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Der Schreibkrampf ist eine Form der fokalen Dystonie, die durch unwillkürliche Verkrampfungen der Hand beim Schreiben gekennzeichnet ist, wobei es zu abnormen und funktionell beeinträchtigenden Fehlstellungen kommen kann. Hinsichtlich der Pathophysiologie vermutet man neben einer defizienten sensomotorischen Integration eine abnorme kortikale Plastizität. So findet sich bei Schreibkrampf-Patienten eine abnorm verstärkte PAS-induzierte LTP-ähnliche Plastizität (Quartarone et al., 2003). Diese weist wie auch die LTD-ähnliche Plastizität einen Verlust der somatotopen Spezifität auf: Veränderungen der motorkortikalen Erregbarkeit können im Gegensatz zu Gesunden auch durch PAS mit nicht-homologer peripher-elektrischer Stimulation induziert werden (Weise et al., 2006). Darüber hinaus scheint die für das Gleichgewicht von neuronalen Netzwerken notwendige homöostatische Metaplastizität beim Schreibkrampf gestört zu sein, wenn die Interaktion zwischen zwei aufeinanderfolgenden TMS-Protokollen getestet wird, die LTP- und LTD-ähnliche Plastizität hervorrufen (Quartarone et al., 2005). Da es sich beim motorischen Lernen um einen LTP-abhängigen Prozess handelt, war zu vermuten, dass dessen homöostatische Regulierung beim Schreibkrampf ebenfalls gestört ist. Diese Hypothese ist Ausgangspunkt der vorliegenden Untersuchungen. Hierfür wurde die als Modell für assoziative LTP- und LTD-ähnliche Plastizität beim Menschen entwickelte PAS bei 10 Schreibkrampf-Patienten und 10 gesunden bezüglich Alter und Geschlecht angepassten Probanden angewandt. Verschiedene PAS-Protokolle, die entweder eine LTP-ähnliche Steigerung (PAS25ms), eine LTD-ähnliche Reduzierung (PAS10ms) oder keine Veränderung (PAS100ms) der Motorkortex-Exzitabilität induzieren, wurden kombiniert mit einem nachfolgenden motorischen Training, bei dem die Teilnehmer schnellstmögliche Daumenabduktionsbewegungen der rechten Hand über einen Zeitraum von 2x15 Minuten durchführen mussten. Bei den gesunden Probanden führte eine Konditionierung durch PAS25ms- und PAS10ms-Protokolle zu einer homöostatischen Regulierung nachfolgender übungsabhängiger Plastizität mit einer Verschlechterung des motorischen Lernens nach dem fazilitierenden PAS25ms-Protokoll und einer Verbesserung des motorischen Lernens nach einem inhibierenden PAS10ms-Protokoll. Bei den Schreibkrampf-Patienten konnte diese homöostatische Metaplastizität nicht nachgewiesen werden. Zusätzlich korrelierte das Ausmaß dieser Störung (Verlust der Herunterregulierung motorischen Lernens nach Konditionierung mit PAS25ms) mit dem klinischen Schweregrad der Dystonie als behavioralem Korrelat, so dass mit den Ergebnissen der vorliegenden Arbeit die Hypothese gestützt werden kann, dass eine gestörte homöostatische Metaplastizität eine wichtige Rolle in der Pathophysiologie des Schreibkrampfes spielt. Inwieweit sich hieraus auch therapeutische Implikationen bzw. Strategien ableiten lassen, soll in weiteren Studien überprüft werden.
Background: The most common spinocerebellar ataxias (SCA)—SCA1, SCA2, SCA3, and SCA6—are caused by (CAG)n repeat expansion. While the number of repeats of the coding (CAG)n expansions is correlated with the age at onset, there are no appropriate models that include both affected and preclinical carriers allowing for the prediction of age at onset.
Methods: We combined data from two major European cohorts of SCA1, SCA2, SCA3, and SCA6 mutation carriers: 1187 affected individuals from the EUROSCA registry and 123 preclinical individuals from the RISCA cohort. For each SCA genotype, a regression model was fitted using a log-normal distribution for age at onset with the repeat length of the alleles as covariates. From these models, we calculated expected age at onset from birth and conditionally that this age is greater than the current age.
Results: For SCA2 and SCA3 genotypes, the expanded allele was a significant predictor of age at onset (−0.105±0.005 and −0.056±0.003) while for SCA1 and SCA6 genotypes both the size of the expanded and normal alleles were significant (expanded: −0.049±0.002 and −0.090±0.009, respectively; normal: +0.013±0.005 and −0.029±0.010, respectively). According to the model, we indicated the median values (90% critical region) and the expectancy (SD) of the predicted age at onset for each SCA genotype according to the CAG repeat size and current age.
Conclusions: These estimations can be valuable in clinical and research. However, results need to be confirmed in other independent cohorts and in future longitudinal studies.
Objective: Deep brain stimulation (DBS) of the ventral intermediate nucleus (VIM) is a mainstay treatment for severe and drug-refractory essential tremor (ET). Although stimulation-induced dysarthria has been extensively described, possible impairment of swallowing has not been systematically investigated yet. Methods: Twelve patients with ET and bilateral VIM-DBS with self-reported dysphagia after VIM-DBS were included. Swallowing function was assessed clinically and using by flexible endoscopic evaluation of swallowing in the stim-ON and in the stim-OFF condition. Presence, severity, and improvement of dysphagia were recorded. Results: During stim-ON, the presence of dysphagia could be objectified in all patients, 42% showing mild, 42% moderate, and 16 % severe dysphagia. During stim-OFF, all patients experienced a statistically significant improvement of swallowing function. Interpretation: VIM-DBS may have an impact on swallowing physiology in ET-patients. Further studies to elucidate the prevalence and underlying pathophysiological mechanisms are warranted.
Background: Essential Tremor (ET) is a progressive neurological disorder characterized by postural and kinetic tremor most commonly affecting the hands and arms. Medically intractable ET can be treated by deep brain stimulation (DBS) of the ventral intermediate nucleus of thalamus (VIM). We investigated whether the location of the effective contact (most tremor suppression with at least side effects) in VIM-DBS for ET changes over time, indicating a distinct mechanism of loss of efficacy that goes beyond progression of tremor severity, or a mere reduction of DBS efficacy.
Methods: We performed programming sessions in 10 patients who underwent bilateral vim-DBS surgery between 2009 and 2017 at our department. In addition to the intraoperative (T1) and first clinical programming session (T2) a third programming session (T3) was performed to assess the effect- and side effect threshold (minimum voltage at which a tremor suppression or side effects occurred). Additionally, we compared the choice of the effective contact between T1 and T2 which might be affected by a surgical induced “brain shift.”
Discussion: Over a time span of about 4 years VIM-DBS in ET showed continuous efficacy in tremor suppression during stim-ON compared to stim-OFF. Compared to immediate postoperative programming sessions in ET-patients with DBS, long-term evaluationshowednorelevantchangeinthechoiceofcontactwithrespecttosideeffects andefficacy.InthemajorityofthecasestheactivecontactatT2didnotcorrespondtothe most effective intraoperative stimulation site T1, which might be explained by a brain-shift due to cerebral spinal fluid loss after neurosurgical procedure.
High glucosylceramides and low anandamide contribute to sensory loss and pain in Parkinson's disease
(2020)
Background: Parkinson's disease (PD) causes chronic pain in two‐thirds of patients, in part originating from sensory neuropathies. The aim of the present study was to describe the phenotype of PD‐associated sensory neuropathy and to evaluate its associations with lipid allostasis, the latter motivated by recent genetic studies associating mutations of glucocerebrosidase with PD onset and severity. Glucocerebrosidase catalyzes the metabolism of glucosylceramides.
Methods: We used quantitative sensory tests, pain ratings, and questionnaires and analyzed plasma levels of multiple bioactive lipid species using targeted lipidomic analyses. The study comprised 2 sets of patients and healthy controls: the first 128 Israeli PD patients and 224 young German healthy controls for exploration, the second 50/50 German PD patients and matched healthy controls for deeper analyses.
Results: The data showed a 70% prevalence of PD pain and sensory neuropathies with a predominant phenotype of thermal sensory loss plus mechanical hypersensitivity. Multivariate analyses of lipids revealed major differences between PD patients and healthy controls, mainly originating from glucosylceramides and endocannabinoids. Glucosylceramides were increased, whereas anandamide and lysophosphatidic acid 20:4 were reduced, stronger in patients with ongoing pain and with a linear relationship with pain intensity and sensory losses, particularly for glucosylceramide 18:1 and glucosylceramide 24:1.
Conclusions: Our data suggest that PD‐associated sensory neuropathies and PD pain are in part caused by accumulations of glucosylceramides, raising the intriguing possibility of reducing PD pain and sensory loss by glucocerebrosidase substituting or refolding approaches. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.