fluctuations Scale for Parkinson's Disease: A Pilot Study.

Mov Disord Clin Pract 2018 May-Jun;5(3):265-272. Epub 2018 Mar 23.

National Center of Epidemiology Carlos III Institute of Health Madrid Spain.

Background: Non-motor fluctuations represent a main source of disability in Parkinson's disease (PD). Among them, neuropsychiatric fluctuations are the most frequent and are often under-recognized by patients and physicians, partly because specific tools for assessment of neuropsychiatric fluctuations are lacking.

Objective: To develop a scale for detecting and evaluating the presence and the severity of neuropsychological symptoms during the ON and OFF phases of non-motor fluctuations.

Methods: Neuropsychiatric symptoms reported by PD patients in the OFF- and the ON-medication conditions were collected using different neuropsychiatric scales (BDI-II, BAI, Young, VAS, etc.). Subsequently, tree phases of a pilot study was performed for cognitive pretesting, identification of ambiguous or redundant items (item reduction), and to obtain preliminary data of acceptability of the new scale. In all the three phases, the scale was applied in both the OFF and ON condition during a levodopa challenge.

Results: Twenty items were selected for the final version of the neuropsychiatric fluctuation scale (NFS): ten items measured the ON neuropsychological symptoms and ten items the OFF neuropsychological manifestations. Each item rated from 0-3, providing respective subscores from 0 to 30.

Conclusions: Once validated, our NFS can be used to identify and quantify neuropsychiatric fluctuations during motor fluctuations. The main novelty is that it could be used in acute settings. As such, the NFS can assess the neuropsychiatric state of the patient at the time of examination. The next step will be to validate the NFS to be used in current practice.
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http://dx.doi.org/10.1002/mdc3.12607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6174472PMC
March 2018

Molecular Imaging of Opioid System in Idiopathic Parkinson's Disease.

Int Rev Neurobiol 2018 13;141:275-303. Epub 2018 Aug 13.

Equipe physiopathologie des Ganglions de la base, Institut des Sciences Cognitives Marc Jeannerot, Centre de Neurosciences Cognitives, UMR 5229, CNRS, Bron, France; Université Lyon 1, Univ de Lyon, Bron, France.

Opioid receptors are localized throughout peripheral and central nervous system and interact with endogenous opioid peptides and drugs including heroin, synthetic opioids, and pain relievers (codeine, morphine). If several opioid PET tracers exist for preclinical studies, only a few have been used in human. Some tracers are selective for one subtype of opioid receptors (e.g., [C]CAF (carfentanil) for μ receptor) while others are not ([C]DPN (diprenorphine)). As shown by imaging studies, the opioid system is involved in pain processing, but also in addiction, neuropsychiatric manifestations (harm avoidance, sadness, novelty seeking behavior), feeding and food disorders and, finally, movement disorders and levodopa-induced dyskinesias. However, no imaging study has analyzed the potential dysfunction of opioid system in pain manifestations in Parkinson's disease. In addition, the involvement of opioid system in impulse control disorders and neuropsychiatric manifestations has never been studied in Parkinson's disease. Thus, there is an urgent need to understand the impact of opioid system dysfunctions in Parkinson's disease.
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http://dx.doi.org/10.1016/bs.irn.2018.07.029DOI Listing
April 2019

What a neurologist should know about PET and SPECT functional imaging for parkinsonism: A practical perspective.

Parkinsonism Relat Disord 2019 02 30;59:93-100. Epub 2018 Aug 30.

Univ Lyon, Institut des Sciences Cognitives Marc Jeannerod, CNRS, UMR 5229, F-69675, Bron, France; Hospices Civils de Lyon, Hôpital Neurologique Pierre Wertheimer, Service de Neurologie C, Centre Expert Parkinson, Lyon, France; Univ Lyon, Faculté de Médecine et de Maïeutique Lyon Sud Charles Mérieux, F-69921, Oullins, France.

The diagnosis of a parkinsonian syndrome based on clinical criteria remains sometimes difficult, especially at disease onset. Brain or heart molecular imaging techniques (SPECT or PET) can provide a major help to improve and speed up diagnosis, influencing treatment strategies. Presynaptic dopaminergic imaging using either [F]-Dopa PET or I -2β-Carbomethoxy-3β-(4-Iodophenyl)- N-(3-Fluoropropyl) Nortropane ([I]-Ioflupane)SPECT demonstrates or rules out the presence of a dopaminergic degenerative process. This allows to distinguish Parkinson's disease, Parkinson "plus" syndromes and dementia with Lewy bodies (reduced radiotracers binding) from essential tremor, psychogenic, post-neuroleptic or vascular parkinsonisms, dopa-responsive dystonia and Alzheimer's disease (normal radiotracers binding). For differential diagnosis between Parkinson's disease and Parkinson "plus" syndromes, brain molecular imaging with [F]-Fluorodeoxyglucose ([F]-FDG) PET or Tc-HMPAO SPECT can provide useful information, whereas [F]-Dopa PET or [I]-Ioflupane does not separate these entities. Finally, sympathetic cardiac [I]-Metaiodobenzylguanidine ([I]-MIBG) scintigraphy or SPECT can help distinguishing Parkinson's disease and dementia with Lew bodies (decreased binding) from multiple system atrophy and progressive supranuclear palsy (normal binding). New radiotracers notably those targeting the pathological process itself such as Tau aggregates are under development and may provide interesting informations to delineate the different Parkinson "plus" syndromes.
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http://dx.doi.org/10.1016/j.parkreldis.2018.08.016DOI Listing
February 2019

Removing deep brain stimulation artifacts from the electroencephalogram: Issues, recommendations and an open-source toolbox.

Clin Neurophysiol 2018 10 13;129(10):2170-2185. Epub 2018 Aug 13.

Université de Lyon, F-69622 Lyon, France; Université Lyon 1, Villeurbanne, France; INSERM U1028, CNRS UMR5292, Centre de Recherche en Neurosciences de Lyon, Lyon, France. Electronic address:

A major question for deep brain stimulation (DBS) research is understanding how DBS of one target area modulates activity in different parts of the brain. EEG gives privileged access to brain dynamics, but its use with implanted patients is limited since DBS adds significant high-amplitude electrical artifacts that can completely obscure neural activity measured using EEG. Here, we systematically review and discuss the methods available for removing DBS artifacts. These include simple techniques such as oversampling, antialiasing analog filtering and digital low-pass filtering, which are necessary but typically not sufficient to fully remove DBS artifacts when each is used in isolation. We also cover more advanced methods, including techniques tracking outliers in the frequency-domain, which can be effective, but are rarely used. The reason for that is twofold: First, it requires advanced skills in signal processing since no user friendly tool for removing DBS artifacts is currently available. Second, it involves fine-tuning to avoid over-aggressive filtering. We highlight an open-source toolbox incorporating most artifact removal methods, allowing users to combine different strategies.
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http://dx.doi.org/10.1016/j.clinph.2018.07.023DOI Listing
October 2018

Pathophysiology of levodopa-induced dyskinesia: Insights from multimodal imaging and immunohistochemistry in non-human primates.

Neuroimage 2018 12 10;183:132-141. Epub 2018 Aug 10.

Univ Lyon, CNRS, Institut des Sciences Cognitives Marc Jeannerod UMR 5229, F-69675, Bron, France. Electronic address:

Background: Dopaminergic and serotonergic degenerations alter pharmacological neurotransmission and structural markers in Parkinson's disease (PD). Alteration of diffusion measures in key brain regions depict MPTP/MDMA lesions in the monkey model of PD. Whether dopatherapy impacts such diffusion measures remains an open question.

Objectives: The aim of this study was to investigate the consequences of l-DOPA treatment on diffusion alterations, PET imaging and immunohistochemical markers in MPTP/MDMA-intoxicated monkeys.

Methods: We acquired PET imaging and measures of mean diffusivity and fractional anisotropy longitudinally and correlated them with behavior and post-mortem fiber quantification.

Results: Severity of l-DOPA-induced dyskinesia was correlated to serotonin transporter radioligand binding increases in the ventral striatum and the anterior cingulate cortex and decreases of mean diffusivity in the ventral striatum. After lesion of serotonergic fibers by MDMA and the second l-DOPA period, diffusion measures were no more altered while the serotonergic binding still increased in all regions of interest, despite abolition of dyskinesia. Interestingly, in the anterior cingulate cortex, the SERT radioligand binding was negatively correlated to the number of SERT fibers.

Conclusion: These results show that the increase of SERT radioligand binding is not systematically paralleled by an increase of SERT fibers and does not always reflect the presence of LID. More specifically, our study suggest that SERT increase may be underpinned by an increased density of serotonergic fibers after MPTP and the first l-DOPA period, and by an elevation of SERT itself after MDMA and the second l-DOPA period. This highlights that DTI is complementary to PET imaging to decipher pathophysiological mechanisms underlying l-DOPA-induced dyskinesia in a non-human primate model of PD.
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http://dx.doi.org/10.1016/j.neuroimage.2018.08.016DOI Listing
December 2018