Freezing of gait is one of the most disturbing motor symptoms of Parkinson's disease (PD). However, the effective connectivity between key brain hubs that are associated with the pathophysiological mechanism of freezing of gait remains elusive.
Objective
The aim of this study was to identify effective connectivity underlying freezing of gait.
Methods
This study applied spectral dynamic causal modeling (DCM) of resting-state functional magnetic resonance imaging in dedicated regions of interest determined using a data-driven approach.
Results
Abnormally increased functional connectivity between the bilateral dorsolateral prefrontal cortex (DLPFC) and the bilateral mesencephalic locomotor region (MLR) was identified in freezers compared with nonfreezers. Subsequently, spectral DCM analysis revealed that increased top-down excitatory effective connectivity from the left DLPFC to bilateral MLR and an independent self-inhibitory connectivity within the left DLPFC in freezers versus nonfreezers (>99% posterior probability) were inversely associated with the severity of freezing of gait. The lateralization of these effective connectivity patterns was not attributable to the initial dopaminergic deficit nor to structural changes in these regions.
Laura Armengou-Garcia,Carlos A Sanchez-Catasus,Iciar Aviles-Olmos,Adolfo Jiménez-Huete,Genoveva Montoya-Murillo,Arantza Gorospe,Antonio Martin-Bastida,Lain Hermes Gonzalez-Quarante,Jorge Guridi,Maria C Rodriguez-Oroz
Björn-Hergen Laabs PhD, Katja Lohmann PhD, Eva-Juliane Vollstedt MD, Tobias Reinberger PhD, Lisa-Marie Nuxoll MSc, Gamze Kilic-Berkmen PhD, Joel S. Perlmutter MD, Sebastian Loens MD, Carlos Cruchaga PhD, Andre Franke PhD, Valerija Dobricic PhD, Frauke Hinrichs, Anne Grözinger BSc, Eckart Altenmüller MD, Steven Bellows MD, Sylvia Boesch MD, MSc, Susan B. Bressman MD, Kevin R. Duque MD, Alberto J. Espay MD, Andreas Ferbert MD, Jeanne S. Feuerstein MD, Samuel Frank MD, Thomas Gasser MD, Bernhard Haslinger MD, Robert Jech MD, PhD, Frank Kaiser PhD, Christoph Kamm MD, Katja Kollewe MD, Andrea A. Kühn MD, Mark S. LeDoux MD, PhD, Ebba Lohmann MD, Abhimanyu Mahajan MD, MHS, Alexander Münchau MD, Trisha Multhaupt-Buell MS, CGC, Alexander Pantelyat MD, Sarah E. Pirio Richardson MD, Deborah Raymond MS, CGC, Stephen G. Reich MD, Rachel Saunders Pullman MD, MPH, MSc, Barbara Schormair PhD, Nutan Sharma MD, PhD, Azadeh Hamzehei Sichani MA, Kristina Simonyan MD, PhD, DrMed, Jens Volkmann MD, Aparna Wagle Shukla MD, Juliane Winkelmann MD, Laura J. Wright MA, Michael Zech MD, Kirsten E. Zeuner MD, Simone Zittel MD, Meike Kasten MD, Yan V. Sun PhD, Tobias Bäumer MD, Norbert Brüggemann MD, Laurie J. Ozelius PhD, Hyder A. Jinnah MD, PhD, Christine Klein MD, Inke R. König PhD
Background
Despite considerable heritability, previous smaller genome-wide association studies (GWASs) have not identified any robust genetic risk factors for isolated dystonia.
Objective
The objective of this study was to perform a large-scale GWAS in a well-characterized, multicenter sample of >6000 individuals to identify genetic risk factors for isolated dystonia.
Methods
Array-based GWASs were performed on autosomes for 4303 dystonia participants and 2362 healthy control subjects of European ancestry with subgroup analysis based on age at onset, affected body regions, and a newly developed clinical score. Another 736 individuals were used for validation.
Results
This GWAS identified no common genome-wide significant loci that could be replicated despite sufficient power to detect meaningful effects. Power analyses imply that the effects of individual variants are likely very small.
Michael T. Barbe MD, Jan Rusz PhD, Kristina Simonyan MD
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Christine Brefel-Courbon MD, Ana Marques MD, PhD, Olivier Rascol MD, PhD, for the NS-Park OXYDOPA study group
<p>We are grateful for the opportunity to respond to the letter entitled “What is in a name” from Daniel Ciampi de Andrade, Veit Mylius, and Santiago Perez Lloret regarding our recent article.<span><sup>1</sup></span> We thank these authors for providing the three steps necessary to identify pain in Parkinson's disease (PD). They are an essential prerequisite for proposing appropriate treatment of pain in PD. As the authors note, our study focused on chronic pain in PD, therefore, fulfilling the first step. The second step was also respected, because we eliminated patients suffering from pain unrelated to PD (called concomitant pain) as defined by the Marques's algorithm.<span><sup>2</sup></span> Finally, in our case, the third step was to classify and diagnose parkinsonian central pain (PCP). We applied our classification<span><sup>2</sup></span> that is very close to that of Mylius et al,<span><sup>3</sup></span> which was published later. Based on this proposed classification, we used an algorithm aimed at disentangling PCP from other subtypes of chronic pain in PD by specifically and sequentially eliminating what is not PCP. Therefore, by respecting these different steps, we believe we have included mainly PCP patients and not patients suffering from other pain mechanisms.</p><p>Before the definition of nociplastic pain, older classifications of pain in PD defined and classified PCP as “central neuropathic pain” and described as boring, constant, ineffable, and diffuse, not limited to a dermatome or specific neural distribution.<span><sup>4, 5</sup></span> We agree with the authors that the term “central neuropathic pain,” which corresponds to a lesion of the central somatosensory system, should no longer be used in PD and must be clearly distinguished from PCP. We confirm that our patients suffered from “central parkinsonian pain,” which fits the definition of nociplastic pain, as previously suggested in our classification.<span><sup>2</sup></span></p><p>Finally, we would like to add a further step in pain identification, which is to determine and validate diagnostic criteria for each type of pain in PD, particularly for PCP, which is often misdiagnosed and probably underestimated because diagnostic criteria are not well defined. Indeed, PCP is diagnosed mainly on the basis of exclusion criteria, whereas we need to identify positive criteria. We would like to emphasize the need to better characterize the different pains in PD, which is a challenge to enable better evaluation of analgesic strategies in PD patients.</p><p>C.B.C. has received consultancy fees from Merz, BIAL, NHC, Orkyn; grants from the French Ministry of Health: projet hospitalier de recherche clinique grants; French Ministry of Research: ANR; France Parkinson, Fondation AXA, Everpharma, Elivie, NHC, and Orkyn; honoraria for speeches from Orkyn, Novartis, and AJR; and support for attending meetings and/or travel from Orkyn, AJR, AbbVie, NHC, and Adelia. A.M. has received consu
{"title":"Reply to: “What Is in a Name”","authors":"Christine Brefel-Courbon MD, Ana Marques MD, PhD, Olivier Rascol MD, PhD, for the NS-Park OXYDOPA study group","doi":"10.1002/mds.29944","DOIUrl":"https://doi.org/10.1002/mds.29944","url":null,"abstract":"<p>We are grateful for the opportunity to respond to the letter entitled “What is in a name” from Daniel Ciampi de Andrade, Veit Mylius, and Santiago Perez Lloret regarding our recent article.<span><sup>1</sup></span> We thank these authors for providing the three steps necessary to identify pain in Parkinson's disease (PD). They are an essential prerequisite for proposing appropriate treatment of pain in PD. As the authors note, our study focused on chronic pain in PD, therefore, fulfilling the first step. The second step was also respected, because we eliminated patients suffering from pain unrelated to PD (called concomitant pain) as defined by the Marques's algorithm.<span><sup>2</sup></span> Finally, in our case, the third step was to classify and diagnose parkinsonian central pain (PCP). We applied our classification<span><sup>2</sup></span> that is very close to that of Mylius et al,<span><sup>3</sup></span> which was published later. Based on this proposed classification, we used an algorithm aimed at disentangling PCP from other subtypes of chronic pain in PD by specifically and sequentially eliminating what is not PCP. Therefore, by respecting these different steps, we believe we have included mainly PCP patients and not patients suffering from other pain mechanisms.</p><p>Before the definition of nociplastic pain, older classifications of pain in PD defined and classified PCP as “central neuropathic pain” and described as boring, constant, ineffable, and diffuse, not limited to a dermatome or specific neural distribution.<span><sup>4, 5</sup></span> We agree with the authors that the term “central neuropathic pain,” which corresponds to a lesion of the central somatosensory system, should no longer be used in PD and must be clearly distinguished from PCP. We confirm that our patients suffered from “central parkinsonian pain,” which fits the definition of nociplastic pain, as previously suggested in our classification.<span><sup>2</sup></span></p><p>Finally, we would like to add a further step in pain identification, which is to determine and validate diagnostic criteria for each type of pain in PD, particularly for PCP, which is often misdiagnosed and probably underestimated because diagnostic criteria are not well defined. Indeed, PCP is diagnosed mainly on the basis of exclusion criteria, whereas we need to identify positive criteria. We would like to emphasize the need to better characterize the different pains in PD, which is a challenge to enable better evaluation of analgesic strategies in PD patients.</p><p>C.B.C. has received consultancy fees from Merz, BIAL, NHC, Orkyn; grants from the French Ministry of Health: projet hospitalier de recherche clinique grants; French Ministry of Research: ANR; France Parkinson, Fondation AXA, Everpharma, Elivie, NHC, and Orkyn; honoraria for speeches from Orkyn, Novartis, and AJR; and support for attending meetings and/or travel from Orkyn, AJR, AbbVie, NHC, and Adelia. A.M. has received consu","PeriodicalId":213,"journal":{"name":"Movement Disorders","volume":"39 9","pages":"1652-1653"},"PeriodicalIF":7.4,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mds.29944","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142244670","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Giulia Lazzeri MD, Marion Houot MSc, Maxime Patout MD, PhD, Cécile Londner MD, Carole Philippe MD, PhD, Stephane Attard MSc, Teddy Delpy MD, Joanna Ruggeri MSc, Bertrand Degos MD, PhD, Florence Cormier MD, Marie Vidailhet MD, Jean Cristophe Corvol MD, PhD, Isabelle Arnulf MD, PhD, David Grabli MD, PhD, Pauline Dodet MD
Background
Sleep-disordered breathing (SDB; including stridor and sleep apnea syndromes) is frequent in multiple system atrophy (MSA), but the immediate effect of continuous positive airway pressure (CPAP) therapy is incompletely determined.
Objective
We sought to evaluate the acute effect and safety of CPAP therapy on SDB and sleep architecture, as well as the clinical characteristics of nonresponders to CPAP therapy.
Methods
The measures of 63 consecutive patients with MSA who underwent a video-polysomnography during two consecutive nights (a first night in ambient air, a second night with or without CPAP, depending on the presence of SDB and availability of CPAP) in routine care were retrospectively collected. Linear mixed models assessed the two-night change in sleep and respiratory measures, comparing those with and without the CPAP therapy on the second night.
Results
SDB was frequent and mainly associated with the cerebellar phenotype. The introduction of CPAP had immediate benefits, including the normalization of the apnea–hypopnea index and a resolution of stridor in more than two-thirds of the cases, decreased arousal index, and increased rapid eye movement sleep. CPAP therapy was well tolerated, and only two patients had emergent central apneas. Nonresponse to CPAP was generally associated with more severe motor disease.
Daniel Ciampi de Andrade MD, PhD, Veit Mylius, Santiago Perez Lloret
<p>We read with interest the OXYDOPA study by Brefel-Courbon et al,<span><sup>1</sup></span> where central pain in people with Parkinson's disease (PwP) was treated by prolonged-release oxycodone, increase in levodopa, or placebo. The authors should be complimented for conducting such a complex multicenter trial on a topic that needs urgent new data and that extended itself through times of coronavirus disease pandemics. Bravo.</p><p>Pain is among the most burdensome non-motor symptoms of Parkinson's disease (PD) and to date no effective evidence-based treatment exists for its control. Different pain types have different mechanisms of disease, which respond differently to therapeutic interventions. This means that clinicians should first assess the pain type PwP have and then proceed to a specific therapy.</p><p>To do that, three steps need to be completed. First, clinicians need to ascertain that pain is chronic (ie, being present most of the days for more than 3 months). Interestingly, several classification systems for pain in PD do not ascertain that pain is chronic. Second, since pain affects at least 20% of the general population, one needs to ascertain that chronic pain in PwP is related to PD. By ignoring this point, one risks misclassifying, for example, migraine, or previously existing fibromyalgia as PD-related pain. More than 20% of PwP have pains not related to the disease. Third, the classification should acknowledge general classification frameworks and previous knowledge generated by the field of PD and pain.<span><sup>2</sup></span></p><p>The present study aimed at chronic pain in PwP, therefore, fulfilling the first step. However, it classified PD-related pain using a classification system that has not yet been validated. There was no reference to the relationship between patient's pain and PD. Therefore, the study sample may have included PwP with different pain mechanisms.</p><p>What is more problematic is the use of “central neuropathic pain.” Central neuropathic pain because of PD does not stand with any current classification of central neuropathic pain (see Table 1).<span><sup>3</sup></span> There is no doubt that the clinical phenotype described as being of central neuropathic pain exists in PwP, but it is rare.<span><sup>4</sup></span></p><p>The authors also mixed the concept of “central neuropathic pain” with “central parkinsonian pain.” The problematic definition of the pain type under study makes the results of this study difficult to apply to the clinical practice.</p><p>“Central parkinsonian pain” fits the definition of nociplastic pain (as suggested in the very same paper used for pain classification in the present study)<span><sup>5</sup></span> (Table 1). The classification of PD-related pains according to its mechanistic descriptors (nociceptive, neuropathic, and nociplastic) has been validated clinically, has shown to provide different profiles of somatosensory and cortical excitability changes in PwP,<span><su
{"title":"What Is In A Name?","authors":"Daniel Ciampi de Andrade MD, PhD, Veit Mylius, Santiago Perez Lloret","doi":"10.1002/mds.29943","DOIUrl":"10.1002/mds.29943","url":null,"abstract":"<p>We read with interest the OXYDOPA study by Brefel-Courbon et al,<span><sup>1</sup></span> where central pain in people with Parkinson's disease (PwP) was treated by prolonged-release oxycodone, increase in levodopa, or placebo. The authors should be complimented for conducting such a complex multicenter trial on a topic that needs urgent new data and that extended itself through times of coronavirus disease pandemics. Bravo.</p><p>Pain is among the most burdensome non-motor symptoms of Parkinson's disease (PD) and to date no effective evidence-based treatment exists for its control. Different pain types have different mechanisms of disease, which respond differently to therapeutic interventions. This means that clinicians should first assess the pain type PwP have and then proceed to a specific therapy.</p><p>To do that, three steps need to be completed. First, clinicians need to ascertain that pain is chronic (ie, being present most of the days for more than 3 months). Interestingly, several classification systems for pain in PD do not ascertain that pain is chronic. Second, since pain affects at least 20% of the general population, one needs to ascertain that chronic pain in PwP is related to PD. By ignoring this point, one risks misclassifying, for example, migraine, or previously existing fibromyalgia as PD-related pain. More than 20% of PwP have pains not related to the disease. Third, the classification should acknowledge general classification frameworks and previous knowledge generated by the field of PD and pain.<span><sup>2</sup></span></p><p>The present study aimed at chronic pain in PwP, therefore, fulfilling the first step. However, it classified PD-related pain using a classification system that has not yet been validated. There was no reference to the relationship between patient's pain and PD. Therefore, the study sample may have included PwP with different pain mechanisms.</p><p>What is more problematic is the use of “central neuropathic pain.” Central neuropathic pain because of PD does not stand with any current classification of central neuropathic pain (see Table 1).<span><sup>3</sup></span> There is no doubt that the clinical phenotype described as being of central neuropathic pain exists in PwP, but it is rare.<span><sup>4</sup></span></p><p>The authors also mixed the concept of “central neuropathic pain” with “central parkinsonian pain.” The problematic definition of the pain type under study makes the results of this study difficult to apply to the clinical practice.</p><p>“Central parkinsonian pain” fits the definition of nociplastic pain (as suggested in the very same paper used for pain classification in the present study)<span><sup>5</sup></span> (Table 1). The classification of PD-related pains according to its mechanistic descriptors (nociceptive, neuropathic, and nociplastic) has been validated clinically, has shown to provide different profiles of somatosensory and cortical excitability changes in PwP,<span><su","PeriodicalId":213,"journal":{"name":"Movement Disorders","volume":"39 9","pages":"1651-1652"},"PeriodicalIF":7.4,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mds.29943","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142236610","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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