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Six α-synuclein (aSyn) point mutations are currently known to be associated with familial parkinsonism: A30P, E46K, H50Q, G51D, A53E, and A53T. We performed a comprehensive in vitro analysis to study the impact of all aSyn mutations on lipid binding and aggregation behavior. Markedly reduced lipid binding of A30P, moderately attenuated binding of G51D, and only very slightly reduced binding for the other mutants were observed. A30P was particularly prone to form metal ion induced oligomers, whereas A53T exhibited only weak tendencies to form oligomers. In turn, fibril formation occurred rapidly in H50Q, G51D, and A53T, but only slowly in A30P, suggesting mutants prone to form oligomers tend to form fibrils to a lesser extent. This was supported by the observation that fibril formation of wild type aSyn, A30P, and A53T was impaired in the presence of ferric iron. Additionally, we found the aggregation kinetics of mixtures of A30P or A53T and wt aSyn to be determined by the faster aggregating aSyn variant. Our results implicate differential mechanisms playing a role in aSyn pathology on the molecular level. This might contribute to a better understanding of Parkinson's disease pathogenesis and provide potential links to develop prevention strategies and disease-modifying therapy.

Introduction: TCS is a well-established technique for diagnosis of Parkinson's disease (PD). Volumetric 3D-TCS is a promising complementary approach for objective acquisition and analysis, in particular for less experienced sonographers. This study provides baselines for Parkinson detection (sensitivity and specificity), cutoff values and inter-rater agreement in 3D-TCS., Methods: We performed 3D-TCS in 52 subjects (healthy controls and PD) bilaterally, and reconstructed in 3D space uni-laterally. Ipsi-lateral hyperechogenicities in the substantia nigra are manually segmented slice-by-slice in the 3D volume by two raters at different experience levels. ROC threshold analysis is performed and compared on features representing 3D volume and axial cross-sections (2.5D) of hyperechogenicities. Pearson correlation and intra-class correlation coefficients were evaluated for assessment of inter-rater agreement., Results: 50 subjects were included. Both raters achieved high classification accuracy with 2.5D/3D features extracted from 3D-TCS volumes (best results sensitivity/specificity/cut-off per rater: 84.6%/88.9%/25.0mm 2 ; 77.8%/88.9%/95.9mm 3 ). The inter-rater agreement in 3D was high (ICC(A,1) = 0.777, p < 10 -3 ), the classification performance of both sonographers was statistically not significantly different., Conclusion: The study presents first baseline values for uni-lateral 3D-TCS examination, and finds no disadvantage of uni-lateral reconstructions compared to previous bi-lateral fusion. Volumetric 3D-TCS has potential for a high inter-rater agreement and accuracy in detection of PD, in particular for sonographers with less experience., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The applause sign, i.e., the inability to execute the same amount of claps as performed by the examiner, was originally reported as a sign specific for progressive supranuclear palsy (PSP). Recent research, however, has provided evidence for the occurrence of the applause sign in various conditions. The aim of this study was to determine the prevalence of the applause sign and correlate its presence with neuropsychological and MRI volumetry findings in frontotemporal lobar degeneration and related conditions. The applause sign was elicited with the three clap test (TCT), with a higher score indicating poorer performance. Data were recorded from 272 patients from the cohort of the German consortium for frontotemporal lobar degeneration (FTLDc): 111 with behavioral variant frontotemporal dementia (bvFTD), 98 with primary progressive aphasia (PPA), 30 with progressive supranuclear palsy Richardson's syndrome, 17 with corticobasal syndrome (CBS) and 16 with amyotrophic lateral sclerosis with frontotemporal dementia (ALS/FTD). For comparison, 29 healthy elderly control subjects (HC) were enrolled in the study. All subjects underwent detailed language and neuropsychological assessment. In a subset of 156 subjects, atlas-based volumetry was performed. The applause sign occurred in all patient groups (40% in PSP, 29.5% in CBS, 25% in ALS/FTD, 13.3% in PPA and 9.0% in bvFTD) but not in healthy controls. The prevalence was highest in PSP patients. It was significantly more common in PSP as compared to bvFTD, PPA and HC. The comparison between the other groups failed to show a significant difference regarding the occurrence of the applause sign. The applause sign was highly correlated to a number of neuropsychological findings, especially to measures of executive, visuospatial, and language function as well as measures of disease severity. TCT scores showed an inverse correlation with the volume of the ventral diencephalon and the pallidum. Furthermore the volume of the ventral diencephalon and pallidum were significantly smaller in patients displaying the applause sign. Our study confirms the occurrence of the applause sign in bvFTD, PSP and CBS and adds PPA and ALS/FTD to these conditions. Although still suggestive of PSP, clinically it must be interpreted with caution. From the correlation with various cognitive measures we suggest the applause sign to be indicative of disease severity. Furthermore we suggest that the applause sign represents dysfunction of the pallidum and the subthalamic nucleus, structures which are known to play important roles in response inhibition.

Background: F-18-fluordeoxyglucose positron emission tomography (FDG-PET) is widely used for discriminative diagnosis of tau-positive atypical parkinsonian syndromes (T+APS). This approach now stands to be augmented with more specific tau tracers. Therefore, we retrospectively analyzed a large clinical routine dataset of FDG-PET images for evaluation of the strengths and limitations of stand-alone FDG-PET. Methods: A total of 117 patients (age 68.4 ± 11.1 y) underwent an FDG-PET exam. Patients were followed clinically for a minimum of one year and their final clinical diagnosis was recorded. FDG-PET was rated visually (positive/negative) and categorized as high, moderate or low likelihood of T+APS and other neurodegenerative disorders. We then calculated positive and negative predictive values (PPV/NPV) of FDG-PET readings for the different subgroups relative to their final clinical diagnosis. Results: Suspected diagnoses were confirmed by clinical follow-up (≥1 y) for 62 out of 117 (53%) patients. PPV was excellent when FDG-PET indicated a high likelihood of T+APS in combination with low to moderate likelihood of another neurodegenerative disorder. PPV was distinctly lower when FDG-PET indicated only a moderate likelihood of T+APS or when there was deemed equal likelihood of other neurodegenerative disorder. NPV of FDG-PET with a low likelihood for T+APS was high. Conclusions: FDG-PET has high value in clinical routine evaluation of suspected T+APS, gaining satisfactory differential diagnosis in two thirds of the patients. One third of patients would potentially profit from further evaluation by more specific radioligands, with FDG-PET serving gatekeeper function for the more expensive methods.

Objectives: We aimed to assess whether postural abnormalities in Progressive Supranuclear Palsy (PSP) and Idiopathic Parkinson's Disease (IPD) are qualitatively different by analysing spontaneous and reactive postural control., Methods: We assessed postural control upon platform tilts in 17 PSP, 11 IPD patients and 18 healthy control subjects using a systems analysis approach., Results: Spontaneous sway abnormalities in PSP resembled those of IPD patients. Spontaneous sway was smaller, slower and contained lower frequencies in both PSP and IPD as compared to healthy subjects. The amount of angular body excursions as a function of platform angular excursions (GAIN) in PSP was qualitatively different from both IPD and healthy subjects (GAIN cut-off value: 2.9, sensitivity of 94%, specificity of 72%). This effect was pronounced at the upper body level and at low as well as high frequencies. In contrast, IPD patients' stimulus-related body excursions were smaller compared to healthy subjects. Using a systems analysis approach, we were able to allocate these different postural strategies to differences in the use of sensory information as well as to different error correction efforts., Conclusions: While both PSP and IPD patients show abnormal postural control, the underlying pathology seems to be different., Significance: The identification of disease-specific postural abnormalities shown here may be helpful for diagnostic as well as therapeutic discriminations of PSP vs. IPD., (Copyright © 2018 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Local field potentials (LFP) of the subthalamic nucleus (STN) recorded during walking may provide clues for determining the function of the STN during gait and also, may be used as biomarker to steer adaptive brain stimulation devices. Here, we present LFP recordings from an implanted sensing neurostimulator (Medtronic Activa PC + S) during walking and rest with and without stimulation in 10 patients with Parkinson's disease and electrodes placed bilaterally in the STN. We also present recordings from two of these patients recorded with externalized leads. We analyzed changes in overall frequency power, bilateral connectivity, high beta frequency oscillatory characteristics and gait-cycle related oscillatory activity. We report that deep brain stimulation improves gait parameters. High beta frequency power (20-30 Hz) and bilateral oscillatory connectivity are reduced during gait, while the attenuation of high beta power is absent during stimulation. Oscillatory characteristics are affected in a similar way. We describe a reduction in overall high beta burst amplitude and burst lifetimes during gait as compared to rest off stimulation. Investigating gait cycle related oscillatory dynamics, we found that alpha, beta and gamma frequency power is modulated in time during gait, locked to the gait cycle. We argue that these changes are related to movement induced artifacts and that these issues have important implications for similar research.

Inhibitory control is an important executive function that is necessary to suppress premature actions and to block interference from irrelevant stimuli. Current experimental studies and models highlight proactive and reactive mechanisms and claim several cortical and subcortical structures to be involved in response inhibition. However, the involved structures, network mechanisms and the behavioral relevance of the underlying neural activity remain debated. We report cortical EEG and invasive subthalamic local field potential recordings from a fully implanted sensing neurostimulator in Parkinson's patients during a stimulus- and response conflict task with and without deep brain stimulation (DBS). DBS made reaction times faster overall while leaving the effects of conflict intact: this lack of any effect on conflict may have been inherent to our task encouraging a high level of proactive inhibition. Drift diffusion modelling hints that DBS influences decision thresholds and drift rates are modulated by stimulus conflict. Both cortical EEG and subthalamic (STN) LFP oscillations reflected reaction times (RT). With these results, we provide a different interpretation of previously conflict-related oscillations in the STN and suggest that the STN implements a general task-specific decision threshold. The timecourse and topography of subthalamic-cortical oscillatory connectivity suggest the involvement of motor, frontal midline and posterior regions in a larger network with complementary functionality, oscillatory mechanisms and structures. While beta oscillations are functionally associated with motor cortical-subthalamic connectivity, low frequency oscillations reveal a subthalamic-frontal-posterior network. With our results, we suggest that proactive as well as reactive mechanisms and structures are involved in implementing a task-related dynamic inhibitory signal. We propose that motor and executive control networks with complementary oscillatory mechanisms are tonically active, react to stimuli and release inhibition at the response when uncertainty is resolved and return to their default state afterwards., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Measuring human gait is important in medicine to obtain outcome parameter for therapy, for instance in Parkinson's disease. Recently, small inertial sensors became available which allow for the registration of limb-position outside of the limited space of gait laboratories. The computation of gait parameters based on such recordings has been the subject of many scientific papers. We want to add to this knowledge by presenting a 4-segment leg model which is based on inverse kinematic and Kalman filtering of data from inertial sensors. To evaluate the model, data from four leg segments (shanks and thighs) were recorded synchronously with accelerometers and gyroscopes and a 3D motion capture system while subjects (n = 12) walked at three different velocities on a treadmill. Angular position of leg segments was computed from accelerometers and gyroscopes by Kalman filtering and compared to data from the motion capture system. The four-segment leg model takes the stance foot as a pivotal point and computes the position of the remaining segments as a kinematic chain (inverse kinematics). Second, we evaluated the contribution of pelvic movements to the model and evaluated a five segment model (shanks, thighs and pelvis) against ground-truth data from the motion capture system and the path of the treadmill., Results: We found the precision of the Kalman filtered angular position is in the range of 2-6° (RMS error). The 4-segment leg model computed stride length and length of gait path with a constant undershoot of 3% for slow and 7% for fast gait. The integration of a 5th segment (pelvis) into the model increased its precision. The advantages of this model and ideas for further improvements are discussed., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Progressive supranuclear palsy (PSP) and late-stage idiopathic Parkinson's disease (IPD) are neurodegenerative movement disorders resulting in different postural instability and falling symptoms. IPD falls occur usually forward in late stage, whereas PSP falls happen in early stages, mostly backward, unprovoked, and with high morbidity. Self-triggered, weighted movements appear to provoke falls in IPD, but not in PSP. Repeated self-triggered lifting of a 0.5-1-kg weight (<2% of body weight) with the dominant hand was performed in 17 PSP, 15 IPD with falling history, and 16 controls on a posturography platform. PSP showed excessive force scaling of weight and body motion with high-frequency multiaxial body sway, whereas IPD presented a delayed-onset forward body displacement. Differences in center of mass displacement apparent at very small weights indicate that both syndromes decompensate postural control already within stability limits. PSP may be subject to specific postural system devolution. IPD are susceptible to delayed forward falling. Differential physiotherapy strategies are suggested.

Progressive supranuclear palsy (PSP) is a neurodegenerative movement disorder characterized by deposition of fibrillar aggregates of 4R tau-protein in neurons and glial cells of the brain. These deposits are a key neuropathological finding, allowing a diagnosis of "definite PSP," which is usually established post mortem. To date criteria for clinical diagnosis of PSP in vivo do not include biomarkers of tau pathology. For intervention trials, it is increasingly important to (i) establish biomarkers for an early diagnosis and (ii) to develop biomarkers that correlate with disease progression of PSP. [ 18 F]-THK5351 is a novel PET-ligand that may afford in vivo visualization and quantification of tau-related alterations. We investigated binding characteristics of [ 18 F]-THK5351 in patients with clinically diagnosed PSP and correlate tracer uptake with clinical findings. Eleven patients (68.4 ± 7.4 year; N = 6 female) with probable PSP according to current clinical criteria and nine healthy controls (71.7 ± 7.2 year; N = 4 female) underwent [ 18 F]-THK5351 PET scanning. Voxel-wise statistical parametric comparison and volume-of-interest based quantification of standardized-uptake-values (SUV) were conducted using the cerebellar cortex as reference region. We correlated disease severity as measured with the help of the PSP Rating Scale (PSPRS) as well as several other clinical parameters with the individual PET findings. By voxel-wise mapping of [ 18 F]-THK5351 uptake in the patient group we delineated typical distribution patterns that fit to known tau topology for PSP post mortem. Quantitative analysis indicated the strongest discrimination between PSP patients and healthy controls based on tracer uptake in the midbrain (+35%; p = 3.01E-7; Cohen's d: 4.0), followed by the globus pallidus, frontal cortex, and medulla oblongata. Midbrain [ 18 F]-THK5351 uptake correlated well with clinical severity as measured by PSPRS ( R = 0.66; p = 0.026). OCT and MRI delineated PSP patients from healthy controls by use of established discrimination thresholds but only OCT did as well correlate with clinical severity ( R = 0.79; p = 0.024). Regional [ 18 F]-THK5351 binding patterns correlated well with the established post mortem distribution of lesions in PSP and with clinical severity. The contribution of possible MAO-B binding to the [ 18 F]-THK5351 signal needs to be further evaluated, but nevertheless [ 18 F]-THK5351 PET may still serve as valuable biomarker for diagnosis of PSP.

Progressive supranuclear palsy (PSP) and late-stage idiopathic Parkinson's disease (IPD) are neurodegenerative movement disorders resulting in different postural instability and falling symptoms. IPD falls occur usually forward in late stage, whereas PSP falls happen in early stages, mostly backward, unprovoked, and with high morbidity. Postural responses to sensory anteroposterior tilt illusion by bilateral dorsal neck vibration were probed in both groups versus healthy controls on a static recording posture platform. Three distinct anteroposterior body mass excursion peaks (P1-P3) were observed. 18 IPD subjects exhibited well-known excessive response amplitudes, whereas 21 PSP subjects' responses remained unaltered to 22 control subjects. Neither IPD nor PSP showed response latency deficits, despite brainstem degeneration especially in PSP. The observed response patterns suggest that PSP brainstem pathology might spare the involved proprioceptive pathways and implies viability of neck vibration for possible biofeedback and augmentation therapy in PSP postural instability.

Introduction: Human multimodal vestibular cortical regions are bilaterally anterior insulae and posterior opercula, where characteristic vestibular-related cortical potentials were previously reported under acoustic otolith stimulation. Galvanic vestibular stimulation likely influences semicircular canals preferentially. Galvanic stimulation was compared to previously established data under acoustic stimulation., Methods: 14 healthy right-handed subjects, who were also included in the previous acoustic potential study, showed normal acoustic and galvanic vestibular-evoked myogenic potentials. They received 2,000 galvanic binaural bipolar stimuli for each side during EEG recording., Results: Vestibular cortical potentials were found in all 14 subjects and in the pooled data of all subjects ("grand average") bilaterally. Anterior insula and posterior operculum were activated exclusively under galvanic stimulation at 25, 35, 50, and 80 ms; frontal regions at 30 and 45 ms. Potentials at 70 ms in frontal regions and at 110 ms at all of the involved regions could also be recorded; these events were also found using acoustic stimulation in our previous study., Conclusion: Galvanic semicircular canal stimulation evokes specific potentials in addition to those also found with acoustic otolith stimulation in identically located regions of the vestibular cortex. Vestibular cortical regions activate differently by galvanic and acoustic input at the peripheral sensory level., Significance: Differential effects in vestibular cortical-evoked potentials may see clinical use in specific vertigo disorders.

Objective: Turning and limitations to step length were shown to trigger progressive shortening of steps, which can lead to freezing of gait. By reducing the base area in which the turn had to take place, we aimed to evaluate the contribution of spatial constraints on 360° axial turns in people with Parkinson's disease with and without freezing., Methods: We evaluated 40 patients with and without freezing and 16 age-matched healthy subjects. We assessed clinical data, and used body-worn inertial sensors to describe stepping and turn duration of 360° in quadratic squares of different sizes marked on the floor., Results: We found that, when subjects had to perform turns in smaller as compared to larger squares, this spatial constraint strongly affected the turning behavior, i.e. increased the number of steps, and the duration of turns. However, turning was significantly more impaired in patients as compared to controls, and patients with freezing were significantly worse as patients without freezing., Conclusion: Our data show that spatial constraint during axial turning has the potential to deteriorate stepping performance, especially in patients reporting freezing of gait., Significance: The size of the base area needs to be defined in any item or scale that makes diagnostic use of turning., (Copyright © 2017 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Short involuntary paroxysmal movements or behavioral patterns are an important differential diagnosis to epileptic seizures, especially when occurring for the first time. Typically, these attacks are not witnessed by medically trained personnel and the patient anamnesis or observations by a third party are often not specific enough to differentiate between epileptic seizures and the differential diagnoses. This review presents the epidemiology, the clinical presentation, the necessary diagnostic steps and the differential diagnostic approach to parasomnias and dyskinesias. The focus is on the clinical aspects, and therapeutic principles are also briefly described.

Measures of performance rates in speech-like or volitional nonspeech oral motor tasks are frequently used to draw inferences about articulation rate abnormalities in patients with neurologic movement disorders. The study objective was to investigate the structural relationship between rate measures of speech and of oral motor behaviors different from speech. A total of 130 patients with neurologic movement disorders and 130 healthy subjects participated in the study. Rate data was collected for oral reading (speech), rapid syllable repetition (speech-like), and rapid single articulator movements (nonspeech). The authors used factor analysis to determine whether the different rate variables reflect the same or distinct constructs. The behavioral data were most appropriately captured by a measurement model in which the different task types loaded onto separate latent variables. The data on oral motor performance rates show that speech tasks and oral motor tasks such as rapid syllable repetition or repetitive single articulator movements measure separate traits.

Purpose: The aim of this study is to evaluate the MR imaging behavior of ferrous (Fe 2+ ) and ferric (Fe 3+ ) iron ions in order to develop a noninvasive technique to quantitatively differentiate between both forms of iron., Methods: MRI was performed at 3 T in a phantom consisting of 21 samples with different concentrations of ferrous and ferric chloride solutions (between 0 and 10 mmol/L). A multi-echo spoiled gradient-echo pulse sequence with eight echoes was used for both T 2 * and quantitative susceptibility measurements. The transverse relaxation rate, R 2 * = 1/T 2 *, was determined by nonlinear exponential fitting based on the mean signals in each sample. The susceptibilities, χ, of the samples were calculated after phase unwrapping and background field removal by fitting the spatial convolution of a unit dipole response to the measured internal field map. Relaxation rate changes, ΔR 2 *(c Fe ), and susceptibility changes, Δχ(c Fe ), their linear slopes, as well as the ratios ΔR 2 *(c Fe ) / Δχ(c Fe ) were determined for all concentrations., Results: The linear slopes of the relaxation rate were (12.5 ± 0.4) s -1 /(mmol/L) for Fe 3+ and (0.77 ± 0.09) s -1 /(mmol/L) for Fe 2+ (significantly different, z test P < 0.0001). The linear slopes of the susceptibility were (0.088 ± 0.003) ppm/(mmol/L) for Fe 3+ and (0.079 ± 0.006) ppm/(mmol/L) for Fe 2+ . The individual ratios ΔR 2 */Δχ were greater than 40 s -1 /ppm for all samples with ferric solution and lower than 20 s -1 /ppm for all but one of the samples with ferrous solution., Conclusion: Ferrous and ferric iron ions show significantly different relaxation behaviors in MRI but similar susceptibility patterns. These properties can be used to differentiate ferrous and ferric samples.

An early and differential diagnosis of parkinsonian syndromes still remains a challenge mainly due to the similarity of their symptoms during the onset of the disease. Recently, 18 F-Desmethoxyfallypride (DMFP) has been suggested to increase the diagnostic precision as it is an effective radioligand that allows us to analyze post-synaptic dopamine D 2/3 receptors. Nevertheless, the analysis of these data is still poorly covered and its use limited. In order to address this challenge, this paper shows a novel model to automatically distinguish idiopathic parkinsonism from non-idiopathic variants using DMFP data. The proposed method is based on a multiple kernel support vector machine and uses the linear version of this classifier to identify some regions of interest: the olfactory bulb, thalamus, and supplementary motor area. We evaluated the proposed model for both, the binary separation of idiopathic and non-idiopathic parkinsonism and the multigroup separation of parkinsonian variants. These systems achieved accuracy rates higher than 70%, outperforming DaTSCAN neuroimages for this purpose. In addition, a system that combined DaTSCAN and DMFP data was assessed.

Background and Purpose: The corticobasal syndrome (CBS) is a clinical diagnosis that comprises a group of rare neurodegenerative diseases manifesting in movement disorder and cognitive impairment. While diagnosis is based upon clinical criteria, there have been a number of molecular imaging studies, albeit in rather small cohorts. Therefore, we investigated the pattern of cerebral glucose metabolism, as well as dopamine transporter (DAT) availability in a large and clinically well-defined cohort., Methods: Thirty-four patients fulfilling either the Armstrong or the Boeve criteria were assessed with [ 18 F]-2-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) and/or [ 123 I]-Ioflupane single-photon-emission-computed tomography (SPECT) for DAT availability. A small subset of patients had also undergone D 2/3 receptor imaging. Imaging data were analyzed using both statistical parametric mapping and a volume-of-interest-based approach relative to data from healthy controls., Results: Significant reductions of the cortical glucose metabolism were observed in the central region and the adjacent frontal and parietal association areas contralateral to the side with predominant motor symptoms. Reductions were also evident in the basal ganglia, notably in the putamen contralateral to the clinically affected side, and in the bilateral thalamus. DAT availability was reduced bilaterally, most distinctly on the side contralateral to the main motor symptoms., Conclusions: We replicated and refined earlier findings of impaired glucose metabolism and nigrostriatal degeneration in CBS, highlighting asymmetric cortical and subcortical hypometabolism, symmetrically reduced metabolism in the thalamus, and only a slightly asymmetric reduction in DAT, while D 2/3 receptors seem to be mainly preserved. These results provide systematic evidence for the usefulness of FDG PET and dopaminergic SPECT imaging to characterize CBS., (Copyright © 2016 by the American Society of Neuroimaging.)

Background: Deep Brain Stimulation (DBS) of the Globus pallidus internus (GPi) is gold standard treatment in medically refractory dystonia. Recent evidence indicates that stimulation effects are also due to axonal modulation and affection of a fibre network. For the GPi, the pallidothalamic tracts are known to be the major motor efferent pathways. The aim of this study is to explore the anatomic vicinity of these tracts and DBS electrodes in dystonia applying diffusion tractography., Methods: Diffusion MRI was acquired in ten patients presenting for DBS for dystonia. We applied both a conventionally used probabilistic tractography algorithm (FSL) as well as a probabilistic streamline tracking approach, based on constrained spherical deconvolution and particle filtering with anatomic priors, to the datasets. DBS electrodes were coregistered to the diffusion datasets., Results: We were able to delineate the pallidothalamic tracts in all patients. Using the streamline approach, we were able to distinguish between the two sub-components of the tracts, the ansa lenticularis and the fasciculus lenticularis. Clinically efficient DBS electrodes displayed a close anatomic vicinity pathway of the pallidothalamic tracts, and their course was consistent with previous tracer labelling studies. Although we present only anatomic data, we interpret these findings as evidence of the possible involvement of fibre tracts to the clinical effect in DBS. Electrophysiological intraoperative recordings would be needed to complement our findings. In the future, a clear and individual delineation of the pallidothalamic tracts could optimize the stereotactic process of optimal electrode localization. Hum Brain Mapp 38:1224-1232, 2017. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Background: Dystonia is a movement disorder with patterned, directional, and often sustained muscle contractions that produce abnormal postures or repetitive movements. Deep brain stimulation (DBS) of the globus pallidus internus (GPi) is an effective and safe treatment for medically refractory dystonia. However, recent studies reported gait problems, gait freezing and falls in patients treated with DBS. Because these symptoms may point to deficient gait initiation processes, we systematically assessed the anticipatory postural adjustments (APAs) prior to stepping in dystonia patients with GPi-DBS., Methods: Thirteen patients with focal/segmental dystonia under GPi-DBS and twelve healthy control subjects were included in the study. Data were collected using pressure sensitive sensors and APAs were studied by centre of pressure measures. We compared APAs of both groups and analysed the influence of GPi-DBS on APAs in patients., Results: Medio-lateral and antero-posterior COP displacements, total COP path, maximal APA velocity and 1st step length were all smaller in patients for both ON (p=0.006, p=0.018, p=0.002, p=0.016, p=0.04) and OFF (p=0.001, p=0.01, p=0.001, p=0.03, p=0.024) condition compared to healthy subjects. GPi-DBS did not change APA parameters in patients., Conclusions: Observations that APAs are impaired in dystonia and are at the same time not affected by the stimulation current are compatible with the assumption that APAs and dystonic symptoms may rely on distinct networks, possibly within the same cortical and basal ganglia structures. With no effect of stimulation on APAs it is unlikely that this would be a mechanism of impaired balance in the patients after the surgery., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: The GPi (globus pallidus internus) is an important target nucleus for Deep Brain Stimulation (DBS) in medically refractory movement disorders, in particular dystonia and Parkinson's disease. Beneficial clinical outcome critically depends on precise electrode localization. Recent evidence indicates that not only neurons, but also axonal fibre tracts contribute to promoting the clinical effect. Thus, stereotactic planning should, in the future, also take the individual course of fibre tracts into account., Objective: The aim of this project is to explore the GPi connectivity profile and provide a connectivity-based parcellation of the GPi., Methods: Diffusion MRI sequences were performed in sixteen healthy, right-handed subjects. Connectivity-based parcellation of the GPi was performed applying two independent methods: 1) a hypothesis-driven, seed-to-target approach based on anatomic priors set as connectivity targets and 2) a purely data-driven approach based on k-means clustering of the GPi., Results: Applying the hypothesis-driven approach, we obtained five major parcellation clusters, displaying connectivity to the prefrontal cortex, the brainstem, the GPe (globus pallidus externus), the putamen and the thalamus. Parcellation clusters obtained by both methods were similar in their connectivity profile. With the data-driven approach, we obtained three major parcellation clusters. Inter-individual variability was comparable with results obtained in thalamic parcellation., Conclusion: The three parcellation clusters obtained by the purely data-driven method might reflect GPi subdivision into a sensorimotor, associative and limbic portion. Clinical and physiological studies indicate greatest clinical DBS benefit for electrodes placed in the postero-ventro-lateral GPi, the region displaying connectivity to the thalamus in our study and generally attributed to the sensorimotor system. Clinical studies relating DBS electrode positions to our GPi connectivity map would be needed to complement our findings., (Copyright © 2016 Elsevier Inc. All rights reserved.)

In bipedal gait, the initiation of the first step is preceded by a complex sequence of movements which shift the centre of mass of the body towards the stance foot to allow for a step of the swing foot. These anticipatory postural adjustments (APAs) have been investigated in order to elucidate movement strategies in healthy and diseased persons. We studied the influence of several external parameters (age, type of step initiation) on APAs and investigated whether Parkinsonian patients may have different APAs. As a result, we found that externally elicited steps were preceded by faster and larger APAs than self-timed steps. Parkinsonian patients without the freezing of gait (FOG) phenomenon showed overall slightly reduced APAs but did not clearly differ from patients with FOG. Multiple APAs were seen in up to 25 % of the steps of the patients and in a much lower percentage of the steps of control subjects. The results indicate that APAs are significantly influenced by the timing of a step, i.e. are larger in externally elicited steps. The patients showed an overall preserved APA pattern but slowed movements and amplitude, indicating that increased bradykinesia due to progressive illness is a plausible explanation for these findings. The freezing phenomenon is not explained by a general absence or massive reduction in APA measures.

Objective: To evaluate the effects of visual cues combined with treadmill training on gait performance in patients with Parkinson's disease and to compare the strategy with pure treadmill training., Design: Pilot, exploratory, non-blinded, randomized controlled trial., Setting: University Hospital of Munich, Germany., Subjects: Twenty-three outpatients with Parkinson's disease (Hoehn and Yahr stage II-IV)., Interventions: Patients received 12 training sessions within five weeks of either visual cues combined with treadmill training (n = 12) or pure treadmill training (n = 11)., Main Measures: Outcome measures were gait speed, stride length and cadence recorded on the treadmill. Functional tests included the Timed Up and Go Test, the Unified Parkinson's Disease Rating Scale and the Freezing of gait-questionnaire. Assessments were conducted at baseline, after the training period and at two months follow-up., Results: After the training period (n = 20), gait speed and stride length had increased in both groups (p ⩽ 0.05). Patients receiving the combined training scored better in the Timed Up and Go Test compared with the patients receiving pure treadmill training (p ⩽ 0.05). At two months follow-up (n = 13), patients who underwent the combined training sustained better results in gait speed and stride length (p ⩽ 0.05) and sustained the improvement in the Timed Up and Go Test (p ⩽ 0.05)., Conclusions: This pilot study suggests that visual cues combined with treadmill training have more beneficial effects on gait than pure treadmill training in patients with a moderate stage of Parkinson's disease. A large-scale study with longer follow-up is required., (© The Author(s) 2015.)

Formation of toxic α-synuclein oligomers appears to be a key underlying pathological mechanism of synucleinopathies such as Parkinson's disease or multiple system atrophy (MSA). Given that Epigallocatechin-gallate has been shown to inhibit α-synuclein aggregation, it might represent a causal treatment option. Therefore, we set out to evaluate the safety, tolerability and a potential disease-modifying effect of Epigallocatechin-gallate in patients with MSA after 48 weeks of treatment. Power calculation was performed on existing natural history data on the progression of the Unified MSA Rating Scale as primary readout parameter. To assess the efficacy of Epigallocatechin-gallate versus placebo regarding the reduction of disease progression measured during the study period (80 % power, 5 % p level, 50 % effect size) 36 patients per group are needed. Considering a drop-out rate of 20 % a total of 86 patients will be recruited in this multicentre study. These data provide a solid rationale to investigate whether supplementation of Epigallocatechin-gallate can delay the progression of the MSA-related disability.

Lightweight inertial sensors are increasingly used for recording of gait in medicine, rehabilitation and sport. Several distinct events during the gait cycle such as heel-strike or toe-off have to be detected in the data obtained from these sensors. We re-investigated the correlation between the data of shank-mounted gyroscopes and three reference systems, namely accelerometers, pressure-sensitive soles and a motion capture system in a group of 14 young healthy men. We confirmed that the heel strike corresponds to a trough in the gyroscope curve, as several previous reports have stated. However, the toe-off moment clearly did not coincide with another trough of the gyroscope trace, as had been assumed in the past. The heel-off moment was reliably at 51% of the step cycle, irrespective of gait velocity, in our data. These findings are crucial for gait recording systems which aim to assess the temporal as well as spatial descriptors of human gait., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Focal dystonia in professional musicians is a movement disorder that manifests itself during playing. It is a multifactorial condition in which a genetic predisposition and exogenous factors both play a role. Evidence suggests that intensive playing is a risk factor for the development of task-specific dystonia in professional musicians., Methods: This review is based on pertinent publications (1950-2013) retrieved by a systematic search in medical and musicological databases. The references of the retrieved publications were also considered in the search., Results: 16 articles with clinical information on a total of 1144 affected musicians were reviewed systematically. Their overall quality was intermediate to poor, and a meta-analysis was therefore not possible. The Bradford Hill criteria were applied to study a possible causative link between intensive playing and musician's dystonia. Musician's dystonia generally arises after at least ten years of intensive playing (corresponding to roughly 10 000 hours of practice). An association was found between the affected limb and the type of instrument: the limb that is subject to the greatest fine motor demands is the one most commonly affected. The average age of onset is 28 to 44 years., Conclusion: The Bradford Hill causality criteria indicate that intensive playing is related to the development of musician's dystonia. In particular, the association of the type of instrument with the site of dystonia supports this thesis. The findings imply that task-specific dystonia in professional musicians should be included in the list of occupational diseases in Germany.

Objective: Deep brain stimulation of the globus pallidus internus (GPi-DBS) is an efficient and safe treatment for medically refractory dystonia. However, recent studies reported gait problems, falls and bradykinesia in patients after the DBS procedure. The aim of this study was to quantify the effect of GPi-DBS on postural performance in patients with cranio-cervical dystonia., Methods: Thirteen patients with focal/segmental dystonia and GPi-DBS participated in the study. We performed two postural tests (pull test and push and release test) in on- and off-stimulation conditions and recorded the movements of the patients with inertial sensors., Results: Under stimulation patients exhibited a higher number of steps (p=0.015), reduced first step length (p=0.011) and lower stepping velocity (p=0.001), compared to off stimulation. We observed a higher number of steps in the push and release test compared to the pull test (p=0.038). The interaction between stimulation condition and test type was significant (p=0.027)., Conclusions: The velocity and amplitude of postural reactions are compromised by GPi-DBS in patients with cranio-cervical dystonia., Significance: This information corresponds to patient's reports of falls and postural instability after GPi-DBS. Pre-operatively, patients should be informed about the possibility of the occurrence of such phenomena., (Copyright © 2015. Published by Elsevier Ireland Ltd.)

Corticobasal syndrome is defined clinically on the basis of symptoms and findings related to dysfunction of the cerebral cortex and the basal ganglia. Usually, marked asymmetry of motor findings is observed. Although aphasia has now been recognized as a frequent feature of corticobasal syndrome, it remains unclear whether it is usually associated with right-sided motor symptoms, pointing to the involvement of the left hemisphere. Hence, we set out to examine the relationship between the presence of language symptoms and the side affected by extrapyramidal symptoms. We analyzed the electronic care records of patients seen in the years 2003-2013 in the Neurology Department of the University Hospital of Munich. The diagnosis of corticobasal syndrome was discussed in ninety-two individuals. Of those, 38 cases fulfilled diagnostic criteria for corticobasal syndrome. Aphasia correlated highly with a predominant right-sided movement disorder (p = 0.002). In contrast, it was less common in patients with left-sided motor presentation. Dysarthria did not show a preferential correlation (p = 0.25). Our analysis suggests a characteristic presentation of corticobasal syndrome in which motor dysfunction of the right side of the body is associated with aphasia.

Background: It has been suggested that dynamical measures such as sample entropy may be more appropriate than conventional measures when analyzing time series data such as postural sway. We evaluated conventional and dynamical measures of postural sway in Parkinson disease (PD) patients with and without freezing episodes., Methods: COP (center of pressure) data were recorded during quiet standing with eyes open, eyes closed and while performing a dual task. Data for 16 patients with freezing of gait, 17 patients with no history of freezing and 24 healthy subjects were analyzed. The amount of postural sway was quantified using conventional measures, whereas for the characterization of the temporal structure of the COP data the normalized sway path and sample entropy was calculated., Results: Mean radius was higher and sample entropy was lower in patients with freezing symptoms as compared to healthy subjects in all three conditions. Dual-tasking significantly increased sway path length in patients with freezing, while normalized sway path did not change over conditions in this group., Conclusions: Our findings show that postural sway is characterized by a combination of large radius, short normalized sway path and high regularity of the COP only in patients with freezing. This pattern becomes most prominent in a dual-task paradigm. This may explain higher occurrence of gait freezing in dual task situations with subsequent higher risk of falls. Results suggested that dynamic measures may add valuable information for characterizing postural stability in PD patients., (Copyright © 2015. Published by Elsevier B.V.)

Introduction: Deep brain stimulation (DBS) is widely used to improve quality of life in movement disorders (MD) and psychiatric diseases. Even though the ability to have children has a big impact on patients' life, only a few studies describe the role of DBS in pregnancy., Objective: To describe risks and management of women treated by DBS for disabling MD or psychiatric diseases during pregnancy and delivery., Methods: We report a retrospective case series of women, followed in two DBS centers, who became pregnant and went on to give birth to a child while suffering from disabling MD or psychiatric diseases [Parkinson's disease, dystonia, Tourette's syndrome (TS), Obsessive Compulsive Disorder (OCD)] treated by DBS. Clinical status, complications and management before, during, and after pregnancy are reported. Two illustrative cases are described in greater detail., Results: DBS improved motor and behavioral disorders in all patients and allowed reduction in, or even total interruption of disease-specific medication during pregnancy. With the exception of the spontaneous early abortion of one fetus in a twin pregnancy, all pregnancies were uneventful in terms of obstetric and pediatric management. DBS parameters were adjusted in five patients in order to limit clinical worsening during pregnancy. Implanted material limited breast-feeding in one patient because of local pain at submammal stimulator site and led to local discomfort related to stretching of the cable with increasing belly size in another patient whose stimulator was implanted in the abdominal wall., Conclusion: Not only is it safe for young women with MD, TS and OCD who have a DBS-System implanted to become pregnant and give birth to a baby but DBS seems to be the key to becoming pregnant, having children, and thus greatly improves quality of life.

Background: Globus pallidus internus deep brain stimulation (GPi-DBS) can be an effective treatment for primary dystonia. However, speech disorders have previously been reported as a common possible side effect of the treatment., Objectives: To study possible deterioration of speech after GPi-DBS and describe this in different dimensions., Methods: Speech was systematically evaluated in 15 patients with predominant torticollis and GPi-DBS. Each patient was tested twice within one day in two stimulation conditions: ON-DBS vs. OFF-DBS. Speech analyses comprised both function-oriented (perceptual scales, acoustic analyses) and communication-related measures (intelligibility, naturalness). A control sample of 15 healthy speakers underwent the same speech assessment., Results: On the group level, patients with dystonia showed mild but significant impairment on the overall dysarthria scale, the intelligibility score, and the naturalness ratings in both stimulation conditions (Mann-Whitney, P < .05). No stimulation-induced deterioration was found. A slight increase in articulation rate was measured in the ON condition. On the single-case level, effects of GPi-DBS on speech were heterogenous. In one patient we observed a deterioration of speech (dysarthria), in a second patient with a history of childhood stuttering we found an aggravation of dysfluency. Impressive benefits could be documented in another patient who also suffered from spasmodic dysphonia., Conclusions: The study provides evidence that speech impairment is not a necessary side-effect of GPi-DBS in primary dystonia. Both, recurring of stuttering and a worsening of dysarthria may be seen in individual patients. The positive effects of GPi-DBS on the symptoms of spasmodic dysphonia merits further research as DBS is not commonly applied in this population., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose: Intra-operative image guidance during deep brain stimulation (DBS) surgery is usually avoided due to cost and overhead of intra-operative MRI and CT acquisitions. Recently, there has been interest in the community towards the usage of non-invasive transcranial ultrasound (TCUS) through the preauricular bone window. In this work, we investigate, for the first time, the feasibility of using 3D-TCUS for imaging of already implanted DBS electrodes. As a first step towards this goal, we report imaging methods and electrode localisation errors outside of the operating room on eight previously operated DBS patients., Methods: We evaluate the feasibility of using 3D-TCUS by registering volumes to pre-operative T1-MRI. US-MRI registration is achieved through a two-step point-based approach. First, a rough surface scan of the subjects' skin surface in 3D-TCUS space is registered to a segmented skin-surface point cloud from MRI. Next, we perform a refinement using rigid registration of multiple pairs of manually marked anatomical landmarks. We validate against post-operative CT scans which are also registered to pre-operative MRI., Results: Qualitative results are given in form of 3D reconstruction examples at 2.5 and 3.5 MHz TCUS image frequency, overlaid on pre-operative T1-MRI and post-operative CT. Quantitative evaluation is performed by reporting the accuracy of electrode tip localisation at 2.5 and 3.5 MHz after our US-MRI approach. As a baseline, we also report RMSE errors for pairs of anatomical landmarks in pre-operative MRI and 3D-TCUS., Conclusion: Multiple image examples show the appearance and quality of 3D-TCUS scans, depending on the bone window. Overall accuracy of anatomic point pairs lies on the order of 3.2 mm, using our registration approach. Compared to this baseline, electrode tip localisation in 3D-TCUS has a mean accuracy on the order of 4.8 mm and a precision on the order of 2.3 mm. While insufficient at first glance, we argue why these results are promising nonetheless. Our work motivates further future work in improved TCUS scanning, advanced TCUS-MRI registration and computer-aided electrode detection in 3D-TCUS.

Objective: Loud acoustic stimuli at 500Hz activate the vestibular system. Intermediate-latency vestibular cortical potentials of multimodal cortex regions were investigated, beyond the 20ms time range., Methods: Eighteen healthy subjects with 32-channel EEG and one epilepsy patient with right-sided intracortical electrodes received three types of stimuli: tone bursts capable of evoking vestibular evoked myogenic potentials (VEMP) in neck muscles and sham stimuli matched for either frequency or amplitude, which cannot evoke myogenic responses., Results: VEMP-capable stimuli activated anterior insula and posterior operculum bilaterally at 20, 30, 60 and 110ms, frontal brain regions at 70 and 110ms, determined by Brain Evoked Source Analysis BESA. Recordings from intracranial electrodes revealed corresponding peaks at identical latencies. Stimulus-locked high and low beta and mu band modulations were found in vestibular, parietal and occipital regions, beyond 20ms. Sham stimuli only evoked late acoustic potentials. Corresponding vestibular potentials were also seen in an eight-channel bipolar Laplacian montage., Conclusions: The sequentially appearing cortical potentials evoked by VEMP-capable stimuli co-locate with data from functional imaging studies. Frequency-specific activity (induced potentials) in these areas may reflect multimodal proprioceptive and visual sensory crosstalk., Significance: Vestibular cortical evoked potentials may see clinical use in vertigo disorders., (Copyright © 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

Arm swing asymmetry during gait may be a sensitive sign for early Parkinson's disease. There is only very limited information about how much asymmetry can be considered to be physiological. To assess the normal range of arm swing asymmetry, we investigated 60 healthy subjects. The influence of age, gender, and additional mental tasks (dual-tasking) on arm swing asymmetry was assessed. Limb kinematics of 60 healthy persons in three age groups (between 40 and 75 years) were measured with an ultrasound motion capture system while subjects walked on a treadmill. Treadmill velocity was varied (3 steps) and mental loads (2 different tasks) were applied in different trials. Additionally, a group of 7 patients with early Parkinson's disease was investigated. Arm swing amplitude as well as arm swing asymmetry varied considerably in the healthy subjects. Elderly subjects swung their arms more than younger participants. Only the more demanding mental load caused a significant asymmetry, i.e., arm swing was reduced on the right side. In the patient group, asymmetry was considerably higher and even more enhanced by mental loads. Our data indicate that an asymmetry index above 50 (i.e., one side has twice the amplitude of the other) may be considered abnormal. Evaluation of arm swing asymmetry may be used as part of a test battery for early Parkinson's disease. Such testing may become even more important when disease-modifying drugs become available for Parkinson's disease., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: Deep brain stimulation (DBS) of the globus pallidus internus is an effective treatment for cervical dystonia (CD). Interestingly, the onset of initial DBS effects is significantly prolonged compared with that in other diseases, such as Parkinson's disease. The return of symptoms after cessation of DBS could be delayed as well, but this has not been studied systematically., Methods: In patients who were treated for CD using DBS and had a good treatment effect, we compared interruption of DBS with sham-OFF in a randomized, double-blind crossover trial., Results: We observed that dystonic features appeared within a few minutes at almost full intensity in all patients after the cessation of DBS., Conclusions: The almost immediate onset of dystonic features in our sample seems to exclude mechanisms with long time constants from the pathophysiology of dystonia. Thus, it is likely that, in these patients, an aberrant pattern of neural activity representing an inappropriate set point value for the position of the head is responsible for dystonia., (© 2013 International Parkinson and Movement Disorder Society.)

Background: Essential tremor is the most common type of tremor, with a prevalence of 0.4% in the overall population and 4-7% in persons over age 65. In general, tremor is so common that patients with tremor are frequently treated not only by neurologists, but also by physicians from other specialties., Method: This review is based on publications retrieved by a selective PubMed search and on guidelines from Germany and abroad., Results: Particular tremor syndromes are usually diagnosed on the basis of their typical clinical presentation and whatever accompanying manifestations may be present. Ancillary tests are usually unnecessary. Unilateral rest tremor accompanied by rigidity and bradykinesia is typical of Parkinson's disease. Essential tremor is a bilateral postural tremor. The most common cause of intention tremor is multiple sclerosis. Mild tremor syndromes can often be treated satisfactorily with drugs. In case of severe tremor, which is rarer, a stereotactic operation can be considered. The usual outcome of such procedures is the complete suppression of tremor., Conclusion: Most patients with tremor can be given a precise diagnosis and offered specific treatment. It is important for the physician to inform the patient about the expected course of tremor over time, its possible genetic causes, and the various available treatments.

Deep brain stimulation (DBS) of the internal pallidal segment (GPi: globus pallidus internus) is gold standard treatment for medically intractable dystonia, but detailed knowledge of mechanisms of action is still not available. There is evidence that stimulation of ventral and dorsal GPi produces opposite motor effects. The aim of this study was to analyse connectivity profiles of ventral and dorsal GPi. Probabilistic tractography was initiated from DBS electrode contacts in 8 patients with focal dystonia and connectivity patterns compared. We found a considerable difference in anterior-posterior distribution of fibres along the mesial cortical sensorimotor areas between the ventral and dorsal GPi connectivity. This finding of distinct GPi connectivity profiles further confirms the clinical evidence that the ventral and dorsal GPi belong to different functional and anatomic motor subsystems. Their involvement could play an important role in promoting clinical DBS effects in dystonia., (© 2013 Elsevier Inc. All rights reserved.)

Objectives: Deep brain stimulation (DBS) for Tourette's syndrome (TS) in various targets has been in the focus for some years. However, there are hardly any data on "psychosocial" outcome after DBS for TS. The aim of the present study therefore was to focus on the functional outcome and "psychosocial changes" in TS patients after DBS., Methods: Six patients with treatment-refractory TS underwent GPi-DBS. The Yale Global Tic Severity Scale (YGTSS) was used to evaluate symptomatic outcome. Psychosocial changes were assessed applying the Global Assessment of Functioning Scale (GAF) and the Gilles-de-la-Tourette-Syndrome Quality-of-Life scale (GTS-QOL) with additionally documenting psychosocial changes. Follow-up ranged between 12 and 72 months., Results: In all symptomatic responders (4 of 6) we found a significant functional improvement (mean GAF increasing from 53.75 (± 7.5) pre-operatively to 83.75 (± 7.5) at last follow-up) along with a positive correlation with the course of GTS-QOL (R(2) = 0.62)., Conclusions: Treatment success should not only be assessed with the classic "tic-scales", but also with the GAF and GTS-QOL. Although improvement of tics seems to be positively correlated with improved functional outcome, symptomatic improvement may lead to unexpected major psychosocial changes - which both the patient and the clinicians in charge - should be prepared for.

Local field potentials (LFPs) recorded from deep brain stimulation electrodes implanted in the globus pallidus internus (GPi) of patients with hyperkinetic movement disorders (dystonia and Tourette's syndrome) have shown desynchronized activity at 8-20 Hz and synchronized activity at 30-90 Hz during voluntary movements. However, the impact of the speed of the motor task on these frequency shifts is still unclear. In the current study, we recorded LFPs bilaterally from the GPi in seven patients with hyperkinetic movement disorders during normal/slow and fast horizontal line drawing movements as well as during rest. In comparison with rest, the low beta band showed a significant decrease in power during the motor tasks. Low beta power was more suppressed with increasing speed of the movement on the contralateral side. In contrast, a significant increase in power was induced by movements in the high beta and gamma bands on the contralateral side. When comparing slow and fast movements, the power of the low gamma frequency band was significantly elevated on the contralateral side with fast movements. In conclusion, an increase in movement speed changes the power of GPi oscillations by means of a reduction of the activity in the low beta band and an elevation of activity in the gamma band. The current study yields new insights into the physiological mechanism of GPi during the execution of the motor task at low and high speed., (© 2013 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

In neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD) and prion diseases, deposits of aggregated disease-specific proteins are found. Oligomeric aggregates are presumed to be the key neurotoxic agent. Here we describe the novel oligomer modulator anle138b [3-(1,3-benzodioxol-5-yl)-5-(3-bromophenyl)-1H-pyrazole], an aggregation inhibitor we developed based on a systematic high-throughput screening campaign combined with medicinal chemistry optimization. In vitro, anle138b blocked the formation of pathological aggregates of prion protein (PrP(Sc)) and of α-synuclein (α-syn), which is deposited in PD and other synucleinopathies such as dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). Notably, anle138b strongly inhibited all prion strains tested including BSE-derived and human prions. Anle138b showed structure-dependent binding to pathological aggregates and strongly inhibited formation of pathological oligomers in vitro and in vivo both for prion protein and α-synuclein. Both in mouse models of prion disease and in three different PD mouse models, anle138b strongly inhibited oligomer accumulation, neuronal degeneration, and disease progression in vivo. Anle138b had no detectable toxicity at therapeutic doses and an excellent oral bioavailability and blood-brain-barrier penetration. Our findings indicate that oligomer modulators provide a new approach for disease-modifying therapy in these diseases, for which only symptomatic treatment is available so far. Moreover, our findings suggest that pathological oligomers in neurodegenerative diseases share structural features, although the main protein component is disease-specific, indicating that compounds such as anle138b that modulate oligomer formation by targeting structure-dependent epitopes can have a broad spectrum of activity in the treatment of different protein aggregation diseases.

Background: Parkinsonism with dopa-sensitivity and a correlating DaTSCAN turned out to be due to a D202N mutation which is associated with the Gerstmann-Sträussler-Scheinker (GSS) disease., Methods/results: We report a 51-year old female who presented with left-dominant parkinsonism and a positive DaTSCAN. She was diagnosed with idiopathic Parkinson's syndrome. Dopaminergic medication reduced her symptoms. In addition, punding-like behavior, deficits in organizing daily life and abnormal sleep behavior were reported. Neuropsychological testing, EEG, polysomnography as well as PET imaging with fluorodexyglucose (FDG), [F-18]-desmethoxyfallypride (DMFP), and [C-11]-6-OH-BTA-1 (PIB) were not diagnostic. Cerebral spinal fluid analysis revealed no 14-3-3 protein, but elevated neuron-specific enolase (NSE) and S100-beta and a very low phospho-tau/total-tau ratio. Analysis of the prion gene disclosed the rare D202N mutation., Conclusions: The D202N prion mutation has been associated with GSS pathology and up to now was only reported post mortem. Our patient is the very first case diagnosed in vivo., (Copyright © 2013 Movement Disorder Society.)

In the field of computer aided medical image analysis, it is often difficult to obtain reliable ground truth for evaluating algorithms or supervising statistical learning procedures. In this paper we present a new method for training a classification forest from images labelled by variably performing experts, while simultaneously evaluating the performance of each expert. Our approach builds upon state-of-the-art randomized classification forest techniques for medical image segmentation and recent methods for the fusion of multiple expert decisions. By incorporating the performance evaluation within the training phase, we obtain a novel forest framework for learning from conflicting expert decisions, accounting for both inter- and intra-expert variability. We demonstrate on a synthetic example that our method allows to retrieve the correct segmentation among other incorrectly labelled images, and we present an application to the automatic segmentation of the midbrain in 3D transcranial ultrasound images.

We present a novel approach to transcranial B-mode sonography for Parkinson's disease (PD) diagnosis by using 3-D ultrasound (3-DUS). We reconstructed bilateral 3-DUS volumes of the midbrain and substantia nigra echogenicities (SNE) and report results of a more objective abnormality detection in (PD). For classification, we analyzed volumetric measurements of midbrain and SNE in subjects with PD and healthy controls (HC). After blinded segmentation of these structures in 22/23 subjects (11 PD, 11 HC) and by two observers with varying prior experience in this technique, the classification algorithm yielded up to 91% sensitivity and 64% specificity using the larger volume of both SNE as a single-dimensional features and up to 90.9% sensitivity and 72.7% specificity using a multidimensional feature set with midbrain and both SNE volumes. This pilot study indicates that our TC-3-D-US approach is technically feasible and less dependent on the investigator's experience and good bone windows. Our pilot study yielded a fairly high sensitivity and specificity in differentiating between subjects with PD and HC., (Copyright © 2012 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

Tauopathies such as Alzheimer's disease or progressive supranuclear palsy are characterized by pathological deposits of aggregated protein tau. It has been shown that truncated tau is present in these deposits, and it was thus hypothesized that truncation of the protein may play a role in pathological aggregation processes. Furthermore, recent findings indicate that pro-aggregatory extracellular tau can be taken up by neurons and induce neurodegeneration. In this study, we investigated the effect of limited proteolysis by matrix-metalloproteinases 3 and 9 (MMP-3, MMP-9) as well as by the proteinases trypsine and Proteinase K (PK) on tau aggregation behavior. We applied single molecule fluorescence techniques to monitor early tau oligomer formation at nanomolar protein concentrations. We observed that tau is a substrate of both MMP-3 and MMP-9, and show that limited proteolysis by MMP-9, but not by MMP-3, PK or trypsine, increases tau oligomer formation. We further characterize tau fragments resulting from limited cleavage, demonstrating a distinct cleavage pattern for both MMP-3 and MMP-9. In summary, our data demonstrate that tau is a substrate of both MMP-3 and MMP-9, and show a differential influence of these enzymes on tau aggregation behavior, implicating a potential role in neurodegeneration., (Copyright © 2012 Elsevier Inc. All rights reserved.)