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During the last 15 years deep brain stimulation (DBS) has been established as a highly-effective therapy for advanced Parkinson’s disease (PD). Patient selection, stereotactic implantation, postoperative stimulator programming and patient care requires a multi-disciplinary team including movement disorders specialists in neurology and functional neurosurgery. To treat medically refractory levodopa-induced motor complications or resistant tremor the preferred target for high-frequency DBS is the subthalamic nucleus (STN). STN-DBS results in significant reduction of dyskinesias and dopaminergic medication, improvement of all cardinal motor symptoms with sustained long-term benefits, and significant improvement of quality of life when compared with best medical treatment. These benefits have to be weighed against potential surgery-related adverse events, device-related complications, and stimulus-induced side effects. The mean disease duration before initiating DBS in PD is currently about 13 years. It is presently investigated whether the optimal timing for implantation may be at an earlier disease-stage to prevent psychosocial decline and to maintain quality of life for a longer period of time.

Aim of this review is to discuss the value of current ongoing research initiatives in Parkinson's disease from the clinicians' point of view. The repeat, recent failures on progress slowing reflect the drifting apart between initially promising experimental and then disappointing clinical outcomes in the translational trials with well selected Parkinson's disease patients. A similar development concerns the emerging gap between novel developed drugs with improved pharmacokinetic behaviour and their limited use in the clinical practice following approval. Restricted regional different worldwide availability and direct, respectively indirect budget limitations for neurologists in private practice are essential hurdles. They prevent the widespread prescription of these compounds. As a result return of investment for the pharmaceutical industry becomes more and more uncertain. The interest for research on novel treatment approaches for the amelioration of motor and non motor symptoms declines. Clinicians crucially scrutinize the claim for an optimum patient care by payers and regulators., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Objective: Awareness of cognitive deficits is related to executive functions and may, therefore, be sensitive to the effects of lumbar puncture (LP) in idiopathic normal pressure hydrocephalus (iNPH). Although a reduction in awareness of cognitive deficits (RACD) has been previously described in iNPH, there is a lack of systematic, psychometrically validated reports. In this study, we investigated RACD and its LP-related changes in iNPH patients and compared them with those in clinical and healthy control groups., Methods: RACD was assessed before and after lumbar puncture (LP) in 24 patients (14 iNPH, 10 other age-associated cognitive syndromes; AACS) and compared with 23 healthy controls (HC), employing two RACD measures alongside cognitive examination. Local metacognition was measured using a visual percentile-based rating system and operationalized as the t-scaled distance between the participants' task-specific performance estimations and their objective test performance (ΔTSPE). Global metacognition, targeting broader estimates of cognitive functioning (ECF), was quantified by subtracting self- from informant-obtained sum scores on a questionnaire evaluating participants' dysexecutive problems (DEX-DS). Within-group and between-group differences in ΔTSPE and DEX-DS scores were compared non-parametrically, focusing on post-LP changes., Results: Averaged ΔTSPE was higher in the patient groups and mirrored the groups' lower objective test performance, while averaged DEX-DS showed no group difference. Following LP, group comparisons revealed iNPH-specific decrease in both RACD measures., Conclusion: Our study revealed LP-related RACD changes in iNPH patients compared to those in AACS and HC participants. The results suggest a mitigation of impaired metacognitive abilities in iNPH, possibly resulting from LP-induced improvements in (local) metacognitive performance, facilitating ECF adjustment alongside a metacognitively stimulating testing procedure., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

MANAGE-PD is a validated, web-based tool to assist physicians in identifying patients with Parkinson's disease (PD) whose symptoms are inadequately controlled by oral medication. Also, a modified patient version of MANAGE-PD (Parkinson Check) is available in Germany. However, prospective research into the clinical utility of MANAGE-PD is lacking. This non-interventional study aimed to assess the real-world clinical utility of the MANAGE-PD and Parkinson Check in PD patients attending a single visit at specialist clinics and neurologist practices in Germany in 2022. Participants' disease control was rated by the physicians using their own judgment, and by completing the MANAGE-PD, and by the patients completing the Parkinson Check. Concordance was calculated between the unassisted physician's assessment and the outcome of MANAGE-PD, as well as the Parkinson Check. A total of 278 patients from 19 sites were included in the analyses, of whom 160 patients (57.6%) were assigned to the same category of disease control by physicians' judgment and the MANAGE-PD. Concordance was higher in patients treated in specialist clinics (63.9%) than in neurologist practices (43.7%). Concordance between physicians' and patients' responses was high (>80%) for each question in the Parkinson Check. MANAGE-PD proved to be especially valuable for general neurologists in identifying patients who should be referred to specialist clinics. The Parkinson Check self-assessment generated promising outcomes that merit its more widespread use.

Background and Objectives: Advanced therapies (ATs; deep brain stimulation [DBS] or pump therapies: continuous subcutaneous apomorphine infusion [CSAI], levodopa/carbidopa intestinal gel [LCIG]) are used in later stages of Parkinson disease (PD). However, decreasing efficacy over time and/or side effects may require an AT change or combination in individual patients. Current knowledge about changing or combining ATs is limited to mostly retrospective and small-scale studies. The nationwide case collection Combinations of Advanced Therapies in PD assessed simultaneous or sequential AT combinations in Germany since 2005 to analyze their clinical outcome, their side effects, and the reasons for AT modifications., Methods: Data were acquired retrospectively by modular questionnaires in 22 PD centers throughout Germany based on clinical records and comprised general information about the centers/patients, clinical (Mini-Mental Status Test/Montréal Cognitive Assessment, Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale [MDS-UPDRS], side effects, reasons for AT modification), and therapeutical (ATs with specifications, oral medication) data. Data assessment started with initiation of the second AT., Results: A total of 148 AT modifications in 116 patients were associated with significantly improved objective (median decrease of MDS-UPDRS Part III 4.0 points [ p < 0.001], of MDS-UPDRS Part IV 6.0 points [ p < 0.001], of MDS-UPDRS Part IV-off-time item 1.0 points [ p < 0.001]) and subjective clinical outcome and decreasing side effect rates. Main reasons for an AT modification were insufficient symptom control and side effects of the previous therapy. Subgroup analyses suggest addition of DBS in AT patients with leading dyskinesia, addition of LCIG for leading other cardinal motor symptoms, and addition of LCIG or CSAI for dominant off-time. The most long-lasting therapy-until requiring a modification-was DBS., Discussion: Changing or combining ATs may be beneficial when 1 AT is insufficient in efficacy or side effects. The outcome of an AT combination is comparable with the clinical benefit by introducing the first AT. The added AT should be chosen dependent on dominant clinical symptoms and adverse effects. Furthermore, prospective trials are needed to confirm the results of this exploratory case collection., Classification of Evidence: This study provides Class IV evidence that, in patients with PD, changing or combining ATs is associated with an improvement in the MDS-UPDRS or subjective symptom reporting., (© 2023 American Academy of Neurology.)

To explore the influence of bilateral subthalamic deep brain stimulation (STN-DBS) on car driving ability in patients with Parkinson's disease (PD), we prospectively examined two age-matched, actively driving PD patient groups: one group undergone DBS-surgery (PD-DBS, n = 23) and one group that was eligible for DBS but did not undergo surgery (PD-nDBS, n = 29). In PD-DBS patients, investigation at Baseline was done just prior and at Follow-up 6-12 month after DBS-surgery. In PD-nDBS patients, time interval between Baseline and Follow-up was aimed to be comparable. To assess the general PD driving level, driving was assessed once in 33 age-matched healthy controls at Baseline. As results, clinical and driving characteristics of PD-DBS, PD-nDBS and controls did not differ at Baseline. At Follow-up, PD-DBS patients drove unsafer than PD-nDBS patients. This effect was strongly driven by two single PD-DBS participants (9%) with poor Baseline and disastrous Follow-up driving performance. Retrospectively, we could not identify any of the assessed motor and non-motor clinical Baseline characteristics as predictive for this driving-deterioration at Follow-up. Excluding these two outliers, comparable driving performance between PD-DBS and PD-nDBS patients not only at Baseline but also at Follow-up was demonstrated. Age, disease duration and severity as well as Baseline driving insecurity were associated with poorer driving performance at Follow-up. This first prospective study on driving safety in PD after DBS surgery indicates that DBS usually does not alter driving safety but might increase the risk for driving deterioration, especially in single subjects with already unsafe driving prior to DBS surgery., (© 2023. The Author(s).)

Data on the use of device-aided therapies (DATs) in people with Parkinson's disease (PwP) are scarce. Analyzing data from the Care4PD patient survey, we (1) evaluated application frequency and type of DAT in a larger, nationwide, cross-sectoral PwP sample in Germany; (2) analyzed the frequency of symptoms indicative for advanced PD (aPD) and need for DAT amongst the remaining patients and (3) compared the most bothersome symptoms and need for professional long-term care (LTC) of patients with and without suspected aPD. Data from 1269 PwP were analyzed. In total, 153 PwP (12%) received DAT, mainly deep brain stimulation (DBS). Of the remaining 1116 PwP without DAT, >50% fulfilled at least one aPD criterion. Akinesia/rigidity and autonomic problems were most bothersome for PwP with and without suspected aPD, with more tremor in the non-aPD and more motor fluctuations and falls in the aPD group. To recapitulate, the German DAT application rate is rather low, although a large proportion of PwP fulfills aPD criteria indicating a need for intensified treatment strategies. Many reported bothersome symptoms could be overcome with DAT with benefits even for LTC patients. Thus, precise and early identification of aPD symptoms (and therapy-resistant tremor) should be implemented in future DAT preselection tools and educational trainings.

Introduction: Cerebral insults lead in many cases not only to cognitive impairment but also to disturbed emotionality. After stroke, one in three survivors develops a depression which impacts quality of life and rehabilitation. Meta-analyses have identified five main predictors of post-stroke depression (PSD): history of mental disorder, stroke severity, physical disability, cognitive impairment, and social support. However, these five established variables have never been conjointly investigated in a sample of stroke survivors. Therefore, their independent predictive values remain unclear. Moreover, predictors are most often used as time-invariant factors (status scores), neglecting the intraindividual dynamics after stroke., Methods: Our study analyses the data of two prospective longitudinal studies, investigating stroke survivors from two rehabilitation hospitals ( N 1 = 273) and one acute care hospital ( N 2 = 226). Baseline assessments included the five established predictors and depressive symptoms. After 6 months, depressive symptoms were reassessed in both studies ( n 1 = 176, n 2 = 183), and physical disability and social support were reassessed in study 2. The predictivity of the five predictors and the additional predictivity of intraindividual dynamics for PSD were examined in multiple linear regression analyses., Results: History of mental disorder was a risk factor for depressive symptoms after stroke at all measurement times ( B = 3.32 to 3.97; p < 0.01). Physical disability was a risk factor at all measurement times ( B = -0.09 to -0.03; p < 0.05) except 6 months after rehabilitation. Social support was a protective factor ( B = -2.69 to -1.91; p < 0.01) outside the acute phase ( R 2 = 0.15-0.39). Intraindividual changes in physical disability and perceived social support were independent predictors of PSD 6 months after the acute phase ( B = -0.08/-0.14; p < 0.01), in addition to status scores on established variables (Δ R 2 = 0.08, p < 0.001)., Discussion: History of mental disorder, physical disability, and social support are independent predictors of depressive symptoms in the first year post-stroke, also when considered conjointly. Future studies should control for these variables when investigating new predictors of PSD. In addition, intraindividual changes in known predictors after stroke play a relevant role in the pathogenesis of PSD and should be considered in clinical practice and future research., Competing Interests: 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., (Copyright © 2023 Ladwig, Werheid, Südmeyer and Volz.)

Background and Purpose: Patients with a corticobasal syndrome (CBS) present a rare form of atypical parkinsonism characterized by asymmetric clinical symptoms and progressive motor and nonmotor impairment, such as apraxia, alien limb phenomenon, aphasia, myoclonus, dystonia, and cognitive impairment. At early stages, clinical differentiation between CBS and idiopathic Parkinson's disease (IPD) can be challenging., Methods: Using high-resolution T1-weighted images and voxel-based morphometry (VBM), we sought to identify disease-specific patterns of brain atrophy in a small sample of CBS and IPD patients at early stages of disease. We acquired MR images of 17 patients diagnosed with CBS and compared them with MR images of 17 subjects affected by IPD. Images were preprocessed and analyzed using VBM., Results: When compared to each other, the CBS and IPD patients of our cohort showed differences in regional gray and white matter volume depending on the diagnosis, specifically in the superior longitudinal fascicle., Conclusions: In our small patients' group, VBM was able to detect changes in regional gray and white matter volume between patients affected by CBS and patients with IPD as early as 1.5-2 years after the onset of the first motor symptoms., (© 2022 American Society of Neuroimaging.)

Idiopathic Parkinson's disease (PD) is a neurodegenerative disorder with a broad spectrum of motor and non-motor symptoms. The neuropathological characteristics of idiopathic PD are the degeneration of dopaminergic neurons in the striatum, and the propagation of aggregates of misfolded α-synuclein in the brain following a specific pattern (Braak et al., 2006). The relationship of this pattern with motor and cognitive symptoms is still equivocal. Therefore, we investigated longitudinally the spatio-temporal patterns of atrophy propagation in PD, their inter-individual variability and associations with clinical symptoms. Magnetic resonance (MR) images of 37 PD patients and 27 controls were acquired at up to 15 time-points per subject, and over observation periods of up to 8.8 years (mean: 3.7 years). MR images were analyzed by Deformation-based Morphometry to measure region volumes and their longitudinal changes. Differences of these regional volume data between patients and controls and their associations with clinical symptoms were calculated. At baseline, group differences in the regional volumes were found mainly in areas of the sensory, motor and orbitofrontal cortices, areas in the frontal operculum, inferior frontal sulcus, hippocampus and entorhinal cortex, and in the substantia nigra, among others. The longitudinal analysis yielded more widespread and more pronounced group differences, with significantly accelerated volume decreases in PD patients in the occipital and temporal lobes, the inferior parietal lobule, as well as in the insula, putamen and nucleus basalis Meynert. The white matter was less affected than the gray matter. Worse clinical scores (MMSE, PDQ-39, UPDRS-III) were in particular associated with volume decreases of cortical areas, amygdala and basal forebrain nuclei, but not of the basal ganglia. The observed longitudinal patterns of accelerated volume decrease in PD patients largely coincide with the pattern of α-synuclein pathology in PD stages 3-5 as proposed by Braak and colleagues. Thus, longitudinal DBM appears to depict already in-vivo the progression of neuropathological changes., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Importance: The entry of artificial intelligence into medicine is pending. Several methods have been used for the predictions of structured neuroimaging data, yet nobody compared them in this context., Objective: Multi-class prediction is key for building computational aid systems for differential diagnosis. We compared support vector machine, random forest, gradient boosting, and deep feed-forward neural networks for the classification of different neurodegenerative syndromes based on structural magnetic resonance imaging., Design, Setting, and Participants: Atlas-based volumetry was performed on multi-centric T1-weighted MRI data from 940 subjects, i.e., 124 healthy controls and 816 patients with ten different neurodegenerative diseases, leading to a multi-diagnostic multi-class classification task with eleven different classes., Interventions: N.A., Main Outcomes and Measures: Cohen's kappa, accuracy, and F1-score to assess model performance., Results: Overall, the neural network produced both the best performance measures and the most robust results. The smaller classes however were better classified by either the ensemble learning methods or the support vector machine, while performance measures for small classes were comparatively low, as expected. Diseases with regionally specific and pronounced atrophy patterns were generally better classified than diseases with widespread and rather weak atrophy., Conclusions and Relevance: Our study furthermore underlines the necessity of larger data sets but also calls for a careful consideration of different machine learning methods that can handle the type of data and the classification task best., (© 2022. The Author(s).)

Background: Depression after stroke is common but often undertreated as increasing depression prevalence and decreasing health care contacts diverge after the event., Objective: To develop an acute-phase prediction scale for prognosis of depression 6 months after stroke., Methods: Participants (N = 226) were consecutively recruited and assessed within the first week after ischemic stroke for history of depression, stroke severity (National Institutes of Health Stroke Scale), and functional independence (Barthel Index). Early depressive symptoms were self-reported via the Patient Health Questionnaire-2 and external-rated by nurses via the Signs of Depression Scale. Six months later, 183 participants were assessed for Diagnostic and Statistical Manual of Mental Disorders, 5th edition diagnosis of depression. Significant predictors of depression were identified in multivariate logistic regression analysis and their coefficients transformed into a risk scale. Measurement precision was identified using receiver operating characteristic curve analysis., Results: Depression was diagnosed in 32 (17.5%) participants 6 months after stroke. History of depression, the Barthel Index, and the Patient Health Questionnaire-2 were significant predictors of depression. Transformation of the coefficients yielded the Post-Stroke Depression Risk Scale that demonstrated good discrimination (area under the receiver operating characteristic curve = 0.84; 95% confidence interval = 0.78/0.90). The optimum cutoff showed a sensitivity of 0.81, a specificity of 0.72, a positive predictive value of 0.38, and a negative predictive value of 0.95., Conclusions: The Post-Stroke Depression Risk Scale accurately identifies people in the acute phase with low risk of depression 6 months later. While the sensitivity indicates that recognition of people with later depression is adequate, positive results in the acute phase show low predictivity. Clinical and methodological reasons for these results as well as implications for future research to increase case-finding ability are discussed., (Copyright © 2021 Academy of Consultation-Liaison Psychiatry. Published by Elsevier Inc. All rights reserved.)

The Care4PD study examined the impact of the COVID-19 pandemic on the care situation of people (PwP) with Parkinson's disease in Germany. A comprehensive, nationwide, anonymous questionnaire for PwP was distributed by the members' journal of the German Parkinson's Disease Association and in several PD specialized in- and outpatient institutions. PwP subjectively evaluated their general care situation and individual impairments during the pandemic. We analyzed 1269 eligible out of 1437 returned questionnaires (88.3%) and compared PwP with (p-LTC) and without (np-LTC) professional long-term care. Both groups rated the general pandemic-related consequences as being rather mild to moderate (e.g., worsening of symptom or concerns). However, familial/social contact restrictions were indicated as most compromising, whereas access to outpatient professional health care providers was less affected. PwP with professional LTC reported more impairment than those without. COVID-19 vaccination rates and acceptance were generally high (p-LTC: 64.3%, np-LTC: 52.3%) at the time of the study, but realization of sanitary measures-especially wearing masks as a patient during care sessions-still needs to be improved. Technical options for telemedicine were principally available but only rarely used. Altogether, during the COVID-19 pandemic, PwP in Germany seemed to have a relatively stable health care access, at least in outpatient settings, while mainly social isolation compromised them. The p-LTC group was more impaired in everyday live compared with the np-LTC group.

Purpose: Parkinson's disease (PD) is primarily defined by motor symptoms and is associated with alterations of sensorimotor areas. Evidence for network changes of the sensorimotor network (SMN) in PD is inconsistent and a systematic evaluation of SMN in PD yet missing. We investigate functional connectivity changes of the SMN in PD, both, within the network, and to other large-scale connectivity networks., Methods: Resting-state fMRI was assessed in 38 PD patients under long-term dopaminergic treatment and 43 matched healthy controls (HC). Independent component analysis (ICA) into 20 components was conducted and the SMN was identified within the resulting networks. Functional connectivity within the SMN was analyzed using a dual regression approach. Connectivity between the SMN and the other networks from group ICA was investigated with FSLNets. We investigated for functional connectivity changes between patients and controls as well as between medication states (OFF vs. ON) in PD and for correlations with clinical parameters., Results: There was decreased functional connectivity within the SMN in left inferior parietal and primary somatosensory cortex in PD OFF. Across networks, connectivity between SMN and two motor networks as well as two visual networks was diminished in PD OFF. All connectivity decreases partially normalized in PD ON., Conclusion: PD is accompanied by functional connectivity losses of the SMN, both, within the network and in interaction to other networks. The connectivity changes in short- and long-range connections are probably related to impaired sensory integration for motor function in PD. SMN decoupling can be partially compensated by dopaminergic therapy., (© 2021. The Author(s).)

Background: Longitudinally extensive transverse myelitis (LETM) is a rare subtype of transverse myelitis (TM) that potentially results in relevant disability. Apart from association to neuromyelitis optica and other chronic demyelinating diseases of the central nervous system, many other aetiologies are known. Particularly systemic infections and vaccination are considered potential triggers for immune mediated inflammation of the spinal cord. In the course of the current Covid-19 pandemic several cases of TM following Covid-19 infection have been described. Here we present a case of LETM following vaccination against Covid-19 with AZD1222, AstraZeneca. An extensive diagnostic work up was performed to rule out alternative causes, including prior and current Covid-19 infection., Conclusion: To our knowledge this is first case of LETM possibly related to Covid-19 vaccination that is published after marketing authorisation of various vaccine candidates., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: A reliable measure of PSP-specific midbrain atrophy, the midbrain-to-pons ratio (MTPR) has been reported to support the differential diagnosis of progressive supranuclear palsy (PSP) from idiopathic Parkinson's disease (IPD). Since longitudinal analyses are lacking so far, the present study aimed to evaluate the diagnostic value of the relative change of MTPR (relΔt&#95;MTPR) over a 1-year period in patients with PSP, IPD, and healthy controls (HC)., Methods: Midsagittal individual MRIs of patients with PSP (n = 15), IPD (n = 15), and healthy controls (HC; n = 15) were assessed and the MTPR at baseline and after 1 year were defined. The diagnostic accuracy of the MTPR and its relative change were evaluated using ROC curve analyses., Results: PSP-patients had a significantly lower MTPR at baseline (M = 0.45 ± 0.06), compared to both non-PSP groups (F (2, 41) = 62.82, p < 0.001), with an overall predictive accuracy of 95.6% for an MTPR ≤ 0.54. PSP-patients also presented a significantly stronger 1-year decline in MTPR compared to IPD (p < 0.001). Though predictive accuracy of relΔ t &#95;MTPR for PSP (M = - 4.74% ± 4.48) from IPD (M =  + 1.29 ± 3.77) was good (76.6%), ROC analysis did not reveal a significant improvement of diagnostic accuracy by combining the MTPR and relΔ t &#95;MTPR (p = 0.670). Still, specificity for PSP increased, though not significantly (p = 0.500)., Conclusion: The present results indicate that the relΔ t &#95;MTPR is a potentially useful tool to support the differential diagnosis of PSP from IPD. For its relative 1-year change, still, more evaluation is needed.

An increasing number of neuroimaging studies addressing patients with corticobasal syndrome use macroscopic definitions of brain regions. As a closer link to functionally relevant units, we aimed at identifying magnetic resonance-based atrophy patterns in regions defined by probability maps of cortical microstructure. For this purpose, three analyses were conducted: (1) Whole-brain cortical thickness was compared between 36 patients with corticobasal syndrome and 24 controls. A pattern of pericentral atrophy was found, covering primary motor area 4, premotor area 6, and primary somatosensory areas 1, 2, and 3a. Within the central region, only area 3b was without atrophy. (2) In 18 patients, longitudinal measures with follow-ups of up to 59 months (mean 21.3 ± 15.4) were analyzed. Areas 1, 2, and 6 showed significantly faster atrophy rates than primary somatosensory area 3b. (3) In an individual autopsy case, longitudinal in vivo morphometry and postmortem pathohistology were conducted. The rate of magnetic resonance-based atrophy was significantly correlated with tufted-astrocyte load in those cytoarchitectonically defined regions also seen in the group study, with area 3b being selectively unaffected., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Although deep brain stimulation of the globus pallidus internus (GPi-DBS) is an established treatment for many forms of dystonia, including generalized as well as focal forms, its effects on brain (dys-)function remain to be elucidated, particularly for focal and segmental dystonia. Clinical response to GPi-DBS typically comes with some delay and lasts up to several days, sometimes even weeks, once stimulation is discontinued., Objective: This study investigated how neural activity during rest and motor activation is affected by GPi-DBS while excluding the potential confound of altered feedback as a result of therapy-induced differences in dystonic muscle contractions., Methods: Two groups of patients with focal or segmental dystonia were included in the study: 6 patients with GPi-DBS and 8 without DBS (control group). All 14 patients had cervical dystonia. Using H 2 15 O PET, regional cerebral blood flow was measured at rest and during a motor task performed with a nondystonic hand., Results: In patients with GPi-DBS (stimulation ON and OFF), activity at rest was reduced in a prefrontal network, and during the motor task, sensorimotor cortex activity was lower than in patients without DBS. Within-group contrasts (tapping > rest) showed less extensive task-induced motor network activation in GPi-DBS patients than in non-DBS controls. Reduced sensorimotor activation amounted to a significant group-by-task interaction only in the stimulation ON state., Conclusions: These findings support previous observations in generalized dystonia that suggested that GPi-DBS normalizes dystonia-associated sensorimotor and prefrontal hyperactivity, indicating similar mechanisms in generalized and focal or segmental dystonia. Evidence is provided that these effects extend into the OFF state, which was not previously demonstrated by neuroimaging. © 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.)

Objective: Evaluation of a data-driven, model-based classification approach to discriminate idiopathic Parkinson's disease (PD) patients from healthy controls (HC) based on between-network connectivity in whole-brain resting-state functional MRI (rs-fMRI)., Methods: Whole-brain rs-fMRI (EPI, TR = 2.2 s, TE = 30 ms, flip angle = 90°. resolution = 3.1 × 3.1 × 3.1 mm, acquisition time ≈ 11 min) was assessed in 42 PD patients (medical OFF) and 47 HC matched for age and gender. Between-network connectivity based on full and L2-regularized partial correlation measures were computed for each subject based on canonical functional network architectures of two cohorts at different levels of granularity (Human Connectome Project: 15/25/50/100/200 networks; 1000BRAINS: 15/25/50/70 networks). A Boosted Logistic Regression model was trained on the correlation matrices using a nested cross-validation (CV) with 10 outer and 10 inner folds for an unbiased performance estimate, treating the canonical functional network architecture and the type of correlation as hyperparameters. The number of boosting iterations was fixed at 100. The model with the highest mean accuracy over the inner folds was trained using an non-nested 10-fold 20-repeats CV over the whole dataset to determine feature importance., Results: Over the outer folds the mean accuracy was found to be 76.2% (median 77.8%, SD 18.2, IQR 69.4 - 87.1%). Mean sensitivity was 81% (median 80%, SD 21.1, IQR 75 - 100%) and mean specificity was 72.7% (median 75%, SD 20.4, IQR 66.7 - 80%). The 1000BRAINS 50-network-parcellation, using full correlations, performed best over the inner folds. The top features predominantly included sensorimotor as well as sensory networks., Conclusion: A rs-fMRI whole-brain-connectivity, data-driven, model-based approach to discriminate PD patients from healthy controls shows a very good accuracy and a high sensitivity. Given the high sensitivity of the approach, it may be of use in a screening setting., Advances in Knowledge: Resting-state functional MRI could prove to be a valuable, non-invasive neuroimaging biomarker for neurodegenerative diseases. The current model-based, data-driven approach on whole-brain between-network connectivity to discriminate Parkinson's disease patients from healthy controls shows promising results with a very good accuracy and a very high sensitivity.

Background: Multiple system atrophy is a rare neurodegenerative disease characterised by aggregation of α-synuclein in oligodendrocytes and neurons. The polyphenol epigallocatechin gallate inhibits α-synuclein aggregation and reduces associated toxicity. We aimed to establish if epigallocatechin gallate could safely slow disease progression in patients with multiple system atrophy., Methods: We did a randomised, double-blind, parallel group, placebo-controlled clinical trial at 12 specialist centres in Germany. Eligible participants were older than 30 years; met consensus criteria for possible or probable multiple system atrophy and could ambulate independently (ie, were at Hoehn and Yahr stages 1-3); and were on stable anti-Parkinson's, anti-dysautonomia, anti-dementia, and anti-depressant regimens (if necessary) for at least 1 month. Participants were randomly assigned (1:1) to epigallocatechin gallate or placebo (mannitol) via a web-generated permuted blockwise randomisation list (block size=2) that was stratified by disease subtype (parkinsonism-predominant disease vs cerebellar-ataxia-predominant disease). All participants and study personnel were masked to treatment assignment. Participants were given one hard gelatin capsule (containing either 400 mg epigallocatechin gallate or mannitol) orally once daily for 4 weeks, then one capsule twice daily for 4 weeks, and then one capsule three times daily for 40 weeks. After 48 weeks, all patients underwent a 4-week wash-out period. The primary endpoint was change in motor examination score of the Unified Multiple System Atrophy Rating Scale (UMSARS) from baseline to 52 weeks. Efficacy analyses were done in all people who received at least one dose of study medication. Safety was analysed in all people who received at least one dose of the study medication to which they had been randomly assigned. This trial is registered with ClinicalTrials.gov (NCT02008721) and EudraCT (2012-000928-18), and is completed., Findings: Between April 23, 2014, and Sept 3, 2015, 127 participants were screened and 92 were randomly assigned-47 to epigallocatechin gallate and 45 to placebo. Of these, 67 completed treatment and 64 completed the study (altough one of these patients had a major protocol violation). There was no evidence of a difference in the mean change from baseline to week 52 in motor examination scores on UMSARS between the epigallocatechin gallate (5·66 [SE 1·01]) and placebo (6·60 [0·99]) groups (mean difference -0·94 [SE 1·41; 95% CI -3·71 to 1·83]; p=0·51). Four patients in the epigallocatechin gallate group and two in the placebo group died. Two patients in the epigallocatechin gallate group had to stop treatment because of hepatotoxicity., Interpretation: 48 weeks of epigallocatechin gallate treatment did not modify disease progression in patients with multiple system atrophy. Epigallocatechin gallate was overall well tolerated but was associated with hepatotoxic effects in some patients, and thus doses of more than 1200 mg should not be used., Funding: ParkinsonFonds Deutschland, German Parkinson Society, German Neurology Foundation, Lüneburg Foundation, Bischof Dr Karl Golser Foundation, and Dr Arthur Arnstein Foundation., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Beta oscillations within motor-cortical areas have been linked to sensorimotor function. In line with this, pathologically altered beta activity in cortico-basal ganglia pathways has been suggested to contribute to the pathophysiology of Parkinson's disease (PD), a neurodegenerative disorder primarily characterized by motor impairment. Although its precise function is still discussed, beta activity might subserve an anticipatory role in preparation of future actions. By reanalyzing previously published data, we aimed at investigating the role of pre-stimulus motor-cortical beta power modulation in motor sequence learning and its alteration in PD. 20 PD patients and 20 healthy controls (HC) performed a serial reaction time task (SRTT) in which reaction time gain presumably reflects the ability to anticipate subsequent sequence items. Randomly varying patterns served as control trials. Neuromagnetic activity was recorded using magnetoencephalography (MEG) and data was reanalyzed with respect to task stimuli onset. Assuming that pre-stimulus beta power modulation is functionally related to motor sequence learning, reaction time gain due to training on the SRTT should vary depending on the amount of beta power suppression prior to stimulus onset. We hypothesized to find less pre-stimulus beta power suppression in PD patients as compared to HC associated with reduced motor sequence learning in patients. Behavioral analyses revealed that PD patients exhibited smaller reaction time gain in sequence relative to random control trials than HC indicating reduced learning in PD. This finding was indeed paralleled by reduced pre-stimulus beta power suppression in PD patients. Further strengthening its functional relevance, the amount of pre-stimulus beta power suppression during sequence training significantly predicted subsequent reaction time advantage in sequence relative to random trials in patients. In conclusion, the present data provide first evidence for the contribution of pre-stimulus motor-cortical beta power suppression to motor sequence learning and support the hypothesis that beta oscillations may subserve an anticipatory, predictive function, possibly compromised in PD., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Akinesia, a cardinal symptom of Parkinson's disease, has been linked to abnormal activation in putamen and posterior medial frontal cortex (pMFC). However, little is known whether clinical severity of akinesia is linked to dysfunctional connectivity of these regions. Using a seed-based approach, we here investigated resting-state functional connectivity (RSFC) of putamen, pMFC and primary motor cortex (M1) in 60 patients with Parkinson's disease on regular medication and 72 healthy controls. We found that in patients putamen featured decreases of connectivity for a number of cortical and subcortical areas engaged in sensorimotor and cognitive processing. In contrast, the pMFC showed reduced connectivity with a more focal cortical network involved in higher-level motor-cognition. Finally, M1 featured a selective disruption of connectivity in a network specifically connected with M1. Correlating clinical impairment with connectivity changes revealed a relationship between akinesia and reduced RSFC between pMFC and left intraparietal lobule (IPL). Together, the present study demonstrated RSFC decreases in networks for motor initiation and execution in Parkinson's disease. Moreover, results suggest a relationship between pMFC-IPL decoupling and the manifestation of akinetic symptoms.

Introduction: Growing evidence suggests that pallidal deep brain stimulation represents a potential new therapeutic avenue in tardive dystonia/dyskinesia, but controlled and blinded randomized studies (RCT) are missing. The present RCT compares dystonia/dyskinesia severity of pallidal neurostimulation in patients with tardive dystonia using a delayed-start design paradigm., Methods: Dystonia/dyskinesia severity was assessed via blinded videos following pallidal neurostimulation at 3 (blinded phase) and 6 months (open extension phase). Primary endpoint was the percentage change of dystonia severity (Burke-Fahn-Marsden-Dystonia-Rating-Scale, BFMDRS) at 3 months between active vs. sham neurostimulation using blinded-video assessment. Secondary endpoints comprised clinical rating scores for movement disorders. Clinicaltrials.gov NCT00331669., Results: Twenty-five patients were randomized (1:1) to active (n = 12) or sham neurostimulation (n = 13). In the intention-to-treat analyses the between group difference of dystonia severity (BFMDRS) between active vs. sham stimulation was not significant at 3 months. Three months post-randomisation dystonia severity improved significantly within the neurostimulation by 22.8% and non-significantly within the sham group (12.0%) compared to their respective baseline severity. During the open-label extension with both groups being actively treated, significant and pronounced improvements of 41.5% were observed via blinded evaluation. Adverse events (n = 10) occurred in 10/25 of patients during the 6 months, mostly related to surgical implantation of the device; all resolved without sequelae., Conclusion: The primary endpoint of this randomized trial was not significant, most likely due to incomplete recruitment. However, pronounced improvements of most secondary endpoints at 3 and 6 months provide evidence for efficacy and safety of pallidal neurostimulation in tardive dystonia., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Motor sequence learning plays a pivotal role in various everyday activities. Motor-cortical beta oscillations have been suggested to be involved in this type of learning. In Parkinson's disease (PD), oscillatory activity within cortico-basal-ganglia circuits is altered. Pathologically increased beta oscillations have received particular attention as they may be associated with motor symptoms such as akinesia. In the present magnetoencephalography (MEG) study, we investigated PD patients and healthy controls (HC) during implicit motor sequence learning with the aim to shed light on the relation between changes of cortical brain oscillations and motor learning in PD with a particular focus on beta power. To this end, 20 PD patients (ON medication) and 20 age- and sex-matched HC were trained on a serial reaction time task while neuromagnetic activity was recorded using a 306-channel whole-head MEG system. PD patients showed reduced motor sequence acquisition and were more susceptible to interference by random trials after training on the task as compared to HC. Behavioral differences were paralleled by changes at the neurophysiological level. Diminished sequence acquisition was paralleled by less training-related beta power suppression in motor-cortical areas in PD patients as compared to HC. In addition, PD patients exhibited reduced training-related theta activity in motor-cortical areas paralleling susceptibility to interference. The results support the hypothesis that the acquisition of a new motor sequence relies on suppression of motor-cortical beta oscillations, while motor-cortical theta activity might be related to stabilization of the learned sequence as indicated by reduced susceptibility to interference. Both processes appear to be impaired in PD.

Phasic dopamine (DA) signals conveyed from the substantia nigra to the striatum and the prefrontal cortex crucially affect learning from feedback, with DA bursts facilitating learning from positive feedback and DA dips facilitating learning from negative feedback. Consequently, diminished nigro-striatal dopamine levels as in unmedicated patients suffering from Parkinson's Disease (PD) have been shown to lead to a negative learning bias. Recent studies suggested a diminished striatal contribution to feedback processing when the outcome of an action is temporally delayed. This study investigated whether the bias towards negative feedback learning induced by a lack of DA in PD patients OFF medication is modulated by feedback delay. To this end, PD patients OFF medication and healthy controls completed a probabilistic selection task, in which feedback was given immediately (after 800 ms) or delayed (after 6800 ms). PD patients were impaired in immediate but not delayed feedback learning. However, differences in the preference for positive/negative learning between patients and controls were seen for both learning from immediate and delayed feedback, with evidence of stronger negative learning in patients than controls. A Bayesian analysis of the data supports the conclusion that feedback timing did not affect the learning bias in the patients. These results hint at reduced, but still relevant nigro-striatal contribution to feedback learning, when feedback is delayed., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Previous whole-brain functional connectivity studies achieved successful classifications of patients and healthy controls but only offered limited specificity as to affected brain systems. Here, we examined whether the connectivity patterns of functional systems affected in schizophrenia (SCZ), Parkinson's disease (PD), or normal aging equally translate into high classification accuracies for these conditions. We compared classification performance between pre-defined networks for each group and, for any given network, between groups. Separate support vector machine classifications of 86 SCZ patients, 80 PD patients, and 95 older adults relative to their matched healthy/young controls, respectively, were performed on functional connectivity in 12 task-based, meta-analytically defined networks using 25 replications of a nested 10-fold cross-validation scheme. Classification performance of the various networks clearly differed between conditions, as those networks that best classified one disease were usually non-informative for the other. For SCZ, but not PD, emotion-processing, empathy, and cognitive action control networks distinguished patients most accurately from controls. For PD, but not SCZ, networks subserving autobiographical or semantic memory, motor execution, and theory-of-mind cognition yielded the best classifications. In contrast, young-old classification was excellent based on all networks and outperformed both clinical classifications. Our pattern-classification approach captured associations between clinical and developmental conditions and functional network integrity with a higher level of specificity than did previous whole-brain analyses. Taken together, our results support resting-state connectivity as a marker of functional dysregulation in specific networks known to be affected by SCZ and PD, while suggesting that aging affects network integrity in a more global way. Hum Brain Mapp 38:5845-5858, 2017. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

Introduction: Pallidal deep brain stimulation (GPi-DBS) is an effective therapy for isolated dystonia, but 10-20% of patients show improvement below 25-30%. We here investigated causes of insufficient response to GPi-DBS in isolated dystonia in a cross-sectional study., Methods: Patients with isolated dystonia at time of surgery, and <30% improvement on the Burke-Fahn-Marsden dystonia-rating-scale (BFMDRS) after ≥6 months of continuous GPi-DBS were videotaped ON and OFF stimulation, and history, preoperative videos, brain MRI, medical records, stimulation settings, stimulation system integrity, lead location, and genetic information were obtained and reviewed by an expert panel., Results: 22 patients from 11 centres were included (8 men, 14 women; 9 generalized, 9 segmental, 3 focal, 1 bibrachial dystonia; mean (range): age 48.7 (25-72) years, disease duration 22.0 (2-40) years, DBS duration 45.5 (6-131) months). Mean BFMDRS-score was 31.7 (4-93) preoperatively and 32.3 (5-101) postoperatively. Half of the patients (n = 11) had poor lead positioning alone or in combination with other problems (combined with: other disease n = 6, functional dystonia n = 1, other problems n = 2). Other problems were disease other than isolated inherited or idiopathic dystonia (n = 5), fixed deformities (n = 2), functional dystonia (n = 3), and other causes (n = 1). Excluding patients with poor lead location from further analysis, non-isolated dystonia accounted for 45.5%, functional dystonia for 27.3%, and fixed deformities for 18.2%. In patients with true isolated dystonia, lead location was the most frequent problem., Conclusion: After exclusion of lead placement and stimulation programming issues, non-isolated dystonia, functional dystonia and fixed deformities account for the majority of GPi-DBS failures in dystonia., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Patients suffering from Parkinson's disease (PD) often show impairments in executive function (EF) like decision-making and action control. The right dorsolateral prefrontal cortex (dlPFC) has been strongly implicated in EF in healthy subjects and has repeatedly been reported to show alterations related to EF impairment in PD. Recently, two key regions for cognitive action control have been identified within the right dlPFC by co-activation based parcellation. While the posterior region is engaged in rather basal EF like stimulus integration and working memory, the anterior region has a more abstract, supervisory function. To investigate whether these functionally distinct subdivisions of right dlPFC are differentially affected in PD, we analyzed resting-state functional connectivity (FC) in 39 PD patients and 44 age- and gender-matched healthy controls. Patients were examined both after at least 12 h withdrawal of dopaminergic drugs (OFF) and under their regular dopaminergic medication (ON). We found that only the posterior right dlPFC subdivision shows FC alterations in PD, while the anterior part remains unaffected. PD-related decreased FC with posterior right dlPFC was found in the bilateral medial posterior parietal cortex (mPPC) and left dorsal premotor region (PMd) in the OFF state. In the medical ON, FC with left PMd normalized, while decoupling with bilateral mPPC remained. Furthermore, we observed increased FC between posterior right dlPFC and the bilateral dorsomedial prefrontal cortex (dmPFC) in PD in the ON state. Our findings point to differential disturbances of right dlPFC connectivity in PD, which relate to its hierarchical organization of EF processing by stronger affecting the functionally basal posterior aspect than the hierarchically higher anterior part.

Background: Several morphometric magnetic resonance imaging parameters may serve for differential diagnosis of parkinsonism. The objective of this study was to identify which performs best in clinical routine., Methods: We acquired multicentric magnetization-prepared rapid gradient echo sequences in patients with Parkinson's disease (n=204), progressive supranuclear palsy (n=106), multiple system atrophy-cerebellar, (n = 21); multiple system atrophy-parkinsonian (n = 60), and healthy controls (n = 73), performed manual planimetric measurements, and calculated receiver operator characteristics with leave-one-out cross-validation to propose cutoff values., Results: The midsagittal midbrain area was reduced in PSP versus all other groups (P < 0.001). The midsagittal pons area was reduced in MSA-cerebellar, MSA-parkinsonian, and PSP versus PD patients and healthy controls (P < 0.001). The midbrain/pons area ratio was lower in PSP (P < 0.001) and higher in MSA-cerebellar and MSA-parkinsonian versus PD and PSP (P < 0.001)., Conclusions: The midsagittal midbrain area most reliably identified PSP, the midsagittal pons area MSA-cerebellar. The midbrain/pons area ratio differentiated MSA-cerebellar and PSP better than the magnetic resonance-Parkinson index. © 2017 International Parkinson and Movement Disorder Society., (© 2017 International Parkinson and Movement Disorder Society.)

Background: The introduction of deep brain stimulation (DBS) about 25 years ago provided one of the major breakthroughs in the treatment of Parkinson's disease (PD). However, a high percentage of patients are reluctant to undergo DBS. Previous research revealed that the critical step on the patient's path to DBS is the decision whether to undergo further diagnostic assessment for surgery at a specialized DBS-center. The aims of the current study were to evaluate how effective the combination of an outpatient DBS screening tool, STIMULUS, with specially developed educational material was to enhance patient education on DBS and to identify motivational aspects which influenced the patients' willingness to undergo further assessment., Methods: In total, 264 patients were identified as appropriate candidates for DBS by general neurologists using the electronic preselection tool STIMULUS. Patient-centered information material was designed and handed out to support education on DBS. Further, several clinical characteristics and details of the patient counseling were documented. Refusal or consent to show up at a DBS center was registered over the following 16 months., Results: 114 (43.2%) patients preselected as eligible for DBS (STIMULUS Score ≥ 6) agreed to show up at a specialized DBS center to undergo further diagnostic assessment. The patients' ages, PD classification as an akinetic-rigid type and the talks' topics side-effects of dopaminergic medication and the optimal time frame had a significant influence on the patients' decisions., Conclusions: The combination of preselection tools as STIMULUS with comprehensive information material is effective to increase DBS-acceptance rate in PD patients. Important topics of the information about DBS cover the optimal time frame for DBS surgery, the side-effects of dopaminergic medication as well as side-effects and complications of DBS surgery.

Interacting with other individuals in a social world requires fast and accurate perception of other individuals' identity, actions, or intentions. Humans are very efficient in these social tasks, as they can extract social information even if the actor is represented only by a handful of point-lights on an otherwise invisible body. Theories have argued that efficient visual perception of actions is based on intact motor system functioning. The motor system provides visuo-motor action representations shaped by the observer's own movements or motor repertoire. If the observer's motor repertoire is impaired, this should lead to impaired visuo-motor representations and ultimately to impaired visual perception of movements. Here we tested this hypothesis in a behavioral study with patients suffering from Parkinson's disease (PD). PD patients are typically impaired in movement execution. We tested these patients and a matched control group in a visual discrimination task on human movement perception. The results showed that PD patients were significantly impaired in the perception of human movements. This impairment was most prominent for transitive (object-related) movements. The results indicate that impaired movement execution critically influences movement perception. The results support the hypothesis that the motor system plays a causal role for the visual perception of human movements., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) provides an effective treatment for Parkinson's disease (PD) motor symptoms. However, findings of effects on cognitive function such as feedback learning remain controversial and rare. The aim of the present study was to gain a better understanding of cognitive alterations associated with STN-DBS. Therefore, we investigated effects of STN-DBS on active and observational feedback learning in PD. 18 PD patients with STN-DBS and 18 matched healthy controls completed active and observational feedback learning tasks. Patients were investigated ON and OFF STN-DBS. Tasks consisted of learning (with feedback) and test phases (without feedback). STN-DBS improved active learning during feedback trials and PD patients ON (but not OFF) STN-DBS showed comparable performance patterns as healthy controls. No STN-DBS effect was found when assessing performance during active test trials without feedback. In this case, however, STN-DBS effects were found to depend on symptom severity. While more impaired patients benefited from STN-DBS, stimulation had no facilitating effect on patients with less severe symptoms. Along similar lines, the severity of motor symptoms tended to be significantly correlated with differences in active test performance due to STN-DBS. For observational feedback learning, there was a tendency for a positive STN-DBS effect with patients reaching the performance level of healthy controls only ON STN-DBS. The present data suggest that STN-DBS facilitates active feedback learning in PD patients. Furthermore, they provide first evidence that STN-DBS might not only affect learning from own but also from observed actions and outcomes., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: Clinical differentiation of parkinsonian syndromes is still challenging., Objectives: A fully automated method for quantitative MRI analysis using atlas-based volumetry combined with support vector machine classification was evaluated for differentiation of parkinsonian syndromes in a multicenter study., Methods: Atlas-based volumetry was performed on MRI data of healthy controls (n = 73) and patients with PD (204), PSP with Richardson's syndrome phenotype (106), MSA of the cerebellar type (21), and MSA of the Parkinsonian type (60), acquired on different scanners. Volumetric results were used as input for support vector machine classification of single subjects with leave-one-out cross-validation., Results: The largest atrophy compared to controls was found for PSP with Richardson's syndrome phenotype patients in midbrain (-15%), midsagittal midbrain tegmentum plane (-20%), and superior cerebellar peduncles (-13%), for MSA of the cerebellar type in pons (-33%), cerebellum (-23%), and middle cerebellar peduncles (-36%), and for MSA of the parkinsonian type in the putamen (-23%). The majority of binary support vector machine classifications between the groups resulted in balanced accuracies of >80%. With MSA of the cerebellar and parkinsonian type combined in one group, support vector machine classification of PD, PSP and MSA achieved sensitivities of 79% to 87% and specificities of 87% to 96%. Extraction of weighting factors confirmed that midbrain, basal ganglia, and cerebellar peduncles had the largest relevance for classification., Conclusions: Brain volumetry combined with support vector machine classification allowed for reliable automated differentiation of parkinsonian syndromes on single-patient level even for MRI acquired on different scanners. © 2016 International Parkinson and Movement Disorder Society., (© 2016 International Parkinson and Movement Disorder Society.)

Patients with advanced Parkinson's disease and motor complications undergoing optimized oral therapy can significantly benefit from continuous intrajejunal levodopa/carbidopa infusion applied by means of a medication pump. However, this requires a correctly positioned PEG-J tube and finely adjusted pump settings. Although this method is a routine procedure in specialist centers, no standard procedure has been defined up to now. For this reason, an expert recommendation regarding the practical application has been developed in order to standardize the procedure and facilitate patient access to this treatment option., (© Georg Thieme Verlag KG Stuttgart · New York.)

Although implicit motor sequence learning is rather well understood in young adults, effects of aging on this kind of learning are controversial. There is first evidence that working memory (WM) might play a role in implicit motor sequence learning in young adults as well as in adults above the age of 65. However, the knowledge about the development of these processes across the adult life span is rather limited. As the average age of our population continues to rise, a better understanding of age-related changes in motor sequence learning and potentially mediating cognitive processes takes on increasing significance. Therefore, we investigated aging effects on implicit motor sequence learning and WM. Sixty adults (18-71 years) completed verbal and visuospatial n-back tasks and were trained on a serial reaction time task (SRTT). Randomly varying trials served as control condition. To further assess consolidation indicated by off-line improvement and reduced susceptibility to interference, reaction times (RTs) were determined 1 h after initial learning. Young and older but not middle-aged adults showed motor sequence learning. Nine out of 20 older adults (compared to one young/one middle-aged) exhibited some evidence of sequence awareness. After 1 h, young and middle-aged adults showed off-line improvement. However, RT facilitation was not specific to sequence trials. Importantly, susceptibility to interference was reduced in young and older adults indicating the occurrence of consolidation. Although WM performance declined in older participants when load was high, it was not significantly related to sequence learning. The data reveal a decline in motor sequence learning in middle-aged but not in older adults. The use of explicit learning strategies in older adults might account for the latter result.

Studies on classification learning suggested that altered dopamine function in Parkinson's Disease (PD) specifically affects learning from feedback. In patients OFF medication, enhanced learning from negative feedback has been described. This learning bias was not seen in observational learning from feedback, indicating different neural mechanisms for this type of learning. The present study aimed to compare the acquisition of stimulus-response-outcome associations in PD patients OFF medication and healthy control subjects in active and observational learning. 16 PD patients OFF medication and 16 controls were examined with three parallel learning tasks each, two feedback-based (active and observational) and one non-feedback-based paired associates task. No acquisition deficit was seen in the patients for any of the tasks. More detailed analyses on the learning strategies did, however, reveal that the patients showed more lose-shift responses during active feedback learning than controls, and that lose-shift and win-stay responses more strongly determined performance accuracy in patients than controls. For observational feedback learning, the performance of both groups correlated similarly with the performance in non-feedback-based paired associates learning and with the accuracy of observed performance. Also, patients and controls showed comparable evidence of feedback processing in observational learning. In active feedback learning, PD patients use alternative learning strategies than healthy controls. Analyses on observational learning did not yield differences between patients and controls, adding to recent evidence of a differential role of the human striatum in active and observational learning from feedback., (Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.)

A typical feature of Parkinson's disease (PD) is pathological activity in the subthalamic nucleus (STN). Here, we tested whether in patients with PD under dopaminergic treatment functional connectivity of the STN differs from healthy controls (HC) and whether some brain regions show (anti-) correlations between functional connectivity with STN and motor symptoms. We used functional magnetic resonance imaging to investigate whole-brain resting-state functional connectivity with STN in 54 patients with PD and 55 HC matched for age, gender, and within-scanner motion. Compared to HC, we found attenuated negative STN-coupling with Crus I of the right cerebellum and with right ventromedial prefrontal regions in patients with PD. Furthermore, we observed enhanced negative STN-coupling with bilateral intraparietal sulcus/superior parietal cortex, right sensorimotor, right premotor, and left visual cortex compared to HC. Finally, we found a decline in positive STN-coupling with the left insula related to severity of motor symptoms and a decline of inter-hemispheric functional connectivity between left and right STN with progression of PD-related motor symptoms. Motor symptom related uncoupling of the insula, a key region in the saliency network and for executive function, from the STN might be associated with well-known executive dysfunction in PD. Moreover, uncoupling between insula and STN might also induce an insufficient setting of thresholds for the discrimination between relevant and irrelevant salient environmental stimuli, explaining observations of disturbed response control in PD. In sum, motor symptoms in PD are associated with a reduced coupling between STN and a key region for executive function., (© 2015 Wiley Periodicals, Inc.)

Background: Inhibitory oscillatory mechanisms subserving tic compensation have been put forward in Tourette syndrome. Modulation of the beta rhythm (15-25 Hz) as the well-established oscillatory movement execution-inhibition indicator was tested during a cognitive-motor task in patients with Tourette syndrome., Methods: Performing a Go/NoGo task, 12 patients with Tourette syndrome and 12 matched controls were recorded using whole-head magnetoencephalography., Results: Compared to healthy participants, patients showed less beta suppression in the sensorimotor area and enhanced beta power in parieto-occipital brain regions contralaterally to the response hand. Average beta power and power gain correlated negatively with tic severity., Conclusions: Increased motor inhibitory as well as visuomotor attentional processes are likely to subserve tic compensation. Correlational results suggest that stronger inhibitory compensation accompanies less tic severity., (© 2016 International Parkinson and Movement Disorder Society.)

Objective: To evaluate the striatal presynaptic dopamine transporter (FP-CIT-SPECT) and postsynaptic D2 receptor (IBZM-SPECT) binding in patients with corticobasal syndrome (CBS)., Background: FP-CIT and IBZM are commercially available and approved SPECT tracers for in vivo molecular imaging of pre- and postsynaptic nigrostriatal neuronal degeneration, but only few data for CBS are available., Methods: 23 patients meeting clinical criteria for early- to mid-stage CBS (disease duration ≤4 years) were examined with SPECT radiotracers FP-CIT and IBZM. All suspected CBS patients underwent a clinical follow-up examination and were re-evaluated after 19.7 ± 15.2 months (mean ± SD). Postmortem diagnosis was available for 2 patients. In patients who met research criteria for probable CBS at the final follow-up visit (n = 19; disease duration: 1.95 ± 0.91 years), SPECT binding values were compared to those of age- and gender-matched Parkinson's disease (PD) patients (n = 18, disease duration: 1.92 ± 0.91 years; clinical follow-up: 32 ± 29.6 months) and neurologically normal control subjects (n = 19)., Results: In comparison to the healthy control subjects, both patient groups showed significant and asymmetric reduction of the striatal presynaptic dopamine transporter binding, but PD patients had significantly lower FP-CIT binding ratios than probable-CBS patients. FP-CIT binding values of probable-CBS patients and healthy controls demonstrated marked overlaps, and in 7 patients (39%) scans revealed no dopaminergic deficit. IBZM uptake did not show significant between-group differences., Conclusion: Our data indicate that in the early- to mid-stage CBS the degree of nigrostriatal impairment is only mild with a significant proportion of preserved dopamine transporter binding., (© 2016 S. Karger AG, Basel.)

Background: This study was conducted to better understand the development of clinical efficacy and impedance levels in the long-term course of deep brain stimulation (DBS) of the subthalamic nucleus (STN) in Parkinson's disease (PD)., Methods: In this retrospective study of twenty PD patients, the motor part of the Unified Parkinson's Disease Rating Scale was periodically assessed i) after withdrawal of medication and inactivated stimulation, ii) after withdrawal of medication with activated stimulation and iii) after challenge with l-Dopa during activated stimulation up to 13 years after surgery., Results: STN-DBS with or without medication significantly improved motor function up to 13 years after surgery. The contribution of axial symptoms increased over time. While the stimulation parameters were kept constant, the therapeutic impedances progressively declined., Conclusion: STN-DBS in PD remains effective in the long-term course of the disease. Constant current stimulation might be preferable over voltage-controlled stimulation, as it would alleviate the impact of impedance changes on the volume of tissue activated., (Copyright © 2015 Elsevier Ltd. All rights reserved.)