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Parkinson's disease (PD) is characterized by the disruption of repetitive, concurrent and sequential motor actions due to compromised timing-functions principally located in cortex-basal ganglia (BG) circuits. Increasing evidence suggests that motor impairments in untreated PD patients are linked to an excessive synchronization of cortex-BG activity at beta frequencies (13-30 Hz). Levodopa and subthalamic nucleus deep brain stimulation (STN-DBS) suppress pathological beta-band reverberation and improve the motor symptoms in PD. Yet a dynamic tuning of beta oscillations in BG-cortical loops is fundamental for movement-timing and synchronization, and the impact of PD therapies on sensorimotor functions relying on neural transmission in the beta frequency-range remains controversial. Here, we set out to determine the differential effects of network neuromodulation through dopaminergic medication (ON and OFF levodopa) and STN-DBS (ON-DBS, OFF-DBS) on tapping synchronization and accompanying cortical activities. To this end, we conducted a rhythmic finger-tapping study with high-density EEG-recordings in 12 PD patients before and after surgery for STN-DBS and in 12 healthy controls. STN-DBS significantly ameliorated tapping parameters as frequency, amplitude and synchrony to the given auditory rhythms. Aberrant neurophysiologic signatures of sensorimotor feedback in the beta-range were found in PD patients: their neural modulation was weaker, temporally sluggish and less distributed over the right cortex in comparison to controls. Levodopa and STN-DBS boosted the dynamics of beta-band modulation over the right hemisphere, hinting to an improved timing of movements relying on tactile feedback. The strength of the post-event beta rebound over the supplementary motor area correlated significantly with the tapping asynchrony in patients, thus indexing the sensorimotor match between the external auditory pacing signals and the performed taps. PD patients showed an excessive interhemispheric coherence in the beta-frequency range during the finger-tapping task, while under DBS-ON the cortico-cortical connectivity in the beta-band was normalized. Ultimately, therapeutic DBS significantly ameliorated the auditory-motor coupling of PD patients, enhancing the electrophysiological processing of sensorimotor feedback-information related to beta-band activity, and thus allowing a more precise cued-tapping performance., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Authors T.R. Schneider, A. Pino, S. Zittel, C. Gerloff, M. Westphal, and A.K. Engel declare no relevant conflicts of interest. Some of the authors (A. Gulberti, C.K.E. Moll, W. Hamel, C. Buhmann, M. Heise). have occasionally been reimbursed for travel expenses from Medtronic Inc. C. Buhmann served on the scientific advisory boards for Bial, Desitin, Kyowa Kirin, Merz, Stadapharm and Zambon and received honoraria for lectures from Abbott, Abbvie, Bial, Desitin, Hormosan, Merz, l, TAD Pharma, UCB and Zambon. S. Zittel served on the scientific advisory board for Biomarin and received honoraria for lectures from Merz Pharmaceuticals. C. Gerloff reports personal fees and other from Bayer Healthcare and Boehringer Ingelheim, personal fees from Abbott, Amgen, BMS, Sanofi Aventis, and Prediction Biosciences. C.K.E. Moll received lecture, teaching and proctoring fees from Abbott. W. Hamel received lecture fees and honoraria for serving on advisory boards and travel grants from Boston Scientific, Medtronic, and Abbott. M. Pötter-Nerger received lecture fees from Abbott and Licher, and served as consultant for Medtronic, Boston Scientific and Abbvie., (Copyright © 2023. Published by Elsevier Inc.)

Dopamine agonists are an important component of Parkinson's therapy. When weighing up the various therapy options, therapy with levodopa has recently been increasingly preferred due to its stronger efficacy and the ostensibly lower rate of side effects. The advantage of the lower incidence of motor complications during therapy with dopamine agonists was neglected. The occurrence of side effects can be explained by the different receptor affinity to the individual dopaminergic and non-dopaminergic receptors of the individual dopamine agonists. However, the different affinity to individual receptors also explains the different effect on individual Parkinson symptoms and can, therefore, contribute to a targeted use of the different dopamine agonists. Since comparative studies on the differential effect of dopamine agonists have only been conducted for individual substances, empirical knowledge of the differential effect is of great importance. Therefore, the guidelines for the treatment of Parkinson's disease do not consider the differential effect of the dopamine agonists. The historical consideration of dopamine agonists within Parkinson's therapy deserves special attention to be able to classify the current discussion about the significance of dopamine agonists., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Blood neurofilament light chain (NfL) is an easily accessible, highly sensitive and reliable biomarker for neuroaxonal damage. Currently, its role in Parkinson's disease (PD) remains unclear. Here, we demonstrate that blood NfL can distinguish idiopathic PD from atypical parkinsonian syndromes (APS) with high sensitivity and specificity. In cross-sectional studies, some found significant correlations between blood NfL with motor and cognitive function, whereas others did not. In contrast, prospective studies reported very consistent associations between baseline blood NfL with motor progression and cognitive worsening. Amongst PD subtypes, especially postural instability and gait disorder (PIGD) subtype, symptoms and scores are reliably linked with blood NfL. Different non-motor PD comorbidities have also been associated with high blood NfL levels suggesting that the neuroaxonal damage of the autonomic nervous system as well as serotonergic, cholinergic and noradrenergic neurons is quantifiable. Numerous absolute NfL cutoff levels have been suggested in different cohort studies; however, validation across cohorts remains weak. However, age-adjusted percentiles and intra-individual blood NfL changes might represent more valid and consistent parameters compared with absolute NfL concentrations. In summary, blood NfL has the potential as biomarker in PD patients to be used in clinical practice for prediction of disease severity and especially progression., (© 2023. The Author(s).)

Catechol O‑methyltransferase (COMT) inhibitors have been established in the treatment of Parkinson's disease for more than 20 years. They are considered the medication of choice for treating motor fluctuations. The available COMT inhibitors, entacapone, opicapone and tolcapone, differ pharmacokinetically in terms of their half-lives with implications for the dose frequency, in their indication requirements and in their spectrum of side effects, including diarrhea and yellow discoloration of urine. Many patients with motor fluctuations are currently not treated with COMT inhibitors and are, therefore, unlikely to receive individually optimized drug treatment. This manuscript summarizes the results of a working group including several Parkinson's disease experts, in which the value of COMT inhibitors was critically discussed., (© 2022. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

The clinical presentation of Parkinson's disease (PD) is both complex and heterogeneous, and its precise classification often requires an intensive work-up. The differential diagnosis, assessment of disease progression, evaluation of therapeutic responses, or identification of PD subtypes frequently remains uncertain from a clinical point of view. Various tissue- and fluid-based biomarkers are currently being investigated to improve the description of PD. From a clinician's perspective, signatures from blood that are relatively easy to obtain would have great potential for use in clinical practice if they fulfill the necessary requirements as PD biomarker. In this review article, we summarize the knowledge on blood-based PD biomarkers and present both a researcher's and a clinician's perspective on recent developments and potential future applications., (© 2022. The Author(s).)

Background: Diabetes is associated with incidence and prevalence of Parkinson's disease (PD). Furthermore, glycated hemoglobin (HbA1c) levels have been linked with motor function and progression., Objectives: We evaluated the relationship between prevalent diabetes and HbA1c levels with serum neurofilament light chain (NfL) levels as marker of neuroaxonal damage., Methods: NfL concentrations were analyzed with Simoa in serum of 195 PD patients with available HbA1c values. Motor (MDS-UPDRS III, Hoehn & Yahr [H&Y]) and cognitive (Montreal Cognitive Assessment [MoCA]) function was assessed and vascular comorbidities were documented from medical records., Results: PD patients with prevalent diabetes had higher serum NfL levels and lower MoCA scores independent of age, body mass index (BMI), and vascular risk factors. Furthermore, diabetes was associated with higher H&Y stages in unadjusted and age/BMI-adjusted models. Higher HbA1c levels were associated with increased NfL in unadjusted and age/BMI-adjusted models., Conclusions: In PD patients, diabetes and high HbA1c are associated with increased neuroaxonal damage and cognitive impairment. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society., (© 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.)

The aim of this study was to assess the effects of novel stimulation algorithms of deep brain stimulation (short pulse and directional stimulation) in the ventrointermediate thalamus and posterior subthalamic area (VIM/PSA-DBS) on tremor in Parkinson's disease (PD) and to compare the effects with those in essential tremor (ET). We recruited six PD patients (70.8 ± 10.4 years) and seven ET patients (64.4 ± 9.9 years) with implanted VIM/PSA-DBS in a stable treatment condition (> 3 months postoperatively). Tremor severity and ataxia were assessed in four different stimulation conditions in a randomized order: DBS switched off (STIM OFF), omnidirectional stimulation with 60 µs (oDBS60), omnidirectional stimulation with 30 µs (oDBS30), directional stimulation at the best segment with 60 µs (dDBS60). In both patient groups, all three DBS stimulation modes reduced the total tremor score compared to STIM OFF, whereas stimulation-induced ataxia was reduced by oDBS30 and partially by dDBS60 compared to oDBS60. Tremor reduction was more pronounced in PD than in ET due to a limited DBS effect on intention and action-specific drawing tremor in ET. In PD and ET tremor, short pulse or directional VIM/PSA-DBS is an effective and well tolerated therapeutic option.Trial registration: The study was registered in the DRKS (ID DRKS00025329, 18.05.2021, German Clinical Trials Register, DRKS-Deutsches Register Klinischer Studien)., (© 2022. The Author(s).)

Introduction: The preoperative evaluation of Parkinson's Disease (PD) patients for subthalamic nucleus deep brain stimulation (STN-DBS) includes the assessment of the neuropsychological status of the patient. A widely used preoperative test is the Mattis Dementia rating scale (MDRS). However, the Montreal cognitive assessment (MoCA) has also been proven to be a sensitive, time-sparing tool with high diagnostic validity in PD. We evaluate the utility of the MoCA as a preoperative screening test for PD patients undergoing bilateral STN-DBS., Methods: In this single-centre, retrospective study, we analysed pre- and postoperative assessments of MoCA, MDRS, Movement disorder society-Unified PD Rating Scale-motor examination, PD Questionnaire-39 and levodopa equivalent daily dose. Longitudinal outcome changes were analysed using paired t-test, Pearson's correlation coefficient, linear regression and CHAID (chi-square automatic interaction detector) regression tree model., Results: Clinical motor and cognitive scores of 59 patients (61.05±7.73 years, 24 females) were analysed. The MoCA, but not the MDRS, identified significant postoperative cognitive decline in PD patients undergoing STN-DBS. The preoperative MoCA score correlated with postoperative quality of life improvement, whereas the MDRS did not. PD patients with a MoCA score ≤ 23 points had a significant decline of quality of life after DBS surgery compared to patients > 23 points., Conclusion: This study identifies the MoCA as an alternative test within the preoperative evaluation of PD patients for the detection of neuropsychological deficits and prediction of the postoperative improvement of quality of life., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: E. Gülke received travel and attendance grants from Abbvie, Abbott, Medtronic and Bial. M. Alsalem reported no financial disclosures. M. Kirsten received travel and attendance grants from Abbott and Abbvie. E. Vetorazzi reported no fincancial disclosures. C. Choe received personal fees from Pfizer. U.Hidding reported no financial disclosures. S. Zittel received research support from Merz Pharmeceuticals and honoraria from Brainlab AG. C. Buhmann served on the scientific advisory boards for Bial and Zambon and received honoraria for lectures from Abbvie, Bial, GE Healthcare, Grünenthal, TAD and UCB. M. Schaper reported no financial disclosures. A. Gulberti received travel reimbursements from Medtronic. C.K.E. Moll served as medico-scientific consultant to Abbott. W. Hamel received lecture fees and honoraria for serving on advisory boards and travel grants from Boston Scientific, Medtronic, and Abbott. J. Koeppen reported no financial disclosures. C. Gerloff reports honoraria from Bayer Healthcare, Boehringer Ingelheim, Acticor Biotech, Sanofi Aventis Amgene, and Prediction Bioscience. M. Pötter-Nerger received lecture fees from Abbott and Licher, and served as consultant for Medtronic, Boston scientific, Abbott and Abbvie. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

The PIGD (postural instability / gait difficulty) subtype of Parkinson´s disease (PD) is associated with faster cognitive and motor decline. So far, there are no quantifiable biomarkers to aid clinical subtyping. Neurofilament light chain (NfL) is a highly specific marker of neuro-axonal damage and can be assessed in blood. Here, we investigated if serum NfL concentrations are associated with PIGD subtype and PIGD scores in PD patients at advanced disease stages. Furthermore, we evaluated if serum NfL is associated with motor and cognitive function assessed with MDS-UPDRS part III and Montreal cognitive assessment (MoCA). Serum NfL levels were analyzed with Single Molecule Assays (Simoa) in blood of 223 PD patients from the bioMARKers in Parkinson's Disease (MARK-PD) study. Serum NfL concentrations were higher in PIGD patients independent of age, sex and disease duration. In linear regression analysis, serum NfL levels were associated with MoCA, MDS-UPDRS III and PIGD scores in unadjusted models, but remained significant after adjustment only with PIGD scores. In conclusion, increased serum NfL levels were associated with PIGD subtype and PIGD scores in patients with advanced PD., (© 2022. The Author(s).)

Background: Based on data regarding the prevalence of Parkinson's disease (PD), the prevalence of impulsive control disorders (ICD) in PD, and the percentage of PD patients driving a car, it has to be assumed that at least 50,000 PD patients with ICD in Germany actively drive a car. However, these patients might be at risk for unsafe driving due to ICD-related dysfunctions such as failure to resist an impulse or temptation, to control an act or other altered neurobehavioral processes., Objective: This study determines the influence of ICD on driving ability in PD., Methods: We prospectively compared driving simulator performance of 23 PD patients with and 23 matched patients without ICD. ICD had to be socially compensated and presence was defined clinically for primary and questionnaire-based (QUIP-RS) for post-hoc analyses. Furthermore, between-group comparisons of driving-relevant neuropsychological tests were executed., Results: Except from a lower blinking frequency when changing lanes, overall driving safety of patients with ICD did not differ significantly from those without-regardless of the clinical or QUIP-RS-based ICD definition. ICD severity did not correlate with driving performance, but the latter correlated significantly with mean reaction times and certain neuropsychiatric tests (MoCA, TMT-A, TAP-M "flexibility" and DBQ "error")., Conclusion: Clinically compensated ICD does not seem to impair driving safety in PD patients. Rather, cognitive and attentional deficits appear to be clinical markers for driving uncertainty.

Sexual dysfunction is one of the commonest non-motor symptoms in Parkinson's disease (PD) and has been found about twice as high in PD patients compared to age-matched controls. The quality of sexual life is reduced in PD patients compared to healthy peers and impairment affects wide aspects of physical sexual function as well as sexual desire, sexual satisfaction and sexual partnership. Overall, male PD patients are more frequently affected by sexual disorders than females and seem to suffer more from sexual impairment. The reported frequencies and presentations of various sexual dysfunctions vary widely in the literature, which is likely related to the patient cohorts examined, in particular with regard to age and gender, duration and severity of disease and applied measurement instruments. This chapter gives an overview of the prevalence, phenotype and clinical presentation of sexual dysfunction in PD and its influence on the partnership., Competing Interests: Disclosures C. Buhmann has received honoraria as speaker and scientific advisory board member from Abbvie, Bial, StadaPharm, TAD Pharma, UCB and Zambon., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Simple water-swallowing screening tools are not predictive of aspiration and dysphagia in patients with Parkinson's Disease (PD). We investigated the diagnostic accuracy of a multi-texture screening tool, the Gugging Swallowing Screen (GUSS) to identify aspiration and dysphagia/penetration in PD patients compared to flexible endoscopic evaluation of swallowing (FEES)., Methods: Swallowing function was evaluated in 51 PD participants in clinical 'on-medication' state with the GUSS and a FEES examination according to standardized protocols. Inter-rater reliability and convergent validity were determined and GUSS- and FEES-based diet recommendations were compared., Key Results: Inter-rater reliability of GUSS ratings was high (r s  = 0.8; p < 0.001). Aspiration was identified by the GUSS with a sensitivity of 50%, and specificity of 51.35% (PPV 28%, NPV 73%, LR+ 1.03, LR- 0.97), dysphagia/penetration was identified with 72.97% sensitivity and 35.71% specificity (PPV 75%, NPV 33.33%, LR+ 1.14, LR- 0.76). Agreement between GUSS- and FEES-based diet recommendations was low (r s  = 0.12, p = 0.42) with consistent NPO (Nil per Os) allocation by GUSS and FEES in only one participant., Conclusions and Inferences: The multi-texture screening tool GUSS in its current form, although applicable with good inter-rater reliability, does not detect aspiration in PD patients with acceptable accuracy. Modifications of the GUSS parameters "coughing," "voice change" and "delayed swallowing" might enhance validity. The GUSS' diet recommendations overestimate the need for oral intake restriction in PD patients and should be verified by instrumental swallowing examination., (© The Authors. Neurogastroenterology & Motility published by John Wiley & Sons Ltd.)

Purpose: Dysphagia is common in patients with Parkinson's disease (PD) and often leads to pneumonia, malnutrition, and reduced quality of life. This study investigates the ability of the Eating Assessment Tool-10 (EAT-10), an established, easy self-administered screening tool, to detect aspiration in PD patients. This study aims to validate the ability of the EAT-10 to detect FEES-proven aspiration in patients with PD., Methods: In a controlled prospective cross-sectional study, a total of 50 PD patients completed the EAT-10 and, subsequently, were examined by Flexible Endoscopic Evaluation of Swallowing (FEES) to determine the swallowing status. The results were rated through the Penetration-Aspiration Scale (PAS) and data were analyzed retrospectively., Results: PAS and EAT-10 did not correlate significantly. Selected items of the EAT-10 could not predict aspiration or residues. 19 (38%) out of 50 patients with either penetration or aspiration were not detected by the EAT-10. The diagnostic accuracy was established at only a sufficient level (AUC 0.65). An optimal cut-off value of ≥ 6 presented a sensitivity of 58% and specificity of 82%., Conclusions: The EAT-10 is not suited for the detection of penetration and aspiration in PD patients. Therefore, it cannot be used as a screening method in this patient population. There is still a need for a valid, simple, and efficient screening tool to assist physicians in their daily diagnostics and to avoid clinical complications.

Objectives: In prospective cohort studies different blood lipid fractions have been identified as risk factors of Parkinson's disease (PD). However, data relating lipoproteins to disease phenotypes and progression in advanced PD patients are sparse. Therefore, we assessed the most common lipoproteins in a case-control design and evaluated their associations with motor and cognitive function and decline in PD patients., Methods: Triglycerides, LDL-cholesterol (LDL-C), HDL-cholesterol (HDL-C), apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB), and lipoprotein a (Lp(a)) were analyzed in 294 PD patients of the MARK-PD study cohort and 588 controls matched for age, sex and cardiovascular risk factors. In PD patients, motor (MDS-UPDRS III, Hoehn-Yahr stage) and cognitive function (MoCA) were examined. In a sub-cohort (n = 98 patients), baseline lipid levels were correlated with motor and cognitive disease progression during a follow-up period of 523 ± 199 days., Results: At baseline, HDL-C levels were lower in PD patients compared to matched controls after adjustment. We observed a very weak association of Lp(a) levels with UDPRS III scores. In cross-sectional analyses, no other lipid fraction revealed a significant and consistent association with motor or cognitive function. During follow-up, no lipid fraction level was associated with motor or cognitive progression., Conclusion: In advanced PD, there is no strong and consistent association of lipid levels with motor or cognitive function and decline., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Little is known about the patients' view on treatment with medical cannabis (MC) for Parkinson's disease (PD)., Objective: To assess the PD community's perception of MC and patients' experience with MC., Methods: Applying a questionnaire-based survey, we evaluated general knowledge and interest in MC as well as the frequency, modalities, efficacy, and tolerability of application. Questionnaires were distributed nationwide via the membership journal of the German Parkinson Association and locally in our clinic to control for report bias., Results: Overall, 1.348 questionnaires (1.123 nationwide, 225 local) were analysed. 51% of participants were aware of the legality of MC application, 28% of various routes of administration (ROA) and 9% of the difference between delta9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD). PD-related cannabis use was reported by 8.4% of patients and associated with younger age, living in large cities and better knowledge about the legal and clinical aspects of MC. Reduction of pain and muscle cramps was reported by more than 40% of cannabis users. Stiffness/akinesia, freezing, tremor, depression, anxiety and restless legs syndrome subjectively improved for more than 20% and overall tolerability was good. Improvement of symptoms was reported by 54% of users applying oral CBD and 68% inhaling THC-containing cannabis. Compared to CBD intake, inhalation of THC was more frequently reported to reduce akinesia and stiffness (50.0% vs. 35.4%; p < 0.05). Interest in using MC was reported by 65% of non-users., Conclusion: MC is considered as a therapeutic option by many PD patients. Nevertheless, efficacy and different ROA should further be investigated.

Background: We assessed if cardiac blood markers are associated with motor and cognitive function in patients with Parkinson's disease (PD)., Methods: High-sensitivity troponin I and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were evaluated in 285 PD patients. Furthermore, N-terminal pro-B-type natriuretic peptide levels were analyzed in 570 age, sex and cardiovascular risk factor matched healthy controls. Motor (UPDRS, Hoehn &Yahr) and cognitive function (Montreal Cognitive Assessemtn) were assessed at baseline in all 285 patients and after 1 year in 101 patients., Results: N-terminal pro-B-type natriuretic peptide were significantly increased in 285 PD patients compared with 570 matched healthy controls. In PD patients, increased high-sensitivity troponin I and N-terminal pro-B-type natriuretic peptide levels were associated with worse motor function at baseline and also with motor decline after 1 year. N-terminal pro-B-type natriuretic peptide and high-sensitivity troponin I were inversely associated with cognitive function at baseline only in unadjusted models., Conclusions: Subclinical cardiac microdamage is associated with motor severity in PD patients. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society., (© 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.)

Dopaminergic deficiency in Parkinson's disease (PD) has been associated with underactivation of the supplementary motor area and a reduction of voluntary actions. In these patients, awareness of intention to act has been shown to be delayed. However, delayed awareness of intention to act has also been shown in patients with hyperdopaminergic states and an excess of unwilled movements, as in Tourette's, and in patients with functional movement disorders. Hence, the role of dopamine in the awareness of intention and action remains unclear. 36 PD patients were tested ON and OFF dopaminergic medication and compared with 35 healthy age-matched controls. In addition, 17 PD patients with subthalamic deep brain stimulation (DBS) were tested ON medication and ON and OFF stimulation. Participants judged either the moment a self-generated action was performed, or the moment the urge to perform the action was felt, using the "Libet method". Temporal judgments of intention and action awareness were comparable between unmedicated PD patients and controls. Dopaminergic medication boosted anticipatory awareness of both intentions and actions in PD patients, relative to an unmedicated condition. The difference between ON/OFF DBS was not statistically reliable. Functional improvement of motor ability in PD through dopaminergic supplementation leads to earlier awareness of both intention, and of voluntary action.

Background and Objectives: The purpose of this study was to assess efficacy and safety of a new patterned theta burst stimulation algorithm of DBS with the aim of expanding the therapeutic window and clinical benefit in PD., Methods: In this single-center, randomized, double-blind, clinical short-term trial, unilateral conventional subthalamic DBS was compared with unilateral patterned stimulation algorithms with intraburst high- or low-frequency theta burst stimulation in 17 PD patients., Results: There were no serious adverse events with theta burst stimulation. During monopolar review, conventional subthalamic DBS and high-frequency theta burst stimulation were comparable, but low-frequency theta burst stimulation differed by requiring higher stimulation amplitudes for symptom reduction, but a larger therapeutic window. High- and low-frequency theta burst stimulation with adapted stimulation amplitude were effective in PD symptom reduction with differential effects on akinesia and tremor, depending on the theta burst stimulation mode., Conclusions: Theta burst stimulation is a safe and effective stimulation mode with potential future application opportunities. © 2020 International Parkinson and Movement Disorder Society., (© 2020 International Parkinson and Movement Disorder Society.)

Competing Interests: C. Buhmann erhielt finanzielle Unterstützung für andere Studien von der Georg & Jürgen Rickertsen Stiftung Hamburg, ist oder war Mitglied eines wissenschaftlichen Beirats für Bial und Zambon und erhielt Honorare für Vorträge von Abbvie, Bial, GE Healthcare, Licher, Orion Pharma, UCB Pharma und Zambon. C. Gerloff wird unterstützt von der Deutschen Forschungsgemeinschaft (DFG Ge 844 / 4-1, Ge 844 / 5-1, SFB 936 / C1, Z1, Z2, TRR 169 / A03) und der EU (RP7-HEALTH-2011- 278,276) und erhielt Honorare als Referent oder Berater von Amgen, Bayer Vital, BMS, Boehringer Ingelheim und Sanofi Aventis. O. Fründt wurde von AbbVie und Abbott / St. Jude Medical bei Symposien / Kongressen unterstützt und erhielt Honorare für Vorträge durch Daiichi-Sankyo. B. Schönwald erhielt Honorare für Vorträge von Abbvie, Licher, UCB Pharma und Zambon. E. Veliqi und P. Sychla haben keine potenziellen Interessenkonflikte.

Objectives: Dysphagia is a frequent and highly relevant symptom in Parkinson's disease (PD) due to high associated morbidity and mortality. To compare the effect of simultaneous stimulation of the subthalamic nucleus (STN) and substantia nigra (SNr) with conventional STN-stimulation on swallowing function in Parkinson's disease., Methods: In this controlled, randomized, double-blind, cross-over clinical trial, 15 PD patients were assessed with DBS switched off (STIM OFF), STN-DBS, STN + SNr-DBS. Patients and 32 age-matched healthy controls were examined clinically and by flexible-endoscopic evaluation of swallowing (FEES) to evaluate the swallowing function. The primary endpoint was the assessment of residues, secondary endpoints were penetration/aspiration, leakage, retained pharyngeal secretions, drooling, and assessments of the patient's self-perception of swallowing on a visual analog scale., Results: Compared with healthy controls PD patients showed significantly more pharyngeal residues in STIM OFF and both DBS modes. Residues or aspiration events were found in 80% of the patients under STN-stimulation. Simultaneous STN + SNr-stimulation had no additional positive effect on objective dysphagia and self-reported swallowing function compared to STN-DBS., Interpretation: Simultaneous STN + SNr-stimulation seems to have no additional beneficial effects on dysphagia when compared with conventional STN-stimulation, but did not deteriorate the swallowing function. If STN + SNr-stimulation is planned to be applied for the improvement of axial symptoms and gait disorders in PD patients, it can be considered safe in terms of dysphagia., (© 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.)

Background: Parkinson's disease is associated with severe nigro-striatal dopamine depletion, leading to motor dysfunction and altered reward processing. We previously showed that drug-naïve patients with Parkinson's disease had a consistent attenuation of reward signalling in the mesolimbic and mesocortical system. Here, we address the neurobiological effects of dopaminergic therapy on reward sensitivity in the mesolimbic circuitry, and how this may contribute to neuropsychiatric symptoms., Objectives: We tested the hypothesis that (1) dopaminergic treatment would restore the attenuated, mesolimbic and mesocortical responses to reward; and (2) restoration of reward responsivity by dopaminergic treatment would predict motor performance and the emergence of impulse control symptoms., Methods: In 11 drug-naïve Parkinson patients, we prospectively assessed treatment-induced changes in reward processing before, and eight weeks after initiation of monotherapy with dopamine agonists. They were compared to 10 non-medicated healthy controls who were also measured longitudinally. We used whole-brain functional magnetic resonance imaging at 3 Tesla to assess the reward responsivity of the brain to monetary gains and losses, while participants performed a simple consequential gambling task., Results: In patients, dopaminergic treatment improved clinical motor symptoms without significantly changing task performance. Dopamine agonist therapy induced a stronger reward responsivity in the right hippocampus with higher doses being less effective. None of the patients developed impulse control disorders in the follow-up period of four years., Conclusions: Short-term treatment with first-ever dopaminergic medication partially restores deficient reward-related processing in the hippocampus in de novo Parkinson's disease., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Pain is a very frequent symptom with influence on the quality of life in Parkinson's disease (PD), but is still underdiagnosed and commonly treated only unsystematically. Pain etiology and pain character are often complex and multi-causal, and data regarding treatment recommendations are limited. Pain can be primarily related to PD but frequently it is associated with secondary diseases, such as arthrosis of the spine or joints. However, even basically PD-unrelated pain often is amplified by motor- or non-motor PD symptoms, such as akinesia or depression. Beyond an optimization of anti-parkinsonian treatment, additional pain treatment strategies are usually needed to properly address pain in PD. A careful pain history and diagnostic work-up is essential to rate the underlying pain pathophysiology and to develop a targeted therapeutic concept. This review gives an overview on how pain is treated in PD patients and how patients assess the effectiveness of these therapies; here, the manuscript focuses on pathophysiology-driven suggestions for a multimodal pain management in clinical practice.

Background: There is still a lack of a clinical test to reliably identify patients with Parkinson's disease (PD) being at risk for aspiration., Methods: In this prospective, controlled, cross-sectional study, we assessed if swallowing speed for water is a useful clinical test to predict aspiration proven by flexible endoscopic evaluation of swallowing (FEES). Due to this, we measured the swallowing speed for 90 mL water in 115 consecutive and unselected PD outpatients of all clinical stages and 32 healthy controls., Key Results: Average swallowing speed was lower in patients compared with controls (6.5 ± 3.9 mL/s vs 8.5 ± 3.2 mL/s; P < .01). The disease-independent widely used threshold of <10 mL/s showed insufficient sensitivity of 88% and specificity of 19% with high false-positive rates of 63% for patients and 69% for controls. Receiver operating characteristic (ROC) analysis was carried out to define a suitable cutoff value for detection of aspiration of water (area under the curve 0.72, P < .001) in PD patients. The optimized cutoff value was 5.5 mL/s with a sensitivity of 69% and a specificity of 64%., Conclusion and Inferences: Measuring swallowing speed is prone to methodological errors and not suitable as a screening instrument to predict aspiration in PD patients., (© 2019 John Wiley & Sons Ltd.)

Introduction : Pain is a common symptom in Parkinson's disease (PD), impairing quality of life. The clinical appearance and the underlying etiologies are diverse. Different subtypes of pain may occur, with musculoskeletal pain considered to be the most frequent. Often there is also a combination of different causes of pain. There is a lack of controlled studies addressing pain therapy in PD. Areas covered : In this review the authors analyzed the currently available data, taking into account the available publications in the databases, especially PubMed. The authors further provided their expert perspectives on the challenges of treating pain in PD patients. Expert opinion : There is both nociceptive and neuropathic pain and in patients with PD, some PD-related pain and some unrelated. Diagnosis requires a thorough and differentiated history and examination, and targeted diagnostics. Therapeutically, many drugs are used, but the data is unfortunately limited and not specific. Medications used include Parkinson-related, mainly dopaminergic drugs, as well as opioids and non-opioid analgetics, anticonvulsives, antidepressants, and more recently cannabinoids. Currently, therapy is performed nonspecifically, without taking into account the special requirements of PD. Unfortunately, in many cases, pain is resistant to these therapies. In the future, both diagnostic and therapeutic efforts should be made to address this issue.

Sexual dysfunction is a major non-motor feature of Parkinson's disease (PD) that may affect the quality of life of many patients. In a Dutch survey, we demonstrated that neurologists often fail to discuss sexuality with their patients. Our objective was to determine to which extent neurologists in Spain and Germany address sexuality with their patients and whether cross-cultural differences exist. A 30-item questionnaire was sent out to 1650 German and 460 Spanish neurologists. The questionnaire addressed attitudes, knowledge, barriers, and feelings of responsibility regarding sexuality in PD. 160 German and 32 Spanish respondents completed and returned the questionnaire. The majority of German and Spanish participants discuss sexual dysfunction 'regularly' with male patients (61.7% and 78.9%, respectively), but 'seldom' with female patients (68.8% and 78.1%, respectively). Important barriers for German and Spanish respondents to discuss sexual dysfunction were patients not expressing sexual complaints spontaneously (52.9% and 75.0%, respectively) and insufficient consultation time (32.2% and 71.9%, respectively). Sexual dysfunction in PD was considered important by 68.3% of German and 96.9% of Spanish participants. German and Spanish neurologists do not routinely discuss sexual dysfunction with their patients, although many of them consider it important to address this topic. It is unclear why this lack of discussing sexual dysfunction is especially found for female patients and whether cultural aspects are involved. We recommend a self-assessment tool for patients to track their symptoms prior to consultation visits and advocate local guidelines that formulate who is responsible for discussing sexual dysfunction.

In the differential diagnosis of Parkinson syndromes, the response to L-Dopa is an essential criterion for the diagnosis of idiopathic Parkinson's syndrome (IPS), and the presence of L-Dopa-induced dyskinesia (LID) is considered a supportive criterion. This implies that in the presence of LID an atypical Parkinson-syndrome (APS) is unlikely. However, dyskinesia, and in particular LID, can also be present in APS such as MSA and PSP, although less frequently, and with varying clinical appearance. We conclude that whilst presence of dyskinesia provides support for a diagnosis of IPD, they do not allow reliable differentiation from APS.

Cannabis and synthetic cannabinoid formulations have now been legally approved in several countries for treatment of patients with Parkinson's disease (PD). Hence, PD patients consult physicians more frequently for prescription of cannabinoids to alleviate symptoms that might not respond well to dopaminergic treatment. Despite the increasing volume of research generated in the field of cannabinoids and their effect on Parkinson's disease, there is still paucity of sufficient clinical data about the efficacy and safety in PD patients. There is increasing understanding of the endocannabinoid system, and the distribution of cannabinoid receptors in basal ganglia structures might suggest potential benefit on parkinsonian symptoms. Concerning clinical research, only one of to date four conducted randomized placebo-controlled trials showed an effect on motor symptoms with alleviation of levodopa-induced dyskinesia. There are a growing number of uncontrolled trials and case reports that suggest beneficial effects of cannabinoids in PD patients. However, the variety of substances investigated, the varying routes of intake, differing doses and time courses make it difficult to compare data. We here provide an overview of the current literature in this field and discuss a pragmatic approach for the clinical use of cannabinoids in PD.

It is well documented that there is a strong relationship between gait asymmetry and the freezing of gait (FOG) in Parkinson's Disease. The purpose of this pilot study was to find a "virtual reality (VR)- based" gait manipulation strategy to improve gait symmetry by equalizing step length. Fifteen male PD patients (mean age of 67.6 years) with FOG were assessed on a GAITRite ® walkway. Natural gait was compared with walking conditions during "VR-based" gait modulation tasks that aimed at equalizing gait symmetry using visual or proprioceptive signals. Compared to natural gait, VR manipulation tasks significantly increased step width and swing time variability for both body sides. Within the VR conditions, only the task with "proprioceptive-visual dissociation" by artificial backward shifting of the foot improved spatial asymmetry significantly with comparable step lengths of both sides. Specific, hypothesis-driven VR tasks represent an efficient tool to manipulate gait features as gait symmetry in PD potentially preventing FOG. This pilot study offers promising "VR-based" approaches for rehabilitative training strategies to achieve gait symmetry and prevent FOG., Competing Interests: The authors declare no conflict of interest.

Objective: To compare the effect of simultaneous deep brain stimulation of the subthalamic nucleus and substantia nigra pars reticulata (STN+SNr-DBS) to conventional subthalamic stimulation (STN-DBS) on sleep quality in Parkinson's disease (PD) patients., Methods: The study was a single-center, randomized, double-blind, cross-over clinical trial to compare the effect of STN-DBS vs. combined STN+SNr-DBS on subjective measures of sleep quality. Fifteen PD patients (2 female, age 62.5 ± 6.7 years) suffering from moderate idiopathic PD (disease duration: 12.0 ± 5.0 years, Hoehn & Yahr stage: 2.2 ± 0.4 in the MED-ON & STN-DBS-ON condition, Hoehn & Yahr stage: 2.6 ± 0.8 in the MED-OFF condition preoperatively) participated in the study. Sleep quality was evaluated in both stimulation conditions using the PDSS-2 score as a self-rating questionnaire covering several aspects of sleep disturbances., Results: PD patients showed mild-moderate sleep disturbances (STN-DBS: PDSS-2 score 17.0 ± 11.0; STN+SNr-DBS: 14.7 ± 9.5) with slight but not significant differences between both stimulation conditions. Considering the different subitems of the PDSS-2, combined STN+SNr stimulation was superior to conventional STN stimulation in improving restless legs symptoms (RLS) at night (STN-DBS = 1.9 ± 2.7 STN+SNr-DBS = 1.0 ± 1.8; W = -2.06, p = 0.039) and immobility at night (STN-DBS = 1.5 ± 1.4 STN+SNr-DBS = 0.6 ± 0.8; W = -2.041, p = 0.041)., Conclusion: This study demonstrates the safety of STN+SNr-DBS compared to conventional STN-DBS on sleep in general with potential beneficial input on RLS symptoms and akinesia at night., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: This study evaluates the prevalence, characteristics, and predictors of the difficulty of swallowing medication in Parkinson's disease (PD)., Methods: In this prospective controlled, cross-sectional cohort study, the ability to swallow four different placebos was assessed using flexible endoscopic evaluation of swallowing (FEES) in 118 PD patients and 32 controls. The association between a patient's swallowing ability for each pill and water, patient characteristics and dopaminergic response was examined. The value of two swallowing screening questions was also evaluated., Results: Substantially impaired ability to swallow pills was found in 28% (n = 33/118) of patients and 16% (n = 5/32) of controls (p = 0.18). Higher disease severity was associated with more problems with swallowing pills (p = 0.03), but PD patients with short disease duration (<2 years), low H&Y stage (1-2), and younger age (<70 years) were also affected (each at least in 20%). Capsules were the easiest to swallow while oval tablets were the most difficult (p < 0.01, r = 0.21). Most patients (73%, n = 24/33) presented with swallowing problems only for a single formulation. Aspiration of water was found in 48% of patients, suggesting a possible increased risk of aspiration when taking dissolved tablets. Standardized questionnaires showed insufficient sensitivity (52% both) but fairly good specificity (69-74%) for dysphagia of pills. Dysphagia for medication was not associated with a lack of dopaminergic response., Conclusions: Dysphagia of medication occurs preferentially in advanced disease stages. An assessment of pill swallowing using FEES is suggested at least in patients reporting swallowing problems. Capsules might be preferentially used when dysphagia is suspected., (Copyright © 2019. Published by Elsevier Ltd.)

Background: Dysphagia is common in Parkinson's disease (PD) and leads to pneumonia, malnutrition, and reduced quality of life. For detecting dysphagia-exposed PD patients, the Munich dysphagia test-Parkinson's disease (MDT-PD) is a patient self-reported tool that has been developed specifically for PD patients. The MDT-PD is available in both German and English. This study aimed to ascertain whether the MDT-PD can detect aspiration in PD patients and, therefore, serve as a suitable screening tool., Methods: In a controlled, cross-sectional, observational study, a total of 119 PD outpatients were examined clinically and were evaluated by the MDT-PD and the one swallowing question (NMS-3) from the nonmotor symptom questionnaire for Parkinson's disease (NMSQuest). The results of the MDT-PD and the NMS-3 were compared to the penetration-aspiration scale (PAS) rating defined by flexible endoscopic evaluation of swallowing (FEES)., Key Results: Half of the patients with aspiration as determined using FEES were not detected by the MDT-PD and NMS-3 self-reported tools. The proportion of false positive patients was high with both tools. The sensitivity of the MDT-PD to detect patients who are at risk for aspiration is insufficient (0.37) and not superior to applying the dysphagia screening question from the NMSQuest (0.5)., Conclusion: This study reveals that the MDT-PD is not suitable for detecting aspiration in PD patients and, therefore, cannot be considered as a screening tool for aspiration. However, at present, there is no alternative validated screening tool that can reliably detect aspiration in PD patients. A readjustment of the MDT-PD is urgently needed., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Do the current swallow-specific subquestions of neurological diagnostic tools reflect the objective swallowing function in Parkinson's disease (PD) patients or are clinical factors superior to predict critical aspiration?, Methods: In a cross-sectional, observational study a total of 119 Parkinson outpatients were examined clinically and by flexible-endoscopic evaluation of swallowing (FEES). Self-reported dysphagia by subquestions of the MDS-UPDRS and NMS questionnaire and history of subjective aspiration signs were collected., Key Results: Nearly, all PD patients showed deglutition abnormalities in FEES (113/119) while only 12%-27% of them reported swallowing problems in the swallow-specific subquestions of neurological standard diagnostic tools (MDS-UPDRS and NMS-Quest), and the answers were heterogeneous and poorly reproducible. With a sensitivity of up to a maximum of 50%, self-reported dysphagia is therefore no reliable tool for identifying dysphagia in PD. While most clinical parameters were linked to dysphagia to some extent, logistic regression analysis revealed high age (Odds Ratio (OR) 1.1 in years, 95% CI 1.03-1.18, P < 0.01), gender (OR 0.3 for females, 95% CI 0.08-0.97, P = 0.04), and affirmed subjective aspiration signs (OR 8.6, 95% CI 3.05-26.52, P < 0.001) as the most significant predictors for critical dysphagia., Conclusions and Inferences: Self-perception of swallowing is no reliable tool for identifying dysphagia and questionnaires are insufficient for detecting previous aspiration. Consequent and specific asking for previous subjective aspiration signs is the single most important measure for identifying PD patients at risk for critical aspiration., (© 2018 John Wiley & Sons Ltd.)

Synchronized oscillations within and between brain areas facilitate normal processing, but are often amplified in disease. A prominent example is the abnormally sustained beta-frequency (∼20 Hz) oscillations recorded from the cortex and subthalamic nucleus of Parkinson's disease patients. Computational modeling suggests that the amplitude of such oscillations could be modulated by applying stimulation at a specific phase. Such a strategy would allow selective targeting of the oscillation, with relatively little effect on other activity parameters. Here, activity was recorded from 10 awake, parkinsonian patients (6 male, 4 female human subjects) undergoing functional neurosurgery. We demonstrate that stimulation arriving on a particular patient-specific phase of the beta oscillation over consecutive cycles could suppress the amplitude of this pathophysiological activity by up to 40%, while amplification effects were relatively weak. Suppressive effects were accompanied by a reduction in the rhythmic output of subthalamic nucleus (STN) neurons and synchronization with the mesial cortex. While stimulation could alter the spiking pattern of STN neurons, there was no net effect on firing rate, suggesting that reduced beta synchrony was a result of alterations to the relative timing of spiking activity, rather than an overall change in excitability. Together, these results identify a novel intrinsic property of cortico-basal ganglia synchrony that suggests the phase of ongoing neural oscillations could be a viable and effective control signal for the treatment of Parkinson's disease. This work has potential implications for other brain diseases with exaggerated neuronal synchronization and for probing the function of rhythmic activity in the healthy brain. SIGNIFICANCE STATEMENT In Parkinson's disease (PD), movement impairment is correlated with exaggerated beta frequency oscillations in the cerebral cortex and subthalamic nucleus (STN). Using a novel method of stimulation in PD patients undergoing neurosurgery, we demonstrate that STN beta oscillations can be suppressed when consecutive electrical pulses arrive at a specific phase of the oscillation. This effect is likely because of interrupting the timing of neuronal activity rather than excitability, as stimulation altered the firing pattern of STN spiking without changing overall rate. These findings show the potential of oscillation phase as an input for "closed-loop" stimulation, which could provide a valuable neuromodulation strategy for the treatment of brain disorders and for elucidating the role of neuronal oscillations in the healthy brain., (Copyright © 2019 Holt et al.)

Background: Pain is highly prevalent in patients with Parkinson's disease (PD), but underlying pathophysiological mechanisms are largely unclear. Alterations in somatosensory processing might contribute to sensory abnormalities in PD., Objective: This study investigated sensory processing in PD patients., Methods: We used the standardized "Quantitative Sensory Testing" (QST) protocol (German Research Network on Neuropathic Pain) to investigate 13 somatosensory parameters in 19 PD patients naïve to dopaminergic medication and 19 healthy controls matched for age, gender, and handedness. We tested for differences in sensory parameters between i) drug-naïve PD patients and healthy controls, ii) patients' more and less affected body side, and iii) for an association of somatosensory parameters with disease-specific factors., Results: We did not observe any significant group differences in somatosensory parameters between PD patients and healthy subjects. In PD patients, QST mean z-scores did not differ between the predominantly and the less affected body side, PD patients with and without PD-specific chronic pain or between different PD subtypes. Age, but not PD disease severity, was associated with a greater loss of function in thermal and mechanical detection thresholds., Conclusions: Somatosensory processing, as assessed with the well-established QST protocol, was normal in drug-naïve PD patients. Thus, somatosensory abnormalities previously reported in medicated PD patients might rather be a result of dopaminergic medication, or may occur later in the course of the disease or with increasing age.

To close a gap between inpatient and outpatient care, the Hamburg Parkinson day-clinic (HPDC) has been developed as a new and comprehensive, individual, interdisciplinary type of treatment for patients with complex Parkinsonian syndromes (PS). First, we describe the HPDC concept, in which a multi-professional medical team of PD specialists provide a time- and personnel-wise intensive care and focuses on the patients' individual deficits and resources. Second, we present short-term outcome results of the first 184 PS patients enrolled during 16 months including objective clinical motor and non-motor scores taken before and after participation in the HPDC, as well as the patients' subjective evaluation of the HPDC. Out of the 184 patients with PS (aged 39-88 years with Hoehn and Yahr scores between 1.0 and 4.5), 169 were diagnosed to have Parkinson disease (PD). HPDC treatment led to improvement of all applied motor (UPDRS III, AIMS) and non-motor (BDI-II, MoCA, PDNMS, PDSS-2, King's PD Pain Scale, QUIP, PDQ-39) scores (p < 0.05) indicating benefits for akinesia, tremor, dyskinesia, cognition, sleep, pain, impulse control disorders and quality of life. Patients evaluated HPDC care positively with values from 1.39 to 2.79 ("very good" to "satisfying") with an overall grade of 1.69 ("good") on a 6-point Likert scale (1-6: best to worst). Patients with advanced PS benefit from the HPDC concept which is considered to close a gap between inpatient and outpatient care.

Competing Interests: Prof. Buhmann erhielt Honorare als wissenschaftlicher Berater oder für Vortrags- und Schulungstätigkeiten von Abbvie, Bial, GE Healthcare, Grünenthal, TAD, UCB Pharma und Zambon.PD Dr. Ip erhielt Forschungsunterstützung von Merz sowie Vortragshonorare oder Reisekostenunterstützung von Allergan, Ipsen, Merz und Teva.Dr. Oehlwein berichtet keine Interessenskonflikte.Prof. Tönges erhielt Honorare als wissenschaftlicher Berater, für Vortrags- und Schulungstätigkeiten oder Autoren- oder Co-Autorenschaften von Abbvie, Bayer, Bial, Desitin, GE und UCB Pharma.PD Dr. Wolz erhielt Vortragshonorare von AbbVie, Bial, Bayer, Teva, Desitin, Licher, UCB Pharma und Zambon.Prof. Reichmann nahm an Advisory Boards teil, hielt Vorträge und erhielt Forschungsförderung durch Abbott, Abbvie, Bayer Health Care, Bial, Boehringer/Ingelheim, Brittania, Cephalon, Desitin, GSK, Lundbeck, Medtronic, Merck-Serono, Neuroderm, Novartis, Orion, Pfizer, TEVA, UCB Pharma, Valeant und Zambon.Prof. Kassubek erhielt Honorare für Vorträge oder Advisory Boards von AbbVie, Bial, Desitin, Medtronic, Novartis, Teva Pharmaceuticals, UCB Pharma und Zambon.

Pathological synchronisation of beta frequency (12-35Hz) oscillations between the subthalamic nucleus (STN) and cerebral cortex is thought to contribute to motor impairment in Parkinson's disease (PD). For this cortico-subthalamic oscillatory drive to be mechanistically important, it must influence the firing of STN neurons and, consequently, their downstream targets. Here, we examined the dynamics of synchronisation between STN LFPs and units with multiple cortical areas, measured using frontal ECoG, midline EEG and lateral EEG, during rest and movement. STN neurons lagged cortical signals recorded over midline (over premotor cortices) and frontal (over prefrontal cortices) with stable time delays, consistent with strong corticosubthalamic drive, and many neurons maintained these dynamics during movement. In contrast, most STN neurons desynchronised from lateral EEG signals (over primary motor cortices) during movement and those that did not had altered phase relations to the cortical signals. The strength of synchronisation between STN units and midline EEG in the high beta range (25-35Hz) correlated positively with the severity of akinetic-rigid motor symptoms across patients. Together, these results suggest that sustained synchronisation of STN neurons to premotor-cortical beta oscillations play an important role in disrupting the normal coding of movement in PD., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Dysphagia is frequent and clinically highly relevant in Parkinson's disease (PD). For a rational dysphagia screening predictors are required. Previous investigations suggested that drooling correlates with dysphagia and may serve as its early sign. The aim of this study was to clarify the interrelationship of drooling and dysphagia., Methods: In a controlled, cross-sectional, observational study, a total of 119 Parkinson outpatients and 32 controls were examined clinically and by flexible-endoscopic evaluation of swallowing (FEES). Drooling, dysphagia including retained pharyngeal secretions, and cognitive function were assessed by established evaluation scales., Key Results: Fifty percent of all PD patients but only 9% of controls had drooling (P < .001). Drooling and dysphagia were related in PD (P = .027) but the data do not support to view drooling as a hallmark symptom for critical dysphagia. Thirty-nine percent of the patients with critical aspiration had no drooling. In contrast, 41% of the patients with severe drooling had no clinically relevant dysphagia in FEES. The oral, but not the pharyngeal secretion management was impaired in PD patients and there was no clear association between drooling and pharyngeal secretion accumulation. Cognitive impaired patients had significantly more drooling (P = .005)., Conclusions & Inferences: Although frequent in PD, drooling and dysphagia are only weakly related and drooling cannot be viewed as an early sign of dysphagia. Our data further suggest that the underlying cause of drooling is located in the voluntary oral phase, which is negatively influenced by cognitive deficits., (© 2017 John Wiley & Sons Ltd.)

To assess the prevalence of dysphagia and its typical findings in unselected "real-world" Parkinson patients using an objective gold-standard method. This was a prospective, controlled, cross-sectional study conducted in 119 consecutive Parkinson patients of all stages independent of subjective dysphagia. Patients and 32 controls were clinically and endoscopically examined by flexible endoscopic evaluation of swallowing (FEES) to evaluate the deglutition with regard to three consistencies (water, biscuit, and bread). Typical findings of dysphagia like penetration and aspiration, residues, and leakage were assessed. Dysphagia was common in Parkinson patients and occurred in all, even early, disease stages. Only 5% (6/119) of patients showed a completely unremarkable deglutition. Aspiration was seen in 25% (30/119) of patients and always related to water. Residues occurred in 93% (111/119), most commonly for bread. Leakage was much less frequent and was found in only 3-18%, depending on consistency. In a significant fraction of patients, objective dysphagia was not subjectively perceived. A total of 16% of asymptomatic patients suffered from critical aspiration. Significant swallowing deficiencies already occurred in early disease. Aspiration was found in 4 of 20 (20%) patients with disease duration of less than 2 years. Seven of 57 patients (12%) with Hoehn and Yahr stage 2 suffered from severe aspiration. Given the high frequency of critical aspiration in Parkinson disease, these patients should be evaluated early for dysphagia to avoid complications and recommend an adequate therapy. FEES is a simple, cost efficient, minimally invasive method that is ideally suited for this purpose.

Cannabis buds and extracts as well as synthetic cannabinoids have been available on prescription to patients with severe diseases since March 2017, with the costs covered by health insurance companies.The prescription of medical marihuana is not restricted to specific symptoms and is therefore also valid for patients with Parkinson's disease. From a legal perspective, patients who are seriously ill even have the right to be treated with cannabis if standard treatment methods are unsuccessful or result in unbearable side effects. This also applies even if only a slight chance of noticeable improvement is predicted as a result of the cannabis treatment.Bearing this in mind and due to an intense media coverage of this topic, more and more patients with Parkinson's disease are requesting cannabis prescription, which is a challenging situation to their neurologists.This article provides an overview of the various cannabis products that can be prescribed, the different modes of administration and the available literature regarding motor- and non-motor symptoms in Parkinson's disease. Furthermore, the authors state their opinion on which indications cannabinoids could be useful in treating patients with Parkinson's disease or in which situation the patient could or even should be prescribed cannabinoids. Additionally, this article presents practical recommendations for the prescription of cannabinoids and patient counseling, e. g., on the effects of medical marijuana on driving capacity., Competing Interests: Die Autoren geben an, dass kein Interessenkonflikt besteht., (Georg Thieme Verlag KG Stuttgart · New York.)

About 60 % of all patients with Parkinson's disease (PD) and about 50 % of PD patients with deep brain stimulation (DBS) in possession of a driving license are active car-drivers. Parkinson patients, however, often display physical and/or psychological weaknesses that can lead to loss of or reduced driving ability. Driving capability can also be affected by Parkinson medication. The attending physician is therefore obliged to advise his patients regarding their ability to be in command of a vehicle. This however can prove difficult in practice. On the one hand, there is no standardised predictive test battery to evaluate driving capability and on the other, levels of motor impairment do not correlate sufficiently with driving skills. This article will provide an overview of motor and non-motor symptoms that affect general and/or Parkinson's disease-related driving capability and which criteria demonstrate a temporary or permanent inability to drive. Furthermore, we will highlight which neuropsychological investigations are beneficial and how PD patients with DBS should be evaluated and subsequently advised regarding their driving fitness., Competing Interests: Interessenkonflikt: Die Autoren geben an, dass kein Interessenkonflikt besteht., (Georg Thieme Verlag KG Stuttgart · New York.)

Levodopa/carbidopa intestinal gel (LCIG) infusion is an effective escalating therapy in patients with Parkinson disease (PD) suffering from motor fluctuations and dyskinesia. Levodopa/carbidopa given continuously as infusion provides an optimized application of the most effective and best tolerable antiparkinsonian drug. It has been proven to have a superior motor effect compared with oral levodopa and to improve also non-motor symptoms. However, invasiveness, discomfort resulting from carrying an external device, and side effects associated with the way of administration limit its application in PD patients. At present, there are no guidelines that delineate to which patients LCIG should be offered as monotherapy, in combination with oral and/or transdermal medication, or as additional therapy to deep brain stimulation (DBS). Based on clinical studies, we propose an expert consensus for neurologists addressing the question when LCIG therapy should be recommended and in which cases LCIG infusion is suggested in combination with other antiparkinsonian drugs and/or DBS. We describe how LCIG should be initiated and what we consider necessary for clinical follow-up. We suggest an algorithm facilitating decision-making with respect to the currently available invasive PD therapies, namely infusion with subcutaneous apomorphine, LCIG, and DBS.

This study aimed at examining the impact of Parkinson disease (PD) on patients' sexuality and relationship and to evaluate gender-specific differences. Using a standardized questionnaire on sexual functioning in chronic diseases (SFCE), the impact of PD diagnosis on 38 domains of sexuality before and since PD diagnosis was evaluated retrospectively in 53 consecutive patients in a relationship. Changes in self-assessed ratings on a four-point Likert scale were determined for all patients. In addition, gender-specific differences and the influence of age, depression (BDI-II), medication, disease severity and disease duration on domains of the SFCE were calculated. The importance of non-sexual relational aspects, such as talking about feelings or tenderness increased for both genders after PD diagnosis, especially in women. Sexual function, such as frequency of intercourse, sexual arousal, subjective abnormal sexual fantasies or sexual satisfaction deteriorated in both genders, especially in men. Some sexual aspects improved in women but worsened in men after PD diagnosis. This includes frequency of orgasm dysfunction, fear not to fulfill sexual expectations of the partner, avoidance of sexual acts, withdrawal from relationship, increase of thoughts about divorce, or increase of dissatisfaction with sexuality and relationship. With age, thoughts about divorce declined. With disease duration, frequency of tenderness with the partner increased. Depression unexpectedly correlated with higher frequency of intercourse. Dopaminergic dosage influenced stability of the relationship negatively. PD influences patients' sexuality negatively, independently of age, disease duration or disease severity and men show greater sexual dysfunction and impairment of their sexual relationship than women.

Pain is a frequent but still neglected nonmotor symptom of Parkinson disease (PD). However, neural mechanisms underlying pain in PD are poorly understood. Here, we explored whether the high prevalence of pain in PD might be related to dysfunctional descending pain control. Using functional magnetic resonance imaging we explored neural responses during the anticipation and processing of heat pain in 21 PD patients (Hoehn and Yahr I-III) and 23 healthy controls (HC). Parkinson disease patients were naive to dopaminergic medication to avoid confounding drug effects. Fifteen heat pain stimuli were applied to the participants' forearm. Intensity and unpleasantness ratings were provided for each stimulus. Subjective pain perception was comparable for PD patients and HC. Neural processing, however, differed between groups: PD patients showed lower activity in several descending pain modulation regions (dorsal anterior cingulate cortex [dACC], subgenual anterior cingulate cortex, and dorsolateral prefrontal cortex [DLPFC]) and lower functional connectivity between dACC and DLPFC during pain anticipation. Parkinson disease symptom severity was negatively correlated with dACC-DLPFC connectivity indicating impaired functional coupling of pain modulatory regions with disease progression. During pain perception PD patients showed higher midcingulate cortex activity compared with HC, which also scaled with PD severity. Interestingly, dACC-DLPFC connectivity during pain anticipation was negatively associated with midcingulate cortex activity during the receipt of pain in PD patients. This study indicates altered neural processing during the anticipation and receipt of experimental pain in drug-naive PD patients. It provides first evidence for a progressive decline in descending pain modulation in PD, which might be related to the high prevalence of pain in later stages of PD.

We aimed to evaluate prevalence, phenotype, and therapeutic realities of pain in patients with Parkinson disease (PD). Therefore, we assessed 181 outpatients with PD using a cross-sectional approach applying the German Pain Questionaire (DSF), the PainDetect, and a self-developed Parkinson Disease Pain Questionaire (UPDPQ) covering detailed therapeutic aspects. Furthermore, we investigated the association between pain and PD-disease characteristics, quality of life (PDQ-39), depression, and anxiety (HADS-D, HADS-A). Overall, prevalence of pain was high (95.4%); 91.1% suffered from chronic pain, but in only 22.3% of them, pain disorder was diagnosed. Pain impaired everyday-life moderately to very severely in 48.4% of patients and was the most distressing symptom in 10.2% of all patients. Pain was localized mainly in the back (71.4%) or joints (52.4%), frequently occurred as pain attacks (79%) but appeared with neuropathic character in only 15.3% of patients. Most patients (74.2%) received some kind of pain treatment, mainly provided by orthopedists (62.0%) or general practitioners (50.0%). Physiotherapy (61.3%), pain killers (54.4%), or massage (35.5%) were the most frequent therapeutic measures. Rehabilitative therapy (96.3%) and physiotherapy (89.5%) were rated as most effective, but with vastly temporary effects. 53.3% of patients attributed PD as the main cause for their pain, but only 33.6% found relief from anti-parkinsonian drugs. High levels of pain were associated with higher scores of depression and anxiety, and lower quality of life. Results suggest that pain in PD is frequent, complex, and quality-of-life-impairing but under-diagnosed and unsystematically treated and indicate need to systematically investigate pathophysiology-based treatment strategies.

Purpose: The retina has been found affected in Parkinson's disease (PD). It is unclear if this is due to neurodegeneration of local dopamine-dependent retinal cells, a result of central nervous degeneration including the optic nerve or retinal small vessel disease. This study aimed to detect changes of the retinal vasculature in PD patients compared to controls., Methods: We examined 49 PD patients and 49 age- and sex-matched healthy controls by spectral domain optical coherence tomography (SD-OCT) with a circular scan centred at the optic disc. Vessels within the retinal nerve fibre layer were identified by an automated algorithm and thereafter manually labelled as artery or vein. Layer segmentation, vessel lumen and direct surrounding tissue were marked automatically with a grey value and the contrast between both values in relation to the surrounding tissue was calculated. The differences in these grey value ratios among subjects were determined and used as an indicator for differences in vessel morphology. Furthermore, the diameters of the veins and arteries were measured and then compared between the groups., Results: The contrast of retinal veins was significantly lower in PD patients compared to controls, which indicates changes in vessel morphology in PD. The contrast of arteries was not significantly different. Disease duration, disease stage according to Hoehn and Yahr or age did not influence the grey value ratios in PD patients. Vessel diameter in either veins or arteries did not differ between subject groups. The contrast of retinal veins contralateral to the clinically predominant and first affected side was significantly lower compared to the ipsilateral side., Conclusion: Our data show a potential difference of the retinal vasculature in PD patients compared to controls. Vascular changes in the retina of PD patients might contribute to vision-related complaints in PD.