Cerebellar Motor Learning Deficits: Structural mapping, neuromodulation and training-related interventions

Movement allows us to interact with our direct environment, manipulate objects and communicate with each other. Moreover, we can adjust our movements to fit a remarkable range of situations and circumstances. The ability to adjust movements in response to changes in the environment and task demands is referred to as motor learning. The cerebellum is a key neural structure for motor learning. As such, disease of the cerebellum, in addition to the clinical symptom of ataxia, results in various motor learning deficits. There is a consensus that supportive therapy (e.g. physiotherapy, occupational therapy or speech therapy) can reduce ataxia symptoms of cerebellar patients, but little is known about the mechanisms underlying the improvements, and how patients can benefit most. Additionally, motor learning deficits are associated with reduced efficacy of supportive therapy. With the work described in this thesis, we sought to unravel the structural components of cerebellar disease and the relationship between cerebellar integrity and motor learning. Furthermore, we investigated whether motor learning deficits in cerebellar patients could be ameliorated with neuromodulation or training-related interventions, under experimental conditions, hoping to support the development of interventions relevant for application in a clinical setting

DNGR1-mediated deletion of A20/Tnfaip3 in dendritic cells alters T and B-cell homeostasis and promotes autoimmune liver pathology

Dendritic cells (DCs) are central regulators of tolerance versus immunity. The outcome depends amongst others on DC subset and activation status. Whereas CD11b+ type 2 conventional DCs (cDC2s) initiate proinflammatory helper T (Th)-cell responses, CD103+ cDC1s are crucial for regulatory T-cell (Treg) induction and CD8+ T-cell activation. DC activation is controlled by the transcription factor NF-κB. Ablation of A20/Tnfaip3, a critical regulator of NF-κB activation, in DCs leads to constitutive DC activation and development of systemic autoimmunity. We hypothesized that the activation status of cDCs controls the development of autoimmunity. To target cDCs, DNGR1(Clec9a)-cre-mediated excision of A20/Tnfaip3 was used through generation of Tnfaip3fl/flxClec9a+/cre (Tnfaip3DNGR1−KO) mice. Immune cell activation was evaluated at 31-weeks of age. We found that DNGR1-cre-mediated deletion of A20/Tnfaip3 resulted in liver pathology characterized by inflammatory infiltrates adjacent to the portal triads. Both cDC subsets as well as monocyte-derived DCs (moDCs) in Tnfaip3DNGR1−KO livers harbored an activated phenotype. Specifically, the costimulatory molecule CD40 in liver cDCs and moDCs was regulated by A20/Tnfaip3 expression. Livers from Tnfaip3DNGR1−KO mice had augmented prop

Long-term effects of cerebellar anodal transcranial direct current stimulation (tDCS) on the acquisition and extinction of conditioned eyeblink responses

Cerebellar transcranial direct current stimulation (tDCS) has been reported to enhance the acquisition of conditioned eyeblink responses (CR), a form of associative motor learning. The aim of the present study was to determine possible long-term effects of cerebellar tDCS on the acquisition and extinction of CRs. Delay eyeblink conditioning was performed in 40 young and healthy human participants. On day 1, 100 paired CS (conditioned stimulus)–US (unconditioned stimulus) trials were applied. During the first 50 paired CS–US trials, 20 participants received anodal cerebellar tDCS, and 20 participants received sham stimulation. On days 2, 8 and 29, 50 paired CS–US trials were applied, followed by 30 CS-only extinction trials on day 29. CR acquisition was not significantly different between anodal and sham groups. During extinction, CR incidences were significantly reduced in the anodal group compared to sham, indicating reduced retention. In the anodal group, learning related increase of CR magnitude tended to be reduced, and timing of CRs tended to be delayed. The present data do not confirm previous findings of enhanced acquisition of CRs induced by anodal cerebellar tDCS. Rather, the present findings suggest a detrimental effect of anodal cerebellar tDCS on CR retention and possibly CR performance

The Incidence of Highly-Obscured Star-Forming Regions in SINGS Galaxies

Using the new capabilities of the Spitzer Space Telescope and extensive multiwavelength data from the Spitzer Infrared Nearby Galaxies Survey (SINGS), it is now possible to study the infrared properties of star formation in nearby galaxies down to scales equivalent to large HII regions. We are therefore able to determine what fraction of large, infrared-selected star-forming regions in normal galaxies are highly obscured and address how much of the star formation we miss by relying solely on the optical portion of the spectrum. Employing a new empirical method for deriving attenuations of infrared-selected star-forming regions we investigate the statistics of obscured star formation on 500pc scales in a sample of 38 nearby galaxies. We find that the median attenuation is 1.4 magnitudes in H-alpha and that there is no evidence for a substantial sub-population of uniformly highly-obscured star-forming regions. The regions in the highly-obscured tail of the attenuation distribution (A_H-alpha > 3) make up only ~4% of the sample of nearly 1800 regions, though very embedded infrared sources on the much smaller scales and lower luminosities of compact and ultracompact HII regions are almost certainly present in greater numbers. The highly-obscured cases in our sample are generally the bright, central regions of galaxies with high overall attenuation but are not otherwise remarkable. We also find that a majority of the galaxies show decreasing radial trends in H-alpha attenuation. The small fraction of highly-obscured regions seen in this sample of normal, star-forming galaxies suggests that on 500pc scales the timescale for significant dispersal or break up of nearby, optically-thick dust clouds is short relative to the lifetime of a typical star-forming region.Comment: Accepted for publication in ApJ; emulateapj style, 30 pages, 18 figures (compressed versions), 3 table

Cerebellar patients do not benefit from cerebellar or M1 transcranial direct current stimulation during force-field reaching adaptation

Several studies have identified transcranial direct current stimulation (tDCS) as a potential tool in the rehabilitation of cerebellar disease. Here, we tested whether tDCS could alleviate motor impairments of subjects with cerebellar degeneration. Three groups took part in this study: 20 individuals with cerebellar degeneration, 20 age-matched controls, and 30 young controls. A standard reaching task with force-field perturbations was used to compare motor adaptation among groups and to measure the effect of stimulation of the cerebellum or primary motor cortex (M1). Cerebellar subjects and age-matched controls were tested during each stimulation type (cerebellum, M1, and sham) with a break of 1 wk among each of the three sessions. Young controls were tested during one session under one of three stimulation types (anodal cerebellum, cathodal cerebellum, or sham). As expected, individuals with cerebellar degeneration had a reduced ability to adapt to motor perturbations. Importantly, cerebellar patients did not benefit from anodal stimulation of the cerebellum or M1. Furthermore, no stimulation effects could be detected in aging and young controls. The present null results cannot exclude more subtle tDCS effects in larger subject populations and between-subject designs. Moreover, it is still possible that tDCS affects motor adaptation in cerebellar subjects and control subjects under a different task or with alternative stimulation parameters. However, for tDCS to become a valuable tool in the neurorehabilitation of cerebellar disease, stimulation effects should be present in group sizes commonly used in this rare patient population and be more consistent and predictable across subjects and tasks. NEW & NOTEWORTHY Transcranial direct current stimulation (tDCS) has been identified as a potential tool in the rehabilitation of cerebellar disease. We investigated whether tDCS of the cerebellum and primary motor cortex could alleviate motor impairments of subjects with cerebellar degeneration. The present study did not find stimulation effects of tDCS in young controls, aging controls, and individuals with cerebellar degeneration during reach adaptation. Our results require a re-evaluation of the clinical potential of tDCS in cerebellar patients

Coronal Diagnostics from Narrowband Images around 30.4 nm

Images taken in the band centered at 30.4 nm are routinely used to map the radiance of the He II Ly alpha line on the solar disk. That line is one of the strongest, if not the strongest, line in the EUV observed in the solar spectrum, and one of the few lines in that wavelength range providing information on the upper chromosphere or lower transition region. However, when observing the off-limb corona the contribution from the nearby Si XI 30.3 nm line can become significant. In this work we aim at estimating the relative contribution of those two lines in the solar corona around the minimum of solar activity. We combine measurements from CDS taken in August 2008 with temperature and density profiles from semiempirical models of the corona to compute the radiances of the two lines, and of other representative coronal lines (e.g., Mg X 62.5 nm, Si XII 52.1 nm). Considering both diagnosed quantities from line ratios (temperatures and densities) and line radiances in absolute units, we obtain a good overall match between observations and models. We find that the Si XI line dominates the He II line from just above the limb up to ~2 R_Sun in streamers, while its contribution to narrowband imaging in the 30.4 nm band is expected to become smaller, even negligible in the corona beyond ~2 - 3 R_Sun, the precise value being strongly dependent on the coronal temperature profile.Comment: 26 pages, 11 figures; to be published in: Solar Physic

Methods for the guideline-based development of quality indicators--a systematic review

<p>Abstract</p> <p>Background</p> <p>Quality indicators (QIs) are used in many healthcare settings to measure, compare, and improve quality of care. For the efficient development of high-quality QIs, rigorous, approved, and evidence-based development methods are needed. Clinical practice guidelines are a suitable source to derive QIs from, but no gold standard for guideline-based QI development exists. This review aims to identify, describe, and compare methodological approaches to guideline-based QI development.</p> <p>Methods</p> <p>We systematically searched medical literature databases (Medline, EMBASE, and CINAHL) and grey literature. Two researchers selected publications reporting methodological approaches to guideline-based QI development. In order to describe and compare methodological approaches used in these publications, we extracted detailed information on common steps of guideline-based QI development (topic selection, guideline selection, extraction of recommendations, QI selection, practice test, and implementation) to predesigned extraction tables.</p> <p>Results</p> <p>From 8,697 hits in the database search and several grey literature documents, we selected 48 relevant references. The studies were of heterogeneous type and quality. We found no randomized controlled trial or other studies comparing the ability of different methodological approaches to guideline-based development to generate high-quality QIs. The relevant publications featured a wide variety of methodological approaches to guideline-based QI development, especially regarding guideline selection and extraction of recommendations. Only a few studies reported patient involvement.</p> <p>Conclusions</p> <p>Further research is needed to determine which elements of the methodological approaches identified, described, and compared in this review are best suited to constitute a gold standard for guideline-based QI development. For this research, we provide a comprehensive groundwork.</p

Prognostic factors for perceived recovery or functional improvement in non-specific low back pain: secondary analyses of three randomized clinical trials

The objective of this study was to report on secondary analyses of a merged trial dataset aimed at exploring the potential importance of patient factors associated with clinically relevant improvements in non-acute, non-specific low back pain (LBP). From 273 predominantly male army workers (mean age 39 ± 10.5 years, range 20–56 years, 4 women) with LBP who were recruited in three randomized clinical trials, baseline individual patient factors, pain-related factors, work-related psychosocial factors, and psychological factors were evaluated as potential prognostic variables in a short-term (post-treatment) and a long-term logistic regression model (6 months after treatment). We found one dominant prognostic factor for improvement directly after treatment as well as 6 months later: baseline functional disability, expressed in Roland–Morris Disability Questionnaire scores. Baseline fear of movement, expressed in Tampa Scale for Kinesiophobia scores, had also significant prognostic value for long-term improvement. Less strongly associated with the outcome, but also included in our final models, were supervisor social support and duration of complaints (short-term model), and co-worker social support and pain radiation (long-term model). Information about initial levels of functional disability and fear-avoidance behaviour can be of value in the treatment of patient populations with characteristics comparable to the current army study population (e.g., predominantly male, physically active, working, moderate but chronic back problems). Individuals at risk for poor long-term LBP recovery, i.e., individuals with high initial level of disability and prominent fear-avoidance behaviour, can be distinguished that may need additional cognitive-behavioural treatment

Central role of dendritic cells in pulmonary arterial hypertension in human and mice

The pathogenesis of idiopathic pulmonary arterial hypertension (IPAH) is not fully under-stood, but evidence is accumulating tha

Potential of FX06 to prevent disease progression in hospitalized non-intubated COVID-19 patients — the randomized, EU-wide, placebo-controlled, phase II study design of IXION

Background: More than 2.7 million hospitalizations of COVID-19-infected patients have occurred in Europe alone since the outbreak of the coronavirus in 2020. Interventions against SARS-CoV-2 are still in high need to prevent admissions to ICUs worldwide. FX06, a naturally occurring peptide in humans and other mammals, has the potential to reduce capillary leak by improving endothelial dysfunction and thus preventing the deterioration of patients. With IXION, we want to investigate the potential of FX06 to prevent disease progression in hospitalized, non-intubated COVID-19 patients. Methods: IXION is an EU-wide, multicentre, placebo-controlled, double-blinded, parallel, randomized (2:1) phase II clinical study. Patient recruitment will start in September 2022 (to Q2/2023) in Germany, Italy, Lithuania, Spain, Romania, Portugal, and France. A total of 306 hospitalized patients (>= 18 years and < 75 years) with a positive SARS-CoV-2 PCR test and a COVID-19 severity of 4-6 according to the WHO scale will be enrolled. After randomization to FX06 or placebo, patients will be assessed until day 28 (and followed up until day 60). FX06 (2 x 200 mg per day) or placebo will be administered intravenously for 5 consecutive days. The primary endpoint is to demonstrate a difference in the proportion of patients with progressed/worsened disease state in patients receiving FX06 compared to patients receiving placebo. Secondary endpoints are lung function, oxygen saturation and breathing rate, systemic inflammation, survival, capillary refill time, duration of hospital stay, and drug accountability. Discussion: With IXION, the multidisciplinary consortium aims to deliver a new therapy in addition to standard care against SARS-CoV-2 for the clinical management of COVID-19 during mild and moderate stages. Potential limitations might refer to a lack of recruiting and drop-out due to various possible protocol violations. While we controlled for drop-outs in the same size estimation, recruitment problems may be subject to external problems difficult to control for