The Effect of Auditory Stimuli on the Quantitative Electroencephalogram in Patients with Parkinson's Disease

Parkinson’s Disease (PD) is the second most common neurodegenerative disorder worldwide with increasing incidence and prevalence. It mainly affects the motor system due to a loss of dopaminergic neurons in the substantia nigra and leads to cardinal symptoms including brady-/akinesia, tremor, muscle stiffness and postural instability. After clinical diagnosis, treatment is primarily based on L- dopa, dopamine agonists and MAO-B inhibitors. Even with therapy, PD continues to progress and remains uncurable. In recent years, music therapy has been established as a complementary therapy due to a variety of positive effects, mainly on the motor system. However, it is still insufficiently explained what exactly renders music therapy so effective. Possible explanations range from an increased dopamine release to a better functional connectivity of different brain areas. The aim of this methodologically innovative study was to find underlying mechanisms for the effectiveness of music therapy based on EEG analysis. The analysis of the EEG was chosen due to its good temporal resolution, fast availability and relatively low costs. The research questions were first, whether it is generally possible to distinguish patients with PD from Healthy Controls (HC) based on their EEG. Second, whether auditory stimuli show an effect on the EEG. Third, which features precisely a differentiation of both groups in the EEG is based on. And fourth, which characteristics render an auditory stimulus effective. The study was conducted in collaboration between the University of British Columbia (UBC) in Vancouver and the Philipps-Universität Marburg. In 2017 and 2018, 12 patients with PD and 4 age- matched HC were tested at the UBC campus. A total of 5 EEGs (conditions) were recorded from each subject at rest and under auditory stimulation. The three stimuli differed in complexity (Rain vs Spring Walk) and modulation (rhythmic and non-rhythmic). For a more precise interpretation of the results, natural sounds were used as stimuli instead of music. Due to the amount of data, a custom-made pattern recognition algorithm (Support Vector Machine) was used, distinguishing both groups through a hyperplane within a high-dimensional feature space. Redundant data was removed in advance by calculating the mutual information quotient to include only relevant data in the final analysis. It could be shown that, first, the differentiation of both groups on the basis of the EEG is generally possible, in this case even with a convincing classification accuracy of up to 90 %. Second, the auditory stimuli mainly had an effect on the EEG samples of HC and made the classification more complex: the EEG samples of the HC approached those of the PD patients within the feature space, rendering a common hyperplane for all conditions ineffective. Based on shared features but with a separate hyperplane in each condition classification accuracy of 80-90 % and thus very good discrimination of both groups could be achieved again even under the influence of auditory stimuli. 68 Third, the by far most important features to distinguish both groups were related to the delta frequency band (0.5-4 Hz) including band power, indices of the delta band, and harmonic parameters. The increased importance of delta in PD matches existing literature, most likely due to cognitive decline. This study enhances existing literature on delta by the harmonic parameters, mainly the center frequency and the spectral value thereof. In addition, the delta frequency band is often linked to relaxation and sleep. Thus, the convergence of the EEG samples is most likely explained by stimulus- induced relaxation. Another important feature seems to be the phase lag index. It is also mentioned in the literature as an indicator of mild cognitive impairment and decreases under the influence of the stimuli. A link between the PLI and functional connectivity, as mentioned in the literature, cannot be shown in this study. Fourth, the convergence of the HC samples towards the PD samples was particularly evident in the rain conditions with misclassifications of up to 80 %. This was the case in both the rhythmic and non- rhythmic variants. Given the importance of rhythm as often shown in literature on music therapy it appears that the intended modulation was not perceived as rhythmic by the subjects. The convergence of samples was less evident in the spring walk condition, where higher frequency bands were relevant too. Auditory stimuli thus seem to need a basic complexity to show an effect on the EEG. Approaches to further research arise. For example, if the delta band is expected to be important, greater epoch lengths than in this study (3 seconds) could be analyzed to avoid false interpretations due to epochs being too short to capture very slow oscillations. In addition, a general slowing of the EEG is probably not specific for PD. For a more specific analysis, the inclusion of participants with mild cognitive impairment (PD-MCI as well as MCI not caused by PD) would be useful. Testing more complex stimuli such as music, an inclusion of motor functions in the analysis or even a measurement of dopamine levels would also remain of interest. Looking at the study design, a more balanced patient population might be beneficial. In order to show an effect of music therapy in the EEG, a convergence of PD samples towards HC samples would have been desirable. Due to the relaxation, the opposite was the case. The chosen methodology, however, seems very appropriate. The classification of both groups was possible on a convincingly high level and recommends this approach for further research, due to its variability beyond neurology and even medicine

Automated Electrophysiology Makes the Pace for Cardiac Ion Channel Safety Screening

The field of automated patch-clamp electrophysiology has emerged from the tension between the pharmaceutical industry’s need for high-throughput compound screening versus its need to be conservative due to regulatory requirements. On the one hand, hERG channel screening was increasingly requested for new chemical entities, as the correlation between blockade of the ion channel coded by hERG and torsades de pointes cardiac arrhythmia gained increasing attention. On the other hand, manual patch-clamping, typically quoted as the “gold-standard” for understanding ion channel function and modulation, was far too slow (and, consequently, too expensive) for keeping pace with the numbers of compounds submitted for hERG channel investigations from pharmaceutical R&D departments. In consequence it became more common for some pharmaceutical companies to outsource safety pharmacological investigations, with a focus on hERG channel interactions. This outsourcing has allowed those pharmaceutical companies to build up operational flexibility and greater independence from internal resources, and allowed them to obtain access to the latest technological developments that emerged in automated patch-clamp electrophysiology – much of which arose in specialized biotech companies. Assays for nearly all major cardiac ion channels are now available by automated patch-clamping using heterologous expression systems, and recently, automated action potential recordings from stem-cell derived cardiomyocytes have been demonstrated. Today, most of the large pharmaceutical companies have acquired automated electrophysiology robots and have established various automated cardiac ion channel safety screening assays on these, in addition to outsourcing parts of their needs for safety screening

Role of the Transient Receptor Potential Canonical 6 ion channel in genetic and acquired forms of proteinuric kidney disease

Podocyte foot processes and the interposed glomerular slit diaphragm are critical components of the permeability barrier in the kidney. Mutations in several podocyte genes have been identified as the cause for progressive kidney failure and focal segmental glomerulosclerosis (FSGS). Podocyte injury is a hallmark of glomerular disease and usually involves the rearrangement of the podocyte actin cytoskeleton. Cell-specific therapies targeting podocyte injury are currently not available. In 2004, a mutation in the TRPC6 ion channel was found to cosegregate with hereditary FSGS. Based on this finding it was hypothesized that TRPC6 is expressed in podocytes, and that TRPC6-mediated Ca2+ signaling contributes to the regulation of the podocyte actin cytoskeleton. According to this model, dysfunction of TRPC6 leads to a disruption of normal cytoskeletal organization, podocyte injury, and proteinuric disease. To test this hypothesis, four specific aims were outlined. First, to explore TRPC6 mutations in genetic FSGS. Second, to investigate its association with the glomerular filtration barrier. Third, to study TRPC6 expression in acquired forms of proteinuric kidney disease. Fourth, to investigate the molecular basis of TRPC6 contribution to the pathophysiology of proteinuric kidney disease In genetic forms of FSGS, additional TRPC6 mutations were identified in five families with a history of FSGS. TRPC6-related FSGS presented as a late-onset disorder in individuals aged 17-57, and was not restricted to certain ethnic groups. All mutations occured in evolutionary conserved sites, and encoded amino acid substitutions at the amino- and carboxy-terminal ends of TRPC6. Two mutants, R895C and E897K, displayed increased current amplitudes, suggesting a pathogenic role of increased channel activity in TRPC6-related FSGS. In an effort to understand the molecular basis for TRPC6 in the kidney, the association of TRPC6 with the glomerular filter was studied. TRPC6 was found to be expressed in podocytes near the glomerular slit diaphragm. TRPC6 colocalized and associated with the slit diaphragm proteins nephrin and podocin. The presence of TRPC6 in podocyte foot processes and its association with slit diaphragm proteins supports a role of TRPC6 in the regulation of glomerular filtration. Since most proteinuric kidney diseases appear not as genetic but acquired disorders, TRPC6 was studied in humans with acquired glomerular diseases and in experimental models thereof. TRPC6 expression was induced in patients with minimal change disease and membranous glomerulopathy, as well as in passive Heymann nephritis (PHN) rats and puromycin aminonucleoside (PAN) rats. PAN-mediated podocyte injury correlated with increased receptor-operated calcium entry in vitro. TRPC6 gene delivery in mice was sufficient to induce proteinuria, and studies in cultured podocytes suggest that TRPC6 overexpression disrupts the actin cytoskeleton. The present data suggest that in both genetic and acquired forms of proteinuric kidney disease, misregulation of TRPC6 – either by presence of mutated hyperactive channels, or by precence of too many wildtype channels – plays a pathogenic role. Together, the results of this work may have broad implications for the pathophysiology of TRPC6-related human kidney diseases, and promote the development of anti-proteinuric drugs interfering with TRPC6 channel function

Bayesian operational modal analysis of closely spaced modes for monitoring wind turbines

In this study, the applicability of Bayesian operational modal analysis (BAYOMA) to an operating onshore concrete-steel hybrid wind turbine tower is investigated. The results of the identification then provide reliable parameters for the structural health monitoring (SHM) of the tower. In the context of wind turbines, typical assumptions of linear time-invariant OMA methods are violated, so the validity of the identification uncertainties of BAYOMA is not necessarily given. In addition, closely spaced modes occur, for which the mode shape in particular is subject to high uncertainty. It can be stated, that the main part of the mode shape uncertainty corresponds to the alignment of these in the mode subspace. Due of these challenges, mode shapes are generally not taken into account when monitoring wind turbine towers. In order to include the mode shape in SHM scheme, the second-order modal assurance criterion (S2MAC) is applied in this study. This metric is able to eliminate the alignment uncertainty by comparing the mode shape with a mode subspace. Besides mode shapes, the reliability of natural frequencies and damping can also be better quantified by knowing the identification uncertainty. This finally enables a well-founded selection of suitable monitoring parameters for the future application of SHM for wind turbines. Preprint submitted to Engineering Structures

DNA methylation analysis of the angiotensin converting enzyme (ACE) gene in major depression.

The angiotensin converting enzyme (ACE) has been repeatedly discussed as susceptibility factor for major depression (MD) and the bi-directional relation between MD and cardiovascular disorders (CVD). In this context, functional polymorphisms of the ACE gene have been linked to depression, to antidepressant treatment response, to ACE serum concentrations, as well as to hypertension, myocardial infarction and CVD risk markers. The mostly investigated ACE Ins/Del polymorphism accounts for ~40%-50% of the ACE serum concentration variance, the remaining half is probably determined by other genetic, environmental or epigenetic factors, but these are poorly understood. The main aim of the present study was the analysis of the DNA methylation pattern in the regulatory region of the ACE gene in peripheral leukocytes of 81 MD patients and 81 healthy controls. We detected intensive DNA methylation within a recently described, functional important region of the ACE gene promoter including hypermethylation in depressed patients (p = 0.008) and a significant inverse correlation between the ACE serum concentration and ACE promoter methylation frequency in the total sample (p = 0.02). Furthermore, a significant inverse correlation between the concentrations of the inflammatory CVD risk markers ICAM-1, E-selectin and P-selectin and the degree of ACE promoter methylation in MD patients could be demonstrated (p = 0.01 - 0.04). The results of the present study suggest that aberrations in ACE promoter DNA methylation may be an underlying cause of MD and probably a common pathogenic factor for the bi-directional relationship between MD and cardiovascular disorders

Surface trap with dc-tunable ion-electrode distance

We describe the design, fabrication, and operation of a novel surface-electrode Paul trap that produces a radio-frequency-null along the axis perpendicular to the trap surface. This arrangement enables control of the vertical trapping potential and consequentially the ion-electrode distance via dc-electrodes only. We demonstrate confinement of single $^{40}$Ca$^+$ ions at heights between $50~\mu$m and $300~\mu$m above planar copper-coated aluminium electrodes. We investigate micromotion in the vertical direction and show cooling of both the planar and vertical motional modes into the ground state. This trap architecture provides a platform for precision electric-field noise detection, trapping of vertical ion strings without excess micromotion, and may have applications for scalable quantum computers with surface ion traps

Assessment of multiresolution segmentation for delimiting drumlins in digital elevation models

Mapping or "delimiting" landforms is one of geomorphology's primary tools. Computer-based techniques such as land-surface segmentation allow the emulation of the process of manual landform delineation. Land-surface segmentation exhaustively subdivides a digital elevation model (DEM) into morphometrically-homogeneous irregularly-shaped regions, called terrain segments. Terrain segments can be created from various land-surface parameters (LSP) at multiple scales, and may therefore potentially correspond to the spatial extents of landforms such as drumlins. However, this depends on the segmentation algorithm, the parameterization, and the LSPs. In the present study we assess the widely used multiresolution segmentation (MRS) algorithm for its potential in providing terrain segments which delimit drumlins. Supervised testing was based on five 5-m DEMs that represented a set of 173 synthetic drumlins at random but representative positions in the same landscape. Five LSPs were tested, and four variants were computed for each LSP to assess the impact of median filtering of DEMs, and logarithmic transformation of LSPs. The testing scheme (1) employs MRS to partition each LSP exhaustively into 200 coarser scales of terrain segments by increasing the scale parameter (SP), (2) identifies the spatially best matching terrain segment for each reference drumlin, and (3) computes four segmentation accuracy metrics for quantifying the overall spatial match between drumlin segments and reference drumlins. Results of 100 tests showed that MRS tends to perform best on LSPs that are regionally derived from filtered DEMs, and then log-transformed. MRS delineated 97% of the detected drumlins at SP values between 1 and 50. Drumlin delimitation rates with values up to 50% are in line with the success of manual interpretations. Synthetic DEMs are well-suited for assessing landform quantification methods such as MRS, since subjectivity in the reference data is avoided which increases the reliability, validity and applicability of results

CAMP@FLASH: an end-station for imaging, electron- and ion-spectroscopy, and pump–probe experiments at the FLASH free-electron laser

The non-monochromatic beamline BL1 at the FLASH free-electron laser facility at DESY was upgraded with new transport and focusing optics, and a new permanent end-station, CAMP, was installed. This multi-purpose instrument is optimized for electron- and ion-spectroscopy, imaging and pump–probe experiments at free-electron lasers. It can be equipped with various electron- and ion-spectrometers, along with large-area single-photon-counting pnCCD X-ray detectors, thus enabling a wide range of experiments from atomic, molecular, and cluster physics to material and energy science, chemistry and biology. Here, an overview of the layout, the beam transport and focusing capabilities, and the experimental possibilities of this new end-station are presented, as well as results from its commissioning

Summary of the ISEV workshop on extracellular vesicles as disease biomarkers, held in Birmingham, UK, during December 2017

This report summarises the presentations and activities of the ISEV Workshop on extracellular vesicle biomarkers held in Birmingham, UK during December 2017. Among the key messages was broad agreement about the importance of biospecimen science. Much greater attention needs to be paid towards the provenance of collected samples. The workshop also highlighted clear gaps in our knowledge about pre-analytical factors that alter extracellular vesicles (EVs). The future utility of certified standards for credentialing of instruments and software, to analyse EV and for tracking the influence of isolation steps on the structure and content of EVs were also discussed. Several example studies were presented, demonstrating the potential utility for EVs in disease diagnosis, prognosis, longitudinal serial testing and stratification of patients. The conclusion of the workshop was that more effort focused on pre-analytical issues and benchmarking of isolation methods is needed to strengthen collaborations and advance more effective biomarkers

KEAP1-modifying small molecule reveals muted NRF2 signaling responses in neural stem cells from Huntington's disease patients

The activity of the transcription factor nuclear factor-erythroid 2 p45-derived factor 2 (NRF2) is orchestrated and amplified through enhanced transcription of antioxidant and antiinflammatory target genes. The present study has characterized a triazole-containing inducer of NRF2 and elucidated the mechanism by which this molecule activates NRF2 signaling. In a highly selective manner, the compound covalently modifies a critical stress-sensor cysteine (C151) of the E3 ligase substrate adaptor protein Kelch-like ECH-associated protein 1 (KEAP1), the primary negative regulator of NRF2. We further used this inducer to probe the functional consequences of selective activation of NRF2 signaling in Huntington's disease (HD) mouse and human model systems. Surprisingly, we discovered a muted NRF2 activation response in human HD neural stem cells, which was restored by genetic correction of the disease-causing mutation. In contrast, selective activation of NRF2 signaling potently repressed the release of the proinflammatory cytokine IL-6 in primary mouse HD and WT microglia and astrocytes. Moreover, in primary monocytes from HD patients and healthy subjects, NRF2 induction repressed expression of the proinflammatory cytokines IL-1, IL-6, IL-8, and TNFα. Together, our results demonstrate a multifaceted protective potential of NRF2 signaling in key cell types relevant to HD pathology