Modulatory effects of levodopa on cerebellar connectivity in Parkinson’s disease

Levodopa has been the mainstay of symptomatic therapy for Parkinson’s disease (PD) for the last five decades. However, it is associated with the development of motor fluctuations and dyskinesia, in particular after several years of treatment. The aim of this study was to shed light on the acute brain functional reorganization in response to a single levodopa dose. Functional magnetic resonance imaging (fMRI) was performed after an overnight withdrawal of dopaminergic treatment and 1 h after a single dose of 250 mg levodopa in a group of 24 PD patients. Eigenvector centrality was calculated in both treatment states using resting-state fMRI. This offers a new data-driven and parameter-free approach, similar to Google’s PageRank algorithm, revealing brain connectivity alterations due to the effect of levodopa treatment. In all PD patients, levodopa treatment led to an improvement of clinical symptoms as measured with the Unified Parkinson’s Disease Rating Scale motor score (UPDRS-III). This therapeutic effect was accompanied with a major connectivity increase between cerebellar brain regions and subcortical areas of the motor system such as the thalamus, putamen, globus pallidus, and brainstem. The degree of interconnectedness of cerebellar regions correlated with the improvement of clinical symptoms due to the administration of levodopa. We observed significant functional cerebellar connectivity reorganization immediately after a single levodopa dose in PD patients. Enhanced general connectivity (eigenvector centrality) was associated with better motor performance as assessed by UPDRS-III score. This underlines the importance of considering cerebellar networks as therapeutic targets in PD

Different brain areas require different analysis models: fMRI observations in Parkinson’s disease

Foreseeing how specific brain areas respond in time to a stimulus can be a prerequisite for a successfully conceived fMRI experiment. We demonstrate that in medicated Parkinson’s disease patients, putamen's activation peaks around the onset of tapping but does not persist throughout the tapping block, whereas sustained activation is observed in the motor cortex. Consequently, in the widely used tapping paradigm “On vs. Off L-DOPA”, the drug effect remains undetected if statistical analysis apply a block design instead of an event-related one. Ignoring this information can lead to fallacious conclusions which suggests using different models to investigate different brain regions

Spatial and temporal characteristics of gait as outcome measures in multiple sclerosis (EDSS 0 to 6.5)

Background: Gait impairment represents one of the most common and disabling symptom of multiple sclerosis. Quantification of the gait is an important aspect of clinical trials. In order to identify which temporal or spatial parameters of gait could be used as outcome measures in interventional studies of patients with different levels of disability, we evaluated characteristics of these parameters in MS patients across the whole spectrum of mobility from EDSS 0 to 6.5. Methods: This is a cross-sectional study of spatial and temporal parameters of gait at self selected speed and at fast speed of walking in 284 patients with multiple sclerosis (108 men, mean age 38 years ± SD 10.8 years, range 18–64) divided into seven levels of disability (EDSS 0 to 1.5, EDSS 2.0 to 2.5, EDSS 3.0 to 3.5, EDSS 4.0 to 4.5, EDSS 5.0 to 5.5, EDSS 6.0, EDSS 6.5). Results: The velocity of gait decreases with increasing EDSS levels. Hovewer, the spatio-temporal parameters of gait that are involved in this process differ across the EDSS levels. The step length is decreased at higher EDSS levels up to the EDSS 6.0, but was not different between EDSS 6.0 and 6.5. The step time is significantly longer at EDSS 6.0 and 6.5, while the step length remains the same at those levels. The increase in percentage of double support time becomes statistically significant at EDSS 3.0-3.5 and continues to increase until EDSS 6.5. Variability of step time, step length or step width did not show significant difference between studied EDSS levels. Conclusions: There is no single spatio-temporal parameter of gait (other than velocity of gait) that would show significant differences among all levels of EDSS. The step length reflects shortening of steps at lower EDSS levels (2.0 to 6.0), and percentage of double support time better reflects changes at higher EDSS levels 3.0 – 6.5. Gait variability is not associated with disability in MS and therefore would not be a suitable outcome measure. T

Improving brain imaging in Parkinson's disease by accounting for simultaneous motor output

Parkinson's disease leads to a variety of movement impairments. While studying the disease with fMRI, the main motivation for the research becomes one of its major obstacles: the motor output is unpredictable. Therefore it is troublesome to access, inside the scanner, performances of motor tasks and reliably relate them to brain measurements. We proposed to overcome this by expanding the patients’ number and restricting statistical criteria from a previous study which used a glove with non-magnetic sensors during scanning. Our results revealed basal ganglia not observed in the previous study confirming the usefulness of the device in fMRI studies

Improving fMRI in Parkinson's disease by accounting for realistic motor output

In Parkinson's disease (PD), the motor loop functioning and the patients’ motor output are unpredictable, due to brain compensatory mechanisms initiated up to decades before diagnosis. Consequently, the accuracy of motor tasks during fMRI is impeded, and deviations of the movement performance affect results. Kinematic modeling based on simultaneous measurements with MR-compatible gloves has been previously proposed as means to address this problem and outperform conventional boxcar modeling (Standard). Here, we adopted this approach in a larger cohort along with conservative statistics employing family-wise error (FWE) correction at the voxel level (p< 0.05) to be less prone to produce false positives

Abnormal activity in the precuneus during time perception in Parkinson’s disease: An fMRI study

Background Parkinson's disease (PD) patients are deficient in time estimation. This deficit improves after dopamine (DA) treatment and it has been associated with decreased internal timekeeper speed, disruption of executive function and memory retrieval dysfunction. Methodology/Findings The aim of the present study was to explore the neurophysiologic correlates of this deficit. We performed functional magnetic resonance imaging on twelve PD patients while they were performing a time reproduction task (TRT). The TRT consisted of an encoding phase (during which visual stimuli of durations from 5s to 16.6s, varied at 8 levels were presented) and a reproduction phase (during which interval durations were reproduced by a button pressing). Patients were scanned twice, once while on their DA medication (ON condition) and once after medication withdrawal (OFF condition). Differences in Blood-Oxygenation-Level-Dependent (BOLD) signal in ON and OFF conditions were evaluated. The time course of activation in the brain areas with different BOLD signal was plotted. There were no significant differences in the behavioral results, but a trend toward overestimation of intervals ≤11.9s and underestimation of intervals ≥14.1s in the OFF condition (p<0.088). During the reproduction phase, higher activation in the precuneus was found in the ON condition (p<0.05 corrected). Time course was plotted separately for long (≥14.1s) and short (≤11.9s) intervals. Results showed that there was a significant difference only in long intervals, when activity gradually decreased in the OFF, but remained stable in the ON condition. This difference in precuneus activation was not found during random button presses in a control task. Conclusions/Significance Our results show that differences in precuneus activation during retrieval of a remembered duration may underlie some aspects of time perception deficit in PD patients. We suggest that DA medication may allow compensatory activation in the precuneus, which results in a more accurate retrieval of remembered interval duration

The Stokes and Poisson problem in variable exponent spaces

We study the Stokes and Poisson problem in the context of variable exponent spaces. We prove the existence of strong and weak solutions for bounded domains with C^{1,1} boundary with inhomogenous boundary values. The result is based on generalizations of the classical theories of Calderon-Zygmund and Agmon-Douglis-Nirenberg to variable exponent spaces.Comment: 20 pages, 1 figur

Jasmonate promotes auxin-induced adventitious rooting in dark-grown Arabidopsis thaliana seedlings and stem thin cell layers by a cross-talk with ethylene signalling and a modulation of xylogenesis

Background: Adventitious roots (ARs) are often necessary for plant survival, and essential for successful micropropagation. In Arabidopsis thaliana dark-grown seedlings AR-formation occurs from the hypocotyl and is enhanced by application of indole-3-butyric acid (IBA) combined with kinetin (Kin). The same IBA + Kin-treatment induces AR-formation in thin cell layers (TCLs). Auxin is the main inducer of AR-formation and xylogenesis in numerous species and experimental systems. Xylogenesis is competitive to AR-formation in Arabidopsis hypocotyls and TCLs. Jasmonates (JAs) negatively affect AR-formation in de-etiolated Arabidopsis seedlings, but positively affect both AR-formation and xylogenesis in tobacco dark-grown IBA + Kin TCLs. In Arabidopsis the interplay between JAs and auxin in AR-formation vs xylogenesis needs investigation. In de-etiolated Arabidopsis seedlings, the Auxin Response Factors ARF6 and ARF8 positively regulate AR-formation and ARF17 negatively affects the process, but their role in xylogenesis is unknown. The cross-talk between auxin and ethylene (ET) is also important for AR-formation and xylogenesis, occurring through EIN3/EIL1 signalling pathway. EIN3/EIL1 is the direct link for JA and ET-signalling. The research investigated JA role on AR-formation and xylogenesis in Arabidopsis dark-grown seedlings and TCLs, and the relationship with ET and auxin. The JA-donor methyl-jasmonate (MeJA), and/or the ET precursor 1-aminocyclopropane-1-carboxylic acid were applied, and the response of mutants in JA-synthesis and -signalling, and ET-signalling investigated. Endogenous levels of auxin, JA and JA-related compounds, and ARF6, ARF8 and ARF17 expression were monitored. Results: MeJA, at 0.01 μM, enhances AR-formation, when combined with IBA + Kin, and the response of the early-JA-biosynthesis mutant dde2–2 and the JA-signalling mutant coi1–16 confirmed this result. JA levels early change during TCL-culture, and JA/JA-Ile is immunolocalized in AR-tips and xylogenic cells. The high AR-response of the late JA-biosynthesis mutant opr3 suggests a positive action also of 12-oxophytodienoic acid on AR-formation. The crosstalk between JA and ET-signalling by EIN3/EIL1 is critical for AR-formation, and involves a competitive modulation of xylogenesis. Xylogenesis is enhanced by a MeJA concentration repressing AR-formation, and is positively related to ARF17 expression. Conclusions: The JA concentration-dependent role on AR-formation and xylogenesis, and the interaction with ET opens the way to applications in the micropropagation of recalcitrant species

Cave spiders choose optimal environmental factors with respect to the generated entropy when laying their cocoon

The choice of a suitable area to spiders where to lay eggs is promoted in terms of Darwinian fitness. Despite its importance, the underlying factors behind this key decision are generally poorly understood. Here, we designed a multidisciplinary study based both on in-field data and laboratory experiments focusing on the European cave spider Meta menardi (Araneae, Tetragnathidae) and aiming at understanding the selective forces driving the female in the choice of the depositional area. Our in-field data analysis demonstrated a major role of air velocity and distance from the cave entrance within a particular cave in driving the female choice. This has been interpreted using a model based on the Entropy Generation Minimization - EGM - method, without invoking best fit parameters and thanks to independent lab experiments, thus demonstrating that the female chooses the depositional area according to minimal level of thermo-fluid-dynamic irreversibility. This methodology may pave the way to a novel approach in understanding evolutionary strategies for other living organisms