Selektive Modulation motorischer Ermüdung mittels transkranieller Hirnstimulation

Hintergrund: Motorische Ermüdbarkeit, eine Kenngröße motorischer Leistung, kann anhand unterschiedlicher Aufgaben charakterisiert und quantifiziert werden. Sie kann physiologische Reaktion auf körperliche Anstrengung, sowie bei z.B. neurologischen Erkrankungen beeinträchtigendes Symptom sein. Es können zentrale und periphere Anteile motorischer Ermüdung z.B. durch Erhebung der kortikospinalen Erregbarkeit (CSE) mittels motorisch evozierter Potentiale (MEP), ausgelöst durch transkranielle Magnetstimulation (TMS), unterschieden werden. Zur Modifikation zentralmotorischer Funktion werden Methoden der transkraniellen elektrischen Stimulation, wie z.B. die Rauschstimulation (tRNS), eingesetzt. In dieser Arbeit wird die Modifikation der motorischen Ermüdbarkeit mittels tRNS untersucht. Dazu wurde zunächst die Reliabilität der Erfassung motorischer Ermüdbarkeit sowie der zentralmotorischen Funktion evaluiert. Methoden: In einer methodischen Studie (22 gesunde Probanden) wurde die Reliabilität der Erfassung zentralmotorischer Funktion anhand der MEP-Varianz bei navigierter TMS (nTMS) im Vergleich zu nicht-navigierter TMS untersucht. Hierbei wurden nicht-physiologische Einflussfaktoren (Spulenlokalisation, -kippung, und – ausrichtung) auf die MEP-Größe identifiziert und die MEPs um diese bereinigt. Eine zweite methodische Studie (30 gesunde Probanden) verglich die Erfassung motorischer Ermüdung beim Fingertapping mittels Kraftsensor mit der standardisierten Erfassungsmethode. Hier wurden bislang nicht systematisch untersuchte Parameter der motorischen Ermüdung, wie die Tappingkraft, erfasst und ausgewertet. Eine dritte Sham-kontrollierte, randomisierte, doppelblinde Studie (30 gesunde Probanden) untersuchte die Modulation motorischer Ermüdung durch tRNS über dem motorischen Kortex während einer Fingertappingaufgabe im Vergleich zu einer Go/Nogo-Aufgabe. Ergebnisse: In der ersten Studie fand sich eine deutlich höhere Reliabilität der Erfassung der CSE mittels nTMS im Vergleich zu nicht-navigierter TMS. Dies belegt die Eignung der nTMS zur Erfassung zentralmotorischer Funktion mit größtmöglicher räumlicher und zeitlicher Auflösung. In der zweiten Studie konnte die Erfassung der motorischen Ermüdbarkeit (Abnahme der Tappinggeschwindigkeit) mittels Kraftsensor in der Fingertappingaufgabe validiert (Intraklassenreliabilität von 0.88-0.91) und eine Zunahme der Tappingkraft als potentielles Korrelat motorischer Ermüdbarkeit gemessen werden. Dies belegt die Eignung der Fingertappingaufgabe und des Kraftsensors zur Detektion motorischer Ermüdbarkeit. In der dritten Studie wurde mittels tRNS eine aufgabenspezifische Modulation zentralmotorischer Funktion nicht aber der motorischen Ermüdbarkeit erreicht. TRNS führte nur in Kombination mit Fingertapping zu einer Zunahme der CSE. Zusammenfassung: Nach Validierung der Reliabilität der Messmethoden nTMS für CSE und Fingertapping für motorische Ermüdbarkeit konnte die zentralmotorische Funktion mittels tRNS moduliert werden, maßgeblich abhängig von dem zugrundeliegenden Zustand des motorischen Systems. Der fehlende Stimulationseffekt auf die motorische Leistung ist durch die optimale Performance der gesunden Studienpopulation erklärbar. Ob sich motorische Ermüdbarkeit bei Patienten mit z.B. Fatigue-Syndrom mittels transkranieller Hirnstimulation modulieren lässt und welche Stimulationsparameter hier entscheidend sind, sollte Gegenstand zukünftiger Studien sein.Background: Motor fatigue, a parameter of motor performance, can be characterized and quantified in various tasks. In healthy subjects a sign of physiological effort, it can pose an early and impairing symptom in e.g. neurological diseases. To characterize motor fatigue, central and peripheral mechanisms need to be distinguished e.g. assessing corticospinal excitability (CSE) using transcranial magnetic stimulation (TMS). Transcranial electrical stimulation, e.g. random noise stimulation (tRNS) can be used to modify motor performance. The modification of motor fatigue by tRNS is subject of this work. Additionally, reliability of motor fatigue and CSE assessments were evaluated. Methods: The first methodological study (22 healthy subjects) investigates the reliability of central motor function assessment, i.e. variability of motor evoked potentials (MEP), using nTMS as compared to non-navigated TMS over the motor cortex. Non-physiological factors (tilt, roll and yaw) responsible for MEP-variability were identified and corrected for to increase accuracy. A second methodological study (30 healthy subjects) compares force sensor assessed motor fatigue in a fingertapping task to the standard assessment. Additionally, new parameters of motor fatigue such as tapping force were measured and analyzed. The third sham-controlled, randomized, double-blinded study (30 healthy subjects) investigates task specific modulation of motor function (CSE and performance) by tRNS while performing a fingertapping or a go/no-go task. Results: The first study showed higher reliability of CSE-assessment for nTMS as compared to non-navigated TMS. Thus, nTMS was shown to assess motor function with a high accuracy of space and time. In the second study, motor task performance was reliably assessed using the force sensor (intraclass correlation 0.88-0.91) and an increase of tapping force was measured. Here, the force sensor was shown to assess tapping parameters correlated to motor function and motor fatigue. The third study showed a fingertapping task specific modulation of motor function after tRNS with an increase of CSE. Conclusion: After validating nTMS to reliably assess CSE and the force sensor to assess motor fatigue in a fingertapping task, modulation of motor function using tRNS during a motor task was shown. Effects were highly dependent on the underlying brain state of the motor system. The lack of modulation of motor fatigue can be partly explained by the study population’s optimal performance (healthy subjects). If and to what extent transcranial brain stimulation methods can serve to modify motor function in patients with e.g. chronic fatigue syndrome remains to be elucidated and should be subject of further research

Safety Aspects, Tolerability and Modeling of Retinofugal Alternating Current Stimulation

Background While alternating current stimulation (ACS) is gaining relevance as a tool in research and approaching clinical applications, its mechanisms of action remain unclear. A review by Schutter and colleagues argues for a retinal origin of transcranial ACS’ neuromodulatory effects. Interestingly, there is an alternative application form of ACS specifically targeting α-oscillations in the visual cortex via periorbital electrodes (retinofugal alternating current stimulation, rACS). To further compare these two methods and investigate retinal effects of ACS, we first aim to establish the safety and tolerability of rACS. ObjectiveThe goal of our research was to evaluate the safety of rACS via finite-element modeling, theoretical safety limits and subjective report. Methods20 healthy subjects were stimulated with rACS as well as photic stimulation and reported adverse events following stimulation. We analyzed stimulation parameters at electrode level as well as distributed metric estimates from an ultra-high spatial resolution magnetic resonance imaging (MRI)-derived finite element human head model and compared them to existing safety limits. ResultsTopographical modeling revealed the highest current densities in the anterior visual pathway, particularly retina and optic nerve. Stimulation parameters and finite element modeling estimates of rACS were found to be well below existing safety limits. No serious adverse events occurred. ConclusionOur findings are in line with existing safety guidelines for retinal and neural damage and establish the tolerability and feasibility of rACS. In comparison to tACS, retinofugal stimulation of the visual cortex provides an anatomically circumscribed model to systematically study the mechanisms of action of ACS

Neurochemical Differences in Spinocerebellar Ataxia Type 14 and 1

Autosomal-dominant spinocerebellar ataxias (SCA) are neurodegenerative diseases characterized by progressive ataxia. Here, we report on neurometabolic alterations in spinocerebellar ataxia type 1 (SCA1; SCA-ATXN1) and 14 (SCA14; SCA-PRKCG) assessed by non-invasive 1H magnetic resonance spectroscopy. Three Tesla 1H magnetic resonance spectroscopy was performed in 17 SCA14, 14 SCA1 patients, and in 31 healthy volunteers. We assessed metabolites in the cerebellar vermis, right cerebellar hemisphere, pons, prefrontal, and motor cortex. Additionally, clinical characteristics were obtained for each patient to correlate them with metabolites. In SCA14, metabolic changes were restricted to the cerebellar vermis compared with widespread neurochemical alterations in SCA1. In SCA14, total N-acetylaspartate (tNAA) was reduced in the vermis by 34%. In SCA1, tNAA was reduced in the vermis (24%), cerebellar hemisphere (26%), and pons (25%). SCA14 patients showed 24% lower glutamate+glutamine (Glx) and 46% lower γ-aminobutyric acid (GABA) in the vermis, while SCA1 patients showed no alterations in Glx and GABA. SCA1 revealed a decrease of aspartate (Asp) in the vermis (62%) and an elevation in the prefrontal cortex (130%) as well as an elevation of myo-inositol (Ins) in the cerebellar hemisphere (51%) and pons (46%). No changes of Asp and Ins were detected in SCA14. Beyond, glucose (Glc) was increased in the vermis of both SCA14 (155%) and SCA1 (247%). 1H magnetic resonance spectroscopy revealed differing neurochemical profiles in SCA1 and SCA14 and confirmed metabolic changes that may be indicative for neuronal loss and dysfunctional energy metabolism. Therefore, 1H magnetic resonance spectroscopy represents a helpful tool for in-vivo tracking of disease-specific pathophysiology

Rebound or Entrainment? The Influence of Alternating Current Stimulation on Individual Alpha

Alternating current stimulation (ACS) is an established means to manipulate intrinsic cortical oscillations. While working towards clinical impact, ACS mechanisms of action remain unclear. For ACS’s well-documented influence on occipital alpha, hypotheses include neuronal entrainment as well as rebound phenomena. As a retinal origin is also discussed, we employed a novel form of ACS with the advantage that it specifically targets occipital alpha-oscillations via retinofugal pathways retinofugal ACS (rACS). We aimed to confirm alpha-enhancement outlasting the duration of stimulation with 10 Hz rACS. To distinguish entrainment from rebound effects, we investigated the correlation between alpha peak frequency change and alpha-enhancement strength. We quantified the alpha band power before and after 10 Hz rACS in 15 healthy subjects. Alpha power enhancement and alpha peak frequency change were assessed over the occipital electrodes and compared to sham stimulation. RACS significantly enhanced occipital alpha power in comparison to sham stimulation (p < 0.05). Alpha peak frequency changed by a mean 0.02 Hz (± 0.04). A greater change in alpha peak frequency did not correlate with greater effects on alpha power. Our findings show an alpha-enhancement consistent with studies conducted for transcranial ACS (tACS) and contribute evidence for a retinal involvement in tACS effects on occipital alpha. Furthermore, the lack of correlation between alpha peak frequency change and alpha-enhancement strength provides an argument against entrainment effects and in favor of a rebound phenomenon

Functionally Relevant Maculopathy and Optic Atrophy in Spinocerebellar Ataxia Type 1

Background: Spinocerebellar ataxia type 1 (SCA-ATXN1) is an inherited progressive ataxia disorder characterized by an adult-onset cerebellar syndrome combined with nonataxia signs. Retinal or optic nerve affection are not systematically described. Objectives: To describe a retinal phenotype and its functional relevance in SCA-ATXN1. Methods: We applied optical coherence tomography (OCT) in 20 index cases with SCA-ATXN1 and 22 healthy controls (HCs), investigating qualitative changes and quantifying the peripapillary retinal nerve fiber layer (pRNFL) thickness and combined ganglion cell and inner plexiform layer (GCIP) volume as markers of optic atrophy and outer retinal layers as markers of maculopathy. Visual function was assessed by high- (HC-VA) and low-contrast visual acuity (LC-VA) and the Hardy-Rand-Rittler pseudoisochromatic test for color vision. Results: Five patients (25%) showed distinct maculopathies in the ellipsoid zone (EZ). Furthermore, pRNFL (P < 0.001) and GCIP (P = 0.002) were reduced in patients (pRNFL, 80.86 ± 9.49 μm; GCIP, 1.84 ± 0.16 mm3) compared with HCs (pRNFL, 97.02 ± 8.34 μm; GCIP, 1.98 ± 0.12 mm3). Outer macular layers were similar between groups, but reduced in patients with maculopathies. HC-VA (P = 0.002) and LC-VA (P < 0.001) were reduced in patients (HC-VA [logMAR]: 0.01 ± 010; LC-VA [logMAR]: 0.44 ± 0.16) compared with HCs (HC-VA [logMAR]: –0.12 ± 0.08; LC-VA [logMAR]: 0.25 ± 0.05). Color vision was abnormal in 2 patients with maculopathies. Conclusions: A distinct maculopathy, termed EZ disruption, as well as optic atrophy add to the known nonataxia features in SCA-ATXN1. Whereas optic atrophy may be understood as part of a widespread neurodegeneration, EZ disruption may be explained by effects of ataxin-1 gene or protein on photoreceptors. Our findings extend the spectrum of nonataxia signs in SCA-ATXN1 with potential relevance for diagnosis and monitoring

Motor Task-Dependent Dissociated Effects of Transcranial Random Noise Stimulation in a Finger-Tapping Task Versus a Go/No-Go Task on Corticospinal Excitability and Task Performance

Background and Objective: Transcranial random noise stimulation (tRNS) is an emerging non-invasive brain stimulation technique to modulate brain function, with previous studies highlighting its considerable benefits in therapeutic stimulation of the motor system. However, high variability of results and bidirectional task-dependent effects limit more widespread clinical application. Task dependency largely results from a lack of understanding of the interaction between externally applied tRNS and the endogenous state of neural activity during stimulation. Hence, the aim of this study was to investigate the task dependency of tRNS-induced neuromodulation in the motor system using a finger-tapping task (FT) versus a go/no-go task (GNG). We hypothesized that the tasks would modulate tRNS’ effects on corticospinal excitability (CSE) and task performance in opposite directions.Methods: Thirty healthy subjects received 10 min of tRNS of the dominant primary motor cortex in a double-blind, sham-controlled study design. tRNS was applied during two well-established tasks tied to diverging brain states. Accordingly, participants were randomly assigned to two equally-sized groups: the first group performed a simple motor training task (FT task), known primarily to increase CSE, while the second group performed an inhibitory control task (go/no-go task) associated with inhibition of CSE. To establish task-dependent effects of tRNS, CSE was evaluated prior to- and after stimulation with navigated transcranial magnetic stimulation.Results: In an ‘activating’ motor task, tRNS during FT significantly facilitated CSE. FT task performance improvements, shown by training-related reductions in intertap intervals and increased number of finger taps, were similar for both tRNS and sham stimulation. In an ‘inhibitory’ motor task, tRNS during GNG left CSE unchanged while inhibitory control was enhanced as shown by slowed reaction times and enhanced task accuracy during and after stimulation.Conclusion: We provide evidence that tRNS-induced neuromodulatory effects are task-dependent and that resulting enhancements are specific to the underlying task-dependent brain state. While mechanisms underlying this effect require further investigation, these findings highlight the potential of tRNS in enhancing task-dependent brain states to modulate human behavior

Spinocerebellar ataxia type 14: refining clinicogenetic diagnosis in a rare adult‐onset disorder

Objectives: Genetic variant classification is a challenge in rare adult-onset disorders as in SCA-PRKCG (prior spinocerebellar ataxia type 14) with mostly private conventional mutations and nonspecific phenotype. We here propose a refined approach for clinicogenetic diagnosis by including protein modeling and provide for confirmed SCA-PRKCG a comprehensive phenotype description from a German multi-center cohort, including standardized 3D MR imaging. Methods: This cross-sectional study prospectively obtained neurological, neuropsychological, and brain imaging data in 33 PRKCG variant carriers. Protein modeling was added as a classification criterion in variants of uncertain significance (VUS). Results: Our sample included 25 cases confirmed as SCA-PRKCG (14 variants, thereof seven novel variants) and eight carriers of variants assigned as VUS (four variants) or benign/likely benign (two variants). Phenotype in SCA-PRKCG included slowly progressive ataxia (onset at 4-50 years), preceded in some by early-onset nonprogressive symptoms. Ataxia was often combined with action myoclonus, dystonia, or mild cognitive-affective disturbance. Inspection of brain MRI revealed nonprogressive cerebellar atrophy. As a novel finding, a previously not described T2 hyperintense dentate nucleus was seen in all SCA-PRKCG cases but in none of the controls. Interpretation: In this largest cohort to date, SCA-PRKCG was characterized as a slowly progressive cerebellar syndrome with some clinical and imaging features suggestive of a developmental disorder. The observed non-ataxia movement disorders and cognitive-affective disturbance may well be attributed to cerebellar pathology. Protein modeling emerged as a valuable diagnostic tool for variant classification and the newly described T2 hyperintense dentate sign could serve as a supportive diagnostic marker of SCA-PRKCG

Clinical and virological characteristics of hospitalised COVID-19 patients in a German tertiary care centre during the first wave of the SARS-CoV-2 pandemic: a prospective observational study

Purpose: Adequate patient allocation is pivotal for optimal resource management in strained healthcare systems, and requires detailed knowledge of clinical and virological disease trajectories. The purpose of this work was to identify risk factors associated with need for invasive mechanical ventilation (IMV), to analyse viral kinetics in patients with and without IMV and to provide a comprehensive description of clinical course. Methods: A cohort of 168 hospitalised adult COVID-19 patients enrolled in a prospective observational study at a large European tertiary care centre was analysed. Results: Forty-four per cent (71/161) of patients required invasive mechanical ventilation (IMV). Shorter duration of symptoms before admission (aOR 1.22 per day less, 95% CI 1.10-1.37, p < 0.01) and history of hypertension (aOR 5.55, 95% CI 2.00-16.82, p < 0.01) were associated with need for IMV. Patients on IMV had higher maximal concentrations, slower decline rates, and longer shedding of SARS-CoV-2 than non-IMV patients (33 days, IQR 26-46.75, vs 18 days, IQR 16-46.75, respectively, p < 0.01). Median duration of hospitalisation was 9 days (IQR 6-15.5) for non-IMV and 49.5 days (IQR 36.8-82.5) for IMV patients. Conclusions: Our results indicate a short duration of symptoms before admission as a risk factor for severe disease that merits further investigation and different viral load kinetics in severely affected patients. Median duration of hospitalisation of IMV patients was longer than described for acute respiratory distress syndrome unrelated to COVID-19

Neurochemical Differences in Spinocerebellar Ataxia Type 14 and 1

Autosomal-dominant spinocerebellar ataxias (SCA) are neurodegenerative diseases characterized by progressive ataxia. Here, we report on neurometabolic alterations in spinocerebellar ataxia type 1 (SCA1; SCA-ATXN1) and 14 (SCA14; SCA-PRKCG) assessed by non-invasive 1H magnetic resonance spectroscopy. Three Tesla 1H magnetic resonance spectroscopy was performed in 17 SCA14, 14 SCA1 patients, and in 31 healthy volunteers. We assessed metabolites in the cerebellar vermis, right cerebellar hemisphere, pons, prefrontal, and motor cortex. Additionally, clinical characteristics were obtained for each patient to correlate them with metabolites. In SCA14, metabolic changes were restricted to the cerebellar vermis compared with widespread neurochemical alterations in SCA1. In SCA14, total N-acetylaspartate (tNAA) was reduced in the vermis by 34%. In SCA1, tNAA was reduced in the vermis (24%), cerebellar hemisphere (26%), and pons (25%). SCA14 patients showed 24% lower glutamate+glutamine (Glx) and 46% lower γ-aminobutyric acid (GABA) in the vermis, while SCA1 patients showed no alterations in Glx and GABA. SCA1 revealed a decrease of aspartate (Asp) in the vermis (62%) and an elevation in the prefrontal cortex (130%) as well as an elevation of myo-inositol (Ins) in the cerebellar hemisphere (51%) and pons (46%). No changes of Asp and Ins were detected in SCA14. Beyond, glucose (Glc) was increased in the vermis of both SCA14 (155%) and SCA1 (247%). 1H magnetic resonance spectroscopy revealed differing neurochemical profiles in SCA1 and SCA14 and confirmed metabolic changes that may be indicative for neuronal loss and dysfunctional energy metabolism. Therefore, 1H magnetic resonance spectroscopy represents a helpful tool for in-vivo tracking of disease-specific pathophysiology