Efficient Acquisition and Denoising of Full-Range Event-Related Potentials Following Transient Stimulation of the Auditory Pathway

This body of work relates to recent advances in the field of human auditory event-related potentials (ERP), specifically the fast, deconvolution-based ERP acquisition as well as single-response based preprocessing, denoising and subsequent analysis methods. Its goal is the contribution of a cohesive set of methods facilitating the fast, reliable acquisition of the whole electrophysiological response generated by the auditory pathway from the brainstem to the cortex following transient acoustical stimulation. The present manuscript is divided into three sequential areas of investigation : First, the general feasibility of simultaneously acquiring auditory brainstem, middle-latency and late ERP single responses is demonstrated using recordings from 15 normal hearing subjects. Favourable acquisition parameters (i.e., sampling rate, bandpass filter settings and interstimulus intervals) are established, followed by signal analysis of the resulting ERP in terms of their dominant intrinsic scales to determine the properties of an optimal signal representation with maximally reduced sample count by means of nonlinear resampling on a logarithmic timebase. This way, a compression ratio of 16.59 is achieved. Time-scale analysis of the linear-time and logarithmic-time ERP single responses is employed to demonstrate that no important information is lost during compressive resampling, which is additionally supported by a comparative evaluation of the resulting average waveforms - here, all prominent waves remain visible, with their characteristic latencies and amplitudes remaining essentially unaffected by the resampling process. The linear-time and resampled logarithmic-time signal representations are comparatively investigated regarding their susceptibility to the types of physiological and technical noise frequently contaminating ERP recordings. While in principle there already exists a plethora of well-investigated approaches towards the denoising of ERP single-response representations to improve signal quality and/or reduce necessary aquisition times, the substantially altered noise characteristics of the obtained, resampled logarithmic-time single response representations as opposed to their linear-time equivalent necessitates a reevaluation of the available methods on this type of data. Additionally, two novel, efficient denoising algorithms based on transform coefficient manipulation in the sinogram domain and on an analytic, discrete wavelet filterbank are proposed and subjected to a comparative performance evaluation together with two established denoising methods. To facilitate a thorough comparison, the real-world ERP dataset obtained in the first part of this work is employed alongside synthetic data generated using a phenomenological ERP model evaluated at different signal-to-noise ratios (SNR), with individual gains in multiple outcome metrics being used to objectively assess algorithm performances. Results suggest the proposed denoising algorithms to substantially outperform the state-of-the-art methods in terms of the employed outcome metrics as well as their respective processing times. Furthermore, an efficient stimulus sequence optimization method for use with deconvolution-based ERP acquisition methods is introduced, which achieves consistent noise attenuation within a broad designated frequency range. A novel stimulus presentation paradigm for the fast, interleaved acquisition of auditory brainstem, middle-latency and late responses featuring alternating periods of optimized, high-rate deconvolution sequences and subsequent low-rate stimulation is proposed and investigated in 20 normal hearing subjects. Deconvolved sequence responses containing early and middle-latency ERP components are fused with subsequent late responses using a time-frequency resolved weighted averaging method based on cross-trial regularity, yielding a uniform SNR of the full-range auditory ERP across investigated timescales. Obtained average ERP waveforms exhibit morphologies consistent with both literature values and the reference recordings obtained in the first part of this manuscript, with all prominent waves being visible in the grand average waveforms. The novel stimulation approach cuts acquisition time by a factor of 3.4 while at the same time yielding a substantial gain in the SNR of obtained ERP data. Results suggest the proposed interleaved stimulus presentation and associated postprocessing methodology to be suitable for the fast, reliable extraction of full-range neural correlates of auditory processing in future studies.Diese Arbeit steht im Zusammenhang mit aktuellen Entwicklungen auf dem Gebiet der ereigniskorrelierten Potentiale (EKP) des humanen auditorischen Systems, insbesondere der schnellen, entfaltungsbasierten EKP-Aufzeichnung sowie einzelantwortbasierten Vorverarbeitungs-, Entrauschungs- und nachgelagerten Analysemethoden. Ziel ist die Bereitstellung eines vollständigen Methodensatzes, der eine schnelle, zuverlässige Erfassung der gesamten elektrophysiologischen Aktivität entlang der Hörbahn vom Hirnstamm bis zum Cortex ermöglicht, die als Folge transienter akustischer Stimulation auftritt. Das vorliegende Manuskript gliedert sich in drei aufeinander aufbauende Untersuchungsbereiche : Zunächst wird die generelle Machbarkeit der gleichzeitigen Aufzeichnung von Einzelantworten der auditorischen Hirnstammpotentiale zusammen mit mittelspäten und späten EKP anhand von Referenzmessungen an 15 normalhörenden Probanden demonstriert. Es werden hierzu geeignete Erfassungsparameter (Abtastrate, Bandpassfiltereinstellungen und Interstimulusintervalle) ermittelt, gefolgt von einer Signalanalyse der resultierenden EKP im Hinblick auf deren dominante intrinsische Skalen, um auf dieser Grundlage die Eigenschaften einer optimalen Signaldarstellung mit maximal reduzierter Anzahl an Abtastpunkten zu bestimmen, die durch nichtlineare Neuabtastung auf eine logarithmische Zeitbasis realisiert wird. Hierbei wird ein Kompressionsverhältnis von 16.59 erzielt. Zeit-Skalen-Analysen der uniform und logarithmisch abgetasteten EKP-Einzelantworten zeigen, dass bei der kompressiven Neuabtastung keine relevante Information verloren geht, was durch eine vergleichende Auswertung der resultierenden, gemittelten Wellenformen zusätzlich gestützt wird - alle prominenten Wellen bleiben sichtbar und sind hinsichtlich ihrer charakteristischen Latenzen und Amplituden von der Neuabtastung weitgehend unbeeinflusst. Die uniforme und logarithmische Signalrepräsentation werden hinsichtlich ihrer Anfälligkeit für die üblicherweise bei der EKP-Aufzeichnung auftretenden physiologischen und technischen Störquellen vergleichend untersucht. Obwohl bereits eine Fülle von gut etablierten Ansätzen für die Entrauschung von EKP-Einzelantwortdarstellungen zur Verbesserung der Signalqualität und/oder zur Reduktion der benötigten Erfassungszeiten existiert, erfordern die wesentlich veränderten Störeigenschaften der vorliegenden, logarithmisch abgetasteten Einzelantwortdarstellungen im Gegensatz zu ihrem uniformen Äquivalent eine Neubewertung der verfügbaren Methoden für diese Art von Daten. Darüber hinaus werden zwei neuartige, effiziente Entrauschungsalgorithmen geboten, die auf der Koeffizientenmanipulation einer Sinogramm-Repräsentation bzw. einer analytischen, diskreten Wavelet-Zerlegung der Einzelantworten basieren und gemeinsam mit zwei etablierten Entrauschungsmethoden einer vergleichenden Leistungsbewertung unterzogen werden. Um einen umfassenden Vergleich zu ermöglichen, werden der im ersten Teil dieser Arbeit erhaltene EKP-Messdatensatz sowie synthetischen Daten eingesetzt, die mithilfe eines phänomenologischen EKP-Modells bei verschiedenen Signal-Rausch-Abständen (SRA) erzeugt wurden, wobei die individuellen Anstiege in mehreren Zielmetriken zur objektiven Bewertung der Performanz herangezogen werden. Die erhaltenen Ergebnisse deuten darauf hin, dass die vorgeschlagenen Entrauschungsalgorithmen die etablierten Methoden sowohl in den eingesetzten Zielmetriken als auch mit Blick auf die Laufzeiten deutlich übertreffen. Weiterhin wird ein effizientes Reizsequenzoptimierungsverfahren für den Einsatz mit entfaltungsbasierten EKP-Aufzeichnungsmethoden vorgestellt, das eine konsistente Rauschunterdrückung innerhalb eines breiten Frequenzbands erreicht. Ein neuartiges Stimulus-Präsentationsparadigma für die schnelle, verschachtelte Erfassung auditorischer Hirnstammpotentiale, mittlelspäter und später Antworten durch alternierende Darbietung von optimierten, dichter Stimulussequenzen und nachgelagerter, langsamer Einzelstimulation wird eingeführt und in 20 normalhörenden Probanden evaluiert. Entfaltete Sequenzantworten, die frühe und mittlere EKP enthalten, werden mit den nachfolgenden späten Antworten fusioniert, wobei eine Zeit-Frequenz-aufgelöste, gewichtete Mittelung unter Berücksichtigung von Regularität über Einzelantworten hinweg zum Einsatz kommt. Diese erreicht einheitliche SRA der resultierenden EKP-Signale über alle untersuchten Zeitskalen hinweg. Die erhaltenen, gemittelten EKP-Wellenformen weisen Morphologien auf, die sowohl mit einschlägigen Literaturwerten als auch mit den im ersten Teil dieses Manuskripts erhaltenen Referenzaufnahmen konsistent sind, wobei alle markanten Wellen deutlich in den Gesamtmittelwerten sichtbar sind. Das neuartige Stimulationsparadigma verkürzt die Erfassungszeit um den Faktor 3.4 und vergrößert gleichzeitig den erreichten SRA erheblich. Die Ergebnisse deuten darauf hin, dass die vorgeschlagene verschachtelte Stimuluspräsentation und die nachgelagerte EKP-Verarbeitungsmethodik zur schnellen, zuverlässigen Extraktion neuronaler Korrelate der gesamten auditorischen Verarbeitung im Rahmen zukünftiger Studien geeignet sind.Bundesministerium für Bildung und Forschung | Bimodal Fusion - Eine neurotechnologische Optimierungsarchitektur für integrierte bimodale Hörsysteme | 2016-201

Neurometabolic Dysfunction in SPG11 Hereditary Spastic Paraplegia

Background: Pathogenic variants in SPG11 cause the most common autosomal recessive complicated hereditary spastic paraplegia. Besides the prototypical combination of spastic paraplegia with a thin corpus callosum, obesity has increasingly been reported in this multisystem neurodegenerative disease. However, a detailed analysis of the metabolic state is lacking. Methods: In order to characterize metabolic alterations, a cross-sectional analysis was performed comparing SPG11 patients (n = 16) and matched healthy controls (n = 16). We quantified anthropometric parameters, body composition as determined by bioimpedance spectroscopy, and serum metabolic biomarkers, and we measured hypothalamic volume by high-field MRI. Results: Compared to healthy controls, SPG11 patients exhibited profound changes in body composition, characterized by increased fat tissue index, decreased lean tissue index, and decreased muscle mass. The presence of lymphedema correlated with increased extracellular fluid. The serum levels of the adipokines leptin, resistin, and progranulin were significantly altered in SPG11 while adiponectin and C1q/TNF-related protein 3 (CTRP-3) were unchanged. MRI volumetry revealed a decreased hypothalamic volume in SPG11 patients. Conclusions: Body composition, adipokine levels, and hypothalamic volume are altered in SPG11. Our data indicate a link between obesity and hypothalamic neurodegeneration in SPG11 and imply that specific metabolic interventions may prevent obesity despite severely impaired mobility in SPG11

Early intervention, treatment and rehabilitation of employees with common mental disorders by using psychotherapeutic consultation at work: study protocol of a randomised controlled multicentre trial (friaa project)

Background: Common mental disorders are one of the leading causes for sickness absence and early retirement due to reduced health. Furthermore, a treatment gap for common mental disorders has been described worldwide. Within this study, psychotherapeutic consultation at work defined as a tailored, module-based and work-related psychotherapeutic intervention will be applied to improve mental health care. Methods: This study comprises a randomized controlled multicentre trial with 1:1 allocation to an intervention and control group. In total, 520 employees with common mental disorders shall be recruited from companies being located around five study centres in Germany. Besides care as usual, the intervention group will receive up to 17 sessions of psychotherapy. The first session will include basics diagnostics and medical indication of treatment, and the second session will include work-related diagnostics. Then, participants of the intervention group may receive work-related psychotherapeutic consultation for up to ten sessions. Further psychotherapeutic consultation during return to work for up to five sessions will be offered where appropriate. The control group will receive care as usual and the first intervention session of basic diagnostics and medical indication of treatment. After enrollment to the study, participants will be followed up after nine (first follow-up) and fifteen (second follow-up) months. Self-reported days of sickness absence within the last 6 months at the second follow-up will be used as the primary outcome and self-efficacy at the second follow-up as the secondary outcome. Furthermore, a cost-benefit assessment related to costs of common mental disorders for social insurances and companies will be performed. Discussion: Psychotherapeutic consultation at work represents a low threshold care model aiming to overcome treatment gaps for employees with common mental disorders. If successfully implemented and evaluated, it might serve as a role model to the care of employees with common mental disorders and might be adopted in standard care in cooperation with sickness and pension insurances in Germany. Trial registration: The friaa project was registered at the German Clinical Trial Register (DRKS) at 01.03.2021 (DRKS00023049): https://www.drks.de/drks web/navigate.do?navigationId=trial.HTML&TRIAL ID=DRKS00023049

Reduced Cancer Incidence in Huntington's Disease: Analysis in the Registry Study

Background: People with Huntington's disease (HD) have been observed to have lower rates of cancers. Objective: To investigate the relationship between age of onset of HD, CAG repeat length, and cancer diagnosis. Methods: Data were obtained from the European Huntington's disease network REGISTRY study for 6540 subjects. Population cancer incidence was ascertained from the GLOBOCAN database to obtain standardised incidence ratios of cancers in the REGISTRY subjects. Results: 173/6528 HD REGISTRY subjects had had a cancer diagnosis. The age-standardised incidence rate of all cancers in the REGISTRY HD population was 0.26 (CI 0.22-0.30). Individual cancers showed a lower age-standardised incidence rate compared with the control population with prostate and colorectal cancers showing the lowest rates. There was no effect of CAG length on the likelihood of cancer, but a cancer diagnosis within the last year was associated with a greatly increased rate of HD onset (Hazard Ratio 18.94, p < 0.001). Conclusions: Cancer is less common than expected in the HD population, confirming previous reports. However, this does not appear to be related to CAG length in HTT. A recent diagnosis of cancer increases the risk of HD onset at any age, likely due to increased investigation following a cancer diagnosis

Clinical and genetic characteristics of late-onset Huntington's disease

Background: The frequency of late-onset Huntington's disease (&gt;59 years) is assumed to be low and the clinical course milder. However, previous literature on late-onset disease is scarce and inconclusive. Objective: Our aim is to study clinical characteristics of late-onset compared to common-onset HD patients in a large cohort of HD patients from the Registry database. Methods: Participants with late- and common-onset (30–50 years)were compared for first clinical symptoms, disease progression, CAG repeat size and family history. Participants with a missing CAG repeat size, a repeat size of ≤35 or a UHDRS motor score of ≤5 were excluded. Results: Of 6007 eligible participants, 687 had late-onset (11.4%) and 3216 (53.5%) common-onset HD. Late-onset (n = 577) had significantly more gait and balance problems as first symptom compared to common-onset (n = 2408) (P &lt;.001). Overall motor and cognitive performance (P &lt;.001) were worse, however only disease motor progression was slower (coefficient, −0.58; SE 0.16; P &lt;.001) compared to the common-onset group. Repeat size was significantly lower in the late-onset (n = 40.8; SD 1.6) compared to common-onset (n = 44.4; SD 2.8) (P &lt;.001). Fewer late-onset patients (n = 451) had a positive family history compared to common-onset (n = 2940) (P &lt;.001). Conclusions: Late-onset patients present more frequently with gait and balance problems as first symptom, and disease progression is not milder compared to common-onset HD patients apart from motor progression. The family history is likely to be negative, which might make diagnosing HD more difficult in this population. However, the balance and gait problems might be helpful in diagnosing HD in elderly patients